PROTOCOLRA0098AMENDMENT 2 thereof. REDACTED COPY
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UCB 29 Sep 2017 Clinical Study Protocol Certolizumab pegol RA0098 Confidential Page 1 of 82 PROTOCOL RA0098 AMENDMENT 2 A MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFE AND EFFECTIVE USE OF AN ELECTRO-MECHANICAL INJECTION DEVICE (E-DEVICE) FOR THE SUBCUTANEOUS SELF-INJECTION OF CERTOLIZUMAB PEGOL SOLUTION BY SUBJECTS WITH MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS, ACTIVE ANKYLOSING SPONDYLITIS, ACTIVE PSORIATIC ARTHRITIS, OR MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE PHASE 3 IND Number: 011197 Sponsor: UCB Biopharma SPRL Allée de la Recherche 60 1070 Brussels BELGIUM Protocol/Amendment number Date Type of amendment Final Protocol 28 Jun 2017 Not applicable Protocol Amendment 1 26 Sep 2017 Nonsubstantial Protocol Amendment 2 29 Sep 2017 Nonsubstantial Confidential Material Confidential This document is the property of UCB and may not – in full or in part – be passed on, reproduced, published, or otherwise used without the express permission of UCB. REDACTED COPY 011 011 ponso ponso Biop Biop llée d llée d upport any marketing authorization application and any extensions or variations thereof. US US N BY N BY VE VE ING ING TIS, O TIS, O N’S D N’S D 197 197 or: or: harma harma de la R de la R 107 107 dment dment any to sup ol ol used to upp Amen Amen to be use ocol A ocol A This document cannot be use t be
Transcript of PROTOCOLRA0098AMENDMENT 2 thereof. REDACTED COPY
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 1 of 82
PROTOCOL RA0098 AMENDMENT 2
A MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFE AND EFFECTIVE USE OF AN ELECTRO-MECHANICAL INJECTION DEVICE (E-DEVICE) FOR THE SUBCUTANEOUS
SELF-INJECTION OF CERTOLIZUMAB PEGOL SOLUTION BY SUBJECTS WITH MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS, ACTIVE ANKYLOSING
SPONDYLITIS, ACTIVE PSORIATIC ARTHRITIS, OR MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
PHASE 3
IND Number: 011197
Sponsor:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Protocol/Amendment number Date Type of amendment
Final Protocol 28 Jun 2017 Not applicable
Protocol Amendment 1 26 Sep 2017 Nonsubstantial
Protocol Amendment 2 29 Sep 2017 Nonsubstantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, published, or otherwise used without the express permission of UCB.
REDACTED COPY 011197
REDACTED COPY 011197
Sponsor:
REDACTED COPY
Sponsor:
Biop
REDACTED COPY
Biop
Allée de la Recherche 60
REDACTED COPY
Allée de la Recherche 60
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EOUS
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EOUS SOLUTION BY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 2 of 82
STUDY CONTACT INFORMATION
Sponsor
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Sponsor Study Physician
Name: MD
Address: UCB BIOSCIENCES GmbH
Alfred-Nobel-Strasse 10
40789 Monheim am Rhein
GERMANY
Phone:
Clinical Project Manager
Name:
Address: UCB Biosciences Inc.
8010 Arco Corporate Drive, Suite 100
Raleigh, NC 27617
USA
Phone:
Clinical Trial Biostatistician
Name:
Address: UCB Biosciences Inc.
8010 Arco Corporate Drive, Suite 100
Raleigh, NC 27617
USA
Phone:
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UCB Biosciences
8010 Arco Corporate Drive, Suite 100REDACTED COPY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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Clinical Monitoring Contract Research Organization
Name: PAREXEL International (IRL) Limited
Address: One Kilmainham Square
Inchicore Road
Kilmainham, Dublin 8
IRELAND
Phone: +3531 473 9500
Fax: +3531 477 3308
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SERIOUS ADVERSE EVENT AND PRODUCT QUALITY COMPLAINTSREPORTING
Serious Adverse Event Reporting (24h)
Email: Global: [email protected]
Fax: US: +1 800 880 6949
+1 866 890 3175
Product Quality Complaints Reporting (24h)
Email: Global: [email protected]
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS.................................................................................................... 9
1 SUMMARY..................................................................................................................... 11
2 INTRODUCTION ........................................................................................................... 12
3 STUDY OBJECTIVES.................................................................................................... 13
3.1 Primary objective ............................................................................................................. 13
3.2 Secondary objective ......................................................................................................... 13
3.3 Other objectives ............................................................................................................... 13
3.4 Safety objective................................................................................................................ 13
4 STUDY VARIABLES..................................................................................................... 13
4.1 Study outcome variables .................................................................................................. 13
4.1.1 Primary outcome variable.................................................................................... 13
4.1.2 Secondary outcome variables .............................................................................. 14
4.1.3 Other outcome variables ........................................................................................ 15
4.2 Safety variables ................................................................................................................ 15
5 STUDY DESIGN............................................................................................................. 15
5.1 Study description ............................................................................................................. 15
5.1.1 Study duration per subject ................................................................................... 16
5.1.2 Planned number of subjects and sites .................................................................. 16
5.1.3 Anticipated regions and countries ....................................................................... 17
5.2 Schedule of study assessments......................................................................................... 17
5.3 Rationale for study design and selection of dose............................................................. 21
6 SELECTION AND WITHDRAWAL OF SUBJECTS................................................... 21
6.1 Inclusion criteria .............................................................................................................. 21
6.2 Exclusion criteria ............................................................................................................. 22
6.3 Withdrawal criteria .......................................................................................................... 23
7 IMP AND INVESTIGATIONAL DEVICE.................................................................... 24
7.1 Description of investigational device............................................................................... 24
7.1.1 Instructions for use of investigational e-Device .................................................. 25
7.2 Treatment to be administered........................................................................................... 25
7.3 Packaging......................................................................................................................... 26
7.4 Labeling ........................................................................................................................... 26
7.5 Handling and storage requirements.................................................................................. 26
7.6 Drug and device accountability ....................................................................................... 26
7.7 Procedures for monitoring subject compliance................................................................ 27
7.8 Concomitant medications/treatments............................................................................... 27
7.8.1 Permitted concomitant treatments (medications and therapies) .......................... 27
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AWAL
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INVESTIGATIONAL DEVI
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INVESTIGATIONAL DEVI
7.1 Description of investigational device................................
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7.1 Description of investigational device................................
Instructions for use of investigational e
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Instructions for use of investigational e
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Treatment to be administered
Packaging
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7.4
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7.5
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7.5
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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7.8.2 Prohibited concomitant treatments (medications and therapies) ......................... 27
7.9 Blinding............................................................................................................................ 27
7.10 Randomization and numbering of subjects...................................................................... 27
8 STUDY PROCEDURES BY VISIT ............................................................................... 27
8.1 Visit 1/ Screening and Study Treatment Period............................................................... 27
8.2 Study procedures by visit for the Q2W group ................................................................. 28
8.2.1 Visit 2 (Week 2)................................................................................................... 28
8.3 Study procedures by visit for the Q4W group ................................................................. 29
8.3.1 Visit 2 (Week 4)................................................................................................... 29
8.4 Safety Follow-Up............................................................................................................. 30
9 ASSESSMENT OF SELF-INJECTION.......................................................................... 30
9.1 Injection Site Pain (VAS) ................................................................................................ 30
9.2 Assessment of Self Injection (ASI).................................................................................. 30
9.3 Self-Injection Preference Questionnaire .......................................................................... 31
9.4 Evaluation of post-use structural integrity of CZP-cassettes ........................................... 31
9.5 Evaluation of post-use structural and functional integrity of the e-Device ..................... 31
9.6 Evaluation of safe and effective self-injection................................................................. 31
10 ASSESSMENT OF SAFETY.......................................................................................... 32
10.1 Adverse events (IMP) ...................................................................................................... 32
10.1.1 Definitions (IMP)................................................................................................. 32
10.1.1.1 Adverse event (IMP) ................................................................................. 32
10.1.1.2 Serious adverse event (IMP) ..................................................................... 32
10.1.1.3 Adverse events of special interest (IMP) .................................................. 34
10.1.2 Procedures for reporting and recording adverse events (IMP)............................ 34
10.1.2.1 Description of adverse events (IMP)......................................................... 35
10.1.2.2 Rule for repetition of an adverse event (IMP)........................................... 35
10.1.2.3 Additional procedures for reporting serious adverse events (IMP)........... 35
10.1.3 Follow up of adverse events (IMP) ..................................................................... 36
10.2 Adverse events (investigational device) .......................................................................... 36
10.2.1 Definitions (investigational device)..................................................................... 36
10.2.1.1 Adverse Events (investigational device) ................................................... 36
10.2.1.2 Serious adverse event (investigational device).......................................... 37
10.2.1.3 Device- or procedure-related..................................................................... 37
10.2.2 Procedures for reporting and recording adverse events (investigational device), adverse device effects, and device deficiencies................................................... 38
10.2.2.1 Adverse events .......................................................................................... 38
10.2.3 Follow up of adverse events (investigational device).......................................... 38
10.2.3.1 Device-related ........................................................................................... 38
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10.1.1.3 Adverse events of special interest (IMP) ................................
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10.1.2 Procedures for reporting and recording adverse events (IMP)............................ 34
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10.1.2.1 Description of adverse events (IMP)................................
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10.2.1 Definitions (investigational de
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10.2.3.2 Rule for repetition of an adverse device effect and/or device deficiency .40
10.3 Pregnancy......................................................................................................................... 40
10.4 Suspected transmission of an infectious agent................................................................. 41
10.5 Overdose of investigational medicinal product ............................................................... 41
10.6 Safety signal detection ..................................................................................................... 41
10.7 Laboratory measurements ................................................................................................ 41
10.8 Other safety measurements .............................................................................................. 42
10.8.1 Vital signs ............................................................................................................ 42
10.8.2 Physical examination ........................................................................................... 42
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 42
11.1 Adherence to protocol ...................................................................................................... 42
11.2 Monitoring ....................................................................................................................... 42
11.2.1 Definition of source data ..................................................................................... 42
11.2.2 Source data verification ....................................................................................... 43
11.3 Data handling ................................................................................................................... 43
11.3.1 Case Report form completion.............................................................................. 43
11.3.2 Database entry and reconciliation........................................................................ 43
11.3.3 Subject Screening and Enrollment log/Subject Identification Code list.............. 44
11.4 Termination of the study.................................................................................................. 44
11.5 Archiving and data retention............................................................................................ 44
11.6 Audit and inspection ........................................................................................................ 44
11.7 Good Clinical Practice ..................................................................................................... 45
12 STATISTICS ................................................................................................................... 45
12.1 Definition of analysis sets ................................................................................................ 45
12.2 General statistical considerations..................................................................................... 45
12.3 Planned analyses .............................................................................................................. 46
12.3.1 Analysis of the primary outcome variable........................................................... 46
12.3.2 Analyses of secondary outcome variables ........................................................... 46
12.3.3 Analyses of other outcome variables ................................................................... 47
12.4 Planned safety analyses.................................................................................................... 47
12.4.1 Safety analyses..................................................................................................... 47
12.5 Handling of protocol deviations....................................................................................... 48
12.6 Handling of dropouts or missing data .............................................................................. 48
12.7 Planned interim analysis and data monitoring ................................................................. 48
12.8 Determination of sample size........................................................................................... 48
13 ETHICS AND REGULATORY REQUIREMENTS...................................................... 48
13.1 Informed consent ............................................................................................................. 48
13.2 Subject identification cards.............................................................................................. 49
REDACTED COPY e Report form completion................................
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11.3.3 Subject Screening and Enrollment log/Subject Identification Code list.............. 44
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13.3 Institutional Review Boards and Independent Ethics Committees.................................. 49
13.4 Subject privacy................................................................................................................. 50
13.5 Protocol amendments....................................................................................................... 50
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 50
15 REFERENCES ................................................................................................................ 50
16 APPENDICES ................................................................................................................. 52
16.1 Injection Site Pain (VAS) ................................................................................................ 52
16.2 Assessment of Self Injection............................................................................................ 53
16.3 Self-Injection Preference Questionnaire .......................................................................... 66
16.4 Cochin Scale .................................................................................................................... 68
16.5 Protocol Amendment 1 .................................................................................................... 73
16.6 Protocol Amendment 2 .................................................................................................... 79
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 81
18 SPONSOR DECLARATION .......................................................................................... 82
LIST OF TABLES
Table 5‒1: Schedule of study assessments for Q2W subjects ........................................... 17
Table 5‒2: Schedule of study assessments for Q4W subjects ........................................... 19
Table 7‒1: Treatments to be administered ......................................................................... 25
Table 10‒1: Anticipated serious adverse events for study population................................. 34
LIST OF FIGURES
Figure 7‒1: CZP e-Device................................................................................................... 24
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LIST OF TA
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LIST OF TABLES
REDACTED COPY BLES
y assessments for Q2W subjects
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y assessments for Q2W subjects
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Treatments to be administered
Anticipated serious adverse events for studREDACTED COPY
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R ................................
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BLES
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Device
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LIST OF ABBREVIATIONS
ADE adverse device effect
AE adverse event
AS ankylosing spondylitis
ASADE anticipated serious adverse device effect
ASI Assessment of Self Injection
BP blood pressure
CD Crohn’s disease
CDMS clinical data management system
CI confidence interval
CPM Clinical Project Manager
CPMP Committee for Proprietary Medicinal Products
CRO contract research organization
CZP certolizumab pegol
DMARD disease-modifying antirheumatic drug
ECG Electrocardiogram
eCRF electronic Case Report form
EudraCT European Union Drug Regulating Authorities Clinical Trials
FAS Full Analysis Set
FDA Food and Drug Administration
GCP Good Clinical Practice
HCP healthcare provider
ICH International Council for Harmonisation
IEC Independent Ethics Committee
IFU Instructions for Use
IMP investigational medicinal product
IRB Institutional Review Board
IXRS interactive response technology
LTB latent tuberculosis
PFS pre-filled syringe
PS Patient Safety
PsA psoriatic arthritis
REDACTED COPY
ing antirheumatic drug
REDACTED COPY
ing antirheumatic drug
lectrocardiogram
REDACTED COPY
lectrocardiogram
electronic Case Report form
REDACTED COPY
electronic Case Report form
European Union Drug Regulating Authorities Clinical TrialsREDACTED COPY
European Union Drug Regulating Authorities Clinical Trials
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Medicinal Products
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ing antirheumatic drug
electronic Case Report form
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electronic Case Report form
European Union Drug Regulating Authorities Clinical Trials
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European Union Drug Regulating Authorities Clinical Trials
ys
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Food and Drug Administration
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healthcare prov
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International
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IR
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IXRS
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IXRS
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 10 of 82
Q2W every 2 weeks
Q4W every 4 weeks
RA rheumatoid arthritis
RR respiratory rate
SADE serious adverse device effect
SAE serious adverse event
sc subcutaneous
SOP Standard Operating Procedure
SS Safety Set
TB tuberculosis
TEAE treatment-emergent adverse events
TNFα tumor necrosis factor alpha
UADE unanticipated adverse device effect
USADE unanticipated serious adverse device effect
VAS Visual Analog Scale
REDACTED COPY
unanticipated serious adverse device effect
REDACTED COPY
unanticipated serious adverse device effect
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unanticipated serious adverse device effect
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 11 of 82
1 SUMMARY
RA0098 is a multicenter, open-label, Phase 3 study of the e-Device in US subjects with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), or Crohn’s disease (CD).
The e-Device offers improved convenience with an enhanced, reusable electromechanical injector that provides full electronic management of the injection process including subject instructions and warnings via a graphical user interface, an electronic log of the injection history, and the speed of injection. The e-Device uses a disposable single-use certolizumab pegol (CZP)-cassette/dose dispensing cartridge (henceforth referred to as CZP-cassette) which houses a (market authorized) pre-filled syringe (PFS) containing CZP 200mg. The CZP-cassette is needle-safe (ie, automatic needle retraction to prevent needle-stick injury), and, once loaded into the e-Device, is electronically recognized (ie, expiry date, drug identity, and use status) by the e-Device. The e-Device and CZP-cassette together provide automatic needle insertion, dose delivery, needle retraction, and adjustable injection speed. They also provide a manual voluntary injection pause and resumption for additional control as well as an automatic stop (with needle retraction) should the e-Device lose contact with the skin during an injection to prevent needle stick injury and to minimize the loss of CZP. A production version of the e-Device will be utilized for this study.
The purpose of this study is to determine whether the e-Device can be used safely and effectively for self-injection by subjects with RA, AS, PsA, or CD after being trained on proper self-injection technique. All eligible subjects should be currently treated with commercial CZP. Eligible subjects with RA, PsA, or AS will perform CZP self-administration on a 2 week (Q2W)or 4 week (Q4W) dosing schedule. Eligible subjects with CD will perform CZP self-administration on a Q4W dosing schedule. As the dosing schedule groups (Q2W vs Q4W)are different regarding number of injections (1 CZP injection for Q2W vs 2 CZP injections per administration for Q4W) and study treatment period (2 weeks vs 4 weeks), these 2 subject populations will be evaluated separately.
The primary objective of the study is to evaluate the ability of subjects in the Q2W and Q4W groups to safely and effectively self-inject CZP using the e-Device.
The primary variable is the proportion (%) of subjects able to self-administer safe and effective injections using the e-Device at Visit 2. Safe and effective self-injection will be evaluated by thehealthcare provider (HCP) and is defined as:
Complete Dose Delivery: Subject self-injected the complete dose of CZP as confirmed by a visual inspection of the CZP-cassette(s) which shows the container PFS to be empty and
No adverse events (AE) related to the use of the e-Device (adverse device effects [ADE])that would preclude continued use of the e-Device for self-injection
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete
REDACTED COPY A production version of the e
REDACTED COPY A production version of the e
o determine whether the e
REDACTED COPY
o determine whether the eRA, AS, PsA, or CD after being trained on proper
REDACTED COPY
RA, AS, PsA, or CD after being trained on proper . All eligible subjects should be currently
REDACTED COPY
. All eligible subjects should be currentlyle subjects with RA, PsA, or AS will perform CZP self-
REDACTED COPY
le subjects with RA, PsA, or AS will perform CZP self-Eligible sREDACTED C
OPY
Eligible sschedule. As the dosing scheduleREDACTED C
OPY
schedule. As the dosing schedule
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f the injection history
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f the injection historycertolizumab pegol
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certolizumab pegol cassette) which houses a
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cassette) which houses a cassette is
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cassette is ), and, once loaded into
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), and, once loaded into y, and use status) by the
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y, and use status) by the cassette together provide automatic needle insertion, dose
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cassette together provide automatic needle insertion, dose also provide a manual voluntary
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also provide a manual voluntaryinjection pause and resumption for additional control as well as an automatic stop
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injection pause and resumption for additional control as well as an automatic stop Device lose contact with the skin during an injection to prevent needle
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Device lose contact with the skin during an injection to prevent needle A production version of the e
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A production version of the e
o determine whether the e
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o determine whether the e-
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-Device can be used safel
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Device can be used safelRA, AS, PsA, or CD after being trained on proper
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RA, AS, PsA, or CD after being trained on proper . All eligible subjects should be currently
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. All eligible subjects should be currentlyle subjects with RA, PsA, or AS will perform CZP self-
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le subjects with RA, PsA, or AS will perform CZP self-Eligible s
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Eligible subjects with CD will perform CZP
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ubjects with CD will perform CZP schedule. As the dosing schedule
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schedule. As the dosing schedulenumber of injections (1
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number of injections (1administration for Q4W) and study
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administration for Q4W) and study treatment period (
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treatment period (administration for Q4W) and study treatment period (administration for Q4W) and study
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administration for Q4W) and study treatment period (administration for Q4W) and studypopulations will be evaluated separatel
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populations will be evaluated separatel
objective of the s
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objective of the study
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tudyy and effectively
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y and effectively
variable is the proportion (%) of subjects able to self
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variable is the proportion (%) of subjects able to selfinjections using the e
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injections using the ehealthcare pro
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healthcare provider
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vider
Complete Dos
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No
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No
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 12 of 82
administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
Approximately 80 subjects ≥18 years of age who are currently being treated with commercial CZP, are self-injecting with the PFS, and are on a stable dosing regimen for at least 3 months will be screened in order to have at least 60 subjects use the e-Device at Visit 1. The 60 subjectsusing the e-Device at Visit 1 will be composed of a minimum of 15 subjects in each of the dosing groups (Q2W vs Q4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function.
2 INTRODUCTION
Cimzia (certolizumab pegol [CZP]) is an anti-TNFα humanized PEGylated Fab’ fragment of a monoclonal antibody. Certolizumab pegol has demonstrated a high affinity for TNFα which has been shown to have a central role in the pathogenesis of RA, AS, PsA, and CD. Certolizumab pegol has received market authorization in the US for the treatment of moderate and severe active RA, active PsA, active AS, and moderately to severely active CD. Certolizumab pegol may be used as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). It is available for subcutaneous (sc) injection as a 200mg lyophilized powder for reconstitution (with 1 mL of sterile water for injection) in a single use vial or as 200mg/mL solution in a single-use 1mL PFS in the US.
The availability and convenience of the PFS device provide subjects with chronic diseases such as RA, AS, PsA, or CD with the option to manually self-inject their medication.
The purpose of this study is to determine whether the e-Device can be used safely and effectively for self-injection by subjects with RA, AS, PsA, or CD after being trained on proper self-injection technique, described in the Instructions for Use (IFU) supplied with the e-Device. Eligible subjects with RA, PsA, or AS will perform CZP self-administration on a Q2W or Q4Wdosing schedule. Eligible subjects with CD will perform CZP self-administration on a Q4W dosing schedule. As the dosing schedule groups (Q2W vs Q4W) are different regarding number of injections (1 CZP injection for Q2W vs 2 CZP injections per administration for Q4W) and study treatment period (2 weeks vs 4 weeks), these 2 subject populations will be evaluated separately. For simplicity and where appropriate, the RA, AS, and PsA subjects on the Q2W dosing regimen will be called the Q2W group, and the RA, AS, PsA, and CD subjects on the Q4W dosing regimen will be called the Q4W group.
Impaired hand function is seen in patients with RA (Durmus et al, 2013), to a lesser extent in patients with PsA (Gottieb et al, 2008), and is uncommon in patients with AS (Tam et al, 2010) or CD (Lossos et al, 1995). Since prompt treatment can reduce inflammation and the level of functional impairment seen in patients with RA or PsA (Goossens et al, 2000), it is not possible to accurately predict the proportion of patients treated with CZP who will have impaired hand
REDACTED COPY has demonstrated a high affinity
REDACTED COPY has demonstrated a high affinity
been shown to have a central role in the pathogenesis of RA, AS, PsA, and CD. C
REDACTED COPY
been shown to have a central role in the pathogenesis of RA, AS, PsA, and CD. Chas received market authorization in the US
REDACTED COPY
has received market authorization in the US for the treatment of moderate and severe
REDACTED COPY
for the treatment of moderate and severe , and moderatel
REDACTED COPY
, and moderately
REDACTED COPY
y or in combinat
REDACTED COPY
or in combination with disease-
REDACTED COPY
ion with disease-aneous (
REDACTED COPY
aneous (reconstitution (with 1 mL of sterile water for injection) in a single use vial or as 200mg/mL REDACTED C
OPY
reconstitution (with 1 mL of sterile water for injection) in a single use vial or as 200mg/mL
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s on the Q4W dosing regimen
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s on the Q4W dosing regimen
treated with commercial
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treated with commercial for at least 3 months
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for at least 3 months . T
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. The 60 subjects
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he 60 subjectsa minimum of 15 subjects
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a minimum of 15 subjects in each of the
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in each of the and
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and a minimum of 10
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a minimum of 10
TNFα humanized PEGy
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TNFα humanized PEGyhas demonstrated a high affinity
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has demonstrated a high affinitybeen shown to have a central role in the pathogenesis of RA, AS, PsA, and CD. C
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been shown to have a central role in the pathogenesis of RA, AS, PsA, and CD. Cfor the treatment of moderate and severe
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for the treatment of moderate and severe y
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y to severel
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to severelion with disease-
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ion with disease-aneous (
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aneous (sc
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sc) injection as a 20
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) injection as a 20reconstitution (with 1 mL of sterile water for injection) in a single use vial or as 200mg/mL
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reconstitution (with 1 mL of sterile water for injection) in a single use vial or as 200mg/mL the
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the US
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US
of the PFS device provide sub
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of the PFS device provide subas RA, AS, PsA, or CD with the option to manually
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as RA, AS, PsA, or CD with the option to manually
y is to determine whether the e
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y is to determine whether the e subjects
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subjects with
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withtechnique
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technique
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, described in the Instructions for Use (IFU) supplied with the e
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, described in the Instructions for Use (IFU) supplied with the ewith
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with RA,
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RA, schedule. Eligible subjects
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schedule. Eligible subjects schedule. As the dosing schedule
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schedule. As the dosing scheduleof injections (1 CZP injection for Q2W vs 2 CZP injections per administration for Q
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of injections (1 CZP injection for Q2W vs 2 CZP injections per administration for Q treatment period (2
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treatment period (2separately
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separately
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dosing regimen
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dosing regimenQ4W dosing regimen
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Q4W dosing regimen
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 13 of 82
function or how easy or difficult it may be to recruit such patients. In a recently published simulated injection study, the author notes that the investigators had difficulties in recruiting patients with high (Cochin score ≥20) versus low (Cochin score <20) hand disability so much so that they decided to stop the recruitment process when only 12 out of 15 subjects with high hand disability were enrolled (Hundry et al, 2017). This suggests that recruiting patients with impaired hand function may be challenging. Given these considerations, this study will recruit a minimum of 10 patients with impaired hand function. Impaired hand function will be measured using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al, 1996) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
3 STUDY OBJECTIVES
3.1 Primary objective
The primary objective of the study is to evaluate the ability of subjects in the Q2W and Q4W groups to safely and effectively self-inject CZP using the e-Device at Visit 2.
3.2 Secondary objective
The secondary objectives are to evaluate the ability of subjects in the Q2W and Q4W groups to safely and effectively self-inject CZP using the e-Device at Visit 1 and the structural integrity of used cassettes via visual examination.
3.3 Other objectives
The other objectives are to evaluate:
The functional status of the e-Device following administration of the final study dose (ie, no visual signs of damage, device functions normally with training cassette)
Subject experience of self-injection as assessed by the Pain Visual Analog Scale (VAS) and Assessment of Self Injection (ASI).
Subject preference for e-Device vs PFS using a self-administered Self-Injection Preference Questionnaire
3.4 Safety objective
The safety objective is to evaluate the safety of CZP self-injection using the e-Device for CZP self-injection.
4 STUDY VARIABLES
4.1 Study outcome variables
4.1.1 Primary outcome variable
The primary outcome variable is the proportion (%) of subjects able to self-administer safe and effective injections using the e-Device at Visit 2. Safe and effective self-injection will be evaluated by the HCP and is defined as:
Complete Dose Delivery: Subject self-injected the complete dose of CZP as confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be empty and
REDACTED COPY of subjects in the Q2W and Q4W groups to
REDACTED COPY of subjects in the Q2W and Q4W groups to
Device
REDACTED COPY
Device
Device following administration of the final studyREDACTED COPY
Device following administration of the final study
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will recruit a minimum
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will recruit a minimum asured using the
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asured using the impaired hand function will be
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impaired hand function will be
of subjects in the Q2W and Q4W
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of subjects in the Q2W and Q4W Device at Visit
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Device at Visit
of subjects in the Q2W and Q4W groups to
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of subjects in the Q2W and Q4W groups to Device
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Device at Visit 1
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at Visit 1
Device following administration of the final study
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Device following administration of the final studyvisual signs of damage, device functions normally
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visual signs of damage, device functions normally
injection as assessed by the Pain
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injection as assessed by the Pain Assessment of Self Injection (ASI).
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Assessment of Self Injection (ASI).
Subject preference for e
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Subject preference for e-Device vs PFS using a self-
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-Device vs PFS using a self-
Safet
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Safety
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y
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y objective is to evaluate the safetinjection
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injection.
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.
4.1
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4.1
4.1.1
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4.1.1
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 14 of 82
No AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
4.1.2 Secondary outcome variables
The secondary outcome variables are:
The proportion (%) of subjects able to self-administer safe and effective injections using the e-Device at Visit 1. Safe and effective self-injection will be evaluated by the HCP and is defined as:
Complete Dose Delivery: Subject self-injected the complete dose of CZP as confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be emptyand
No AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why thecomplete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
Percentage of used CZP-cassettes identified as having structural integrity issues based on visual examination (ie, clear evidence of damage/compromised structural integrity, not superficial cosmetic imperfections)
REDACTED COPY
administer safe and effective injections using the
REDACTED COPY
administer safe and effective injections using the injection will be evaluated by
REDACTED COPY
injection will be evaluated by
: Subject self
REDACTED COPY
: Subject selfa visual inspection of the CZPREDACTED C
OPY
a visual inspection of the CZP-REDACTED COPY
-cassette(s) which shows the PFS REDACTED COPY
cassette(s) which shows the PFS
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If the subject is unable to complete the
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If the subject is unable to complete the
lf
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lf-
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-lf-lf
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the complete dose was regarding an
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regarding an
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: Subject self
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-: Subject self-: Subject self
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: Subject self-: Subject self injected the complete dose of CZP as confirmed b
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injected the complete dose of CZP as confirmed bcassette(s) which shows the PFS
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cassette(s) which shows the PFS
related to use of the e
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related to use of the e-Device (ADEs)
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-Device (ADEs)injection
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injection
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injection, if the skin sensor at the injection port losDevice will withdraw the needle and stop
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clean injection site and resume and complete the secomplete the self
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-injection and deliver the entire dose of medication (ie, the device indicates complete the self-injection and deliver the entire dose of medication (ie, the device indicates complete the self
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complete the self-injection and deliver the entire dose of medication (ie, the device indicates complete the selfincomplete administration and the CZP
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incomplete administration and the CZPthe self
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-the self-the self
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the self-the self injection will document the incomplete self
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complete dose was
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complete dose was subject
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subject
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For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 15 of 82
4.1.3 Other outcome variables
The other outcome variables are:
Injection site pain due to self-injection (using a VAS; 100mm) by visit at all visits after self-injection using the e-Device
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitwill complete the Pain VAS after the second injection at each of the 2 visits. For subjects on the Q4W dosing regimen, the Pain VAS will record the overall pain associated with both self-injections.
Responses to the preinjection ASI at Visit 1
Responses to the postinjection ASI by visit at all visits after self-injection using the e-Device
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit will complete the postinjection ASI after the second injection at each of the 2 visits. For subjects on the Q4W dosing regimen, the postinjection ASI will collect the overall self-injection experience associated with both self-injections.
Responses to the Self-Injection Preference Questionnaire
In vitro functional evaluation of the e-Device following the final use per subject:
The percentage of e-Devices found to be functionally compromised (ie, visual signs of damage, device does not function normally with training cassette)
4.2 Safety variables
The safety variables are:
Occurrence of AEs and ADEs
Vital signs
5 STUDY DESIGN
5.1 Study description
In this Phase 3, open-label study of the e-Device, subjects diagnosed with RA, PsA, or AS (treated on Q2W dosing schedule, Q2W group), or RA, PsA, AS, or CD (treated on a Q4Wdosing schedule, Q4W group) will be recruited and evaluated. Subjects in the Q2W and Q4Wgroup should currently be treated with commercial CZP and be performing self-administration using the PFS. Hand function will be assessed at the screening visit by the Cochin Impaired Hand Function questionnaire. This study will recruit a minimum of 10 patients with impaired hand function. Impaired hand function will be measured using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al, 1996) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
Participating subjects must be at least 18 years of age and on a stable CZP dosing regimen for at least 3 months before Visit 1.
Visit 1 should be scheduled to coincide with the individual treatment schedule for each subject. The study will consist of 2 site visits and a follow-up telephone call. Following an initial
REDACTED COPY Injection Preference Questionnaire
REDACTED COPY Injection Preference Questionnaire
-Device following the final use per subject:
REDACTED COPY
-Device following the final use per subject:
-Devices found to be fu
REDACTED COPY
-Devices found to be functionally
REDACTED COPY
nctionallydamage, device does not function normally
REDACTED COPY
damage, device does not function normally
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on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit
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on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitFor subjects
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For subjects on
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on ated with both
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ated with both
injection using the e
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injection using the e
inject twice (2×200mg CZP) at each visit
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inject twice (2×200mg CZP) at each visit injection at each of the 2
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injection at each of the 2overall self
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overall self
Injection Preference Questionnaire
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Injection Preference Questionnaire
-Device following the final use per subject:
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-Device following the final use per subject:
nctionally
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nctionallydamage, device does not function normally
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damage, device does not function normally with training cassette)
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with training cassette) damage, device does not function normally with training cassette) damage, device does not function normally
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damage, device does not function normally with training cassette) damage, device does not function normally
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STUDY DESIGN
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STUDY DESIGN
y
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y description
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description
In this Phase 3, open
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In this Phase 3, open-
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-label
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label (treated on Q2W dosing schedule, Q2W group), or
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(treated on Q2W dosing schedule, Q2W group), or dosing schedule
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dosing schedule
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, Q4W group) will be recruited and evaluated. Subjects in the Q2W
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, Q4W group) will be recruited and evaluated. Subjects in the Q2Wgroup should current
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group should currentusing the PFS.
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using the PFS. Hand Function questionnaire.
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Hand Function questionnaire.
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hand function. Impaired hand function will be measu
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hand function. Impaired hand function will be measual, 2000; Duruöz et al
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al, 2000; Duruöz et alC
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C
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 16 of 82
eligibility check at Visit 1, all eligible subjects will enter the Study Treatment Period at that same visit. Subjects will self-inject using the e-Device immediately following training at Visit 1.
For subjects in the Q2W group, subjects will self-inject CZP 200mg using the e-Device (ie, 1×200mg injection). To meet the individual treatment schedule of the subjects, Visit 1 andVisit 2 should be consistent with their scheduled CZP dose (ie, 2 weeks between their last doseand Visit 1, and 2 weeks between Visit 1 and Visit 2).
For subjects in the Q4W group, subjects will self-inject CZP 400mg using the e-Device (ie, 2×200mg injections). To meet the individual treatment schedule of the subjects, Visit 1 and Visit 2 should be consistent with their scheduled CZP dose (ie, 4 weeks between their last dose and Visit 1, and 4 weeks between Visit 1 and Visit 2).
For both groups, a follow-up telephone call will be conducted 1 week after the final study drug administration as a safety follow-up call. Follow-up requirements for adverse events (IMP and investigational device) and pregnancy are outlined in Section 10.1.3, Section 10.2.3, and Section 10.3, respectively. Subjects who have a positive pregnancy test and who have self-administered at least 1 study dose of CZP who then discontinue CZP therapy will have a safety follow-up telephone call 70 days after the last study dose of CZP in addition to the 1-week Safety Follow-Up.
At both study visits, subjects may be provided with a brochure that summarizes an independent post-RA0098 market research study to be conducted by an independent external third party vendor. The market research study will evaluate the patient’s experience with the e-Device and the pre and postinjection questionnaire. If interested in the post-RA0098 market research study, the brochure will ask that patients contact the external third party vendor.
5.1.1 Study duration per subject
The study duration for each subject in the Q2W group on the Q2W dosing regimen is 3 weeks. The study duration for each subject in the Q4W group on the Q4W dosing regimen is 5 weeks.
Subjects will be required to perform a Safety Follow-Up by phone 1 week after their last study dose of CZP. Subjects who have a positive pregnancy test and who have self-administered at least 1 study dose of CZP who then discontinue CZP therapy will have a safety follow-up telephone call 70 days after the last study dose of CZP in addition to the 1-week Safety Follow-Up.
The end of the study is defined as the date of the last telephone follow-up call for the last subject in the study.
5.1.2 Planned number of subjects and sites
Approximately 80 subjects who are currently being treated with commercial CZP and are on a stable dosing regimen for at least 3 months will be screened in order to have at least 60 subjects use the e-Device at Visit 1 at approximately 45 sites. The 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjects in each of the dosing groups (Q2W vsQ4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function. Impaired hand function will be measured using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al, 1996) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
REDACTED COPY
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use the e
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 17 of 82
5.1.3 Anticipated regions and countries
The study is planned to be conducted in the US.
5.2 Schedule of study assessments
Table 5‒1: Schedule of study assessments for Q2W subjects
Assessments Visit 1
(Week 0)
Visit 2(Week 2)
(±3 days)
Follow-Upa
(Week 3)
(±3 days)
Screening Study Treatment Period
Written informed consent X
Demographic data X
Subject completes Cochin Impaired Hand Function questionnaire
X
Verification of inclusion/exclusion criteria X
Withdrawal criteria X
General medical/procedures history X
Physical examination b X
Vital signs c X X
Urine pregnancy test (βHCG)d X X
Contact IXRS X X
Recording of concomitant medication X X
Subject completes preinjection ASI X
Training with e-Device prior to self-administration
X
Subject self-administers CZP using e-Device
X X
HCP evaluates self-injection X X
Subject completes pain VAS (postinjection)e
X X
Subject completes postinjection ASIf X X
Assessment of structural integrity for CZP-cassette
X X
In vitro functional evaluation of e-Device X
Subject completes Self-Injection Preference Questionnaire
X
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 18 of 82
Table 5‒1: Schedule of study assessments for Q2W subjects
Assessments Visit 1
(Week 0)
Visit 2(Week 2)
(±3 days)
Follow-Upa
(Week 3)
(±3 days)
Screening Study Treatment Period
Recording of AEs and ADEs X X X
ADE=adverse device effect; AE=adverse event; AS=ankylosing spondylitis; ASI=Assessment of Self Injection; CZP=certolizumab pegol; HCP=healthcare provider; βHCG=beta human chorionic gonadotropin; IXRS= interactive response technology; Q2W=every 2 weeks; PsA=psoriatic arthritis; RA=rheumatoid arthritis; VAS=visual analog scale
Note: The visit window is ±3 days.a Subjects will be required to perform a Safety Follow-Up by phone 1 week after their last study dose of CZP.
Subjects who are withdrawn from CZP treatment during the course of the study due to pregnancy will be required to perform a safety follow-up call 70 days following their final CZP administration in addition to the 1-week Safety Follow-Up.
b Includes height and weight.c Includes blood pressure, pulse, body temperature, and respiratory rate.d For women of childbearing potential. A serum pregnancy test will be performed in the event of a positive
urine result.e Immediately postinjection (within 15 minutes).f Within 30 minutes postinjection.
REDACTED COPY Includes blood pressure, pulse, body temperature, and respiratory rate.
REDACTED COPY Includes blood pressure, pulse, body temperature, and respiratory rate.
potential. A serum pregnancy test w
REDACTED COPY
potential. A serum pregnancy test w
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X
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X
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Assessment of Self Injection;
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Assessment of Self Injection; CZP=certolizumab pegol; HCP=healthcare provider; βHCG=beta human chorionic gonadotropin;
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CZP=certolizumab pegol; HCP=healthcare provider; βHCG=beta human chorionic gonadotropin; IXRS=
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IXRS= weeks; PsA=psoriatic arthritis; RA=rheumatoid arthritis;
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weeks; PsA=psoriatic arthritis; RA=rheumatoid arthritis;
after their
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Subjects who are withdrawn from CZP treatment during the course of the study due to pregnancy days following their final CZP administration
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 19 of 82
Table 5‒2: Schedule of study assessments for Q4W subjects
Assessments Visit 1
(Week 0)
Visit 2(Week 4)
(±3 days)
Follow-Upa
(Week 5)
(±3 days)
Screening Study Treatment Period
Written informed consent X
Demographic data X
Subject completes Cochin Impaired Hand Function questionnaire
X
Verification of inclusion/exclusion criteria X
Withdrawal criteria X
General medical/procedures history X
Physical examination b X
Vital signs c X X
Urine pregnancy test (βHCG)d X X
Contact IXRS X X
Recording of concomitant medication X X
Subject completes preinjection ASI X
Training with e-Device prior to self-administration
X
Subject self-administers CZP using e-Device
X X
HCP evaluates self-injection X X
Subject completes pain VAS (postinjection)e
X X
Subject completes postinjection ASIf X X
Assessment of structural integrity for CZP-cassette
X X
In vitro functional evaluation of e-Device X
Subject completes Self-Injection Preference Questionnaire
X
Recording of AEs and ADEs X X X
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
X
REDACTED COPY
X
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
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inisters CZP using
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CZP-
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-cassette
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Subject completes
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Subject completes
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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Table 5‒2: Schedule of study assessments for Q4W subjects
Assessments Visit 1
(Week 0)
Visit 2(Week 4)
(±3 days)
Follow-Upa
(Week 5)
(±3 days)
Screening Study Treatment Period
ADE=adverse device effect; AE=adverse event; ASI=Assessment of Self Injection; CD=Crohn’s disease; CZP=certolizumab pegol; HCP=healthcare practitioner; βHCG=beta human chorionic gonadotropin; IXRS= interactive response technology; Q4W=every 4 weeks; VAS=visual analog scaleNote: The visit window is ±3 days.a Subjects will be required to perform a Safety Follow-Up by phone 1 week after their last study dose of CZP.
Subjects who are withdrawn from CZP treatment during the course of the study due to pregnancy will be required to perform a safety follow-up call 70 days following their final CZP administration in addition to the 1-week Safety Follow-Up.
b Includes height and weight.c Includes blood pressure, pulse, body temperature, and respiratory rate.d For women of childbearing potential. A serum pregnancy test will be performed in the event of a positive
urine result.e Immediately postinjection (within 15 minutes).f Within 30 minutes postinjection.
REDACTED COPY
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ASI=Assessment of Self Injection; CD=Crohn’s disease;
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ASI=Assessment of Self Injection; CD=Crohn’s disease; gonadotropin; IXRS=
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gonadotropin; IXRS=
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last study dose of CZPare withdrawn from CZP treatment during the course of the study due to pregnancy
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are withdrawn from CZP treatment during the course of the study due to pregnancy
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days following their final CZP administration
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days following their final CZP administration
ill be performed in the event of a positive
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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5.3 Rationale for study design and selection of dose
UCB has developed a reusable e-Device for the self-administration of a sc dose of CZP. The e-Device provides subjects with another option to self-inject their medication. The e-Device offers improved convenience with an enhanced, reusable electromechanical injector that provides full electronic management of the injection process including subject instructions and warnings via a graphical user interface, and an electronic log of the injection history. A production version of the e-Device will be utilized for the purpose of this study.
Impaired hand function is seen in patients with RA (Durmus et al, 2013), to a lesser extent in patients with PsA (Gottieb et al, 2008), and is uncommon in patients with AS (Tam et al, 2010) or CD (Lossos et al, 1995). Since prompt treatment can reduce inflammation and the level of functional impairment seen in patients with RA or PsA (Goossens et al, 2000), it is not possible to accurately predict the proportion of patients treated with CZP who will have impaired hand function or how easy or difficult it may be to recruit such patients. In a recently published simulated injection study, the author notes that the investigators had difficulties in recruiting patients with high (Cochin score ≥20) versus low (Cochin score <20) hand disability so much so that they decided to stop the recruitment process when only 12 out of 15 subjects with high hand disability were enrolled (Hundry et al, 2017). This suggests that recruiting patients with impaired hand function may be challenging. Given these considerations, this study will recruit a minimum of 10 patients with impaired hand function. Impaired hand function will be measured using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al, 1996) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
The study will be open-label. All eligible subjects should be currently treated with commercial CZP, on a stable dosing regimen for the prior 3 months, and self-administering CZP using the PFS on a Q2W (RA, PsA, or AS) or Q4W (RA, PsA, AS, or CD) dosing regimen, as appropriate.
6 SELECTION AND WITHDRAWAL OF SUBJECTS
6.1 Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject.
2. Subject is considered reliable and capable of adhering to the protocol (eg, able to understand and complete questionnaires, able to use investigational device according to the Instructions for Use [IFU], visit schedule, or medication intake via self-administration) according to the judgment of the Investigator.
3. Subject is male or female and must be at least 18 years old at Visit 1.
4. Subject must have been diagnosed at least 6 months prior to Visit 1 with documented moderate to severe active RA, active PsA, active AS (in US), or moderately to severely active CD (in US).
REDACTED COPY ). This suggests
REDACTED COPY ). This suggests
be challenging. Given these considerations, t
REDACTED COPY
be challenging. Given these considerations, tmpaired hand function will be me
REDACTED COPY
mpaired hand function will be meal, 2000; Duruöz et al
REDACTED COPY
al, 2000; Duruöz et al, 1996
REDACTED COPY
, 1996ents who have a Cochin score
REDACTED COPY
ents who have a Cochin score ≥
REDACTED COPY
≥13.5 at baseline.
REDACTED COPY
13.5 at baseline.
label. All eligible subjects should be currently
REDACTED COPY
label. All eligible subjects should be currentlyfor the prior 3 months,REDACTED C
OPY
for the prior 3 months,
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r extent in
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r extent in AS (Tam et al, 2010)
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AS (Tam et al, 2010) ). Since prompt treatment can reduce inflammation and the level of
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en in patients with RA or PsA (Goossens et al, 2000), it is not possible
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who will have impaired hand n a recently
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n a recently, the author notes that the investigators had difficulties in recruiti
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, the author notes that the investigators had difficulties in recruiti20) versus low (Cochin score <20) hand disability
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20) versus low (Cochin score <20) hand disabilityout of 15
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out of 15). This suggests
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). This suggests that recruiting patients with impaired
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that recruiting patients with impaired be challenging. Given these considerations, t
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be challenging. Given these considerations, tmpaired hand function will be me
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mpaired hand function will be me, 1996
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, 1996) and impaired hand function will be
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) and impaired hand function will be 13.5 at baseline.
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13.5 at baseline.
label. All eligible subjects should be currently
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label. All eligible subjects should be currentlyfor the prior 3 months,
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for the prior 3 months,or Q4W (RA, PsA, AS, or
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or Q4W (RA, PsA, AS, or
6 SELECTION A
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6 SELECTION AND WITHDR
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ND WITHDR
Inclusion criteria
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Inclusion criteria
To be eligible to participate in this study
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To be eligible to participate in this study
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written
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1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written formed Consent form is signed and dated b
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formed Consent form is signed and dated b
Subject is considered reliable and capable of adhering to the protoco
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Subject is considered reliable and capable of adhering to the protocoand complete questionnaires, able to use investigational device according to the I
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and complete questionnaires, able to use investigational device according to the I
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for Use [IFU], visit schedule, or medication intake via self-
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judgment of the
3.
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3. Subject is
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Subject is
4. Subject must have been diagnosed at least 6 months prior to Visit 1 with documented
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4. Subject must have been diagnosed at least 6 months prior to Visit 1 with documented
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 22 of 82
5. A minimum of 10 subjects will have impaired hand function. Impaired hand function will be measured using the Cochin scale (Duruöz et al, 1996; Poiraudeau et al, 2000) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
6. Subjects must have been prescribed CZP and must have been self-injecting CZP using the PFS for at least 3 months prior to Visit 1. Subjects with RA, PsA, or AS must have been on a stable Q2W or Q4W CZP dosing regimen for at least 3 months prior to Screening. Subjects with CD must have been on a stable Q4W CZP dosing regimen for at least 3 months prior to Visit 1.
7. Subjects must have been screened according to the applicable national tuberculosis (TB)screening guidelines (to be documented) or provide a documented TB screening activity (TB questionnaire, IGRA test, or chest x-ray) within the past 12 months prior to Visit 1.
8. Female subjects of childbearing potential should have a negative pregnancy test at Visit 1 and should be using a medically accepted method of contraception during the entire duration of the study. Medically accepted methods of contraception are: hormonal contraception for at least 2 cycles prior to screening, intrauterine device, implant device, diaphragm with spermicide, bilateral tubal ligation, monogamous relationship with vasectomized partner (for at least 2 months prior to screening), or using condoms with spermicide gel. Abstinence is not an acceptable method of contraception for the study. Female subjects who are postmenopausal for at least 2 years or have undergone a complete hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy, or have a congenital sterility are considered not of childbearing potential.
6.2 Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject is <18 years of age at Visit 1.
2. Subject has participated in another study of an investigational medicinal product (IMP) or an investigational device) within the previous 3 months or is currently participating in another study of an IMP or an investigational device.
3. Subject has a history of chronic alcohol or drug abuse within the previous 6 months.
4. Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or <6 months of the last study CZP dose.
5. Subject has a history of significant cardiovascular, respiratory, gastrointestinal, hepatic, endocrine, renal, dermatological, neurological, psychiatric, hematological, or bleeding disorders.
6. Subjects with known TB infection and at high risk of acquiring TB infection. Subjects with latent TB (LTB) who have not completed the prophylactic treatment regimen for LTB 3 months prior to enrollment.
a. Known TB infection whether present or past is defined as:
i) Active TB infection or clinical signs and symptoms suspicious for TB (pulmonary or extra pulmonary)
REDACTED COPY at least 2 months prior to screening), or using condoms with spermicide gel. Abstinence is
REDACTED COPY at least 2 months prior to screening), or using condoms with spermicide gel. Abstinence is
r the study
REDACTED COPY
r the studyears or have undergone a complete hy
REDACTED COPY
ears or have undergone a complete hy
REDACTED COPY
oophorectomy
REDACTED COPY
oophorectomy, or have a congenital sterility
REDACTED COPY
, or have a congenital sterility
Subjects are not permitted to enroll in the studyREDACTED COPY
Subjects are not permitted to enroll in the study
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PFS for at least 3 months prior to Visit 1. Subjects with RA, PsA, or AS must have been on a
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PFS for at least 3 months prior to Visit 1. Subjects with RA, PsA, or AS must have been on a CZP dosing regimen for at least 3 months prior to Screening. Subjects
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CZP dosing regimen for at least 3 months prior to Screening. Subjects with CD must have been on a stable Q4W CZP dosing regimen for at least 3 months prior to
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with CD must have been on a stable Q4W CZP dosing regimen for at least 3 months prior to
7. Subjects must have been screened according to the applicable national tuberculosis (TB)
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7. Subjects must have been screened according to the applicable national tuberculosis (TB)screening guidelines (to be documented) or provide a documented TB screening activity
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screening guidelines (to be documented) or provide a documented TB screening activity) within the past 12 months prior to Visit 1.
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) within the past 12 months prior to Visit 1.
8. Female subjects of childbearing potential should have a negative pregnancy
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8. Female subjects of childbearing potential should have a negative pregnancy test
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test8. Female subjects of childbearing potential should have a negative pregnancy test8. Female subjects of childbearing potential should have a negative pregnancy
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8. Female subjects of childbearing potential should have a negative pregnancy test8. Female subjects of childbearing potential should have a negative pregnancy accepted method of contraception during the entire duration
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accepted method of contraception during the entire duration y accepted methods of contraception are: hormonal contraception for at
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y accepted methods of contraception are: hormonal contraception for at lant device, diaphragm with
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lant device, diaphragm with spermicide, bilateral tubal ligation, monogamous relationship with vasectomized partner (for
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spermicide, bilateral tubal ligation, monogamous relationship with vasectomized partner (for at least 2 months prior to screening), or using condoms with spermicide gel. Abstinence is
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at least 2 months prior to screening), or using condoms with spermicide gel. Abstinence is r the study
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r the study. Female subjects who are
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. Female subjects who are ears or have undergone a complete hy
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ears or have undergone a complete hy
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, or have a congenital sterility
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, or have a congenital sterility
Subjects are not permitted to enroll in the study
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Subjects are not permitted to enroll in the study
ears of age at Visit 1.
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ears of age at Visit 1.
Subject has participated in another stud
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Subject has participated in another studvice) within the previous
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vice) within the previous n investigational
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n investigational
Subject has a history of chronic alcohol or drug abuse within the previous 6 months.
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Subject has a history of chronic alcohol or drug abuse within the previous 6 months.
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4. Female subjects who are breastfeeding, pregnant,
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4. Female subjects who are breastfeeding, pregnant, or <6 months of the last study
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or <6 months of the last study
Subject has a history
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Subject has a historyendocrine, renal, dermatological, neurological, ps
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endocrine, renal, dermatological, neurological, ps
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disorders.
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disorders.
6. Subjects with known TB infection and at high risk of acquiring TB infection. Subjects with
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6. Subjects with known TB infection and at high risk of acquiring TB infection. Subjects with
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 23 of 82
ii) History of active TB infection involving any organ system or findings in other organ systems consistent with TB infection
iii) Any evidence by radiography or other imaging modalities consistent with previously active TB infection that is not reported in the subject’s medical history.
b. High risk of acquiring TB infection is defined as:
i) Known exposure to another person with active TB infection within the 3 months prior to Screening
ii) Time spent in a healthcare delivery setting or institution where individuals infected with TB are housed and where the risk of transmission of infection is high.
c. Latent TB infection (unless appropriate prophylaxis is completed 3 months prior to study enrollment. Subjects must have completed the full course of LTB prophylaxis treatment).
7. Subject has an active chronic/latent infection including but not limited to TB (untreated latent or active), hepatitis virus (HV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
8. Subject has a current malignancy or a history of malignancy. Subjects with less than 3 completely excised basal cell carcinomas or with cervical carcinoma in situ successfully treated surgically more than 5 years prior to Screening may be included.
9. Subject is in a situation or has any condition which in the opinion of the Investigator or Sponsor, may interfere with the optimal participation in the study or produce a significant risk to the subject.
10. Subject has had major surgery (including joint surgery) within 8 weeks prior to Visit 1, or has a scheduled surgery during the study.
6.3 Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued care. Subjects should be withdrawn from the study if any of the following events occur:
1. Subject develops an illness that would interfere with his/her continued participation.
2. Subject is noncompliant with the study procedures or medications in the opinion of the Investigator.
3. Subject withdraws his/her consent.
4. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy test.
5. The Sponsor or a regulatory agency requests withdrawal of the subject.
6. Subject undergoes surgery related to an exacerbation of their disease.
7. The Investigator is of the opinion that the subject’s continued participation in the study is not in the best interest of the subject.
REDACTED COPY of malignancy
REDACTED COPY of malignancy
excised basal cell carcinomas or with cervical carcinoma in s
REDACTED COPY excised basal cell carcinomas or with cervical carcinoma in s
ears prior to Screening may
REDACTED COPY
ears prior to Screening may
y condition which in the opinion of the
REDACTED COPY
y condition which in the opinion of the interfere with the optimal participation in the study
REDACTED COPY
interfere with the optimal participation in the study
(including joint surgeryREDACTED COPY
(including joint surgery
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with active TB infection within the 3 months prior
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with active TB infection within the 3 months prior
setting or institution where individuals infected
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setting or institution where individuals infected with TB are housed and where the risk of transmission of infection is high.
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with TB are housed and where the risk of transmission of infection is high.
laxis is completed 3 months prior to study
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laxis is completed 3 months prior to studyment. Subjects must have completed the full course of LTB prophy
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ment. Subjects must have completed the full course of LTB prophylaxis treatment).
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laxis treatment).
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7. Subject has an active chronic/latent infection including but not limited to TB (untreated latent human immunodeficiency
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human immunodeficiency
of malignancy
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of malignancy. Subjects with less than
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. Subjects with less than excised basal cell carcinomas or with cervical carcinoma in s
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ears prior to Screening may
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y condition which in the opinion of the interfere with the optimal participation in the study
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interfere with the optimal participation in the study
(including joint surgery
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(including joint surgery during the study
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during the study
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Withdrawal criteria
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Withdrawal criteria
Subjects are free to withdraw from the study
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Subjects are free to withdraw from the studySubjects should be withdrawn from the study
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Subjects should be withdrawn from the study
1. Subject develops an illness that would interfere with his/her continued participation.
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1. Subject develops an illness that would interfere with his/her continued participation.
Subject is noncompliant with the study
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nvestigator.
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test.
5.
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6.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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8. Subject experiences a severe or serious injection site reaction (eg, bleeding, bruising, or pain) or a serious adverse event (SAE) that would, in the opinion of the Investigator, preclude the subject’s further participation in the study.
Investigators should attempt to obtain information on subjects in the case of withdrawal or discontinuation. For subjects considered as lost to follow up, the Investigator should make an effort (at least 1 phone call and 1 written message to the subject), and document his/her effort (date and summary of the phone call and copy of the written message in the source documents), to complete the final evaluation. All results of these evaluations and observations, together with a narrative description of the reason(s) for removing the subject, must be recorded in the source documents. The electronic Case Report form (eCRF) must document the primary reason for withdrawal or discontinuation.
Investigators should contact the Medical Monitor in advance, whenever possible, to discuss the withdrawal of a subject.
7 IMP AND INVESTIGATIONAL DEVICE
In this study, the term investigational medicinal product (IMP) means the CZP drug substance. The term investigational device means the CZP-cassette and e-Device.
7.1 Description of investigational device
The reusable e-Device (auto-injector and CZP-cassette) is shown in Figure 7‒1.
Each single-use cassette contains 1 PFS with needle. The needle is covered by a needle cap until the CZP-cassette has been successfully inserted into the e-Device and the cap removed.
Figure 7‒1: CZP e-Device
Auto-injector Cassette
The e-Device plus e-Device cassettes (containing CZP 200mg) will be supplied by UCB.
REDACTED COPY
vestigationa
REDACTED COPY
vestigational device
REDACTED COPY l device
-cassette) is shown
REDACTED COPY
-cassette) is shown
PFS with needle. The needle is covered by
REDACTED COPY
PFS with needle. The needle is covered byy inserted into the
REDACTED COPY
y inserted into the
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of the written message in the source documents),
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of the written message in the source documents), to complete the final evaluation. All results of these evaluations and observations, together with a
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to complete the final evaluation. All results of these evaluations and observations, together with a on(s) for removing the subject, must be recorded in the source
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reason for
Investigators should contact the Medical Monitor in advance, whenever possi
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Investigators should contact the Medical Monitor in advance, whenever possible, to discuss the
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ble, to discuss the
y, the term investigational medicinal product (IMP) means the CZP drug substance.
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y, the term investigational medicinal product (IMP) means the CZP drug substance. cassette and e
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cassette and e-
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-Device
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Device
l device
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l device
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-cassette) is shown
PFS with needle. The needle is covered by
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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7.1.1 Instructions for use of investigational e-Device
At Visit 1, prior to the first self-administration with the e-Device, subjects will be trained on proper self-injection technique and will receive and have the opportunity to review e-Device instruction materials that will be included with the e-Device kit. After the final self-injection and completion of the visual inspection and in vitro functional testing, site staff will print a hardcopy of the e-Device injection log. This log must be retained in the study file prior to disposing of the device. The injection log data may be used in the evaluation of device malfunctions or deficiencies. Details on how the injection log can be downloaded and printed can be found in theIFU.
There is no recommended injection speed for self-injection using the e-Device. The e-Device offers the subject 4 injection speeds: “fastest” (8 seconds), “fast” (11 seconds), “slow” (14 seconds), or “slowest” (17 seconds). The e-Device will come set at the default “fast” (11 seconds) injection speed. As subjects enrolled in this study will be experienced in CZP self-injection using the PFS, they may have a preference for a fast or slow injection based on their experience with PFS self-injection. Subjects will be asked to select 1 of the 4 injection speeds; if they express no preference, then the default injection speed should be used. In either case, the injection speed used should be recorded for each self-injection with the e-Device.
7.2 Treatment to be administered
The treatments are summarized in Table 7‒1.
Table 7‒1: Treatments to be administered
Delivery system Reusable e-Device with single-use cassette
Manufacturer UCB
Content Loaded with a single-use cassette that houses a PFS containing 200mg/mL, 1mL of CZP liquid formulation in 10mM sodium acetate, 125mM sodium chloride pH 4.7
CZP=certolizumab pegol; PFS=pre-filled syringe
Each dose will be administered as sc injections in either the right or left lateral abdominal wall or the right or left thigh. Treatment of the injection site with an anesthetic cream prior to dosing is not permitted.
Each injection should be administered at a separate injection site, and rotation between the injection sites should be observed.
At Visit 1 and Visit 2, Q2W group subjects will self-inject CZP 200mg (1×200mg injection) using the e-Device. At Visit 1 and Visit 2, Q4W group subjects will self-inject CZP 400mg (2×200mg injections) using the e-Device.
Before injection, the CZP-cassette should be brought to room temperature by removing from the refrigerator and placing on a table at room temperature for 30 to 45 minutes. Subjects will beobserved onsite for 30 minutes after self-injection with CZP using the e-Device for any AEs. Subjects will be asked to contact the designated site personnel in case any AEs occur outside of the site visits.
REDACTED COPY
Treatment to be administered
REDACTED COPY
Treatment to be administered
Treatments to be administered
REDACTED COPY
Treatments to be administered
Reusable e
REDACTED COPY
Reusable e
REDACTED COPY
UCBREDACTED COPY
UCBREDACTED COPY
REDACTED COPY
REDACTED COPY
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the
Details on how the injection log can be downloaded and printed can be found in the
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Details on how the injection log can be downloaded and printed can be found in the
Device. The e
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Device. The e-
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-Device
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Device offers the subject 4 injection speeds: “fastest” (8 seconds), “fast” (11 seconds), “slow”
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offers the subject 4 injection speeds: “fastest” (8 seconds), “fast” (11 seconds), “slow” Device will come set at the default “fast”
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Device will come set at the default “fast” will be experienced in CZP
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will be experienced in CZP have a preference for a fast or slow injection based on
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have a preference for a fast or slow injection based on their experience with PFS self-injection. Subjects will be asked to select 1 of the 4 injection
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their experience with PFS self-injection. Subjects will be asked to select 1 of the 4 injection express no preference, then the default injection speed should be used. In either
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express no preference, then the default injection speed should be used. In either case, the injection speed used should be recorded for each self
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case, the injection speed used should be recorded for each self-
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-case, the injection speed used should be recorded for each self-case, the injection speed used should be recorded for each self
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case, the injection speed used should be recorded for each self-case, the injection speed used should be recorded for each self injection with the e
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injection with the e
Treatments to be administered
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Treatments to be administered
Reusable e
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Reusable e-D
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-D
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UCB
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Loaded with a single
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Loaded with a singlecontaining 200mg/mL, 1mL of CZP liquid formulation in
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containing 200mg/mL, 1mL of CZP liquid formulation in
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; PFS=pre
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; PFS=pre-
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-filled
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filled
Each dose will be administered as
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Each dose will be administered asthe right or left thigh. Treatment of the injection site with an anesthetic cream prior to dosing is
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the right or left thigh. Treatment of the injection site with an anesthetic cream prior to dosing is
Each injection should be adm
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Each injection should be adminjection sites should be observed.
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injection sites should be observed.
At Visit
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using the e(2
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(2×200mg injections) using the e-
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×200mg injections) using the e-
Before injection, the CZP-
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 26 of 82
7.3 Packaging
The site will receive uniquely numbered e-Devices and CZP-cassettes for use in this study. The CZP-cassettes will be provided in the intended final packaging.
7.4 Labeling
Clinical drug and investigational device supplies will be labeled in accordance with the current International Council for Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practice and will include any locally required statements. If necessary, labels will be translated into the local language.
7.5 Handling and storage requirements
Certolizumab pegol (CZP-cassettes) must be securely stored at 2ºC to 8ºC, ie, in a refrigerator that is either in a locked room or in the pharmacy. Appropriate storage conditions must be ensured by controlled fridge temperature either using automated temperature monitoring and recording system or by using a minimum/maximum thermometer and completing a daily temperature log in accordance with local requirements. In case out of range temperature is noted, the Sponsor or designee must be notified so that the Sponsor or designee can determine whether the product should be used or not.
Each investigational e-Device must be individually stored (per subject) in a secured, limited access area at room temperature. The Investigator or hospital Pharmacist is responsible for the appropriate storage and accountability of the investigational device/CZP (CZP-cassettes) at the site, and documentation of appropriate storage and accountability.
7.6 Drug and device accountability
The Investigator will receive numbered treatments that will be assigned to eligible subjects by an interactive response technology (IXRS) at Visit 1. All drug administrations will be observed by the Investigator or his/her appropriately trained designee.
UCB, or its representatives, will supply a Drug Accountability form, to be kept up to date with record of all IMP administrations, ie, injections by means of the e-Device. This form will serve as source documentation during the course of the study. In addition, a Device Accountability form will be used to record investigational device used on a by-subject basis and will serve as source documentation during the course of the study. Details of any loss (e-Device auto-injectors or e-Device cassettes) due to breakage or wastage, not used, destructed at the study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. All supplies and pharmacy documentation must be made available throughout the study for UCB (or designee) to review.
The Investigator (or designee) is responsible for retaining all used, unused, and partially used IMP until returned or destroyed. The Investigator may assign some of the Investigator’s duties for drug accountability at the study site to an appropriate pharmacist/designee.
The IMP and investigational device (including e-Device auto-injectors and e-Device cassettes) intended for the study cannot be used for any other purpose than that described in this protocol.
REDACTED COPY
Device must be individually
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Device must be individually stored (per
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stored (per Device must be individually stored (per Device must be individually
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Device must be individually stored (per Device must be individuallyaccess area at room temperature. The Investigator or hospital Pharmacist is responsible for
REDACTED COPY
access area at room temperature. The Investigator or hospital Pharmacist is responsible for of the investigational device/CZP (CZP
REDACTED COPY
of the investigational device/CZP (CZPsite, and documentation of appropriate storage and accountabilit
REDACTED COPY
site, and documentation of appropriate storage and accountabilit
accountabilityREDACTED C
OPY
accountability
The Investigator will receive numbered treatments that wilREDACTED C
OPY
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nvestigational device supplies will be labeled in accordance with the current
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nvestigational device supplies will be labeled in accordance with the current Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and
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site, and documentation of appropriate storage and accountabilit
accountability
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accountability
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(IXRS) at Visit 1. nvestigator or his/her appropriately
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record of all IMP administrations, ie, injections by means of as source documentation during the course of the study
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Device cassettes) due to breakage or wastage, not used, destructed at the study
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Device cassettes) due to breakage or wastage, not used, destructed at the studyreturned to the Sponsor or designee must also be recorded on the appropriate forms. All supplies
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returned to the Sponsor or designee must also be recorded on the appropriate forms. All supplies and pharmacy
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and pharmacydesignee) to review.
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designee) to review.
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The Investigator (or designee) is responsible for retaining all used, unused, and partiall
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The Investigator (or designee) is responsible for retaining all used, unused, and partiallIMP until returned or destroy
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for drug accountability
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 27 of 82
7.7 Procedures for monitoring subject compliance
As all CZP self-administrations will be scheduled, performed at the site, and observed by the Investigator or his/her designee, monitoring subject compliance is not applicable.
7.8 Concomitant medications/treatments
7.8.1 Permitted concomitant treatments (medications and therapies)
Subjects are permitted to continue on their prescribed medical therapy for the disease in accordance with the instructions of their treating physician. Concomitant medications/treatments, including over-the-counter products and supplements, must be recorded in the subject’s notes (source documentation) and provided on the eCRF. This record should include the name of the drug, the dose, the route, and date(s) of administration, and the indication for use.
7.8.2 Prohibited concomitant treatments (medications and therapies)
Use of topical analgesics at the injection site are prohibited concomitant medications in this study.
7.9 Blinding
This is an open-label study.
7.10 Randomization and numbering of subjects
There will be no randomization in this study. A subject number assigned by an IXRS at Visit 1will serve as the subject identifier throughout the study.
8 STUDY PROCEDURES BY VISIT
As the dosing schedule groups (Q2W vs Q4W) are different regarding number of injections (1 CZP injection for Q2W vs 2 CZP injections per administration for Q4W) and study treatment period (2 weeks vs 4 weeks), the schedule of assessments for the 2 subject populations differs.
8.1 Visit 1/ Screening and Study Treatment Period
Prior to any study activities, all subjects will be asked to read and sign an Informed Consent formthat has been approved by an IRB/IEC and which complies with regulatory requirements. Subjects will be given adequate time to consider any information concerning the study, described to them by the Investigator or designee. As part of the informed consent procedure, subjects will be given the opportunity to ask the Investigator any questions regarding potential risks and benefits of participation in the study.
The following procedures will be performed:
Recording of demographic data
Verification of eligibility criteria
General medical and procedures history
Physical examination, including height and weight
Measurement of vital signs (BP, pulse, body temperature, respiratory rate [RR])
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Randomization and numbering of subjects
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Randomization and numbering of subjects
A subject
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A subject as the subject identifier throughout the study
REDACTED COPY
as the subject identifier throughout the study
STUDY PROCEDURES BY REDACTED C
OPY
STUDY PROCEDURES BY
(Q2W vs Q4W)REDACTED COPY
(Q2W vs Q4W)
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accordance with the instructions of their treating physician. Concomitant medications/treatments,
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accordance with the instructions of their treating physician. Concomitant medications/treatments, counter products and supplements, must be recorded in the subject’s notes
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counter products and supplements, must be recorded in the subject’s notes umentation) and provided on the eCRF. This record should include the name of the
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drug, the dose, the route, and date(s) of administration, and the indication for use.
Prohibited concomitant treatments (medications and therapies)
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Prohibited concomitant treatments (medications and therapies)
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Randomization and numbering of subjects
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Randomization and numbering of subjects
A subject
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as the subject identifier throughout the study
STUDY PROCEDURES BY
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STUDY PROCEDURES BY
(Q2W vs Q4W)
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(1 CZP injection for Q2W vs 2 CZP injections per adminis4 weeks), the schedule of assessments for the 2 subject populations differs.
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4 weeks), the schedule of assessments for the 2 subject populations differs.
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Screening
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activities, all
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that has been approved by an Subjects will be given adequate time to consider any
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autho
rizati
on ap
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nsion
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ariati
ons t
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the Investigator or designee. As part obe given the opportunity to ask the Investigator any
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be given the opportunity to ask the Investigator anybenefits of participation in the study
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benefits of participation in the study
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The following procedures will be performed:
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The following procedures will be performed:
Recording of demographic data
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Recording of demographic data
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 28 of 82
Urine pregnancy test (female subjects of childbearing potential)
Contact IXRS
Subject completes Cochin Impaired Hand Function questionnaire
Recording of concomitant medication
Recording of AEs and ADEs
Once all entry criteria have been verified, the following procedures will be performed:
Preinjection ASI
Training on use of e-Device
Self-administration of CZP using e-Device
HCP evaluates self-injection
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Assessment of structural integrity of CZP-cassette
Pain VAS (immediately postinjection [within 15 minutes])
Postinjection ASI (within 30 minutes postinjection)
Recording of AEs and ADEs
8.2 Study procedures by visit for the Q2W group
8.2.1 Visit 2 (Week 2)
The following procedures will be performed:
Review withdrawal criteria
Measurement of vital signs (BP, pulse, body temperature, RR)
Urine pregnancy test (female subjects of childbearing potential)
Contact IXRS
Recording of concomitant medication
Self-administration of CZP using e-Device
HCP evaluates self-injection
REDACTED COPY clean injection site and resume and complete the se
REDACTED COPY clean injection site and resume and complete the self
REDACTED COPY lf
iver the entire dose of medication (ie, the device indicates
REDACTED COPY
iver the entire dose of medication (ie, the device indicates cassette is not
REDACTED COPY
cassette is notinjection will document the incomplete self
REDACTED COPY
injection will document the incomplete selfnot administered, and using his/
REDACTED COPY
not administered, and using his/y further dosing
REDACTED COPY
y further dosing.
REDACTED COPY
.
y of CZPREDACTED COPY
y of CZP
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es contact with the skin, the
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es contact with the skin, the Device will withdraw the needle and stop administration o
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nsion
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Device will withdraw the needle and stop administration of CZP. If less than five minutes
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eting
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f CZP. If less than five minutes f contact with skin, the subject can reposition the e-
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f contact with skin, the subject can reposition the e-injection.
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injection. iver the entire dose of medication (ie, the device indicates
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iver the entire dose of medication (ie, the device indicates cassette is not
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eting
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cassette is not seen to be empt
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seen to be emptinjection will document the incomplete self
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injection will document the incomplete selfnot administered, and using his/
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not administered, and using his/
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y of CZP
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y of CZP
postinjection [
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postinjection [
30 minutes postinjection)
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30 minutes postinjection)
and ADEs
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and ADEs
y
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y procedures by
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procedures by
8.2.1 Visit 2 (Week 2)
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8.2.1 Visit 2 (Week 2)
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The following procedures will be performed:
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The following procedures will be performed:
Review withdrawal criteria
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on ap
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Review withdrawal criteria
Measurement of vital signs (BP,
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Measurement of vital signs (BP,
Urine pregnancy
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Urine pregnancy
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 29 of 82
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Assessment of structural integrity of CZP-cassette
In vitro functional evaluation of e-Device
Pain VAS (immediately postinjection [within 15 minutes])
Postinjection ASI (within 30 minutes postinjection)
Self-Injection Preference Questionnaire
Recording of AEs and ADEs
8.3 Study procedures by visit for the Q4W group
8.3.1 Visit 2 (Week 4)
The following procedures will be performed:
Review withdrawal criteria
Measurement of vital signs (BP, pulse, body temperature, RR)
Urine pregnancy test (female subjects of childbearing potential)
Contact IXRS
Recording of concomitant medication
Self-administration of CZP using e-Device
HCP evaluates self-injection
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Assessment of structural integrity of CZP-cassette
In vitro functional evaluation of e-Device
REDACTED COPY
isit for the Q4W group
REDACTED COPY
isit for the Q4W group
he following procedures will be performed:
REDACTED COPY
he following procedures will be performed:
Measurement of vital signs (BP, pulse, bodREDACTED COPY
Measurement of vital signs (BP, pulse, bod
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evaluating
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evaluating
cal judgment, advise the
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cal judgment, advise the
isit for the Q4W group
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isit for the Q4W group
Measurement of vital signs (BP, pulse, bod
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Measurement of vital signs (BP, pulse, bod
test (female subjects of childbearing potential)
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test (female subjects of childbearing potential)
Recording of concomitant medication
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Recording of concomitant medication
administration of CZP using
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administration of CZP using
HCP evaluates self
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HCP evaluates selfHCP evaluates self-HCP evaluates self
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HCP evaluates self-HCP evaluates self injection
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injection
During self
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During self-
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-During self-During self
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During self-During self injection, if the skin sensor at the injection port los
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injection, if the skin sensor at the injection port los
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Device will withdraw the needle and stop administr
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Device will withdraw the needle and stop administrhave elapsed since loss o
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have elapsed since loss oclean injection site and resume and complete the se
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clean injection site and resume and complete the secomplete the self
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complete the selfincomplete administration and the CZP
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incomplete administration and the CZP
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 30 of 82
Pain VAS (immediately postinjection [within 15 minutes])
Postinjection ASI (within 30 minutes postinjection)
Self-Injection Preference Questionnaire
Recording of AEs and ADEs
8.4 Safety Follow-Up
A Safety Follow-Up by telephone will be conducted 1 week after the subject’s final site visitusing the e-Device. Any AEs or ADEs will be recorded.
Subjects who are withdrawn from CZP treatment during the course of the study due to pregnancywill be required to perform a safety follow-up telephone call 70 days following their final CZP administration in addition to the 1-week Safety Follow-Up.
9 ASSESSMENT OF SELF-INJECTION
9.1 Injection Site Pain (VAS)
A VAS will be used to assess overall injection pain due to self-injection postinjection at everyvisit during the Study Treatment Period. Subjects will be required to indicate their injection pain by placing a mark on a 100mm line from 0 (no pain) to 100 (worst possible pain). The VAS will be assessed immediately postinjection (within 15 minutes). The subject will complete the VAS prior to completion of the postinjection ASI.
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitwill complete the Pain VAS after the second injection at each of the 2 visits. For subjects on the Q4W dosing regimen, the Pain VAS will record the overall pain associated with both self-injections.
9.2 Assessment of Self Injection (ASI)
The preinjection ASI is composed of 6 items grouped into 2 domains. The postinjection ASI is composed of 44 items grouped into 6 domains. The domains are feeling about injections, self-image, self-confidence, pain and skin reactions during and after injections, ease of use of the self-injection device, and satisfaction with self-injection.
The preinjection ASI will be completed preinjection at Visit 1, and the postinjection will be completed within 30 minutes postinjection at each visit during the Study Treatment Period. The ASI has been developed from the Self-Injection Assessment Questionnaire and modified to reflect the improved features of the e-Device and is being piloted in this study. It will be validated using a separate psychometric analysis plan.
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitwill complete the postinjection ASI after the second injection at each of the 2 visits. For subjectson the Q4W dosing regimen, the postinjection ASI will collect the overall self-injection associated with both self-injections.
REDACTED COPY will be
REDACTED COPY will be
placing a mark on a 100mm line from 0 (no pain) to 100 (worst possible pain).
REDACTED COPY
placing a mark on a 100mm line from 0 (no pain) to 100 (worst possible pain).15
REDACTED COPY
15 minutes
REDACTED COPY
minutes
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit
REDACTED COPY
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitVAS after the second injection at each of the
REDACTED COPY
VAS after the second injection at each of the VAS will record the overall pain associREDACTED C
OPY
VAS will record the overall pain associ
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final site visit
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final site visit
due to pregnancy
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due to pregnancys following their final CZP
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s following their final CZP
due to self
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-injection
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placing a mark on a 100mm line from 0 (no pain) to 100 (worst possible pain).minutes
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minutes). The subject will complete the VAS
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). The subject will complete the VAS
Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit
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Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitVAS after the second injection at each of the
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VAS will record the overall pain associ
sessment of Self Injection
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sessment of Self Injection
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is composed of 6 items grouped into 2 domains. The
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is composed of 6 items grouped into 2 domains. The items grouped into 6 domains. The domains are feeling about injections, self
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items grouped into 6 domains. The domains are feeling about injections, self-confidence, pain and skin reactions during and after injections, ease of use of the
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-confidence, pain and skin reactions during and after injections, ease of use of the injection device, and satisfaction with self
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injection device, and satisfaction with self
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injection ASI
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ASI will be completed pre
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will be completed prewithin
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within
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30 minutes postinjection at each visit during the Study
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30 minutes postinjection at each visit during the Studyhas been developed from the Self
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has been developed from the Selfreflect the improved features of the e
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reflect the improved features of the evalidated using a separate psychometric anal
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validated using a separate psychometric anal
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Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit
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Subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visitwill complete the
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on the Q4W dosing regimen, the postinjection
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 31 of 82
9.3 Self-Injection Preference Questionnaire
The 9-item Self-Injection Preference Questionnaire was developed, based on patient input, to assess the self-injection experience and patient preference between the e-Device and PFS. The Self-Injection Preference Questionnaire will be completed by the subject at Visit 2 after the VAS and postinjection ASI have been completed.
9.4 Evaluation of post-use structural integrity of CZP-cassettes
The used CZP-cassettes will be inspected to determine if the entire dose was delivered based on whether the PFS housed in the CZP-cassette is empty or not (as per primary endpoint). During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing. The visual inspection of the used CZP-cassette will also check for structural integrity and damage (ie, clear evidence of damage/compromised structural integrity—not superficial, cosmetic imperfections). All evaluations will be performed by appropriately trained site staff.
9.5 Evaluation of post-use structural and functional integrity of the e-Device
Following the subject’s final self-administration using the e-Device, the e-Device will be visually inspected for structural integrity and damage (ie, clear evidence of damage/compromised structural integrity—not superficial, cosmetic imperfections). The e-Device will also be evaluated for functional integrity (ie, proper functioning) using a training cassette as specified in the in vitro e-Device functional testing directions. All evaluations will be performed by appropriately trained site staff.
9.6 Evaluation of safe and effective self-injection
Safe and effective self-injection will be evaluated by the HCP. Subject self-injection of the complete dose of CZP will be confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be empty. During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing. The self-injection will be considered safe if there are no AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection.
REDACTED COPY -cassette will also check for structural integrit
REDACTED COPY -cassette will also check for structural integrit
ompromised structural integrity
REDACTED COPY
ompromised structural integrity—
REDACTED COPY
—ompromised structural integrity—ompromised structural integrity
REDACTED COPY
ompromised structural integrity—ompromised structural integrity not superficial, cosmetic impe
REDACTED COPY
not superficial, cosmetic impeappropriately
REDACTED COPY
appropriately trained site staff.
REDACTED COPY
trained site staff.appropriately trained site staff.appropriately
REDACTED COPY
appropriately trained site staff.appropriately
use structural and functional integrity
REDACTED COPY
use structural and functional integrity
administration using the eREDACTED C
OPY
administration using the e inspected for structural integritR
EDACTED COPY
inspected for structural integrit
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cassettes will be inspected to determine if the entire dose was delivered based on
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cassettes will be inspected to determine if the entire dose was delivered based on endpoint).
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endpoint). During
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withdraw the needle and stop administration of CZP. If less than five minutes have elapsed scan reposition the e-Device on a new clean injection site
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If the subject is unable to complete the self-ice indicates incomplete administration and
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administration using the e
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damage/compromised structural integrity—
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e-Device will also be evaluated for functional integritcassette as specified in the in vitro e-Device functional testing directions. All evaluations will be
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Safe and effective self
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shows the PFS container to be emptyes contact with the
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reposition the eIf the subject is unable to complete the self
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For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
10 ASSESSMENT OF SAFETY
In this study, safety reporting requirements apply to the IMP and to all constituents of the investigational device (including the e-Device auto-injector, and the CZP-cassette) per 21 CFR 312.32, 21 CFR 812.150, and 21 CFR 812.3. Subjects in the study are experienced at self-injection and will be aware of their usual injection experience and events typically seen during the normal course of an injection. Effects that are considered usual by the subject and the HCP (eg, minor pain, bruising, or bleeding) during the course of self-injection are not to be classified as AEs.
10.1 Adverse events (IMP)
10.1.1 Definitions (IMP)
10.1.1.1 Adverse event (IMP)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after the signing of the Informed Consent form), including any pretreatment and posttreatment periods required by the protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be recorded as AEs only if their nature changes considerably or their frequency or intensity increases in a clinically significant manner as compared to the clinical profile known to the Investigator from the subject’s history or the Baseline Period.
10.1.1.2 Serious adverse event (IMP)
Once it is determined that a subject experienced an AE, the seriousness of the AE must be determined. An SAE must meet 1 or more of the following criteria:
Death
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in a more severe form.)
Significant or persistent disability/incapacity
REDACTED COPY untoward medical occurrence in a patient or clinical investigation
REDACTED COPY untoward medical occurrence in a patient or clinical investigation
cal product that does not necessarily
REDACTED COPY
cal product that does not necessarilyrelationship with this treatment. An AE can therefore be an
REDACTED COPY
relationship with this treatment. An AE can therefore be an finding), s
REDACTED COPY
finding), sym
REDACTED COPY
ymptom, or disease temporally
REDACTED COPY
ptom, or disease temporallyal (investigational) product, whether or not related to the medicinal
REDACTED COPY
al (investigational) product, whether or not related to the medicinal
data collection, all AEs occurring during the studyREDACTED COPY
data collection, all AEs occurring during the study
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injection are not
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untoward medical occurrence in a patient or clinical investigation cal product that does not necessarily
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cal product that does not necessarilyrelationship with this treatment. An AE can therefore be an
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relationship with this treatment. An AE can therefore be anptom, or disease temporally
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data collection, all AEs occurring during the studythe signing of the Informed Consent form), including an
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the signing of the Informed Consent form), including an
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y the protocol, must be reported in the
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y the protocol, must be reported in the procedures were conducted. This includes all AEs not present prior to the initial visit and
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procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs that recurred or worse
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all AEs that recurred or worsened after the initial visit.
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ned after the initial visit.
ptoms of the condition/disease for which the IMP is being studied should be
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y if their nature changes considerablincreases in a clinicall
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nvestigator from the subject’s history or the Baseline Period.
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nvestigator from the subject’s history or the Baseline Period.
Serious adverse event (IMP)
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Serious adverse event (IMP)
Once it is determined that a subject experienced an AE, the seriousness of the AE must be
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Once it is determined that a subject experienced an AE, the seriousness of the AE must be determined. An SAE must meet 1 or more of the following criteria:
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determined. An SAE must meet 1 or more of the following criteria:
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Death
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Congenital anomaly/birth defect (including that occurring in a fetus)
Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious
(Important medical events may include, but are not limited to potential Hy’s Law [see Section 10.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.)
Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the criteria for the initial inpatient hospitalization. An emergency room visit that results in admission to the hospital would also qualify for the initial inpatient hospitalization criteria. However, emergency room visits that do not result in admission to the hospital would not qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned surgery or elective surgery for a pre-existing condition that has not worsened or manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a subject has a condition recorded on his/her medical history and later has a preplanned surgery for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. Please note that, if the pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, this would then qualify as an AE and, if necessary, the seriousness of the event would need to be determined.)
10.1.1.2.1 Anticipated serious adverse events (IMP)
The following Anticipated SAEs are anticipated to occur in the population studied in this protocol at some frequency that is independent of drug exposure.
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated SAEs) as detailed in Section 10.1.1.2.
REDACTED COPY Hospitalizations for reasons not associated with the occurrence of an AE [eg,
REDACTED COPY Hospitalizations for reasons not associated with the occurrence of an AE [eg,
-existing condition that has not worsened or manifested
REDACTED COPY
-existing condition that has not worsened or manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a
REDACTED COPY
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a subject has a condition recorded on his/her medical history
REDACTED COPY
subject has a condition recorded on his/her medical historyfor this condition, it is not appropriate to record the surgery
REDACTED COPY
for this condition, it is not appropriate to record the surgerysince there is no AE upon which to assess the serious criteria. Please note that, if the
REDACTED COPY
since there is no AE upon which to assess the serious criteria. Please note that, if the -existing condition has worsened or manifested in an unusual or uncharacteristic manne
REDACTED COPY
-existing condition has worsened or manifested in an unusual or uncharacteristic manne as an AE and, if necessary, the seriousness of the event would need to REDACTED C
OPY
as an AE and, if necessary, the seriousness of the event would need to
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(A patient admitted to a hospital, even if he/she is released on the same day, meets the
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for 1 of the other criteria in the threatening adverse experience, important medical event].
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threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg,
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-existing condition that has not worsened or manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a
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in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a subject has a condition recorded on his/her medical history
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subject has a condition recorded on his/her medical historyfor this condition, it is not appropriate to record the surgery
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for this condition, it is not appropriate to record the surgerysince there is no AE upon which to assess the serious criteria. Please note that, if the
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as an AE and, if necessary, the seriousness of the event would need to
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as an AE and, if necessary, the seriousness of the event would need to
ticipated serious adverse events
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ticipated serious adverse events
The following Anticipated SAEs are anticipated to occur in the population studied in this
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The following Anticipated SAEs are anticipated to occur in the population studied in this some frequency
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some frequency that is independent of drug exposure.
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that is independent of drug exposure. some frequency that is independent of drug exposure. some frequency
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some frequency that is independent of drug exposure. some frequency
This list does not change the
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This list does not change the SAEs) as detailed in
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SAEs) as detailed in Section
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Section
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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Table 10‒1: Anticipated serious adverse events for study population
Population Anticipated SAE
Rheumatoid arthritis Rheumatoid arthritis
Crohn's disease Crohn’s disease
Perianal abscess
Abdominal pain
Psoriatic arthritis Psoriatic arthritis
Ankylosing spondylitis Ankylosing spondylitis
SAE=serious adverse event
10.1.1.3 Adverse events of special interest (IMP)
An AE of special interest is any AE that a regulatory authority has mandated be reported on an expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a UCB product/compound. For the present study, the AEs of special interest are as follows:
Serious infections, including opportunistic infections
Malignancies, including lymphoma
Congestive heart failure
Demyelinating-like disorders
Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia
Serious bleeding events
Lupus and lupus-like syndrome
Serious skin reactions (ie, Stevens Johnson Syndrome, toxic epidermal necrosis, and erythema multiforme)
Potential Hy’s Law, defined as ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any additional etiologic investigations to have been concluded). Follow-up information should then be reported if an alternative etiology is identified during investigation and monitoring of the subject.
10.1.2 Procedures for reporting and recording adverse events (IMP)
The subject will be given the opportunity to report AEs spontaneously. A general prompt will also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
REDACTED COPY
, including opportunistic infections
REDACTED COPY
, including opportunistic infections
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has mandated be reported on an expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the
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expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the For the present stud
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For the present study, the AEs of
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, including opportunistic infections
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, including opportunistic infections
topenia, thrombocy
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topenia, thrombocy
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drome
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hema multiforme)
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’s Law, defined as
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’s Law, defined as aspartate aminotransferase (
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aspartate aminotransferase (≥2xUL
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≥2xULbiochemical abnormality
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biochemical abnormalityithout waiting for any additional etiologic investigations to have been concluded). Follow
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ithout waiting for any additional etiologic investigations to have been concluded). Followinformation should then be reported if an alternative etiology
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information should then be reported if an alternative etiologyand monitoring of the subject.
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and monitoring of the subject.
10.1.2
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10.1.2
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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In addition, the Investigator should review any self-assessment procedures employed in the study.
10.1.2.1 Description of adverse events (IMP)
When recording an AE, the Investigator should use the overall diagnosis or syndrome using standard medical terminology, rather than recording individual symptoms or signs. The eCRFand source documents should be consistent. Any discrepancies between the subject’s own words on his/her own records (eg, diary card) and the corresponding medical terminology should be clarified in the source documentation.
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) are described in the eCRF Completion Guidelines.
10.1.2.2 Rule for repetition of an adverse event (IMP)
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:
The outcome date of the first AE that is not related to the natural course of the disease being the same as the start date of the repeated AE, and the outcome of “worsening”
The AE verbatim term being the same for the first and repeated AE, so that the repeated AE can be easily identified as the worsening of the first one
10.1.2.3 Additional procedures for reporting serious adverse events (IMP)
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting section at the front of the protocol). The Investigator must forward to UCB (or its representative) a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) provided by UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order to draw any conclusions. Information recorded on this form will be entered into the global safety database.
An Investigator SAE report form will be provided to the Investigator. The Investigator SAE Report form must be completed in English.
It is important for the Investigator, when completing the SAE report form, to include the assessment as to a causal relationship between the SAE and the IMP administration. This insight from the Investigator is very important for UCB to consider in assessing the safety of the IMP and in determining whether the SAE requires reporting to the regulatory authorities in an expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be provided within 24 hours. All documents in the local language must be accompanied by a translation in English, or the relevant information included in the same document must be summarized in the Investigator SAE report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to completion of the follow-up visit for each subject, and to also inform participating subjects of the need to inform the Investigator of any SAE within this period. Serious AEs that the Investigator
REDACTED COPY The AE verbatim term being the same for the first and repeated AE, so that the repeated AE
REDACTED COPY The AE verbatim term being the same for the first and repeated AE, so that the repeated AE
can be easily identified as the worsening of the first one
REDACTED COPY can be easily identified as the worsening of the first one
ditional procedures for reporting
REDACTED COPY
ditional procedures for reporting
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by
REDACTED COPY
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information bythe site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting
REDACTED COPY
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting ol). The
REDACTED COPY
ol). The Investigator must forward to UCB (or its representative)
REDACTED COPY
Investigator must forward to UCB (or its representative) completed “Investigator SAE Report Form for Development Drug” (SAE report form) REDACTED C
OPY
completed “Investigator SAE Report Form for Development Drug” (SAE report form)
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discrepancies between the subject’s own words
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should be
(including judgment of relationship to I
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(including judgment of relationship to I
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of an AE should lead to the repetition of the AE being reported with:
The outcome date of the first AE that is not related to the natural course of the disease being
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e as the start date of the repeated AE, and the outcome of “worsening”
The AE verbatim term being the same for the first and repeated AE, so that the repeated AE
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can be easily identified as the worsening of the first one
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serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by
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the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting Investigator must forward to UCB (or its representative)
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Investigator must forward to UCB (or its representative) completed “Investigator SAE Report Form for Development Drug” (SAE report form)
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completed “Investigator SAE Report Form for Development Drug” (SAE report form) y UCB, even if the data are incomplete, or if it is obvious that more data will be
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conclusions. Information recorded on this form will be entered into
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conclusions. Information recorded on this form will be entered into
An Investigator SAE report form will be provided to the
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Report form must be completed in English.
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nvestigator, when completing the SAE report form, to include the assessment as to a causal relationship between the SAE and the IMP administration. This insight
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assessment as to a causal relationship between the SAE and the IMP administration. This insight nvestigator is very
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and in determining whether the SAE requires reporting to the regulatory
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summarized in the I
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thinks may be associated with the IMP must be reported to UCB regardless of the time between the event and the end of the study.
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s Brochure.
10.1.3 Follow up of adverse events (IMP)
An AE should be followed until it has resolved, has a stable sequelae, the Investigator determines that it is no longer clinically significant, or the subject is lost to follow up. This follow-up requirement applies to AEs, SAEs, and AEs of special interest.
If an AE is ongoing at the end of the study for a subject, follow up should be provided until resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is clinically significant, or until the subject is lost to follow up. If no follow up is provided, the Investigator must provide a justification.
Information on SAEs obtained after clinical database lock will be captured through the Patient Safety (PS) database without limitation of time.
10.2 Adverse events (investigational device)
10.2.1 Definitions (investigational device)
10.2.1.1 Adverse Events (investigational device)
An AE for an investigational device is any untoward medical occurrence, unintended disease or injury, or untoward clinical sign (including abnormal laboratory findings) in subjects enrolled in the study, including any pre- and posttreatment periods (as required by the protocol). This includes the following:
Events considered unrelated or related to the investigational medical device
Events related to the procedures involved (even if no investigational device was used).
For users or other persons (eg, caregivers), AEs for a device are restricted to only events related to the investigational medical device.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after the signing of the Informed Consent form), including any pretreatment and posttreatment periods required by the protocol, must be reported in the eCRF even if no investigational device was used but specific study procedures were conducted. This includes all AEs not present prior to theinitial visit and all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the Investigational Device is being studied should be recorded as AEs only if their nature changes considerably or their frequency or intensity increases in a clinically significant manner as compared to the clinical profile known to the Investigator from the subject’s history or the Baseline Period.
REDACTED COPY verse events (investigational device)
REDACTED COPY verse events (investigational device)
Definitions (investigational device)
REDACTED COPY
Definitions (investigational device)
(investigational device)
REDACTED COPY
(investigational device)
for an investigational device is an
REDACTED COPY
for an investigational device is any untoward medical occurrence, unintended disease or
REDACTED COPY
y untoward medical occurrence, unintended disease or , or untoward clinical sign (including abnormal laboratory
REDACTED COPY
, or untoward clinical sign (including abnormal laboratoryand postREDACTED C
OPY
and posttreatment periods (as required byREDACTED COPY
treatment periods (as required by
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y significant, or the subject is lost to follow up. This
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y significant, or the subject is lost to follow up. This
provided until
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nvestigator no longer deems that it is significant, or until the subject is lost to follow up. If no follow up is provided, the
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significant, or until the subject is lost to follow up. If no follow up is provided, the
formation on SAEs obtained after clinical database lock will be captured through the Patient
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formation on SAEs obtained after clinical database lock will be captured through the Patient
verse events (investigational device)
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verse events (investigational device)
Definitions (investigational device)
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Definitions (investigational device)
(investigational device)
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(investigational device)
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y untoward medical occurrence, unintended disease or , or untoward clinical sign (including abnormal laboratory
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, or untoward clinical sign (including abnormal laboratorytreatment periods (as required by
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Events considered unrelated or related to the investigational medical device
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Events considered unrelated or related to the investigational medical device
Events related to the procedures involved (even if no investigational device was used)
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Events related to the procedures involved (even if no investigational device was used)
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the signing of the Informed Coy the protocol, must be reported in the
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initial visit and all AEs that recurred or worsened after the initial visit.
Signs or s
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10.2.1.2 Serious adverse event (investigational device)
Once it is determined that a subject experienced an AE for an investigational device, the seriousness of the AE must be determined. An SAE must meet 1 or more of the following criteria:
Death
Serious deterioration in the health of the subject that results in at least 1 of the following:
Life-threatening illness or injury
Permanent impairment of a body structure or body function
Inpatient or prolonged hospitalization
Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or body function
Fetal distress, fetal death, or a congenital abnormality or birth defect
Planned hospitalization for a pre-existing condition, or a procedure required by the protocol, without serious deterioration in health, is not considered a serious adverse event.
10.2.1.3 Device- or procedure-related
10.2.1.3.1 Adverse device effect (investigational device)
An adverse device effect (ADE) is an AE related to the use of an investigational device. An ADE must meet 1 or more of the following criteria:
Adverse event resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the implantation, the installation, the operation, or any malfunction of the investigational medical device.
Adverse event that is a result of a use error or intentional misuse.
10.2.1.3.1.1 Unanticipated adverse device effect (investigational device)
An unanticipated adverse device effect (UADE) is any ADE that meets 1 or more of the following criteria:
Serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application
Any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.
10.2.1.3.2 Serious adverse device effect (investigational device)
A serious adverse device effect (SADE) is an ADE that has resulted in any of the consequences characteristic of a SAE, as described in Section 10.2.1.2. Serious adverse device effects are classified as anticipated (anticipated serious adverse device effect; ASADE) and unanticipated (USADE) (definitions provided below).
An ASADE is a SADE which by its nature, incidence, severity, or outcome has been identified.
REDACTED COPY without serious deterioration in health, is not considered a serious
REDACTED COPY without serious deterioration in health, is not considered a serious
verse device effect (investigational device)
REDACTED COPY
verse device effect (investigational device)
An adverse device effect (ADE) is an AE related to the use of an investigational device. An ADE
REDACTED COPY
An adverse device effect (ADE) is an AE related to the use of an investigational device. An ADE must meet 1 or more of the following criteria:
REDACTED COPY
must meet 1 or more of the following criteria:
g from insufficiencies or inadequacies in the instructions for use, the REDACTED COPY
g from insufficiencies or inadequacies in the instructions for use, the
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verse device effect (investigational device)
An adverse device effect (ADE) is an AE related to the use of an investigational device. An ADE
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An adverse device effect (ADE) is an AE related to the use of an investigational device. An ADE must meet 1 or more of the following criteria:
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10.2.1.3.2
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10.2.1.3.2
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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An USADE is a SADE which by its nature, incidence, severity, or outcome has not been identified.
10.2.1.3.3 Device deficiency (investigational device)
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety, or performance. Device deficiencies include malfunctions, use errors, and inadequate labeling.
10.2.2 Procedures for reporting and recording adverse events (investigational device), adverse device effects, and device deficiencies
The subject will be given the opportunity to report AEs, ADEs, and device deficiencies spontaneously. A general prompt will also be given at each study visit to detect AEs, ADEs, and device deficiencies. Below is an example prompt:
“Did you notice anything unusual about the device?”
10.2.2.1 Adverse events
Details for completion of the Adverse Event eCRF (including judgment of relationship to Investigational Device or Study procedure) are described in the eCRF Completion Guidelines.
10.2.2.1.1 Serious adverse events
See Section 10.1.1.2 for details.
10.2.3 Follow up of adverse events (investigational device)
See Section 10.1.3.
10.2.3.1 Device-related
10.2.3.1.1 Reporting of adverse device effects
An Investigator Adverse Device Effect and Device Deficiency Form will be provided to the Investigator. The Investigator Adverse Device Effect and Device Deficiency Form must be completed in English.
An Investigator shall submit to UCB a report of any adverse device effect and device deficiency occurring during the study within 24 hours after the Investigator first learns of the event using the Adverse Device Effect and Device Deficiency Form.
10.2.3.1.1.1 Reporting of unanticipated adverse device effects by the Investigator
An Investigator shall submit a report of any unanticipated adverse device effect occurring during an investigation to:
UCB within 24h, UCB will conduct an evaluation of the reported unanticipated adverse device effect and report the results of such evaluation to FDA and to all reviewing IRB’s and participating Investigators within 10 working days after UCB first receives notice of the effect.
The site IRB and reviewing IRB as soon as possible, but in no event later than 10 working days after the Investigator first learns of the effect.
REDACTED COPY are described in the
REDACTED COPY are described in the
Follow up of adverse events (investigational device)
REDACTED COPY
Follow up of adverse events (investigational device)
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to report AEs, ADEs, and device deficiencies
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to report AEs, ADEs, and device deficiencies visit to detect AEs, AD
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visit to detect AEs, AD
hing unusual about the device?”
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hing unusual about the device?”
(including judgment of relationship to
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(including judgment of relationship to are described in the
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are described in the
Follow up of adverse events (investigational device)
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Follow up of adverse events (investigational device)
Reporting of adverse device effects
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Reporting of adverse device effects
An Investigator Adverse Device Effect and Device Deficiency
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An Investigator Adverse Device Effect and Device Deficiency. The Investigator Adverse Device Effect and Device Deficiency
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. The Investigator Adverse Device Effect and Device Deficiency
Investigator shall submit to UCB a report of any
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Investigator shall submit to UCB a report of anyoccurring during the study within 24 hours after the Investigator first learns of the event using
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occurring during the study within 24 hours after the Investigator first learns of the event using Adverse Device Effect and Device Deficiency Form
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Adverse Device Effect and Device Deficiency Form
10.2.3.1.1.1
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10.2.3.1.1.1
An Investigator shall submit a report of an
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An Investigator shall submit a report of an
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an investigation
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an investigation
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10.2.3.1.2 Reporting of serious adverse device effects
10.2.3.1.2.1 Reporting of serious adverse device effect including device deficiencies with risk of SAE
If an SADE or a device deficiency that could have led to a serious adverse event, if:
Either suitable action had not been taken or
Intervention had not been made or
Circumstances had been less fortunate
is reported, UCB must be informed within 24 hours of receipt of this information by the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting section at the front of the protocol). The Investigator must forward to UCB (or its representative) a duly completed “SAE Report Form for Investigational Medical Device” (SAE report form) provided by UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order to draw any conclusions.
A SAE report form will be provided to the Investigator. The Investigator SAE Report form must be completed in English.
It is important for the Investigator, when completing the SAE report form, to include the assessment as to a causal relationship between the SAE and the investigational device and/or study procedure.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be provided within 24 hours. All documents in the local language must be accompanied by a translation in English, or the relevant information included in the same document must be summarized in the Investigator SAE report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any SADEs or device deficiency with risk of SAE (even if the Investigator is certain that they are in no way associated with the Investigational device), up to completion of the follow-up visit for each subject, and to also inform participating subjects of the need to inform the Investigator of any SAE within this period. Serious AEs that the Investigator thinks may be associated with the investigational device must be reported to UCB regardless of the time between the event and the end of the study.
10.2.3.1.3 Reporting of device deficiencies
If a device deficiency related to the identity, quality, durability, reliability, safety, or performance of the investigational device is reported (even if the investigational device was not used), UCB must be informed within 1 business day of receipt of this information by the site. The Investigator must forward to UCB (or its representative) a duly completed Investigator Adverse Device Effect and Device Deficiency Form provided by UCB, even if the data are incomplete or if it is obvious that more data will be needed in order to draw any conclusions.
An Investigator Adverse Device Effect and Device Deficiency Form will be provided to the Investigator. The Investigator Adverse Device Effect and Device Deficiency Form must be completed in English.
REDACTED COPY
nvestigator, when completing the SAE report form, to include the
REDACTED COPY
nvestigator, when completing the SAE report form, to include the assessment as to a causal relationship between the SAE and the investigational device and/or
REDACTED COPY
assessment as to a causal relationship between the SAE and the investigational device and/or
y or laboratory reports) received b
REDACTED COPY
y or laboratory reports) received bprovided within 24 hours. All documents in the local language must be accompanied by
REDACTED COPY
provided within 24 hours. All documents in the local language must be accompanied bytranslation in English, or the relevant information included in the same document must be REDACTED C
OPY
translation in English, or the relevant information included in the same document must be
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tion by
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tion by the site (see
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the site (see tion by the site (see tion by
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tion by the site (see tion bycontact information for SAE reporting listed in the Serious Adverse Event Reporting section at
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contact information for SAE reporting listed in the Serious Adverse Event Reporting section at must forward to UCB (or its representative) a duly
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must forward to UCB (or its representative) a dulynal Medical Device” (SAE report form)
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nal Medical Device” (SAE report form) UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order
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UCB, even if the data are incomplete, or if it is obvious that more data will be needed in order
nvestigator. The Investigator SAE Report form must
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nvestigator. The Investigator SAE Report form must
nvestigator, when completing the SAE report form, to include the
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nvestigator, when completing the SAE report form, to include the assessment as to a causal relationship between the SAE and the investigational device and/or
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assessment as to a causal relationship between the SAE and the investigational device and/or
y or laboratory reports) received b
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y or laboratory reports) received bprovided within 24 hours. All documents in the local language must be accompanied by
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provided within 24 hours. All documents in the local language must be accompanied bytranslation in English, or the relevant information included in the same document must be
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translation in English, or the relevant information included in the same document must be nvestigator SAE report form.
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nvestigator SAE report form.
requested to collect and report to UCB (or its representative) any
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requested to collect and report to UCB (or its representative) any
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with risk of SAE (even if the
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with risk of SAE (even if the ated with the Investigational device), up to completion of the follow
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ated with the Investigational device), up to completion of the followeach subject, and to also inform participating subjects of the need to inform the
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each subject, and to also inform participating subjects of the need to inform the SAE within this period. Serious AEs that the
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SAE within this period. Serious AEs that the investigational device must be reported to UCB regardless of the time between the event and the
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investigational device must be reported to UCB regardless of the time between the event and the y.
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y.
Reporting of device deficiencies
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Reporting of device deficiencies
If a device deficiency
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If a device deficiency
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of the investigational device is reported (even if the investigational device was not used), UCB
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of the investigational device is reported (even if the investigational device was not used), UCB must be informed with
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must be informed withInvestigator
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InvestigatorDevice Effect and Device Deficiency
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Device Effect and Device Deficiency
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 40 of 82
It is important for the Investigator, when completing the Investigator Adverse Device Effect and Device Deficiency Form, to include an assessment and documentation of whether the device deficiency could have led to a serious adverse event if any of the following occurred:
Suitable action had not been taken or
Intervention had not been made or
Circumstances had been less fortunate
All defective devices must be returned to UCB.
10.2.3.2 Rule for repetition of an adverse device effect and/or device deficiency
See Section 10.1.2.2 for details.
10.3 Pregnancy
If an Investigator is notified that a subject has become pregnant before or after the first dose IMP via e-Device, the Investigator must immediately notify UCB’s Patient Safety (PS) department by providing the completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting information at the beginning of this protocol). The subject should be withdrawn from the study as soon as pregnancy is known (by positive pregnancy test), and the following should be completed:
The subject should immediately stop the intake of the IMP.
A safety follow-up call should be scheduled for 70 days after the last administration of CZP study dose (via e-Device).
The Investigator must inform the subject of information currently known about potential risks and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be followed up using the Pregnancy Report and Outcome form in which the Investigator has to report on the health of the mother and of the child. Every reasonable attempt should be made tofollow the health of the child for 30 days after birth for any significant medical issues. In certain circumstances, UCB may request that follow up is continued for a period longer than 30 days. If the subject is lost to follow up and/or refuses to give information, written documentation of attempts to contact the subject needs to be provided by the Investigator and filed at the site. UCB’s PS department is the primary contact for any questions related to the data collection for the pregnancy, eventual birth, and follow up.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the Investigator or designee is asked to contact the subject to request consent of the partner via the Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should be available in the Investigator site file. In case of questions about the consent process, the Investigator may contact the UCB/contract research organization (CRO) contract monitor for the study. The Investigator will complete the Pregnancy Report and Outcome form and send it to UCB’s PS department (for contact details see Serious Adverse Event reporting information at the
REDACTED COPY Adverse Event reporting information at the beginning of this protocol). The subject should be
REDACTED COPY Adverse Event reporting information at the beginning of this protocol). The subject should be
is known (by
REDACTED COPY
is known (by
stop the intake of the I
REDACTED COPY
stop the intake of the I
should be scheduled for 70
REDACTED COPY
should be scheduled for 70
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Rule for repetition of an adverse device effect and/or device
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Rule for repetition of an adverse device effect and/or device
If an Investigator is notified that a subject has become pregnant before or after the first dose
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If an Investigator is notified that a subject has become pregnant before or after the first dose Patien
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Patient Safety
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t Safety Report and Outcome form (for contact details see Serious
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Report and Outcome form (for contact details see Serious Adverse Event reporting information at the beginning of this protocol). The subject should be
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Adverse Event reporting information at the beginning of this protocol). The subject should be is known (by
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is known (by positive pregnancy
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positive pregnancy is known (by positive pregnancy is known (by
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is known (by positive pregnancy is known (by
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should be scheduled for 70
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should be scheduled for 70
The Investigator must inform the subject of information currentl
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and about available treatment alternatives.
will be documented on the Pregnancy
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will be documented on the Pregnancyression of the pregnancy
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ression of the pregnancyfollowed up using the Pregnancy
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follow the health of the child for 30 daycircumstances, UCB may request that follow up is continued for a period longer than 30 day
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circumstances, UCB may request that follow up is continued for a period longer than 30 daythe subject is lost to follow up and/or refuses to give information, written documentation of
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attempts to contact the subject needs to be provided byUCB’s PS department is the primary
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the pregnancy
In cases where the partner of a male subject enrolled in a clinical study
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In cases where the partner of a male subject enrolled in a clinical studyInvestigator or designee is asked to contact the subject to request consent of the partner via the
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Investigator or designee is asked to contact the subject to request consent of the partner via the
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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beginning of this protocol) only after the partner has agreed that additional information can be captured and has provided the signed Partner Pregnancy Consent form. UCB’s PS department is also the primary contact for any questions related to the data collection for the partner pregnancy, eventual birth, and follow up.
A pregnancy becomes a serious adverse event (SAE) in the following circumstances: miscarriage, abortion (elective or spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital anomaly/birth defect of the baby. Those SAEs must be additionally reported using the Investigator SAE Report form.
10.4 Suspected transmission of an infectious agent
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal product should be considered as an SAE; such cases must be reported immediately, recorded in the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent.
There is no evidence that there is a risk of transmission of an infectious agent with the investigational device.
10.5 Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of taking the excess medicine itself is an AE or SAE (eg, suicide attempt).
There is no evidence that there is a risk of overdose with the IMP with the investigational device.
10.6 Safety signal detection
Selected data from this study will be reviewed periodically to detect as early as possible any safety concern(s) related to the IMP or investigational device so that Investigators, clinical study subjects, regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative.
As appropriate for the stage of development and accumulated experience with the IMP and investigational device, medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital signs, laboratory or electrocardiogram [ECG] results) for which data will be periodically reviewed during the course of the study.
10.7 Laboratory measurements
For women of childbearing potential, a urine pregnancy test will be performed at Visit 1 and Visit 2. A serum pregnancy test will be performed in the event of a positive urine result.
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ent via a medicinal product should be considered as an SAE; such cases must be reported immediatel
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product should be considered as an SAE; such cases must be reported immediatelother SAE. Any organism, virus, or infectious
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other SAE. Any organism, virus, or infectious ible spongiform encephalopathy), pathogenic or
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ible spongiform encephalopathy), pathogenic or
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ond that prescribed in the protocol and including overdose) should be SAE or nonserious AE associated with excessive dosing must be
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ymptoms or if the act of taking the excess medicine itself
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ptoms or if the act of taking the excess medicine itself
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suicide attempt).
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signal detection
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signal detection
Selected data from this study
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Selected data from this study will be reviewed periodically
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will be reviewed periodicallySelected data from this study will be reviewed periodicallySelected data from this study
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Selected data from this study will be reviewed periodicallySelected data from this studyy concern(s) related to the I
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sician or medicallyof SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative.
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of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative.
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investigational device, medicallmeasures (eg,
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measures (eg,will be periodicall
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 42 of 82
10.8 Other safety measurements
10.8.1 Vital signs
Vital signs will include systolic and diastolic BP, pulse, RR, and body temperature. Subjectsshould be supine for 5 minutes before and during the collection of BP and pulse measurements.Vital signs will be measured at Visit 1 and Visit 2.
10.8.2 Physical examination
The physical examination will include general appearance; ear, nose, and throat; eyes, hair, and skin; respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological (including limb reflexes); and mental status. Height and weight will also be measured. The physical examination will be performed at Visit 1. Any clinically significant changes since the physical examination at Visit 1 will be recorded as AEs.
11 STUDY MANAGEMENT AND ADMINISTRATION
11.1 Adherence to protocol
The Investigator should not deviate from the protocol. However, the Investigator should take any measure necessary in deviation from or not defined by the protocol in order to protect clinical study subjects from any immediate hazard to their health and safety. In this case, this action should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or Sponsor.
After implementation of such measure, the Investigator must notify the Clinical Project Managerof the Sponsor within 24 hours and follow any local regulatory requirements.
11.2 Monitoring
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard Operating Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are adequate. Monitoring of the study may be delegated by UCB to a CRO or a contract monitor.
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be available during the monitoring visits to answer questions sufficiently and to provide any missing information. The Investigator(s)/institution(s) will permit direct access to source data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory inspection(s).
The Investigator will allow UCB (or designee) to periodically review all eCRFs and corresponding source documents (eg, hospital and laboratory records for each study participant). Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol requirements, applicable authorities regulations, and Investigator’s obligations are being fulfilled, and resolve any inconsistencies in the study records.
11.2.1 Definition of source data
All source documents must be accurate, clear, unambiguous, permanent, and capable of being audited. They should be made using some permanent form of recording (ink, typing, printing,
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es, hair, and
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r; gastrointestinal; musculoskeletal; hepatic; neurological Height and weight will also be measured.
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Height and weight will also be measured. The
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The significant changes since the
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INISTRA
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INISTRATION
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TION
However
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, the
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the the protocol in order to protect clinical
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the protocol in order to protect clinical immediate hazard to their health and safet
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immediate hazard to their health and safetout prior notification of the
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out prior notification of the
nvestigator must notify
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nvestigator must notifyand follow an
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and follow any local
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y local
UCB (or designee) will monitor the study
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UCB (or designee) will monitor the studyGCP guideline, and applicable regulatory
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GCP guideline, and applicable regulatory initiation, conduct, and closure are adequate. Monitoring of the study
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initiation, conduct, and closure are adequate. Monitoring of the studyCRO
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CRO or a contract monitor.
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or a contract monitor.
gator and his/her staff are expected to cooperate with UCB (or designee) and to be
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gator and his/her staff are expected to cooperate with UCB (or designee) and to be available during the monitoring visits to answer questions sufficiently
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available during the monitoring visits to answer questions sufficientlymissing information. The
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missing information. The data/documents for stud
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data/documents for studinspection(s).
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inspection(s).
Investigator will allow UCB (or designee) to periodicall
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Investigator will allow UCB (or designee) to periodicallcorresponding source documents (
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corresponding source documents (
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Monitoring visits will provide UCB (or designee) with the opportunity
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Monitoring visits will provide UCB (or designee) with the opportunityof the study
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of the studyrequirements, applicable authorities regul
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requirements, applicable authorities regul
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optical disc). They should not be obscured by correction fluid or have temporary attachments (such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered acceptable source documents.
Source documents are original records in which raw data are first recorded. These may include hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, pharmacy records, care records, ECG or other printouts, completed scales, or quality of life questionnaires, for example. Source documents should be kept in a secure, limited access area.
Source documents that are computer generated and stored electronically must be printed for review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated by the Investigator and become a permanent part of the subject’s source documents. The Investigator will facilitate the process for enabling the monitor to compare the content of the printout and the data stored in the computer to ensure all data are consistent.
Electronic data records, such as Holter monitor records or electroencephalogram records, must be saved and stored as instructed by UCB (or designee).
11.2.2 Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During monitoring visits, reported data are reviewed with regard to being accurate, complete, and verifiable from source documents (eg, subject files, recordings from automated instruments, tracings [ECG], x-ray films, laboratory notes). All data reported on the eCRF should be supported by source documents, unless otherwise specified in Section 11.2.1.
11.3 Data handling
11.3.1 Case Report form completion
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the eCRFs and in all required reports.
Any change or correction to the eCRF after saving must be accompanied by a reason for the change.
Corrections made after the Investigator’s review and approval (by means of a password/electronic signature) will be reapproved by the Investigator.
The Investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the CRF Completion Guidelines.
11.3.2 Database entry and reconciliation
Case Report forms/external electronic data will be entered/loaded into a validated electronic database using a clinical data management system (CDMS). Computerized data cleaning checks will be used in addition to manual review to check for discrepancies and to ensure consistency of the data. The data are entered into the eCRFs once and are subsequently verified.
An electronic audit trail system will be maintained within the CDMS to track all data changes in the database once the data have been saved initially into the system or electronically loaded. Regular backups of the electronic data will be performed.
REDACTED COPY and credibility
REDACTED COPY and credibility
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from
REDACTED COPY
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from from automated instruments, tracings [ECG],
REDACTED COPY
from automated instruments, tracings [ECG], notes). All data reported on the
REDACTED COPY
notes). All data reported on the documents, unless otherwise specified in Section
REDACTED COPY
documents, unless otherwise specified in Section
Case Report form completionREDACTED COPY
Case Report form completion
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questionnaires, for example. Source documents should be kept in a secure, limited access area.
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questionnaires, for example. Source documents should be kept in a secure, limited access area.
y must be printed for
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y must be printed for ECG reports). Once printed, these copies should be signed and dated
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ECG reports). Once printed, these copies should be signed and dated nvestigator and become a permanent part of the subject’s source documents. The
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nvestigator and become a permanent part of the subject’s source documents. The nvestigator will facilitate the process for enabling the monitor to compare the
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nvestigator will facilitate the process for enabling the monitor to compare the content of the
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content of the printout and the data stored in the computer to ensure all data are consistent.
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printout and the data stored in the computer to ensure all data are consistent.
Electronic data records, such as Holter monitor records or electroencephalogram records, must
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Electronic data records, such as Holter monitor records or electroencephalogram records, must
of the data obtained. During monitoring
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of the data obtained. During monitoring visits, reported data are reviewed with regard to being accurate, complete, and verifiable from
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visits, reported data are reviewed with regard to being accurate, complete, and verifiable from from automated instruments, tracings [ECG],
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from automated instruments, tracings [ECG], notes). All data reported on the
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notes). All data reported on the eCRF
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eCRFdocuments, unless otherwise specified in Section
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documents, unless otherwise specified in Section 11.2.1
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11.2.1
Case Report form completion
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Case Report form completion
Investigator is responsible for prompt reporting of accurate, complete, and legible data in the
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Investigator is responsible for prompt reporting of accurate, complete, and legible data in the eCRFs and in all required reports.
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eCRFs and in all required reports.
change or correction to the
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change or correction to the e
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eCR
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CR
Corrections made after the
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Corrections made after the Investigator’s review and approval (b
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Investigator’s review and approval (bpassword/electronic signature) will be reapproved by
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password/electronic signature) will be reapproved by
nvestigator should maintain a list of pe
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nvestigator should maintain a list of pe
Detailed instructions will be provided in the CRF Completion Guidelines.
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Detailed instructions will be provided in the CRF Completion Guidelines.
11.3.2
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11.3.2
Case Report forms/external electronic data will be entered/loaded into a validated electronic
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Case Report forms/external electronic data will be entered/loaded into a validated electronic databas
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databaswill be used in addition to manual review to check for discrepancies and to ensure consistency
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will be used in addition to manual review to check for discrepancies and to ensure consistency
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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11.3.3 Subject Screening and Enrollment log/Subject Identification Code list
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment log.
The Investigator will keep a Subject Identification Code list. This list remains with the Investigator and is used for unambiguous identification of each subject.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical record. These data should identify the study and document the dates of the subject’s participation.
11.4 Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the Investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension, in accordance with applicable regulatory requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the termination or suspension by the Sponsor or by the Investigator/institution, as specified by the applicable regulatory requirement(s). In addition, arrangements will be made for the return of all unused IMP and investigational devices, and other material in accordance with UCB procedures for the study.
11.5 Archiving and data retention
The Investigator will maintain adequate records for the study, including CRFs, medical records, laboratory results, Informed Consent documents, drug dispensing and disposition records, safety reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of the IMP. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or by an agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The Investigator will contact UCB for authorization prior to the destruction of any study records or in the event of accidental loss or destruction of any study records. The Investigator will also notify UCB should he/she relocate or move the study-related files to a location other than that specified in the Sponsor’s trial master file.
11.6 Audit and inspection
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of the subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing
REDACTED COPY the reason(s) for the termination or suspension, in accordance with applicable regulatory
REDACTED COPY the reason(s) for the termination or suspension, in accordance with applicable regulatory
B/IEC should also be informed and provided with reason(s) for the
REDACTED COPY
B/IEC should also be informed and provided with reason(s) for the y the
REDACTED COPY
y the I
REDACTED COPY
Investigator/institution, as specified b
REDACTED COPY
nvestigator/institution, as specified b requirement(s). In addition, arrangements will be made for the return
REDACTED COPY
requirement(s). In addition, arrangements will be made for the returnand other material in accordance with UCB procedures
REDACTED COPY
and other material in accordance with UCB procedures
chiving and data retentionREDACTED COPY
chiving and data retention
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requirement(s). In addition, arrangements will be made for the returnand other material in accordance with UCB procedures
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and other material in accordance with UCB procedures
chiving and data retention
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reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained b
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rial master file.
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master file.
11.6
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11.6
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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study procedures) are appropriate for the study, and that all data relevant for the evaluation of the IMP have been processed and reported in compliance with the planned arrangements, the protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory requirements.
The Investigator will provide direct access to all study documents, source records, and source data. If an inspection by a regulatory authority is announced, the Investigator will immediately inform UCB (or designee).
11.7 Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action by UCB to secure compliance. Continued noncompliance may result in the termination of the site’s involvement in the study.
12 STATISTICS
A description of statistical methods follows and will be described in more detail in the Statistical Analysis Plan.
12.1 Definition of analysis sets
The Safety Set (SS) will consist of all subjects of the study who have received at least 1 dose of CZP during the study (e-Device).
Safety variables will be analyzed using the Safety Set (SS).
The Full Analysis Set (FAS) will consist of all subjects in the SS who received at least 1 dose of CZP using the e-Device in the study. All outcome variables will be analyzed using the FAS.
12.2 General statistical considerations
This is an estimation study design with no formal statistical hypothesis testing. The study will estimate the true population proportion and/or mean. Each endpoint will be summarized by dosing regimen (Q2W or Q4W) and by indication.
Summary statistics for continuous variables will include:
Number of available observations
Mean, standard deviation, minimum, median, and maximum
For categorical variables, the number and proportion of subjects, along with the 90% confidence interval (CI) based on the Exact Binomial method, will be presented.
The Baseline value is defined as the last nonmissing measurement prior to self-injection at Visit 1. Results from the Cochin Impaired Hand Function questionnaire at Visit 1 will be summarized.
No imputation of missing data will be performed.
All data recorded in the eCRF and questionnaires will be listed.
REDACTED COPY
y Set (SS) will consist of all subjects of the study who have received at least 1 dose of
REDACTED COPY
y Set (SS) will consist of all subjects of the study who have received at least 1 dose of
zed using the Safety
REDACTED COPY
zed using the Safety
will consist of all subjects in the SS who received at least 1 dose of REDACTED C
OPY
will consist of all subjects in the SS who received at least 1 dose of Device in the study REDACTED C
OPY
Device in the study AllREDACTED COPY
All
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will immediately
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the will lead to prompt action
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will lead to prompt action result in the termination of the
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result in the termination of the
A description of statistical methods follows and will be described in more detail in the Statistical
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A description of statistical methods follows and will be described in more detail in the Statistical
y Set (SS) will consist of all subjects of the study who have received at least 1 dose of
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y Set (SS) will consist of all subjects of the study who have received at least 1 dose of
zed using the Safety
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zed using the Safety Set (SS)
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zed using the Safety Set (SS)zed using the Safety
will consist of all subjects in the SS who received at least 1 dose of
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will consist of all subjects in the SS who received at least 1 dose of All
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All outcome
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outcome
General statistical
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General statistical considerations
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considerations
This is an estimation study design with no formal statistical hy
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This is an estimation study design with no formal statistical hyestimate the true population proportion and/or mean. Each endpoint will be summarized by
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estimate the true population proportion and/or mean. Each endpoint will be summarized by
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dosing regimen (Q2W or Q4W) and by
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dosing regimen (Q2W or Q4W) and by
y statistics for continuous variables will include:
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Number of available observations
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Number of available observations
Mean, standard deviation, minimum, median, and maximum
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Mean, standard deviation, minimum, median, and maximum
For categorical variables, the number and proportion of subjects, along with the 90% confidence
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The Baseline value is defined as the last nonmissing measurement prior to self
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The Baseline value is defined as the last nonmissing measurement prior to selfVisit
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Visitsummarized.
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summarized.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 46 of 82
12.3 Planned analyses
All statistical analyses will be descriptive in nature. No inferential statistical analyses are planned.
12.3.1 Analysis of the primary outcome variable
The primary outcome variable is the proportion (%) of all subjects able to self-administer safe and effective injections using the e-Device at Visit 2. Safe and effective self-injection will be evaluated by the HCP and is defined as:
Complete Dose Delivery: Subject self-injected the complete dose of CZP as confirmed by a visual inspection of the CZP-cassette(s) which shows the container PFS to be empty and
No AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection
For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
The number and proportion of subjects with safe and effective self-injections will be tabulated for the FAS overall, by dosing group, and by indication. A subgroup analysis will be performed for subjects in the FAS with impaired hand function. The 90% CIs for the proportion based on the Exact Binomial method will be reported as well.
12.3.2 Analyses of secondary outcome variables
The secondary outcome variables include:
The proportion (%) of subjects able to self-administer safe and effective injections using the e-Device at Visit 1. Safe and effective self-injection will be evaluated by the HCP and is defined as:
Complete Dose Delivery: Subject self-injected the complete dose of CZP as confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be emptyand
No AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection.
For subjects on the Q4W dosing regimen who will self-inject twice (2×200mg CZP) at each visit, each injection will be evaluated for safety and effectiveness using the above criteria. The primary endpoint of safe and effective self-injection for subjects on the Q4W dosing regimen will be met only if both self-injections are determined to be safe and effective.
Percentage of used CZP-cassettes identified as having structural integrity issues based on visual examination (ie, clear evidence of damage/compromised structural integrity, not superficial cosmetic imperfections)
REDACTED COPY
The number and proportion of subjects with safe and effective self
REDACTED COPY
The number and proportion of subjects with safe and effective selfy indication.
REDACTED COPY
y indication.for subjects in the FAS with impaired hand function.
REDACTED COPY
for subjects in the FAS with impaired hand function. the Exact Binomial method will be reported as well.
REDACTED COPY
the Exact Binomial method will be reported as well.
ses of secondary
REDACTED COPY
ses of secondary outcome
REDACTED COPY
outcome
variables include:REDACTED COPY
variables include:
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-injection will be
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outcome
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variables include:
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. Safe and effective self-
Complete Dose Delivery
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Complete Dose Deliverya visual inspection of the CZP
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related to use of the e
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Device for self
For subjects
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on the Q4W dosing regimen who will selfvisit, each injection will be evaluated for safet
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visit, each injection will be evaluated for safetprimary
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primary endpoint of safe and effective self
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endpoint of safe and effective selfprimary endpoint of safe and effective selfprimary
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primary endpoint of safe and effective selfprimary
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will be met only
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The secondary outcome variables will be summarized using descriptive statistics. All summary statistics will be presented for the FAS overall, by dosing group, and by indication. A subgroup analysis will performed for subjects in the FAS with impaired hand function.
12.3.3 Analyses of other outcome variables
Other outcome variables are:
Injection site pain due to self-injection (using a Visual Analog Scale [VAS]; 100mm) by visit at all visits after self-injection using the e-Device
Responses to the preinjection ASI at Visit 1
Responses to the postinjection ASI by visit at all visits after self-injection using the e-Device
In vitro functional evaluation of the e-Device following the final use per subject:
The percentage of e-Devices found to be functionally compromised
The other outcome variables will be summarized using descriptive statistics. All other exploratory variables will be summarized for the FAS overall, by dosing group, and by indication.
12.4 Planned safety analyses
12.4.1 Safety analyses
Safety endpoints include AEs and changes from baseline in vital signs. Analyses of the safety data will be done on the SS.
All summaries of continuous safety variables will be presented at scheduled time points. No statistical testing will be conducted on the safety parameters. All AE data will be listed. Only treatment-emergent adverse events (TEAEs) will be included in the summary tables. Treatment-emergent AEs are defined as AEs starting after the time of first injection in the study up to 70 days after the last self-administration of study medication. All AEs will be coded and classified by system organ class, high level term, and preferred term according to the latest version of the Medical Dictionary for Regulatory Activities (MedDRA®).
In this study, safety reporting requirements apply to all constituents of the IP (including CZP, the e-Device auto-injector, and the CZP-cassette) per 21 CFR 320. Adverse events related to use of the e-Device (ADEs) (including the CZP-cassette) will be summarized separately. Adverse events will be summarized by the frequency and percent of subjects having one or more of the events in question. Planned summaries include overall AEs, AEs by intensity, AEs by relationship to study drug, SAEs, AEs leading to withdrawal, AEs leading to death, ADEs, SADEs, and AEs of special interest.
Physical examination findings will be recorded in the eCRF only at Screening. Clinically relevant changes in subsequent physical examinations will be recorded as AEs.
Physical examination findings at Screening will be listed.
REDACTED COPY
s and changes from baseline in vital signs. Analyses of the safet
REDACTED COPY
s and changes from baseline in vital signs. Analyses of the safet
y variables will be presented at scheduled time points. No REDACTED C
OPY
y variables will be presented at scheduled time points. No statistical testing will be conducted on the safetREDACTED C
OPY
statistical testing will be conducted on the safet
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(using a Visual Analog Scale [VAS]; 100mm) by
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(using a Visual Analog Scale [VAS]; 100mm) by visit
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visit (using a Visual Analog Scale [VAS]; 100mm) by visit (using a Visual Analog Scale [VAS]; 100mm) by
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(using a Visual Analog Scale [VAS]; 100mm) by visit (using a Visual Analog Scale [VAS]; 100mm) by
injection using the e
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injection using the e
-Device following the final use per subject:
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-Device following the final use per subject:
compromised
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compromised
variables will be summarized using descriptive statistics. All other
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variables will be summarized using descriptive statistics. All other by
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by dosing group
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dosing groupby dosing groupby
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by dosing groupby
s and changes from baseline in vital signs. Analyses of the safet
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s and changes from baseline in vital signs. Analyses of the safet
y variables will be presented at scheduled time points. No
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y variables will be presented at scheduled time points. No statistical testing will be conducted on the safet
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statistical testing will be conducted on the safetemergent adverse events (TEAE
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emergent adverse events (TEAE-emergent AEs are defined as AEs starting after the time of first inje
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administration of studytem organ class, high level term, and preferre
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tem organ class, high level term, and preferreversion of the Medical Dictionary
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version of the Medical Dictionary
y, safety reporting requirements appl
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y, safety reporting requirements applinjector,
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injector,-Device (ADEs) (including the CZP-
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-Device (ADEs) (including the CZP-will be summarized by
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will be summarized byevents in question. Planned summaries include overall AEs, AEs b
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events in question. Planned summaries include overall AEs, AEs brelationship to study
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relationship to studySADEs, and AEs of
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SADEs, and AEs of
Phy
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Physical examination findings will be recorded in the eCRF only
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sical examination findings will be recorded in the eCRF onlyrelevant changes in subsequent phy
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relevant changes in subsequent phy
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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12.5 Handling of protocol deviations
Important protocol deviations are deviations from the protocol which potentially could have ameaningful impact on the primary objective of the study. The criteria for identifying importantprotocol deviations and the classification of important protocol deviations will be defined withinthe project Data Cleaning Plan. To the extent feasible the rules for identifying protocoldeviations will be defined without review of the data and without consideration of the frequencyof occurrence of such deviations. Whenever possible, criteria for identifying important protocoldeviations will be implemented algorithmically to ensure consistency in the classification ofimportant protocol deviations across all subjects.
12.6 Handling of dropouts or missing data
There will be no special procedures for handling missing data. All imputation of missing or partial dates for safety assessments will be detailed in the Statistical Analysis Plan.
12.7 Planned interim analysis and data monitoring
No interim analysis is planned.
There will be no Data Monitoring Committee established for this study.
12.8 Determination of sample size
This study will not be powered with respect to any endpoint and sample size is based on practical considerations. The number of subjects and their diagnosed conditions are summarized below.
Approximately 80 subjects who are currently being treated with commercial CZP and are on a stable dosing regimen for at least 3 months will be screened in order to have at least 60 subjects use the e-Device at Visit 1. The 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjects in each of the dosing groups (Q2W vs Q4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function. Impaired hand function will be measured using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al, 1996) and impaired hand function will be defined as patients who have a Cochin score ≥13.5 at baseline.
13 ETHICS AND REGULATORY REQUIREMENTS
13.1 Informed consent
Subject’s informed consent must be obtained and documented in accordance with local regulations, ICH-GCP requirements, and the ethical principles that have their origin in the principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of complexity understandable to the subject in both oral and written form by the Investigator (or designee). Each subject will have the opportunity to discuss the study and its alternatives with the Investigator.
Prior to participation in the study, the Informed Consent form should be signed and personally dated by the subject and by the person who conducted the informed consent discussion (Investigator or designee). The subject must receive a copy of the signed and dated Informed
REDACTED COPY
Determination of sample size
REDACTED COPY
Determination of sample size
will not be powered with respect to any endpoint and sample size is based on practical
REDACTED COPY
will not be powered with respect to any endpoint and sample size is based on practical of subjects and their diagnosed conditions are summarized below.
REDACTED COPY
of subjects and their diagnosed conditions are summarized below.
80 subjects who are currentl
REDACTED COPY
80 subjects who are currently being treated with commercial CZP and are on a
REDACTED COPY
y being treated with commercial CZP and are on a stable dosing regimen for at least 3 months will be screened in order to have
REDACTED COPY
stable dosing regimen for at least 3 months will be screened in order to have 60 subjectsREDACTED C
OPY
60 subjects
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quency
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quencying important protocol
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ing important protocol in the classification of
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in the classification of
There will be no special procedures for handling missing data. All imputation of missing or
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There will be no special procedures for handling missing data. All imputation of missing or tatistical Analysis Plan
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tatistical Analysis Plan
sis and data monitoring
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sis and data monitoring
There will be no Data Monitoring Committee established for this study
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There will be no Data Monitoring Committee established for this study
will not be powered with respect to any endpoint and sample size is based on practical
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will not be powered with respect to any endpoint and sample size is based on practical of subjects and their diagnosed conditions are summarized below.
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of subjects and their diagnosed conditions are summarized below.
y being treated with commercial CZP and are on a
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y being treated with commercial CZP and are on a stable dosing regimen for at least 3 months will be screened in order to have
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stable dosing regimen for at least 3 months will be screened in order to have 60 subjects
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60 subjects using the e
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using the ein each of the dosing groups (Q2W vs Q4W)
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in each of the dosing groups (Q2W vs Q4W)
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a minimum of 10
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a minimum of 10red using the Cochin scale (Poiraudeau et al, 2000; Duruöz et al
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red using the Cochin scale (Poiraudeau et al, 2000; Duruöz et aland impaired hand function will be defined as patie
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and impaired hand function will be defined as patie
ETHICS A
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ETHICS A
Informed
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Informed
Subject’s informed consent must be obtained and documented in accordance with local
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mark
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Subject’s informed consent must be obtained and documented in accordance with local regulations, I
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regulations, I
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CH
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CHprinciples of the Declaration of Helsinki.
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principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of
This do
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Prior to obtaining informed consent, information should be given in a language and at a level of complexity
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complexitydesignee). Each subject will have the opportunity to discuss the study
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designee). Each subject will have the opportunity to discuss the study
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Consent form. As part of the consent process, each subject must consent to direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection.
If the Informed Consent form is amended during the study, the Investigator (or the Sponsor, if applicable) must follow all applicable regulatory requirements pertaining to the approval of the amended Informed Consent form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the United States must include the use of a Health Insurance Portability and Accountability Act Authorization form.
The subject may withdraw his/her consent to participate in the study at any time. A subject is considered as enrolled in the study when he/she has signed the Informed Consent form. An eCRFmust not be started, nor may any study-specific procedure be performed for a given subject, without having obtained his/her written consent to participate in the study.
13.2 Subject identification cards
Upon signing the Informed Consent form, the subject will be provided with a subject identification card in the language of the subject. The Investigator will fill in the subject identifying information and medical emergency contact information. The Investigator will instruct the subject to keep the card with him/her at all times.
13.3 Institutional Review Boards and Independent Ethics Committees
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with the requirements of the current ICH-GCP version or applicable country-specific regulations will be responsible for the initial and continuing review and approval of the clinical study. Prior to initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other subject-related documents to be used for the study to the IRB/IEC for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the responsible IRB/IEC for the protocol.
The Investigator will also promptly report to the IRB/IEC all changes in the study, all unanticipated problems involving risks to human subjects or others, and any protocol deviations, to eliminate immediate hazards to subjects.
The Investigator will not make any changes in the study or study conduct without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to the subjects. For minor changes to a previously approved protocol during the period covered by the original approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as allowed.
REDACTED COPY contact infor
REDACTED COPY contact infor
instruct the subject to keep the card with him/her at all times.
REDACTED COPY
instruct the subject to keep the card with him/her at all times.
Institutional Review Boards and Independent Ethics
REDACTED COPY
Institutional Review Boards and Independent Ethics
will be conducted under the auspices of an I
REDACTED COPY
will be conducted under the auspices of an I-GCP, and in accordance with the ethical principles that have their origin in the Declaration
REDACTED COPY
-GCP, and in accordance with the ethical principles that have their origin in the Declaration
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ies conducted at centers in the United States must include the use of a Health Insurance
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ies conducted at centers in the United States must include the use of a Health Insurance
time. A subject is
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time. A subject is Informed Consent form. A
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Informed Consent form. A-specific procedure be performed for a given subject,
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-specific procedure be performed for a given subject, y.
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y.
will be provided with a subject
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will be provided with a subject Investigator
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Investigator will fill in the subject
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will fill in the subject contact infor
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contact information. The
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mation. The instruct the subject to keep the card with him/her at all times.
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instruct the subject to keep the card with him/her at all times.
Institutional Review Boards and Independent Ethics
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Institutional Review Boards and Independent Ethics
will be conducted under the auspices of an I
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will be conducted under the auspices of an I-GCP, and in accordance with the ethical principles that have their origin in the Declaration
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-GCP, and in accordance with the ethical principles that have their origin in the Declaration
nvestigator/UCB will ensure that an appropriately
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nvestigator/UCB will ensure that an appropriatelythe requirements of the current ICH
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the requirements of the current ICH
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-
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-GCP version or appli
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GCP version or applibe responsible for the initial and continuing review and approval of the clinical study
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be responsible for the initial and continuing review and approval of the clinical studyInvestigator
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InvestigatorConsent form, Investigator
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Consent form, Investigator’s Brochure,
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’s Brochure, advertisement (if applicable), and all other subject
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advertisement (if applicable), and all other subjectRB/IEC for its review and approval.
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RB/IEC for its review and approval.
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Before initiating a study
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Before initiating a studyresponsible IRB/IEC for the protocol.
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responsible IRB/IEC for the protocol.
Investigator
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Investigatorunanticipated problems involving risks to human subjects or others, and any
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unanticipated problems involving risks to human subjects or others, and any
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to eliminate immediate hazards to subjects.
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to eliminate immediate hazards to subjects.
The
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The
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As part of the IRB/IEC requirements for continuing review of approved studies, the Investigatorwill be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC requirements), at intervals appropriate to the degree of subject risk involved, but no less than once per year. The Investigator should provide a final report to the IRB/IEC following study completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory authorities and all active Investigators in accordance with applicable regulatory requirements. The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified by the applicable regulatory requirements in each concerned country. Where applicable, Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC notification.
13.4 Subject privacy
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this study, all data forwarded to UCB (or designee) will be identified only by the subject number assigned at Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the subject’s primary medical records that directly concerns this study (including, but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital admissions occurring during a subject’s study participation, and autopsy reports for deaths occurring during the study).
13.5 Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the statistical evaluations of sample size and the likelihood of the study fulfilling its primary objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being implemented.
14 FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO agreements, as applicable.
15 REFERENCES
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Durmus D, Uzuner B, Durmaz Y, Bilgici A, Kuru O. Michigan Hand Outcomes Questionnaire in rheumatoid arthritis patients: relationship with disease activity, quality of life, and handgrip strength. J Back Musculoskelet Rehabil. 2013;26(4):467–73.
REDACTED COPY authorities will be allowed to review that portion of the
REDACTED COPY authorities will be allowed to review that portion of the
y concerns this study (including, but not limited to,
REDACTED COPY
y concerns this study (including, but not limited to, test result reports, ECG reports, admission/discharge summaries for hospital
REDACTED COPY
test result reports, ECG reports, admission/discharge summaries for hospital admissions occurring during a subject’s study
REDACTED COPY
admissions occurring during a subject’s study participation, and autopsy
REDACTED COPY
participation, and autopsyadmissions occurring during a subject’s study participation, and autopsyadmissions occurring during a subject’s study
REDACTED COPY
admissions occurring during a subject’s study participation, and autopsyadmissions occurring during a subject’s study
Protocol amendmentsREDACTED C
OPY
Protocol amendments
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, all data forwarded to UCB (or designee) will be identified only by
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by, all data forwarded to UCB (or designee) will be identified only by, all data forwarded to UCB (or designee) will be identified only
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participation, and autopsy
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statistical evaluations of sample size and the likelihood of the study
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gnificant changes to the protocol will onlyUCB, the I
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FINA
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FINANCE, INSURANCE,
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NCE, INSURANCE,
Insurance coverage
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Finance, insurance, and publication rights are addressed in the agreements, as applicable.
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agreements, as applicable.
15
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CPMP/I
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CPMP/I
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Duruöz MT, Poiraudeau S, Fermanian J, Menkes CJ, Amor B, Dougados M, et al. Development and validation of a rheumatoid hand functional disability scale that assesses functional handicap. J Rheumatol. 1996;23(7):1167–72.
Goossens PH, Heemskerk B, van Tongeren J, Zwinderman AH, Vliet Vlieland TP, Huizinga TW. Reliability and sensitivity to change of various measures of hand function in relation to treatment of synovitis of the metacarpophalangeal joint in rheumatoid arthritis. Rheumatology. 2000; 39(8): 909-13.
Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2 Psoriatic arthritis: overview and guidelines of car for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851–64.
Hudry C, Lebrun A, Moura B, Zinovieva E, Backers O, Herman-Demars H. Evaluation of Usability and Acceptance of a New Autoinjector Intended for Methotrexate Subcutaneous Self-Administration in the Management of Rheumatoid Arthritis. Rheumatol Ther. 2017;4(1):183–94.
Lossos A, River Y, Eliakim A, Steiner I. Neurologic aspects of inflammatory bowel disease. Neurology. 1995;45(3 Pt 1):416–21.
Poiraudeau S, Lefevre-Colau MM, Fermanian J, Revel M. The ability of the Cochin rheumatoidarthritis hand functional scale to detect change during the course of disease. Arthritis Care Res. 2000;13(5):296–303.
Tam LS, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol. 2010;6(7):399–405.
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Colau MM, Fermanian J, Revel M. The ability
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Colau MM, Fermanian J, Revel M. The abilityarthritis hand functional scale to detect change during the course of disease. Arthritis Care Res.
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arthritis hand functional scale to detect change during the course of disease. Arthritis Care Res.
S, Gu J, Yu D. Pathogenesis of anky
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S, Gu J, Yu D. Pathogenesis of ankylosing spondy
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losing spondy
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ynovitis of the metacarpophalangeal joint in rheumatoid arthritis. Rheumatology.
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ebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2 Psoriatic arthritis: overview and
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for the management of psoriasis and psoriatic arthritis: Section 2 Psoriatic arthritis: overview and Dermatol.
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and Acceptance of a New Autoinjector Intended for Methotrexate Subcutaneous SelfAdministration in the Management of Rheumatoid Arthritis. Rheumatol Ther. 2017;4(1):183–
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Administration in the Management of Rheumatoid Arthritis. Rheumatol Ther. 2017;4(1):183–
. Neurologic aspects of inflammatory bowel disease.
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16 APPENDICES
16.1 Injection Site Pain (VAS)
This scale should be completed immediately postinjection (within 15 minutes).
Injection site pain due to self-injection immediately (within 15 minutes) after injection
Please mark a vertical line on the scale below to show how much pain you experience at the injection site right now
No Pain Most severe pain
0 100
REDACTED COPY
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Most severe pain
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16.2 Assessment of Self Injection
The ASI comprises 2 modules, the PRE-self-injection and the POST-self-injection modules. The PRE-self-injection module should be administered before subjects start their first self-injection in this study. The POST-self-injection module should be administered within 30 minutes after each self-injection in this study. Subjects should complete the ASI alone and in a quiet place. The questionnaire should be reviewed only for completeness by healthcare professionals; the content of the subjects’ answers should not be queried.
REDACTED COPY
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y for completeness by healthcare professionals; the content
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Assessment of Self-Injection (ASI)
[and draft new items]
PRE-Self-Injection
Introduction
The following questions ask about injections in general and your feelings about giving yourself an injection. Thank you for completing this questionnaire by yourself, preferably in a quiet environment. Take as much time as you need to complete it. There are no right or wrong answers. Your answers will remain strictly confidential and anonymous.
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
FEELINGS ABOUT INJECTIONS
The following questions concern your feelings about injections.
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
1. In general, how afraid are you of needles?
Not at all1
A little2
Moderately3
Very
4
Extremely5
2. In general, how afraid are you of having an injection?
Not at all1
A little2
Moderately3
Very4
Extremely5
3. How anxious do you feel about giving yourself an injection?
Not at all1
A little2
Moderately3
Very4
Extremely5
REDACTED COPY
EELINGS ABOUT INJECT
REDACTED COPY
EELINGS ABOUT INJECT
REDACTED COPY
REDACTED COPY
feelings about
REDACTED COPY
feelings about
Please answer each question below by circling the number that best represents your opinion
REDACTED COPY
Please answer each question below by circling the number that best represents your opinion rcle only one number per question).REDACTED C
OPY
rcle only one number per question).
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giving yourself
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giving yourself Thank you for completing this questionnaire by yourself, preferably in a quiet
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Thank you for completing this questionnaire by yourself, preferably in a quiet environment. Take as much time as you need to complete it. There are no right or wrong
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environment. Take as much time as you need to complete it. There are no right or wrong
Please answer each question below by circling the number that best represents your opinion
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Please answer each question below by circling the number that best represents your opinion
EELINGS ABOUT INJECT
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EELINGS ABOUT INJECTIONS
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IONS
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Please answer each question below by circling the number that best represents your opinion
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In general, how afraid are you of needles?
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A little
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A little2
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2
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In general, how afraid are you of having an injection?
Not at all
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1
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3.
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 55 of 82
SELF-CONFIDENCE
The following questions concern your confidence about giving yourself an injection.
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
4. How confident are you about … Not at all A little Moderately Very Extremely
a. Giving yourself an
injection in the right
way?
1 2 3 4 5
b. Giving yourself an
injection in a clean and
sterile way?
1 2 3 4 5
c. Giving yourself an
injection safely? 1 2 3 4 5
THANK YOU FOR COMPLETING THIS QUESTIONNAIRE
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
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Extremely
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Extremely
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1 2 3 4 5
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1 2 3 4 5
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3
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3
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T
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THANK YOU FOR COMPLET
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HANK YOU FOR COMPLET
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 56 of 82
Assessment of Self-Injection (ASI)
[and draft new items]
POST-Self-InjectionIntroduction
The following questions concern the self-injection of your medication and must be answered after giving yourself an injection using the [prefilled syringe / AutoClicks prefilled pen / ava®].
Thank you for completing this questionnaire by yourself, preferably in a quiet environment. Take as much time as you need to complete it. There are no right or wrong answers. Your answers will remain strictly confidential and anonymous.
FEELINGS ABOUT INJECTIONS
The following questions concern your feelings about injections.
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
1. In general, how afraid are you of needles?
Not at all1
A little2
Moderately3
Very3
Extremely4
2. In general, how afraid are you of having an injection?
Not at all1
A little2
Moderately3
Very4
Extremely5
3. How anxious do you feel about giving yourself an injection?
Not at all1
A little2
Moderately3
Very4
Extremely5
REDACTED COPY
Please answer each question below by circling the number that best represents your opinion
REDACTED COPY
Please answer each question below by circling the number that best represents your opinion
In general, how afraid are you of needles?
REDACTED COPY
In general, how afraid are you of needles?
ModeratelyREDACTED C
OPY
ModeratelyREDACTED C
OPY
REDACTED COPY
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ariati
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injection of your medication and must be answered
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on ap
plica
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injection of your medication and must be answered refilled syringe / AutoClicks prefilled pen / ava®].
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e use
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mark
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refilled syringe / AutoClicks prefilled pen / ava®].
preferably in a quiet environment.
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mark
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on ap
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preferably in a quiet environment. Take as much time as you need to complete it. There are no right or wrong answers. Your
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mark
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Take as much time as you need to complete it. There are no right or wrong answers. Your
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injections
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injections.
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.
Please answer each question below by circling the number that best represents your opinion
This do
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Please answer each question below by circling the number that best represents your opinion
In general, how afraid are you of needles?
This do
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not b
e use
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eting
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In general, how afraid are you of needles?
Moderately
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Moderately
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In general, how afraid are you of having an injection?
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In general, how afraid are you of having an injection?
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A little
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
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nsion
s or v
ariati
ons t
hereo
f.
A little
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nd an
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nsion
s or v
ariati
ons t
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f.
2
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nsion
s or v
ariati
ons t
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f.
2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
How anxious do you feel about giving yourself an injection?
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
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nsion
s or v
ariati
ons t
hereo
f.
How anxious do you feel about giving yourself an injection?
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
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nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
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nd an
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nsion
s or v
ariati
ons t
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f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
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nsion
s or v
ariati
ons t
hereo
f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 57 of 82
SELF-IMAGE
The following questions concerns your self-image when using the [prefilled syringe / AutoClicks prefilled pen / ava®].
Please answer the questions below by circling the number that best represents your opinion (circle only one number per question).
4. How self-consciouswould you feel about using the prefilled syringe / AutoClicks prefilled pen / ava®…
Not at all A little Moderately Very Extremely
a. … around your family?1 2 3 4 5
b. … around your friends?1 2 3 4 5
c. … around people you
don’t know? 1 2 3 4 5
REDACTED COPY
REDACTED COPY
REDACTED COPY
1 2 3 4 5
REDACTED COPY
1 2 3 4 5
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
2
REDACTED COPY
2
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Please answer the questions below by circling the number that best represents your opinion
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Please answer the questions below by circling the number that best represents your opinion
Very
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
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nsion
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ariati
ons t
hereo
f.
Very
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cumen
t can
not b
e use
d to s
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mark
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rizati
on ap
plica
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nsion
s or v
ariati
ons t
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f.
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cumen
t can
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uppo
rt any
mark
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rizati
on ap
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nsion
s or v
ariati
ons t
hereo
f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nsion
s or v
ariati
ons t
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f.
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cumen
t can
not b
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d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nsion
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ariati
ons t
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cumen
t can
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e use
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rt any
mark
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autho
rizati
on ap
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ariati
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3
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rt any
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ariati
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3
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cumen
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not b
e use
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rt any
mark
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on ap
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nsion
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ariati
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f.
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cumen
t can
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rt any
mark
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autho
rizati
on ap
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nsion
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ariati
ons t
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f.
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cumen
t can
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ariati
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f.
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cumen
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1 2 3 4 5
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1 2 3 4 5
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nsion
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cumen
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autho
rizati
on ap
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nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
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d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
tion a
nd an
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nsion
s or v
ariati
ons t
hereo
f.
2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
tion a
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nsion
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ariati
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2
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cumen
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not b
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d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
tion a
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nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nsion
s or v
ariati
ons t
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f.
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cumen
t can
not b
e use
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uppo
rt any
mark
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autho
rizati
on ap
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nsion
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ariati
ons t
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f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
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nsion
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ariati
ons t
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f.
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cumen
t can
not b
e use
d to s
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rt any
mark
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autho
rizati
on ap
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s or v
ariati
ons t
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f.
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cumen
t can
not b
e use
d to s
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rt any
mark
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autho
rizati
on ap
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nsion
s or v
ariati
ons t
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This do
cumen
t can
not b
e use
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rizati
on ap
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ariati
ons t
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f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 58 of 82
SELF-CONFIDENCE
The following questions concern your confidence about giving yourself an injection using the [prefilled syringe / AutoClicks prefilled pen / ava®].
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
5. How confident are you about … Not at all A little Moderately Very Extremely
a. Giving yourself an
injection in the right
way?
1 2 3 4 5
b. Giving yourself an
injection in a clean and
sterile way?
1 2 3 4 5
c. Giving yourself an
injection safely? 1 2 3 4 5
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Extremely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Extremely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
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cumen
t can
not b
e use
d to s
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rt any
mark
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autho
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on ap
plica
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nsion
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ariati
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f.
This do
cumen
t can
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e use
d to s
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rt any
mark
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f.
This do
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t can
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e use
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on ap
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ariati
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f.
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cumen
t can
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mark
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rizati
on ap
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ariati
ons t
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f.
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cumen
t can
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mark
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ariati
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t can
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e use
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1 2 3 4 5
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1 2 3 4 5
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autho
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ariati
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This do
cumen
t can
not b
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mark
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autho
rizati
on ap
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ariati
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This do
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rt any
mark
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autho
rizati
on ap
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ariati
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This do
cumen
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rt any
mark
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autho
rizati
on ap
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nsion
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rizati
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ariati
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3
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not b
e use
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autho
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3
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e use
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rizati
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nsion
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f.
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cumen
t can
not b
e use
d to s
uppo
rt any
mark
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autho
rizati
on ap
plica
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nsion
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ariati
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f.
This do
cumen
t can
not b
e use
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rt any
mark
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rizati
on ap
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nsion
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ariati
ons t
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f.
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cumen
t can
not b
e use
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mark
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ariati
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t can
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e use
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rizati
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plica
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nsion
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ariati
ons t
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f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 59 of 82
PAIN AND SKIN REACTIONS DURING OR AFTER THE INJECTION
The following questions ask about pain and skin reactions you may have experienced during or after the injection using the [prefilled syringe / AutoClicks prefilled pen / ava®].
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
6. During and/or after the
injection, how bothered
were you by:
Not at all A little Moderately Very Extremely
a. pain?1 2 3 4 5
b. burning sensation?1 2 3 4 5
c. cold sensation?1 2 3 4 5
d. itching at the
injection site? 1 2 3 4 5
e. redness at the
injection site? 1 2 3 4 5
f. swelling at the
injection site? 1 2 3 4 5
g. bruising at the
injection site? 1 2 3 4 5
h. hardening at the
injection site? 1 2 3 4 5
i. bleeding from the
injection site? 1 2 3 4 5
j. medication leaking
from the skin at the
injection site?
1 2 3 4 5
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
1 2 3 4 5
REDACTED COPY
1 2 3 4 5
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
1 2 3 4 5REDACTED COPY
1 2 3 4 5REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
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y exte
nsion
s or v
ariati
ons t
hereo
f.
Extremely
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cumen
t can
not b
e use
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rt any
mark
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on ap
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ariati
ons t
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f.
Extremely
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t can
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f.
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t can
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f.
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t can
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4
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4
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1 2 3 4 5
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1 2 3 4 5
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 60 of 82
EASE OF USE OF THE SELF-INJECTION DEVICE
The following questions ask about the ease of use of the [prefilled syringe / AutoClicks prefilled pen / ava®].
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
7. How difficult or easy was it to:
Very
difficult
Difficult Somewha
t difficult
Somewha
t easy
Easy Very
easy
a. read and follow the prefilled syringe / AutoClicks prefilled pen / ava® instructions?
1 2 3 4 5 6
b. learn how to usethe prefilled syringe / AutoClicksprefilled pen / ava®?
1 2 3 4 5 6
c. Remove the needle cap of the prefilled syringe / AutoClicks prefilled pen / ava®?
1 2 3 4 5 6
d. hold the prefilled syringe / AutoClicks prefilled pen / ava® while preparing it and giving yourself medication?
1 2 3 4 5 6
REDACTED COPY
REDACTED COPY
1 2 3 4 5 6
REDACTED COPY
1 2 3 4 5 6
REDACTED COPY
REDACTED COPY
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Very
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Very
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1 2 3 4 5 6
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refilled
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refilled syringe /
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syringe / AutoClicks
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tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ava® while preparing it and
This do
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e use
d to s
uppo
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mark
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autho
rizati
on ap
plica
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nsion
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ariati
ons t
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preparing it and
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e use
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rizati
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plica
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nsion
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ariati
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 61 of 82
7. How difficult or easy was it to:
Very
difficult
Difficult Somewha
t difficult
Somewha
t easy
Easy Very
easy
e. hold the prefilled syringe / AutoClicks prefilled pen / ava® at the correct angle for injection?
1 2 3 4 5 6
f. depress the plunger or buttonon the prefilled syringe / AutoClicks prefilled pen / ava®?
1 2 3 4 5 6
g. administer the injection without any help?
1 2 3 4 5 6
h. control the injection speed? 1 2 3 4 5 6
i. pause when giving
yourself an
injection?1 2 3 4 5 6
j. stop when giving yourself an injection?
1 2 3 4 5 6
k. be sure that the injection gave you the correct amount of medication?
1 2 3 4 5 6
l. know when the injection is complete?
1 2 3 4 5 6
m. remember when to take my next injection?
1 2 3 4 5 6
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
1 2 3 4 5 6
REDACTED COPY
1 2 3 4 5 6
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
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uppo
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nsion
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nsion
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nsion
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1 2 3 4 5 6
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1 2 3 4 5 6
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amount
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rt any
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nsion
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ariati
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nsion
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ariati
ons t
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f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 62 of 82
7. How difficult or easy was it to:
Very
difficult
Difficult Somewha
t difficult
Somewha
t easy
Easy Very
easy
n. store the prefilled syringe / AutoClicks prefilled pen / ava®?
1 2 3 4 5 6
o. travel with the prefilled syringe / AutoClicks prefilled pen / ava®
1 2 3 4 5 6
p. use the prefilled
syringe /
AutoClicks
prefilled pen /
ava®?
1 2 3 4 5 6
8.How does the [prefilled syringe / AutoClicks prefilled pen / ava®] fit in your hand?
Very uncomfortably
1
Uncomfortably
2
Somewhat uncomfortably
3
Somewhat comfortably
4
Comfortably
5
Very comfortably
6
REDACTED COPY 1 2 3 4 5 6
REDACTED COPY 1 2 3 4 5 6
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
refilled syringe / AutoClicks prefilled pen / ava®]
REDACTED COPY
refilled syringe / AutoClicks prefilled pen / ava®]
REDACTED COPY
Somewhat REDACTED C
OPY
Somewhat uncomfortablyREDACTED C
OPY
uncomfortablyREDACTED COPY
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cumen
t can
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e use
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f.
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t can
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5
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5
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1 2 3 4 5 6
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refilled syringe / AutoClicks prefilled pen / ava®]
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refilled syringe / AutoClicks prefilled pen / ava®]
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uncomfortably
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 63 of 82
SATISFACTION WITH SELF-INJECTION
The following questions ask about your satisfaction with the [prefilled syringe / AutoClicks prefilled pen / ava®].
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
9. How satisfied are you with the way the [prefilled syringe / AutoClicks prefilled pen / ava®] deliversyour medication (syringe needle or medication cassette)?
Very dissatisfied
1
Dissatisfied
2
Neither dissatisfied nor satisfied
3
Satisfied
4
Very satisfied
5
10. After this study, how confident would you be to give yourself injections at home with the [prefilled syringe / AutoClicks prefilled pen / ava®]?
Not at all1
A little2
Moderately3
Very4
Extremely5
11. How easy was it to give yourself an injection with the [prefilled syringe / AutoClicks
prefilled pen / ava®]?
Not at all1
A little2
Moderately3
Very4
Extremely5
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
was it to give yourself an injection with the [
REDACTED COPY
was it to give yourself an injection with the [
ModeratelyREDACTED COPY
ModeratelyREDACTED COPY
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How satisfied are you with the way the [prefilled syringe / AutoClicks prefilled pen / ava®]
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How satisfied are you with the way the [prefilled syringe / AutoClicks prefilled pen / ava®]
Very satisfied
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refilled syringe / AutoClicks prefilled pen / ava®]?
Very
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Very
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was it to give yourself an injection with the [
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was it to give yourself an injection with the [
Moderately
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Moderately
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 64 of 82
12. How satisfied are you with your ability to control your injection (e.g., stop, pause,
change speed) with the [prefilled syringe / AutoClicks prefilled pen / ava®]?
Very dissatisfied
1
Dissatisfied
2
Neither dissatisfied nor satisfied
3
Satisfied
4
Very satisfied
5
13. How satisfied are you with the time it takes to inject the medication with the [prefilled
syringe / AutoClicks prefilled pen / ava®]?
Very dissatisfied
1
Dissatisfied
2
Neither dissatisfiednor satisfied
3
Satisfied
4
Very satisfied
5
14. Overall, how convenient is the [prefilled syringe / AutoClicks prefilled pen / ava®]?
Veryinconvenient
1
Inconvenient
2
Neither inconvenient nor convenient
3
Convenient
4
Very convenient
5
15. After this study, would you choose to continue self-injecting your medication with the
[prefilled syringe / AutoClicks prefilled pen / ava®]?
Definitely not1
Probably not2
I don’t know3
Yes, probably4
Yes, definitely5
REDACTED COPY
Neither inconvenient
REDACTED COPY
Neither inconvenient nor convenient
REDACTED COPY
nor convenient
REDACTED COPY
REDACTED COPY
REDACTED COPY
choose to continue REDACTED C
OPY
choose to continue
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time it takes to inject the medication with the
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refilled
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refilled syringe / AutoClicks prefilled pen / ava®]?
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mark
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refilled syringe / AutoClicks prefilled pen / ava®]?
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Convenient
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Convenient
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Neither inconvenient
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Neither inconvenient
3
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3
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choose to continue
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choose to continue
[prefilled syringe / AutoClicks prefilled pen / ava®]?
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not b
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[prefilled syringe / AutoClicks prefilled pen / ava®]?
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Probably not
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Probably not2
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2
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f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 65 of 82
16. Overall, how satisfied are you with the [Prefilled syringe / AutoClicks prefilled pen /
ava®]?
Very dissatisfied
1
Dissatisfied
2
Neither dissatisfied nor satisfied
3
Satisfied
4
Very satisfied
5
THANK YOU FOR COMPLETING THIS QUESTIONNAIRE
REDACTED COPY
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cumen
t can
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e use
d to s
uppo
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mark
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nsion
s or v
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mark
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on ap
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nsion
s or v
ariati
ons t
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f.
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mark
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on ap
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nsion
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ariati
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f.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 66 of 82
16.3 Self-Injection Preference Questionnaire
SELF-INJECTION PREFERENCE QUESTIONNAIRE
The following questions concern your preferences about injections.
Please answer each question below by circling the number that best represents your opinion (circle only one number per question).
1. Which self-injection device do you prefer based on how safe the device is to use?ava®
1
your latest device1
2
no preference
3
2. Which self-injection device do you prefer based on how confident you are when using the device?
ava®
1
your latest device1
2
no preference
3
3. Which self-injection device do you prefer based on how easy the device is to hold?ava®
1
your latest device1
2
no preference
3
4. Which self-injection device do you prefer based on your ability to control your injection (for example, stop, pause, change speed)?
ava®
1
your latest device
2
no preference
3
5. Which self-injection device do you prefer based on how easy the device is to store?ava®
1
your latest device1
2
no preference
3
1Pre-filled syringe or AutoClick pre-filled pen
REDACTED COPY
REDACTED COPY
injection device do you prefer based on how
REDACTED COPY
injection device do you prefer based on how your latest deviceREDACTED C
OPY
your latest deviceREDACTED C
OPY
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eting
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ariati
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f.
Please answer each question below by circling the number that best represents your opinion (circle only
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Please answer each question below by circling the number that best represents your opinion (circle only
fe the device is to use?
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no preference
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no preference
3
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3
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confident you are when using
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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6. Which self-injection device do you prefer based on how easy it is to travel with the device?
ava®
1
your latest device1
2
no preference
3
7. Which self-injection device do you prefer based on the time needed to perform your injection?
ava®
1
your latest device1
2
no preference
3
8. Which self-injection device do you prefer based on how convenient the device is to use?
ava®
1
your latest device1
2
no preference
3
9. Overall, which self-injection device do you prefer?
ava®
1
your latest device1
2
no preference
3
THANK YOU FOR COMPLETING THIS QUESTIONNAIRE
1Pre-filled syringe or AutoClick pre-filled pen
REDACTED COPY
REDACTED COPY
-injection device do you prefer
REDACTED COPY
-injection device do you prefer
REDACTED COPY
REDACTED COPY
your latest deviceREDACTED COPY
your latest deviceREDACTED COPY
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time needed to perform your
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no preference
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no preference
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1
2
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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16.4 Cochin Scale
REDACTED COPY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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REDACTED COPY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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REDACTED COPY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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REDACTED COPY
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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REDACTED COPY
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16.5 Protocol Amendment 1
Rationale for the amendment
The purpose of this protocol amendment is to clarify subjects in the Q4W dosing regimen, the process of self-injection, and informed consent.
In additions, minor grammatical and typographical errors were corrected.
Modifications and changes
Global changes
The following global change has been made throughout the protocol:
Clarification was added that the Q4W dosing regimen may include subjects with RA, PsA, orAS.
Specific changes
Change #1
Section 1 Summary, after fifth paragraph
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #2
Section 4.1.1 Primary outcome and variable, after first bullet
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was
REDACTED COPY
, after fifth paragraph
REDACTED COPY
, after fifth paragraph
The following paragraph has been added:
REDACTED COPY
The following paragraph has been added:
-injection, if the skin sensor at the
REDACTED COPY
-injection, if the skin sensor at the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
REDACTED COPY
e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have f contact with skin, the subjectREDACTED C
OPY
f contact with skin, the subject
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include subjects with
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include subjects with
-injection, if the skin sensor at the
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-injection, if the skin sensor at the injection port los
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injection port lose-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
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e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have f contact with skin, the subject
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f contact with skin, the subjectand resume and complete the se
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and resume and complete the seinjection and deliver the entire dose of medication (ie, the device indicates incomplete
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injection and deliver the entire dose of medication (ie, the device indicates incomplete cassette is not
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cassette is notinjection will document the incomplete self
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injection will document the incomplete selfnot administered, and using his/
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not administered, and using his/
Section 4.1.1 Primary
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Section 4.1.1 Primary
The following paragraph has been added:
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The following paragraph has been added:
During self
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During selfe-Device will withdraw the needle and stop administration of CZP. If less than
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e-Device will withdraw the needle and stop administration of CZP. If less thanelapsed since loss o
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elapsed since loss o
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #3
Section 4.1.2 Secondary variable, after first bullet
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #4
Section 8.1 Visit 1/Screening and Study Treatment Period, after fourteenth bullet
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #5
Section 8.2.1 Visit 2 (Week 2), after seventh bullet
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-
REDACTED COPY
dy
REDACTED COPY
dy Treatment Period, after fourteenth bullet
REDACTED COPY
Treatment Period, after fourteenth bulletdy Treatment Period, after fourteenth bulletdy
REDACTED COPY
dy Treatment Period, after fourteenth bulletdy
The following paragraph has been added:
REDACTED COPY
The following paragraph has been added:
injection, if the skin sensor at the injection port losREDACTED C
OPY
injection, if the skin sensor at the injection port losDevice will withdraw the needle and stop administration of CZP. If less REDACTED C
OPY
Device will withdraw the needle and stop administration of CZP. If less
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es contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
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e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have -Device on a new clean
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If the subject is unable to complete the injection and deliver the entire dose of medication (ie, the device indicates incomplete
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injection and deliver the entire dose of medication (ie, the device indicates incomplete ), the HCP evaluating the se
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the complete dose was injection, note the reason why the complete dose was injection, note the reason why
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injection, note the reason why the complete dose was injection, note the reason whycal judgment, advise the subject
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cal judgment, advise the subject
Treatment Period, after fourteenth bullet
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Treatment Period, after fourteenth bullet
The following paragraph has been added:
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The following paragraph has been added:
injection, if the skin sensor at the injection port los
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injection, if the skin sensor at the injection port losDevice will withdraw the needle and stop administration of CZP. If less
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Device will withdraw the needle and stop administration of CZP. If less f contact with skin, the subject
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f contact with skin, the subjectinjection site and resume and complete the se
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injection site and resume and complete the se
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injection and deliver the entire
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injection and deliver the entire dose of medication (ie, the device indicates incomplete
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dose of medication (ie, the device indicates incomplete -
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-cassette is not
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cassette is notinjection will document the incomplete self
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injection will document the incomplete selfered, and using his/
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ered, and using his/
Change #
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Change #
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5
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5
Section 8.2.1 Visit 2 (Week 2)
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Section 8.2.1 Visit 2 (Week 2)
The following paragraph has been added:
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The following paragraph has been added:
During self
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During selfe-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
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e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #6
Section 8.3.1 Visit 2 (Week 4), after seventh bullet
The following paragraph has been added:
During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
Change #7
Section 9.4 Evaluation of post-use structural integrity of CZP-cassettes
The used CZP-cassettes will be inspected to determine if the entire dose was delivered based on whether the PFS housed in the CZP-cassette is empty or not (as per primary endpoint). The visual inspection of the used CZP-cassette will also check for structural integrity and damage (ie, clear evidence of damage/compromised structural integrity—not superficial, cosmetic imperfections). All evaluations will be performed by appropriately trained site staff.
Has been changed to:
The used CZP-cassettes will be inspected to determine if the entire dose was delivered based on whether the PFS housed in the CZP-cassette is empty or not (as per primary endpoint). During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing. The visual inspection of the used CZP-cassette will also check for structural integrity and damage (ie, clear evidence of damage/compromised structural integrity—not superficial, cosmetic imperfections). All evaluations will be performed by appropriately trained site staff.
REDACTED COPY
use structural integrity
REDACTED COPY
use structural integrity
cassettes will be inspected to determine if the entire dose was delivered based on
REDACTED COPY
cassettes will be inspected to determine if the entire dose was delivered based on cassette is emptyREDACTED C
OPY
cassette is empty
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es contact with the skin, the
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es contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have
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e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have -Device on a new clean
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-Device on a new clean If the subject is unable to complete the
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If the subject is unable to complete the the device indicates incomplete
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the device indicates incomplete ), the HCP evaluating the self
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), the HCP evaluating the selfinjection, note the reason why
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injection, note the reason whycal judgment, advise the subject
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cal judgment, advise the subject
use structural integrity
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use structural integrity
cassettes will be inspected to determine if the entire dose was delivered based on
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cassettes will be inspected to determine if the entire dose was delivered based on cassette is empty
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cassette is emptycassette will also check for structural integrity
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cassette will also check for structural integrityompromised structural integrit
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ompromised structural integritimperfections). All evaluations will be performed by
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imperfections). All evaluations will be performed by
cassettes will be inspected to determine if the entire dose was delivered based on
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cassettes will be inspected to determine if the entire dose was delivered based on
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whether the PFS housed in the CZP
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whether the PFS housed in the CZP-injection, if the skin sensor at the injection port loses contact with the skin, the e-
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-injection, if the skin sensor at the injection port loses contact with the skin, the e-will withdraw the needle and stop administration of CZP. If less than five minutes have
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will withdraw the needle and stop administration of CZP. If less than five minutes have nce loss of contact with skin, the subject can reposition the e
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nce loss of contact with skin, the subject can reposition the eclean injection site and resume and complete the self
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clean injection site and resume and complete the selfcomplete the self
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complete the selfincomplete administration and the CZP
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incomplete administration and the CZPevaluating the self-
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evaluating the self-why the complete dose was not administered, and using his/her best medi
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why the complete dose was not administered, and using his/her best mediadvise the subject regarding any further dosing.
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advise the subject regarding any further dosing.
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
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Change #8
Section 9.6 Evaluation of safe and effective self-injection
Safe and effective self-injection will be evaluated by the HCP. Subject self-injection of the complete dose of CZP will be confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be empty. The self-injection will be considered safe if there are no AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection.
Has been changed to:
Safe and effective self-injection will be evaluated by the HCP. Subject self-injection of the complete dose of CZP will be confirmed by a visual inspection of the CZP-cassette(s) which shows the PFS container to be empty. During self-injection, if the skin sensor at the injection port loses contact with the skin, the e-Device will withdraw the needle and stop administration of CZP. If less than five minutes have elapsed since loss of contact with skin, the subject can reposition the e-Device on a new clean injection site and resume and complete the self-injection. If the subject is unable to complete the self-injection and deliver the entire dose of medication (ie, the device indicates incomplete administration and the CZP-cassette is not seen to be empty), the HCP evaluating the self-injection will document the incomplete self-injection, note the reason why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing.
The self-injection will be considered safe if there are no AEs related to use of the e-Device (ADEs) that would preclude continued use of the e-Device for self-injection.
Change #9
Section 12.1 Definition of analysis sets, third paragraph
The Full Analysis Sets for subjects in the Q2W group (FASa) and for subjects in the Q4W group (FASb) will consist of all subjects in the SS who received at least 1 dose of CZP using the e-Device in the study. All variables will be analyzed using the FASa and FASb.
Has been changed to:
The Full Analysis Sets (FAS) for subjects in the Q2W group (FASa) and for subjects in the Q4W group (FASb) will consist of all subjects in the SS who received at least 1 dose of CZP using the e-Device in the study. All outcome variables will be analyzed using the FASa and FASb.
Change #10
Section 12.2 General statistical considerations, first paragraph, third sentence
Each endpoint will be summarized by dosing regimen (Q2W or Q4W) and within the Q2W group by indication.
Has been changed to:
REDACTED COPY seen to be empty), the HCP evaluating the self
REDACTED COPY seen to be empty), the HCP evaluating the self
on why the complete dose was not administered,
REDACTED COPY
on why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing
REDACTED COPY
and using his/her best medical judgment, advise the subject regarding any further dosing-injection will be considered safe if there are no
REDACTED COPY
-injection will be considered safe if there are noe continued use of the e
REDACTED COPY
e continued use of the e
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Device for
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cassette(s) which injection, if the skin sensor at the injection
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seen to be empty), the HCP evaluating the selfon why the complete dose was not administered,
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on why the complete dose was not administered, and using his/her best medical judgment, advise the subject regarding any further dosing
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and using his/her best medical judgment, advise the subject regarding any further dosing-injection will be considered safe if there are no
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-injection will be considered safe if there are noe continued use of the e
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-Device for self
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Device for self
Section 12.1 Definition of analy
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Section 12.1 Definition of analysis sets, third paragraph
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sis sets, third paragraph
is Sets for subjects in the Q2W group (FASa) and for subjects in the Q4W group
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is Sets for subjects in the Q2W group (FASa) and for subjects in the Q4W group (FASb) will consist of all subjects in
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(FASb) will consist of all subjects in . All variables will be analyzed using the FASa and FASb.
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. All variables will be analyzed using the FASa and FASb.
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ys
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ysis Set
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is SetASb)
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ASb) will consist of all subjects in the SS who received at least 1 dose of CZP using the
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will consist of all subjects in the SS who received at least 1 dose of CZP using the
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Device in the study
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Device in the study
Change #10
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Change #10
Section 12.2 General statistical considerations, first paragraph,
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Section 12.2 General statistical considerations, first paragraph,
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 77 of 82
Each endpoint will be summarized by dosing regimen (Q2W or Q4W) and within the Q2W group by indication.
Change #11
Section 12.3.1 Analysis of the primary outcome variable, third paragraph
The number and proportion of subjects with safe and effective self-injections will be tabulated for the FASa and FASb and by indication for the FASa. A subgroup analysis will be performed for subjects in the FASa or FASb with impaired hand function. The 90% CIs for the proportion based on the Exact Binomial method will be reported as well.
Has been changed to:
The number and proportion of subjects with safe and effective self-injections will be tabulated for the FASa and FASb overall, by dosing group, and by indication for the FASa. A subgroup analysis will be performed for subjects in the FASa or FASb with impaired hand function. The 90% CIs for the proportion based on the Exact Binomial method will be reported as well
Change #12
Section 12.3.2 Analysis of secondary variables, third paragraph
The secondary variables will be summarized using descriptive statistics. All summary statistics will be presented for the FASa and FASb, and by indication for the FASa. A subgroup analysis will performed for subjects in the FASa or FASb with impaired hand function.
Has been changed to:
Section 12.3.2 Analysis of secondary outcome variables
The secondary outcome variables will be summarized using descriptive statistics. All summary statistics will be presented for the FASa and FASb, overall, by dosing group, and by indication for the FASa. A subgroup analysis will performed for subjects in the FASa or FASb with impaired hand function.
Change #13
Section 12.3.3 Analysis of the other variables, second paragraph
The other variables will be summarized using descriptive statistics. All other exploratory variables will be summarized for the FASa and FASb, and by indication for the FASa.
Has been changed to:
Section 12.3.3 Analysis of the other outcome variables
The other outcome variables will be summarized using descriptive statistics. All other exploratory variables will be summarized for the FASa and FASb, overall, by dosing group,and by indication for the FASa.
REDACTED COPY
ariables, third paragraph
REDACTED COPY
ariables, third paragraph
variables will be summarized using descriptive stat
REDACTED COPY
variables will be summarized using descriptive statwill be presented for the FASa and FASb, and b
REDACTED COPY
will be presented for the FASa and FASb, and bwill performed for subjects in the FASa
REDACTED COPY
will performed for subjects in the FASa or FASbREDACTED C
OPY
or FASb
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injections will be tabulated
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injections will be tabulated is will be per
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is will be performed
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formed The 90% CIs for the proportion
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injections will be tabulated
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for the FASa
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impaired hand function.
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impaired hand function. s for the proportion based on the Exact Binomial method will be reported as well
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variables will be summarized using descriptive statwill be presented for the FASa and FASb, and b
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will be presented for the FASa and FASb, and by
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or FASb
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variables will be summarized using descriptive statistics. All summary
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variables will be summarized using descriptive statistics. All summarystatistics will be presented for the FAS
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statistics will be presented for the FAS. A subgroup anal
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. A subgroup analimpaired hand function.
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impaired hand function.
Change #13
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Change #13
Section 12.3.3 A
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Section 12.3.3 A
The other variables will be summarized using descriptive statistics. All other exploratory
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The other variables will be summarized using descriptive statistics. All other exploratory
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variables will be summa
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variables will be summa
Has been changed to:
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Has been changed to:
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 78 of 82
Change #14
Section 12.4.1 Safety analyses, third paragraph, second sentence
Adverse events will be summarized separately as AEs associated with the study drug and those AEs related to use of the e-Device (ADEs) (including the CZP-cassette).
Has been changed to:
Adverse events related to use of the e-Device (ADEs) (including the CZP-cassette) will be summarized separately as AEs associated with the study drug and those AEs related to use of the e-Device (ADEs) (including the CZP-cassette).
Change #15
Section 12.5 Handling of protocol deviations, first sentence
Only subjects who had no important protocol deviations affecting the primary outcome variable, as confirmed during ongoing data cleaning meetings prior to database lock, will be included in the FASa/FASb.
Has been removed.
Change #16
Section 13.1 Informed consent, third paragraph
Prior to participation in the study, the Informed Consent form should be signed and personally dated by the subject, or his/her legal representative, and by the person who conducted the informed consent discussion (Investigator or designee). The subject or his/her legal representative must receive a copy of the signed and dated Informed Consent form. As part of the consent process, each subject must consent to direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection.
Has been changed to:
Prior to participation in the study, the Informed Consent form should be signed and personally dated by the subject, or his/her legal representative, and by the person who conducted the informed consent discussion (Investigator or designee). The subject or his/her legal representative must receive a copy of the signed and dated Informed Consent form. As part of the consent process, each subject must consent to direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection
Change #17
Section 13.2 Subject identification cards
Upon signing the Informed Consent form, the subject or legal representative will be provided with a subject identification card in the language of the subject. The Investigator will fill in the
REDACTED COPY
Section 13.1 Informed consent, third
REDACTED COPY
Section 13.1 Informed consent, third paragraph
REDACTED COPY
paragraph
, the REDACTED COPY
, the Informed Consent form should be signed and personally REDACTED COPY
Informed Consent form should be signed and personally y the subject, or his/her legal representative, and bREDACTED C
OPY
y the subject, or his/her legal representative, and b
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drug and those AEs related to use of the
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no important protocol deviations affecting the primary
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no important protocol deviations affecting the primaryas confirmed during ongoing data cleaning meetings prior to database lock, will be included in
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as confirmed during ongoing data cleaning meetings prior to database lock, will be included in
paragraph
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paragraph
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Informed Consent form should be signed and personally y the subject, or his/her legal representative, and b
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y the subject, or his/her legal representative, and bnvestigator or designee). The
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y of the signed and dated Informed Consent form. As part of the consent process, each subject must consent to direct access to his/her medical records for
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Prior to participation in the study
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, or his/her legal representative,
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informed cons
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informed consent discussion (I
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ent discussion (Irepresentative
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representative must receive a copy
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must receive a copy
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the consent process, each subject must consent to direct access to his/her medical records
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the consent process, each subject must consent to direct access to his/her medical records study
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study-related monitoring, auditing, IRB/
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-related monitoring, auditing, IRB/
Change #
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Change #
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 79 of 82
subject identifying information and medical emergency contact information. The Investigator will instruct the subject to keep the card with him/her at all times.
Has been changed to:
Upon signing the Informed Consent form, the subject or legal representative will be provided with a subject identification card in the language of the subject. The Investigator will fill in the subject identifying information and medical emergency contact information. The Investigator will instruct the subject to keep the card with him/her at all times.
16.6 Protocol Amendment 2
Rationale for the amendment
The purpose of this protocol amendment is to clarify the composition of subjects in the samplesize.
Modifications and changes
Specific changes
Change #1
Section 1 Summary, last paragraph, last sentence
These 60 subjects will be composed of a minimum of 15 subjects with either RA, PsA, or AS in each of the dosing groups (Q2W and Q4W); a minimum of 15 subjects with CD; and a minimum of 10 subjects with impaired hand function.
Has been changes to:
These 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjectswith either RA, PsA, or AS in each of the dosing groups (Q2W and vs Q4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function.
Change #2
Section 5.1.2 Planned number of subjects and sites, second sentence
These 60 subjects will be composed of a minimum of 15 subjects with either RA, PsA, or AS in each of the dosing groups (Q2W and Q4W); a minimum of 15 subjects with CD; and a minimum of 10 subjects with impaired hand function.
Has been changed to:
These 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjectswith either RA, PsA, or AS in each of the dosing groups (Q2W and vs Q4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function.
Change #3
REDACTED COPY
last sentence
REDACTED COPY
last sentence
will be composed of a minimum of 15 subjects with
REDACTED COPY
will be composed of a minimum of 15 subjects with each of the dosing groups (Q2W and Q4W);
REDACTED COPY
each of the dosing groups (Q2W and Q4W); a minimum of
REDACTED COPY
a minimum ofof 10 subjects with impaired hand function
REDACTED COPY
of 10 subjects with impaired hand function
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contact information. The Investigator
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contact information. The Investigator
the composition of subjects in the sample
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the composition of subjects in the sample
last sentence
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last sentence
will be composed of a minimum of 15 subjects with
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will be composed of a minimum of 15 subjects with a minimum of
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a minimum of
Device at Visit 1
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Device at Visit 1in each of the dosing groups (Q2W and
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in each of the dosing groups (Q2W andand a minimum of 10 subjects with impaired hand function.
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and a minimum of 10 subjects with impaired hand function.
Section 5.1.2 Planned number of subjects and sites, second sentence
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Section 5.1.2 Planned number of subjects and sites, second sentence
hese 60 subjects
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hese 60 subjects will be composed of a minimum of 15 subjects with
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will be composed of a minimum of 15 subjects with each of the dosing groups (Q2W and Q4W);
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each of the dosing groups (Q2W and Q4W); of 10 subjects with impaired hand function
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of 10 subjects with impaired hand function
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Has been changed to:
The
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Thewith either RA, PsA, or AS
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with either RA, PsA, or AS
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 80 of 82
Section 12.8 Determination of sample size, second sentence
The 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjects with either RA, PsA, or AS in each of the dosing groups (Q2W vs Q4W); a minimum of 15 subjects with CD; and a minimum of 10 subjects with impaired hand function.
Has been changed to:
These 60 subjects using the e-Device at Visit 1 will be composed of a minimum of 15 subjectswith either RA, PsA, or AS in each of the dosing groups (Q2W and vs Q4W) with a minimum of 15 subjects with CD and a minimum of 10 subjects with impaired hand function.
REDACTED COPY
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a minimum of 15 subjects
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a minimum of 15 subjectsa minimum of
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a minimum of
UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 81 of 82
17 DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this clinical study as outlined in this protocol, according to current Good Clinical Practice and locallaws and requirements.
I will ensure that all subinvestigators and other staff members read and understand all aspects of this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated confidentially, and will not be made available to third parties without prior authorization by UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a separate contract.
Investigator:
Printed name Date/Signature
REDACTED COPY
Date/Signature
REDACTED COPY
Date/Signature
REDACTED COPY
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will ensure that all subinvestigators and other staff members read and understand all aspects of
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will ensure that all subinvestigators and other staff members read and understand all aspects of
well as the results deriving from it will be treated
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well as the results deriving from it will be treated , and will not be made available to third parties without prior authorization by
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, and will not be made available to third parties without prior authorization by
All rights of publication of the results reside with UCB, unless other agreements were made in a
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All rights of publication of the results reside with UCB, unless other agreements were made in a
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Date/Signature
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Date/Signature
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UCB 29 Sep 2017Clinical Study Protocol Certolizumab pegol RA0098
Confidential Page 82 of 82
18 SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this clinical study as outlined in this protocol and according to current Good Clinical Practice.
REDACTED COPY
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REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
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