Study Protocol - heart.bmj.com
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Study Protocol
Randomised controlled trial of the LoDED (Limit of Detection of Troponin
and ECG Discharge) strategy versus usual care in adult chest pain
patients attending the Emergency Department.
Version 3.1, Final - Dated 17/01/2019
Chief Investigator: Dr Edward Carlton
Emergency Department
Southmead Hospital
North Bristol NHS Trust
Southmead Road
Bristol, BS10 5NB
Tel 01174144985
Study Sponsor: North Bristol NHS Trust
IRAS Number: 235662
ISRCTN:
REC Ref: 18/SW/0038
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LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 2 of 33
TABLE OF CONTENTS
Section Page
1 SIGNATURE PAGE 4
2 KEY CONTACT DETAILS 5
3 LIST OF ABBREVIATIONS 7
4 STUDY SUMMARY 8
5 BACKGROUND AND RATIONALE 8
6 AIMS AND OBJECTIVES 10
6.1 Aim 10
6.2 Objectives 10
7 TRIAL DESIGN 10
7.1 Summary of trial design 10
7.2 Blinding and strategies for minimising
bias
12
7.3 Duration of participation 12
8 TRIAL ENDPOINTS 12
8.1 Primary Outcome 12
8.2 Secondary Outcomes 12
9 PARTICIPANT SELECTION 12
9.1 Inclusion Criteria 13
9.2 Exclusion Criteria 13
10 CLINICAL PROCEDURES 13
10.1 Baseline ECG 13
10.2 Baseline blood sampling 14
10.3 Repeat troponin tests 14
10.4 Laboratory analysis 14
11 SCREENING,RECRUITMENT AND
CONSENT
14
12 RANDOMISATION 15
13 TRIAL STRATEGIES 15
13.1 Usual rule-out strategies (control) 15
13.2 LoDED strategy (intervention) 16
14 POST INVESTIGATION PROCEDURES 16
14.1 Clinical management 16
14.2 Participant advice 16
14.3 Patient satisfaction survey and EQ-5D 16
15 FOLLOW-UP PROCESSES 16
15.1 Participants with an initial hs-troponin
below the LoD
17
15.2 Remaining participants 17
16 DATA TO BE COLLECTED 18
17 OUTCOME ADJUDICATION 19
18 INTEGRATED QUALITATIVE STUDY 18
18.1 Qualitative analysis 19
19 SAFETY 20
19.1 Definitions 20
19.2 Reporting non-serious adverse events 21
19.3 Reporting serious adverse events 21
20 STUDY COMPLETION 21
20.1 Premature termination of the study 22
21 PARTICIPANT WITHDRAWAL 22
21.1 Withdrawal from intervention 22
21.2 Withdrawal from follow-up 22
22 DATA MANAGEMENT 22
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22.1 Subject numbering 22
22.2 Data collection personnel 23
22.3 Source data and source documents 23
22.4 Data collection forms 23
22.5 Clinical record-keeping 23
22.6 Follow-up data collection 23
22.7 Data handling and record keeping 23
22.8 Data security, data protection and
patient confidentiality
24
22.9 Access to data 24
22.10 Archiving 25
23 STATISTICAL CONSIDERATIONS 25
23.1 Sample size 25
23.2 Statistical analysis 25
24 ECONOMIC EVALUATION 26
24.1 Health economic data collection 26
24.2 Health economic analysis 26
25 DATA MONITORING AND QUALITY
ASSURANCE
26
26 TRIAL OVERSIGHT 27
26.1 Trial Management Group (TMG) 27
26.2 Trial Steering Committee (TSC) 27
26.3 Competing interests for the CI and
members of oversight committees
27
26.4 Patient and Public Involvement (PPI) 28
27 ETHICS AND REGULATORY
APPROVALS
28
27.1 Study Sponsor 28
27.1 Research Governance 28
28 STATEMENT OF INDEMNITY 28
29 DISSEMINATION POLICY 29
30 FINANCE 29
REFERENCES 30
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1 SIGNATURE PAGE
Role Name Signature Date
Chief Investigator Dr Edward Carlton
Statistician Mrs Hazel Taylor
Sponsor’s representative
Ms Helen Lewis-White
Principal Investigator
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2 KEY CONTACT DETAILS
Chief Investigator
Dr Edward Carlton
Emergency Department, Southmead Hospital
North Bristol NHS Trust
Southmead Road
Bristol
BS10 5NB
Email: [email protected]
Sponsor Representative
Ms Helen Lewis-White
Operations Manager, Research and Innovation
Floor 3 Learning and Research
Southmead Hospital
Southmead Road
Bristol
BS10 5NB
Email: [email protected]
Study Statistician
Mrs Hazel Taylor
University Hospitals Bristol NHS Foundation Trust
Upper Maudlin Street
Bristol, BS2 8HW
Email: [email protected]
Health Economist
Dr Rebecca Kandiyali
University of Bristol
Oakfield House
Oakfield Grove
Bristol, BS8 2BN
Email: [email protected]
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Qualitative Research Lead
Dr Jenny Ingram
Senior Research Fellow
Centre for Child and Adolescent Health
University of Bristol
Oakfield House
Oakfield Grove
Bristol, BS8 2BN
Email: [email protected]
Senior Trial Manager
Sarah Campbell
Peninsula Clinical Trials Unit
N16/17 ITTC Building 1
Plymouth Science Park
Davy Road
Plymouth
PL6 8BX
Email: [email protected]
Assistant Trial Manager
Rebecca Chapman
Peninsula Clinical Trials Unit
N16/17 ITTC Building 1
Plymouth Science Park
Davy Road
Plymouth
PL6 8BX
Email: [email protected]
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LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 7 of 33
3 LIST OF ABBREVIATIONS
ACS
AE
Acute Coronary Syndrome
Adverse Event
AMI
CI
Acute Myocardial Infarction
Chief Investigator
CRF Case Report Form
CTU
ECG
Clinical Trials Unit
Electrocardiogram
ED
EDOU
EQ-5D
GHAA
HEART
Emergency Department
Emergency Department Observation Unit
EuroQoL 5D-5L health status questionnaire
Group Health Association of America
History, ECG, Age, Risk Factors and Troponin
Hs-troponin
ICH GCP
High-sensitivity troponin
International Conference on Harmonisation Good Clinical Practice
LoD Limit of Detection
LoDED Limit of Detection of troponin and ECG Discharge strategy
MACE
MACS
Major Adverse Cardiac Event
Manchester Acute Coronary Syndromes
NICE
NIHR
National Institute for Health and Care Excellence
National Institute for Health Research
PAG
PenCTU
PIS
Patient Advisory Group
Peninsula Clinical Trial Unit
Participant Information Sheet
PPI
REC
SAE
SOP
TIMI
TMG
TSC
Patient and Public Involvement
Research Ethics Committee
Serious Adverse Event
Standard Operating Procedure
Thrombolysis in Myocardial Infarction
Trial Management Group
Trial Steering Committee
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4 STUDY SUMMARY
Title Randomised controlled trial of the LoDED (Limit of Detection of Troponin and ECG
Discharge) strategy versus usual care in adult chest pain patients attending the Emergency
Department.
Study Location NHS Emergency Departments in England and Wales
Study Question Does a novel diagnostic strategy for ruling out major adverse cardiac events (MACE) in
emergency department patients with suspected cardiac chest pain increase rates of early
discharge, reduce resource use and prove acceptable to patients, when compared to usual
care?
Study Objectives 1. Conduct a randomised controlled trial of the LoDED strategy compared to usual care to
compare the proportion of patients successfully discharged within four hours of arrival,
with no MACE during the following 30 days.
2. Measure admission rates, hospital bed usage, length of stay, resource use and patient
satisfaction, facilitating a health economic evaluation.
3. Determine whether the LoDED strategy is acceptable to patients.
Study Design Pragmatic multi-centre 1:1 randomised controlled trial
Main inclusion
criteria
• Age ≥18 years
• Presenting to ED with chest pain and triggering the chest pain investigation pathway
i.e. treating clinician intends to perform investigation to rule out a cardiac cause
• Peak symptoms occurred <6 hours prior to presentation to the ED
Main exclusion
criteria
• ST-elevation myocardial infarction or ischaemic ECG (new T wave inversion >3mm or
ST depression >1mm) as judged by the treating clinician
• Clear non-ACS cause for chest pain found at presentation (e.g. pulmonary embolism,
pneumonia, aortic dissection)
• Initial hs-troponin result known to the treating clinician
• Admission indicated due to other medical/social reasons
• Chest pain due to arrhythmia
• Unable/unwilling to provide written informed consent
• Pain too severe to provide written informed consent
• Follow-up will be impossible i.e. live abroad/no fixed abode
• Previous inclusion in the study
Planned sample 594 participants
Study Interventions
Control arm Participant admitted or discharged based on usual rule-out strategy operating in that
hospital (varies between recruiting centres). Usual care includes ECG on arrival and usually
two hs-troponin tests. All centres take the first sample at presentation, but the minimum
time delay between the two samples varies.
Intervention arm
(LoDED Strategy)
Participant discharged after a single hs-troponin test at presentation to ED if hs-troponin is
below the LoD. Participant not fulfilling discharge criteria will have a second hs-troponin
test after 1-6 hours as per usual care.
Summary of outcome measures
Primary Successful early discharge, defined as discharge from hospital within four hours of arrival,
without MACE occurring within 30 days of ED attendance.
Secondary 1. Length of ED/ED Observation Unit (EDOU) stay, measured in hours
2. Hospital admission and subsequent length of stay
3. Incidence of MACE, within 30 days of the index ED attendance
4. Comparative costs.
5. Patient satisfaction (quantitative survey).
6. Acceptability to patients (qualitative methodology).
Study schedule
End of Trial 30 (+5) days after the date the last participant is recruited
5 BACKGROUND AND RATIONALE
The number of patients attending Emergency Departments (EDs) across England and Wales
continues to rise, with over 22 million attendances in 2014.1 Chest pain makes up nearly 10% of ED
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attendances and is the most common reason for emergency hospital admission.2 The majority of
patients with chest pain have prolonged hospital stays during which they undergo testing to rule
out acute myocardial infarction (AMI), yet 90% of patients are found to have a benign cause of
chest pain, such as gastro-oesophageal reflux.2 Prolonged assessment leads to increased NHS
costs, patient anxiety, and ED overcrowding.3
The need for prolonged assessment is driven by limitations in current diagnostic strategies.
Clinicians rely on three elements to rule out AMI: patient history, ECG and blood test biomarkers.
Patient history is an unreliable predictor of AMI4 and few patients (14%) have an ECG that is
diagnostic,2 therefore the majority of patients require biomarker testing. The current biomarker
used to rule-out AMI is troponin, a protein released into the blood when myocardial injury occurs.
Recently highly sensitive troponin (hs-troponin) assays have been developed, meaning that very
low concentrations can be measured.5 This has led to improved diagnostic accuracy earlier after
chest pain onset.6 Current consensus guidelines recommend that rule-out hs-troponin testing can
be undertaken using two samples taken at presentation and 1 to 3 hours later.7,8 Due to
limitations clinical and laboratory processing times with strategies reliant on two blood tests, most
patients will still not be discharged until at least 4 hours after ED attendance.9 A substantial
proportion of patients could potentially be discharged much earlier with a single hs-troponin test
taken at presentation to ED.10
It has been proposed that a single hs-troponin test at presentation to ED, could be used to rule-out
AMI in 9-60% of patients with very high diagnostic accuracy,11-17 using an “undetectable” cut-off
for ruling out AMI. This undetectable cut-off is called the Limit of Detection (LoD; lowest analyte
concentration at which detection is feasible). Current data supporting the LoD cut-off are from
observational studies and in patients who were not actually discharged based on hs-troponin
results. Evaluating new diagnostic technology with observational research alone has important
limitations. It is possible that beneficial effects will be diluted because clinicians do not abide by
their recommendations. Furthermore, unanticipated effects such as rebound overuse of resources
have previously been reported and have meant that apparently safe strategies are not cost-
effective.18,19 Therefore the clinical and cost-effectiveness of the LoD cut-off remains unknown.
There are two hs-troponin assays currently approved by NICE: Roche hs-troponin T and Abbott hs-
troponin I.7 The majority of centres within LoDED study use the Roche hs-troponin T assay,
reflecting current UK practice (information from manufacturer). The LoD for this assay is <5ng/L.
Some centres will use the Abbott hs-troponin I assay. The LoD for this assay is <2ng/L. In addition,
an emerging hs-troponin I assay (Beckman Coulter Access hs-troponin I) meets criteria to be
defined as a high-sensitivity assay but is yet to be evaluated by NICE.20 Similarly, the LoD for this
assay is <2ng/L. Performance of all three assays at the LoD appears similar, with similar
proportions of patients being eligible for safe early discharge.17,19 The LoD alone does not have the
required diagnostic accuracy for clinical implementation.10 However, combining the LoD with ECG
findings improves diagnostic accuracy (LoDED strategy). In a meta-analysis of over 9000 patients
evaluating the LoDED strategy with hs-troponin T, pooled sensitivity for 30-day major adverse
cardiac events (MACE), was 98.0% (95% Confidence Interval [CI] 94.7% to 99.3%), with 30% of
patients eligible for early discharge.16 For the Abbott hs-troponin I assay a pooled analysis of 3155
patients, pooled sensitivity for MACE was 97.9% (95% CI 95.4% to 99.2%), with 25% of patients
eligible for discharge.15 For the Beckman hs-troponin I assay, sensitivity for the rule-out of AMI has
been shown to be >99%, in an analysis of 1871 patients, with 34% of patients eligible for
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LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 10 of 33
discharge.17 These data demonstrate efficacy (safety) of the LoDED strategy, yet they are all from
observational cohort studies, where no patient was discharged based on their recommendations,
therefore the clinical effectiveness of LoDED across populations remains unknown.
The 2016 update to the NICE “chest pain of recent onset” guidelines also support the use of hs-
troponin with a cut-off at the LoD. However, the strategy recommended by NICE22 requires that
the LoD cut-off be combined with a risk score, such as the Thrombolysis in Myocardial Infarction
(TIMI) score,23 rather than a normal electrocardiogram (ECG) as we propose in the LoDED strategy.
Importantly, we have validated the NICE approach and demonstrate that approximately 15% of
patients will be suitable for early discharge using the NICE approach, in contrast to 30% using the
LoDED strategy.21
The LoDED strategy is a straightforward diagnostic tool. Current observational evidence suggests it
is safe for implementation. However, further evidence is needed to establish whether the LoDED
strategy works under real-life conditions, when compared to usual care. The critical question this
trial will answer is whether the LoDED strategy works when implemented in practice, with
clinicians actually discharging patients early in significant numbers, without rebound increases in
downstream costs and in a way that is acceptable to patients.
6 AIMS AND OBJECTIVES
6.1 Aim
The aim of this study is to establish whether a novel diagnostic strategy for ruling out major
adverse cardiac events (MACE) in Emergency Department patients with suspected cardiac chest
pain increases rates of early discharge, reduces resource use and is acceptable to patients, when
compared to usual care.
6.2 Objectives
1. Conduct a randomised controlled trial of the LoDED strategy versus usual care to compare the
proportion of patients successfully discharged within four hours of arrival, with no MACE during
the following 30 days.
2. Measure admission rates, hospital bed usage, length of stay, resource use and patient
satisfaction, facilitating a health economic evaluation.
3. Determine whether the LoDED strategy is acceptable to patients.
7 TRIAL DESIGN
7.1 Summary of trial design
This is a pragmatic, multi-centre, randomised controlled parallel group trial in adult patients
presenting to the ED with suspected cardiac chest pain and who trigger the chest pain
investigation pathway. Five hundred and ninety four participants will be randomised in a 1:1 ratio
to be managed according to the LoDED strategy (allowing discharge after a single hs-troponin test
at presentation to ED if a participant has no new ischaemic ECG changes and the hs-troponin is
below the LoD) or usual care rule-out strategy in current clinical use at each study site (Figure 1).
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Usual care will usually include two hs-troponin blood tests taken between 1-6 hours after
presentation and may vary between sites.
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Figure 1: Participant flow diagram
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7.2 Blinding and strategies for minimising bias
This is an open study. Participants’ study allocations will only be blinded to those performing
central review of data for the assessment of MACE and the statistician analysing the results. All
patients will be consented and randomised before their initial hs-troponin results are known.
Patients will be ineligible to participate in the trial once the initial hs-troponin result is known to
the treating clinician in order to prevent selection bias. The decision to discharge a patient will be
made after clinical assessment by the treating clinician. In the event of ongoing clinical concern
the clinician may proceed with further testing and/or admission at their discretion, and contrary to
the allocated strategy. Information on protocol adherence will be collected in order to complete a
per-protocol analysis as well as the primary intention to treat analysis.
7.3 Duration of participation
For all participants, individual trial participation will be from the time of written informed consent
until 30 (+5) days after initial ED attendance at which point the presence or absence of MACE
occurring up to that point will be recorded. A subset of 25 participants will be selected through
purposive sampling to undertake a detailed telephone interview for the integrated qualitative
study. This will be completed within 60 days of initial attendance to the ED.
8 TRIAL ENDPOINTS
8.1 Primary Outcome
The primary outcome is successful early discharge, defined as discharge from hospital within four
hours of arrival, without MACE occurring within 30 days of ED attendance.
The safety endpoint of MACE occurring within 30 days, included within the primary outcome, will
be defined as cardiac death, AMI or emergency revascularisation occurring within 30 days of
attendance (including the index presentation). AMI will be defined according to the universal
definition, which states that a rise and/or fall of troponin above the 99th percentile value confirms
the diagnosis.24 A significant rise and/or fall will be defined as an absolute change in troponin over
time of at least half the 99th percentile value of either assay.25
8.2 Secondary Outcomes
1. Length of ED/EDOU stay, measured in hours.
2. Hospital admission and subsequent length of stay
3. Incidence of MACE occurring within 30 days of ED attendance.
4. Comparative costs.
5. Participant satisfaction (quantitative survey).
6. Acceptability to patients (qualitative methodology).
9 PARTICIPANT SELECTION
The screening and recruitment of patients, delivery of intervention and recording of outcomes will
be carried out within participating EDs in the UK. Participants will be recruited from adult patients
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LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 14 of 33
attending these EDs with chest pain who trigger the cardiac chest pain investigation pathway i.e.
the treating clinician intends to perform investigation to rule out a cardiac cause.
9.1 Inclusion criteria
Potential participants must satisfy the following criteria to be enrolled in the study:
• Age ≥18 years
• Presenting to the ED with chest pain and triggering the chest pain investigation pathway
i.e. the treating clinician intends to perform investigation to rule out a cardiac cause
• Peak symptoms occurred <6 hours prior to presentation to the ED
9.2 Exclusion criteria
Potential participants who meet any of the following criteria will be excluded from participation:
• ST-elevation myocardial infarction or ischaemic ECG (new T wave inversion >3mm or ST
depression >1mm) as judged by the treating clinician
• Clear non-ACS cause for chest pain found at presentation (e.g. pulmonary embolism,
pneumonia, aortic dissection)
• Initial hs-troponin result known to the treating clinician
• Hospital admission indicated due to other medical/social reasons
• Chest pain due to arrhythmia (new-onset atrial fibrillation, atrial flutter, sustained
supraventricular tachycardia, second-degree or complete heart block, or sustained or
recurrent ventricular arrhythmias)
• Unable to provide written informed consent (lacks capacity)
• Unwilling to provide written informed consent
• Pain too severe to provide written informed consent
• Follow-up will be impossible i.e. lives abroad or no fixed abode
• Previous inclusion in the study
• Prisoners
• Pregnancy
• Pre-existing renal failure requiring dialysis
10 CLINICAL PROCEDURES
Study participants will have undergone the standard clinical assessment of patients with chest
pain in the ED undertaken at presentation. This includes a triage history assessment, routine
initial observations of pulse, blood pressure, respiratory rate, oxygen saturation and the recording
of a 12 lead electrocardiogram (ECG). Standard clinical practice dictates that routine blood
sampling for the assessment of full blood count, urea and electrolytes and troponin is undertaken
at presentation.
10.1 Baseline ECG
A baseline 12 lead ECG will be recorded in all patients with chest pain as part of standard clinical
care. Patients identified by treating clinicians as having an ECG diagnostic of an ST-Elevation
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myocardial infarction or evidence of new ischaemia (new T-wave inversion >3mm or ST depression
>1mm) will be ineligible.
10.2 Baseline blood sampling
All participants will have a blood sample taken for troponin measurement on, or shortly after
arrival as part of the standard clinical assessment of patients with chest pain. No additional blood
sampling is required for study purposes. All study centres have access to high-sensitivity troponin
assays which already form part of standard care.
Given the pragmatic nature of the trial, “presentation” blood sampling will be defined as the first
blood sample taken after arrival in the ED. Blood sample results will not be delayed for trial
purposes. Some blood test results, in particular hs-troponin, may therefore be available to
treating clinicians prior to assessment and the decision to trigger the chest pain investigation
pathway. Patients will be ineligible to participate in the trial if the initial hs-troponin result is
already known to the treating clinician, in order to prevent selection bias.
Standard laboratory reporting of hs-troponin results and other routine baseline blood tests will be
used for both clinical assessment and for data collection purposes. At all sites this is through an
electronic clinical record. Data from the laboratory system will be anonymously recorded within
the CRF.
10.3 Repeat troponin tests
The default strategy will be existing rule-out strategies used in study centres (the control group).
Therefore, a second hs-troponin test may be taken within these strategies so as not to delay
routine clinical care. However, if allocation is to the LoDED strategy, clinicians will not be required
to obtain the results of the second hs-troponin test and immediate discharge can occur.
10.4 Laboratory analysis
Clinical blood samples will be analysed locally in central hospital laboratories for the Elecsys hs-
troponin T assay (Roche Diagnostics, 99th percentile 14ng/L, co-efficient of variation <10%, LoD
5ng/L), Architect STAT high sensitive troponin I (Abbott Diagnostics, 99th percentile cut-off of
26ng/L, co-efficient of variation 4%, LoD 2ng/L) or Access hs-troponin I (Beckman Coulter, 99th
percentile cut-off of 18ng/L, co-efficient of variation <10%, LoD 2ng/L). Results will be made
available to clinicians using laboratory reporting systems as per routine clinical care.
11 SCREENING, RECRUITMENT AND CONSENT
Potentially eligible patients will be identified at the time of arrival in ED by clinical staff or research
nurses. During triage or initial assessment, the patient will be given the written study participant
information sheet (PIS) by a member of the ED clinical team or research nurse. This might be
before the chest pain investigation pathway has been triggered, so that a number of patients who
have been given the participant information sheet to read may subsequently be ineligible to enter
the study. Due to the time taken for laboratory processing of blood samples (>60 minutes after
presentation) and time waiting to be assessed by a doctor, it is anticipated that eligible
participants will have over one hour to consider the PIS prior to being approached for consent.
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Patients will be screened for inclusion in the study by clinical staff or research nurses, and
fulfilment of initial eligibility criteria will be recorded on a study-specific screening form. The
written consent process will be undertaken by an appropriately trained (ICH Good Clinical
Practice) attending clinician or an appropriate member of the research team depending on
individual circumstances. All members of the clinical and/or research team delegated by the
Principal Investigator to undertake the consent procedure must be listed on the study delegation
log at the relevant site.
Once any questions have been answered satisfactorily, patients who are eligible and willing to
participate in the study will be asked to complete and sign a Consent Form, which will be
countersigned by the staff member receiving consent. A record of the patient’s consent to
participate will be documented in the patient’s Emergency Department records, using a pre-
prepared sticker. A copy of the completed consent form should be provided to the patient, a copy
filed in the investigator site file and a further copy must be filed with a copy of the study PIS in the
participant’s ED records.
12 RANDOMISATION
For all participants, randomisation will occur before initial hs-troponin results are known, to reflect
clinical practice where rule-out strategies are applied to a whole group of patients once it has
been determined by clinicians that rule-out testing is required.
After written consent has been obtained, participants will be randomised to be evaluated using
either the existing rule-out strategy used in study centres (control) or the LoDED strategy
(intervention) in a 1:1 ratio. The Peninsula Clinical Trials Unit (PenCTU), in conjunction with the
study statistician, will provide web-based randomisation, stratified by centre and minimised by
age and gender. Appropriate staff at all sites, as delegated by the PI, will be provided with log-in
details for the study website.
To randomise a participant, the recruiting doctor, ED nurse or research nurse will access the
secure website and enter brief participant details (initials, date of birth, gender, study site). Once
the randomisation process is complete, the computer screen will indicate to treating clinicians
which diagnostic strategy to follow, including details of the local rule-out strategy for control
participants as a reminder for site staff. A print-out of the allocation generated by the
randomisation website will be taken and filed in the participant’s ED records.
13 TRIAL STRATEGIES
Participants fulfilling the inclusion/exclusion criteria will be randomised to be managed according
to the existing local rule-out strategy (control) or the LoDED strategy (intervention).
13.1 Usual rule-out strategies (control)
Usual care varies between study sites but includes ECG on arrival and usually two hs-troponin
tests. All sites take the first sample at presentation, but the minimum time delay between the two
samples varies. The existing rule-out strategy in use at each study site will be documented at study
commencement and filed in the relevant investigator site file. The PI at each site is responsible for
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reporting any changes in clinical practice during the study to the Chief Investigator so that changes
in clinical practice can be documented and the randomisation website kept updated.
13.2 LoDED strategy (intervention)
Participants randomised to the LoDED strategy arm will be eligible for discharge after a single hs-
troponin test at presentation to ED if the hs-troponin is below the Limit of Detection for the assay
in use at the study centre.
Any participant not fulfilling this discharge criterion will revert to the existing rule-out strategy in
use at that study site and have a second hs-troponin test after 1-6 hours as per usual care.
The decision to discharge a patient will be made after clinical assessment by the treating clinician.
In the event of ongoing clinical concern the clinician may proceed with further testing and/or
admission at their discretion, and contrary to the allocated strategy. Information on adherence to
the protocol will be collected in order to complete a per-protocol analysis as well as the primary
intention to treat analysis.
14 POST INVESTIGATION PROCEDURES
14.1 Clinical management
Once hs-troponin results are available (for either control or intervention pathways) the discharge
decision will be entirely at the discretion of the treating clinician. Onward referral for outpatient
investigation, such as chest pain clinics, will follow local guidance and will not be altered for trial
purposes.
14.2 Participant advice
All participants discharged according to the LoDED strategy will be given a study-specific leaflet
containing written information about the tests they have had done during their stay and what to
do should their chest pain returns, or if they have any concerns. Feedback will be sought during
the study on the content of this information sheet and its wording refined for patient use if the
LoDED strategy is adopted clinically (Section 18: Integrated Qualitative Study).
14.3 Patient satisfaction survey and EQ-5D
All participants, irrespective of group allocation, with the exception of those admitted to an
inpatient ward bed for further clinical management, will be asked to complete a bespoke written
patient satisfaction questionnaire17 upon discharge from the ED (or ED observation ward) to
compare satisfaction of their treatment during their ED attendance, between the two study
groups. Completed questionnaires will be returned to the CTU by the research nurse or another
member of the team.
Participants with an initial hs-troponin below the LoD (irrespective of group allocation) will also be
asked to complete a baseline EQ-5D health status questionnaire upon ED/EDOU discharge
(Section 24: Economic Evaluation).
15 FOLLOW-UP PROCESSES (Table 1)
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15.1 Participants with an hs-troponin at presentation below the LoD
All participants with an initial hs-troponin below the LoD (irrespective of group allocation) will be
followed-up by telephone by the research nurse, or by e-mail, at 30 (+5) days after index
presentation to capture information about any adverse events and any primary care or secondary
care health service use since discharge from the ED. At the request of the participant, follow up
questionnaires can be sent to them by the CTU.
If the participant indicates that s/he has attended any health service provider in any capacity since
discharge from the ED, but there is concern over patient recall of events, then research nurses will
review hospital records (where available) to verify outcomes.
To explore the acceptability of the LoDED strategy to participants and inform patient discharge
information resources, a qualitative research assistant will undertake semi-structured interviews
with a sample of trial participants within 90 days of index admission (Section 18: Integrated
Qualitative Study).
15.2 Remaining participants
Participants with an initial hs-troponin above the LoD will be sent a screening text message after
30 (+5) days by the study team. This text will ask: “Since you came to the Emergency Department
with chest pain have you needed to see your GP or re-attend an Emergency Department or visit an
outpatient clinic for assessment of chest pain?” Patients answering “No” will require no further
follow-up. Participants who fail to respond, or answer “Yes”, will be followed-up by telephone by
the research nurse or routine data will be collected from local hospital electronic patient records
on initial diagnosis, local re-attendance and outpatient follow-up.
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Table 1 : Summary of information provision, survey and follow-up processes
Randomisation LoDED Strategy
Usual Care
Participant Group Undetectable hs-
troponin*
hs-troponin
above LoD**
Undetectable hs-
troponin
Remaining
participants
Study specific “early discharge”
information sheet ●
Satisfaction survey completed
upon discharge ● ● ● ●
Baseline EQ-5D
(on discharge) ● ●
If admitted as in-patient,
discharge summary and
diagnosis recorded
● ● ● ●
30-Day follow-up
(telephone/by e-mail): EQ-
5D,patient reported resource
use and AE review
● ●
30-Day follow-up text message
for MACE screening and phone
call or notes review if “yes” to
text
● ●
Qualitative telephone
interview (n=25) ● ●
Non-serious AEs recorded (if possibly, probably or definitely
related to the study)
● ●
SAEs ● ● ● ●
* In the event of ongoing clinical concern the clinician may proceed with further testing and/or admission at their
discretion, and contrary to the allocated strategy
**Participants with an hs-troponin above LoD at presentation, allocated to the LoDED strategy, will revert to usual
care and have a second hs-troponin test after 1-6 hours.
16 DATA TO BE COLLECTED
Demographic and clinical data will be recorded after randomisation by the treating clinician or
member of the study team, using a paper Case Report Form (CRF). Routine creatinine and eGFR
levels from initial presentation will be recorded. Simple clinical data to calculate the Thrombolysis
in Myocardial Infarction (TIMI) score23, History, ECG, Age, Risk Factors and Troponin (HEART)
score19 and Manchester Acute Coronary Syndromes (MACS) rule26 will be collected by research
staff to assess for the added value of incorporating a risk score into the LoDED strategy for
secondary analysis. Data on time to troponin sampling, time to availability of troponin results and
time to discharge from the ED/EDOU will be recorded after interrogation of laboratory and ED
electronic systems. Clinicians will be asked to record any reasons for not discharging a patient
according to the LoDED strategy if allocated to this arm.
Discharge from the ED within four hours of attendance will be measured using electronic patient
tracking systems in use at all study sites, according to the time the patient left the ED (including ED
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observation units). In the event that a participant is transferred from the ED, to an observation
unit or inpatient bed within four hours of attendance and subsequently discharged, length of stay
(minutes/hours) will be calculated from electronic patient records and tracking systems.
The length of any subsequent inpatient stay (in days) and the final destination of the patient
following discharge will also be recorded.
Resource use data to be collected from all participants with an initial hs-troponin below the LoD,
at 30 (+5) days by telephone/by e-mail and electronic patient records (to include GP records
where available) will include: use of health services in the last 30 days, length of any subsequent
hospital stays (since initial visit to ED); hospital tests carried out during any subsequent hospital
admissions, and time off work in the last 30 days.
Participants with an initial hs-troponin below the LoD (irrespective of group allocation) will also be
asked to complete a second EQ-5D health status questionnaire during their 30 day follow up
(Section 24: Economic Evaluation).
Participants with an initial hs-troponin above the LoD who failed to respond to their text message,
or answered “Yes” to the question “Since you came to the Emergency Department with chest pain
have you needed to see your GP or re-attend an Emergency Department or visit an outpatient
clinic for assessment of chest pain?” will have their electronic patient records reviewed for the
presence of MACE.
17 OUTCOME ADJUDICATION
Incidence of MACE occurring within 30 days of ED attendance will be recorded on the SAE form, by
the local ED Principal Investigator or designee with reference to relevant clinical information and
responses to 30 day follow-up telephone assessments uploaded to the study database. All
participant data will be reviewed by an independent adjudication committee at the end of the
study to confirm the primary outcome.
18 INTEGRATED QUALITATIVE STUDY
The qualitative component of this study aims to explore experiences of the patient’s stay in the
ED, any concerns or anxieties they might have and how best to word patient discharge
information. To explore the acceptability of the LoDED strategy to participants and inform patient
discharge information resources, a qualitative research assistant will undertake semi-structured
interviews with a sample of trial participants. At their 30 day follow-up contact, all participants
with hs-troponin levels below the LoD will be invited to be interviewed. All participants will be
informed about this additional study in the main Participant Information Sheet and agree to be
contacted about the study when they consent to the main study. The research nurse will record on
the study database whether or not the participant is happy to be contacted by the qualitative
researcher. From those participants who consent to being interviewed, a purposive sample will be
selected across all sites to maximise variation in terms of age, sociodemographic status and sex.
Up to 25 participant interviews (lasting approximately 30 minutes) will be conducted by phone
using a topic guide to explore experiences of the participant’s stay in ED, any concerns or anxieties
they might have and how best to word the written patient discharge information. Consent to take
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part in this study will be collected before the interview is carried out. Topic guides will be
developed from the literature, input from the patient advisory group and team discussions.
Two GP and practice nurse focus groups will be held towards the end of the recruitment period to
explore their views about the information that they would like to be provided to patients who are
discharged early. Findings from the participant interviews will contribute to these focus group
discussions.
18.1 Qualitative analysis
Interviews and focus groups will be recorded, transcribed, anonymised and analysed using
thematic methods facilitated by NVivo software. Analysis will be ongoing and iterative. Transcripts
will be coded and global themes developed from the codes. Two researchers will code a sample of
transcripts independently, compare coding, discuss and resolve any discrepancies within the
research team to achieve a coding consensus and ensure robust analysis.
Findings from the interviews and focus groups will inform the development of the leaflet that will
be given to participants discharged early according to the LoDED strategy to take home with them.
The format and content will be reviewed by the PAG and their changes incorporated.
19 SAFETY
Participant safety will be monitored by the trial management group and Trial Steering Committee.
Adverse events (AEs) may be non-serious or serious (see definitions below). Adverse events to be
recorded in this study are:-
• All non-serious AEs considered to be related to the study (in the participants with hs-troponin
levels below the LoD only)
• All Serious Adverse Events (in all participants)
AEs/SAEs occurring from the time of consent until the 30 day follow-up time point should be
recorded in the CRF.
19.1 Definitions
An adverse event (AE) is defined as any unfavourable and unintended sign or symptom that
develops or worsens during trial participation, whether or not it is considered to be related to the
study.
An adverse event is classified as a Serious Adverse Event (SAE) if it:
• Results in death
• Is life threatening
• Requires hospitalisation or prolongation of existing hospitalisation
• Results in persistent or significant disability or incapacity
• Or is considered by the investigator to be an important medical event
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A non-serious adverse event (AE) is an adverse event which does not satisfy the above definition
of an SAE. Only those non-serious AEs in participants with hs-troponin levels below the LoD
considered by the PI, or authorised delegate, to be possibly, probably or definitely related to the
study will be reported.
The CTU will prepare regular summary reports of reported (S)AEs for discussion at TMG meetings.
Reports and minutes of TMG meetings will be copied to the Sponsor.
19.2 Reporting non-serious adverse events (AE)
AEs may be volunteered by the participant or detected by a member of the research team through
questioning or observation, during either the index ED attendance or the follow-up telephone call.
AEs will be recorded by the research nurse or other member of the research team on the CRF and
in the participants’ clinical notes. These may include unplanned re-attendance to the Emergency
Department.
19.3 Reporting serious adverse events
Any SAE occurring in any participant after discharge from the hospital, must be reported by
emailing or faxing an initial SAE form to the CTU within 24 hours of the research team becoming
aware of the event. If the SAE is considered a MACE, this should be indicated on the SAE form,
and will be adjudicated at the end of the study, as detailed in Section 17. The CTU will notify the
Chief Investigator and Sponsor by email of all reported SAEs. If the PI considers that the SAE is not,
or is unlikely to be, related to the trial, the CTU will obtain a second assessment of causality from
the CI (or other delegated clinician). If a patient is hospitalised during the index visit due to clinical
concern, even if the patient is eligible for discharge using the LoDED strategy, this need not be
recorded as an SAE since the information will be captured elsewhere for study purposes.
Following the initial report, the SAE form must be fully completed within seven days of the event,
signed by the PI and returned to the CTU. Completion of the SAE form must include the PI’s (or
authorised clinician’s) assessment of causality i.e. whether there is a reasonable causal
relationship between the SAE and the study. Following the initial report to the CI of any study
related SAEs, the CI will notify the Chair of the Trial Steering Committee (TSC) within 48 hours of
the event. The Chair will arrange an ad hoc meeting of the TSC to discuss the SAE, and agree any
actions as needed. (See section 26.2 for details of the TSC).
All SAEs will be followed until resolution. The CTU will provide a summary of all SAEs to the Trial
Steering Committee (TSC) and Sponsor on a three-monthly basis. Investigators should also comply
with any internal SAE reporting requirements within their host institution.
There are no expected adverse events related to the study. The Research Ethics Committee (REC)
will be informed within 48 hours if any related and unexpected SAE occurs.
20 STUDY COMPLETION
Individual participants will complete the study after the 30 day follow-up has been completed.
The study itself will end on the date the last participant has completed the 30 day follow-up.
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20.1 Premature termination of the study
In the event that the Trial Steering Committee or Sponsor recommends early termination of the
study for any reason, the CTU will notify the REC. The Chief Investigator will be responsible for
informing participating sites of the premature termination of the study.
21 PARTICIPANT WITHDRAWAL
Participants may withdraw from the study at any time and do not have to provide a reason for
doing so. Standard care will not be affected by a participant’s decision to withdraw from the trial.
Participants who withdraw from the study at any stage following randomisation will not be
replaced within the study.
21.1 Withdrawal from intervention
Participants may withdraw from the intervention at any time (e.g. following consent, but before
discharge) if they wish, without having to give a reason. If known, the reason for withdrawal should
be clearly documented using a study-specific form in accordance with a written procedure and in
the participant’s ED records. All randomised participants will be encouraged to complete study
follow-up (30-day follow-up) regardless of study arm or compliance with allocated strategy.
21.2 Withdrawal from follow-up
Participants may withdraw from follow-up at any time without it affecting their care. Participants
should be asked to explain their reason for withdrawing, but are under no obligation to do so.
Withdrawal from trial follow-up, and the reason, if known, should be reported to the CTU using a
study-specific form in accordance with a written procedure. If possible, the withdrawal should also
be clearly documented in the participant’s clinical records.
Data collected prior to withdrawal will be included in the study analysis unless a participant
specifically requests that their data are removed from the database. The research team should
inform the CTU if a participant has requested that their data be destroyed. If the participant does
not make a specific request for their data to be destroyed, their data will be stored and included in
the study analysis
Should a participant lose capacity to consent during the study period after completion of the
consent form, the participant’s data will be used for trial purposes, however 30-day follow-up
questionnaires will not be completed. If the loss of capacity is due to the presence of a Major
Adverse Cardiac Event (such as cardiac arrest) this information will be recorded as an SAE and will
be integral to reporting of the safety of the LoDED strategy.
22 DATA MANAGEMENT
22.1 Subject numbering
Each participant will be allocated a unique study number upon randomisation, from the study
website. Participants will be identified in all study-related documentation by their study number
and initials. All data collected and analysed during the study will be pseudo-anonymised by the use
of this unique identifier. A record of trial participants’ names and contact details, hospital numbers
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and assigned trial numbers will be maintained by the research nurse at each site and stored
securely for administrative purposes.
22.2 Data collection personnel
Study data will be collected by GCP-trained ED staff or research practitioners at each site. All persons
authorised to collect and record study data will be listed on the relevant study site delegation logs,
signed by the site PI.
22.3 Source data and source documents
Source documents will include hospital ED and in-patient records, where relevant. All data not
routinely captured during the ED attendance or any subsequent hospital admission but recorded
straight into the CRF will also be classified as source data.
22.4 Data collection forms
Study data collected by the research team at each site will be recorded on study specific data
collection forms provided by the CTU.
Data for the purpose of confirming patient eligibility will be captured on a screening form; data
collected during the patient’s attendance at the ED, and at follow-up, will be collected in the Case
Report Form (CRF).
The data to be collected during the patient’s ED visit itself have been kept to a minimum. Further
demographic and ED visit data will be recorded retrospectively into the CRF from ED records at the
convenience of study site staff, as soon as possible following the ED attendance. The final CRF data
capture relates to the 30 day telephone follow-up visit.
The original completed CRF will be checked, signed and dated by a member of the study site team
before being sent by post to the CTU, in accordance with written instructions within the CRF. Pre-
addressed, Freepost (prepaid) envelopes will be supplied for this purpose. A copy of each CRF page
will be kept at the study site.
22.5 Clinical record-keeping
As a minimum, a record should be made in the participant’s ED record or hospital notes of:
• the participant’s consent and eligibility for study (a pre-written adhesive label is supplied for this
purpose)
• randomisation (printout of allocation filed in notes)
• any adverse event experienced during the ED attendance or any subsequent hospital admission
(as described in Section 19)
22.6 Follow-up data collection
Follow-up information collected during at 30 (+5) days (see section 15) should be recorded directly
on to the relevant CRF page before being transferred to CTU, with a copy held at site.
22.7 Data handling and record keeping
The CTU data management team is responsible for data management, including data entry. Original
CRF pages will be posted to the CTU at agreed time points for double-data entry on to a SQL Server
database using a bespoke, password-protected, website, designed and maintained by the CTU data
programming team. All data collection forms will be tracked by CTU using a web-based trial
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management system. Completed CRFs will be checked on receipt at CTU and any obvious errors or
omissions rectified as far as possible by means of a formalised data query/clarification procedure.
Double-entered data will be compared for discrepancies using a stored procedure and discrepant
data will be verified using the original paper data forms. Before database lock, a proportion of
original paper records will be checked against the database to ensure accuracy of the final dataset.
22.8 Data security, data protection and patient confidentiality
The CTU data manager is the data custodian for the duration of the study.
Research teams at all study sites will ensure that participant confidentiality is maintained at all
times. All investigators and study site staff must comply with the requirements of the Data
Protection Act (1998)/General Data Protection Regulation 2018 with regards to the collection,
storage, processing and disclosure of personal information and will uphold the Act’s core principles.
Each study site will keep an enrolment log of all participating patients (with sufficient information
to identify participants and link records for regulatory audit/inspection purposes) as well as all
original signed informed consent forms. Any document linking participant study numbers with
identifiable data will be stored securely at each site by the local research team and separate from
the study data. Pseudonymised copies of signed consent forms, for randomised participants only,
will be sent to the CTU for monitoring purposes.
With the participant’s consent, the participant’s name, e-mail address and contact telephone
number will be recorded by the relevant local research team in order to carry out the 30 day follow-
up. This information will be stored securely at site and be accessible only to the site staff for the
purpose of conducting the follow-up. Once the study is completed, these contact details should be
destroyed.
Within the CTU, pseudo-anonymised paper-based study data will be stored in locked filing cabinets
within a locked office. Electronic records will be stored in a SQL Server database on a restricted
access, secure server maintained by Plymouth University. Data in the SQL Server database will be
backed up as part of Plymouth University’s standard back-up process. The website will be encrypted
using SSL. Direct access to the study data will be restricted to members of the research team and
the CTU, with access granted to the Sponsor on request. Access to the database will be overseen
by the CTU data manager and trial manager. Copies of study data retained at study sites will be
securely stored for the duration of the study prior to archiving.
Any data transfer (e.g. from CTU to the study statistician for analysis purposes) will be done using a
format and method suitable to the requirements of the data being transferred. As a minimum, data
will be secured in a password protected encrypted file and will be anonymised according to the
requirements of the data transfer. All data will be transferred in accordance with the Data
Protection Act and PenCTU standard operating procedures (SOPs).
In the event that any copies of clinical source data need to be forwarded from site to the CTU (e.g.
as part of SAE reporting or follow-up), site staff will be responsible for ensuring that personal
identifiers are removed or obscured and the documents are marked with the participant’s study
number before leaving the site.
22.9 Access to data
Direct access to study site documentation and participants’ clinical notes will be granted to
authorised representatives from the Sponsor, the CTU and the regulatory authorities to permit
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trial-related monitoring, audits and inspections. Permission to access participants’ clinical records
will be explicitly requested in the Informed Consent Form for the study.
22.10 Archiving
Following completion of trial data analysis, the Sponsor will be responsible for archiving the study
data and essential documentation in a secure location for at least five years after the end of the
trial, in accordance with the Sponsor’s SOP. No trial-related records should be destroyed unless or
until the Sponsor gives authorisation to do so. Medical case notes containing source data or other
trial-related information should be identified by a label “Keep until dd/mm/yyyy” where the date
given is five years after the last participant’s final visit.
23 STATISTICAL CONSIDERATIONS
23.1 Sample size
Current observational research gives estimates of the proportion of patients with an hs-troponin
<5ng/L in the intervention group of the RCT (LoDED) between 10% and 60%.11-17 United Kingdom
observational data suggest that these patients will be discharged within a median time of 3.5hrs
(taking into account laboratory processing and 60 minutes of decision making time).10 Data
provided to us from a recent pragmatic RCT9 evaluating a 0/2hour hs-troponin rule-out strategy
has demonstrated that only 10% of patients will be discharged within four hours using this
approach. Clinical protocols using rule-out strategies at later time points (e.g. three hours) will be
expected to have even fewer patients discharged within the four hour time frame; similarly the
0/1hour strategy may expect to see a marginal increase in discharges before four hours. These
differences have been taken into account within the power calculation. For the overall population
we anticipate 8% will be discharged within 4 hours using usual care and at least 17% using the
LoDED strategy. Therefore, this study will be powered to detect a 9% difference between the early
discharge rates with 90% power and 5% statistical significance. This will require 282 patients in
each arm and 564 patients in total with primary outcome data. Assuming a 95% follow-up rate,
594 patients need to be recruited.
23.2 Statistical analysis
A statistical analysis plan, detailing the exact analysis to be conducted and reported, will be
developed prior to any comparative analysis. All analysis will be conducted blind to group
allocation by using codes for group allocation which do not indicate which specific group they
refer to. A CONSORT diagram will be used to report numbers of patients screened, recruited and
randomised. It will also detail numbers allocated to each arm and rates of the primary outcome.
The primary outcome of discharge within four hours will be analysed by logistic regression using all
those randomised in an intention to diagnose analysis. The analysis will be stratified by centre to
allow for differences between the proportion discharged within four hours in the control arm at
each of the study sites. Heterogeneity of the odds of early discharge at each centre will be
investigated and only pooled if appropriate. The odds ratio of early discharge controlling for age,
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sex and centre will be presented with a 95% confidence interval for each centre individually and
combined across centres. In the event of significant heterogeneity in the control group but
homogeneity within the intervention group the results will be presented as the rate of early
discharge in the intervention group together with 95% confidence intervals. Adherence with the
allocated rule-out strategy will be presented as percentage with 95% confidence intervals.
The analysis of the quantitative secondary outcomes will also control for age, sex and centre; with
a multiple regression analysis and difference in means reported for the comparison of length of
hospital stay between groups and for the total score from the patient satisfaction survey obtained
from summing the individual items. The responses for the individual items of the patient
satisfaction survey will also be reported by group but an adjusted analysis will not be carried out.
The incidence of MACE occurring within 30 days of ED attendance in those discharged according to
the LoDED strategy vs usual care will also be reported with 95% confidence intervals. As the event
rate is expected to be low, it is unlikely to be possible to carry out an adjusted analysis.
There are no pre-planned interim analyses.
24 ECONOMIC EVALUATION
24.1 Health economic data collection
Local secondary and primary care resource use, between index hospital admission and the
following 30 days, will be collected by phone call, by e-mail or review of electronic patient records
and tracking systems for all participants with an initial hs-troponin below the LoD (irrespective of
group allocation) by the research nurse between 30 and 60 days after index presentation.
24.2 Health economic analysis
The primary economic analysis will include all randomised participants (intention to diagnose
analysis) and compare secondary care costs. Secondary care resource use will be valued using
national sources of unit costs. A subgroup analysis will provide extra detail on the primary and
community care costs (in addition to the secondary care costs) and consequences (quality-
adjusted life-years (QALYs)) for any participant with an hs-troponin below the LoD. This applies to
both trial arms. Data collection for the additional primary and community care costs will be based
on participant self-report following administration of a structured resource use questionnaire at
30 days and standard methods of unit costing. QALYs will be derived from the EQ-5D (5 level
version) using the set of preference weights as advised by NICE at the time of analysis.
25 DATA MONITORING AND QUALITY ASSURANCE
The research nurse or other member of the research team will check completed CRFs for missing
data or obvious errors before they are posted to the CTU. Data will be monitored centrally for
quality and completeness by the CTU and every effort will be made to recover data from
incomplete CRFs where possible. The CTU data manager will oversee data tracking and data entry
and initiate processed to resolve data queries where necessary. The CTU trial manager will devise
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a monitoring plan specific to the study which will include both central monitoring strategies and
study site visits as appropriate.
All trial procedures will be conducted in compliance with the protocol and according to the
principles of Good Clinical Practice. Procedures specifically conducted by the CTU team (e.g.
randomisation, data management, trial management and study monitoring) will be conducted in
compliance with CTU SOPs. The Principal Investigators and the participating NHS Trusts will be
required to permit the CTU trial manager or deputy to undertake trial-related monitoring to
ensure compliance with the approved trial protocol and applicable SOPs, providing direct access to
source data and documents as requested.
26 TRIAL OVERSIGHT
The CI will be responsible for the overall running of the trial. The CTU will coordinate day-to-day
trial-related activities and provide overall trial management and monitoring. The CTU will also
provide randomisation, build the study database, provide data management services and oversee
safety reporting activities.
26.1 Trial Management Group (TMG)
The project will be led by the trial management group (TMG) which will include the CI, the CTU
trial manager, trial statistician and other relevant personnel (e.g. clinical colleagues, CTU data
manager, Sponsor representative, as required). The TMG will meet regularly (usually monthly)
throughout the duration of the trial to ensure development of study documentation and
approvals, monitor progress (including participant recruitment), resolve day-to-day problems as
they arise, review the budget, discuss analysis, results, draft reports and dissemination.
26.2 Trial Steering Committee (TSC)
The TSC will oversee the conduct and safety of the trial, ensuring that milestones are achieved and
general scientific probity is maintained. The TSC will monitor progress of the trial, adherence to
the protocol and consider new information of relevance to the research question. In the absence
of an independent Data Monitoring Committee, the TSC will also oversee the safety and ethics of
the trial, reviewing recruitment, primary outcome data completeness and adverse events data.
The TSC will include an independent chair (ED clinician), independent cardiologist, an independent
lay representative, an independent statistician, a senior member of the research team and the CI.
26.3 Competing interests for the CI and members of oversight committees
The Chief Investigator and TSC committee members will sign a declaration form to disclose any
financial or other competing interests including, but not limited to:
• any ownership interests that may be related to products, services, or interventions
considered for use in the trial or that may be significantly affected by the trial
• commercial ties including, but not restricted to, any pharmaceutical, behaviour
modification, and/or technology company
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LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 29 of 33
• any non-commercial potential conflicts e.g. professional collaborations that may impact
on academic promotion.
These declaration forms will be filed as part of the Trial Master File.
26.4 Patient and Public Involvement (PPI)
The study has a Patient Advisory Group (PAG) comprising four members who will meet on four
occasions to advise the management team. The PAG will be actively involved in the design and
development of trial-specific patient information resources, follow-up questionnaires, topic guides
for interviews and methods for enhancing recruitment and follow-up rates. They will also
contribute to the development of patient discharge information for clinical implementation.
PAG members will be offered a study specific induction pack which will include the INVOLVE Public
Information Pack and relevant study information. Training workshops will also be provided by
People and Research West of England. PAG members will have their travel expenses and meeting
time reimbursed either with vouchers or a meeting payment based on INVOLVE guidance. The
PAG will be consulted at the point of analysis and interpretation of the data from this study, with
findings presented in lay terms at a PAG meeting. The group will be invited to interpret the
significance of the findings, their perception of the efficiency of the LoDED strategy and the clinical
significance of any risks of misdiagnosis, and will advise on routes and formats for dissemination to
patient groups.
27 ETHICS AND REGULATORY APPROVALS
27.1 Study Sponsor
The study Sponsor is North Bristol NHS Trust. Selected sponsorship responsibilities will be formally
delegated to the Peninsula Clinical Trials Unit (PenCTU) under the terms of an appropriate
agreement.
27.2 Research Governance
The study will be undertaken at several UK sites, subject to appropriate Research Ethics
Committee (REC) approval and Health Research Authority approval. The trial will be conducted in
accordance with the protocol, the principles of the Declaration of Helsinki and ICH GCP. Any
amendments of the protocol will be submitted to the REC for approval. On request, the study
investigators and their institutions will permit trial-related monitoring and audits by the Sponsor
and relevant Research Ethics Committee by providing direct access to source data and other
documents (i.e. patients’ hospital notes, laboratory test reports, X-ray reports etc where relevant).
28 STATEMENT OF INDEMNITY
This is an NHS-sponsored research trial. If an individual suffers negligent harm as a result of
participating in the trial, NHS indemnity covers NHS staff and those people responsible for
conducting the trial who have honorary contracts with the relevant NHS Trust. In the case of non-
negligent harm, the NHS is unable to agree in advance to pay compensation, but an ex-gratia
payment may be considered in the event of a claim.
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29 DISSEMINATION POLICY
The Chief Investigator and Trial Management Group will establish a writing committee which will
be responsible for preparing scientific reports of the study findings. The aim will be to publish a
primary manuscript in a high impact general medical journal, published as open access, with
secondary analyses described in specialty journals. Primary findings will also be presented at key
meetings e.g. the Annual Conference of the Royal College of Emergency Medicine, the European
Society of Cardiology Annual Congress, the European Society of Emergency Medicine Congress and
the International Conference on Emergency Medicine.
30 FINANCE
The trial is funded by a grant from the National Institute for Health Research (NIHR) Research for
Patient Benefit (RfPB) programme. Study finances will be managed by North Bristol NHS Trust.
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