Vaginal Preparation at Caesarean Section to Reduce ... · Title: Vaginal Preparation at Caesarean...

PREPS PROTOCOL _____________________________________________________________________________

PROTOCOL Version 2.0 11.01.2018 of 49

Vaginal Preparation at Caesarean

Section to Reduce Endometritis and

Prevent Sepsis – A Feasibility Study of

Chlorhexidine

Protocol Version 2.0 11th January 2018

TRIAL PROTOCOL

PREPS PROTOCOL _____________________________________________________________________________


Chief Investigator: Dr R Katie Morris

Version Number: 2.0

Version Date: 11th January 2018

Protocol Amendments

The following amendments and/or administrative changes have been made to this protocol since the

implementation of the first approved version.

Amendment

number

Date of

amendment

Protocol

version

number

Type of

amendment Summary of amendment

1.0 11th January

2018 V2.0 Substantial

To clarify trial procedures.

To clarify the feasibility

outcomes.

Funder

Funding Organisation National Institute of Health Research

Funding Scheme (if applicable) Research for Patient Benefit (RfPB)

Funder’s reference number PB-PG-1215-20013

Statement regarding the role of the funder.

Department of Health disclaimer

The views expressed are those of the author(s) and not necessarily those of the NHS, the

NIHR or the Department of Health.

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Chief Investigator Signature Page

This protocol has been approved by:

Trial Name: PREPS

Protocol Version Number: Version: 2.0

Protocol Version Date: 11/01/2018

CI Name: Dr R Katie Morris

Trial Role: Chief Investigator

Signature and date:

_________________________ __ __ / __ __ / __ __ __ __

Sponsor statement:

Birmingham Women’s and Children’s NHS Foundation Trust by acting as sponsor of this trial confirm

approval of this protocol.

Signature and date:

PREPS PROTOCOL _____________________________________________________________________________


PI Signature Page

The undersigned confirm that the following protocol has been agreed and accepted and that the

Principal Investigator agrees to conduct the trial in compliance with the approved protocol.

I agree to ensure that the confidential information contained in this document will not be used for any

other purpose other than the evaluation or conduct of the clinical investigation without the prior written

consent of the Sponsor.

This protocol has been approved by:

Trial Name:

Protocol Version Number: Version: __ __

Protocol Version Date: __ __ / __ __ / __ __ __ __

PI Name:

Name of Site:

Signature and date:

_________________________ __ __ / __ __ / __ __ __ __

Sponsor

Birmingham Women’s and Children’s NHS

Foundation Trust

J8 Norton Court, Mindelson Way, Birmingham,

B15 2TG

Contact Details: Kelly Hard

Email: [email protected]

mailto:[email protected]

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Administrative Information

Reference Numbers

EudraCT number Not applicable

Sponsor number 17/BW/MAT/PO02

ISRCTN reference number ISRCTN33435996

http://www.isrctn.com/ISRCTN33435996

IRAS reference number 17/LO/0874

Chief Investigator

Dr R Katie Morris Senior Clinical Lecturer and Consultant in

Maternal and Fetal Medicine

Academic Floor, 3rd Floor

Birmingham Women’s and Children’s NHS

Foundation Trust

Edgbaston

Birmingham

B15 2TG

Telephone Number

[email protected]

Trial Oversight Committee

Dr Jennifer Myers (Chair) - University of Manchester

Mr Stephen Keay – Consultant at University Hospitals Coventry & Warwickshire

Elaine Stamp (Statistician) – University of Newcastle

Trial Management Group – TMG

Dr R Katie Morris – Chief Investigator

Amie Wilson

Pollyanna Hardy

Catherine Hewitt

Victoria Hodgetts Morton

Annalise Weckesser

Kelly Hard

David Lissauer

Max Feltham

Principle Investigators

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Birmingham Heartlands Hospital – Dr Sharon Morad

Shrewsbury and Telford – Dr Sheena Hodgett

Birmingham Women’s Hospital – Dr Nina Johns, Dr Victoria

Hodgetts Morton

Royal Sunderland Royal Hospital – Mr Kim Hinshaw

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Trial Office Contact Details

Amie Wilson

Trial Co-ordinator

Birmingham Clinical Trials Unit

Public Health Building

University of Birmingham

Birmingham

B15 2TT

[email protected]

Amie Wilson 0121 415 9110 /[email protected]

Dr R Katie Morris - Chief Investigator

Dr Victoria Hodgetts Morton – Clinical Fellow

Pollyanna Hardy – Lead Statistician

Catherine Hewitt – Trial Statistician

Annalise Weckesser – Qualitative Research

Kelly Hard - Sponsor

David Lissauer

Max Feltham – Women’s Health Team Lead

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

Randomisation website/ telephone number 0800 2802 307

Trial website www.birmingham.ac.uk/prepstrial

Trial social media Twitter @PrepsTrialCS

Facebook @PrepsTrialCS





https://mail.bham.ac.uk/owa/redir.aspx?C=L00ARgyPOwdG7RtsbIxBYMYSP2KWwNatl2akE2UxreFpt1iHjZDUCA..&URL=mailto%3ac.a.hewitt%40bham.ac.uk





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ABBREVIATIONS

AE Adverse Event

AR Adverse Reaction

BCTU Birmingham Clinical Trials Unit

BWCNFT Birmingham Women’s & Children’s NHS Foundation Trust

CI Chief Investigator

CRF Case Report Form

CS Caesarean Section

DMC Data Monitoring Committee

DSUR Developmental Safety Update Report

GCP Good Clinical Practice

IB Investigator Brochure

ICF Informed Consent Form

IMP Investigational Medicinal Product

IoL Induction of Labour

ISF Investigator Site File

MHRA Medicines and Healthcare Products Regulatory Agency

MLC Midwife Led Care

NHS National Health Service

NICE National Institute for Health and Care Excellence

PIS Participant Information Sheet

R&D Research and Development

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REC Research Ethics Committee

RR Relative Risk

RSI Reference Safety Information

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SmPC Summary of Product Characteristics

SUSAR Suspected Unexpected Serious Adverse Reaction

TMF Trial Master File

TMG Trial Management Group

TOC Trial Oversight Committee

TSC Trial Steering Committee

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Term Acronym Description

Adverse Event

AE Any untoward medical occurrence in a participant or clinical trial

subject participating in the trial which does not necessarily have a

causal relationship with the intervention received. See section 8.

Related Event

An event which resulted from the administration of any of the

research procedures.

Serious Adverse

Event

SAE An untoward occurrence that:

Results in death

Is life-threatening*

Requires hospitalisation or prolongation of existing

hospitalisation

Results in persistent or significant disability or incapacity

Consists of a congenital anomaly/ birth defect

Or is otherwise considered medically significant by the

Investigator**

See section 8.3

Unexpected and

Related Event

An event which meets the definition of both an Unexpected Event

and a Related Event

Unexpected

Event

The type of event that is not listed in the protocol as an expected

occurrence.

Source data All information in original records and certified copies of original

records of clinical findings, observations, or other activities in a

clinical trial necessary for the reconstruction and evaluation of the

trial

Birmingham

Clinical Trials

Unit

BCTU The co-ordinating centre for the trial.

Elective

caesarean

section

This term relates to the timing of the caesarean section. All

category 4 (at a time to suit the woman and maternity services)

caesarean sections will be considered an elective caesarean

section. This term will be used when describing recruitment and

consent procedures.

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Emergency

caesarean

section

This term relates to the timing of the caesarean section.

All category 1 (immediate threat to life of woman or fetus), 2 (no

immediate threat to life of woman or fetus) or 3 (requires early

delivery) caesarean sections will be considered an emergency

caesarean section. This term will be used when describing

recruitment and consent procedures.

In labour

caesarean

section

This term relates to the risk factors for infections and thus in

labour is considered as any woman with regular painful

contractions and cervical change (dilatation or effacement),

and/or ruptured membranes. This term will be used when

specifying prognostic factors and in the collection of outcomes.

This is a clinical interpretation of the clinician caring for the

woman and we are asking for a clinical judgement of whether the

woman is in labour/not in labour.

Not in labour

caesarean

section

The term relates to the risk factors for infection and thus not in

labour is considered to be any woman who has no uterine activity,

intact membranes and a closed cervix (all three factors must be

present to be determined not in labour). This term will be used

when specifying prognostic factors and in the collection of

outcomes.

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TRIAL SUMMARY

Title: Vaginal Preparation at Caesarean Section to Reduce Endometritis and Prevent Sepsis –

A Feasibility Study of Chlorhexidine. Aims: The overarching aim of this research is to reduce infectious morbidity from caesarean

sections, which is the most common major surgical procedure worldwide. Specific aims for

this feasibility study include:

1. To determine appropriate recruitment and randomisation processes.

2. To assess if women can remain blinded to the trial intervention.

3. To determine the sample size required for a definitive trial.

4. To inform if the intervention can be conducted in a multi-centre RCT.

5. To develop women focused outcome measures and method of data collection.

6. To assess data collection of clinical outcomes up to 6 weeks.

7. To assess withdrawals.

Trial Design: A feasibility randomised controlled trial of vaginal cleansing at caesarean

section (CS) with chlorhexidine gluconate or acetate compared to no cleansing, including a

qualitative aspect to develop women centred outcomes of wellbeing after delivery.

Participant Population and Sample Size:

Participants

Women undergoing elective or emergency CS, who are at least 34 weeks’ pregnant,

recruited from 4 NHS maternity units.

Sample size

For the feasibility randomised controlled trial the target sample size is 250 women (125 in

each arm). The qualitative study will involve 2 focus groups, each with 7-10 women.

Eligibility Criteria

Women aged 16 years or over and greater than or equal to 34 weeks’ pregnant having a CS,

regardless of indication or number of fetuses.

Interventions: Chlorhexidine gluconate 0.05% (Unisept) or chlorhexidine acetate 0.05%

vaginal cleansing before CS, an antiseptic solution that is routinely applied to the abdominal

skin to reduce surgical site infection, and can also be applied inside the vagina (safety profile

established in other obstetric and gynaecological procedures).

The comparator is standard treatment which is no vaginal cleansing.

Outcome Measures:

Feasibility outcomes

The success of the feasibility study will be assessed by criteria related to the feasibility

measurements to ascertain if a larger study is feasible in its current format, needs

modification or is unfeasible, and includes recruitment, adherence, follow-up and

withdrawal measures.

Clinical primary outcome for main study

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The development of endometritis in the postnatal period (Day 0 day of delivery – 30 post-delivery) according to the CDC definition of endometritis.

Lay Summary

One in four women delivering a baby in the UK has a caesarean section. Most women

recover quickly and without complications. However, some women develop an infection;

this may be inside the womb, in the scar on the skin or a severe infection that is present in

the blood stream. An infection makes the woman's recovery following a caesarean more

difficult and complicated. We would like to research how to reduce the number of women

that develop infection after a caesarean section. The antiseptic solution that is applied to

the abdomen to clean the skin and reduce the risk of infection before a caesarean section

can also be applied inside the vagina. The antiseptic solution is routinely used for some

surgical procedures in pregnancy and is safe. In order to investigate if this is effective, we

need to develop a study that would include a large number of women. The research study

being developed would randomly assign women to have either the cleansing of the vagina

with the antiseptic solution or no cleansing (standard practice), if they have a caesarean

section. Women will then be asked to receive follow-up telephone interviews at 2 and 6

weeks after delivery to find out if any infection has developed. We will also look at their

medical notes. Before we start this proposed study, we need to complete a smaller ‘test’

study. This is to find out if it is possible to carry out the necessary procedures that a larger

study would need to fully answer if vaginal cleansing is beneficial. For example, we would

like to test if women would be happy to take part in the study and if we can reliably collect

all the information needed to find out if this treatment works. This ‘test’ study would be

very similar to the larger study. We will also be asking women to help us determine what

are the best measures of infection and wellbeing after their caesarean section.

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TABLE OF CONTENTS

1. BACKGROUND AND RATIONALE ........................................................................ 17

1.1. Background ........................................................................................................................... 17

1.2. Trial Rationale ....................................................................................................................... 18

2. AIMS AND OBJECTIVES ....................................................................................... 19

2.1. Aims and Objectives ............................................................................................................. 19

3. TRIAL DESIGN AND SETTING .............................................................................. 21

3.1. Trial Design ........................................................................................................................... 21

3.1.1. Qualitative study design: ....................................................................................................... 21

3.1.2. Feasibility study design: ........................................................................................................ 21

3.2. Trial Setting ........................................................................................................................... 21

3.3. Identification of participants ................................................................................................... 21

3.4. Sub-studies ........................................................................................................................... 22

4. ELIGIBILITY............................................................................................................ 22

4.1. Inclusion Criteria ................................................................................................................... 22

4.2. Exclusion Criteria .................................................................................................................. 23

4.3. Co-enrolment......................................................................................................................... 23

5. CONSENT ............................................................................................................... 24

6. ENROLMENT AND RANDOMISATION .................................................................. 27

6.1. Enrolment and Screening ...................................................................................................... 27

6.2. Randomisation ...................................................................................................................... 27

6.3. Informing the participant’s GP ............................................................................................... 28

6.4. Blinding .................................................................................................................................. 28

6.5. Treatment(s) .......................................................................................................................... 29

6.6. Accountability Procedures ..................................................................................................... 29

6.7. Treatment Supply and Storage ............................................................................................. 29

7. OUTCOMES............................................................................................................ 29

7.1. Clinical and Patient Reported Measures ............................................................................... 29

7.1.1. Stop-Go Criteria .................................................................................................................... 28

7.1.2. Other feasibility outcomes ..................................................................................................... 29

7.2. Clinical and Patient Reported Outcome Measures ............................................................... 29

Schedule of Assessments ................................................................................................................. 32

7.3. Participant Withdrawal .......................................................................................................... 32

8. ADVERSE EVENT REPORTING ............................................................................ 34

8.1. Reporting Requirements ....................................................................................................... 34

8.2. Adverse Events (AE) ............................................................................................................. 34

8.3. Serious Adverse Advents (SAE) ........................................................................................... 34

8.4. Reporting period – At Site ..................................................................................................... 34

8.4.1. Adverse Events ..................................................................................................................... 34

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8.4.2. Serious Adverse Events ........................................................................................................ 35

8.4.3. Provision of follow-up information ......................................................................................... 36

8.5. Reporting Procedure – BCTU Trials Team ........................................................................... 36

8.6. Reporting to the Research Ethics Committee ....................................................................... 36

8.6.1. Unexpected and Related Serious Adverse Events ............................................................... 36

8.6.2. Other safety issues identified during the course of the trial .................................................. 36

8.7. Investigators .......................................................................................................................... 36

9. DATA HANDLING AND RECORD KEEPING ......................................................... 37

9.1. Source Data .......................................................................................................................... 37

9.2. Case Report Form (CRF) Completion .................................................................................. 37

9.3. Data Management ................................................................................................................. 37

9.4. Data Security ......................................................................................................................... 37

9.5. Archiving ................................................................................................................................ 38

10. QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 38

10.1. Site Set-up and Initiation ....................................................................................................... 38

10.2. Onsite Monitoring .................................................................................................................. 39

10.3. Central Monitoring ................................................................................................................. 39

10.4. Audit and Inspection .............................................................................................................. 39

10.5. Notification of Serious Breaches ........................................................................................... 39

11. END OF TRIAL DEFINITION .................................................................................. 40

12. STATISTICAL CONSIDERATIONS ........................................................................ 41

12.1. Sample Size .......................................................................................................................... 41

12.2. Analysis of Outcome Measures ............................................................................................ 41

12.2.1. Missing Data and Sensitivity Analyses ................................................................................. 40

12.3. Planned Interim Analysis ....................................................................................................... 41

13. TRIAL ORGANISATIONAL STRUCTURE .............................................................. 43

13.1. Sponsor ................................................................................................................................. 43

13.2. Coordinating Centre .............................................................................................................. 43

13.1. Trial Oversight Committee .................................................................................................... 43

13.2. Finance .................................................................................................................................. 43

14. ETHICAL CONSIDERATIONS ................................................................................ 44

15. CONFIDENTIALITY AND DATA PROTECTION ..................................................... 45

16. Insurance and Indemnity ...................................................................................... 46

17. Publication Policy.................................................................................................. 47

18. Reference List ........................................................................................................ 48

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1. BACKGROUND AND RATIONALE

1.1. Background

1.1.1. Justification for participant population

Worldwide caesarean section (CS) delivery is the most common major operation. Approximately 25

percent of pregnant women undergo a CS in the United Kingdom for delivery of their babies. This

equates to approximately 2000 women per year at Birmingham Women’s Hospital alone and

approximately 171,000 CS per year in England alone.

Sepsis and postnatal infection constitute significant maternal mortality and morbidity, varying from

requirement for high dependency/ intensive care to milder infections that are managed in the

community, but have significant impact on postnatal recovery and maternal wellbeing. Infection

following a CS has a number of primary sources including endometritis occurring in 7-17% of women

depending on the method of data collection. Risk factors for endometritis following CS include in

labour caesarean section and ruptured membranes with or without vaginal colonisation with group

B streptococcus.

Sepsis reduction and reduction in antibiotic use has been identified as a national and international

priority. Although there have been significant reductions in maternal mortality rates from sepsis, this

is due to the introduction of sepsis care bundles and active treatment rather than reduction in rates

of infection and there is still significant morbidity with this treatment.

1.1.2. Justification for intervention

Prophylactic antibiotics at the time of surgery, have been demonstrated to be beneficial in a number

of large randomised controlled trials (RCT) and continue to reduce infection rates [1]. Yet we must

seek strategies to reduce this burden further. Being diligent to aseptic procedures in theatre is an

important component of reducing infection rates. Current practice is for only skin preparation prior

to incision at CS [2] with a recent RCT demonstrating the superiority of a chlorhexidine over an

iodine based solution for skin preparation [3]. In addition to skin preparation with an antiseptic

solution, cleansing inside the vagina with povidone iodine has been evaluated in a Cochrane review

[4]. Seven trials randomising 2816 women (2635 analysed) estimated the effects of vaginal cleansing

(all with povidone-iodine) on post-caesarean infectious morbidity [4]. The risk of bias was generally

low, with the quality of most of the studies being high. Vaginal preparation immediately before

caesarean delivery significantly reduced the incidence of post caesarean endometritis from 8.3% in

control groups to 4.3% in vaginal cleansing groups (average risk ratio (RR) 0.45, 95% confidence

interval (CI) 0.25 to 0.81, seven trials, 2635 women). The risk reduction was particularly strong for

women who were already in labour at the time of the caesarean delivery (7.4% in the vaginal

cleansing group versus 13.0% in the control group; RR 0.56, 95% CI 0.34 to 0.95, three trials, 523

women) and for women with ruptured membranes (4.3% in the vaginal cleansing group versus

17.9% in the control group; RR 0.24, 95% CI 0.10 to 0.55, three trials, 272 women [4]). The above

would appear an effective and important strategy to reduce morbidity at CS yet this has not been

adopted within obstetric practice internationally and does not feature within the NICE Intrapartum

guideline [5]. This is due to concerns with exposure of the fetus to iodine based substances,

concerns with vaginal staining and allergy to iodine. Iodine is a recognized antibacterial agent, but

local skin irritation and skin staining limits its use, which is overcome by the introduction of a

stabilizing moiety, povidone. Povidone, which is water soluble, does not require a dissolvent such as

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alcohol and, thus, is less irritating to skin and mucosa surfaces. With povidone iodine, some women

will still develop sensitivity and there are concerns including incorporation of iodine in body cavities

unprotected by a keratinized epithelium, such as the vagina. In normal vaginal pH (3.8– 4.5), iodine’s

disinfecting properties are decreased and povidone iodine is inactivated by the presence of blood,

invariably present in the vagina during a CS[6]. Thus, there are a number of reasons to believe that

vaginal cleansing with Chlorhexidine would be an appropriate alternative to povidone iodine.

Chlorhexidine acts by causing destruction of bacterial cell membranes, leading to the leakage of

cellular components and a decrease in bacterial counts. Some studies show greater reduction in skin

flora after application of chlorhexidine (0.5% and 4%)[6] compared with povidone-iodine agents.

Also, chlorhexidine may have a greater residual activity after application than other preparations

and, unlike povidone iodine; it is not inactivated by the presence of blood. To avoid irritation,

chlorhexidine with high concentrations of alcohol (e.g, 70% isopropyl alcohol, commonly used for

skin preparation) should not be used in the vagina. Solutions that contain lower concentrations, such

as the commonly used chlorhexidine gluconate and acetate (0.05%) are usually well tolerated and

may be used for vaginal preparation [6].With this preparation there are no reported cases of allergy.

There is one small randomised controlled trial comparing povidone iodine with chlorohexidine

gluconate for vaginal cleansing at CS. This, suggested that chlorohexidine may be superior and

further research was needed [7].

A Cochrane review of cleansing the vagina in normal vaginal delivery with chlorhexidine showed no

evidence of an effect on maternal or neonatal infections with low to moderate confidence, although

further large scale trials to detect small but clinically important differences were needed.

Importantly no safety concerns for the mother or baby have been identified within these studies [8].

1.1.3. Choice of intervention

Chlorhexidine gluconate 0.05% (or chlorhexidine acetate 0.05%) is used as a vaginal antiseptic in

other obstetric procedures such as cervical cerclage and in gynaecological surgery and has an

established safety profile. The active ingredient is chlorhexidine 0.05%. We have decided to test

chlorhexidine as the intervention in women undergoing CS as these women are at high risk of

infection and sepsis and are the largest group of women to potentially benefit from this

intervention. Throughout the protocol we refer to either “the intervention” or chlorhexidine

gluconate as this is used at the majority of centres.

1.1.4. Justification for design

We are undertaking a feasibility randomised controlled trial design so that we can test the consent

and randomisation processes for women requiring a CS, and the follow-up processes up until the

immediate postnatal period, to ensure we can overcome the challenges this poses.

1.2. Trial Rationale

Post-partum infection/sepsis is a significant global problem. With the increasing evidence regarding

antimicrobial resistance and the development of bacterial resistance there is concern that without

action, common procedures such as CS will carry significant risks. We must, therefore, seek

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strategies that reduce this risk. We aim to perform a feasibility study for a larger multi-centre

randomised controlled trial (RCT) comparing vaginal cleansing with chlorhexidine versus standard

practice of no vaginal cleansing immediately before CS to reduce post-partum endometritis and

sepsis. There are a number of difficulties in performing a RCT in pregnant women undergoing CS,

particularly in an emergency procedure where there is a short interval between decision and

delivery. Additionally, the follow-up of women post CS is unlike other surgical procedures: mothers

are discharged from obstetric care quickly with no routine post-operative follow-up. They are

motivated to recover and care for their baby. It is therefore necessary to perform this feasibility trial

to assess both our ability to recruit women and adequately follow them up.

2. AIMS AND OBJECTIVES

2.1. Aims and Objectives

2.1.1. Aims:

The overarching aim of this research is to reduce infectious morbidity from caesarean sections.

Specific aims for this feasibility study include:

1. To determine appropriate recruitment and randomisation processes.


3. To determine the sample size required for a definitive trial.

4. To inform if the intervention can be conducted in a multi-centre RCT.




2.1.2. Objectives: 1. To determine appropriate recruitment and randomisation processes

1.1 To assess the number of women agreeing to be recruited.

1.2 To test recruitment and consent processes, ensuring adequate identification of eligible

women undergoing both elective and emergency CS.

1.3 To ensure our randomisation method is appropriate and timely, in women undergoing

an emergency CS.


2.1 Blinding cannot be achieved by the clinician performing the intervention. We will

endeavour to blind the woman to the intervention, and will assess whether this has been

maintained by asking the woman at the 14 day telephone interview if she was aware of her

intervention during surgery.

3. To determine the sample size required for a definitive trial

3.1 Ascertainment of the control group event rates for a range of clinically important

outcomes.

4. To inform if the intervention can be evaluated in a multi-centre RCT.

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4.1 To evaluate if the RCT processes can be applied similarly across different maternity units.

4.2 To determine the time/staff needed to recruit and follow-up women so we can

accurately anticipate support needed at additional sites in a full multi-centre RCT.

4.3 To determine any barriers to adherence of allocated intervention.


5.1 To identify trial outcomes that matter to women (patient reported) following a CS.

5.2 To develop a telephone interview schedule that adequately collects maternal reported

outcomes.

5.3 To test the collection of these outcomes via a 14 day and 30 day telephone interview.


6.1 To ensure that the planned follow-up process adequately collects clinical

outcome information up to 6 weeks postpartum.


7.1 To assess number and type of withdrawals from the study.

7.2 To assess reasons for women withdrawing.

7.3 To assess reasons for clinicians withdrawing from intervention.

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3. TRIAL DESIGN AND SETTING

3.1. Trial Design

3.1.1 Qualitative study design:

A qualitative study will inform the outcomes that will be collected on women in the feasibility RCT.

Two focus groups will be performed at the lead site (Birmingham Women’s Hospital) of

approximately 7-10 women in each group who have undergone a CS and would like to contribute to

the development of women centred outcomes.

Women will be recruited via adverts placed on Birmingham Women’s Hospital notice boards, on the

post-natal wards, through social media platforms, community midwives will be asked to identify

women, hospital re-attendance and through patient engagement services at BWH. We will ask

women who have had a CS within the previous 6 months to contribute to focus groups on important

women centred outcomes for research into infection and complications following a CS.

The focus groups will be performed prior to commencement of recruitment to the feasibility RCT

and thus used to decide on outcomes for inclusion in the feasibility trial that the women feel are

important for post-natal quality of life and recovery.

All women will have demographic data collected. The focus groups will be recorded and transcribed

anonymously. The data will be analysed thematically and managed using the Framework Method

[9].

An experienced qualitative researcher will run the focus groups, with the support of a research

associate and the clinical research fellow.

From informal discussions with women who have undergone CS, the outcomes are likely to be

composed of the following themes.

Length of midwife follow-up.

Prolonged use of analgesics.

Ability to care for self.

Time to leaving house with family/independently.

Ability to care for baby.

3.1.2 Feasibility study design:

Unblinded parallel group feasibility RCT comparing vaginal cleansing using chlorhexidine gluconate

versus no cleansing (standard practice) at CS to reduce infection. Allocation to treatment will be on a

1:1 ratio.

3.2. Trial Setting

The trial will be undertaken in four maternity hospitals; Birmingham Women’s Hospital, Birmingham

Heartlands Hospital, Shrewsbury and Telford Hospital (West Midlands) and Sunderland Royal

Hospital, to ensure the trial can be extrapolated to a larger multi-centre trial

3.3. Identification of participants

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Given recruitment, consent and randomisation processes will differ for emergency and elective CS

due to differences in planning for surgery, the processes for each type of surgery will be detailed

separately.

All women booking at any of the hospitals over the study period and who are greater than 34 weeks’

pregnant while recruitment is running will be posted a patient information leaflet. This is to ensure

that all women are aware of the study before delivery of their baby/babies. This will be accompanied

with patient information leaflets and study information being available in antenatal clinics and triage

waiting rooms. Study posters will also be displayed in prominent positions through the hospitals.

Elective caesarean sections:

Women undergoing elective CS will be approached and invited to take part in the study, at either the

time of booking of an elective CS in the antenatal clinic, during the preoperative visit or on the

labour ward on the day of surgery. A suitably qualified research midwife or doctor will introduce the

study to the woman, a patient information leaflet will be given and then time to consider the study

will be given. Women will be given adequate opportunity to ask questions, and consider their

participation in the trial prior to written consent being obtained.

Emergency caesarean sections:

Women will be identified by clinicians and midwives when the decision to perform an emergency CS

has been made. This identification will occur on the delivery suite, on the induction suite or on the

antenatal wards. Women will have received the patient information leaflets in the antenatal period

and there will be further opportunities to receive patient information leaflets in the above locations.

If time allows, written consent will be taken but if time is limited, women will provide verbal consent

for the intervention with written consent taken prior to discharge from hospital. If written consent is

not obtained prior to discharge from hospital then confirmation of consent will be sort by sending a

PIL and consent to women in the post. If written consent is not obtained then the data will not be

used in the analysis and this informs an important component of the feasibility of this trial.

3.4. Sub-studies

Where possible and immediately prior to vaginal cleansing we will take vaginal swabs for future

microbiome studies. The evaluation of these swabs will be performed outside the scope of this

research project. Consent for taking, storage and future evaluation will be taken at the time of

consenting to the feasibility study. This is an optional component of the study.

4. ELIGIBILITY

4.1. Inclusion Criteria

Women will be included in the trial if they are:

greater than or equal to 34 weeks’ pregnant

having a CS regardless of indication or number of fetuses

able to give informed written consent

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able to receive a telephone interview at 14 and 30 days post-natal

aged 16 years or over.

4.2. Exclusion Criteria

Women will be excluded from the trial if they:

have a known allergy to chlorhexidine gluconate or any of its ingredients

are receiving prophylactic intravenous antibiotics for group B streptococcus (GBS)

colonisation

are receiving intravenous antibiotics for suspected infection (standard CS intravenous

prophylaxis is not an exclusion criteria)

are currently enrolled in an RCT for an intervention intended to reduce post-operative

surgical site infection.

4.3. Co-enrolment

All women already enrolled in an interventional study are permitted to be co-enrolled into PREPS, as

long as the intervention is not intended to reduce infection. After consent and randomisation to

PREPS, women will not be permitted to enter a further interventional study if the study is evaluating

the prevention of infection. Co-enrolment in all observational studies is permitted.

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5. CONSENT

Elective caesarean sections:

A suitably qualified research midwife or doctor will introduce the study to the woman at their pre-

operative assessment.

A Participant Information Leaflet (PIL) will be provided to facilitate this process. Investigators will

ensure that they adequately explain the aim, trial treatment, anticipated benefits and potential

hazards of taking part in the trial to the woman. They will also stress that participation is voluntary

and that the woman is free to refuse to take part and may withdraw from the trial at any time. The

woman will be given adequate time to read the PIL and to discuss their potential participation and

be given the opportunity to ask questions. If the woman expresses an interest in participating in the

trial, they will be asked to sign and date the latest version of the Informed Consent Form (ICF).

The woman will be asked for her consent to be randomly allocated to the intervention or standard

treatment, for collection of outcome data from their medical records and a telephone interview at

14 and 30 days postnatally that will take approximately 5-15 minutes. The woman will be asked to

give explicit consent for the regulatory authorities, members of the research team and or

representatives of the sponsor to be given direct access to their medical records.

It will be the responsibility of the investigator to obtain written informed consent for each

participant prior to performing any trial related procedure. Research midwives and doctors can both

take informed consent for the trial as long as this responsibility has been delegated to them by the

Principal Investigator (PI) as captured on the Site Delegation Log.

The consent form will be provided in triplicate to facilitate the process on a busy labour ward. Each

box on the consent form should be initialled by the woman and the form signed by the woman and

the delegated research staff. This is with the exception of the optional element of the trial for the

consent to provide a vaginal swab. A copy of the consent form will be given to the woman, a copy

filed in the medical records with the PIL and a copy will be sent to the trial office if the trial office

requests. The original signed consent form will be filed in the investigator site file (ISF). Once the

woman is entered into the trial, the woman’s trial number will be entered on the ICF maintained in

the Investigator Site file.

Details of the informed consent discussions will be recorded in the woman’s medical notes. This will

include date of discussion, the name of the trial, summary of discussion, version number of the PIL

given to the participant and version number of the ICF signed and date consent received. Where

consent is obtained on the same day that the trial related assessments are due to start, a note

should be made in the medical notes as to what time the consent was obtained and what time the

procedures started.

At any further visits and prior to the telephone interview the woman’s willingness to continue in the

trial will be ascertained and documented. Throughout the trial the woman will have the opportunity

to ask questions about the trial. At the time of taking consent the woman will provide contact

details to facilitate the telephone interview.

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Emergency caesarean section:

In the majority of emergency CS, the woman will be asked to consent as per the elective procedure.

It is expected that the majority of women undergoing emergency CS will provide written consent

prior to trial related procedures commencing.

It is appreciated that time can be limited in the undertaking of an emergency CS, especially where

there is suspected maternal or fetal compromise. In keeping with the Royal College of Obstetricians

and Gynaecologist consent advice for women participating in research, as long as information is

available antenatally it is reasonable to take consent in labour [10]. Therefore, all women booking at

sites will receive information regarding the trial in the antenatal period and if appropriate in the

intrapartum period such as during an induction of labour. The common incidence of CS (an event

that occurs in 25% of women) and the expectation of women in labour that CS is a possibility means

that giving information to all women would not overburden them and is unlikely to cause anxiety or

deviate women from the normal birth process. In the emergency situation where time is limited,

verbal consent for the intervention will be obtained prior to randomisation with written consent to

continue with the trial taken following the CS procedure and before discharge.

In an emergency, where verbal consent is being taken, a suitably qualified research midwife or

doctor will discuss the study to the women. A verbal discussion will include confirmation that the

woman has previously received information regarding the trial, understands that the choice of

intervention will be made randomly and is happy to take part.

After the procedure, a PIL will be provided highlighting the follow-up and confirmation of willingness

to continue to participate. They will also stress that participation is voluntary and that she is free to

refuse to take part and may withdraw from the trial at any time. If she is happy to continue to

participate in the trial, she will be asked to sign and date the latest version of the ICF. Details of the

informed consent discussions will be recorded in the participant’s medical notes. This will include

date of discussion, the name of the trial, summary of discussion, version number of the PIL given to

the participant and version number of the ICF signed and date consent received.

The woman will be asked to consent to the collection of outcome data from her medical records and

a telephone interview at 14 and 30 days postnatally that will take approximately 5-15 minutes. The

woman will give explicit consent for the regulatory authorities, members of the research team and

or representatives of the sponsor to be given direct access to the participant’s medical records.

Each box on the consent form should be initialled and the form signed by the woman and the

delegated research staff. A copy of the consent form will be given to the woman, a copy filed in the

medical records with the PIL and a copy will be sent to the trial office (if requested).

Research midwives and doctors can both take informed consent for the trial as long as this

responsibility has been delegated to them by the Principal Investigator (PI) as captured on the Site

Delegation Log. Once the woman is entered into the trial, the woman’s trial number will be entered

on the ICF maintained in the Investigator consent file

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At any further visits and prior to the telephone interview the woman’s willingness to continue in the

trial will be ascertained and documented. Throughout the trial the woman will have the opportunity

to ask questions about the trial. At the time of taking consent the woman will provide contact

details to facilitate the telephone interview.

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6. ENROLMENT AND RANDOMISATION

6.1 Recruitment

Information about the trial will be widely available throughout the maternity unit and community

clinics in the form of posters and leaflets. To facilitate recruitment of women having an emergency

CS all women at participating centres will be provided with written information about the trial once

they become eligible at 34 weeks via the posting of a PIL to their home address. All women

undergoing an elective CS will be approached at their pre-operative assessment. On admission to the

maternity unit, all women in labour or admitted for induction will be reminded about the trial by

their healthcare professional. Information about the trial will be provided if not previously seen.

After the clinical decision for CS is made and the woman has given consent for CS, the woman will be

approached by her midwife, obstetrician or research midwife as described in section 5.0

6.1. 1. Enrolment and Screening

Each site will keep records of all women who undergo a CS during the study period; the majority of

these women will be eligible for participation. Therefore these records will allow calculations of

possible eligible patients against approached. In addition, all women assessed for eligibility will be

recorded on a Screening and Randomisation Form and collated on to the screening and enrolment

log. This log will be sent to the trial team weekly.

With the woman’s prior consent, her General Practitioner (GP) will also be informed that they are

taking part in the trial, with a copy of the letter sent to the GP filed in the ISF.

6.2. Randomisation

After the woman’s eligibility has been confirmed and informed consent has been received, the

woman can be randomised into the trial. Randomisation can be performed by all members of the

research team and clinical team, and is most likely to be performed by dedicated research midwives.

Randomisation will be provided by a secure automated telephone randomisation system available

24 hours a day/ 7 days a week provided by the University of Aberdeen. The telephone randomisation

service will comply with research and governance standards.

The telephone randomisation service will be available through a Freephone service by dialling 0800

2802 307.

The randomised allocation will be documented in the main hospital records on the anaesthetic

chart, on a dedicated sticker within the notes and on the Screening and Randomisation Form. The

allocation will not be disclosed to the woman or recorded in the post natal hand held notes.

Women will be randomised at the level of the individual in a 1:1 ratio to either chlorohexidine

gluconate or acetate 0.05% vaginal cleansing or standard treatment of no vaginal cleansing. A

minimisation algorithm will be used to ensure balance in the treatment allocation over the following

variables:

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Randomising centre

In labour and not in labour CS.

A ‘random element’ will be included in the minimisation algorithm, so that each patient has a

probability (unspecified here), of being randomised to the opposite treatment that they would have

otherwise received.

Investigators will keep their own study file log which links women with their allocated trial number

in the Recruitment and Identification Log.

The Investigator must maintain this document, which is not for submission to the Trials Office. The

Investigator will also keep and maintain the Screening and Enrolment Log which will be kept in the

ISF, and should be available to be sent to the Trials Office upon request. The Recruitment and

Identification Log and the Screening and Enrolment Log should be held in strict confidence.

6.3. Informing the participant’s GP

The participant’s GP should be notified that they are in the PREPS trial, using the PREPS GP Letter.

6.4. Blinding

The trial cannot be blinded to the operator or the clinical care team in theatre providing care to the

women due to the nature of the intervention. Randomisation will be performed by a wide range of

staff from theatre runners to consultants. Randomisation may be performed by dedicated research

midwives who will also collect outcome data from the notes but there will be no recording of the

allocation in the postnatal notes.

Attempts will be made to blind the women as the intervention will be applied at the time of the

catheter insertion and the woman should not be aware of the application due to anaesthesia.

All data collection from the maternal notes will be blinded since there will only be recording of

whether the intervention was applied on the theatre operation note and anaesthetic/operation

chart, which are not held in the maternal post natal notes. Aa part of the monitoring process 10% of

medical records will be independently monitored and data collection verified by the trial sponsor on-

site.

The research midwife conducting the telephone follow-up interviews will be blinded to the

treatment group and so will not bias collection of outcomes. The research midwife will not have

access to the medical records or any data collection forms at the time of telephone interviews.

At the end of the 14 day interview the midwife will ask the woman whether she feels she received

the intervention or not, to assess whether blinding of the woman is an achievable aim.

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6.5. Treatment(s)

Chlorohexidine gluconate 0.05% (Unisept) or Chlorohexidine acetate 0.05% will be used to perform

vaginal cleansing. This is indicated within the British National Formulary for swabbing in obstetrics.

Fifty mls of antiseptic (Unisept or Chorohexidine acetate 0.05%) will be emptied into a sterile pot. A

single swab/sponge mounted on a sponge holder soaked in the antiseptic will be used to clean the

vagina prior to CS at the time of urinary catheter insertion, for guidance we suggest the vaginal

cleansing should take 30 seconds. Following the CS procedure the vagina will be cleaned of excess

blood as is standard practice with a dry swab.

The application of the intervention is quick and familiar to the doctors performing the surgery due to

their experience in gynaecological surgery where it is routine practice. We have evaluated providing

additional equipment but feel the most efficient way of doing this is to follow the established

method used in major gynaecological surgery where one swab on a stick is placed on the catheter

trolley with a galley pot of chlorhexidine for the surgeon to cleanse the vagina at the time of routine

catheter insertion.

All theatres’ standard operating procedures regarding swabs and instrument counts should be

adhered to, to ensure patient safety.

6.6. Accountability Procedures

At all sites staff will be asked to record if they have performed vaginal cleansing and if performed

which antiseptic was used, on the CS operation note within the hospital notes.

6.7. Treatment Supply and Storage

6.7.1. Treatment Supplies

The chlorohexidine gluconate 0.05% will be obtained through the NHS supply chain. It is available to

purchase through NHS suppliers and its use will be approved. No relabelling or modification of the

available preparation will be needed.

7. OUTCOMES

7.1. Outcomes for the feasibility study

All feasibility outcomes will be assessed overall and by centre (objective 4.1).

7.1.1. Stop-go criteria

The decision to continue to a full trial will be decided by pre-defined stop-go criteria (defined in section 12.4) based on the following outcomes:

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The proportion of women randomised into the trial of the 250 recruitment target (objective 1.1).

The proportion of women who received their allocated intervention out of all those randomised (objective 4.3).

The proportion of women remaining in the trial (i.e. not withdrawn as per criteria below) who successfully complete the planned follow-up process for both the 14 and 30 day telephone interview (objective 5.3).

Withdrawal from the study (as detailed in 7.3 based on withdrawal categories 2, 3 and 4). (objective 7.1).

7.1.2. Other feasibility outcomes

The proportion of eligible women approached to take part (objective 1.2).

The proportion of women randomised who have an elective/emergency CS (objective 1.2).

The proportion of women who are randomised into the PREPS trial with verbal consent from

the number of women whom have an emergency CS (objective 1.3).

The proportion of women randomised who can successfully identify what treatment they

received (i.e. vaginal cleansing or no vaginal cleansing) (objective 2.1).

The proportion of complete data for each of the clinical and woman reported outcomes

(listed below in section 7.2), of women randomised (objective 5.3 and 6).

Time taken to perform the telephone interviews (objective 4.2).

Reasons for withdrawal (objective 7.2 and 7.3)

All objectives not assessed quantitatively will be addressed qualitatively via the focus groups

(objectives 5.1 and 5.2).

7.2. Clinical and patient reported outcomes

The following clinical outcomes will be collected to inform sample size calculations for the main RCT

(objective 3).

7.2.1. Development of CDC defined endometritis in the postnatal period (Day 0-30)

Development of endometritis meeting the CDC definition, in the postnatal period (day 0 day of delivery) is the proposed primary outcome for the full RCT.. Endometritis will be defined as per the definitions set out by the US Centre’s for Disease Control and Prevention (Centre’s for Disease Control and Prevention 2017) [11]. For a detailed description of the definition see appendix 1.

7.2.2. Clinical diagnosis of endometritis in the postnatal period (Day 0-30)

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Diagnosis of endometritis by a clinician which does not meet the CDC definition or cannot be verified to meet the definition. e.g. a woman treated in the community for suspected endometritis where it is not feasible to establish that this meets the CDC definition or where the diagnosis does not meet the criteria.

7.2.3. Maternal sepsis (Day 0-42)

Defined according to the NICE sepsis guideline (released July 2016) [11].

7.2.4. Length of hospital stay

Length of hospital stay from randomisation to discharge home or transfer to another hospital following CS, or up to 6 weeks after randomisation if not discharged.

7.2.5. Readmission to hospital after CS for suspected or confirmed infection (Day 0-

42)

Defined as readmission to hospital post-discharge home up until 6 weeks postnatally.

7.2.6. Antibiotic prescriptions

Antibiotics prescribed as an inpatient and hospital prescribed outpatient (Day 0-42) and antibiotics

prescriptions for suspected/confirmed surgical site infection relating to the woman’s CS (uterine,

pelvic, abdominal wound and perineal).

7.2.7. Requiring level 2 or level 3 critical care (or obstetric HDU type care) due to

infection (Day 0-42)

Defined as requiring level 2 or 3 critical care (or obstetric HDU type care) as a result of an infection up until 6 weeks postnatally. The endometritis outcomes are collected up until day 30 to be consistent with the CDC definition of endometritis and the sepsis related outcomes are collected up until 6 weeks to be consistent with the national collection of postnatal sepsis.

7.2.8. Patient reported outcomes

These will be determined by the qualitative component of this feasibility study and reported as an

outcome of the feasibility study along with summary statistics (objective 5.3) pre-specified in the

statistical analysis plan .

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Schedule of Assessments

Visit Screening Baseline

In

Patie

nt

Dischar

ge

Telepho

ne call

at 14

days

post

natal

Telepho

ne call

at 30

days

post

natal

Medical

records

check at 6

weeks post

natal

Additional

initiated

assessment

Eligibility check x

Valid informed consent x

x

Randomisation x

Caesarean section details x

Standard clinical

examination x x x

Outcome collection x x x x

Community Midwife

concern or Patient concern

return to trial site.

x

7.3. Participant Withdrawal

Informed consent is defined as the process of learning the key facts about a clinical trial before deciding whether or not to participate. It is a continuous and dynamic process and women should be asked about their ongoing willingness to continue participation with the telephone interviews before the interview questions commence.

Women should be aware at the beginning that they can freely withdraw (discontinue participation) from the trial (or part of the trial) at any time.

Types of withdrawal as defined are:

1. The woman would like to withdraw from trial treatment, before the intervention is applied but is willing to be followed up in accordance with the schedule of assessments and if applicable using any central UK NHS bodies for long term outcomes (i.e. the woman has agreed that data can be collected and used in the trial analysis)

2. The woman would like to withdraw from the trial after the allocation is applied and does not wish to participate in the telephone interview but is willing to be followed up at any visits and if applicable using any central UK NHS bodies for long term outcomes (i.e. the woman has agreed that data can be collected at standard visits and used in the trial analysis, including data collected as part of long term outcomes)

3. The woman would like to withdraw from the trial after the allocation is applied and is not willing to be followed up in any way for the purposes of the trial and for no further data to be collected (i.e. only data collected prior to the withdrawal can be used in the trial analysis)

4. The woman wishes to withdraw completely (i.e. from trial treatment and all follow up) and is not willing to have any of their data, including that already collected, to be used in any future trial analysis

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The details of withdrawal (date, reason and type of withdrawal) should be clearly documented in the woman’s medical notes.

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8. ADVERSE EVENT REPORTING

8.1. Reporting Requirements

The collection and reporting of Adverse Events (AEs) will be in accordance with the Research

Governance Framework for Health and Social Care and the requirements of the Health Research

Authority (HRA). Definitions of different types of AEs are listed in the table of abbreviations and

definitions. The Investigator should assess the seriousness and causality (relatedness) of all AEs

experienced by the trial participant this should be documented in the source data with reference to

the protocol.

No neonatal AEs or SAEs are required to be reported as the intervention is licensed for use in

obstetrics over 34 weeks for swabbing as per the SmPC.

8.2. Adverse Events (AE)

There are certain AEs which are commonly expected in participants as a result of pregnancy and/or

CS. As these events are well characterised, it is highly unlikely that this trial will reveal any new

safety information relating to this intervention. The recording of selected AEs will therefore not

affect the safety of participants or the aims of the trial. Thus there will be no AEs recorded.

8.3. Serious Adverse Events (SAE)

All events which meet the definition of serious will be collected and recorded in the participant

notes and the Case Report Form (CRF). SAEs will, in addition, be reported to the trials office

immediately and within 24 hours of the principal investigator being made aware of the event.

Events not considered an SAE in PREPS include:

Hospitalisation for delivery of the baby.

The development of infection and sepsis in the postnatal period that requires inpatient

treatment or prolongation of hospitalisation as this is an outcome of the trial.

Obstetric haemorrhage

Damage to bowel or bladder during surgery

Prolonged hospitalisation due to neonatal complications

Thromboembolic events

Allergic reaction to chlorohexidine requiring treatment will be considered a serious adverse advent.

All other events not detailed above that meet the definition of a SAE should be reported as detailed

in 8.4

8.4. Reporting period – At Site

8.4.1. Adverse Events

No specific reporting of AEs is required.

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8.4.2. Serious Adverse Events

AEs defined as serious and which require reporting as an SAE should be reported on an SAE Form.

When completing the form, the PI will be asked to define the causality and the severity of the AE.

Causality will be assessed as definitely related; probably related; possibly related; unlikely to

be related or unrelated

Category Definition

Definitely There is clear evidence to suggest a causal relationship, and other possible

contributing factors can be ruled out

Probably There is evidence to suggest a causal relationship, and the influence of other

factors is unlikely

Possibly There is some evidence to suggest a causal relationship, however, the influence of

other factors may have contributed to the event (e.g. the patient’s clinical condition,

other concomitant events or medication)

Unlikely There is little evidence to suggest there is a causal relationship; there is another

reasonable explanation for the event (e.g. the patient’s clinical condition, other

concomitant events or medication)

Not related There is no evidence of any causal relationship

On becoming aware that a woman has experienced an SAE, the Investigator “or delegate(s)” should

report the SAE to their own Trust in accordance with local practice and to the BCTU trials office.

To report an SAE to the BCTU trials office, the Investigator “or delegate(s)” must complete, sign and

date the trial specific BCTU SAE form. The completed form should be faxed to the BCTU trials team

using one of the numbers listed below as soon as possible and no later than 24 hours after first

becoming aware of the event:

To report an SAE, fax or email the SAE Form to:

0121 415 9136

[email protected]

On receipt of an SAE form, the BCTU trials team will allocate each SAE a unique reference number

and return this via fax or email to the site as proof of receipt. If the site has not received

confirmation of receipt of the SAE from the BCTU or if the SAE has not been assigned a unique SAE

identification number, the site should contact the BCTU trials team within 1 working day. The site

and the BCTU trials team should ensure that the SAE reference number is quoted on all

correspondence and follow-up reports regarding the SAE and filed with the SAE in the Site File.

Where an SAE Form has been completed by someone other than the Investigator, the original SAE

form will be required to be countersigned by the Investigator to confirm agreement with the

causality and severity assessments.


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8.4.3. Provision of follow-up information

Following reporting of an SAE, the women should be followed up until resolution or stabilisation of

the event. Follow-up information should ideally be provided on a new SAE Form, using the SAE

reference number provided by the BCTU trials team. Once the SAE has been resolved, all follow-up

information has been received and the paperwork is complete, the original SAE form that was

completed at site must be returned to the BCTU trials office and a copy kept in the Site File.

8.5. Reporting Procedure – BCTU Trials Team

On receipt of a SAE form from the site, the BCTU trials team will allocate each SAE form with a

unique reference number and enter this onto the SAE form in the section for office use only. The

SAE form (containing the unique reference number completed) will be forwarded to the site as proof

of receipt within 1 working day. The SAE reference number will be quoted on all correspondence

and follow-up reports regarding the SAE and filed with the SAE in the Trial Management File (TMF).

On receipt of an SAE Form, the Chief Investigator (CI) “or delegate(s)” will independently determine

the seriousness and causality of the SAE. An SAE judged by the PI or CI “or delegate(s)” to have a

reasonable causal relationship with the intervention will be regarded as a related SAE. The causality

assessment given by the PI will not be downgraded by the CI “or delegate(s)”. If the CI “or

delegate(s)” disagrees with the PI’s causality assessment, the opinion of both parties will be

documented, and where the event requires further reporting, the opinion will be provided with the

report.

The CI “or delegate(s)” will also assess all related SAEs for expectedness. If the event is unexpected

(i.e. is not defined in the protocol as an expected event) it will be classified as an unexpected and

related SAE.

8.6. Reporting to the Research Ethics Committee

8.6.1. Unexpected and Related Serious Adverse Events

BCTU will report all events categorised as Unexpected and Related SAEs to the main Research Ethics Committee (REC) within 15 days.

8.6.2. Other safety issues identified during the course of the trial

The main REC and sponsor will be notified immediately if a significant safety issue is identified during

the course of the trial.

8.7. Investigators

Details of all Unexpected and Related SAEs and any other safety issue which arises during the course

of the trial will be reported to PI. A copy of any such correspondence should be filed in the site file

and TMF.

The independent Trial Oversight Committee will review all SAEs at the agreed scheduled meetings.

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9. DATA HANDLING AND RECORD KEEPING

9.1. Source Data

To allow for the accurate reconstruction of the trial and clinical management of the subject, source

data will be accessible and maintained.

The women’s medical notes will be the source data for this trial while the women are in hospital and

during outpatient visit. Data recorded during follow up telephone interview will recorded on CRFs

and will be considered source data for this follow up telephone visits. In all cases, data collected on

paper CRFs will be entered on the trial database.

9.2. Case Report Form (CRF) Completion

Data reported on each form will be consistent with the source data and any discrepancies will be explained. All missing and ambiguous data will be queried. Staff delegated to complete CRFs will be trained to complete the forms via the site initiation visit.

In all cases it remains the responsibility of the site’s PI to ensure that the CRF has been completed correctly and that the data are accurate. This will be evidenced by the signature of the site’s PI, “or delegate(s)”, on the CRF. Only a copy of the randomisation note pad CRF will need to be sent to BCTU all other CRFs can be entered directly on the study database.

9.3. Data Management

Processes will be employed to facilitate the accuracy of the data included in the final report. These

processes will be detailed in the trial specific data management plan. Coding and validation will be

agreed between the trial’s coordinator, statistician and programmer and the trial database will be

signed off once the implementation of these has been assured.

9.4. Data Security

The security of the trial database is governed by the policies of the University of Birmingham. The

University’s Data Protection Policy and the Conditions of Use of Computing and Network Facilities

set out the security arrangements under which sensitive data should be processed and stored. All

studies at the University of Birmingham have to be registered with the Data Protection Officer and

data held in accordance with the Data Protection Act. The University will designate a Data

Protection Officer upon registration of the study. The Study Centre has arrangements in place for

the secure storage and processing of the study data which comply with the University of Birmingham

policies.

The System incorporates the following security countermeasures:

Physical security measures: restricted access to the building, supervised onsite repairs and storages of back-up tapes/disks are stored in a fire-proof safe.

PREPS PROTOCOL ________________________________________________________________________________


Logical measures for access control and privilege management: including restricted accessibility, access controlled servers, separate storage of non-identifiable data etc.

Network security measures: including site firewalls, antivirus software, separate secure network protected hosting etc.

System Management: the System shall be developed by the BCTU Programming Team and will be implemented and maintained by the BCTU Programming Team.

System Design: the system shall comprise of a database and a data entry application with firewalls, restricted access, encryption and role based security controls.

Operational Processes: the data will be processed and stored within the Study Centre (University of Birmingham).

Data processing: Statisticians will only have access to anonymised data.

System Audit: The System shall benefit from the following internal/external audit arrangements:

o Internal audit of the system

o An annual IT risk assessment

Data Protection Registration: The University of Birmingham has Data Protection Registration to cover the purposes of analysis and for the classes of data requested. The University’s Data Protection Registration number is Z6195856.

9.5. Archiving

It is the responsibility of the PI to ensure all essential trial documentation and source documents

(e.g. signed ICFs, Investigator Site Files, Pharmacy Files, participants’ hospital notes, copies of CRFs

etc.) at their site are securely retained for at least 25 years.

10. QUALITY CONTROL AND QUALITY ASSURANCE

10.1. Site Set-up and Initiation

The CI is required to sign a Birmingham Women’s and Children’s Hospital CI agreement to document

the expectations of both parties. The CI agreement document must be completed prior to

participation. The CI is also required to sign a Clinical Trials Task Delegation Log which documents

the agreements between the CI and BCTU. In addition, all local PIs will be asked to sign the

necessary agreements including a Site Signature and Delegation log between the PI and the CTU and

supply a current CV and Good Clinical Practice (GCP) certificate to BCTU. All members of the site

research team are required to sign the Site Signature Delegation Log, which details which tasks have

been delegated to them by the PI.

Prior to commencing recruitment, each recruiting site will undergo a process of initiation, either a

meeting or a teleconference, at which key members of the site research team are required to

attend, covering aspects of the trial design, protocol procedures, adverse event reporting, collection

and reporting of data and record keeping. Sites will be provided with an Investigator Site File

containing essential documentation, instructions, and other documentation required for the conduct

of the trial. The BCTU trials team must be informed immediately of any change in the site research

team.

PREPS PROTOCOL ________________________________________________________________________________


10.2. Onsite Monitoring

Monitoring is carried out as required following trial specific risk assessment and as documented in

the monitoring plan. For this trial we will monitor all sites at least once, this will facilitate both

ensuring safety and compliance of this trial and identification of problems that can be rectified in a

further definitive trial. Any monitoring activities will be reported to the trials team and any issues

noted will be followed up to resolution. Additional on-site monitoring visits may be triggered, for

example by poor CRF return, poor data quality, low SAE reporting rates, excessive number of

participant withdrawals or deviations. If a monitoring visit is required the Trials team will contact

the site to arrange a date for the proposed visit and will provide the site with written confirmation.

Investigators will allow the PREPS monitoring staff access to source documents as requested. The

monitoring will be conducted by Birmingham Women’s and Children’s NHS Foundation Trust

monitoring team.

10.3. Central Monitoring

Trials staff will be in regular contact with the site research team to check on progress and address

any queries that they may have. Trials staff will check incoming ICFs and CRFs for compliance with

the protocol, data consistency, missing data and timing. Sites will be sent CRFs requesting missing

data or clarification of inconsistencies or discrepancies.

10.4. Audit and Inspection

The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory

inspection(s) at their site, providing direct access to source data/documents. The investigator will

comply with these visits and any required follow up. Sites are also requested to notify BCTU of any

relevant inspections.

10.5. Notification of Serious Breaches

The sponsor is responsible for notifying the REC of any serious breach of the conditions and

principles of GCP in connection with that trial or the protocol relating to that trial. Sites are therefore

requested to notify the Trials Office of any suspected trial-related serious breach of GCP and/or the

trial protocol. Where the Trials Office or Birmingham Women’s and Children’s Hospital is

investigating whether or not a serious breach has occurred sites are also requested to cooperate

with requests in providing sufficient information to report the breach to the REC where required and

in undertaking any corrective and/or preventive action.

Sites may be suspended from further recruitment in the event of serious and persistent non-

compliance with the protocol and/or GCP, and/or poor recruitment. Any major problems identified

during monitoring may be reported to Trial Oversight Committee and the REC. This includes

reporting serious breaches of GCP and/or the trial protocol to the REC.

PREPS PROTOCOL ________________________________________________________________________________


11. END OF TRIAL DEFINITION

The end of trial is the date when the database is locked. The BCTU trial team will notify the main REC

and sponsor that the trial has ended and a summary of the clinical trial report will be provided

within 12 months of the end of trial.

PREPS PROTOCOL ________________________________________________________________________________


12. STATISTICAL CONSIDERATIONS

12.1. Sample Size

Since this is a feasibility study, no formal sample size calculations have been undertaken. The

feasibility study is not designed or powered to detect a statistically significant difference in efficacy

between the two treatment arms.

Preliminary sample size calculations were computed for the full RCT. Vaginal cleansing with

povidone iodine has been evaluated in a Cochrane review which comprised of seven trials

randomising 2816 women (2635 analysed) estimating the effects of vaginal cleansing ( povidone-

iodine) on post-caesarean infectious morbidity. The risk of bias was generally low, with the quality of

most of the studies being high. Vaginal preparation immediately before caesarean delivery

significantly reduced the incidence of post caesarean endometritis from 8.3% in control groups to

4.3% in vaginal cleansing groups. To detect a difference of this size with 90% power and alpha at 5%

we would require 1548 participants. In addition, to account for an anticipated 10% loss to follow-up

we would need a total of 1720 participants. A recruitment target of 250 participants has been

chosen for this feasibility study as we expect this number will be sufficient to provide estimates of

the feasibility outcomes. Furthermore, a total sample size of 250 participants would agree with

existing literature which suggests that the size of the feasibility study should be at least 10% of the

anticipated size of the substantive study [12].

12.2. Analysis of Outcome Measures

A separate Statistical Analysis Plan for the PREPS feasibility study will provide a detailed description

of the planned statistical analyses. A brief outline of the planned analyses is given below.

All clinical outcomes will be analysed according to the treatment arm to which they were

randomised (i.e. vaginal cleansing or no cleansing) irrespective of compliance with the randomised

treatment allocation, as per the intention to treat principle. Women who did not undergo a CS will

be excluded from the analyses.

Feasibility outcomes will be analysed pooling the two randomised groups and presenting overall

estimates of proportions with 95% confidence intervals, as well as estimates by centre.

All outcomes will primarily take the form of simple descriptive statistics (e.g. proportions and

percentages, means and standard deviations) and where appropriate, point estimates of effects

sizes (e.g. mean differences and relative risks) and associated 95% confidence intervals.

12.2.1. Planned Subgroup Analyses

No subgroup analyses are planned for this feasibility study.

12.2.2. Missing Data and Sensitivity Analyses

Every attempt will be made to collect full follow-up data on all study participants; it is thus

anticipated that missing data will be minimal and the strategies needed to achieve this are part of

this feasibility RCT. The main analysis will use available data only, however, the amount of missing

PREPS PROTOCOL ________________________________________________________________________________


data will be assessed, and if necessary, sensitivity analyses will be undertaken. Full details will be

included in the Statistical Analysis Plan.

12.3. Planned Interim Analysis

No interim analyses are planned for this feasibility study.

12.4. Decision to Continue to a Definitive Trial

The decision to continue to a full trial will be decided by pre-defined stop-go criteria. A traffic light system has been designed that will determine progression. Stop-go criteria

Recruitment rates: the proportion of women randomised into the trial of the 250 recruitment target (objective 1.1).

Adherence to the allocated intervention: the proportion of women who received their allocated intervention out of all those randomised (objective 4.3).

Successful completion of follow-up: the proportion of women remaining in the trial (i.e. not withdrawn as per criteria below) who successfully complete the planned follow-up process for both the 14 and 30 day telephone interview (objective 5.3).

Study drop-out: Withdrawal from the study (as detailed in 7.3 based on withdrawal categories 2, 3 and 4) (objective 7.1).

Traffic light system Green light: recruitment rate >90%; adherence rate >75%, follow-up rate >90% and dropout rate <15%. If all four criteria are met we will proceed to a full trial with the protocol unchanged (unless there is a clear message from the focus groups that would improve the protocol). Amber light: recruitment rate 80-90%, adherence rate 50-75%, follow-up rate 75-90% or dropout rate 15-30%. If one or more of our amber light criteria are met, we will plan to adapt the protocol in light of the feedback from the focus groups and our experience to improve whichever criteria are not at the “green-light” level before proceeding to full trial. We will assess whether adaption of the protocol will require a further feasibility study or pilot study before progressing. Red light: recruitment rate <80%, adherence rate <50%, follow-up rate <75% or dropout rate >30%. If one or more of these criteria are met we would consider the current protocol not feasible and not progress to a full RCT. The Trial Oversight Committee will take into consideration statistical uncertainty around these rates using 95% confidence intervals.

PREPS PROTOCOL ________________________________________________________________________________


13. TRIAL ORGANISATIONAL STRUCTURE

13.1. Sponsor

Birmingham Women’s and Children’s NHS foundation Trust is acting as the sponsor.

13.2. Coordinating Centre

Birmingham Clinical Trials Unit at the University of Birmingham

13.1. Trial Oversight Committee

Given this is a feasibility study, the trial oversight committee will comprise of a joint trial steering

committee and data monitoring committee and will meet three times through the proposed 15

months’ study. The Committee will provide supervision and advice for the study, and ensure the

study is conducted as applicable to the MRC Guidelines for Good Clinical Practice in Clinical Trials.

Trial data provided to the Trial Oversight Committee (TOC) will be anonymised but study group

allocation may be provided, if it is necessary for their deliberations regarding serious adverse events.

There is no planned interim analysis.

13.2. Finance

The research costs of the trial are funded by a grant from the NIHR Health Research for Patient

Benefit awarded to the BWCNFT.

The trial has been designed to minimise service support costs for participating hospitals and will

include identifying potential participants and gaining consent, which are estimated in the Contract

agreement. These costs should be met by accessing the Trust’s Support for Science budget provided

by the local Clinical Research Network.

PREPS PROTOCOL ________________________________________________________________________________


14. ETHICAL CONSIDERATIONS

The trial will be performed in accordance with the recommendations guiding physicians in

biomedical research involving human subjects, adopted by the 18th World Medical Association

General Assembly, Helsinki, Finland, 1964, amended by the 48th WMA General Assembly, Somerset

West, Republic of South Africa, 1996 (website:

http://www.wma.net/en/30publications/10policies/b3/index.html).

The trial will be conducted in accordance with the Research Governance Framework for Health and

Social Care, the applicable UK Statutory Instruments, (which include the Data Protection Act 1998

and Human Tissue Act 2008 and the Principles of GCP). The protocol will be submitted to and

approved by the main REC prior to circulation.

Before any participants are enrolled into the trial, the trial office will obtain HRA approval and the PI

at each site will obtain local R&D approval/assurance. Sites will not be permitted to enrol

participants until written confirmation of R&D approval/assurance is received by the BCTU trials

team.

It is the responsibility of the PI to ensure that all subsequent amendments gain the necessary local

approval prior to implementation. This does not affect the individual clinicians’ responsibility to take

immediate action if thought necessary to protect the health and interest of individual participants.

http://www.wma.net/en/30publications/10policies/b3/index.html

PREPS PROTOCOL ________________________________________________________________________________


15. CONFIDENTIALITY AND DATA PROTECTION

Personal data recorded on all documents will be regarded as strictly confidential and will be handled

and stored in accordance with the Data Protection Act 1998.

Women will always be identified using their unique trial identification number, on the Case Report

Form and any trial related correspondence. Women will give their explicit consent for the

movement of their consent form, giving permission for BCTU to be sent a copy. This will be used to

perform in-house monitoring of the consent process.

The Investigator must maintain documents not for submission to BCTU (e.g. Participant

Identification Logs) in strict confidence. In the case of specific issues and/or queries from the

regulatory authorities, it will be necessary to have access to the complete trial records, provided that

participant confidentiality is protected.

BCTU will maintain the confidentiality of all participants’ data and will not disclose information by

which participants may be identified to any third party. Representatives of the PREPS trial team and

sponsor may be required to have access to participant’s notes for quality assurance purposes but

participants should be reassured that their confidentiality will be respected at all times.

PREPS PROTOCOL ________________________________________________________________________________


16. Insurance and Indemnity

This is a clinician-initiated study and the Sponsor (BWCNFT) holds the relevant insurance for Clinical

Trials (negligent harm). Participants may be able to claim compensation, if they can prove that the

BWCNFT has been negligent. However, as this clinical trial is being carried out in a hospital setting,

NHS Trust and Non-Trust Hospitals have a duty of care to the patients being treated. Compensation

is only available via NHS indemnity in the event of clinical negligence being proven. Participants who

sustain injury and wish to make a claim for compensation should do so in writing in the first instance

to the CI, who will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office and BCTU. There

are no specific arrangements for compensation made in respect of any SAE occurring though

participation in the trial, whether from the side effects listed, or others yet unforeseen.

Hospitals selected to participate in this trial shall provide clinical negligence insurance cover for

harm caused by their employees and a copy of the relevant insurance policy or summary should be

provided to BWCNFT, upon request.

PREPS PROTOCOL ________________________________________________________________________________


17. Publication Policy

Results of this trial will be submitted for publication in a peer reviewed journal. The manuscript will

be prepared by the chief investigator and authorship will be determined by the trial publication

policy. Authors must acknowledge that the trial was performed with the support of BWCNFT and

NIHR RfPB.

PREPS PROTOCOL ________________________________________________________________________________


18. Reference List

1. Mackeen, A.D., et al., Timing of intravenous prophylactic antibiotics for preventing postpartum infectious morbidity in women undergoing cesarean delivery. Cochrane Database Syst Rev, 2014. 12: p. CD009516.

2. McKibben, R.A., et al., Practices to Reduce Surgical Site Infections Among Women Undergoing Cesarean Section: A Review. Infect Control Hosp Epidemiol, 2015. 36(8): p. 915-21.

3. Tuuli, M.G., et al., A Randomized Trial Comparing Skin Antiseptic Agents at Cesarean Delivery. N Engl J Med, 2016. 374(7): p. 647-55.

4. Haas, D.M., S. Morgan, and K. Contreras, Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev, 2014. 12: p. CD007892.

5. Intrapartum Care: Care of Healthy Women and Their Babies During Childbirth. 2014, London: 2014 National Collaborating Centre for Women's and Children's Health.

6. Committee Opinion No. 571: Solutions for surgical preparation of the vagina. Obstet Gynecol, 2013. 122(3): p. 718-20.

7. Tewfik H, I.A., Hanafi S, Fahmy A, Khaled M. Abdelrazak, Ibrahim A Abdelazim, Preoperative Vaginal Preparation using Povidone Iodine versus Chlorhexidine Solutions in Prevention of Endometritis in Elective Cesarean Section. Int.J.Curr.Microbiol.App.Sci., 2015. 4(8): p. 486-492.

8. Ohlsson, A., V.S. Shah, and B.C. Stade, Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. Cochrane Database Syst Rev, 2014. 12: p. CD003520.

9. Gale, N.K., et al., Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol, 2013. 13: p. 117.

10. RCOG obtaining valid consent guideline number 6. https://www.rcog.org.uk/en/guidelines-

research-services/guidelines/clinical-governance-advice, 2015

11. Centre for Disease Control and Prevention.

https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf January 2017

https://www.rcog.org.uk/en/guidelines-%20%20%20%20%20%20%20%20%20%20%20research-services/guidelines/clinical-governance-advice

https://www.rcog.org.uk/en/guidelines-%20%20%20%20%20%20%20%20%20%20%20research-services/guidelines/clinical-governance-advice

https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf%20January%202017

PREPS PROTOCOL ________________________________________________________________________________


Appendix 1 Definitions of primary outcome. Primary Outcome:

Development of Endometritis in the postnatal period (Day 0-30) Endometritis will be defined as per the definitions set out by the US Centre’s for Disease Control and Prevention (Centre’s for Disease Control and Prevention 2017) [11]. An episode of endometritis requires meeting at least one of the following criteria: 1. Organisms are cultured from fluid (including amniotic fluid) or tissue from endometrium obtained during an invasive procedure or biopsy. Not taken as part of surveillance. 2. Woman exhibits at least two of the following signs or symptoms: fever (>38°C), abdominal pain*, uterine tenderness*, or purulent drainage from uterus*. *With no other recognised cause. This is important as many women will have abdominal pain and uterine tenderness as part of the recovery process from a CS and therefore there must not be another more reasonable identifiable cause or explanation, within 30 days from the primary procedure. Women will therefore receive a telephone interview at 14 days and 30 days aiming to determine if women they have developed endometritis as per the CDC definition. Women in whom there is suspicion of untreated infection at the 14 day or 30 day post-delivery telephone interview will be invited to a clinical review at the hospital. This review will be performed by a clinician trained in trial processes to assess the women clinically and treat any infections and determine if the women meets the criteria for endometritis according to the CDC definition.

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