Chlorhexidine vaginal preparation versus standard treatment at caesarean section to reduce endometritis and prevent sepsis—a feasibility study protocol (the PREPS trial)

Chlorhexidine vaginal preparation versus standard treatment at caesarean section to reduce... Background: Worldwide caesarean section (CS) delivery is the most common major operation. Approximately 25% of pregnant women undergo a CS in the UK for delivery of their babies. Sepsis and post-natal infection constitute significant maternal mortality and morbidity. Infection following a CS has a number of primary sources including endometritis occurring in 7–17% of women. Sepsis reduction and reduction in antibiotic use have been identified as a national and international priority. The overarching aim of this research is to reduce infectious morbidity from caesarean sections. Methods: This is a parallel group feasibility randomised controlled trial comparing vaginal cleansing using chlorhexidine gluconate versus no cleansing (standard practice) at CS to reduce infection. Women will be recruited from four National Health Service maternity units. Two hundred fifty women (125 in each arm) undergoing elective or emergency CS, who are aged 16 years and above, and at least 34 weeks pregnant will be randomised. Allocation to treatment will be on a 1:1 ratio. The study includes a qualitative aspect to develop women centred outcomes of wellbeing after delivery. Discussion: 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. Trial registration: The PREPS trial has been registered with ISRCTN (ISRCTN 33435996). Keywords: Caesarean section, Chlorhexidine, Endometritis, Sepsis, Post-natal infection, Vaginal cleansing, Feasibility Background Sepsis and post-natal infection constitute significant ma- Justification for participant population ternal mortality and morbidity, as well as having significant Worldwide caesarean section (CS) delivery is the most impact on post-natal recovery and maternal wellbeing. In- common major operation. Approximately 25% of preg- fection following a CS has numerous primary sources in- nant women undergo a CS in the UK for delivery of cluding endometritis, occurring in 7–17% of women; this their babies. This equates to approximately 171,000 cae- equates to approximately 27,000 cases of infection per year sarean sections per year in England alone. in England only. Risk factors for endometritis following CS include in labour caesarean section and ruptured mem- branes with or without vaginal colonisation with group B streptococcus. Sepsis reduction and reduction in antibiotic * Correspondence: R.K.Morris@bham.ac.uk usehavebeenidentifiedasnational and international prior- Institute of Metabolism and Systems Research, College of Medical and ities, improving maternal health and neonatal wellbeing Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK through the facilitation of ongoing breast feeding. Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 2 of 10 Justification for intervention to moderate confidence, although further large scale Prophylactic antibiotics at the time of surgery have been trials to detect small but clinically important differ- demonstrated to be beneficial in a number of large ran- ences were needed. Importantly, no safety concerns domised controlled trials (RCT) and continue to reduce for the mother or baby have been identified within infection rates [1]. Current practice of skin preparation these studies [8]. [2] is guided by a recent RCT demonstrating the super- iority of a chlorhexidine over an iodine-based solution Methods [3]. In addition to skin preparation with an antiseptic so- Aims lution, cleansing inside the vagina with povidone iodine The overarching aim of this research is to reduce infec- has been evaluated [4]. A Cochrane review of seven trials tious morbidity from caesarean sections. Specific objec- randomising 2816 women (2635 analysed) estimated the tives for this feasibility study include: effects of vaginal cleansing (all with povidone-iodine) on post-caesarean infectious morbidity [4]. Vaginal prepar-  To determine appropriate recruitment and ation immediately before caesarean delivery significantly randomisation processes reduced the incidence of post-caesarean endometritis  To assess if women can remain blinded to the trial from 8.3% in control groups to 4.3% in vaginal cleansing intervention groups (average risk ratio (RR) 0.45, 95% confidence  To determine the sample size required for a interval (CI) 0.25 to 0.81, seven trials, 2635 women). definitive trial The risk reduction was particularly strong for women  To inform if the intervention can be conducted in a who were already in labour at the time of the caesarean multi-centre RCT delivery (7.4% in the vaginal cleansing group versus 13.  To develop women focused outcome measures and 0% in the control group; RR 0.56, 95% CI 0.34 to 0.95, method of data collection three trials, 523 women) and for women with ruptured  To assess data collection of clinical outcomes up to membranes (4.3% in the vaginal cleansing group versus 6 weeks 17.9% in the control group; RR 0.24, 95% CI 0.10 to 0.  To assess withdrawals 55, three trials, 272 women [4]). The above would ap- pear an effective and important strategy to reduce mor- Qualitative study design bidity at CS, yet this has not been adopted within A qualitative study will inform the outcomes that will be obstetric practice internationally and does not feature collected on women in the feasibility RCT. Two focus within the NICE Intrapartum guideline [5]. This is due groups will be performed at the lead site (Birmingham to concerns with exposure of the fetus to iodine-based Women’s and Children’s Hospital BWCH) of approxi- substances, concerns with vaginal staining and allergy to mately 7 to 10 women in each group who have undergone iodine. Iodine is a recognised antibacterial agent, but in- a CS and would like to contribute to the development of activity by the presence of blood [6] limits its use. Thus, women-centred outcomes. there are a number of reasons to believe that vaginal Women will be recruited via adverts placed on BWCH cleansing with chlorhexidine would be an appropriate al- notice boards and on the post-natal wards, through so- ternative to povidone iodine. Some studies show greater cial media platforms; community midwives will be asked reduction in skin flora after application of chlorhexidine to identify women, as well as hospital midwives if (0.5 and 4%) [6] compared with povidone-iodine agents. women re-attend and through patient engagement ser- Also, chlorhexidine may have a greater residual activity vices at BWCH. We will ask women who have had a CS after application than other preparations and, unlike within the previous 6 months to contribute to focus povidone iodine, it is not inactivated by the presence of groups on important women-centred outcomes for re- blood. Solutions that contain lower concentrations, such search into infection and complications following a CS. as the commonly used chlorhexidine gluconate and acet- The focus groups will be performed prior to com- ate (0.05%), are usually well tolerated and may be used mencement of recruitment to the feasibility RCT and for vaginal preparation [6]. With this preparation, there thus used to decide on outcomes for inclusion in the are no reported cases of allergy. There is one small ran- feasibility trial that the women feel are important for domised controlled trial comparing povidone iodine with post-natal quality of life and recovery. All women will chlorohexidine gluconate for vaginal cleansing at CS. have demographic data collected. The focus groups will This suggested that chlorohexidine may be superior, and be recorded and transcribed anonymously. The data will further research was needed [7]. be analysed thematically and managed using the Frame- A Cochrane review of cleansing the vagina in normal work Method [9]. An experienced qualitative researcher vaginal delivery with chlorhexidine showed no evidence will run the focus groups, with the support of a research of an effect on maternal or neonatal infections with low associate and the clinical research fellow. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 3 of 10 From informal discussions with women who have  Aged 16 years or over undergone CS, the outcomes are likely to be composed of the following themes: Women will be excluded from the trial if they: Length of midwife follow-up  Have a known allergy to chlorhexidine gluconate or Prolonged use of analgesics any of its ingredients Ability to care for self  Are receiving prophylactic intravenous antibiotics Time to leaving house with family/independently for group B streptococcus (GBS) colonisation Ability to care for a baby  Are receiving intravenous antibiotics for suspected infection (standard CS intravenous prophylaxis is Feasibility study design not an exclusion criteria) Blinded to women and personnel performing outcome  Are currently enrolled in an RCT for an intervention collection, parallel group, feasibility RCT compared vagi- intended to reduce post-operative surgical site infection nal cleansing using chlorhexidine gluconate or acetate versus no cleansing (standard practice) at CS to reduce All women already enrolled in an interventional study infection. Allocation to treatment will be on a 1:1 ratio. are permitted to be co-enrolled into PREPS, as long as A feasibility randomised controlled trial design is being the intervention is not intended to reduce infection. undertaken to test the consent and randomisation pro- After consent and randomisation to PREPS, women will cesses for women requiring a CS, and the follow-up pro- not be permitted to enter a further interventional study cesses up until the immediate post-natal period, to ensure if the study is evaluating the prevention of infection. Co- we can overcome the challenges this poses. enrolment in all observational studies is permitted. Trial setting Randomisation The trial will be undertaken in maternity hospitals: After the woman’s eligibility has been confirmed and in- Birmingham Women’s and Children’s Hospital, Birming- formed consent has been received, the woman can be ham Heartlands Hospital, Shrewsbury and Telford randomised into the trial (Fig. 1). Randomisation can be Hospital (West Midlands) and Sunderland Royal Hospital, performed by all members of the research team and clin- to ensure the trial can be extrapolated to a larger multi- ical team and is most likely to be performed by dedi- centre trial. cated research midwives. Randomisation will be provided by a secure automated Identification of participants telephone randomisation system available 24 h a day/ Given recruitment, consent and randomisation processes 7 days a week provided by the University of Aberdeen. will differ for emergency and elective CS due to differ- The telephone randomisation service will comply with ences in planning for surgery; the processes for each research and governance standards. type of surgery will be detailed separately. All women The randomised allocation will be documented in the booking at any of the hospitals over the study period main hospital records on the anaesthetic chart, on a and who are greater than 34 weeks pregnant while re- dedicated sticker within the patient notes and on the cruitment is running will be posted a patient informa- relevant case report forms. The allocation will not be tion leaflet. This is to ensure that all women are aware disclosed to the woman or recorded in the post-natal of the study before delivery of their baby/babies. This hand-held notes. will be accompanied with patient information leaflets Women will be randomised at the level of the individ- and study information being available in antenatal clinics ual in a 1:1 ratio to either chlorohexidine gluconate or and triage waiting rooms. Study posters will also be dis- acetate 0.05% vaginal cleansing or standard treatment of played in prominent positions through the hospitals. no vaginal cleansing. A minimisation algorithm will be used to ensure balance in the treatment allocation over Eligibility criteria and co-enrolment the following variables: Women will be included in the trial if they are as follows:  Randomising centre In labour and not in labour CS Greater than or equal to 34 weeks pregnant Having a CS A ‘random element’ will be included in the minimisa- Able to give informed written consent tion algorithm so that each patient has a probability (un- Able to receive a telephone interview at 14 and specified here) of being randomised to the opposite 30 days post-natal treatment that they would have otherwise received. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 4 of 10 Fig. 1 Trial participant flow Blinding intervention was applied on the theatre operation note The trial cannot be blinded to the operator or the and anaesthetic/operation chart, which are not held in clinical care team in theatre providing care to the the maternal post-natal notes. As a part of the monitor- women due to the nature of the intervention. Ran- ing process, 10% of medical records will be independ- domisation will be performed by a wide range of staff ently monitored and data collection will be verified by from theatre runners to consultants. Randomisation the trial sponsor on-site. may be performed by dedicated research midwives The research midwife conducting the telephone who will also collect outcome data from the notes, follow-up interviews will be blinded to the treatment but there will be no recording of the allocation in the group so that there will be no bias in the collection of post-natal notes. outcomes. The research midwife will not have an access Attempts will be made to blind the women as the to the medical records or any data collection forms at intervention will be applied at the time of the catheter the time of telephone interviews. insertion, and the woman should not be aware of the ap- At the end of the 14-day interview, the midwife will plication due to anaesthesia. ask the woman whether she feels she received the inter- All data collection from the maternal notes will be vention or not to assess whether blinding of the woman blinded since there will only be recording of whether the is an achievable aim. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 5 of 10 Intervention  The proportion of women who are randomised into Chlorohexidine gluconate 0.05% or chlorohexidine acet- the PREPS trial with verbal consent from the ate 0.05% will be used to perform vaginal cleansing. The number of women whom have an emergency CS active ingredient is chlorhexidine 0.05%. This is indi-  The proportion of women randomised who can cated within the British National Formulary for swab- successfully identify what treatment they received bing in obstetrics. (i.e. vaginal cleansing or no vaginal cleansing) Fifty millilitres of antiseptic (chlorohexidine gluconate  The proportion of complete data for each of the 0.05% or chlorohexidine acetate 0.05%) will be emptied clinical and woman reported outcomes of women into a sterile pot. A single swab/sponge mounted on a randomised sponge holder soaked in the antiseptic will be used to  Time taken to perform the telephone interviews clean the vagina prior to CS at the time of urinary cath-  Reasons for withdrawal eter insertion, for guidance, we suggest the vaginal cleansing should take 30 s. Following the CS procedure, Clinical outcomes the vagina will be cleaned of excess blood as is standard The following clinical outcomes will be collected to in- practice with a dry swab. The application of the inter- form sample size calculations for the main RCT. vention is quick and familiar to the doctors performing the surgery due to their experience in gynaecological Development of CDC defined endometritis in the post-natal surgery where it is routine practice. All theatres’ stand- period (days 0–30) ard operating procedures regarding swabs and instru- The development of endometritis meeting the CDC def- ment counts should be adhered to, to ensure patient inition, in the post-natal period (day 0 of delivery), is the safety. At all sites, staff will be asked to record if they proposed primary outcome for the full RCT. Endometritis have performed vaginal cleansing, and if performed, will be defined as per the definitions set out by the US which antiseptic was used, on the CS operation note Centre’s for Disease Control and Prevention (Centre’sfor within the hospital notes. Disease Control and Prevention 2017) [10]. Clinical diagnosis of endometritis in the post-natal period Outcomes (days 0–30) All feasibility outcomes will be assessed overall and by Diagnosis of endometritis by a clinician which does not centre. Recruitment will take place for a minimum of meet the CDC definition or cannot be verified to meet 12 weeks and a maximum of 20 weeks, across the four the definition, e.g. a woman treated in the community maternity sites. for suspected endometritis where it is not feasible to es- tablish that this meets the CDC definition or where the diagnosis does not meet the criteria. Stop-go criteria The decision to continue to a full trial will be decided by Maternal sepsis (days 0–42) pre-defined stop-go criteria based on the following Defined according to the NICE sepsis guideline (released outcomes: July 2016) [10]. The proportion of women randomised into the trial Length of hospital stay of the 250 recruitment target The length of hospital stay from randomisation to dis- The proportion of women who received their charge home or transfer to another hospital following CS allocated intervention out of all those randomised or up to 6 weeks after randomisation if not discharged. The proportion of women remaining in the trial (i.e. not withdrawn) who successfully complete the Readmission to hospital after CS for suspected or confirmed planned follow-up process for both the 14- and infection (days 0–42) 30-day telephone interview It is defined as readmission to hospital post-discharge Withdrawal from the study home up until 6 weeks postnatally. Other feasibility outcomes Antibiotic prescriptions These are antibiotics prescribed as an inpatient and hos- The proportion of eligible women approached to pital prescribed outpatient (days 0–42) and antibiotic take part prescriptions for suspected/confirmed surgical site infec- The proportion of women randomised who have an tion relating to the woman’s CS (uterine, pelvic, abdom- elective/emergency CS inal wound and perineal). Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 6 of 10 Requiring level 2 or level 3 critical care Complete withdrawal This is defined as requiring level 2 or 3 critical care (or The woman wishes to withdraw completely (i.e. from obstetric HDU type care) as a result of an infection up trial treatment and all follow-ups) and is not willing to until 6 weeks postnatally (days 0–42). have any of their data, including that already collected, The endometritis outcomes are collected up until day to be used in any future trial analysis. 30 to be consistent with the CDC definition of endomet- ritis, and the sepsis related outcomes are collected up Adverse events and serious adverse events until 6 weeks to be consistent with the national collec- The collection and reporting of adverse events (AEs) will tion of post-natal sepsis. be in accordance with the Research Governance Frame- work for Health and Social Care and the requirements of the Health Research Authority (HRA). No neonatal Patient-reported outcomes AEs or SAEs are required to be reported as the interven- These will be determined by the qualitative component tion is licenced for use in obstetrics over 34 weeks for of this feasibility study and reported as an outcome of swabbing as per the SmPC and has a demonstrated the feasibility study along with summary statistics pre- safety record in many trials in neonates above 34 weeks specified in the statistical analysis plan. gestation [11]. Participant withdrawal Adverse events (AE) Informed consent is defined as the process of learning There are certain AEs which are commonly expected in the key facts about a clinical trial before deciding participants as a result of pregnancy and/or CS. As these whether or not to participate. It is a continuous and dy- events are well characterised, it is highly unlikely that namic process, and women should be asked about their this trial will reveal any new safety information relating ongoing willingness to continue participation with the to this intervention. Thus, there will be no AEs telephone interviews before the interview questions recorded. commence. Women should be aware at the beginning that they can freely withdraw (discontinue participation) Serious adverse events (SAE) from the trial (or part of the trial) at any time. All events which meet the definition of serious will be Types of withdrawal as defined are as follows: collected and recorded in the participant notes and the Case Report Form (CRF). SAEs will, in addition, be re- ported to the trials office immediately and within 24 h of Before the intervention the principal investigator being made aware of the event. The woman would like to withdraw from trial treatment, Allergic reaction to chlorohexidine requiring treatment before the intervention, is applied but is willing to be will be considered a serious adverse advent. followed up in accordance with the schedule of assess- Events not considered an SAE in PREPS include: ments and if applicable using any central UK NHS bod- ies for long-term outcomes (i.e. the woman has agreed Hospitalisation for delivery of the baby that data can be collected and used in the trial analysis). The development of infection and sepsis in the post-natal period that requires inpatient treatment After the intervention or prolongation of hospitalisation as this is an The woman would like to withdraw from the trial after outcome of the trial the allocation is applied and does not wish to participate Obstetric haemorrhage in the telephone interview but is willing to be followed Damage to bowel or bladder during surgery up at any visits and if applicable using any central UK Prolonged hospitalisation due to neonatal NHS bodies for long-term outcomes (i.e. the woman has complications agreed that data can be collected at standard visits and Thromboembolic events used in the trial analysis, including data collected as part of long-term outcomes). All other events not detailed above that meet the def- inition of a SAE should be reported as detailed below. Without follow-up SAEs should be reported on an SAE Form. When The woman would like to withdraw from the trial after completing the form, the PI will be asked to define the the allocation is applied and is not willing to be followed causality and the severity of the SAE. Causality will be up in any way for the purposes of the trial and for no assessed as definitely related, probably related, possibly further data to be collected (i.e. only data collected prior related, unlikely to be related or unrelated. On becoming to the withdrawal can be used in the trial analysis). aware that a woman has experienced an SAE, the Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 7 of 10 Investigator or delegate(s) should report the SAE to their statistical analyses. A brief outline of the planned analyses own Trust in accordance with local practice and to the is given below. BCTU trials office. On receipt of an SAE form, the Chief All clinical outcomes will be analysed according to the Investigator (CI) or delegate(s) will independently deter- treatment arm to which they were randomised (i.e. vaginal mine the seriousness and causality of the SAE. An SAE cleansing or no cleansing) irrespective of compliance with judged by the PI or CI or delegate(s) to have a reasonable the randomised treatment allocation, as per the intention causal relationship with the intervention will be regarded to treat principle. Women who did not undergo a CS will as a related SAE. The causality assessment given by the PI be excluded from the analyses. will not be downgraded by the CI or delegate(s). If the CI All feasibility outcomes will be analysed pooling the or delegate(s) disagrees with the PI’s causality assessment, two randomised groups and presenting overall estimates the opinion of both parties will be documented, and where of proportions with 95% confidence intervals, as well as the event requires further reporting, the opinion will be estimates by centre. provided with the report. The CI “or delegate(s)” will also All outcomes will primarily take the form of simple assess all related SAEs for expectedness. If the event is un- descriptive statistics (e.g. proportions and percentages, expected (i.e. is not defined in the protocol as an expected means and standard deviations) and where appropriate, event), it will be classified as an unexpected and related point estimates of effect sizes (e.g. mean differences and SAE. BCTU will report all events categorised as unex- relative risks) and associated 95% confidence intervals. pected and related SAEs to the main Research Ethics Committee (REC) within 15 days. The main REC and Decision to continue to a definitive trial sponsor will be notified immediately if a significant safety The decision to continue to a full trial will be decided by issue is identified during the course of the trial. pre-defined stop-go criteria. A traffic light system has been designed that will determine progression. Sample size and data analysis Sample size Stop-go criteria Since this is a feasibility study, no formal sample size calculations have been undertaken. The feasibility study  Recruitment rates: the proportion of women is not designed or powered to detect a statistically sig- randomised into the trial of the 250 recruitment target. nificant difference in efficacy between the two treatment  Adherence to the allocated intervention: the arms. A total sample size of 250 participants would proportion of women who received their allocated agree with existing literature which suggests that the size intervention out of all those randomised. of the feasibility study should be at least 10% of the an-  Successful completion of follow-up: the proportion ticipated size of the substantive study [12]. A recruit- of women remaining in the trial (i.e. not withdrawn ment target of 250 participants has been chosen for this as per criteria below) who successfully complete the feasibility study as we expect this number will be suffi- planned follow-up process for both the 14- and 30- cient to provide estimates of the feasibility outcomes. day telephone interview. Preliminary sample size calculations were computed  Study drop-out: withdrawal from the study. for the full RCT. Vaginal cleansing with povidone iodine has been evaluated in a Cochrane review which com- Traffic light system prised of seven trials randomising 2816 women (2635 Green light: recruitment rate > 90%, adherence rate > 75%, analysed) estimating the effects of vaginal cleansing follow-up rate > 90% and dropout rate < 15%. If all four (povidone-iodine) on post-caesarean infectious morbid- criteria are met, we will proceed to a full trial with the ity. The risk of bias was generally low, with the quality protocol unchanged (unless there is a clear message from of most of the studies being high. Vaginal preparation the focus groups that would improve the protocol). immediately before caesarean delivery significantly re- Amber light: recruitment rate 80–90%, adherence rate duced the incidence of post-caesarean endometritis from 50–75%, follow-up rate 75–90% or dropout rate 15–30%. 8.3% in control groups to 4.3% in vaginal cleansing If one or more of our amber light criteria are met, we will groups. To detect a difference of this size with 90% plan to adapt the protocol in light of the feedback from power and alpha at 5%, we would require 1548 partici- the focus groups and our experience to improve which- pants. In addition, to account for an anticipated 10% loss ever criteria are not at the ‘green-light’ level before pro- to follow-up, we would need a total of 1720 participants. ceeding to full trial. We will assess whether adaption of the protocol will require a further feasibility study or pilot Analysis of outcome measures study before progressing. A separate statistical analysis plan for the PREPS feasibility Red light: recruitment rate < 80%, adherence rate < 50%, study will provide a detailed description of the planned follow-up rate < 75% or dropout rate > 30%. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 8 of 10 If one or more of these criteria are met, we would con- Birmingham have to be registered with the Data Protec- sider the current protocol not feasible and not progress tion Officer and data held in accordance with the Data to a full RCT. Protection Act. The University will designate a Data Pro- The Trial Oversight Committee will take into consid- tection Officer upon registration of the study. The study eration statistical uncertainty around these rates using centre has arrangements in place for the secure storage 95% confidence intervals. and processing of the study data which comply with the Missing data: Every attempt will be made to collect full University of Birmingham policies. follow-up data on all study participants; it is thus antici- pated that missing data will be minimal and the strat- Discussion egies needed to achieve this are part of this feasibility Post-partum infection/sepsis is a significant global prob- RCT. The main analysis will use available data only; lem. With the increasing evidence regarding antimicrobial however, the amount of missing data will be assessed, resistance and the development of bacterial resistance and if necessary, sensitivity analyses will be undertaken. there, is concern that without action, common procedures such as CS will carry significant risks. We must, therefore, Trial and data management seek strategies that reduce this risk. We aim to perform a Sponsor feasibility study for a larger multi-centre randomised The PREPS trial is sponsored by Birmingham Women’s controlled trial (RCT) comparing vaginal cleansing with and Children’s NHS Foundation Trust. chlorhexidine versus standard practice of no vaginal cleansing immediately before CS to reduce post-partum Coordinating centre endometritis and sepsis. There are a number of difficulties The coordinating centre is the Birmingham Clinical Tri- in performing a RCT in pregnant women undergoing CS, als Unit at the University of Birmingham. 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 Trial oversight committee procedures: mothers are discharged from obstetric care Given this is a feasibility study, the Trial Oversight quickly with no routine post-operative follow-up. They Committee (TOC) will comprise of a joint trial steer- are motivated to recover and care for their baby. It is ing committee and data monitoring committee and therefore necessary to perform this feasibility trial to as- will meet three times through the proposed 15-month sess both our ability to recruit women and adequately fol- study. The TOC will provide supervision and advice low them up. The main limitation of this feasibility study for the study and ensure the study is conducted as is that it is being performed within units motivated to per- applicable to the MRC Guidelines for Good Clinical form the feasibility trial and this may not accurately repre- Practice in Clinical Trials. Trial data provided to the sent recruitment in all sites. TOC will be anonymised, but study group allocation may be provided, if it is necessary for their delibera- tions regarding serious adverse events. There is no Conclusion planned interim analysis. This is a feasibility randomised controlled trial, assessing the feasibility of performing a trial of vaginal chlorohexidine cleansing to prevent post-natal infection. Testing newly de- Data management veloped verbal consent, randomisation and follow-up pro- Processes will be employed to facilitate the accuracy of cesses in this population. 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 status trial’s coordinator, statistician and programmer, and the The PREPS trial opened to recruitment on 11th November trial database will be signed off once the implementation 2017. At the time of submitting this protocol for publica- of these has been assured. tion, the trial was actively recruiting participants. Data security Abbreviations AEs: Adverse events; BCTU: Birmingham Clinical Trials Unit; The security of the trial database is governed by the pol- BWCH: Birmingham Women’s and Children’s Hospital; CDC: Centre for icies of the University of Birmingham. The University’s Disease Control and Prevention; CI: Chief investigator; CRF: Case report form; Data Protection Policy and the Conditions of Use of CS: Caesarean section; HRA: Health Research Authority; NHS: National Health Service; NICE: National Institute for Clinical Excellence; PI: Principal Computing and Network Facilities set out the security investigator; PIL: Patient information leaflet; RCT: Randomised controlled trial; arrangements under which sensitive data should be REC: Research Ethics Committee; RR: Risk ratio; SAE: Serious adverse events; processed and stored. All studies at the University of SmPC: Summary of product characteristics Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 9 of 10 Acknowledgements Authors’ contributions Thank you to the women who participated in the focus groups and helped VMH conceived and is the clinical lead on the trial. RKM is the Chief Investigator inform the trial outcomes. This paper presents independent research funded by of the trial. AW is coordinating the trial with NF as lead research midwife. AWe the National Institute for Health Research (NIHR) under its Research for Patient is leading the qualitative component. PH is the lead statistician, and CH is the Benefit (RfPB) Programme (Grant Reference Number PB-PG-1215-20013). The trial statistician. VMH, AW, AWe, NF, DL, CH, PH and RKM contributed to the views expressed are those of the author(s) and not necessarily those of the preparation of the protocol. All authors read and approved the final manuscript. NHS, the NIHR or the Department of Health and Social Care. Ethics approval and consent to participate The trial will be performed in accordance with the recommendations guiding Elective caesarean section physicians in biomedical research involving human subjects, adopted by the A suitably qualified research midwife or doctor will introduce the study to 18th World Medical Association General Assembly, Helsinki, Finland, 1964, the woman at their pre-operative assessment. A patient information leaflet amended by the 48th WMA General Assembly, Somerset West, Republic of (PIL) will be provided to facilitate this process. Investigators will ensure that South Africa, 1996. The trial will be conducted in accordance with the Research they adequately explain the aim, trial treatment, anticipated benefits and Governance Framework for Health and Social Care and the applicable UK potential hazards of taking part in the trial to the woman. They will also Statutory Instruments (which include the Data Protection Act 1998 and Human stress that participation is voluntary and that the woman is free to refuse Tissue Act 2008 and the Principles of GCP). The protocol was approved by the to take part and may withdraw from the trial at any time. The woman will London City & East Research Ethics Committee (17/LO/0874) before any be given adequate time to read the PIL and to discuss their potential participants are enrolled into the trial, the trial office will obtain HRA approval participation and be given the opportunity to ask questions. If the woman and the PI at each site will obtain local R&D approval/assurance. Sites will not expresses an interest in participating in the trial, they will be asked to sign be permitted to enrol participants until written confirmation of R&D approval/ and date the latest version of the Informed Consent Form. The woman will assurance is received by the BCTU trials team. 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 Consent for publication take approximately 5–15 min. It will be the responsibility of the investigator Results of this trial will be submitted for publication in a peer reviewed journal. to obtain written informed consent for each participant prior to performing The manuscript will be prepared by the chief investigator, and authorship will any trial related procedure. be determined by the trial publication policy. Authors must acknowledge that A copy of the consent form will be given to the woman, a copy filed in the the trial was performed with the support of BWCNFT and NIHR RfPB. medical records with the PIL. The original signed consent form will be filed in the investigator site file. Competing interests The authors declare that they have no competing interests. Emergency caesarean section In the majority of emergency CS, the woman will be asked to consent as per Publisher’sNote the elective procedure. It is expected that the majority of women undergoing Springer Nature remains neutral with regard to jurisdictional claims in published emergency CS will provide written consent prior to trial-related procedures maps and institutional affiliations. commencing. It is appreciated that time can be limited in the undertaking of an emergency Author details CS, especially where there is suspected maternal or foetal compromise. In Institute of Metabolism and Systems Research, College of Medical and keeping with the Royal College of Obstetricians and Gynaecologist consent Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. advice for women participating in research, as long as information is available Birmingham Clinical Trials Unit, Institute of Applied Health Sciences, College antenatally, it is reasonable to take consent in labour [13]. The common of Medical and Dental Sciences, University of Birmingham, Birmingham B15 incidence of CS (an event that occurs in 25% of women) and the expectation 2TT, UK. School of Health and Social Care, Birmingham City University, of women in labour that CS is a possibility means that giving information to all Birmingham B15 3TN, UK. Birmingham Women’s and Children’s Hospital women would not overburden them and is unlikely to cause anxiety or deviate NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK. women from the normal birth process. In the emergency situation where time is limited, verbal consent for the intervention will be obtained prior to Received: 13 February 2018 Accepted: 18 April 2018 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 References discussion will include confirmation that the woman has previously received 1. Mackeen AD, et al. Timing of intravenous prophylactic antibiotics for information regarding the trial, understands that the choice of intervention preventing postpartum infectious morbidity in women undergoing will be made randomly and is willing to take part. cesarean delivery. Cochrane Database Syst Rev. 2014;12:CD009516. After the procedure, a PIL will be provided highlighting the follow-up and 2. McKibben RA, et al. Practices to reduce surgical site infections among confirmation of willingness to continue to participate. They will also stress women undergoing cesarean section: a review. Infect Control Hosp that participation is voluntary and that she is free to refuse to take part and Epidemiol. 2015;36(8):915–21. may withdraw from the trial at any time. If the woman is willing to continue 3. Tuuli MG, et al. A randomized trial comparing skin antiseptic agents at to participate in the trial, she will be asked to sign and date the latest version cesarean delivery. N Engl J Med. 2016;374(7):647–55. of the ICF. 4. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev. 2014;12:CD007892. Ancillary and post-trial care 5. Intrapartum Care. Care of healthy women and their babies during Participants can be referred to the Patient Advisory Liaison Service if required. childbirth. London: 2014 National Collaborating Centre for Women’s and Children’s Health; 2014. Funding 6. American College of Obstetricians and Gynecologists Women's Health Care The PREPS Trial is funded by the National Institute of Health Research under Physicians; Committee on Gynecologic Practice. Committee opinion no. the Research for Patient Benefit (RfPB) scheme (PB-PG-1215-20013). The 571: solutions for surgical preparation of the vagina. Obstet Gynecol. 2013; sponsor is BWCNFT Mrs. K Hard Kelly.Hard@bwnft.nhs.uk. 122(3):718–20. 7. Tewfik H, Ibrahim A, Hanafi S, Fahmy A, Khaled MA, Abdelazim IA. Availability of data and materials Preoperative vaginal preparation using povidone iodine versus The datasets generated and/or analysed during the current study are available chlorhexidine solutions in prevention of endometritis in elective cesarean from the corresponding author on reasonable request. section. Int J Curr Microbiol App Sci. 2015;4(8):486–92. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 10 of 10 8. Ohlsson A, Shah VS, Stade BC. Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. Cochrane Database Syst Rev. 2014;12:CD003520. 9. Gale NK, et al. Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol. 2013;13:117. 10. Centre for Disease Control and Prevention. https://www.cdc.gov/nhsn/pdfs/ pscmanual/pcsmanual_current.pdf. Accessed 3 Feb 2017. 11. Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N. Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. Cochrane Database Syst Rev. 2015;(3):CD007835. https://doi.org/10.1002/14651858. CD007835.pub2. 12. Connelly LM. Pilot studies. Medsurg Nurs. 2018;17(6):411–2. 13. RCOG obtaining valid consent guideline number 6. 2015. https://www.rcog.org. uk/en/guidelines-research-services/guidelines/clinical-governance-advice-6/. 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Chlorhexidine vaginal preparation versus standard treatment at caesarean section to reduce endometritis and prevent sepsis—a feasibility study protocol (the PREPS trial)

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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general; Statistics for Life Sciences, Medicine, Health Sciences
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Abstract

Background: Worldwide caesarean section (CS) delivery is the most common major operation. Approximately 25% of pregnant women undergo a CS in the UK for delivery of their babies. Sepsis and post-natal infection constitute significant maternal mortality and morbidity. Infection following a CS has a number of primary sources including endometritis occurring in 7–17% of women. Sepsis reduction and reduction in antibiotic use have been identified as a national and international priority. The overarching aim of this research is to reduce infectious morbidity from caesarean sections. Methods: This is a parallel group feasibility randomised controlled trial comparing vaginal cleansing using chlorhexidine gluconate versus no cleansing (standard practice) at CS to reduce infection. Women will be recruited from four National Health Service maternity units. Two hundred fifty women (125 in each arm) undergoing elective or emergency CS, who are aged 16 years and above, and at least 34 weeks pregnant will be randomised. Allocation to treatment will be on a 1:1 ratio. The study includes a qualitative aspect to develop women centred outcomes of wellbeing after delivery. Discussion: 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. Trial registration: The PREPS trial has been registered with ISRCTN (ISRCTN 33435996). Keywords: Caesarean section, Chlorhexidine, Endometritis, Sepsis, Post-natal infection, Vaginal cleansing, Feasibility Background Sepsis and post-natal infection constitute significant ma- Justification for participant population ternal mortality and morbidity, as well as having significant Worldwide caesarean section (CS) delivery is the most impact on post-natal recovery and maternal wellbeing. In- common major operation. Approximately 25% of preg- fection following a CS has numerous primary sources in- nant women undergo a CS in the UK for delivery of cluding endometritis, occurring in 7–17% of women; this their babies. This equates to approximately 171,000 cae- equates to approximately 27,000 cases of infection per year sarean sections per year in England alone. in England only. Risk factors for endometritis following CS include in labour caesarean section and ruptured mem- branes with or without vaginal colonisation with group B streptococcus. Sepsis reduction and reduction in antibiotic * Correspondence: R.K.Morris@bham.ac.uk usehavebeenidentifiedasnational and international prior- Institute of Metabolism and Systems Research, College of Medical and ities, improving maternal health and neonatal wellbeing Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK through the facilitation of ongoing breast feeding. Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 2 of 10 Justification for intervention to moderate confidence, although further large scale Prophylactic antibiotics at the time of surgery have been trials to detect small but clinically important differ- demonstrated to be beneficial in a number of large ran- ences were needed. Importantly, no safety concerns domised controlled trials (RCT) and continue to reduce for the mother or baby have been identified within infection rates [1]. Current practice of skin preparation these studies [8]. [2] is guided by a recent RCT demonstrating the super- iority of a chlorhexidine over an iodine-based solution Methods [3]. In addition to skin preparation with an antiseptic so- Aims lution, cleansing inside the vagina with povidone iodine The overarching aim of this research is to reduce infec- has been evaluated [4]. A Cochrane review of seven trials tious morbidity from caesarean sections. Specific objec- randomising 2816 women (2635 analysed) estimated the tives for this feasibility study include: effects of vaginal cleansing (all with povidone-iodine) on post-caesarean infectious morbidity [4]. Vaginal prepar-  To determine appropriate recruitment and ation immediately before caesarean delivery significantly randomisation processes reduced the incidence of post-caesarean endometritis  To assess if women can remain blinded to the trial from 8.3% in control groups to 4.3% in vaginal cleansing intervention groups (average risk ratio (RR) 0.45, 95% confidence  To determine the sample size required for a interval (CI) 0.25 to 0.81, seven trials, 2635 women). definitive trial The risk reduction was particularly strong for women  To inform if the intervention can be conducted in a who were already in labour at the time of the caesarean multi-centre RCT delivery (7.4% in the vaginal cleansing group versus 13.  To develop women focused outcome measures and 0% in the control group; RR 0.56, 95% CI 0.34 to 0.95, method of data collection three trials, 523 women) and for women with ruptured  To assess data collection of clinical outcomes up to membranes (4.3% in the vaginal cleansing group versus 6 weeks 17.9% in the control group; RR 0.24, 95% CI 0.10 to 0.  To assess withdrawals 55, three trials, 272 women [4]). The above would ap- pear an effective and important strategy to reduce mor- Qualitative study design bidity at CS, yet this has not been adopted within A qualitative study will inform the outcomes that will be obstetric practice internationally and does not feature collected on women in the feasibility RCT. Two focus within the NICE Intrapartum guideline [5]. This is due groups will be performed at the lead site (Birmingham to concerns with exposure of the fetus to iodine-based Women’s and Children’s Hospital BWCH) of approxi- substances, concerns with vaginal staining and allergy to mately 7 to 10 women in each group who have undergone iodine. Iodine is a recognised antibacterial agent, but in- a CS and would like to contribute to the development of activity by the presence of blood [6] limits its use. Thus, women-centred outcomes. there are a number of reasons to believe that vaginal Women will be recruited via adverts placed on BWCH cleansing with chlorhexidine would be an appropriate al- notice boards and on the post-natal wards, through so- ternative to povidone iodine. Some studies show greater cial media platforms; community midwives will be asked reduction in skin flora after application of chlorhexidine to identify women, as well as hospital midwives if (0.5 and 4%) [6] compared with povidone-iodine agents. women re-attend and through patient engagement ser- Also, chlorhexidine may have a greater residual activity vices at BWCH. We will ask women who have had a CS after application than other preparations and, unlike within the previous 6 months to contribute to focus povidone iodine, it is not inactivated by the presence of groups on important women-centred outcomes for re- blood. Solutions that contain lower concentrations, such search into infection and complications following a CS. as the commonly used chlorhexidine gluconate and acet- The focus groups will be performed prior to com- ate (0.05%), are usually well tolerated and may be used mencement of recruitment to the feasibility RCT and for vaginal preparation [6]. With this preparation, there thus used to decide on outcomes for inclusion in the are no reported cases of allergy. There is one small ran- feasibility trial that the women feel are important for domised controlled trial comparing povidone iodine with post-natal quality of life and recovery. All women will chlorohexidine gluconate for vaginal cleansing at CS. have demographic data collected. The focus groups will This suggested that chlorohexidine may be superior, and be recorded and transcribed anonymously. The data will further research was needed [7]. be analysed thematically and managed using the Frame- A Cochrane review of cleansing the vagina in normal work Method [9]. An experienced qualitative researcher vaginal delivery with chlorhexidine showed no evidence will run the focus groups, with the support of a research of an effect on maternal or neonatal infections with low associate and the clinical research fellow. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 3 of 10 From informal discussions with women who have  Aged 16 years or over undergone CS, the outcomes are likely to be composed of the following themes: Women will be excluded from the trial if they: Length of midwife follow-up  Have a known allergy to chlorhexidine gluconate or Prolonged use of analgesics any of its ingredients Ability to care for self  Are receiving prophylactic intravenous antibiotics Time to leaving house with family/independently for group B streptococcus (GBS) colonisation Ability to care for a baby  Are receiving intravenous antibiotics for suspected infection (standard CS intravenous prophylaxis is Feasibility study design not an exclusion criteria) Blinded to women and personnel performing outcome  Are currently enrolled in an RCT for an intervention collection, parallel group, feasibility RCT compared vagi- intended to reduce post-operative surgical site infection nal cleansing using chlorhexidine gluconate or acetate versus no cleansing (standard practice) at CS to reduce All women already enrolled in an interventional study infection. Allocation to treatment will be on a 1:1 ratio. are permitted to be co-enrolled into PREPS, as long as A feasibility randomised controlled trial design is being the intervention is not intended to reduce infection. undertaken to test the consent and randomisation pro- After consent and randomisation to PREPS, women will cesses for women requiring a CS, and the follow-up pro- not be permitted to enter a further interventional study cesses up until the immediate post-natal period, to ensure if the study is evaluating the prevention of infection. Co- we can overcome the challenges this poses. enrolment in all observational studies is permitted. Trial setting Randomisation The trial will be undertaken in maternity hospitals: After the woman’s eligibility has been confirmed and in- Birmingham Women’s and Children’s Hospital, Birming- formed consent has been received, the woman can be ham Heartlands Hospital, Shrewsbury and Telford randomised into the trial (Fig. 1). Randomisation can be Hospital (West Midlands) and Sunderland Royal Hospital, performed by all members of the research team and clin- to ensure the trial can be extrapolated to a larger multi- ical team and is most likely to be performed by dedi- centre trial. cated research midwives. Randomisation will be provided by a secure automated Identification of participants telephone randomisation system available 24 h a day/ Given recruitment, consent and randomisation processes 7 days a week provided by the University of Aberdeen. will differ for emergency and elective CS due to differ- The telephone randomisation service will comply with ences in planning for surgery; the processes for each research and governance standards. type of surgery will be detailed separately. All women The randomised allocation will be documented in the booking at any of the hospitals over the study period main hospital records on the anaesthetic chart, on a and who are greater than 34 weeks pregnant while re- dedicated sticker within the patient notes and on the cruitment is running will be posted a patient informa- relevant case report forms. The allocation will not be tion leaflet. This is to ensure that all women are aware disclosed to the woman or recorded in the post-natal of the study before delivery of their baby/babies. This hand-held notes. will be accompanied with patient information leaflets Women will be randomised at the level of the individ- and study information being available in antenatal clinics ual in a 1:1 ratio to either chlorohexidine gluconate or and triage waiting rooms. Study posters will also be dis- acetate 0.05% vaginal cleansing or standard treatment of played in prominent positions through the hospitals. no vaginal cleansing. A minimisation algorithm will be used to ensure balance in the treatment allocation over Eligibility criteria and co-enrolment the following variables: Women will be included in the trial if they are as follows:  Randomising centre In labour and not in labour CS Greater than or equal to 34 weeks pregnant Having a CS A ‘random element’ will be included in the minimisa- Able to give informed written consent tion algorithm so that each patient has a probability (un- Able to receive a telephone interview at 14 and specified here) of being randomised to the opposite 30 days post-natal treatment that they would have otherwise received. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 4 of 10 Fig. 1 Trial participant flow Blinding intervention was applied on the theatre operation note The trial cannot be blinded to the operator or the and anaesthetic/operation chart, which are not held in clinical care team in theatre providing care to the the maternal post-natal notes. As a part of the monitor- women due to the nature of the intervention. Ran- ing process, 10% of medical records will be independ- domisation will be performed by a wide range of staff ently monitored and data collection will be verified by from theatre runners to consultants. Randomisation the trial sponsor on-site. may be performed by dedicated research midwives The research midwife conducting the telephone who will also collect outcome data from the notes, follow-up interviews will be blinded to the treatment but there will be no recording of the allocation in the group so that there will be no bias in the collection of post-natal notes. outcomes. The research midwife will not have an access Attempts will be made to blind the women as the to the medical records or any data collection forms at intervention will be applied at the time of the catheter the time of telephone interviews. insertion, and the woman should not be aware of the ap- At the end of the 14-day interview, the midwife will plication due to anaesthesia. ask the woman whether she feels she received the inter- All data collection from the maternal notes will be vention or not to assess whether blinding of the woman blinded since there will only be recording of whether the is an achievable aim. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 5 of 10 Intervention  The proportion of women who are randomised into Chlorohexidine gluconate 0.05% or chlorohexidine acet- the PREPS trial with verbal consent from the ate 0.05% will be used to perform vaginal cleansing. The number of women whom have an emergency CS active ingredient is chlorhexidine 0.05%. This is indi-  The proportion of women randomised who can cated within the British National Formulary for swab- successfully identify what treatment they received bing in obstetrics. (i.e. vaginal cleansing or no vaginal cleansing) Fifty millilitres of antiseptic (chlorohexidine gluconate  The proportion of complete data for each of the 0.05% or chlorohexidine acetate 0.05%) will be emptied clinical and woman reported outcomes of women into a sterile pot. A single swab/sponge mounted on a randomised sponge holder soaked in the antiseptic will be used to  Time taken to perform the telephone interviews clean the vagina prior to CS at the time of urinary cath-  Reasons for withdrawal eter insertion, for guidance, we suggest the vaginal cleansing should take 30 s. Following the CS procedure, Clinical outcomes the vagina will be cleaned of excess blood as is standard The following clinical outcomes will be collected to in- practice with a dry swab. The application of the inter- form sample size calculations for the main RCT. vention is quick and familiar to the doctors performing the surgery due to their experience in gynaecological Development of CDC defined endometritis in the post-natal surgery where it is routine practice. All theatres’ stand- period (days 0–30) ard operating procedures regarding swabs and instru- The development of endometritis meeting the CDC def- ment counts should be adhered to, to ensure patient inition, in the post-natal period (day 0 of delivery), is the safety. At all sites, staff will be asked to record if they proposed primary outcome for the full RCT. Endometritis have performed vaginal cleansing, and if performed, will be defined as per the definitions set out by the US which antiseptic was used, on the CS operation note Centre’s for Disease Control and Prevention (Centre’sfor within the hospital notes. Disease Control and Prevention 2017) [10]. Clinical diagnosis of endometritis in the post-natal period Outcomes (days 0–30) All feasibility outcomes will be assessed overall and by Diagnosis of endometritis by a clinician which does not centre. Recruitment will take place for a minimum of meet the CDC definition or cannot be verified to meet 12 weeks and a maximum of 20 weeks, across the four the definition, e.g. a woman treated in the community maternity sites. for suspected endometritis where it is not feasible to es- tablish that this meets the CDC definition or where the diagnosis does not meet the criteria. Stop-go criteria The decision to continue to a full trial will be decided by Maternal sepsis (days 0–42) pre-defined stop-go criteria based on the following Defined according to the NICE sepsis guideline (released outcomes: July 2016) [10]. The proportion of women randomised into the trial Length of hospital stay of the 250 recruitment target The length of hospital stay from randomisation to dis- The proportion of women who received their charge home or transfer to another hospital following CS allocated intervention out of all those randomised or up to 6 weeks after randomisation if not discharged. The proportion of women remaining in the trial (i.e. not withdrawn) who successfully complete the Readmission to hospital after CS for suspected or confirmed planned follow-up process for both the 14- and infection (days 0–42) 30-day telephone interview It is defined as readmission to hospital post-discharge Withdrawal from the study home up until 6 weeks postnatally. Other feasibility outcomes Antibiotic prescriptions These are antibiotics prescribed as an inpatient and hos- The proportion of eligible women approached to pital prescribed outpatient (days 0–42) and antibiotic take part prescriptions for suspected/confirmed surgical site infec- The proportion of women randomised who have an tion relating to the woman’s CS (uterine, pelvic, abdom- elective/emergency CS inal wound and perineal). Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 6 of 10 Requiring level 2 or level 3 critical care Complete withdrawal This is defined as requiring level 2 or 3 critical care (or The woman wishes to withdraw completely (i.e. from obstetric HDU type care) as a result of an infection up trial treatment and all follow-ups) and is not willing to until 6 weeks postnatally (days 0–42). have any of their data, including that already collected, The endometritis outcomes are collected up until day to be used in any future trial analysis. 30 to be consistent with the CDC definition of endomet- ritis, and the sepsis related outcomes are collected up Adverse events and serious adverse events until 6 weeks to be consistent with the national collec- The collection and reporting of adverse events (AEs) will tion of post-natal sepsis. be in accordance with the Research Governance Frame- work for Health and Social Care and the requirements of the Health Research Authority (HRA). No neonatal Patient-reported outcomes AEs or SAEs are required to be reported as the interven- These will be determined by the qualitative component tion is licenced for use in obstetrics over 34 weeks for of this feasibility study and reported as an outcome of swabbing as per the SmPC and has a demonstrated the feasibility study along with summary statistics pre- safety record in many trials in neonates above 34 weeks specified in the statistical analysis plan. gestation [11]. Participant withdrawal Adverse events (AE) Informed consent is defined as the process of learning There are certain AEs which are commonly expected in the key facts about a clinical trial before deciding participants as a result of pregnancy and/or CS. As these whether or not to participate. It is a continuous and dy- events are well characterised, it is highly unlikely that namic process, and women should be asked about their this trial will reveal any new safety information relating ongoing willingness to continue participation with the to this intervention. Thus, there will be no AEs telephone interviews before the interview questions recorded. commence. Women should be aware at the beginning that they can freely withdraw (discontinue participation) Serious adverse events (SAE) from the trial (or part of the trial) at any time. All events which meet the definition of serious will be Types of withdrawal as defined are as follows: collected and recorded in the participant notes and the Case Report Form (CRF). SAEs will, in addition, be re- ported to the trials office immediately and within 24 h of Before the intervention the principal investigator being made aware of the event. The woman would like to withdraw from trial treatment, Allergic reaction to chlorohexidine requiring treatment before the intervention, is applied but is willing to be will be considered a serious adverse advent. followed up in accordance with the schedule of assess- Events not considered an SAE in PREPS include: ments and if applicable using any central UK NHS bod- ies for long-term outcomes (i.e. the woman has agreed Hospitalisation for delivery of the baby that data can be collected and used in the trial analysis). The development of infection and sepsis in the post-natal period that requires inpatient treatment After the intervention or prolongation of hospitalisation as this is an The woman would like to withdraw from the trial after outcome of the trial the allocation is applied and does not wish to participate Obstetric haemorrhage in the telephone interview but is willing to be followed Damage to bowel or bladder during surgery up at any visits and if applicable using any central UK Prolonged hospitalisation due to neonatal NHS bodies for long-term outcomes (i.e. the woman has complications agreed that data can be collected at standard visits and Thromboembolic events used in the trial analysis, including data collected as part of long-term outcomes). All other events not detailed above that meet the def- inition of a SAE should be reported as detailed below. Without follow-up SAEs should be reported on an SAE Form. When The woman would like to withdraw from the trial after completing the form, the PI will be asked to define the the allocation is applied and is not willing to be followed causality and the severity of the SAE. Causality will be up in any way for the purposes of the trial and for no assessed as definitely related, probably related, possibly further data to be collected (i.e. only data collected prior related, unlikely to be related or unrelated. On becoming to the withdrawal can be used in the trial analysis). aware that a woman has experienced an SAE, the Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 7 of 10 Investigator or delegate(s) should report the SAE to their statistical analyses. A brief outline of the planned analyses own Trust in accordance with local practice and to the is given below. BCTU trials office. On receipt of an SAE form, the Chief All clinical outcomes will be analysed according to the Investigator (CI) or delegate(s) will independently deter- treatment arm to which they were randomised (i.e. vaginal mine the seriousness and causality of the SAE. An SAE cleansing or no cleansing) irrespective of compliance with judged by the PI or CI or delegate(s) to have a reasonable the randomised treatment allocation, as per the intention causal relationship with the intervention will be regarded to treat principle. Women who did not undergo a CS will as a related SAE. The causality assessment given by the PI be excluded from the analyses. will not be downgraded by the CI or delegate(s). If the CI All feasibility outcomes will be analysed pooling the or delegate(s) disagrees with the PI’s causality assessment, two randomised groups and presenting overall estimates the opinion of both parties will be documented, and where of proportions with 95% confidence intervals, as well as the event requires further reporting, the opinion will be estimates by centre. provided with the report. The CI “or delegate(s)” will also All outcomes will primarily take the form of simple assess all related SAEs for expectedness. If the event is un- descriptive statistics (e.g. proportions and percentages, expected (i.e. is not defined in the protocol as an expected means and standard deviations) and where appropriate, event), it will be classified as an unexpected and related point estimates of effect sizes (e.g. mean differences and SAE. BCTU will report all events categorised as unex- relative risks) and associated 95% confidence intervals. pected and related SAEs to the main Research Ethics Committee (REC) within 15 days. The main REC and Decision to continue to a definitive trial sponsor will be notified immediately if a significant safety The decision to continue to a full trial will be decided by issue is identified during the course of the trial. pre-defined stop-go criteria. A traffic light system has been designed that will determine progression. Sample size and data analysis Sample size Stop-go criteria Since this is a feasibility study, no formal sample size calculations have been undertaken. The feasibility study  Recruitment rates: the proportion of women is not designed or powered to detect a statistically sig- randomised into the trial of the 250 recruitment target. nificant difference in efficacy between the two treatment  Adherence to the allocated intervention: the arms. A total sample size of 250 participants would proportion of women who received their allocated agree with existing literature which suggests that the size intervention out of all those randomised. of the feasibility study should be at least 10% of the an-  Successful completion of follow-up: the proportion ticipated size of the substantive study [12]. A recruit- of women remaining in the trial (i.e. not withdrawn ment target of 250 participants has been chosen for this as per criteria below) who successfully complete the feasibility study as we expect this number will be suffi- planned follow-up process for both the 14- and 30- cient to provide estimates of the feasibility outcomes. day telephone interview. Preliminary sample size calculations were computed  Study drop-out: withdrawal from the study. for the full RCT. Vaginal cleansing with povidone iodine has been evaluated in a Cochrane review which com- Traffic light system prised of seven trials randomising 2816 women (2635 Green light: recruitment rate > 90%, adherence rate > 75%, analysed) estimating the effects of vaginal cleansing follow-up rate > 90% and dropout rate < 15%. If all four (povidone-iodine) on post-caesarean infectious morbid- criteria are met, we will proceed to a full trial with the ity. The risk of bias was generally low, with the quality protocol unchanged (unless there is a clear message from of most of the studies being high. Vaginal preparation the focus groups that would improve the protocol). immediately before caesarean delivery significantly re- Amber light: recruitment rate 80–90%, adherence rate duced the incidence of post-caesarean endometritis from 50–75%, follow-up rate 75–90% or dropout rate 15–30%. 8.3% in control groups to 4.3% in vaginal cleansing If one or more of our amber light criteria are met, we will groups. To detect a difference of this size with 90% plan to adapt the protocol in light of the feedback from power and alpha at 5%, we would require 1548 partici- the focus groups and our experience to improve which- pants. In addition, to account for an anticipated 10% loss ever criteria are not at the ‘green-light’ level before pro- to follow-up, we would need a total of 1720 participants. ceeding to full trial. We will assess whether adaption of the protocol will require a further feasibility study or pilot Analysis of outcome measures study before progressing. A separate statistical analysis plan for the PREPS feasibility Red light: recruitment rate < 80%, adherence rate < 50%, study will provide a detailed description of the planned follow-up rate < 75% or dropout rate > 30%. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 8 of 10 If one or more of these criteria are met, we would con- Birmingham have to be registered with the Data Protec- sider the current protocol not feasible and not progress tion Officer and data held in accordance with the Data to a full RCT. Protection Act. The University will designate a Data Pro- The Trial Oversight Committee will take into consid- tection Officer upon registration of the study. The study eration statistical uncertainty around these rates using centre has arrangements in place for the secure storage 95% confidence intervals. and processing of the study data which comply with the Missing data: Every attempt will be made to collect full University of Birmingham policies. follow-up data on all study participants; it is thus antici- pated that missing data will be minimal and the strat- Discussion egies needed to achieve this are part of this feasibility Post-partum infection/sepsis is a significant global prob- RCT. The main analysis will use available data only; lem. With the increasing evidence regarding antimicrobial however, the amount of missing data will be assessed, resistance and the development of bacterial resistance and if necessary, sensitivity analyses will be undertaken. there, is concern that without action, common procedures such as CS will carry significant risks. We must, therefore, Trial and data management seek strategies that reduce this risk. We aim to perform a Sponsor feasibility study for a larger multi-centre randomised The PREPS trial is sponsored by Birmingham Women’s controlled trial (RCT) comparing vaginal cleansing with and Children’s NHS Foundation Trust. chlorhexidine versus standard practice of no vaginal cleansing immediately before CS to reduce post-partum Coordinating centre endometritis and sepsis. There are a number of difficulties The coordinating centre is the Birmingham Clinical Tri- in performing a RCT in pregnant women undergoing CS, als Unit at the University of Birmingham. 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 Trial oversight committee procedures: mothers are discharged from obstetric care Given this is a feasibility study, the Trial Oversight quickly with no routine post-operative follow-up. They Committee (TOC) will comprise of a joint trial steer- are motivated to recover and care for their baby. It is ing committee and data monitoring committee and therefore necessary to perform this feasibility trial to as- will meet three times through the proposed 15-month sess both our ability to recruit women and adequately fol- study. The TOC will provide supervision and advice low them up. The main limitation of this feasibility study for the study and ensure the study is conducted as is that it is being performed within units motivated to per- applicable to the MRC Guidelines for Good Clinical form the feasibility trial and this may not accurately repre- Practice in Clinical Trials. Trial data provided to the sent recruitment in all sites. TOC will be anonymised, but study group allocation may be provided, if it is necessary for their delibera- tions regarding serious adverse events. There is no Conclusion planned interim analysis. This is a feasibility randomised controlled trial, assessing the feasibility of performing a trial of vaginal chlorohexidine cleansing to prevent post-natal infection. Testing newly de- Data management veloped verbal consent, randomisation and follow-up pro- Processes will be employed to facilitate the accuracy of cesses in this population. 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 status trial’s coordinator, statistician and programmer, and the The PREPS trial opened to recruitment on 11th November trial database will be signed off once the implementation 2017. At the time of submitting this protocol for publica- of these has been assured. tion, the trial was actively recruiting participants. Data security Abbreviations AEs: Adverse events; BCTU: Birmingham Clinical Trials Unit; The security of the trial database is governed by the pol- BWCH: Birmingham Women’s and Children’s Hospital; CDC: Centre for icies of the University of Birmingham. The University’s Disease Control and Prevention; CI: Chief investigator; CRF: Case report form; Data Protection Policy and the Conditions of Use of CS: Caesarean section; HRA: Health Research Authority; NHS: National Health Service; NICE: National Institute for Clinical Excellence; PI: Principal Computing and Network Facilities set out the security investigator; PIL: Patient information leaflet; RCT: Randomised controlled trial; arrangements under which sensitive data should be REC: Research Ethics Committee; RR: Risk ratio; SAE: Serious adverse events; processed and stored. All studies at the University of SmPC: Summary of product characteristics Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 9 of 10 Acknowledgements Authors’ contributions Thank you to the women who participated in the focus groups and helped VMH conceived and is the clinical lead on the trial. RKM is the Chief Investigator inform the trial outcomes. This paper presents independent research funded by of the trial. AW is coordinating the trial with NF as lead research midwife. AWe the National Institute for Health Research (NIHR) under its Research for Patient is leading the qualitative component. PH is the lead statistician, and CH is the Benefit (RfPB) Programme (Grant Reference Number PB-PG-1215-20013). The trial statistician. VMH, AW, AWe, NF, DL, CH, PH and RKM contributed to the views expressed are those of the author(s) and not necessarily those of the preparation of the protocol. All authors read and approved the final manuscript. NHS, the NIHR or the Department of Health and Social Care. Ethics approval and consent to participate The trial will be performed in accordance with the recommendations guiding Elective caesarean section physicians in biomedical research involving human subjects, adopted by the A suitably qualified research midwife or doctor will introduce the study to 18th World Medical Association General Assembly, Helsinki, Finland, 1964, the woman at their pre-operative assessment. A patient information leaflet amended by the 48th WMA General Assembly, Somerset West, Republic of (PIL) will be provided to facilitate this process. Investigators will ensure that South Africa, 1996. The trial will be conducted in accordance with the Research they adequately explain the aim, trial treatment, anticipated benefits and Governance Framework for Health and Social Care and the applicable UK potential hazards of taking part in the trial to the woman. They will also Statutory Instruments (which include the Data Protection Act 1998 and Human stress that participation is voluntary and that the woman is free to refuse Tissue Act 2008 and the Principles of GCP). The protocol was approved by the to take part and may withdraw from the trial at any time. The woman will London City & East Research Ethics Committee (17/LO/0874) before any be given adequate time to read the PIL and to discuss their potential participants are enrolled into the trial, the trial office will obtain HRA approval participation and be given the opportunity to ask questions. If the woman and the PI at each site will obtain local R&D approval/assurance. Sites will not expresses an interest in participating in the trial, they will be asked to sign be permitted to enrol participants until written confirmation of R&D approval/ and date the latest version of the Informed Consent Form. The woman will assurance is received by the BCTU trials team. 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 Consent for publication take approximately 5–15 min. It will be the responsibility of the investigator Results of this trial will be submitted for publication in a peer reviewed journal. to obtain written informed consent for each participant prior to performing The manuscript will be prepared by the chief investigator, and authorship will any trial related procedure. be determined by the trial publication policy. Authors must acknowledge that A copy of the consent form will be given to the woman, a copy filed in the the trial was performed with the support of BWCNFT and NIHR RfPB. medical records with the PIL. The original signed consent form will be filed in the investigator site file. Competing interests The authors declare that they have no competing interests. Emergency caesarean section In the majority of emergency CS, the woman will be asked to consent as per Publisher’sNote the elective procedure. It is expected that the majority of women undergoing Springer Nature remains neutral with regard to jurisdictional claims in published emergency CS will provide written consent prior to trial-related procedures maps and institutional affiliations. commencing. It is appreciated that time can be limited in the undertaking of an emergency Author details CS, especially where there is suspected maternal or foetal compromise. In Institute of Metabolism and Systems Research, College of Medical and keeping with the Royal College of Obstetricians and Gynaecologist consent Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. advice for women participating in research, as long as information is available Birmingham Clinical Trials Unit, Institute of Applied Health Sciences, College antenatally, it is reasonable to take consent in labour [13]. The common of Medical and Dental Sciences, University of Birmingham, Birmingham B15 incidence of CS (an event that occurs in 25% of women) and the expectation 2TT, UK. School of Health and Social Care, Birmingham City University, of women in labour that CS is a possibility means that giving information to all Birmingham B15 3TN, UK. Birmingham Women’s and Children’s Hospital women would not overburden them and is unlikely to cause anxiety or deviate NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK. women from the normal birth process. In the emergency situation where time is limited, verbal consent for the intervention will be obtained prior to Received: 13 February 2018 Accepted: 18 April 2018 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 References discussion will include confirmation that the woman has previously received 1. Mackeen AD, et al. Timing of intravenous prophylactic antibiotics for information regarding the trial, understands that the choice of intervention preventing postpartum infectious morbidity in women undergoing will be made randomly and is willing to take part. cesarean delivery. Cochrane Database Syst Rev. 2014;12:CD009516. After the procedure, a PIL will be provided highlighting the follow-up and 2. McKibben RA, et al. Practices to reduce surgical site infections among confirmation of willingness to continue to participate. They will also stress women undergoing cesarean section: a review. Infect Control Hosp that participation is voluntary and that she is free to refuse to take part and Epidemiol. 2015;36(8):915–21. may withdraw from the trial at any time. If the woman is willing to continue 3. Tuuli MG, et al. A randomized trial comparing skin antiseptic agents at to participate in the trial, she will be asked to sign and date the latest version cesarean delivery. N Engl J Med. 2016;374(7):647–55. of the ICF. 4. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Syst Rev. 2014;12:CD007892. Ancillary and post-trial care 5. Intrapartum Care. Care of healthy women and their babies during Participants can be referred to the Patient Advisory Liaison Service if required. childbirth. London: 2014 National Collaborating Centre for Women’s and Children’s Health; 2014. Funding 6. American College of Obstetricians and Gynecologists Women's Health Care The PREPS Trial is funded by the National Institute of Health Research under Physicians; Committee on Gynecologic Practice. Committee opinion no. the Research for Patient Benefit (RfPB) scheme (PB-PG-1215-20013). The 571: solutions for surgical preparation of the vagina. Obstet Gynecol. 2013; sponsor is BWCNFT Mrs. K Hard Kelly.Hard@bwnft.nhs.uk. 122(3):718–20. 7. Tewfik H, Ibrahim A, Hanafi S, Fahmy A, Khaled MA, Abdelazim IA. Availability of data and materials Preoperative vaginal preparation using povidone iodine versus The datasets generated and/or analysed during the current study are available chlorhexidine solutions in prevention of endometritis in elective cesarean from the corresponding author on reasonable request. section. Int J Curr Microbiol App Sci. 2015;4(8):486–92. Hodgetts Morton et al. Pilot and Feasibility Studies (2018) 4:84 Page 10 of 10 8. Ohlsson A, Shah VS, Stade BC. Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. Cochrane Database Syst Rev. 2014;12:CD003520. 9. Gale NK, et al. Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol. 2013;13:117. 10. Centre for Disease Control and Prevention. https://www.cdc.gov/nhsn/pdfs/ pscmanual/pcsmanual_current.pdf. Accessed 3 Feb 2017. 11. Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N. Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. Cochrane Database Syst Rev. 2015;(3):CD007835. https://doi.org/10.1002/14651858. CD007835.pub2. 12. Connelly LM. Pilot studies. Medsurg Nurs. 2018;17(6):411–2. 13. RCOG obtaining valid consent guideline number 6. 2015. https://www.rcog.org. uk/en/guidelines-research-services/guidelines/clinical-governance-advice-6/. Accessed 16 Feb 2017.

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Pilot and Feasibility StudiesSpringer Journals

Published: Jun 4, 2018

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