Title: A pragmatic adaptive sequential placebo controlled randomised trial to determine the effectiveness of Glyceryl trinitrate for retained placenta (Got-it trial)
Funder: Chief Scientist Office, Scotland

Abstract: GOT-IT TRIAL: A pragmatic group sequential placebo controlled randomised trial to determine the effectiveness of Glyceryl trinitrate for retained placenta. A retained placenta (RP) is a complication after a normal birth, which affects nearly 11,000 women in the UK a year. This is where the placenta is not delivered spontaneously after giving birth. It is a major cause of postpartum haemorrhage (major loss of blood) which can lead to the death of the mother. The recommended treatment for RP is a surgical procedure - manual removal of placenta (MROP). This is a painful and unpleasant intervention for the women, involving additional hospital stay, and is an expensive outcome for the NHS. It is widely recognised that non-surgical management options for RP are limited and it has been recommended that research is needed into new medical treatments for RP. New effective treatments for RP would dramatically reduce the number of women requiring MROP with the operation being restricted to the small minority of women with particularly stuck placentae. The reduction in operative interventions would have cost benefits for the NHS and also for women in terms of increased satisfaction, less separation of mother and baby immediately after birth, and reduced morbidity. We HYPOTHESISE that a known treatment for angina, Glyceryl trinitrate (GTN) administered as a sublingual spray will be clinically effective in treating RP after vaginal delivery by reducing the need for MROP. The OVERALL AIM of the randomised placebo controlled double blind pragmatic UK-wide GOT-IT trial RCT (with internal pilot study) is to determine the clinical and cost-effectiveness of GTN compared with placebo (dummy drug) in avoiding MROP in women with RP. OVERVIEW: The GOT-IT Trial will be conducted in two phases. The first phase will involve an INTERNAL PILOT RCT where the aim will be to test out and refine trial procedures in a small number of hospital sites. The second phase will be the main trial where recruitment will be extended to a larger number of hospitals in order to determine clinical and cost effectiveness. The internal pilot with embedded qualitative studies will determine realistic recruitment rates, the likely event rate of MROP without GTN treatment, participant/staff satisfaction, questionnaire development and pilot and will help refine trial-specific pathways for recruitment and consent. The main RCT will determine the clinical and cost-effectiveness of sublingual GTN spray for RP. The substantive trial will use a FLEXIBLE GROUP SEQUENTIAL DESIGN allowing the trial to stop early for either overwhelming evidence of benefit (e.g. large treatment effect and/or low variability in the outcome measure) or due to pre-defined futility (i.e. likely ineffectiveness). DESIGN: An internal pilot study (with embedded qualitative research) leading to a definitive randomised placebo controlled double blind pragmatic UK-wide trial to determine the clinical and cost-effectiveness of GTN for RP. SETTING: Delivery wards in around 20 UK maternity hospitals of varying size and location. TARGET POPULATION: All women with RP at risk of needing MROP after vaginal birth after failure of current management (defined as a third stage of labour lasting more than 30 or 60mins, after either i) active management (oxytocin and controlled cord traction), or ii) physiological followed by active management, respectively). This pragmatic trial will exclude on safety considerations, instrumental delivery in theatre or multiple pregnancy. HEALTH TECHNOLOGIES: GTN spray (800mcg; 2 puffs) delivered sublingually as soon as possible after diagnosis of RP. The comparator technology is a matched placebo spray. Sequential block randomisation will be used. MEASUREMENT OF COSTS AND OUTCOMES: PRIMARY OUTCOMES for the INTERNAL PILOT RCT with EMBEDDED QUALITATIVE RESEARCH will be: 1) Demonstration that trial processes for approaching women, gaining consent, randomising, treating and assessing outcomes are fit for purpose and if they are not, that processes are modified as required; 2) Determination of achievable recruitment rates; 3) Establishment of the likely effect size to inform sample size calculation and 4) Finalization of postnatal questionnaires for assessment of patient satisfaction and collection of health service use outcomes. PRIMARY OUTCOMES for the MAIN TRIAL will be measured over four inter-related domains 1) CLINICAL: decision for MROP (defined as placenta undelivered 15 mins post treatment and/or being required within 15 mins of treatment due to safety concerns); 2) SAFETY: side effect profile for GTN and volume of blood lost between randomisation and transfer to the postnatal ward; 3) PATIENT-SIDED: satisfaction with treatment assessed by questionnaire and, 4) ECONOMIC: cost–effectiveness (in terms of cost per case of MROP averted). SECONDARY CLINICAL, SAFETY AND ECONOMIC OUTCOMES will include fall in haemoglobin of more than 15% between recruitment and 24hrs postnatal; time from administration of treatment to placental delivery; need for earlier than planned MROP on the basis of the clinical condition, fall in systolic or diastolic blood pressure of more than 15mmHg and/or increase in pulse of more than 20 beats/min between baseline and 5 and 15mins post-administration of study drug, sustained uterine relaxation after placental removal requiring uterotonics, need for a blood transfusion, need for general anaesthesia, maternal pyrexia, and NHS costs in relation to the primary outcome and range of secondary outcomes expected to differ between arms of the trial, using a cost-consequence balance sheet approach. SAMPLE SIZE: 1) The INTERNAL PILOT RCT will take place in 7 centres. We estimate that 2% of vaginal deliveries (70% of all births) have RP, thus a typical hospital (3500 vaginal deliveries p.a.[per annum]) will have 70 RP p.a. Based on previous trials, about 20% of these will be ineligible to be recruited mainly due to actual/perceived risk of haemorrhage and a further 40% will be either unwilling to be randomised or will not be approached. A typical unit should be able to randomise about 28 per year or 2-3/month (mth). To achieve data saturation for the embedded qualitative research around 25 women and 20 health professionals will be interviewed. 10-15 women who decline to participate will also be interviewed. 2) MAIN RCT using a FLEXIBLE GROUP SEQUENTIAL DESIGN (with a Lan-DeMets alpha spending function with O’Brien Fleming boundaries and 5 planned interim evaluations, pre-specifying a two sided test, with asymmetry for efficacy and futility boundaries) we will need to recruit no more than 1086 women (20 centres) to demonstrate a 10% change from 50% on placebo to 40% on GTN spray at 90% power and 5% level of significance. APPLICANT EXPERTISE: 1) UK multicentre RCTs in pregnancy; 2) Nitric oxide donors; 3) Qualitative expertise; 4) Clinical translation; 5) Health economics; 6) Lay advice; 7) Charity sector.

Lay abstract: We want to find out whether glyceryl trinitrate (GTN) is effective in treating a stuck or retained placenta (RP) after a woman has had a vaginal delivery. RP occurs when the placenta is not delivered after a baby is born. If the placenta is not delivered, women can bleed heavily. In the UK, nearly 11,000 women every year experience RP after giving birth. The only treatment currently available for women with a RP is an operation called a Manual Removal of Placenta (MROP). This is an invasive procedure that requires an anaesthetic and skilled staff. The mother and newborn baby are also separated during the operation which could be traumatic and could delay mother-baby bonding. There is therefore a need for a new medical (non-surgical) treatment for RP. GTN relaxes muscles and when given sublingually (under the tongue) it is absorbed quickly and causes the womb and cervix to relax within five minutes. Small studies suggest that GTN may be very good at managing RP. However these promising results have not been supported by a more recent larger study. It is also not clear whether women will be willing to take GTN and whether the costs of using GTN compare favourably (or not) with current surgical management. We are looking to see whether GTN reduces the need for women with a RP to have MROP. We plan to do this by comparing women who have GTN or a placebo (dummy drug that contains no treatment) in a multicentre randomised clinical trial across the UK (GOT-IT Trial). The GOT-IT Trial will be carried out in 2 phases. The first phase will involve an internal pilot study where the aim will be to test out and refine trial procedures in a small number of hospital sites. This first stage will help us see how many women are willing to take part in the research. Women who take part, those who decide not to take part and delivery suite staff who have worked on the trial will be invited to take part in in-depth interviews to talk about their experiences. This information will be used to improve the way we carry out the research if necessary. The second phase will be the main trial where recruitment will be extended to a larger number of hospitals (at least 20 delivery units in the UK) in order to determine whether GTN works (clinical effectiveness) and whether it reduces costs for the NHS (cost effectiveness). We think we will need to recruit up to 1086 women with RP to answer these questions. Any woman who has a vaginal delivery and then develops the complication of RP is eligible to take part as long as she meets the entry criteria for the study. We want the results of the trial to be relevant to as many women with RP as possible. We have therefore kept the entry criteria very broad and aim to only exclude women from taking part if they are allergic to GTN, are unwell with bleeding, have a multiple pregnancy or are having an instrumental delivery in theatre. After receiving information about the study and deciding to take part, women will be randomly allocated to get either GTN spray or a placebo spray that looks and tastes the same as GTN. The placebo spray will not contain any active drug and we would not expect a placebo to release a RP. We will randomly allocate women, meaning that study investigators cannot choose which spray to give to women, so that we can compare the two groups fairly. The woman will be asked to spray the study drug (either GTN or placebo) under her tongue. After 5 minutes, if her placenta has not delivered, the midwife (or doctor) looking after her will try and deliver the placenta by gently pulling on the umbilical cord. If the placenta remains undelivered 15 minutes after taking the study drug, we think that it is very unlikely that the placenta will deliver by itself. At that stage, the decision will be made to transfer the woman to theatre as soon a theatre and skilled staff are available to perform the operation. To find out whether GTN helps deliver RP, is safe and acceptable to women, and reduces costs for the NHS, we will assess costs and a number of ‘outcomes’. To assess clinical effectiveness, we will compare the proportions of women who need to have their placenta surgically removed between the two study groups. For our safety outcome, we will compare the amount of blood loss from the time of randomisation until the woman is admitted to the postnatal ward or other clinical area. We will also look at other measures including need for additional drugs to contract the womb, blood pressure and heart rate after being given the study drug and whether a woman needed a blood transfusion or not. To assess patient satisfaction, we will also ask women what they think about the treatment they received for retained placenta. Finally, we will compare the costs associated with managing a RP in women who receive GTN to the costs associated with current (surgical) management of RP. To conduct this complex trial, we have a team comprising a range of health professionals, researchers and members of the public. Our team includes academic obstetricians, a clinical trialist, a qualitative expert, an economist, a midwife with experience in midwifery and obstetrician delivery suites and clinical trials and lay advisors. The trial will be managed by the established Centre for Healthcare Randomised Trials Unit in Aberdeen and by an experienced Trial Manager and Administrator based in Edinburgh. In any clinical trial, it is important that it is carried out correctly, that participants are kept safe and that sufficient women are recruited to answer the research questions. We will therefore have a Project Management Group (PMG), Trial Steering Committee (TSC) and an independent Data Monitoring Committee (iDMC). The role of the PMG, which will include study investigators, will be look to after the day-to-day running of the trial and ensure that the trial protocol is followed. Our TSC will provide overall supervision of the trial and ensure that it is conducted in accordance with the law. Our iDMC will look at the trial data as it is collected, suggest modifications to the recruitment schedule and bring any safety issues to the attention of the study investigators, participants and the TSC. Finally, we will also hold Collaborators meetings so that the local research teams across the UK can share best practice.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH