A pragmatic adaptive sequential placebo controlled randomised trial to determine the effectiveness of Glycerin trinitrate for retained placenta (Got-it trial)

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,