A randomised placebo-controlled trial of mifepristone and misoprostol versus misoprostol alone in the medical management of missed miscarriage: The MIFEMISO trial

DESIGN: A randomised, double-blind, placebo controlled multi-centre study, health economic evaluation and qualitative research. SETTING: Early pregnancy units and gynaecology departments. TARGET POPULATION: Women diagnosed with missed miscarriage in the first 13+6 weeks of pregnancy. EXCLUSION CRITERIA: Age <16 years, women opting for expectant or surgical management, women with incomplete miscarriage, women with life threatening bleeding, contraindications to mifepristone or misoprostol. HEALTH TECHNOLOGIES BEING ASSESSED: Oral mifepristone 200mg, followed by vaginal or oral misoprostol 800ug 2 days later, will be compared with an oral placebo tablet followed by vaginal or oral misoprostol 800ug 2 days later. The dose of 200mg mifepristone orally is justified because: a) it was the most commonly used dose for the medical management of miscarriage when the combination of mifepristone and misoprostol was in common use, and b) it is the most commonly studied dose in published trials investigating its efficacy in the medical management of miscarriage. The dose of 800ug misoprostol vaginally or orally has been justified by the NICE CG154 (2). MEASUREMENTS OF COSTS and OUTCOMES: Passage of the gestational sac within 7 days after initiation of medical management of miscarriage. Outcome assessed by clinical assessment, with pelvic ultrasonography as required. Secondary outcomes include need for further doses of misoprostol, unplanned surgery, blood transfusion, days of bleeding, infection requiring outpatient antibiotics treatment, infection requiring inpatient treatment, pregnancy test result 21 days after start of medical treatment, time from start of medical treatment to discharge, satisfaction and experience of missed miscarriage and its medical management, side effects, and death or serious complications. Resource use and cost outcomes will be gathered to facilitate a cost-effectiveness analysis. SAMPLE SIZE: We plan to randomise 710 women, 355 participants in each group. 670 women need to be randomised to detect a Minimally Important Difference (MID) of 10% in miscarriage resolution rate (from 75% to 85%), assuming 90% power and a type I error rate of 5%. However, assuming and adjusting for a worst case scenario of 5% attrition, the total number of participants required will be 710. The 75% [95% CI: 73% to 77%] control group estimate is taken from our systematic review and the 10% MID from our clinician survey. PROJECT TIMETABLE: Audits of early pregnancy units show that 1,084 women per year have medical management of missed miscarriage at the 30 planned recruiting centres; 80% of these women are estimated to fulfil the inclusion criteria (867). Given that recruitment into the trial takes place at an acute phase in clinical care, we expect approximately 45% of the eligible women may take part (390), necessitating 24 months of recruitment. We therefore expect a total study duration of 3 years (6 months: set-up, 24 months: recruitment, 6 months: follow-up, analysis and health economics). EXPERTISE IN TEAM: Our multi-disciplinary research team has an outstanding track record in conducting randomised trials, including NIHR funded studies in miscarriage care (PROMISE, TABLET and PRISM). The trial will be co-ordinated by a mature clinical trials unit (BCTU). The team comprises of miscarriage researchers and clinicians, patient and public representatives, health economists, statisticians and qualitative researchers.