Title: A randomised placebo-controlled trial of mifepristone and misoprostol versus misoprostol alone in the medical management of missed miscarriage: The MIFEMISO trial
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: BACKGROUND Miscarriage is the most common complication of pregnancy. As many as 15-25% of pregnancies end in miscarriage, and the number of miscarriages in England is estimated to be approximately 125,000 per year. Miscarriage often brings not only physical pain, bleeding and risks of infection, but also profound psychological impact on women and their families. Women suffering a miscarriage are faced with difficult decisions about treatment. In some cases the womb empties itself completely, but in other cases it does not. Therefore medical treatment (tablets) or surgery (an operation) may be offered to manage the process. Approximately 25% of patients choose to take tablets to treat their miscarriage. The National Institute for Health and Care Excellence (NICE) currently recommends that a drug called misoprostol (a vaginal tablet that makes the womb contract) should be used in the medical treatment of miscarriage. It does not recommend combination with other drugs. But before this recommendation was released in 2012, it was common for another drug called mifepristone (an oral tablet that reduces pregnancy hormones) to be given along with misoprostol. Many still believe that using misoprostol alone - while cheaper - may not be as effective as the combination treatment. Therefore to identify the most effective medical treatment for miscarriage, NICE has called for more research to investigate whether a combination of mifepristone and misoprostol is more effective than misoprostol alone. In response, a national team of researchers together with Tommy’s Charity and the Miscarriage Association propose to carry out a large and high-quality clinical trial using a well-established research network. The team has reviewed previously published studies about the medical treatment of miscarriage and conducted a survey of patients, doctors and nurses to ensure the best study design. The published studies and surveys show that research is particularly needed to identify the most effective tablets for women whose pregnancy sac remains inside the womb (sometimes called missed miscarriage). Therefore the trial will focus on this question. THE RESEARCH TRIAL We plan to ask women diagnosed with a missed miscarriage (up to 13+6 weeks of pregnancy) to participate in this study. Participants will be allocated to receive either mifepristone followed by misoprostol, or a dummy drug followed by misoprostol. The allocation will be decided at random by a computer, and neither the participants nor the researchers will know what allocation is decided, which is necessary to test the treatments fairly. The main outcome of interest will be whether miscarriage is complete within 7 days of starting the tablets. If miscarriage is not complete then further treatment (more tablets or surgery) will be offered. A number of other key outcomes, such as the need for an operation, will also be assessed. We will also study the views and experience of the participants regarding the tablet treatment. We anticipate that 710 women will be required to take part in the study to answer this question with confidence. We estimate that we would be able to recruit this many women in two years.

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