Title: Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial)
Funder: Department of Health and Social Care

Abstract: The PRISM trial is a large, double blind, placebo-controlled trial to test the hypothesis that in women presenting with vaginal bleeding in the first trimester, progesterone (400mg vaginal capsules, twice daily) continued to 16 completed weeks of gestation, compared with placebo, increases maternities with live births beyond 34 completed weeks by at least 5%. The project also explores the effects of progesterone in prognostic subgroups, according to maternal age, fetal heart activity, gestation at presentation, amount of bleeding and body mass index. We hope the findings of the study will represent a major breakthrough in the prevention of miscarriage. DESIGN: A randomised, double-blind, placebo-controlled multicentre trial, with health economic evaluation. SETTING: Early pregnancy units and gynaecology departments in NHS hospitals. TARGET POPULATION: Women presenting with recent vaginal bleeding (within the last 4 days) in the first 12 weeks of pregnancy with an intrauterine gestation sac visible on ultrasonography. EXCLUSION CRITERIA: Women of age less than 18 years, or 40 years or more at randomisation; women with life-threatening bleeding; women already taking progesterone supplementation therapy or participating in other blinded, placebo-controlled trials of investigational medicinal products; contraindications to progesterone use; pregnancies with a crown-rump length measuring 7mm or more with no visible heartbeat; and pregnancies with a gestation sac of 25mm or more with no visible fetal pole on ultrasonography. STUDY INTERVENTION: Progesterone (Utrogestan) pessaries 400mg twice daily from confirmation of an intrauterine gestation sac on ultrasonography, to 16 completed weeks of pregnancy or until miscarriage is confirmed. COMPARISON: Identical appearance placebo (both progesterone and placebo will be provided as overencapsulated tablets). DOSE: Our choice of 400mg twice daily was made after an extensive review of: all the relevant research literature; current healthcare practice; a survey of clinicians from across the UK; and other related evidence. The Summary of Product Characteristics and the British National Formulary suggest a dose of up to 400mg twice daily. Progesterone vaginal capsules are commonly used for luteal support in Assisted Conception at a treatment dose of 400mg twice daily, with no specific concerns on safety raised on this dose. Moreover, the PROMISE trial (HTA 08/38/01), that has already randomised over 810 women to 400mg of progesterone or placebo twice daily, has not identified any acceptability or adverse effect issues. Hence we consider the dosage of 400 mg twice daily of vaginal progesterone to be the optimal choice in order to ensure a clinically effective dose, and to minimise the risk of a negative trial result from therapy with a suboptimal dose. ROUTE: An immuno-modulatory effect of progesterone within the uterus is the key presumed mechanism for preventing miscarriage. The vaginal route is therefore rational since it delivers a greater proportion of the drug to the uterus. Furthermore, existing miscarriage studies and preterm birth studies have shown effectiveness when given via the vaginal route. For instance, 14 of 36 studies of second/third trimester progesterone to prevent preterm birth (identified by a recent systematic review) used vaginal progesterone, with significant improvements being observed for various clinical outcomes, confirming the biological effects of vaginal progesterone. Finally, a survey of women has found very high acceptability for the vaginal route. PRIMARY OUTCOME: Live births beyond 34 completed weeks of gestation, as a proportion of all women randomised. SECONDARY OUTCOMES: Time to pregnancy end; ongoing pregnancy at 12 weeks (range 11 - 13 weeks) gestation; miscarriage rate; pregnancy end outcomes (such as ectopic pregnancy, stillbirth); gestation at delivery; mode of delivery; birth weight; arterial and venous cord pH and base excess; APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scores; antenatal complications (such as pre-eclampsia, pre-labour rupture of membranes); intrapartum complications (such as chorioamnionitis, intrauterine growth restriction); postpartum and maternal complications; neonatal complications (such as infection, respiratory distress syndrome, necrotising enterocolitis, chromosomal and congenital abnormalities, ventilation or oxygen support); survival at 28 days of neonatal life; serious adverse events. RESOURCE USE OUTCOMES: Antenatal, outpatient or emergency visits; inpatient admissions (nights in hospital); maternal admissions to a High Dependency Unit or Intensive Therapy Unit (nights); and neonatal admissions to a Special Care Baby Unit or Neonatal Unit (nights). OUTCOMES FOR FUTURE STUDIES: We will obtain women’s consent for future evaluation of themselves, their child and the health records of both, and babies will be flagged with the Office of National Statistics (ONS) or equivalent. Although long-term follow-up will remain outside the scope of this trial, we plan to conduct further studies on outcomes such as the composite endpoint of death or neurodevelopmental impairment at 2 years of age, the Bailey III cognitive scale cognitive scale standardised score at 2 years of chronological age, and disability classified into domains according to professional consensus. The NHS number of each baby will be recorded to facilitate future follow-up studies. SAMPLE SIZE: We plan to randomise 4,150 women in total (2,075 participants each in the progesterone and placebo arms). To detect a Minimally Important Difference (MID) of 5% in live birth beyond 34 weeks, it will be necessary to randomise a total of 3,940 women to the intervention and placebo groups. However, assuming and adjusting for a 5% attrition rate, the total number of participants required will be 4,150. PROJECT TIMETABLE: It is anticipated that the trial will last for 45 months. Before grant activation: Protocol development and regulatory approvals (NHS Research Ethics Committee authorisation; Clinical Trial Authorisation from MHRA; Research and Development approvals); development of patient information sheets and consent forms; execution of contracts. Months 1-6: Staff recruitment; development of trial management and data capture databases; development of trial related Standard Operating Procedures; establishment of the Trial Steering Committee and Data Monitoring Committee; pharmacy and dispensing arrangements. Months 7-39: Recruitment and randomisation. Months 19-40: Follow up for pregnancy and neonatal outcomes. Months 40-45: Final data gathering and cleaning, analysis, and report preparation. EXPERTISE: Our multi-disciplinary research team includes clinicians, patient and public representatives, health economists and statisticians with an outstanding track record in conducting randomised trials, including numerous NIHR funded studies. The trial will be co-ordinated by an accredited and mature Clinical Trials Unit.

Lay abstract: Miscarriage is the most common complication of pregnancy, affecting 1 in 5 pregnancies, and there are an estimated 168,000 cases per year in England alone, often resulting in profound distress and bereavement to the families involved. Miscarriage also has the potential to cause physical harm, including severe haemorrhage, infection, perforation of the womb during surgery for the condition, and occasionally death. The most recent (2011) triennial Confidential Enquiry into Maternal Deaths identified 7 women who had died from miscarriage related complications. The cost of miscarriage is estimated to be over £81 million per year to the NHS. This estimate includes the costs of diagnosis and immediate treatment, and hospital bed costs, but it does not include the management of complications (such as womb perforation, infection or bleeding) and any long-term health consequences. Thus the total costs – and any additional societal costs – are likely to be much higher. There is evidence from 7 small studies that giving progesterone hormone treatment to women with bleeding in early pregnancy may reduce the risk of miscarriage, but there is insufficient confidence in these studies to support a national clinical recommendation for use. In response to calls from clinicians, policy makers and patients for a large and robust randomised controlled trial to settle the question, we have formed a research group in partnership with the Association of Early Pregnancy Units and the Miscarriage Association (a national patient support organisation) to conduct the work. We plan to ask women who have bleeding in early pregnancy (up to 12 weeks of pregnancy) whether they would be willing to take part in the study. If they are found to be eligible to take part in the study and give written permission, they will be given either progesterone or placebo (inactive) pessaries, at a dose of 400mg, to insert vaginally twice a day. The treatment will be given up to 16 weeks of pregnancy. Neither the women nor their healthcare practitioners will know what treatment (progesterone or placebo) they have been given, to ensure we obtain an unprejudiced answer as to whether progesterone is effective in preventing miscarriage. A cost-effectiveness analysis will be carried out from NHS and societal perspectives. The primary outcome of the trial will be live births beyond 34 completed weeks of gestation, as a proportion of all women randomised. The secondary outcomes will be: gestation at delivery; viable pregnancy at 12 weeks, miscarriage rate, survival at 28 days of neonatal life, chromosomal and congenital abnormalities, and adverse events. Resource use data will be collected on the frequency and duration of antenatal, intrapartum, postnatal and neonatal care episodes and events. We anticipate that the total study duration will be 3 years, allowing adequate time for set-up, recruitment, follow-up and analysis. In order to obtain the large number of patients (4,150) needed to provide statistically reliable answers, and to maximise the clinical relevance of the findings, the project has been designed to fit in with routine hospital practice as far as possible. Our research team includes individuals and hospital departments with an established track record of conducting high quality studies in early pregnancy. The study will be co-ordinated by an experienced Clinical Trials Unit and overseen by a Study Steering Committee and an independent Data Monitoring Committee. The study is supported by the Association of Early Pregnancy Units (AEPU), the Miscarriage Association and the Early Pregnancy Clinical Studies Group of the Royal College of Obstetricians and Gynaecologists. The findings of the study are expected to be incorporated into national guidelines.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH