HTA - 08/38/01: PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation
|Project title||PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation|
|Research type||Primary Research|
|Start date||October 2009|
|Link to journal publication|
|Chief Investigator||Dr Raj Rai|
|Co-investigators||Professor Peter Braude (King's College London), Dr Annette Briley (King's College London), Dr Nicholas Brook, Professor Arri Coomarasamy (University of Birmingham), Dr Mariette Goddijn (University of Amsterdam), Emeritus Professor Christine Godfrey (University of York), Mr Yacoub Khalaf (Guy's & St Thomas' NHS Foundation Trust), Professor Mark Kilby (University of Birmingham), Professor Tin-Chiu Li (Sheffield Teaching Hospitals NHS Foundation Trust), Professor Siobhan Quenby (University of Warwick), Professor Lesley Regan (Imperial College London), Mr Paul Seed (King's College London)|
|Contractor||Imperial College London|
|Plain English summary||Recurrent miscarriage (RM), the loss of three or more early pregnancies, affects over 6000 couples in the UK every year. It is estimated to cost the NHS £28 million/ year. The costs to society, with days off work and out-of-pocket expenses for patients and partners are likely to be far greater. RM also carries substantial physical and psychological impact; for instance, studies have shown that the level of distress and the bereavement reaction associated with miscarriages are no less when compared to women who had suffered a stillbirth of a term baby. Over the decades, women with RM have been subjected to treatments based on anecdotal evidence, historical beliefs and the results of small poor quality studies. We propose to evaluate therapy with progesterone, a natural pregnancy supporting hormone, in women with a history of RM. Our specific research question is that 'in women with a history of recurrent miscarriages without an identifiable cause, who have conceived spontaneously within 1 year of agreeing to take part in the study, would progesterone pessaries (400mg, twice a day) started as soon as possible after a positive pregnancy test and continued to 12 weeks of gestation, improve the chances of live birth beyond 24 weeks gestation and reduce miscarriages?' We have comprehensively reviewed all the existing evidence for this question. We identified four experimental studies (randomised trials). The quality of the studies was generally poor and the participant numbers were small. However, all four studies suggested a benefit with 42 - 69% decrease in miscarriage rate, although statistical testing showed that we could not be certain of this benefit. Statistical pooling (meta-analysis) of the four studies, however, showed a promising effect of a 51% reduction in miscarriage rates with progesterone therapy in those with RM. We, therefore, surveyed UK clinicians (number of questionnaires sent =114, response rate 89%) to evaluate their view on the role of progesterone in RM: 2% clinicians use progesterone routinely and 3% use it selectively in pregnant women with a history of recurrent miscarriages; over 95% do not use progesterone for this indication; however, the vast majority (>90%) were willing to support a study evaluating the role of progesterone. The commonest reason cited by clinicians for not using progesterone was the fact that the existing studies were of poor quality and small, and cannot therefore be relied upon. Similarly, we conducted a survey of patients' views on 88 women with a history of RM in which the majority of women stated they will be willing to be take part in this study (83/88=94.3%). Our proposed study is large and will be conducted to a high quality to ensure we produce a definitive answer. If the benefit shown in the existing studies is confirmed in our study, we expect the uptake of this treatment to be rapid and widespread given the low cost of progesterone, its well-known safety profile and convenience (outpatient use, taken as pessaries). Progesterone is already in clinical use for the prevention of preterm births. ETHICAL ISSUES: The primary ethical issue is the administration of a drug without full knowledge of its effects, although the existing evidence suggests a large potential benefit. As highlighted above, there is overwhelming support from the patients for this trial. Furthermore, we held discussions with representatives of patient bodies (please see Detailed Project Description) and there was strong support for the trial from them. There is substantial evidence of safety of progesterone in pregnancy, and progesterone is already in widespread use in pregnancy for other reasons such as prevention of preterm birth. However, we will put in place robust mechanisms for addressing potential adverse events. All participants will be asked to report adverse events to their local research nurse; if the local trial nurse is unavailable for any reason, they will be able to report the events to the trial manager or trial co-ordinator who will be accessible on a mobile telephone 24 hours a day. The second issue of the potential for distress, discomfort, and inconvenience was explored during our interviews and consultations with patients and representatives of patient societies. It emerged that the likely distress, discomfort and inconvenience from the trial are limited, and would be of an acceptable level to most women. TEAM EXPERTISE: The research team incorporates individuals and centres which possess all the multi-disciplinary skills and resources required to ensure the successful completion of this trial. This includes clinical expertise and a proven track record of research in recurrent miscarriage (St Mary's Hospital, Liverpool Women's Hospital, Sheffield and Amsterdam); expertise in research methods and the conduct of multicentre clinical trials (King's College, London, Birmingham University, Liverpool University) and Health Economics (Centre for Health Economics, University of York Health Services Management Centre). WHY IS A TRIAL NEEDED NOW? 1. The existing trials, although small and of poor quality, suggest a large benefit in a condition with substantial consequences and costs. 2. A recent Guideline by the Royal College of Obstetricians and Gynaecologists and a Cochrane Review have called for a definitive trial to evaluate this research question. 3. Surveys of patients and clinicians show that this trial is needed. 4. If proven to be effective, the intervention would represent a low-cost, safe and easily deliverable therapy.|
|Scientific summary||1. Women with a history of recurrent miscarriages (RM) are referred to and seen in a recurrent miscarriage clinic (standard practice), where appropriate baseline investigations are performed (standard clinical practice). If a woman fulfils the inclusion/exclusion criteria, she is offered information about the PROMISE trial, and invited to participate. 2. If she agrees to participate in the trial, further information and instructions relating to the trial are given, and written consent is obtained by the clinician or research nurse. Contact and baseline data are collected in the electronic Integrated Trial Management System. 3. The woman is given instructions to notify the research nurse by telephone as soon as she conceives (a positive urinary pregnancy test). It is expected that she will be about 4 weeks pregnant (4 weeks from last menstrual period) at this stage. When the research nurse receives the call from the woman, she will obtain details about this pregnancy and recheck the woman's history to ensure she is still eligible for the trial. If the woman remains eligible, the nurse will randomise her to one of the two trial interventions. 4. The research nurse will dispatch the trial intervention pessaries (either progesterone or placebo) to the woman within 72 hours of the telephone call via courier. 5. The woman is expected to start the trial intervention on the day it is received, and continue until 12 completed weeks of gestation. In the event of the pessaries being mislaid, the woman will be instructed to call the research nurse who will liaise with the trial management team to arrange a further supply of the same type of intervention. 6. The first outcome assessment (OA1-"clinical pregnancy") will be an ultrasound scan performed between 6-8 weeks of gestation. An early scan at this gestational age is standard practice and routinely undertaken for women with RM attending a recurrent miscarriage clinic. If such provision is not available at the woman's local hospital, the research nurse will arrange for the woman to be scanned at one of the trial centres. 7. The second outcome assessment (OA2-"ongoing pregnancy") will be at 12-14 weeks of gestation. This is standard practice in most RM clinics. However, if it is not routinely available, it will be arranged by the research nurse. 8. The third outcome assessment (OA3) is conducted after delivery to gather data on various outcomes. Prompts on the Integrated Trial Management System will alert the research nurse when each trial participant reaches her due delivery date. The local research nurse will also check birth registers and in-patient records to track hospital admissions and pregnancy outcomes. 9. The fourth and final outcome assessment (OA4) is conducted after 28 days of delivery to gather data on various outcomes. 10. At the conclusion of the trial, all participants, participating centres, relevant patient groups and interested communities will be informed of the findings of the trial.|
Protocol (PDF File - 985.2 KB)
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