About the MifeMiso trial

The MifeMiso trial is a double blind, placebo-controlled trial to test the hypothesis that treatment with mifepristone plus misoprostol is superior to misoprostol alone for the resolution of miscarriage within 7 days in women diagnosed with missed miscarriage by pelvic ultrasound scan in the first 13+6 weeks of pregnancy.

Should the MifeMiso trial demonstrate a benefit from the intervention, it would provide important evidence for the combined use of these treatments for the timely resolution of miscarriage.

In order to recruit the required number of women needed to provide statistically reliable answers, and to maximise the clinical relevance of the findings, the trial is designed to fit in with routine hospital practice as far as possible, imposing minimal additional workload by keeping extra clinic-based tests and evaluations to a minimum.

Trial design - A randomised, parallel group, double-blind, placebo-controlled multicentre study, with health economic and mixed-methods evaluation.

Setting - Early pregnancy units and gynaecology departments.

Number of participants - We plan to randomise 710 women in total (355 participants each in the mifepristone and placebo arms).

Study interventions - A single dose of oral mifepristone 200mg, followed by a single dose of vaginal, oral or sublingual misoprostol  800mcg 2 days later, will be compared with an oral placebo tablet followed by a single dose of vaginal, oral or sublingual misoprostol 800mcg 2 days later.

Duration of study - It is anticipated that the trial will last for three years.

Randomisation - Participants will be randomised on-line via a secure internet facility in a 1:1 ratio through a third party independent Integrated Trial Management System (MedSciNet Clinical Trial Framework). A “minimisation” procedure using a computer-based algorithm will be used to avoid chance imbalances in the following important variables:

Maternal age (<30, ≥30 years), body mass index (<35, ≥35 kg/m2), previous parity (nulliparous, parous women), gestational age (<70, ≥70 days), amount of bleeding (PBAC score; ≤2, ≥3) and randomising centre

Potential participants will be identified and approached by clinic doctors, nurses, and research nurses/midwives in the Early Pregnancy Assessment Units (EPAUs) of participating centres. They will be clearly advised that participation in the study is entirely voluntary with the option of withdrawing from the study at any stage, and that participation or non-participation will not affect their usual care. Potential participants will be provided with a study Participant Information Sheet (PIS) and given time to consider their involvement. Women who give consent will proceed to randomisation if they are eligible to participate in the trial. Consent will be recorded on the approved consent form, which must be retained in the site file and medical notes, with a copy given to the participant and a copy sent to the MifeMiso Trial Office. Further consent will be obtained from those patients that are approached and agree to take part in the semi-structured mixed-methods interview.

Immediately after all eligibility criteria have been confirmed, consent has been obtained and all baseline prognostic factors gathered, a woman will be randomised into the trial. Women will be randomised into the trial by a secure online randomisation system which is available via the MedSciNet Clinical Trial Framework (www.medscinet.net/mifemiso). Unique log-in usernames and passwords will be provided to those who are required to use the online system and/or who have been delegated the role of randomising participants into the study as detailed on the MifeMiso Trial Signature and Delegation Log. The online randomisation system will be available 24 hours a day, 7 days a week, apart from short periods of scheduled maintenance. A telephone toll-free randomisation service (0800 953 0274) is available Monday to Friday, 09:00 to 17:00 UK time, except for bank holidays and University of Birmingham closed days.

Registration paperwork will be provided to investigators and may be used to collate the necessary information prior to randomisation. All the questions and data items on the registration paperwork must be answered before a trial number and pack number may be given. If some data items are missing, randomisation will be suspended but may be resumed once the information is available. Only when all the eligibility criteria and baseline data items have been provided, will the trial and treatment pack numbers be given and a confirmatory email sent to the randomising investigator, the local Principal Investigator,the research midwife/nurse, the local pharmacist and the MifeMiso trial office. The trial number will be linked to a treatment pack number that will be available in the local hospital pharmacy.

Inclusion Criteria:

• Women diagnosed with missed miscarriage by pelvic ultrasound scan in the first 13+6 weeks of pregnancy that choose to have medical management of miscarriage.
• Age 16 years and over.
• Willing and able to give informed consent.

Exclusion Criteria:

• Women opting for alternative methods of miscarriage management (expectant or surgical)
• Diagnosis of incomplete miscarriage.
• Life threatening bleeding.
• Contraindications to mifepristone or misoprostol use for example chronic adrenal failure, known hypersensitivity to either drug, haemorrhagic disorders and anticoagulant therapy, prosthetic heart valve or history of endocarditis, existing cardiovascular disease, severe asthma uncontrolled by therapy or inherited porphyria.
• Participation in any other blinded, placebo-controlled trials of investigational medicinal products in pregnancy.
• Previous participation in the MifeMiso trial
• Woman not able to attend for day 6-7 ultrasound scan