Clinical trial NCT03065660: Mifepristone and Misoprostol Versus Misoprostol Alone in the Medical Management of Missed Miscarriage
Official title: A Randomised Placebo-controlled Trial of Mifepristone and Misoprostol Versus Misoprostol Alone in the Medical Management of Missed Miscarriage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Missed Miscarriage
Keywords: Missed miscarriage
Mifepristone
Misoprostol
Medical management
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Birmingham Women's NHS Foundation Trust
name: Royal Infirmary of Edinburgh
name: Royal Victoria Infirmary
name: City Hospitals Sunderland NHS Foundation Trust
name: Liverpool Women's NHS Foundation Trust
name: The Leeds Teaching Hospitals NHS Trust
name: Barts & The London NHS Trust
name: Queen's Medical Center
name: Heart of England NHS Trust
name: University Hospitals Coventry and Warwickshire NHS Trust
name: Oxford University Hospitals NHS Trust
name: St Mary's Hospital, London
name: University College London Hospitals
name: University Hospital Southampton NHS Foundation Trust
name: King's College Hospital NHS Trust
name: University of Edinburgh
name: University of Nottingham
name: Queen Mary University of London
name: University of Warwick
name: University of Southampton
First posted: 2017-02-28
Enrollment: 711
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomised, parallel group, double-blind, placebo-controlled multicentre study, with health economic and mixed-methods evaluation.
Primary purpose: TREATMENT

Brief summary: 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 psychological impacts on women and their families. This study will focus on women whose pregnancy sac remains inside the womb (known as a missed miscarriage) and opt for medical management of their miscarriage up to 13+6 weeks of pregnancy. NICE currently recommends that a drug called misoprostol (a vaginal pessary or oral tablet that makes the womb contract) should be used in the medical treatment of miscarriage. However, there is evidence to suggest that combining this drug with mifepristone (an oral tablet that reduces pregnancy hormones) may be more effective in treating miscarriage. Therefore, to test this in a clinical trial, participants will be allocated at random to receive either mifepristone followed by misoprostol, or a dummy drug (placebo) followed by misoprostol. 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 randomisation. 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.

Detailed description: Aim: To investigate the clinical and cost-effectiveness of MifeMiso combination (mifepristone and misoprostol) versus misoprostol alone in the management of missed miscarriage.

Primary clinical objective: 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.

Key secondary objective:To test the hypothesis that the addition of mifepristone reduces the need for surgical intervention to resolve the miscarriage.

Other secondary objectives:

1. To evaluate if the addition of mifepristone reduces the need for further doses of misoprostol.
2. To evaluate if the addition of mifepristone improves other clinical outcomes including surgical intervention up to and including 7 days post-randomisation and after 7 days post-randomisation, duration of bleeding, infection, negative pregnancy test at 21 days post-randomisation, time from randomisation to discharge from EPU care, side effects and complications.
3. To evaluate if the addition of mifepristone improves patient satisfaction
4. To assess the cost-effectiveness of the combination of mifepristone and misoprostol in the medical management of missed miscarriage.

Economic objectives: To assess the cost-effectiveness of the combination of mifepristone and misoprostol in the medical management of missed miscarriage based on an outcome of additional cost per additional successfully managed miscarriage and additional cost per additional quality-adjusted life-year (QALY). Using a model-based economic evaluation we will further explore the cost-effectiveness of the medical management of missed miscarriage, as explored in the proposed trial, with alternative management strategies, such as surgical and expectant, based on available secondary sources.

Mixed-method evaluation objectives: To explore the satisfaction of patients who complete the trial protocol. The results of the satisfaction survey (CSQ-8) will act as a sampling frame to conduct semi-structured interviews to further investigate patient experiences and satisfaction with medical management of missed miscarriage.

Eligibility criteria: 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

Primary outcomes:
measure: Failure to spontaneously pass the gestational sac within 7 days after randomisation
timeFrame: Within 7 days after randomisation
Secondary outcomes:
measure: Surgical intervention to resolve the miscarriage (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Surgical intervention to resolve the miscarriage up to and including day 7 post-randomisation
timeFrame: From randomisation until day 7 post-randomisation
measure: Surgical intervention to resolve the miscarriage after day 7 post-randomisation to discharge from EPU care
timeFrame: From day 8 post-randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Need for further doses of misoprostol up to day 7 post-randomisation
timeFrame: After initial 800mcg dose of misoprostol at day 2 until day 7 post-randomisation
measure: Need for further doses of misoprostol up to discharge from EPU care
timeFrame: After initial 800mcg dose of misoprostol at day 2 until discharge from EPU care; assessed up to approximately 8 weeks
measure: Overall patient satisfaction score (measured using the CSQ-8 questionnaire and collected upon discharge from EPU care).
timeFrame: Within 6 weeks of discharge from EPU care
measure: Patient quality of life (Index value and overall health status measured using the EQ-5D-5L questionnaire
timeFrame: Completion on date of randomisation, day 6-7 post-randomisation or day of follow-up USS if different to day 6-7 and day 21 +/- 2 days post-randomisation. Completion of all patient quality of life assessments up to approximately 8 weeks post-randomisation
measure: Duration of bleeding reported by woman (days). (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Diagnosis of infection associated with miscarriage requiring outpatient antibiotic treatment (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Diagnosis of infection associated with miscarriage requiring inpatient antibiotic treatment (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Negative pregnancy test result 21 days (± 2 days) after randomisation.
timeFrame: 21 days (± 2 days) after randomisation.
measure: Time from randomisation to discharge from EPU care (described using summary statistics only)
timeFrame: Time from randomisation to discharge from EPU care; assessed up to approximately 8 weeks
measure: Blood transfusion required (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Side effects (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Death (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Any serious complications (collected up to discharge from EPU care)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Other outcomes:
measure: Outpatient or emergency visits
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
measure: Inpatient admissions (nights in hospital)
timeFrame: From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Locations:
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Women's Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Bristol
country: United Kingdom
facility: St Michael's Hospital
city: Burnley
country: United Kingdom
facility: Burnley General Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Epsom
country: United Kingdom
facility: Epsom Hospital
city: Epsom
country: United Kingdom
facility: St Helier Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Women's Hospital
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: Newham University Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: St Thomas' Hospital
city: London
country: United Kingdom
facility: University College Hospital London
city: London
country: United Kingdom
facility: West Middlesex Hospital
city: London
country: United Kingdom
facility: Whipps Cross University Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Southampton
country: United Kingdom
facility: Princess Anne Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Swansea
country: United Kingdom
facility: Princess of Wales Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Telford
country: United Kingdom
facility: Princess Royal Hospital
Study officials:
affiliation: University of Birmingham
name: Arri Coomarasamy
role: PRINCIPAL_INVESTIGATOR
References: