Mifepristone and Misoprostol Versus Misoprostol Alone in the Medical Management of Missed Miscarriage (MifeMiso)

A Randomised Placebo-controlled Trial of Mifepristone and Misoprostol Versus Misoprostol Alone in the Medical Management of Missed Miscarriage

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.

Study Overview

• Status: Completed
• Conditions: Missed Miscarriage
• Intervention / Treatment: Drug: Mifepristone, Oral, 200 Mg; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 711
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • Birmingham, United Kingdom
    • Birmingham Women's Hospital
  • Bristol, United Kingdom
    • Southmead Hospital
  • Bristol, United Kingdom
    • St Michael's Hospital
  • Burnley, United Kingdom
    • Burnley General Hospital
  • Coventry, United Kingdom
    • University Hospital Coventry
  • Edinburgh, United Kingdom
    • Royal Infirmary of Edinburgh
  • Epsom, United Kingdom
    • Epsom Hospital
  • Epsom, United Kingdom
    • St Helier Hospital
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • Glasgow, United Kingdom
    • Queen Elizabeth University Hospital
  • Liverpool, United Kingdom
    • Liverpool Women's Hospital
  • London, United Kingdom
    • Kings College Hospital
  • London, United Kingdom
    • Royal London Hospital
  • London, United Kingdom
    • Chelsea and Westminster Hospital
  • London, United Kingdom
    • West Middlesex Hospital
  • London, United Kingdom
    • St Thomas' Hospital
  • London, United Kingdom
    • Newham University Hospital
  • London, United Kingdom
    • University College Hospital London
  • London, United Kingdom
    • Whipps Cross University Hospital
  • Newcastle, United Kingdom
    • Royal Victoria Infirmary
  • Nottingham, United Kingdom
    • Queen's Medical Centre
  • Portsmouth, United Kingdom
    • Queen Alexandra Hospital
  • Southampton, United Kingdom
    • Princess Anne Hospital
  • Sunderland, United Kingdom
    • Sunderland Royal Hospital
  • Swansea, United Kingdom
    • Singleton Hospital
  • Swansea, United Kingdom
    • Princess of Wales Hospital
  • Telford, United Kingdom
    • Princess Royal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mifepristone; A single dose of oral mifepristone 200mg, followed by a single dose of vaginal, oral or sublingual misoprostol 800mcg 2 days later	Drug: Mifepristone, Oral, 200 Mg; The Investigational Medicinal Product (IMP) is a single dose of 200mg mifepristone to be taken orally after confirmation of missed miscarriage by pelvic ultrasound scan.; Other Names: Mifegyne
Placebo Comparator: Placebo; Oral placebo tablet followed by a single dose of vaginal, oral or sublingual misoprostol 800mcg 2 days later.	Drug: Placebo Oral Tablet; The placebo will be an oral tablet in the same form as the IMP, and identical in appearance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure to spontaneously pass the gestational sac within 7 days after randomisation	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.	Within 7 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical intervention to resolve the miscarriage (collected up to discharge from EPU care)	Surgical intervention to resolve the miscarriage	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Surgical intervention to resolve the miscarriage up to and including day 7 post-randomisation	Surgical intervention to resolve the miscarriage	From randomisation until day 7 post-randomisation
Surgical intervention to resolve the miscarriage after day 7 post-randomisation to discharge from EPU care	Surgical intervention to resolve the miscarriage	From day 8 post-randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Need for further doses of misoprostol up to day 7 post-randomisation	Need for further doses of misoprostol up to day 7 post-randomisation	After initial 800mcg dose of misoprostol at day 2 until day 7 post-randomisation
Need for further doses of misoprostol up to discharge from EPU care	Need for further doses of misoprostol up to discharge from EPU care	After initial 800mcg dose of misoprostol at day 2 until discharge from EPU care; assessed up to approximately 8 weeks
Overall patient satisfaction score (measured using the CSQ-8 questionnaire and collected upon discharge from EPU care).	Overall patient satisfaction score (measured using the CSQ-8 questionnaire and collected upon discharge from EPU care).	Within 6 weeks of discharge from EPU care
Patient quality of life (Index value and overall health status measured using the EQ-5D-5L questionnaire	Patient quality of life (Index value and overall health status measured using the EQ-5D-5L questionnaire and collected 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. If a woman obtains an initial positive pregnancy test result at day 21 +/- 2 days post-randomisation then a further EQ-5D-5L questionnaire is collected upon discharge from EPU care).	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
Duration of bleeding reported by woman (days). (collected up to discharge from EPU care)	Duration of bleeding reported by woman (days). (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Diagnosis of infection associated with miscarriage requiring outpatient antibiotic treatment (collected up to discharge from EPU care)	Diagnosis of infection associated with miscarriage requiring outpatient antibiotic treatment (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Diagnosis of infection associated with miscarriage requiring inpatient antibiotic treatment (collected up to discharge from EPU care)	Diagnosis of infection associated with miscarriage requiring inpatient antibiotic treatment (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Negative pregnancy test result 21 days (± 2 days) after randomisation.	Negative pregnancy test result 21 days (± 2 days) after randomisation.	21 days (± 2 days) after randomisation.
Time from randomisation to discharge from EPU care (described using summary statistics only)	Time from randomisation to discharge from EPU care.	Time from randomisation to discharge from EPU care; assessed up to approximately 8 weeks
Blood transfusion required (collected up to discharge from EPU care)	Blood transfusion required (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Side effects (collected up to discharge from EPU care)	Side effects (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Death (collected up to discharge from EPU care)	Death (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Any serious complications (collected up to discharge from EPU care)	Any serious complications (collected up to discharge from EPU care)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Outpatient or emergency visits	Number of outpatient or emergency visits	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks
Inpatient admissions (nights in hospital)	Number of inpatient admissions (nights in hospital)	From randomisation until discharge from EPU care; assessed up to approximately 8 weeks

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: King's College Hospital NHS Trust; University College London Hospitals; University of Nottingham; The Leeds Teaching Hospitals NHS Trust; University of Southampton; Barts & The London NHS Trust; Queen Mary University of London; University of Edinburgh; University Hospital Southampton NHS Foundation Trust; University of Warwick; Queen's Medical Center; Oxford University Hospitals NHS Trust; St Mary's Hospital, London; University Hospitals Coventry and Warwickshire NHS Trust; Royal Infirmary of Edinburgh; Heart of England NHS Trust; City Hospitals Sunderland NHS Foundation Trust; Royal Victoria Infirmary; Birmingham Women's NHS Foundation Trust; Liverpool Women's NHS Foundation Trust
• Investigators: Principal Investigator: Arri Coomarasamy, University of Birmingham

Publications and helpful links

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2017
• Primary Completion (Actual): January 9, 2020
• Study Completion (Actual): January 9, 2020

Study Registration Dates

• First Submitted: February 10, 2017
• First Submitted That Met QC Criteria: February 22, 2017
• First Posted (Actual): February 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 8, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Mifepristone; Medical management; Misoprostol; Missed miscarriage
• Additional Relevant MeSH Terms: Pregnancy Complications; Abortion, Spontaneous; Abortion, Missed; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Abortifacient Agents; Luteolytic Agents; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Mifepristone
• Other Study ID Numbers: RG_16-076; 15/160/02 (Other Grant/Funding Number: NIHR HTA); 2016-005097-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No