Plain English Summary
Background and study aims
Miscarriage is where a woman loses the baby she is carrying. It is the most common complication of pregnancy, affecting 15-25% of pregnancies bringing the total in England to approximately 125,000 per year. Miscarriage often brings not only physical pain, bleeding and risks of infection, but also emotional issues on women and their families. A missed miscarriage, also known as a missed abortion or a silent miscarriage, occurs when the baby dies, but the body does not recognise this and so the pregnancy sac (where the baby grows) stays inside the body. Women who have had a missed miscarriage often opt for medical management up to 13+6 weeks of pregnancy. NICE currently recommends that a drug called misoprostol (a vaginal pessary (medication inserted into the vagina) or 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. The aim of this study is to find out whether treating women with mifepristone followed by misoprostol, is more effective than misoprostol alone at resolving missed miscarriage.
Who can participate?
Women aged 16 years and over who have been diagnosed with a missed miscarriage
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive mifepristone followed by misoprostol and those in the second group receive a dummy drug (placebo) followed by misoprostol. Neither the participants nor the researchers know which women receive which drug. Women in both groups are then monitored for 7 days to find out how many miscarriages are resolved (complete) in each group. If miscarriage is not complete then further treatment (more tablets or surgery) is offered.
What are the possible benefits and risks of participating?
It is not known whether women will benefit personally from taking part in this study, but the knowledge gained thanks to their help will inform future treatment and potentially lead to improved treatment of miscarriage for women in the future. Mifepristone blocks the action of the hormone progesterone to help speed up the process of miscarriage. As a consequence, patients may experience increased vaginal bleeding. All patients who take part will receive misoprostol, which helps the uterus contract to push out the pregnancy tissue and can cause period-like cramps, sickness, diarrhoea and flu-like symptoms. If patients have any concerns, they are advised to contact the research nurse/midwife at their hospital. Patients will be provided with a card to carry and give to anyone treating them, informing them that they are taking part in this study.
Where is the study run from?
1. Birmingham Women’s Hospital (UK)
2. Queen Alexandra Hospital, Portsmouth (UK)
3. Queen’s Medical Centre, Nottingham (UK)
4. Sunderland Royal Hospital (UK)
5. University Hospital Coventry (UK)
6. Royal London Hospital (UK)
7. Whipps Cross Hospital (UK)
8. Newham University Hospital (UK)
9. Birmingham Heartlands Hospital (UK)
10. Glasgow Royal Infirmary (UK)
11. Queen Elizabeth University Hospital, Glasgow (UK)
12. King’s College Hospital (UK)
13. Liverpool Women’s Hospital (UK)
14. Princess Anne Hospital, Southampton (UK)
15. Royal Infirmary of Edinburgh (UK)
16. Royal Victoria Infirmary, Newcastle (UK)
17. St Thomas’ Hospital (UK)
18. St Michael’s University Hospital, Bristol (UK)
19. University College Hospital, London (UK)
When is the study starting and how long is it expected to run for?
February 2017 to January 2020
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
Mrs Leanne Beeson
l.e.beeson@bham.ac.uk
Trial website
Contact information
Type
Public
Primary contact
Mrs Leanne Beeson
ORCID ID
http://orcid.org/0000-0003-0980-9837
Contact details
Birmingham Clinical Trials Unit
Institute of Applied Health Research
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 9011
l.e.beeson@bham.ac.uk
Additional identifiers
EudraCT number
2016-005097-35
ClinicalTrials.gov number
NCT03065660
Protocol/serial number
RG_16-076
Study information
Scientific title
A randomised placebo-controlled trial of mifepristone and misoprostol versus misoprostol alone in the medical management of missed miscarriage
Acronym
MifeMiso
Study hypothesis
Current study hypothesis as of 10/05/2018:
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.
Previous study hypothesis:
Treatment with mifepristone plus misoprostol is superior to misoprostol alone for the resolution of miscarriage within 7 days by at least 10% in women diagnosed with missed miscarriage by pelvic ultrasound scan in the first 13+6 weeks of pregnancy.
Ethics approval
14/02/2017, ref: 17/WM/0017
Study design
Randomised; Interventional; Design type: Treatment, Drug
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Specialty: Reproductive health and childbirth, Primary sub-specialty: General Gynaecology; UKCRC code/ Disease: Reproductive Health and Childbirth/ Other maternal disorders predominantly related to pregnancy
Intervention
Current interventions as of 10/05/2018:
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.
710 women in total will be randomised; 355 participants each in the mifepristone and placebo arms.
Participants in the mifepristone arm will receive a single dose of oral mifepristone 200 mg, followed by a single dose of vaginal, oral or sublingual misoprostol 800 mcg 2 days later. Participants in the placebo arm will receive a single oral placebo tablet followed by a single dose of vaginal, oral or sublingual misoprostol 800 mcg 2 days later
All women will be clinically followed up until they are discharged upon confirmation of a negative pregnancy test result and resolution of the miscarriage. Upon discharge all women will be requested to complete a follow up EQ-5D-5L questionnaire and Qualitative Patient Satisfaction Questionnaire which should be returned as soon as possible following discharge. A subset of women will be selected for an in depth interview to discuss the treatment they received up to 6 weeks after discharge based on their responses to the Qualitative Patient Satisfaction Questionnaire.
Previous interventions:
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.
710 women in total will be randomised; 355 participants each in the mifepristone and placebo arms.
Participants in the mifepristone arm will receive a single dose of oral mifepristone 200mg, followed by a single dose of vaginal or oral misoprostol 800mcg 2 days later. Participants in the placebo arm will receive a single oral placebo tablet followed by a single dose of vaginal or oral misoprostol 800mcg 2 days later.
All women will be clinically followed up until they are discharged upon confirmation of a negative pregnancy test result and resolution of the miscarriage. Upon discharge all women will be requested to complete a follow up EQ-5D-5L questionnaire and Qualitative Patient Satisfaction Questionnaire which should be returned as soon as possible following discharge. A subset of women will be selected for an in depth interview to discuss the treatment they received up to 6 weeks after discharge based on their responses to the Qualitative Patient Satisfaction Questionnaire.
Intervention type
Drug
Phase
Phase III
Drug names
Mifepristone
Primary outcome measure
Current primary outcome measure as of 10/05/2018:
Failure to spontaneously pass the gestational sac within 7 days after randomisation is assessed within 7 days after randomisation by pelvic ultrasound scan
Previous primary outcome measure:
Failure to spontaneously pass gestational sac within 7 days after start of the medical treatment is assessed within 7 days after start of medical treatment by pelvic ultrasound scan.
Secondary outcome measures
Current secondary outcome measures as of 10/05/2018:
1. Need for further doses of misoprostol up to day 7 post-randomisation is assessed after initial 800 mcg dose of misoprostol at day 2 until day 7 post-randomisation (information collected on Outcomes case report form [CRF])
2. Need for further doses of misoprostol up to discharge from EPU care is assessed after initial 800 mcg dose of misoprostol at day 2 until discharge by clinical review (information collected on Outcomes case report form [CRF])
3. Time from randomisation to passage of gestational sac is assessed up to approximately 8 weeks by calculating the days between randomisation (recorded on the Randomisation form) and passage of the gestational sac (recorded on the Outcomes CRF)
4. Time from active treatment (defined as mifepristone in the active group and misoprostol in the placebo group) commencement to passage of gestational sac is assessed up to approximately 8 weeks by calculating the days between active treatment commencement (mifepristone/misoprostol; recorded on the Outcomes CRF) and passage of the gestational sac (also recorded on the Outcomes CRF)
5. Surgical intervention to resolve the miscarriage (collected up to discharge from EPU care) is assessed from randomisation until discharge up to approximately 8 weeks by clinical review (surgical intervention information recorded on the Outcomes CRF)
6. Overall patient satisfaction score is assessed within 6 weeks of discharge from EPU care using the CSQ-8 Client Satisfaction Questionnaire
7. Patient quality of life (Index value and overall health status) is assessed 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)
8. Blood transfusion required is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (information recorded on the Outcomes CRF)
9. Duration of bleeding reported by woman (days) is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by the patient self-reporting (information recorded on the Outcomes CRF)
10. Diagnosis of infection associated with miscarriage requiring outpatient antibiotic treatment is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (information recorded on the Outcomes CRF)
11. Diagnosis of infection associated with miscarriage requiring inpatient antibiotic treatment is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (information recorded on the Outcomes CRF)
12. Negative pregnancy test result 21 days (+/- 2 days) after randomisation is assessed 21 days (+/- 2 days) after randomisation by patient performed pregnancy test (information recorded on the Outcomes CRF)
13. Time from randomisation to discharge from EPU care is measured in days, assessed up to approximately 8 weeks by calculating the days between randomisation (recorded on the Randomisation form) and discharge from EPU care (recorded on the Outcomes CRF)
14. Side effects are measured from randomisation until discharge from EPU care, assessed up to approximately 8 weeks by clinical review and/or patient self-reporting (adverse events and serious adverse events recorded on respective forms
15. Death is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (recorded on SAE form)
16. Any serious complications is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (recorded on SAE form)
17. Outpatient or emergency visits are recorded from randomisation until discharge from EPU care, up to approximately 8 weeks by reviewing patient notes (recorded on the Outcomes CRF)
18. Inpatient admissions (nights in hospital) are assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by reviewing patient notes (recorded on the Outcomes CRF)
Previous secondary outcome measures:
1. Need for further doses of misoprostol is assessed after initial 800mcg dose of misoprostol at day 2 until discharge by clinical review (information collected on Outcomes case report form [CRF])
2. Time from randomisation to passage of gestational sac is assessed up to 8 weeks by calculating the days between randomisation (recorded on the Randomisation form) and passage of the gestational sac (recorded on the Outcomes CRF)
3. Time from active treatment commencement to passage of gestational sac is assessed up to 8 weeks by calculating the days between active treatment commencement (mifepristone/misoprostol; recorded on the Outcomes CRF) and passage of the gestational sac (also recorded on the Outcomes CRF)
4. Expulsion of the gestational sac without the need for surgery is assessed from randomisation until discharge up to 8 weeks by clinical review (surgical intervention information recorded on the Outcomes CRF)
5. Unplanned surgery is assessed from randomisation until discharge, up to 8 weeks by clinical review (surgical intervention information recorded on the Outcomes CRF)
6. Patient satisfaction is assessed within 6 weeks of discharge using the CSQ-8 Client Satisfaction Questionnaire
7. Patient quality of life is assessed at baseline, 6-7 days after start of medical treatment and upon discharge using the EQ-5D-5L questionnaire
8. Blood transfusion rate is assessed from randomisation until discharge, up to 8 weeks by clinical review (information recorded on the Outcomes CRF)
9. Days of bleeding is assessed from randomisation until discharge, up to 8 weeks by the patient self-reporting (information recorded on the Outcomes CRF)
10. Infection requiring outpatient antibiotics treatment is assessed from randomisation until discharge, up to 8 weeks by clinical review (information recorded on the Outcomes CRF)
11. Infection requiring inpatient treatment rate is assessed from randomisation until discharge, up to 8 weeks by clinical review (information recorded on the Outcomes CRF)
12. Negative pregnancy test result is assessed 21 days after start of medical treatment by patient performed pregnancy test (information recorded on the Outcomes CRF)
13. Time from start of medical treatment to discharge is measured in days, assessed up to 8 weeks by calculating the days between start of medical treatment (mifepristone/placebo; recorded on the Outcomes CRF) and passage of the gestational sac (recorded on the Outcomes CRF)
14. Side effects are measured from randomisation until discharge, assessed up to 8 weeks by clinical review and/or patient self-reporting (adverse events and serious adverse events recorded on respective forms)
15. Death or serious complication rate is assessed from randomisation until discharge, up to 8 weeks by clinical review (death information recorded on SAE form)
16. Outpatient or emergency visits are recorded from randomisation until discharge, up to 8 weeks by reviewing patient notes (recorded on the Outcomes CRF)
17. Inpatient admissions (nights in hospital) are assessed from randomisation until discharge, up to 8 weeks by reviewing patient notes (recorded on the Outcomes CRF)
Overall trial start date
01/02/2017
Overall trial end date
31/01/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Women diagnosed with missed miscarriage by pelvic ultrasound scan in the first 13+6 weeks of pregnancy
2. Age 16 years and over
3. Willing and able to give informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
Planned Sample Size: 710; UK Sample Size: 710
Participant exclusion criteria
Current participant exclusion criteria as of 10/05/2018:
1. Women opting for alternative methods of miscarriage management (expectant or surgical)
2. Diagnosis of incomplete miscarriage
3. Life-threatening bleeding
4. 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
5. Participation in any other blinded, placebo-controlled trials of investigational medicinal products in pregnancy
6. Previous participation in the MifeMiso trial
7. Woman not able to attend for day 6-7 ultrasound scan
Previous participant exclusion criteria:
1. Women opting for alternative methods of miscarriage management (expectant or surgical)
2. Diagnosis of incomplete miscarriage
3. Life threatening bleeding
4. Contraindications to mifepristone or misoprostol use including 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
5. Participation in any other blinded, placebo-controlled trials of investigational medicinal products in pregnancy
Recruitment start date
20/09/2017
Recruitment end date
01/08/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Birmingham Women’s Hospital
Mindelsohn Way
Birmingham
B15 2TG
United Kingdom
Trial participating centre
Queen Alexandra Hospital
Portsmouth
PO6 3LY
Trial participating centre
Queen’s Medical Centre
Nottingham
NG7 2UH
Trial participating centre
Sunderland Royal Hospital
SR4 7TP
Trial participating centre
University Hospital Coventry
CV2 2DX
Trial participating centre
Royal London Hospital
E1 1BB
Trial participating centre
Whipps Cross Hospital
E11 1NR
Trial participating centre
Newham University Hospital
E13 8SL
Trial participating centre
Birmingham Heartlands Hospital
B9 5SS
Trial participating centre
Glasgow Royal Infirmary
G4 0SF
Trial participating centre
Queen Elizabeth University Hospital
Glasgow
G51 4TF
Trial participating centre
King’s College Hospital
SE5 9RS
Trial participating centre
Liverpool Women’s Hospital
L8 7SS
Trial participating centre
Princess Anne Hospital
Southampton
SO16 5YA
Trial participating centre
Royal Infirmary of Edinburgh
EH16 4SA
Trial participating centre
Royal Victoria Infirmary
Newcastle
NE1 4LP
Trial participating centre
St Thomas’ Hospital
SE1 7EH
Trial participating centre
St Michael’s University Hospital
Bristol
BS2 8EG
Trial participating centre
University College Hospital
London
NW1 2BU
Trial participating centre
+ 7 other sites in England
N/A
United Kingdom
Sponsor information
Organisation
University of Birmingham
Sponsor details
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 415 8011
researchgovernance@contacts.bham.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
National Institute for Health Research
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
1. Planned publication of study findings in prestigious peer reviewed journals with a high impact factor
2. Planned dissemination of completed papers to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the AEPU
3. The findings will be presented and disseminated via national and international conferences of AEPU and other relevant organisations
IPD Sharing plan:
The datasets generated during and/or analysed during the current study may be available upon request from a.coomarasamy@bham.ac.uk
Intention to publish date
01/05/2020
Participant level data
Available on request
Basic results (scientific)
Publication list