A trial to test if using a combination of drugs (mifepristone followed by misoprostol) is better than giving misoprostol alone to more quickly resolve a miscarriage
| ISRCTN | ISRCTN17405024 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17405024 |
| EudraCT/CTIS number | 2016-005097-35 |
| ClinicalTrials.gov number | NCT03065660 |
| Secondary identifying numbers | RG_16-076 |
- Submission date
- 27/02/2017
- Registration date
- 01/03/2017
- Last edited
- 11/08/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Pregnancy and Childbirth
Plain English summary of protocol
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)
20. Epsom Hospital (UK)
21. Southmead Hospital (UK)
22. West Middlesex Hospital (UK)
23. Chelsea and Westminster Hospital (UK)
24. Princess Royal Hospital (UK)
25. Singleton Hospital (UK)
26. Princess of Wales Hospital (UK)
27. Burnley General Hospital (UK)
28. St Helier Hospital (UK)
When is the study starting and how long is it expected to run for?
February 2017 to July 2020 (updated 31/03/2020, previously: 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
Contact information
Public
Birmingham Clinical Trials Unit
Institute of Applied Health Research
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
 ORCID ID |
0000-0003-0980-9837 |
|---|---|
| Phone | +44 (0)121 414 9011 |
| l.e.beeson@bham.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | A randomised placebo-controlled trial of mifepristone and misoprostol versus misoprostol alone in the medical management of missed miscarriage |
| Study acronym | MifeMiso |
| Study objectives | 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(s) | 14/02/2017, ref: 17/WM/0017 |
| Health condition(s) or problem(s) studied | Miscarriage |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Mifepristone |
| Primary outcome measure | Current primary outcome measure as of 09/08/2019: Failure to spontaneously pass the gestational sac within 7 days after randomisation is assessed within 7 days after randomisation by pelvic ultrasound scan (where possible) Previous primary outcome measure from 10/05/2018 to 09/08/2019: Failure to spontaneously pass the gestational sac within 7 days after randomisation is assessed within 7 days after randomisation by pelvic ultrasound scan Original 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 09/08/2019: Key Secondary Outcome: 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) Other Secondary Outcomes: 1. Surgical intervention to resolve the miscarriage up to and including day 7 post-randomisation is assessed from randomisation until day 7 post-randomisation by clinical review (surgical intervention information recorded on the Outcomes CRF) 2. Surgical intervention to resolve the miscarriage after day 7 post-randomisation to discharge from EPU care is assessed from day 8 post-randomisation until discharge up to approximately 8 weeks by clinical review (surgical intervention information recorded on the Outcomes CRF) 3. 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]) 4. 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]) 5. Overall patient satisfaction score is assessed within 6 weeks of discharge from EPU care using the CSQ-8 Client Satisfaction Questionnaire 6. 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) 7. 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) 8. 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) 9. 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) 10. 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) 11. Time from randomisation to discharge from EPU care (described using summary statistics only) 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) 12. 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) 13. 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) Safety Outcomes: 1. 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) 2. 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) 3. Death is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (recorded on SAE form) 4. Any serious complications is assessed from randomisation until discharge from EPU care, up to approximately 8 weeks by clinical review (recorded on SAE form) Previous secondary outcome measured from 10/05/2018 to 09/08/2019: 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) Original 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 study start date | 01/02/2017 |
| Completion date | 31/07/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Female |
| Target number of participants | Planned Sample Size: 710; UK Sample Size: 710 |
| Total final enrolment | 711 |
| Key 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 |
| Key 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 |
| Date of first enrolment | 20/09/2017 |
| Date of final enrolment | 31/07/2019 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Birmingham
B15 2TG
United Kingdom
PO6 3LY
United Kingdom
NG7 2UH
United Kingdom
SR4 7TP
United Kingdom
CV2 2DX
United Kingdom
E1 1BB
United Kingdom
E11 1NR
United Kingdom
E13 8SL
United Kingdom
B9 5SS
United Kingdom
G4 0SF
United Kingdom
G51 4TF
United Kingdom
SE5 9RS
United Kingdom
L8 7SS
United Kingdom
SO16 5YA
United Kingdom
EH16 4SA
United Kingdom
NE1 4LP
United Kingdom
SE1 7EH
United Kingdom
BS2 8EG
United Kingdom
NW1 2BU
United Kingdom
Birmingham
B15 2TG
United Kingdom
Epsom
KT18 7EG
United Kingdom
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom
Isleworth
TW7 6AF
United Kingdom
Chelsea
London
SW10 9NH
United Kingdom
Apley
Telford
TF1 6TF
United Kingdom
Sketty
Swansea
SA2 8QA
United Kingdom
Bridgend
CF31 1RQ
United Kingdom
Burnley
BB10 2PQ
United Kingdom
Carshalton
SM5 1AA
United Kingdom
Sponsor information
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 415 8011 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/08/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/09/2020 | 27/08/2020 | Yes | No |
| Results article | cost-effectiveness results | 01/08/2021 | 01/06/2021 | Yes | No |
| Results article | results | 01/11/2021 | 26/11/2021 | Yes | No |
| Protocol file | version 5.0 | 27/06/2019 | 11/08/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
11/08/2022: Uploaded protocol (not peer-reviewed) as an additional file.
26/11/2021: Publication reference added.
01/06/2021: Publication reference added.
27/08/2020: Publication reference added.
04/08/2020: The intention to publish date was changed from 01/07/2020 to 31/08/2020.
31/03/2020: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2020 to 31/07/2020.
2. The plain English summary was updated to reflect these changes.
12/08/2019: Trial participating centres added.
09/08/2019: The following changes were made to the trial record:
1. The primary and secondary outcome measures were updated.
2. The intention to publish date was changed from 01/05/2020 to 01/07/2020.
3. Trial participating centres added.
06/08/2019: The total final enrolment was added.
31/07/2019: The recruitment end date was changed from 01/08/2019 to 31/07/2019.
28/03/2019: The condition has been changed from "Specialty: Reproductive health and childbirth, Primary sub-specialty: General Gynaecology; UKCRC code/ Disease: Reproductive Health and Childbirth/ Other maternal disorders predominantly related to pregnancy" to "Miscarriage" following a request from the NIHR.
10/05/2018: The following changes have been made:
1. The study hypothesis has been changed.
2. The interventions have been changed.
3. The primary outcome measure has been changed.
4. The secondary outcome measures have been changed.
5. The participant exclusion criteria have been changed.
21/09/2017: The recruitment start date was changed from 01/08/2017 to 20/09/2017.
