Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: study protocol for a randomized double blinded placebo-controlled comparison (Triple M Trial)

Abstract

BackgroundEarly pregnancy failure (EPF) is a common complication of pregnancy. If women do not abort spontaneously, they will undergo medical or surgical treatment in order to remove the products of conception from the uterus. Curettage, although highly effective, is associated with a risk of complications; medical treatment with misoprostol is a safe and less expensive alternative. Unfortunately, after 1 week of expectant management in case of EPF, medical treatment with misoprostol has a complete evacuation rate of approximately 50%. Misoprostol treatment results may be improved by pre-treatment with mifepristone; its effectiveness has already been proven for other indications of pregnancy termination.This study will test the hypothesis that, in EPF, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation (primary outcome), patient satisfaction, complications, side effects and costs (secondary outcomes).MethodsThe trial will be performed multi-centred, prospectively, two-armed, randomised, double-blinded and placebo-controlled. Women with confirmed EPF by ultrasonography (6–14 weeks), managed expectantly for at least 1 week, can be included and randomised to pre-treatment with oral mifepristone (600 mg) or oral placebo (identical in appearance). Randomisation will take place after receiving written consent to participate. In both arms pre-treatment will be followed by oral misoprostol, which will start 36–48 h later consisting of two doses 400 μg (4 hrs apart), repeated after 24 h if no tissue is lost. Four hundred sixty-four women will be randomised in a 1:1 ratio, stratified by centre.Ultrasonography 2 weeks after treatment will determine short term treatment effect. When the gestational sac is expulsed, expectant management is advised until 6 weeks after treatment when the definitive primary endpoint, complete or incomplete evacuation, will be determined. A sonographic endometrial thickness < 15 mm using only the allocated therapy by randomisation is considered as successful treatment. Secondary outcome measures (patient satisfaction, complications, side effects and costs) will be registered using a case report form, patient diary and validated questionnaires (Short Form 36, EuroQol-VAS, Client Satisfaction Questionnaire, iMTA Productivity Cost Questionnaire).DiscussionThis trial will answer the question if, in case of EPF, after at least 1 week of expectant management, sequential treatment with mifepristone and misoprostol is more effective than misoprostol alone to achieve complete evacuation of the products of conception.Trial registrationClinicaltrials.gov (d.d. 02-07-2017): NCT03212352.Trialregister.nl (d.d. 03-07-2017): NTR6550.EudraCT number (d.d. 07-08-2017): 2017–002694-19.File number Commisie Mensgebonden Onderzoek (d.d. 07-08-2017): NL 62449.091.17.

Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M trial): A double-blind placebo-controlled randomised trial

“…A Data Safety Monitoring Board oversaw the study and assessed the results of the interim analysis after 50% of inclusions regarding primarily effectivity and secondarily safety. A pre-defined stopping rule, according to O'Brien-Fleming, was used to assess the primary outcome, complete evacuation after 6À8 weeks [24]. Following this stopping rule, when analysis of the primary outcome would show a difference between both study groups with a p-value <0.0054, a premature halt of the trial would be justified.…”

“…The study protocol is available from https://doi.org/10.1186/s12884À019À2497-y. 24 This trial was registered at the following registers: Clinicaltrials.gov: NCT03212352. Trialregister.nl: Trial NL 6366 EudraCT number: 2017-002694-19.…”

Economic evaluation of a randomized controlled trial comparing mifepristone and misoprostol with misoprostol alone in the treatment of early pregnancy loss

“…This economic evaluation was performed alongside the Triple M Trial, a nationwide multicentre double-blinded placebo-controlled RCT conducted in 17 Dutch hospitals [ 16 ]. A CONSORT checklist and further details about study design, sample size calculation, study procedures and outcome have been described previously [ 19 ].…”

Predictor assessment of complete miscarriage after medical treatment for early pregnancy loss in women with previous cesarean section

“…Alternatively, medical treatment has emerged and been pursued by both healthcare providers and patients to minimize the complications of surgical interventions. [ 6 , 10 , 11 ]…”

“…Alternatively, medical treatment has emerged and been pursued by both healthcare providers and patients to minimize the complications of surgical interventions. [6,10,11] Medical management using misoprostol with or without mifepristone for early pregnancy failure has been examined by several studies and demonstrated to be safe and effective, with success rates ranging between 50% and 96.5%, [12][13][14] even in women with previous cesarean section. [15] A recent study suggested that a previous cesarean section (odds ratio [OR]: 5.15, 95% confidence interval [CI]: 1.15-23.05, P = .032) was a significant predictor for incomplete miscarriage.…”