Comparing Two Medical Treatments for Early Pregnancy Failure.

NCT03212352 | Terminated Phase 4 DMC

• 1 other identifier: 62449
• Study Type: interventional
• Target: 342
• Locations: 1 country
• Sites: 13

Brief Summary

This study aims to compare whether a combination of two drugs (Mifepristone and misoprostol) are superior compared to using only one of these drugs (Misoprostol) as medical treatment for a miscarriage. Women in whom early pregnancy failure, 6-14 weeks postmenstrual, is ultrasonographically confirmed qualify for this study. It is expected that the combination of Mifepristone and Misoprostol is more effective in reaching complete evacuation, and therefore can prevent more invasive treatment such as curettage.

Conditions

Early Pregnancy Failure

Keywords

miscarriage; mifepristone; misoprostol; medical treatment; patient satisfaction; abortifacient agents

Outcome Measures

Primary Outcomes (1)

• Complete evacuation

  Whether or not complete evacuation (total endometrial thickness \<15 mm) has been acquired will be assessed through ultrasonography.

  six weeks after initial treatment

Secondary Outcomes (6)

• patient satisfaction

  At baseline, day four, two and six weeks after treatment

• complications

  six weeks after treatment

• side effects

  six weeks after treatment

• costs

  up to six weeks after treatment

• Overall quality of health, as experienced by the patient.

  At baseline, day four, and two and six weeks after initial treatment.

Study Arms (2)

Misoprostol

PLACEBO COMPARATOR

Before medical treatment with misoprostol (two doses 400mcg (four hours apart), repeated after 24 hours if no tissue is lost), patients receive an oral placebo.

Drug: Misoprostol

Misoprostol and Mifepristone

EXPERIMENTAL

Before medical treatment with misoprostol (two doses 400mcg (four hours apart), repeated after 24 hours if no tissue is lost), patients receive oral mifepristone (600mg).

Drug: Mifepristone; Drug: Misoprostol

Interventions

Mifepristone DRUG

Adding 600 mg of Mifepristone to the regular treatment with Misoprostol 800 mcg.

Also known as: Mifegyne

Misoprostol and Mifepristone

Misoprostol DRUG

Regular treatment with Misoprostol 800 mcg.

Also known as: Cytotec

Misoprostol; Misoprostol and Mifepristone

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Early pregnancy failure, 6-14 weeks postmenstrual with
• a crown-rump length ≥ 6mm and no cardiac activity OR
• a crown-rump length \<6mm and no fetal growth at least one week later OR
• a gestational sac with absent embryonic pole for at least one week.
• At least one week after diagnosis OR a discrepancy of at least one week between crown-rump length and calendar gestational age
• Intra-uterine pregnancy
• Women aged above 16 years
• Hemodynamic stable patient
• No signs of infection
• No signs of incomplete abortion
• No contraindications for mifepristone or misoprostol

You may not qualify if:

• Inability to give informed consent
• Known clotting disorder or use of anticoagulants
• Known risk factors for, or presence of, a cardiovascular disease
• Language barrier

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Innovatiefonds Zorgverzekeraars: collaborator
• Canisius-Wilhelmina Hospital: collaborator

Study Sites (13)

Rijnstate

Arnhem, Gelderland, 6815 AD, Netherlands

Location

Radboud University Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Canisius Wilhelmina Hospital

Nijmegen, Gelderland, 6532 SZ, Netherlands

Location

Maasstad Ziekenhuis

Rotterdam, South Holland, 3079 DZ, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

Amphia Hospital

Breda, Netherlands

Location

Catharina Hospital

Eindhoven, Netherlands

Location

Martini Hospital

Groningen, Netherlands

Location

Zuyderland Medical Centre

Heerlen, Netherlands

Location

St. Antonius Hospital

Nieuwegein, Netherlands

Location

Laurentius Hosptial

Roermond, Netherlands

Location

Haaglanden Medical Centre

The Hague, Netherlands

Location

VieCuri Medical Centre

Venlo, Netherlands

Location

Related Publications (31)

• Graziosi GC, Mol BW, Reuwer PJ, Drogtrop A, Bruinse HW. Misoprostol versus curettage in women with early pregnancy failure after initial expectant management: a randomized trial. Hum Reprod. 2004 Aug;19(8):1894-9. doi: 10.1093/humrep/deh344. Epub 2004 Jun 10.

  PMID: 15192065 BACKGROUND

• You JH, Chung TK. Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod. 2005 Oct;20(10):2873-8. doi: 10.1093/humrep/dei163. Epub 2005 Jun 24.

  PMID: 15979988 BACKGROUND

• Hooker AB, Lemmers M, Thurkow AL, Heymans MW, Opmeer BC, Brolmann HA, Mol BW, Huirne JA. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update. 2014 Mar-Apr;20(2):262-78. doi: 10.1093/humupd/dmt045. Epub 2013 Sep 29.

  PMID: 24082042 BACKGROUND

• Lemmers M, Verschoor MA, Hooker AB, Opmeer BC, Limpens J, Huirne JA, Ankum WM, Mol BW. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum Reprod. 2016 Jan;31(1):34-45. doi: 10.1093/humrep/dev274. Epub 2015 Nov 2.

  PMID: 26534897 BACKGROUND

• Soulat C, Gelly M. [Immediate complications of surgical abortion]. J Gynecol Obstet Biol Reprod (Paris). 2006 Apr;35(2):157-62. doi: 10.1016/s0368-2315(06)76389-x. French.

  PMID: 16575361 BACKGROUND

• Niinimaki M, Jouppila P, Martikainen H, Talvensaari-Mattila A. A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. Fertil Steril. 2006 Aug;86(2):367-72. doi: 10.1016/j.fertnstert.2005.12.072. Epub 2006 Jun 9.

  PMID: 16764872 BACKGROUND

• Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006 Jul 19;2006(3):CD002253. doi: 10.1002/14651858.CD002253.pub3.

  PMID: 16855990 BACKGROUND

• van den Berg J, Gordon BBM, Snijders MPML, Vandenbussche FPHA, Coppus SFPJ. The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: a systematic review of the literature. Eur J Obstet Gynecol Reprod Biol. 2015 Dec;195:18-26. doi: 10.1016/j.ejogrb.2015.09.027. Epub 2015 Sep 30.

  PMID: 26461963 BACKGROUND

• Lemmers M, Verschoor MAC, Oude Rengerink K, Naaktgeboren C, Bossuyt PM, Huirne JAF, Janssen IAH, Radder C, Klinkert ER, Langenveld J, van der Voet L, Siemens FF, Bongers MY, van Hooff MH, van der Ploeg M, Sjors FPJ, Coppus SFPJ, Ankum WM, Mol BWJ; MisoREST study group. MisoREST: Surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: A cohort study. Eur J Obstet Gynecol Reprod Biol. 2017 Apr;211:83-89. doi: 10.1016/j.ejogrb.2017.01.019. Epub 2017 Jan 27.

  PMID: 28209537 BACKGROUND

• Lemmers M, Verschoor MA, Oude Rengerink K, Naaktgeboren C, Opmeer BC, Bossuyt PM, Huirne JA, Janssen CA, Radder C, Klinkert ER, Langenveld J, Catshoek R, Van der Voet L, Siemens F, Geomini P, Van Hooff MH, Van der Ploeg JM, Coppus SF, Ankum WM, Mol BW; MisoREST study group. MisoREST: surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: a randomized controlled trial. Hum Reprod. 2016 Nov;31(11):2421-2427. doi: 10.1093/humrep/dew221. Epub 2016 Sep 2.

  PMID: 27591236 BACKGROUND

• Say L, Kulier R, Gulmezoglu M, Campana A. Medical versus surgical methods for first trimester termination of pregnancy. Cochrane Database Syst Rev. 2005 Jan 25;2002(1):CD003037. doi: 10.1002/14651858.CD003037.pub2.

  PMID: 15674900 BACKGROUND

• Kulier R, Kapp N, Gulmezoglu AM, Hofmeyr GJ, Cheng L, Campana A. Medical methods for first trimester abortion. Cochrane Database Syst Rev. 2011 Nov 9;2011(11):CD002855. doi: 10.1002/14651858.CD002855.pub4.

  PMID: 22071804 BACKGROUND

• Maria B, Chaneac M, Stampf F, Ulmann A. [Early pregnancy interruption using an antiprogesterone steroid: Mifepristone (RU 486)]. J Gynecol Obstet Biol Reprod (Paris). 1988;17(8):1089-94. French.

  PMID: 3235788 BACKGROUND

• Grimes DA, Mishell DR Jr, Shoupe D, Lacarra M. Early abortion with a single dose of the antiprogestin RU-486. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 1):1307-12. doi: 10.1016/0002-9378(88)90361-4.

  PMID: 2454578 BACKGROUND

• van den Berg J, van den Bent JM, Snijders MP, de Heus R, Coppus SF, Vandenbussche FP. Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: a retrospective study. Eur J Obstet Gynecol Reprod Biol. 2014 Dec;183:16-9. doi: 10.1016/j.ejogrb.2014.10.010. Epub 2014 Oct 14.

  PMID: 25461345 BACKGROUND

• Stockheim D, Machtinger R, Wiser A, Dulitzky M, Soriano D, Goldenberg M, Schiff E, Seidman DS. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril. 2006 Oct;86(4):956-60. doi: 10.1016/j.fertnstert.2006.03.032.

  PMID: 17027362 BACKGROUND

• Wagaarachchi PT, Ashok PW, Narvekar N, Smith NC, Templeton A. Medical management of early fetal demise using a combination of mifepristone and misoprostol. Hum Reprod. 2001 Sep;16(9):1849-53. doi: 10.1093/humrep/16.9.1849.

  PMID: 11527887 BACKGROUND

• Gronlund A, Gronlund L, Clevin L, Andersen B, Palmgren N, Lidegaard O. Management of missed abortion: comparison of medical treatment with either mifepristone + misoprostol or misoprostol alone with surgical evacuation. A multi-center trial in Copenhagen county, Denmark. Acta Obstet Gynecol Scand. 2002 Nov;81(11):1060-5.

  PMID: 12421175 BACKGROUND

• Coughlin LB, Roberts D, Haddad NG, Long A. Medical management of first trimester miscarriage (blighted ovum and missed abortion): is it effective? J Obstet Gynaecol. 2004 Jan;24(1):69-71. doi: 10.1080/01443610310001620332.

  PMID: 14675986 BACKGROUND

• Schreiber CA, Creinin MD, Reeves MF, Harwood BJ. Mifepristone and misoprostol for the treatment of early pregnancy failure: a pilot clinical trial. Contraception. 2006 Dec;74(6):458-62. doi: 10.1016/j.contraception.2006.07.007. Epub 2006 Sep 7.

  PMID: 17157102 BACKGROUND

• Kollitz KM, Meyn LA, Lohr PA, Creinin MD. Mifepristone and misoprostol for early pregnancy failure: a cohort analysis. Am J Obstet Gynecol. 2011 May;204(5):386.e1-6. doi: 10.1016/j.ajog.2010.12.026. Epub 2011 Feb 8.

  PMID: 21306697 BACKGROUND

• Torre A, Huchon C, Bussieres L, Machevin E, Camus E, Fauconnier A. Immediate versus delayed medical treatment for first-trimester miscarriage: a randomized trial. Am J Obstet Gynecol. 2012 Mar;206(3):215.e1-6. doi: 10.1016/j.ajog.2011.12.009. Epub 2011 Dec 16.

  PMID: 22381604 BACKGROUND

• Luise C, Jermy K, May C, Costello G, Collins WP, Bourne TH. Outcome of expectant management of spontaneous first trimester miscarriage: observational study. BMJ. 2002 Apr 13;324(7342):873-5. doi: 10.1136/bmj.324.7342.873.

  PMID: 11950733 BACKGROUND

• Rulin MC, Bornstein SG, Campbell JD. The reliability of ultrasonography in the management of spontaneous abortion, clinically thought to be complete: a prospective study. Am J Obstet Gynecol. 1993 Jan;168(1 Pt 1):12-5. doi: 10.1016/s0002-9378(12)90877-7.

  PMID: 8420312 BACKGROUND

• Creinin MD, Harwood B, Guido RS, Fox MC, Zhang J; NICHD Management of Early Pregnancy Failure Trial. Endometrial thickness after misoprostol use for early pregnancy failure. Int J Gynaecol Obstet. 2004 Jul;86(1):22-6. doi: 10.1016/j.ijgo.2004.02.004.

  PMID: 15207665 BACKGROUND

• Chung TK, Cheung LP, Sahota DS, Haines CJ, Chang AM. Evaluation of the accuracy of transvaginal sonography for the assessment of retained products of conception after spontaneous abortion. Gynecol Obstet Invest. 1998;45(3):190-3. doi: 10.1159/000009954.

  PMID: 9565145 BACKGROUND

• Jauniaux E, Johns J, Burton GJ. The role of ultrasound imaging in diagnosing and investigating early pregnancy failure. Ultrasound Obstet Gynecol. 2005 Jun;25(6):613-24. doi: 10.1002/uog.1892.

  PMID: 15861413 BACKGROUND

• Verschoor MA, Lemmers M, Wekker MZ, Huirne JA, Goddijn M, Mol BW, Ankum WM. Practice variation in the management of first trimester miscarriage in the Netherlands: a nationwide survey. Obstet Gynecol Int. 2014;2014:387860. doi: 10.1155/2014/387860. Epub 2014 Nov 4.

  PMID: 25538770 BACKGROUND

• Hamel CC, Vart P, Vandenbussche FPHA, Braat DDM, Snijders MPLM, Coppus SFPJ. Predicting the likelihood of successful medical treatment of early pregnancy loss: development and internal validation of a clinical prediction model. Hum Reprod. 2022 May 3;37(5):936-946. doi: 10.1093/humrep/deac048.

  PMID: 35333346 DERIVED

• Hamel C, Coppus S, van den Berg J, Hink E, van Seeters J, van Kesteren P, Merien A, Torrenga B, van de Laar R, Terwisscha van Scheltinga J, Gaugler-Senden I, Graziosi P, van Rumste M, Nelissen E, Vandenbussche F, Snijders M. 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. EClinicalMedicine. 2021 Jan 6;32:100716. doi: 10.1016/j.eclinm.2020.100716. eCollection 2021 Feb.

  PMID: 33681738 DERIVED

• van den Berg J, Hamel CC, Snijders MP, Coppus SF, Vandenbussche FP. 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). BMC Pregnancy Childbirth. 2019 Nov 27;19(1):443. doi: 10.1186/s12884-019-2497-y.

  PMID: 31775677 DERIVED

Related Links

• The management of early pregnancy loss. Royal College of Obstetricians and Gynaecologists, Green-top Guideline No. 25.
• Zwangerschapsafbreking tot 24 weken. Richtlijn Nederlandse Vereniging voor Obstetrie \& Gynaecologie.
• Cytotec UK SPC (Summary of Product Characteristics).
• Mifegyne 200 mg tablets: Summary of Product Characteristics (SmPC)
• Mifepristone - Mifegyne
• Erytrocytenimmunisatie en zwangerschap. Versie 2.1, 2009.

MeSH Terms

Conditions

Abortion, Spontaneous; Patient Satisfaction

Interventions

Mifepristone; Misoprostol

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Treatment Adherence and Compliance; Health Behavior; Behavior

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Prostaglandins E, Synthetic; Prostaglandins, Synthetic; Prostaglandins; Eicosanoids; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Autacoids; Inflammation Mediators; Biological Factors

Study Officials

• Frank P. Vandenbussche, Prof. Dr.

  Radboud University Medical Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Before medical treatment with misoprostol (two doses 400mcg (four hours apart), repeated after 24 hours if no tissue is lost), patients will be randomized to oral mifepristone (600mg) or oral placebo (identical in appearance).

Study Record Dates

• First Submitted: July 2, 2017
• First Posted: July 11, 2017
• Study Start: June 27, 2018
• Primary Completion: January 23, 2020
• Study Completion: March 16, 2020
• Last Updated: May 1, 2020

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (13)