Comparing Two Medical Treatments for Early Pregnancy Failure.

Early Pregnancy Failure Clinical Trial

— Triple M  

Official title:

Mifepristone and Misoprostol Versus Misoprostol Alone for Uterine Evacuation After Early Pregnancy Failure: a Randomized Double Blind Placebo-controlled Comparison (Triple M Trial)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03212352
• Other study ID #: 62449
• Status: Terminated
• Phase: Phase 4
• Start date: June 27, 2018
• Est. completion date: March 16, 2020

Study information

• Verified date: September 2019
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This study will test the hypothesis that, in early pregnancy failure, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation of products of conception (primary outcome), patient satisfaction, complications, side effects and costs (secondary outcomes). The trial will be performed multi-centred (hospitals), prospectively, two-armed, randomized, double-blinded and placebo-controlled.

Women with ultrasonographically confirmed early pregnancy failure (6-14 weeks postmenstrual), managed expectantly for at least one week, can be included. 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). The investigators aim to randomize 460 women in a 1:1 ratio, stratified by centre.

After six weeks, the primary endpoint, complete or incomplete evacuation, will be determined

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 342
• Est. completion date: March 16, 2020
• Est. primary completion date: January 23, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

• Patient does not meet inclusion criteria, discovered after randomization

• Inability to give informed consent

• Known clotting disorder or use of anticoagulants

• Known risk factors for, or presence of, a cardiovascular disease

• Language barrier

Related Conditions & MeSH terms

• Early Pregnancy Failure

Intervention

Drug:
• Mifepristone
Adding 600 mg of Mifepristone to the regular treatment with Misoprostol 800 mcg.
• Misoprostol
Regular treatment with Misoprostol 800 mcg.

Locations

Country	Name	City	State
Netherlands	OLVG	Amsterdam
Netherlands	Rijnstate	Arnhem	Gelderland
Netherlands	Amphia Hospital	Breda
Netherlands	Catharina Hospital	Eindhoven
Netherlands	Martini Hospital	Groningen
Netherlands	Zuyderland Medical Centre	Heerlen
Netherlands	St. Antonius Hospital	Nieuwegein
Netherlands	Canisius Wilhelmina Hospital	Nijmegen	Gelderland
Netherlands	Radboud University Medical Centre	Nijmegen	Gelderland
Netherlands	Laurentius Hosptial	Roermond
Netherlands	Maasstad Ziekenhuis	Rotterdam	Zuid-Holland
Netherlands	Haaglanden Medical Centre	The Hague
Netherlands	VieCuri Medical Centre	Venlo

Sponsors (3)

Lead Sponsor	Collaborator
Radboud University	Canisius-Wilhelmina Hospital, Innovatiefonds Zorgverzekeraars

Country where clinical trial is conducted

Netherlands, 

References & Publications (28)

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2004 Jun 10. — View Citation

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. — View Citation

Grønlund A, Grønlund L, Clevin L, Andersen B, Palmgren N, Lidegaard Ø. 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. — View Citation

Hooker AB, Lemmers M, Thurkow AL, Heymans MW, Opmeer BC, Brölmann 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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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

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. Review. — View Citation

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. Epub 2016 Sep 2. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006 Jul 19;(3):CD002253. Review. Update in: Cochrane Database Syst Rev. 2019 Jun 17;6:CD002253. — View Citation

Niinimäki 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. Epub 2006 Jun 9. — View Citation

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. — View Citation

Say L, Kulier R, Gülmezoglu M, Campana A. Medical versus surgical methods for first trimester termination of pregnancy. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003037. Review. — View Citation

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. Epub 2006 Sep 7. — View Citation

Soulat C, Gelly M. [Immediate complications of surgical abortion]. J Gynecol Obstet Biol Reprod (Paris). 2006 Apr;35(2):157-62. Review. French. — View Citation

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. — View Citation

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. — View Citation

van den Berg J, Gordon BB, Snijders MP, Vandenbussche FP, Coppus SF. 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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2005 Jun 24. — View Citation

* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	patient satisfaction	To assess how satisfied patient are with the treatment they underwent. Patient satisfaction with treatment will be measured using The Client Satisfaction Questionnaire (CSQ-8, digital)	At baseline, day four, two and six weeks after treatment
Secondary	complications	How many and which complications have occured?	six weeks after treatment
Secondary	side effects	Which side effects have patients experienced and to what degree?	six weeks after treatment
Secondary	costs	To evaluate which medical treatment strategy is cost-effective, volumes of health care consumed will additionally be measured prospectively alongside the clinical trial together with cost associated with productivity losses. Costs of medical interventions (direct costs) and costs resulting from productivity loss (indirect costs) will be taken into account. Resource uses will be recorded in the case report forms. Standardized unit costs will be calculated using the Dutch manual for costing in economic evaluations and standardised costs.	up to six weeks after treatment
Secondary	Overall quality of health, as experienced by the patient.	To measure the quality of the health status of the patients, a validated so-called health-related quality of life (HRQoL) instrument will be used: the Short Form 36 health survey	At baseline, day four, and two and six weeks after initial treatment.
Secondary	Overall quality of health, as experienced by the patient.	To measure the quality of the health status of the patients,a validated so-called health-related quality of life (HRQoL) instrument will be used: the EuroQol-5D.	At baseline, day four, and two and six weeks after initial treatment.

External Links

•   Cytotec UK SPC (Summary of Product Characteristics).
•   Erytrocytenimmunisatie en zwangerschap. Versie 2.1, 2009.
•   Mifegyne 200 mg tablets: Summary of Product Characteristics (SmPC)
•   Mifepristone - Mifegyne
•   Misoprostol Recommendations. International Federation of Gynecology and Obstetrics (FIGO)
•   open data from the Nederlandse Zorgautoriteit (Dutch Healthcare Authority)
•   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.