Comparing Two Medical Treatments for Early Pregnancy Failure. |
|- candidate number||27469|
|- NTR Number||NTR6550|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||3-jul-2017|
|- Secondary IDs||62449 ABR nummer |
|- Public Title||Comparing Two Medical Treatments for Early Pregnancy Failure. |
|- Scientific Title||Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: a randomized double blind placebo-controlled comparison (Triple M Studie).|
|- ACRONYM||Triple M Studie|
|- hypothesis||In EPF, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation of products of conception, patient satisfaction, complications, side effects and costs.|
|- Healt Condition(s) or Problem(s) studied||Miscarriage|
|- Inclusion criteria||nclusion 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 crownrump length and calendar gestational age
• Intrauterine pregnancy
• Women aged above 18 years
• Hemodynamic stable patient
• No signs of infection
• No signs of incomplete abortion
• No contraindications for mifepristone or misoprostol
• No high risk of thrombosis
|- Exclusion criteria||Patient does not meet inclusion criteria, discovered after randomization. Inability to give informed consent|
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||13-jun-2018|
|- planned closingdate||1-jul-2020|
|- Target number of participants||460|
|- Interventions||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).|
The control arm receives an oral placebo.
|- Primary outcome||Complete evacuation/ succesful treatment|
Whether or not complete evacuation (total endometrial thickness <15 mm) has been acquired will be assessed 15-20 days after the initial treatment. If so, this will be considered a complete evacuation and thus successful treatment. If the total endometrial thickness is ≥ 15 mm, ultrasonography will be repeated six weeks after initial treatment. Once again, if the total endometrial thickness is <15 mm this will be considered as a complete evacuation and thus a successful treatment.
|- Secondary outcome||patient satisfaction, complications, side effects and costs. |
|- Timepoints||Ultrasound will be performed 15-20 days after initial treatment. If treatment is not successful at that time another ultrasound wil be performed six weeks after initial treatment. |
|- Trial web site|
|- CONTACT FOR PUBLIC QUERIES||Drs C.C. Hamel|
|- CONTACT for SCIENTIFIC QUERIES||Drs C.C. Hamel|
|- Sponsor/Initiator ||Canisius Wilhelmina Hospital, Radboud University Medical Center Nijmegen|
(Source(s) of Monetary or Material Support)
|Canisius-Wilhelmina hospital, Radboud University Medical Center Nijmegen, Innovatiefonds zorgverzekeraars|
|- Publications||1. Open data van de Nederlandse Zorgautoriteit (2014-2016) [ http://www.opendisdata.nl/. 25-05-2017]|
2. 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, 19(8):1894-1899.
3. You JH, Chung TK: Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod 2005, 20(10):2873-2878.
4. 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. Human reproduction update 2013.
5. 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, 31(1):34-45.
6. Soulat C, Gelly M: [Immediate complications of surgical abortion]. Journal de gynecologie, obstetrique et biologie de la reproduction 2006, 35(2):157-162.
7. Niinimaki M, Jouppila P, Martikainen H, Talvensaari-Mattila A: A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. Fertility and sterility 2006, 86(2):367-372.
8. Hinshaw K, Fayyad A, Munjuluri P: The management of early pregnancy loss. Royal College of Obstetricians and Gynaecologists, Green-top Guideline No. 25. http://www.rcog.org.uk/. In.; 2006.
9. Zwangerschapsafbreking tot 24 weken. Richtlijn Nederlandse Vereniging voor Obstetrie & Gynaecologie. [https://www.nvog.nl 08-06-2017]
10. Cytotec UK SPC (Summary of Product Characteristics). [http://www.medicines.org.uk/emc/medicine/9352 21-10-2016]
11. Neilson JP, Hickey M, Vazquez J: Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev 2009, 3:CD002253.
12. Misoprostol Recommendations. International Federation of Gynecology and Obstetrics (FIGO). [http://www.figo.org/publications/miscellaneous_publications/Misoprostol_Recommendation_2012 24-04-2017]
13. 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. European journal of obstetrics, gynecology, and reproductive biology 2015, 195:18-26.
14. Lemmers M, Verschoor MA, Oude Rengerink K, Naaktgeboren C, Bossuyt PM, Huirne JA, Janssen IA, Radder C, Klinkert ER, Langenveld J et al: MisoREST: Surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: A cohort study. European journal of obstetrics, gynecology, and reproductive biology 2017, 211:83-89.
15. Lemmers M, Verschoor MA, Oude Rengerink K, Naaktgeboren C, Opmeer BC, Bossuyt PM, Huirne JA, Janssen CA, Radder C, Klinkert ER et al: 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, 31(11):2421-2427.
16. Mifegyne 200 mg tablets: Summary of Product Characeteristics (SmPC) [https://www.exelgyn.com 24-04-2017]
17. Mifepriston - Mifegyne [http://www.farmacotherapeutischkompas.nl 06-10-2011]
18. Say L, Kulier R, Gulmezoglu M, Campana A: Medical versus surgical methods for first trimester termination of pregnancy. Cochrane Database Syst Rev 2005(1):CD003037.
19. Kulier R, Gulmezoglu AM, Hofmeyr GJ, Cheng LN, Campana A: Medical methods for first trimester abortion. Cochrane Database Syst Rev 2008(2):CD002855.
20. . In: Clinical Practice Handbook for Safe Abortion. edn. Geneva; 2014.
21. Maria B, Chaneac M, Stampf F, Ulmann A: [Early pregnancy interruption using an antiprogesterone steroid: Mifepristone (RU 486)]. Journal de gynecologie, obstetrique et biologie de la reproduction 1988, 17(8):1089-1094.
22. Grimes DA, Mishell DR, Jr., Shoupe D, Lacarra M: Early abortion with a single dose of the antiprogestin RU-486. American journal of obstetrics and gynecology 1988, 158(6 Pt 1):1307-1312.
23. 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. European journal of obstetrics, gynecology, and reproductive biology 2014, 183:16-19.
24. 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. Fertility and sterility 2006, 86(4):956-960.
25. 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, 16(9):1849-1853.
26. 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 obstetricia et gynecologica Scandinavica 2002, 81(11):1060-1065.
27. Coughlin LB, Roberts D, Haddad NG, Long A: Medical management of first trimester miscarriage (blighted ovum and missed abortion): is it effective? Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 2004, 24(1):69-71.
28. Schreiber CA, Creinin MD, Reeves MF, Harwood BJ: Mifepristone and misoprostol for the treatment of early pregnancy failure: a pilot clinical trial. Contraception 2006, 74(6):458-462.
29. Kollitz KM, Meyn LA, Lohr PA, Creinin MD: Mifepristone and misoprostol for early pregnancy failure: a cohort analysis. American journal of obstetrics and gynecology 2011, 204(5):386 e381-386.
30. Torre A, Huchon C, Bussieres L, Machevin E, Camus E, Fauconnier A: Immediate versus delayed medical treatment for first-trimester miscarriage: a randomized trial. American journal of obstetrics and gynecology 2012, 206(3):215 e211-216.
31. 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, 324(7342):873-875.
32. Erytrocytenimmunisatie en zwangerschap. Versie 2.1, 2009. [http://nvog-documenten.nl/ 10-06-2017]
33. Rulin MC, Bornstein SG, Campbell JD: The reliability of ultrasonography in the management of spontaneous abortion, clinically thought to be complete: a prospective study. American journal of obstetrics and gynecology 1993, 168(1 Pt 1):12-15.
34. Creinin MD, Harwood B, Guido RS, Fox MC, Zhang J, Trial NMoEPF: Endometrial thickness after misoprostol use for early pregnancy failure. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2004, 86(1):22-26.
35. 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. Gynecologic and obstetric investigation 1998, 45(3):190-193.
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37. MisoREST: What should be done in women with an incomplete evacuation of the uterus after treatment with misoprostol for miscarriage? An analysis of effects.
38. 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.
|- Brief summary||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 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 EPF (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). We 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. An endometrial thickness <15mm (maximum anterior-posterior diameter) by ultrasonography and no evidence of retained products of conception using only the allocated therapy, is considered as successful treatment result. Secondary outcome measures are registered using the case report form, a patient diary and validated digital questionnaires.
|- Main changes (audit trail)||16-jan-2018: Approval METC |
|- RECORD||3-jul-2017 - 24-jun-2018|
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