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Advised by DSMB based on interim-analysis, highly significant difference.
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| Name | Class |
|---|---|
| Innovatiefonds Zorgverzekeraars | OTHER |
| Canisius-Wilhelmina Hospital | OTHER |
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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mifepristone | Drug | Adding 600 mg of Mifepristone to the regular treatment with Misoprostol 800 mcg. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| complications |
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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.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Frank P. Vandenbussche, Prof. Dr. | Radboud University Medical Center | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rijnstate | Arnhem | Gelderland | 6815 AD | Netherlands | ||
| Radboud University Medical Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15192065 | Background | 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. | |
| 15979988 | 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. |
| Label | URL |
|---|---|
| The management of early pregnancy loss. Royal College of Obstetricians and Gynaecologists, Green-top Guideline No. 25. | View source |
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| Type | Date | Date Unknown |
|---|---|---|
| Release | Mar 8, 2021 | |
| Reset | Mar 31, 2021 | |
| Release | Apr 4, 2025 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 20, 2019 | Mar 4, 2020 |
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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).
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| Misoprostol | Drug | Regular treatment with Misoprostol 800 mcg. |
|
|
How many and which complications have occured? |
| six weeks after treatment |
| side effects | Which side effects have patients experienced and to what degree? | six weeks after treatment |
| 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 |
| 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. |
| 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. |
| Nijmegen |
| Gelderland |
| 6500 HB |
| Netherlands |
| Canisius Wilhelmina Hospital | Nijmegen | Gelderland | 6532 SZ | Netherlands |
| Maasstad Ziekenhuis | Rotterdam | South Holland | 3079 DZ | Netherlands |
| OLVG | Amsterdam | Netherlands |
| Amphia Hospital | Breda | Netherlands |
| Catharina Hospital | Eindhoven | Netherlands |
| Martini Hospital | Groningen | Netherlands |
| Zuyderland Medical Centre | Heerlen | Netherlands |
| St. Antonius Hospital | Nieuwegein | Netherlands |
| Laurentius Hosptial | Roermond | Netherlands |
| Haaglanden Medical Centre | The Hague | Netherlands |
| VieCuri Medical Centre | Venlo | Netherlands |
| 24082042 | 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. |
| 26534897 | 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. |
| 16575361 | 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. |
| 16764872 | 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. |
| 16855990 | 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. |
| 26461963 | 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. |
| 28209537 | 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. |
| 27591236 | 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. |
| 15674900 | 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. |
| 22071804 | 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. |
| 3235788 | 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. |
| 2454578 | 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. |
| 25461345 | 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. |
| 17027362 | 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. |
| 11527887 | 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. |
| 12421175 | 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. |
| 14675986 | 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. |
| 17157102 | 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. |
| 21306697 | 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. |
| 22381604 | 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. |
| 11950733 | 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. |
| 8420312 | 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. |
| 15207665 | 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. |
| 9565145 | 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. |
| 15861413 | 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. |
| 25538770 | 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. |
| 35333346 | Derived | 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. |
| 33681738 | 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. |
| 31775677 | 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. |
| Zwangerschapsafbreking tot 24 weken. Richtlijn Nederlandse Vereniging voor Obstetrie \& Gynaecologie. | View source |
| Cytotec UK SPC (Summary of Product Characteristics). | View source |
| Mifegyne 200 mg tablets: Summary of Product Characteristics (SmPC) | View source |
| Mifepristone - Mifegyne | View source |
| Erytrocytenimmunisatie en zwangerschap. Versie 2.1, 2009. | View source |
| Reset | Apr 18, 2025 |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 3, 2020 | Mar 4, 2020 | SAP_001.pdf |
Not provided
| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Mar 8, 2021 | Mar 31, 2021 | |||
| Apr 4, 2025 | Apr 18, 2025 |
| ID | Term |
|---|---|
| D000022 | Abortion, Spontaneous |
| D017060 | Patient Satisfaction |
| ID | Term |
|---|---|
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000074822 | Treatment Adherence and Compliance |
| D015438 | Health Behavior |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D015735 | Mifepristone |
| D016595 | Misoprostol |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011459 | Prostaglandins E, Synthetic |
| D011465 | Prostaglandins, Synthetic |
| D011453 | Prostaglandins |
| D015777 | Eicosanoids |
| D005231 | Fatty Acids, Unsaturated |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |
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