A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization

Herman Tournaye, Gennady T Sukhikh, Elke Kahler, Georg Griesinger, Herman Tournaye, Gennady T Sukhikh, Elke Kahler, Georg Griesinger

Abstract

Study question: Is oral dydrogesterone 30 mg daily (10 mg three times daily [TID]) non-inferior to micronized vaginal progesterone (MVP) 600 mg daily (200 mg TID) for luteal support in in vitro fertilization (IVF), assessed by the presence of fetal heartbeats determined by transvaginal ultrasound at 12 weeks of gestation?

Summary answer: Non-inferiority of oral dydrogesterone versus MVP was demonstrated at 12 weeks of gestation, with a difference in pregnancy rate and an associated confidence interval (CI) that were both within the non-inferiority margin.

What is known already: MVP is routinely used in most clinics for luteal support in IVF, but it is associated with side effects, such as vaginal irritation and discharge, as well as poor patient acceptance. Dydrogesterone may be an alternative treatment due to its patient-friendly oral administration.

Study design, size, duration: Lotus I was an international Phase III randomized controlled trial, performed across 38 sites, from August 2013 to March 2016. Subjects were premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF. A centralized electronic system was used for randomization, and the study investigators, sponsor's study team, and subjects remained blinded throughout the study.

Participants/materials, setting, methods: In total, 1031 subjects were randomized to receive either oral dydrogesterone (n = 520) or MVP (n = 511). Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer.

Main results and the role of chance: In the full analysis set (FAS), 497 and 477 subjects in the oral dydrogesterone and MVP groups, respectively, had an embryo transfer. Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates at 12 weeks of gestation of 37.6% and 33.1% in the oral dydrogesterone and MVP treatment groups, respectively (difference 4.7%; 95% CI: -1.2-10.6%). Live birth rates of 34.6% (172 mothers with 213 newborns) and 29.8% (142 mothers with 158 newborns) were obtained in the dydrogesterone and MVP groups, respectively (difference 4.9%; 95% CI: -0.8-10.7%). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP.

Limitations, reasons for caution: The analysis of the results was powered to consider the clinical pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the differences between treatments in live birth rate, observed in this study, should therefore be made with caution.

Wider implications of the findings: Oral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment.

Study funding/competing interest(s): Sponsored and supported by Abbott Established Pharmaceuticals Division. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring and Mithra (now Allergan) and H.T. has received consultancy fees from Finox, Ferring, Abbott, ObsEva and Ovascience. G.S. has nothing to disclose. E.K. is an employee of Abbott GmbH. G.G. has received investigator fees from Abbott during the conduct of the study; outside of this submitted work, G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, Glycotope, as well as personal fees from VitroLife, NMC Healthcare LLC, ReprodWissen LLC and ZIVA LLC.

Trial registration number: NCT01850030 (clinicaltrials.gov).

Trial registration date: 19 April 2013.

Date of first patient's enrollment: 23 August 2013.

Keywords: in vitro fertilization; live birth rate; luteal phase support; micronized vaginal progesterone; oral dydrogesterone.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1
Figure 1
Patient disposition (CONSORT flow-diagram).
Figure 2
Figure 2
Pregnancy status post-treatment. Positive pregnancy rates at 4, 8 and 12 weeks of gestation, and the live birth rates are shown for both the FAS and PPS. A non-inferiority margin of 10% was used, whereby the test drug is non-inferior if the lower bound of the 95% CI excludes a difference greater than 10% in favor of the comparator. CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; PPS, per protocol sample.

References

    1. Baker VL, Jones CA, Doody K, Foulk R, Yee B, Adamson GD, Cometti B, DeVane G, Hubert G, Trevisan S et al. . A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization. Hum Reprod 2014;29:2212–2220.
    1. Barbosa MW, Silva LR, Navarro PA, Ferriani RA, Nastri CO, Martins WP. Dydrogesterone versus progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol 2015;48:161–170.
    1. Chakravarty BN, Shirazee HH, Dam P, Goswami SK, Chatterjee R, Ghosh S. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol 2005;97:416–420.
    1. Chambers GM, Hoang VP, Zhu R, Illingworth PJ. A reduction in public funding for fertility treatment - an econometric analysis of access to treatment and savings to government. BMC Health Serv Res 2012;12:142.
    1. Davies MJ, Moore VM, Willson KJ, Van EP, Priest K, Scott H, Haan EA, Chan A. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366:1803–1813.
    1. Doody KJ, Schnell VL, Foulk RA, Miller CE, Kolb BA, Blake EJ, Yankov VI. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril 2009;91:1012–1017.
    1. Dyer S, Chambers GM, de Mouzon J, Nygren KG, Zegers-Hochschild F, Mansour R, Ishihara O, Banker M, Adamson GD. International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2008, 2009 and 2010. Hum Reprod 2016;31:1588–1609.
    1. Fatemi HM, Bourgain C, Donoso P, Blockeel C, Papanikolaou EG, Popovic-Todorovic B, Devroey P. Effect of oral administration of dydrogestrone versus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept. Hum Reprod 2007;22:1260–1263.
    1. Food and Drug Administration (FDA) Drug Approval Package: Endometrin (Progesterone) Vaginal Insert 100 mg 2009. (21 October 2016, date last accessed).
    1. Ganesh A, Chakravorty N, Mukherjee R, Goswami S, Chaudhury K, Chakravarty B. Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoing in vitro fertilization: a randomized clinical study. Fertil Steril 2011;95:1961–1965.
    1. Ghanem ME, Al-Boghdady LA. Luteal Phase Support in ART: an Update 2012. (21 October 2016, date last accessed).
    1. Kleinstein J. Efficacy and tolerability of vaginal progesterone capsules (Utrogest 200) compared with progesterone gel (Crinone 8%) for luteal phase support during assisted reproduction. Fertil Steril 2005;83:1641–1649.
    1. Kupferminc MJ, Lessing JB, Amit A, Yovel I, David MP, Peyser MR. A prospective randomized trial of human chorionic gonadotrophin or dydrogesterone support following in-vitro fertilization and embryo transfer. Hum Reprod 1990;5:271–273.
    1. Lockwood G, Griesinger G, Cometti B. Subcutaneous progesterone versus vaginal progesterone gel for luteal phase support in in vitro fertilization: a noninferiority randomized controlled study. Fertil Steril 2014;101:112–119.
    1. Ludwig M, Schwartz P, Babahan B, Katalinic A, Weiss JM, Felberbaum R, Al-Hasani S, Diedrich K. Luteal phase support using either Crinone 8% or Utrogest: results of a prospective, randomized study. Eur J Obstet Gynecol Reprod Biol 2002;103:48–52.
    1. Mirza FG, Patki A, Pexman-Fieth C. Dydrogesterone use in early pregnancy. Gynecol Endocrinol 2016;32:97–106.
    1. Palomba S, Santagni S, La Sala GB. Progesterone administration for luteal phase deficiency in human reproduction: an old or new issue. J Ovarian Res 2015;8:77.
    1. Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol 2007;23:68–72.
    1. Practice Committee of the American Society for Reproductive Medicine Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin. Fertil Steril 2008;90:S150–S153.
    1. Queisser-Luft A. Dydrogesterone use during pregnancy: overview of birth defects reported since 1977. Early Hum Dev 2009;85:375–377.
    1. Saharkhiz N, Zamaniyan M, Salehpour S, Zadehmodarres S, Hoseini S, Cheraghi L, Seif S, Baheiraei N. A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles. Gynecol Endocrinol 2016;32:213–217.
    1. Salehpour S, Tamimi M, Saharkhiz N. Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): a randomized clinical trial. Iran J Reprod Med 2013;11:913–918.
    1. Schindler AE. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas 2009;65:S3–S11.
    1. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH. Classification and pharmacology of progestins. Maturitas 2008;61:171–180.
    1. Shapiro D, Boostanfar R, Silverberg K, Yanushpolsky EH. Examining the evidence: progesterone supplementation during fresh and frozen embryo transfer. Reprod Biomed Online 2014;29:S1–14.
    1. Tomic V, Tomic J, Klaic DZ, Kasum M, Kuna K. Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2015;186:49–53.
    1. Vaisbuch E, Leong M, Shoham Z. Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey. Reprod Biomed Online 2012;25:139–145.
    1. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 2015;7:CD009154.

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