Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial

Abstract

Study question: Is oral dydrogesterone 30 mg daily non-inferior to 8% micronized vaginal progesterone (MVP) gel 90 mg daily for luteal phase support in IVF?

Summary answer: Oral dydrogesterone demonstrated non-inferiority to MVP gel for the presence of fetal heartbeats at 12 weeks of gestation (non-inferiority margin 10%).

What is known already: The standard of care for luteal phase support in IVF is the use of MVP; however, it is associated with vaginal irritation, discharge and poor patient compliance. Oral dydrogesterone may replace MVP as the standard of care if it is found to be efficacious with an acceptable safety profile.

Study design, size, duration: Lotus II was a randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide, from August 2015 until May 2017. In total, 1034 premenopausal women (>18 to <42 years of age) undergoing IVF were randomized 1:1 (stratified by country and age group), using an Interactive Web Response System, to receive oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily.

Participants/materials, setting, methods: Subjects received either oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation. The primary outcome measure was the presence of fetal heartbeats at 12 weeks of gestation, as determined by transvaginal ultrasound.

Main results and the role of chance: Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates in the full analysis sample (FAS) at 12 weeks of gestation of 38.7% (191/494) and 35.0% (171/489) in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). Live birth rates in the FAS of 34.4% (170/494) and 32.5% (159/489) were obtained for the oral dydrogesterone and MVP gel groups, respectively (adjusted difference 1.9%; 95% CI: -4.0 to 7.8). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP gel.

Limitations, reasons for caution: The analysis of the results was powered to consider the ongoing pregnancy rate, but a primary objective of greater clinical interest may have been the live birth rate. This study was open-label as it was not technically feasible to make a placebo applicator for MVP gel, which may have increased the risk of bias for the subjective endpoints reported in this study. While the use of oral dydrogesterone in fresh-cycle IVF was investigated in this study, further research is needed to investigate its efficacy in programmed frozen-thawed cycles where corpora lutea do not exist.

Wider implications of the findings: This study demonstrates that oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF.

Study funding/competing interests(s): This study was sponsored and supported by Abbott. G.G. has received investigator fees from Abbott during the conduct of the study. Outside of this submitted work, G.G. has received non-financial support from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope and Gedeon Richter, as well as personal fees from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope, VitroLife, NMC Healthcare, ReprodWissen, Biosilu, Gedeon Richter and ZIVA. C.B. is the President of the Belgian Society of Reproductive Medicine (unpaid) and Section Editor of Reproductive BioMedicine Online. C.B. has received grants from Ferring Pharmaceuticals, participated in an MSD sponsored trial, and has received payment from Ferring, MSD, Biomérieux, Abbott and Merck for lectures. G.S. has no conflicts of interest to be declared. A.P. is the General Secretary of the Indian Society of Assisted Reproduction (2017-2018). B.D. is President of Pune Obstetric and Gynecological Society (2017-2018). D.-Z.Y. has no conflicts of interest to be declared. Z.-J.C. has no conflicts of interest to be declared. E.K. is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott. C.P.-F. is an employee of Abbott GmbH & Co. KG, Wiesbaden, Germany and owns shares in Abbott. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Origio, Besins, Ferring and Mithra (now Allergan); and H.T. has received consultancy fees from Finox-Gedeon Richter, Merck, Ferring, Abbott and ObsEva.

Trial registration number: NCT02491437 (clinicaltrials.gov).

Trial registration date: 08 July 2015.

Date of first patient’s enrollment: 17 August 2015.

Figure 1

Subject disposition (CONSORT flow diagram). ^aDetermined by inclusion/exclusion criteria. ^bThree subjects in the oral dydrogesterone group were discontinued prior to embryo transfer due to study drug-related issues; these subjects were included in the FAS as failures. DYD, dydrogesterone; ET, embryo transfer; FAS, full analysis sample; IVF, in vitro fertilization; MVP, micronized vaginal progesterone; PPS, per-protocol sample; SS, safety sample.

Figure 2

Pregnancy and live birth rates post-treatment. Pregnancy rates at 4, 8 and 12 weeks of gestation, and the live birth rates (all statistically adjusted for country and age group) are shown for the FAS and PPS. A non-inferiority margin of 10% was used, whereby the test drug is non-inferior to the comparator if the lower-bound 95% CI excludes a difference greater than −10%. ^aDenominators: Four subjects were removed from the oral dydrogesterone PPS (N = 490) compared with the FAS (N = 494) because all four subjects had more than three IVF attempts, which was an exclusion criterion. ^bNominators at 12 weeks of gestation (primary endpoint): Eleven subjects were removed from the oral dydrogesterone PPS (n = 180) compared with the FAS (n = 191) because nine pregnant subjects took additional progesterone before 12 weeks of gestation (counted as success in FAS, but failure in PPS), and two subjects had major protocol deviations (excluded from the PPS). ^cDenominators: Eight subjects were removed from the MVP gel PPS (N = 481) compared with the FAS (N = 489) because seven subjects had more than three IVF attempts, which was an exclusion criterion, and one additional subject did not meet the inclusion criteria. ^dNominators at 12 weeks of gestation (primary endpoint): Four subjects were removed from the MVP gel PPS (n = 167) compared with the FAS (n = 171) because three pregnant subjects took additional progesterone before 12 weeks of gestation (counted as success in FAS, but failure in PPS), and one subject had a major protocol deviation (excluded from the PPS). CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; IVF, in vitro fertilization; MVP, micronized vaginal progesterone; PPS, per-protocol sample.