Search

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. [ABSTRACT FROM AUTHOR]

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: −3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: −2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]