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.
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?



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.



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.



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.



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.



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.



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.



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.



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.



NCT01850030 (clinicaltrials.gov).



19 April 2013.



23 August 2013.
Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium.
Herman
H
Tournaye
Research Center for Obstetrics, Gynecology and Perinatology, Akademika Oparina Street, 4, 117497, Moscow, Russia.
Gennady T
GT
Sukhikh
Clinical Development, Established Pharmaceuticals, Abbott Laboratories GmbH, Freundalllee 9A, 30173 Hannover, Germany.
Elke
E
Kahler
Department of Gynecological Endocrinology and Reproductive Medicine, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Georg
G
Griesinger
D000282:Administration, Intravaginal; D000284:Administration, Oral; D000328:Adult; D001723:Birth Rate; D004394:Dydrogesterone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004624:Embryo Transfer / Q000379:methods; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D006801:Humans; D008183:Luteal Phase; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D011374:Progesterone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020554:Sperm Injections, Intracytoplasmic / Q000379:methods; D016896:Treatment Outcome
D011374:Progesterone; D004394:Dydrogesterone
in vitro fertilization; live birth rate; luteal phase support; micronized vaginal progesterone; oral dydrogesterone