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

Abstract

STUDY QUESTIONIs 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 ANSWERNon-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 ALREADYMVP 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, DURATIONLotus 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, METHODSIn 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 CHANCEIn 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 CAUTIONThe 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 FINDINGSOral 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....

Endogenous progesterone levels could predict reproductive outcome in frozen embryo replacement cycles supplemented with synthetic progestogens: A retrospective cohort study

“…In a recent systematic review and meta‐analysis involving eight randomized clinical trials, dydrogesterone was found to be as effective as vaginal progesterone for luteal‐phase support in stimulated IVF cycles. This was also corroborated by a more recent, large, multicentric phase III trial involving 1301 randomized subjects confirming the noninferiority of dydrogesterone (30 mg/d) to micronized vaginal progesterone (600 mg/d) in the setting of conventional IVF treatment cycles . However, up to day, there are no similar studies involving dydrogesterone in the setting of FER cycles.…”

Pregnancy Rate Following Luteal Phase Support in Polycystic Ovary Women Using Letrozole With or Without Gonadotropin as Ovulation Induction

“…In terms of route of administration, progesterone used as LPS in our study was oral Dydrogesterone (10 mg twice daily). This route of use in the study was supported by systematic review and meta-analysis of RCT done by Barbosa et al who ended up in a conclusion that the use of oral dydrogesterone seems to be as effective as vaginal progesterone for LPS in ART cycles and appears to be better tolerated [21]; furthermore, oral route efficacy confirmed in IVF by Phase III-RCT that compares the efficacy, safety, and tolerability of oral dydrogesterone versus micronized vaginal progesterone for LPS [22]. Similar reports on equivalent efficacy were documented from RCTs in Iran and India [23,24].…”

Oral Dydrogesterone versus Vaginal Micronized Progesterone in Luteal Phase Support after Controlled Ovarian Stimulation Using Long Gonadotropin-Releasing Hormone Agonist in Women Undergoing in Vitro Fertilization/Intracytoplasmic Sperm Injection

“…One of the apparent limitations in the current trial is absence of blinding of both interventions to the patient and the investigator. In the LOTUS I trial [19] oral placebo was added to the vaginal group and a vaginal placebo was added to the oral group. Such blinding was not adopted in the current trial, as the principal secondary outcome was women's satisfaction.…”

“…Therefore, we intentionally restricted the routes of admin- Another limitation of the current trial was lack of data regarding the potential risk of congenital malformations. Results from the LOTUS I study found comparable rates of congenital malformations in both interventions [19]. In addition, both dydrogesterone and micronized progesterone are long-studied and well-known medications with a high safety profile [15] [16] [17] [23].…”