Procedures

During the screening process, subjects signed an informed consent form and the following parameters were analyzed: vital signs, concomitant medication, laboratory blood values, and pregnancy status (by transvaginal ultrasound if the last transvaginal examination was older than 14 days). On the day of oocyte retrieval (Day 1), subjects were randomly assigned to receive either oral dydrogesterone 10 mg tablets (Duphaston^®; Abbott Biologicals, Netherlands) three times daily or 8% MVP gel 90 mg (Crinone^®; Central Pharma Ltd, UK) once daily and luteal phase support was started. The dose of oral dydrogesterone for the Lotus clinical trial program was chosen based on the results of previous randomized controlled trials (Chakravarty et al., 2005; Patki and Pawar, 2007; Ganesh et al., 2011), histological data (Fatemi et al., 2007) and recommendations by IVF specialists.

Embryo transfer was performed on Day 3–6 after oocyte retrieval according to the clinic-specific IVF protocol. On Day 17–20 (Day 15 ± 3 after embryo transfer; 4 weeks of gestation), subjects had a pregnancy test (serum measurement of beta human chorionic gonadotropin). If pregnancy was confirmed on Day 43 ± 3 (Week 6; 8 weeks of gestation), luteal phase support was continued up to Day 71 ± 3 (Week 10; 12 weeks of gestation), at which point the presence of a fetal heartbeat was determined by transvaginal ultrasound. Treatment emergent adverse events (TEAEs) and concomitant treatment were recorded throughout the study. At delivery, gestational age and newborn parameters were obtained; 30 ± 3 days after delivery, the mother’s and newborn’s safety and wellbeing were recorded. The 10-week duration of luteal phase support was agreed by the Medical Evaluations Board to align with the dosing schedule of MVP capsules (Utrogestan^®; Besins Healthcare, Belgium) used as the comparator in Lotus I (Tournaye et al., 2017).

The safety sample included all randomized subjects who received at least one drug administration. The full analysis sample (FAS) consisted of all subjects in the safety sample who had a successful embryo transfer or discontinued before embryo transfer due to study drug-related issues. The per-protocol sample (PPS) consisted of all subjects in the FAS who did not present any major protocol deviations.