Safety evaluation of a novel progesterone vaginal ring (PVR) for luteal phase support: SARA trial

After manufacturing changes, the safety and tolerability of the progesterone vaginal ring (PVR) was compared to findings from the similarly designed phase 3 trial. This prospective, open-label, single-arm, multi-center U.S. trial was conducted with women with tubal, idiopathic, male factor, ovulatory dysfunction, or endometriosis-linked infertility. Women underwent ovarian stimulation with highly purified human menotropin 225 IU/day in a standardized long agonist protocol. Weekly administration of PVR started the day after oocyte retrieval (OR), followed by ICSI and fresh blastocyst transfer, and continued for up to 10 weeks. The primary endpoint was spontaneous abortion rate, defined as 2 positive β-hCG tests and an empty intrauterine gestational sac or lacking a fetal heartbeat, or the absence of a viable fetus up to 12 weeks after OR. 254 women were treated with PVR at 14 sites July 2018–July 2019 (mean age 30.8 years, BMI 26.5 kg/m2, AMH 2.8 ng/mL, FSH 7.0 mIU/mL). Adverse events occurring in ≥ 5% of the population included nausea (8.7%) and headache (5.1%). Incidence of predefined vaginal/cervical adverse events was 2.0%. Fresh embryo transfer was performed in 243 subjects (95.7%). The spontaneous abortion rate was 7.4%, with the upper bound of the 95% confidence interval (11.5%) below the predefined threshold of 15.0%. Clinical pregnancy rates 10 weeks post OR were 43.2%. This trial established a safety bridge between PVR produced via enhanced manufacturing processes and the legacy PVR, with comparable rates of spontaneous abortion. Weekly administration of PVR was well-tolerated with good pregnancy outcomes. Trial registration: NCT03565211 (https://clinicaltrials.gov/study/NCT03565211), registration June 21, 2018, first enrollment July 26, 2018