Estetrol-Drospirenone Combination Oral Contraceptive: North American Phase 3 Efficacy and Safety Results

ABSTRACT OBJECTIVE To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15mg and drospirenone (DRSP) 3mg. STUDY DESIGN Women aged 16-50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16-35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl Index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle. RESULTS We enrolled 1,864 women of whom 1,674 were 16-35 years. Women 16-35 years had a PI of 2.65 (95% CI 1.73-3.88), method-failure PI of 1.43 (95% CI .7-2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3-22.1% during Cycles 2-4 and remained stable (15.5-19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred. CONCLUSION E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates. IMPLICATIONS STATEMENT A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.