Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia

Abstract

Objectives: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.

Design: Multicenter, open-label, phase 3 trial.

Setting: Sixty-nine sites in Europe and Russia.

Population: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m² .

Methods: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary.

Main outcome measures: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs.

Results: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events.

Conclusion: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile.

Tweetable abstract: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Keywords: Bleeding pattern; combined oral contraception; contraceptive efficacy; drospirenone; estetrol; native estrogen; safety.

Figure 1

Disposition of participants in a phase 3 study of E4/DRSP oral contraception for up to 13 cycles (12 months). *Including two pregnancies with an estimated conception date before the start of study treatment. Screened: all women who signed an informed consent form. All women in the ITT population who received at least one dose of E4/DRSP were included in the safety population; all women in the ITT population who had at least one cycle in the denominator were included in the efficacy analysis; all women in the ITT population who had at least one evaluable cycle for bleeding were included in the bleeding analysis.

Figure 2

Percentage of participants with any type of bleeding and/or spotting over time by study day in phase 3 study of E4/DRSP oral contraception for up to 13 cycles (12 months). Arrows delineate pill cycles (from Day 1 to Day 28). Red lines delineate the scheduled bleeding period that occurs between Day 25 and Day 3 of the next cycle. *Cycle 13 data are not reported since the last 3 days of the scheduled bleeding period of Cycle 13 (i.e. days 1 to 3 after completion of the cycle) were not collected in the participants’ diaries.