Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17β-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing

Purpose: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing (R) (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. Methods: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 mu g 17 beta-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 mu g/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 mu g/day), or the active control NuvaRing (R) (ENG/ethinylestradiol 120/15 mu g), for three 28-day cycles. Results: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 mu g/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing (R) with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. Conclusions: Contraceptive rings releasing 300 mu g E2 and 75-125 mu g/day of ENG or 500-900 mu g/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing (R) was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.