Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system : results of two multicentre, open-label, single-arm, phase 3 trials

A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0.15 mg segesterone acetate and 0.013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use. In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18-40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341. Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57.5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2.98 (95% CI 2.13-4.06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97.5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months. Interpretation The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months78e1054e1064We thank The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD), the US Agency for International Development (USAID), and WHO for funding the phase 3 studies. We also acknowledge all participating study investigators (appendix p 1) and coordinators at the 27 clinical sites for conduct of the two phase 3 clinical trials and the over 2200 women participants from eight countries. We further acknowledge the medical writing assistance of Kathleen Ohleth (Precise Publications; Bedminster. NJ, USA) supported by TherapeuticsMD (Boca Raton, FL, USA). The NICHD (contract no HHSN27500403372) funded and conducted the US study and USAID (grant no GPO-A-00-04-00019-00) funded the international study, which was conducted by the Population Council. WHO Department of Reproductive Health and Research funded two international study sites. Medical writing support for manuscript submission and resubmission was supported by TherapeuticsMD. The authors acknowledge the major contribution of Daniel R Mishell Jr (deceased), from the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine (Los Angeles, CA, USA) who invented the concept of the vaginal system to deliver contraceptive steroids, did many of the clinical studies for the segesterone acetate and ethinylestradiol contraceptive vaginal system, and was a principle investigator for the 300 B phase 3 study analysed in this Article while a member of the International Committee for Contraceptive Research (ICCR) of the Population Council. The authors also gratefully acknowledge the contribution of Horacio B Croxatto, from the University of Chile (Santiago, Chile), who established the clinical centre in Chile, participated in all pivotal clinical studies for this ring, and provided guidance for the full development of this new contraceptive while a member of the ICC

Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: A randomized, crossover drug–drug interaction study

Objectives: To evaluate the effects of concurrent administration of three vaginal miconazole nitrate formulations on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol from a novel contraceptive vaginal ring (NES/EE CVR). Study design: This was an open-label, randomized, crossover, drug-drug interaction study conducted over three menstrual cycles in healthy women with regular menses. We compared systemic exposure to NES and EE by determining area under the curve (AUC_8–21d) with CVR-only and CVR with each miconazole treatment. Three different miconazole formulations (single dose suppository, multiple dose suppository or multiple dose cream) were administered in a single dose on day 8 or multiple doses on days 8–10 after CVR insertion. We evaluated safety and tolerability of the CVR in the presence of antimycotic co-medication. Results: 45 participants were randomized and 29 completed participation. Systemic exposure to NES and EE released from the CVR increased with single or multiple doses of miconazole suppositories but not with multiple dose cream. The maximum EE geometric mean ratio (GMR) for AUC_8–21d was 1.67 (1.51–1.86) for single dose and 1.42 (1.21–1.66) for multiple dose suppositories. By contrast, systemic exposure to NES and EE was comparable with and without miconazole cream (all GMRs and confidence intervals within 0.80 to 1.25). Adverse events (AEs) were similar with CVR only and with all miconazole treatment groups. There were no serious treatment related AEs. Conclusions: Miconazole vaginal suppositories were associated with increased systemic levels of NES and EE, while systemic exposure with miconazole vaginal cream was comparable to no-miconazole exposure. Implications: Co-administration of miconazole suppositories with the investigational NES/EE CVR led to higher systemic exposure of both hormones, while co-administration with miconazole cream did not affect hormone levels. Women utilizing the NES/EE CVR may be advised to use an oral formulation or miconazole cream rather than suppository to treat vaginal candidiasis

Prevalence and cumulative incidence rates of vaginal infections and urogenital infections in women in the substudy and remainder of women in Phase III trial.

<p>Prevalence and cumulative incidence rates of vaginal infections and urogenital infections in women in the substudy and remainder of women in Phase III trial.</p

Change in vaginal infections and selected vaginal microbiota by assessment visit and the comparison of vaginal culture and ring culture.

<p>Visit timing: Cycle 6 (targeted at Day 144 [beginning of Cycle 6], range 2 to 251); Cycle 13 (targeted at Day 358 [12 cycles plus 21 days of use during cycle 13], range 252 to 358).</p><p># One subject without Nugent Score data at screening.</p><p>* McNemar’s tests: p<0.05.</p><p>** Performed at study exit (Cycle 13 [n = 58] or early discontinuation visit [n = 14]).</p><p>Change in vaginal infections and selected vaginal microbiota by assessment visit and the comparison of vaginal culture and ring culture.</p

Demographic and baseline characteristics among substudy participants.

<p>*p<0.05</p><p>**Multiple choices allowed per subject. Seven subjects did not respond.</p><p>*** Other includes abstinence, rhythm method, and transdermal patch.</p><p>Demographic and baseline characteristics among substudy participants.</p