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

Methods for female contraception: A model for innovation in drug delivery systems

In 2007, 1.7 billion women were in need of contraception, but only 57% of them were using modern contraceptives.1 During a woman\u27s 30-year reproductive life, her contraceptive needs may vary from postponing childbearing to spacing out the births of her children and, finally, to limiting family size. Modern contraceptive methods and their delivery systems reflect these changing needs as well as the challenges associated with the long-term regulation of conception, which are similar to the challenges encountered in developing therapeutics for chronic medical conditions

Risk of pregnancy in breastfeeding mothers: Role of the progesterone vaginal ring on birth spacing

The progesterone vaginal ring (PVR) Progering® has been shown to be effective as a contraceptive in breastfeeding women who need safe and effective methods of spacing pregnancies. Previous clinical trials, of 1-year duration, demonstrated its efficacy to be similar to that of the intra-uterine device (IUD) during lactation. The duration of lactational amenorrhoea is significantly prolonged in PVR users in comparison with IUD users with fewer median numbers of bleeding/spotting episodes and days. This delivery system designed for 3-month use needs to be renewed every 3 months as long as breastfeeding continues, for up to 1 year. The frequency of breastfeeding, breast milk volume, and infant growth were not different in PVR or IUD users, and the safety of this new method has been well documented. This article reviews the literature and describes the mechanism of action of the PVR during lactation to bring additional protection over exclusive breastfeeding only, during the first year postpartum. Further evaluation of the PVR acceptability in different populations where breastfeeding is popular and highly recommended for the infant’s benefit is warranted

The ins and outs of drug-releasing vaginal rings: A literature review of expulsions and removals

Introduction: There is considerable interest in vaginal ring technology for sustained/controlled release of pharmaceutical drugs to the human vagina. Seven drug-releasing vaginal ring products have reached market and have many other experimental devices are in preclinical/clinical development. Although most women who have use vaginal rings are satisfied and find them acceptable, involuntary ring expulsions and voluntary ring removals are known to occur and are widely reported in the scientific literature. There have been no previous efforts to review the historical data and understand the contributing factors leading to expulsions. Areas covered: This article is intended to help researchers, clinicians and product developers understand the pertinent factors and issues around ring expulsions and removals, and to inform new research aimed at optimising the design of new ring products. The review contains four sections: (i) introduction to vaginal ring technology; (ii) a discussion of the anatomical, physiological, device, and user factors potentially affecting ring expulsion; (iii) a literature review around involuntary ring expulsions; (iv) a literature review around voluntary ring removals; and (v) concluding remarks and opinions. Expert opinion: Further research is needed to better understand the factors contributing to involuntary ring expulsions and removals so that rings can be designed from the outset to minimise rates of expulsion and to reduce removals. Determination of optimum ring dimensions and stiffness for each ring product are likely key factors, alongside better counselling around ring removal and reinsertion

Factors associated with non-adherence to instructions for using the Nestorone®/ethinyl estradiol contraceptive vaginal ring

Objectives: We sought to identify factors associated with non-adherence to instructions for using a novel contraceptive providing 1-year of protection. Study design: Data from a multi-country Phase 3 trial of the Nestorone® (segesterone acetate)/ethinyl estradiol (NES/EE) CVR were analyzed. Participants were instructed to use the CVR over 13 cycles and follow a 21/7 regimen. Their reports of CVR removals\u3e2 h outside scheduled removal periods served as a proxy for non-adherence. We used multivariate logistic regression to determine factors associated with such use. Results: Of 905 participants, 120 (13%) reported CVR removals\u3e2 h. Removals for washing (OR 3.96, 95%CI 2.50–6.27) or sexual intercourse (OR 3.19, 95%CI 2.03–4.99), and finding CVR insertion difficult (OR 2.80, 95%CI 1.36–5.80) were factors associated with removals\u3e2 h. Lower educational attainment also predicted ring removal \u3e 2 h (OR 3.23, 95%CI 1.55–6.75). Women residing in Europe or Australia were less likely to remove the ring for \u3e 2 h compared with women in the US (OR 0.44, 95%CI 0.24–0.83 and OR 0.13, 95%CI 0.02–0.98, respectively). Participants who reported removals \u3e 2 h were more likely to discontinue CVR use (OR 1.93, 95%CI 1.24–2.95), report dissatisfaction (OR 2.20, 95%CI 1.32–3.69), and become pregnant during the study (OR 4.07, 95%CI 1.58–10.50). Conclusions: Removing the CVR for washing and before intercourse are factors associated with non-adherence to ring use. These are important topics for counseling women who are considering or using vaginal rings, including the NES/EE CVR. Implications: Findings from this study may be useful in guiding counseling for current and prospective vaginal ring users. Anticipatory guidance should focus on how the ring feels in the vagina and during sex. Asking about ring removals may help identify women who are at increased risk for having an unplanned pregnancy

Factors predicting improper use of a woman-controlled long-acting reversible contraceptive: Results from the acceptability study of a novel contraceptive vaginal ring

Objectives: Improper contraceptive use accounts for a large proportion of unintended pregnancies. We sought predictors of improper use of an investigational 1-year, reusable contraceptive vaginal ring that is woman controlled