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

Creating and Implementing a Protocol for the Management of Patients in Skeletal Traction: A Quality Improvement Project

Introduction.Skeletal traction use generally has decreased over generations and is used most often for temporary fracture stabilization. Proper nursing management of patients in skeletal traction is crucial. A hospital protocol was created and implemented to educate and direct registered nurses (RNs) in the care of patients requiring skeletal traction. Method.A skeletal traction management protocol was drafted and implemented as hospital policy. Twenty-nine RNs from an orthopaedic unit at a level 1 trauma center attended a financially compensated, 45-minute, in-person, off-shift educational session. An anonymous pre-test utilizing a 5-point Likert scale was completed to assess RN knowledge and comfort regarding the following topics of traction care: pin care, manual traction, frame assembly, weight application and removal, skin evaluation, neurovascular checks, and reporting issues. The RNs were provided with a copy of the new hospital policy and key points were highlighted and demonstrated. After the demonstration, the RNs were given a post-test to assess their perceived knowledge and comfort with traction care. Results.Statistically significant improvements in RN knowledge and comfort were seen in six of the seven evaluated topics. The greatest increase was seen in the manual traction topic. No significant change regarding neurovascular checks was observed with this topic having the highest pre-test scores. Conclusion. A hospital protocol was created successfully and implemented that significantly improved the level of RN knowledge and comfort with the management of patients requiring skeletal traction. Future studies should assess the effectiveness of annual education regarding the traction policy

Successful postcoital testing of Ovaprene: An investigational non-hormonal monthly vaginal contraceptive

ObjectiveEvaluate reduction in progressively motile sperm per high power field (HPF) in midcycle cervical mucus after intercourse with Ovaprene: an investigational monthly non-hormonal vaginal contraceptive consisting of a vaginal ring and mechanical barrier, releasing spermiostatic ferrous gluconate.Study designOpen-label, multicenter study enrolling heterosexually-active women with previous permanent contraception. Participants underwent a baseline postcoital test cycle with no device to confirm the presence of sperm, followed by one diaphragm postcoital test cycle, one Ovaprene safety cycle, and two Ovaprene postcoital test cycles. In each postcoital test cycle, participants underwent a midcycle cervical mucus evaluation to confirm an Insler score ≥10 and absence of sperm, and then returned two to four hours after vaginal intercourse for repeat cervical mucus evaluation. We considered <5 progressively motile sperm/HPF indicative of preliminary contraceptive effectiveness.ResultsWe enrolled 38 participants; 23 completed the study. All participants had ≥5 progressively motile sperm/HPF in the baseline cycle and <5 progressively motile sperm/HPF in all 49 Ovaprene cycles and all 35 diaphragm cycles, meeting the definition of a successful postcoital test. This was true regardless of examiner blinding, prior vaginal delivery or vaginal ring use, body mass index, or dislodgements noted by the participant or investigator. The mean of 27.2 (±17.9) progressively motile sperm/HPF in baseline postcoital test cycles was reduced to 0.5 (±1.1) and 0.5 (±1.3) progressively motile sperm/HPF in the first and second Ovaprene cycles, respectively. Ovaprene fit all participants and all could insert, position, and remove it.ConclusionUse of Ovaprene resulted in meeting the prespecified criterion for contraceptive effect by all participants during all postcoital test cycles.ImplicationsThe finding that use of Ovaprene, an investigational monthly non-hormonal vaginal contraceptive, resulted in postcoital testing of cervical mucus that met the pre-specified definition of success (<5 progressively motile sperm/HPF) supports further evaluation of contraceptive efficacy of the device in users at risk for pregnancy

A new combination of testosterone and nestorone transdermal gels for male hormonal contraception

Context: Combinations of testosterone (T) and nestorone (NES; a nonandrogenic progestin) transdermal gels may suppress spermatogenesis and prove appealing to men for contraception. Objective: The objective of the study was to determine the effectiveness of T gel alone or combined with NES gel in suppressing spermatogenesis. Design and Setting: This was a randomized, double-blind, comparator clinical trial conducted at two academic medical centers. Participants: Ninety-nine healthy male volunteers participated in the study. Interventions: Volunteers were randomized to one of three treatment groups applying daily transdermal gels (group 1: T gel 10 g + NES 0 mg/placebo gel; group 2: T gel 10 g + NES gel 8 mg; group 3: T gel 10 g + NES gel 12 mg). Main Outcome Variable: The main outcome variable of the study was the percentage of men whose sperm concentration was suppressed to 1 million/ml or less by 20-24 wk of treatment. Results: Efficacy data analyses were performed on 56 subjects who adhered to the protocol and completed at least 20 wk of treatment. The percentage of men whose sperm concentration was 1 million/ml or less was significantly higher for T + NES 8 mg (89%, P \u3c 0.0001) and T + NES 12 mg (88%, P = 0.0002) compared with T + NES 0 mg group (23%). The median serum total and free T concentrations in all groups were maintained within the adult male range throughout the treatment period. Adverse effects were minimal in all groups. Conclusion: A combination of daily NES + T gels suppressed sperm concentration to 1 million/ml or less in 88.5% of men, with minimal adverse effects, and may be further studied as a male transdermal hormonal contraceptive

Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone® gels

Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5–10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to /mL after 24 weeks. Indeed, luteinizing hormone or follicle-stimulating hormone concentrations greater than 1 IU/L after 4 weeks of transdermal testosterone/nestorone treatment were 97% sensitive for predicting failure to suppress spermatogenesis after 24 weeks of treatment. Serum nestorone concentrations were significantly associated with suppression, but serum testosterone concentrations were not. Early suppression of gonadotropins is associated with, but does not ensure, adequate suppression of spermatogenesis. This information may allow for rapid identification of non-responders in male hormonal contraceptive trials

Safety Testing of Ovaprene: an Investigational Non-Hormonal Monthly Vaginal Contraceptive

ObjectiveEvaluate safety of Ovaprene, an investigational non-hormonal vaginal contraceptive designed for monthly use.Study designOpen-label, multicenter study enrolling heterosexually-active women with previous permanent contraception who underwent assessments during five menstrual cycles: baseline postcoital test cycle, diaphragm postcoital test cycle, Ovaprene safety cycle, and two Ovaprene postcoital test cycles. Safety outcomes included treatment emergent adverse events (TEAEs), systemic laboratory findings, pelvic examinations, colposcopies, Nugent scores, determination of community state types of vaginal microbiota, and anti-Escherichia coli activity and inflammatory markers in cervicovaginal fluids.ResultsWe enrolled 38 participants. Of these, 33 used Ovaprene and completed 77 Ovaprene cycles. The most common product-related urogenital TEAEs were bacterial vaginosis (BV) and vaginal odor. The frequency of transitioning from Lactobacillus-dominated community state type to community state type IV (not Lactobacillus-dominated) was similar before Ovaprene use and afterwards. Mean Nugent scores were <4 at each visit without a discernable upward trend. Inflammatory markers showed wide variation but no upward trend, and E. coli inhibitory activity of cervical secretions did not change. We found no Staphylococcus aureus, the causative agent in Toxic Shock Syndrome, on used Ovaprenes or in vaginal samples. No clinically important changes in systemic laboratory findings, pelvic examinations, or colposcopies occurred during Ovaprene use.ConclusionOvaprene use did not result in cervicovaginal irritation or adverse effects on resident vaginal microbiota, and did not impact transitions from a Lactobacillus-dominated community state type to community state type IV.ImplicationsThe finding that use of Ovaprene, an investigational monthly user-controlled nonhormonal vaginal contraceptive, does not appear to result in adverse changes in vaginal health during short term use supports further evaluation of the contraceptive potential of the device

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone)

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study\u27s primary outcome is the rate of pregnancy in couples during the study\u27s 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. Implications: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive

Combined Nestorone–testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men

Background: Novel male‐based contraceptives are needed to broaden family planning choices. A progestin, Nestorone® (Nes) gel, plus a testosterone (T) gel suppresses sperm concentrations to levels associated with effective contraception in normal men. However, administration of two gels on different parts of the body daily is impractical. Objective: Compare the effectiveness of daily application of a single, combined 8.3 mg Nes‐62.5 mg T gel (Nes‐T) vs. 62.7 mg T gel to suppress serum FSH and LH concentrations to ≤1.0 IU/L (a threshold associated with suppression of sperm concentrations to ≤1 million and effective contraception) and to compare the pharmacokinetics of serum Nes and T concentrations between the gel groups. Design: We conducted a 28‐day, double‐blind, controlled trial of 44 healthy men randomized to daily Nes‐T or T gel with measurement of hormones at baseline, treatment, and recovery and during 24‐h pharmacokinetic studies on days 1 and 28 of treatment. Results: Of the subjects who met pre‐defined inclusion criteria, 84% of the Nes‐T group suppressed serum gonadotropin concentrations to ≤ 1.0 IU/L at days 21–28 vs. 16.7% in the T group (p \u3c 0.001). On day 1, Nes concentrations rose significantly above baseline by 2 h and continued to rise up to 24 h after Nes‐T gel application. Nes concentrations were not detectable in the T group. Serum total T concentrations rose and were significantly higher in the T gel group compared to the Nes‐T group at 24 h on day 1 and days 11, 14, and 21 (p \u3c 0.01). There were no serious adverse events in either group. About 80% of the subjects reported satisfaction with both gels. Conclusion: Daily Nes‐T gel effectively and safely suppresses serum gonadotropins and is acceptable to most men. It should be studied further in efficacy trials of hormonal male contraception