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Objectives We sought to identify factors associated with nonadherence to instructions for using a novel contraceptive providing 1 year of protection. Study design Data from a multicountry Phase 3 trial of the Nestorone® (segesterone acetate)/ethinyl estradiol (NES/EE) contraceptive vaginal ring (CVR) were analyzed. Participants were instructed to use the CVR over 13 cycles and follow a 21/7 regimen. Their reports of CVR removals >2 h outside scheduled removal periods served as a proxy for nonadherence. We used multivariate logistic regression to determine factors associated with such use. Results Of 905 participants, 120 (13%) reported CVR removals >2 h. Removals for washing [odds ratio (OR) 3.96, 95% confidence interval (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 >2 h. Lower educational attainment also predicted ring removal >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 >2 h compared with women in the United States (OR 0.44, 95% CI 0.24–0.83 and OR 0.13, 95% CI 0.02–0.98, respectively). Participants who reported removals >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 removing it before intercourse are factors associated with nonadherence 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.

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 (AUC8–21d) 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 comedication. Results Forty-five 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 AUC8–21d 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 Coadministration of miconazole suppositories with the investigational NES/EE CVR led to higher systemic exposure of both hormones, while coadministration 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.

Objectives To describe bleeding patterns among users of the segesterone acetate (SA) and ethinyl estradiol (EE) contraceptive vaginal system (CVS), and identify factors associated with unscheduled bleeding/spotting (B/S). Study design We pooled results from two multicenter, single-arm, open-label, pivotal, phase 3 studies of the SA/EE CVS conducted in 17 US and 7 international sites. Participants (age 18–40 years; BMI ≤29 kg/m2) followed a 21/7-day in/out schedule of CVS use for up to 13 cycles and recorded vaginal bleeding daily in paper diaries. Scheduled and unscheduled B/S were summarized by cycle. We used multiple logistic regression to identify factors associated with unscheduled bleeding/spotting, based on the first 4 cycles only. Results Analysis included data from 2070 participants (16,408 cycles). Ninety-eight percent documented scheduled B/S [mean (SD): 4.9 (1.1) days/cycle)]. Absence of scheduled B/S was 5–8% of women/cycle. Unscheduled B/S ranged from 13.2% to 21.7% of women per cycle. Few women (1.8%) discontinued prematurely due to unacceptable bleeding. Black women were more likely to report unscheduled B/S than White women [Adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI) = 1.14–1.94]. Women with fewer years of schooling [ Conclusions Participants using the SA/EE CVS up to 13 cycles reported good cycle control. Discontinuation due to unacceptable bleeding was very low. Further research into demographic/other differences with reported unscheduled bleeding is warranted. Implications Since good cycle control is a key factor influencing contraceptive selection, adherence and continuation of combined hormonal contraceptives, the favorable bleeding profiles experienced by women during the SA/EE CVS clinical trials provide reassuring information for prospective users.

Objective To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. Design A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. Methods Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. Results Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. Conclusions PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Objectives Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150 mcg Nestorone® (NES) and 15 mcg ethinyl estradiol (EE). Study design A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). Results Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. Conclusion NES/EE CVR for up to 13 cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. Implications Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC.

Summary Background 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. Methods 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 . Findings 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 months. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department.

A randomized, placebo-controlled, efficacy trial of Carraguard was unable to demonstrate a reduction in women's risk of HIV infection, which may have been due, in part, to low adherence (gel used in 42 % of vaginal sex acts, on average). A secondary analysis was undertaken to understand baseline factors associated with high adherence (gel used in aeyen85 % of sex acts). Women who reported aeyen1 vaginal sex act, returned aeyen1 opened applicator, and had aeyen1 conclusive post-enrollment HIV test (N = 5990) were included. Adherence was estimated as the ratio of average weekly applicator insertions (based on a dye stain assay indicating vaginal insertion)/average weekly sex acts (by self-report). Multivariate logistic regression modeling indicated that coital frequency, site, contraception, and partner age difference had a significant impact on adherence. Women reporting > 1 and aecurrency sign2 vaginal sex acts per week, on average, were half as likely to be adherent as those reporting 1 vaginal sex act per week or less [adjusted odds ratio (AOR): 0.48; 95 % CI 0.38-0.61]; women from the Western Cape had one-third the odds of being adherent compared to women from KZN (AOR: 0.31; 95 % CI 0.23-0.41); compared to women using injectable contraception, women using any other or no method were more likely to be adherent (AOR: 1.30; 95 % CI 1.04-1.63); and women who had a larger age gap from their partners were more likely to be adherent (AOR: 1.03; 95 % CI 1.01-1.05; p = 0.001). Despite low adherence, overall, 13 % of participants achieved nearly perfect adherence, indicating a potential niche for a coitally dependent microbicide. More research is needed on the impact of sexual patterns and HIV risk perception on product acceptability and adherence to improve counseling in ongoing trials and when products are eventually introduced.

Objectives: To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. Design/methods: We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular. Results: Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users. Conclusions: In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies. (C) 2012 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkins

To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles.This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns.All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding.The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring.The 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

Objectives Develop and test a theoretical acceptability model for the Nestorone®/ethinyl estradiol contraceptive vaginal ring (CVR); explore whether domains of use within the model predict satisfaction, method adherence and CVR continuation. Study Design Four domains of use were considered relative to outcome markers of acceptability, that is, method satisfaction, adherence and continuation. A questionnaire to evaluate subjects' experiences relative to the domains, their satisfaction (Likert scale) and adherence to instructions for use was developed and administered to 1036 women enrolled in a 13-cycle Phase 3 trial. Method continuation was documented from the trial database. Stepwise logistic regression (LR) analysis was conducted and odds ratios (ORs) calculated to assess associations of satisfaction with questions from the four domains. Fisher's Exact Test was used to determine the association of satisfaction with outcome measures. Results A final acceptability model was developed based on the following determinants of CVR satisfaction: ease of use, side effects, expulsions/feeling the CVR and sexual activity including physical effects during intercourse. Satisfaction was high (89%) and related to higher method adherence [OR, 2.6 (1.3, 5.2)] and continuation [OR, 5.5 (3.5, 8.4)]. According to the LR analysis, attributes of CVR use representing items from the four domains — finding it easy to remove, not complaining of side effects, not feeling the CVR while wearing it and experiencing no change or an increase in sexual pleasure and/or frequency — were associated with higher odds of satisfaction. Conclusion Hypothesized domains of CVR use were related to satisfaction, which was associated with adherence and continuation. Results provide a scientific basis for introduction and future research. Implications Statement Acceptability research is important when introducing a new method of contraception and determining whether it can be a successful option in meeting the reproductive health needs of women and men. This study was designed to test a conceptual model of acceptability and identify factors associated with successful use of a new contraceptive delivery modality. Original research was conducted for this publication.

Purpose This article explores the ethics and feasibility of enrolling adolescent females in microbicide trials using data from 16- to 17-year-old participants of the Phase 3 trial of the candidate vaginal microbicide, Carraguard. Methods Secondary analysis was conducted to compare health, behavioral, and operational outcomes between 16- to 17-year-olds and 18- to 19-year-olds screened for and enrolled in the trial. Analytical approaches included Kaplan–Meier survival analysis, Cox proportional hazards modeling, and generalized estimating equations for nonsurvival end points. Results Results reveal no significant differences between the two age groups for health (sexually transmitted infection, adverse event), risk behavior, or operational (adherence, follow-up) outcomes. However, data suggest that after 1 year of trial participation, human immunodeficiency virus (HIV) and pregnancy incidence were higher and increased more rapidly for the 16- to 17-year-olds than for 18- to 19-year-olds; this finding is entirely consistent with other incidence data for HIV infection among South African youth and cannot be attributed to study participation without a comparison outside the trial. Conclusions Data from the Carraguard trial provide no evidence that inclusion of 16- to 17-year-olds in the trial had any detrimental effect on trial participants or on the conduct of research. These data provide an argument motivating the inclusion of sexually active adolescents aged 16–17 years into future trials in order to avoid delaying access to an effective product for adolescents at high risk of HIV acquisition. Careful support for adolescent-inclusive protocols (including appropriate counseling) must be incorporated into study design.

Summary Background Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. Methods We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. Findings For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3·3 per 100 woman-years (95% CI 2·8–3·9) in the Carraguard group (134 events) and 3·8 per 100 woman-years (95% CI 3·2–4·4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0·30). The covariate-adjusted hazard ratio was 0·87 (95% CI 0·69–1·09). Rates of self-reported gel use (96·2% Carraguard, 95·9% placebo) and condom use (64·1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42·1% of sex acts, on average (41·1% Carraguard, 43·1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). Interpretation This study did not show Carraguard's efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded. Funding US Agency for International Development, Bill & Melinda Gates Foundation.