Risk factors for and outcomes of ring expulsions with a 1-year contraceptive vaginal system.

BACKGROUND: The US Food and Drug Administration-approved segesterone acetate and ethinyl estradiol ring-shaped contraceptive vaginal system, known as Annovera (Sever Pharma Solutions/QPharma, Malmö, Sweden), was inserted and removed under a woman's control for a 21 day in and 7 day out regimen for up to 13 cycles of use. OBJECTIVE: We aimed to describe the patterns of ring expulsion over time, to identify potential predictors of expulsion, and to evaluate the impact of expulsions on method discontinuation and pregnancy risk. STUDY DESIGN: Using data from 2064 participants who were enrolled in 2 multinational phase 3 clinical trials on the use of this contraceptive vaginal system, we examined data from participants' daily diaries for documentation of complete ring expulsion. We modeled the odds of reported expulsions over time with adjustment for background and demographic characteristics using mixed-effects logistic regression models with random intercepts. We compared the probability of continuation between those who did and those who did not report expulsions in the first cycle of use using survival analysis and hazards modeling. To determine if expulsions during the first cycle of use affected the risk for pregnancy, we calculated Pearl Indices. RESULTS: Most participants (75%) never experienced any expulsions during any cycle of use, and 91% to 97% did not experience an expulsion during any 1 cycle. The incidence of expulsion was highest in cycle 1 (9%). The odds of experiencing expulsions decreased by half in cycles 2 to 8 when compared with cycle 1 (0.48; 95% confidence interval, 0.40-0.58), and in cycles 9 to 13, expulsions were about a third of that in cycle 1 (0.32; 95% confidence interval, 0.26-0.41). Of those who did experience expulsions, most (62%-84%) experienced ≤2 expulsions per cycle. Participants from study sites in Latin America vs those in the United States had higher odds of not experiencing an expulsion (odds ratio, 1.95; 95% confidence interval, 1.45-2.63). Women with a higher education level had higher odds of experiencing an expulsion. Notably, parity, age, and body mass index were not associated with expulsion. Participants who experienced any expulsions in cycle 1 were more likely to discontinue use early (hazard ratio, 1.28; 95% confidence interval, 1.14-1.43) than participants who did not have an expulsion. The Pearl Index for participants who had expulsions during cycle 1 was 3.99 (95% confidence interval, 1.29-9.31), which was higher than that among participants who reported no expulsions (Pearl Index, 2.39; 95% confidence interval, 1.61-3.41), but the overlapping confidence intervals indicate that there is not sufficient evidence to demonstrate an association between expulsions and pregnancy risk. CONCLUSION: Expulsions were infrequent overall, decreased with subsequent cycles of use, and were not associated with body mass index or parity. Early discontinuation of product use was higher among participants who experienced an expulsion during cycle 1. Although it is unclear whether pregnancy risk was associated with expulsions, early recognition of expulsions among users may identify those at higher risk for discontinuation and may highlight when enhanced anticipatory counselling and guidance may be advantageous.

New approaches for developing biomarkers of hormonal contraceptive use.

To identify biomarkers of hormonal contraceptive (HC) use in urine and saliva, we conducted a pilot study with 30 women initiating levonorgestrel (LNG) containing combined oral contraceptives (COCs) or depot medroxyprogesterone acetate (DMPA) (15/group). Based on established COC pharmacokinetics, we collected serum and urine samples before COC ingestion and during Days one and three of use, or before DMPA injection and on Days 21 and 60 post-injection. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure serum/urine LNG and MPA. LNG was undetectable at baseline (specificity 100%); post ingestion, most urine samples had detectable LNG levels (sensitivity: 80% 6 h post Dose one, 93% 6 h post Dose three). We used a DetectX LNG immunoassay kit and showed 100% sensitivity measuring urine LNG. Urine MPA levels were undetectable in 14/15 women at baseline (specificity 91%); post-injection all urine samples had detectable MPA levels (sensitivity: 100% days 21 and 60). Results suggest urine sampling can be used to identify a biomarker of LNG and MPA use. Based on evidence from other steroidal hormonal studies showing changes affecting the transcriptome profile of saliva at 24 h, we used the same (COC, DMPA) timepoints to collect saliva. We performed transcriptome analysis and detected several differentially expressed genes in DMPA users' saliva on Days 21 and 60 compared to baseline; none among COC users. We plan further research of differential gene expression in saliva as a HC biomarker of DMPA use, and will explore longer periods of COC use and saliva collection times, and application of microRNA sequencing to support using saliva as a COC biomarker.

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.

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.

Factors associated with nonadherence to instructions for using the Nestorone®/ethinyl estradiol contraceptive vaginal ring.

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.

Effects of a One Year Reusable Contraceptive Vaginal Ring on Vaginal Microflora and the Risk of Vaginal Infection: An Open-Label Prospective Evaluation.

BACKGROUND: A contraceptive vaginal ring (CVR) containing Nestorone® (NES) and ethinyl estradiol (EE) that is reusable for 1- year (13 cycles) is under development. This study assessed effects of this investigational CVR on the incidence of vaginal infections and change in vaginal microflora. METHODS: There were 120 women enrolled into a NES/EE CVR Phase III trial and a microbiology sub-study for up to 1- year of cyclic product use. Gynecological examinations were conducted at baseline, the first week of cycle 6 and last week of cycle 13 (or during early discontinuation visits). Vaginal swabs were obtained for wet mount microscopy, Gram stain and culture. The CVR was removed from the vagina at the last study visit and cultured. Semi-quantitative cultures for Lactobacillus, Gardnerella vaginalis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, anaerobic gram negative rods (GNRs), Candida albicans and other yeasts were performed on vaginal and CVR samples. Vaginal infections were documented throughout the study. RESULTS: Over 1- year of use, 3.3% of subjects were clinically diagnosed with bacterial vaginosis, 15.0% with vulvovaginal candidiasis, and 0.8% with trichomoniasis. The detection rate of these three infections did not change significantly from baseline to either Cycle 6 or 13. Nugent scores remained stable. H2O2-positive Lactobacillus dominated vaginal flora with a non-significant prevalence increase from 76.7% at baseline to 82.7% at cycle 6 and 90.2% at cycle 13, and a median concentration of 107 colony forming units (cfu) per gram. Although anaerobic GNRs prevalence increased significantly, the median concentration decreased slightly (104 to 103cfu per gram). There were no significant changes in frequency or concentrations of other pathogens. High levels of agreement between vaginal and ring surface microbiota were observed. CONCLUSION: Sustained use of the NES/EE CVR did not increase the risk of vaginal infection and was not disruptive to the vaginal ecosystem. TRIAL REGISTRATION: ClinicalTrials.gov NCT00263341, NCT00455156.

Acceptability of the Nestorone®/ethinyl estradiol contraceptive vaginal ring: development of a model; implications for introduction.

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.