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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

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

ObjectiveTo evaluate heavy menstrual bleeding treatment outcomes with levonorgestrel 52-mg intrauterine device (IUD) use in participants without body mass index (BMI) or parity restrictions.MethodsInvestigators included participants aged 18-50 years with no pelvic or systemic pathology causing heavy menstrual bleeding at 29 U.S. centers in a prospective trial. Participants had up to three screening cycles with menstrual product collection for alkaline hematin blood-loss measurements. Investigators enrolled those with two menses with blood loss of 80 mL or more (values averaged for baseline blood loss), placed the IUD, and followed participants for up to six 28-day cycles. Participants collected any menstrual products used during cycles 3 and 6 for blood-loss measurement. We evaluated outcomes in participants with at least one follow-up assessment for the primary outcome of median absolute blood-loss change and, secondarily, treatment success , defined as the proportion with a final measured blood loss less than 80 mL and at least 50% reduction from baseline. We evaluated exploratory outcomes of differences in blood-loss changes by BMI and parity using Wilcoxon rank sum test.ResultsOf 105 enrolled participants, 47 (44.8%) had obesity (BMI 30.0 or higher) and 29 (27.6%) were nulliparous. Baseline mean blood loss ranged from 73 to 520 mL (median 143 mL, interquartile range 112-196 mL). Eighty-nine (84.8%) had at least one evaluable follow-up evaluation. Participants had median (interquartile range) absolute blood-loss decreases at cycles 3 (n=86) and 6 (n=81) of 93.3% (86.1-97.7%) and 97.6% (90.4-100%), respectively. At cycle 6, participants without obesity (n=43) and with obesity (n=38) had similar median [interquartile range] decreases (97.6% [91.8-100%] and 97.5% [90.3-100%], respectively; P =.89), with comparable findings for nulliparous (n=25) and parous (n=56) participants (97.0% [91.7-99.1%] and 98.1% [89.9-100%], respectively; P =.43). Treatment success occurred in 81.8% (95% CI 74.2-89.4%) of 99 participants, excluding those with no outcomes due to lost to follow-up or consent withdrawal, and did not vary by BMI or parity. The most common adverse events leading to discontinuation were bleeding or cramping (n=6 [5.7%]) and expulsion (n=5 [4.8%]).ConclusionThis levonorgestrel 52-mg IUD reduces blood loss by more than 90% over 6 months compared with baseline for most users with heavy menstrual bleeding.Funding sourceMedicines360.Clinical trial registrationClinicalTrials.gov , NCT03642210.

ObjectiveTo assess the relationship of adherence and pregnancy in participants using an estetrol and drospirenone combined oral contraceptive.MethodsWe performed a secondary analysis for which we pooled data from two parallel, multicenter, phase 3 trials (United States and Canada, Europe and Russia) that enrolled participants 16-50 years of age to receive estetrol 15 mg and drospirenone 3 mg in a 24 hormone and four placebo pills regimen for up to 13 cycles. Participants reported pill intake, sexual intercourse, and other contraceptive use on paper diaries. We limited this efficacy analysis to at-risk cycles (one or more reported acts of intercourse and no other contraceptive use) in participants 16-35 years of age at screening. We excluded cycles with other contraceptive use unless pregnancy occurred in that cycle. We assessed primarily the relationship between number of pills not taken per cycle and pregnancies and, secondarily, when pregnancies occurred during product use with a test for trend and χ 2 analyses as appropriate.ResultsAmong 2,837 participants in this analysis, 31 on-treatment pregnancies occurred during 26,455 at-risk cycles. Pregnancies occurred in 0.09%, 0.25%, 0.83%, and 1.6% of cycles in which participants reported they took all hormone pills (n=25,613 cycles) or did not take one (n=405 cycles), two (n=121 cycles), and more than two (n=314 cycles) hormone-containing pills, respectively ( P

ObjectiveTo evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen.Study designWe pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors.ResultsAnalyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI

ObjectivesTo evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials.Study designThe two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings.ResultsOf 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment.ConclusionsE4/DRSP is associated with a favorable tolerability and safety profile.Implications statementPooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

ObjectiveTo evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen.Study designWe pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes.ResultsWe included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event.ConclusionE4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns.Implications statementMost estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

BackgroundThe most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users.MethodsThis 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17-40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment.FindingsBetween June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini (n = 744) or the TCu380A (n = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9-84·5%] vs. 70·2% [95% CI: 59·7-80·7], p = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p = 0·023), respectively.InterpretationThe NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy.FundingBill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium).

ObjectiveTo assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.Study designWomen aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle.ResultsWe enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73-3.88), method-failure PI of 1.43 (95% CI 0.7-2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred.ConclusionE4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates.Implications statementA new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.

ObjectiveAssess the relationship between parity and prior route of delivery to levonorgestrel 52 mg intrauterine system (IUS) expulsion during the first 72 months of use.Study designWe evaluated women enrolled in the ACCESS IUS multicenter, Phase 3, open-label clinical trial of the Liletta levonorgestrel 52 mg IUS. Investigators evaluated IUS presence at 3 and 6 months after placement and then every 6 months and during unscheduled visits. We included women with successful placement and at least one follow-up assessment. We evaluated expulsion rates based on obstetric history; for prior delivery method subanalyses, we excluded 12 participants with missing delivery data. We determined predictors of expulsion using multivariable regression analyses.ResultsOf 1714 women with IUS placement, 1710 had at least one follow-up assessment. The total population included 986 (57.7%) nulliparous women. Sixty-five (3.8%) women experienced expulsion within 72 months, 50 (76.9%) within the first 12 months. Expulsion rates among nulliparous women (22/986 [2.2%]) or parous women with any pregnancy ending with a Cesarean delivery (6/195 [3.1%]) differed from parous women who only experienced vaginal deliveries (37/517 [7.2%]) (p < 0.001). In multivariable regression, obesity (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI] 1.3-3.7), parity (aOR 2.2, 95% CI 1.2-4.1), and non-white race (aOR 1.8, 95% CI 1.1-3.2) predicted expulsion. Among parous women, obesity (aOR 2.2, 95% CI 1.2-4.2) increased the odds and having ever had a cesarean delivery (aOR 0.4, 95% CI 0.1-0.9) decreased the odds of expulsion.ConclusionIUS expulsion occurs in less than 4% of users over the first 6 years of use and occurs mostly during the first year. Expulsion is more likely among obese and parous women.ImplicationsLevonorgestrel 52 mg intrauterine system expulsion occured more commonly in parous than nulliparous women; the increase in parous women is primarily in women who had vaginal deliveries only. The association between obesity, delivery route, and IUS expulsion needs further elucidation.

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism.Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.ResultsSixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were 40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.ConclusionsEstradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use.ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.

INTRODUCTION:: A new contraceptive vaginal system (CVS) for 13 cycles of use has been developed that releases a daily mean of segesterone acetate (SA) 0.15 mg and ethinyl estradiol (EE) 0.013 mg. We evaluated endometrial safety during use of the SA/EE CVS for up to 13 cycles. METHODS:: In this multicenter, open-label, phase 3 study, 2308 women used the SA/EE CVS on a 21-day in/7-day out regimen for up to 13 cycles. Women could choose to participate in an endometrial safety sub-study at 5 study sites. Three blinded pathologists histologically examined endometrial biopsies at screening, at cycle 6 in the first 25 women reaching 6 cycles, and at the end of study (cycle 12/13) or early study termination in the remainder. Women with endometrial hyperplasia or cancer at baseline were excluded. We evaluated histologic changes in women with both screening and follow-up biopsies. RESULTS:: Of the 156 women who participated, 83 had follow-up biopsies. Pathologists identified no cases of endometrial hyperplasia or carcinoma at cycle 6 (n=24), cycles 12/13 (n=30) or other end of therapy times (n=29). The most frequent histologic diagnoses were atrophic/inactive or secretory: atrophic/inactive (29%, 27% and 28%, respectively), secretory (29%, 37%, and 45%, respectively), proliferative (17%, 7%, and 21%, respectively), mixed (17%, 10% and 3%, respectively), menstrual (4%, 7%, and 0%, respectively), or insufficient/no tissue (0%, 10%, and 3%, respectively). CONCLUSION:: Use of the SA/EE CVS for up to 13 cycles did not result in any unexpected endometrial safety effects based on endometrial histology.

INTRODUCTION:: Liletta is a levonorgestrel 52 mg contraceptive intrauterine system (IUS) currently approved for contraception for up to four years based on an ongoing multicenter trial currently planned to continue for up to eight years of use. We evaluated the five-year efficacy and safety data for Liletta. METHODS:: Women aged 16-45 years were enrolled; those women aged 36-45 years received the IUS for safety evaluation only. We followed 1,568 women aged 16-35 years and 146 women aged 36-45 years after successful IUS placement. We assessed five-year pregnancy rates and safety outcomes. RESULTS:: The 16-35 year old subjects included 1,011 (57.7%) nulliparous and 438 (25.1%) obese women. Among these women, nine pregnancies occurred including four in nulliparous women and one in an obese woman. One pregnancy occurred following perforation and one following expulsion. Six (67%) pregnancies were ectopic. The Pearl Index in the first year was .15 (95% CI .02-.55). Cumulative life-table pregnancy rates through years three and five were .59 (95% CI .28-1.25) and .92 (95% CI .46-1.82), respectively. Perforation following IUS placement occurred in two (0.1%) women; both were diagnosed within the first year. Expulsion occurred in 63 (3.7%) participants, most (50 [80.6%]) during the first year of use. Pelvic infection was diagnosed in 11 (.6%) women. Only 39 (2.3%) women discontinued due to bleeding complaints, primarily (n=29 [74.3%]) in the first year. CONCLUSION:: Liletta is highly effective and has an excellent safety profile over five years of use; most expulsions and discontinuation for bleeding occur during the first year of use.

INTRODUCTION:: Liletta is a levonorgestrel 52 mg contraceptive intrauterine system (IUS) currently approved for contraception for up to three years based on an ongoing multicenter trial evaluating the product for up to seven years of use. We evaluated four-year efficacy and safety data for Liletta. METHODS:: Women aged 16-45 years were enrolled and followed in the clinical trial. Women aged 36-45 years received the IUS for safety evaluation only. We assessed four-year pregnancy rates (by Pearl Index and life-table analysis) and safety outcomes. RESULTS:: Successful IUS placement occurred in 1,568 (98%) women aged 16-35 years and 146 (97%) women aged 36-45 years, including 1,011 (57.7%) nulliparous and 438 (25.1%) obese women. Among women 16-35 years at enrollment, eight pregnancies occurred including one following perforation and one following expulsion. Six (75%) pregnancies were ectopic. The eight pregnancies included three nulliparous women and one obese woman. The Pearl Index in the first year was .15 (95% CI .02-.55). Cumulative life-table pregnancy rates through years two, three and four were .49 (95% CI .22-1.09), .60 (95% CI .28-1.26) and .78 (95% CI .37, 1.60). Perforation following IUS placement occurred in two (0.1%) women; both were diagnosed within the first year. Expulsion was reported in 63 (3.7%) participants, most (50 [80.6%]) during the first year of use. Pelvic infection was diagnosed in 12 (.7%) women. Only 38 (2.2%) women discontinued due to bleeding complaints. CONCLUSION:: Liletta is highly effective and safe over four years of use in nulliparous and parous women as well as non-obese and obese women.

To evaluate if ibuprofen 800mg reduces pain with intrauterine device (IUD) insertion among U.S. women.We conducted a randomized, double-blind, placebo-controlled trial of women undergoing IUD insertion approximately 2-6weeks following first-trimester uterine aspiration. Subjects were randomized to receive ibuprofen 800mg or placebo 30-45min prior to IUD insertion. A 100-mm visual analog scale (VAS) was administered to measure pain after speculum insertion (baseline) and immediately following IUD insertion.A total of 202 women were enrolled, with 101 randomized to each group (ibuprofen or placebo). Sociodemographic characteristics and baseline VAS scores were similar between groups. The median pain score with IUD insertion was 41.5mm in the placebo group and 38.0mm in the ibuprofen group (p=.50). Mean and median pain scores did not differ between placebo and ibuprofen when nulliparous and parous women were analyzed independently. Overall, median pain scores were 17.5mm higher in nulliparous women than parous women (p=.004). Median pain scores did not differ by age, IUD-type, history of dysmenorrhea or time since aspiration.Administration of ibuprofen 800mg prior to IUD insertion does not reduce pain associated with the procedure for U.S. women. Overall, nulliparous women report more pain with IUD insertion than multiparous women.