BACKGROUND:Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE:To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN:This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS:A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION:Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

OBJECTIVE: To evaluate the safety and efficacy of elagolix 150 mg once-daily monotherapy in patients with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: A phase 4, randomized, double-blind, placebo-controlled, 6-month treatment study was conducted in premenopausal patients aged 18–51 years with heavy menstrual bleeding (defined as menstrual blood loss greater than 80 mL during one menstrual cycle) associated with uterine leiomyomas. Patients were randomized 2:1 to receive elagolix 150 mg once daily or placebo. The primary endpoint was reduction in menstrual blood loss volume to less than 80 mL at the final month and at least a 50% reduction in menstrual blood loss volume from baseline to the final month. RESULTS: Of 82 randomized patients, 54 received elagolix 150 mg and 28 received placebo. With elagolix, 49.4% (95% CI 35.1–63.8%) of patients met the primary endpoint, compared with 23.3% (95% CI 7.2–39.5%) of patients who received placebo ( P =.035). Statistically significant differences between elagolix and placebo in mean reduction of menstrual blood loss from baseline were seen as early as month 1 ( P <.05 for months 1–3 and 5). Significantly more patients receiving elagolix experienced suppression of bleeding compared with placebo ( P =.036). Greater improvements were observed in the elagolix group (vs placebo) in the proportion of patients with amenorrhea, in hemoglobin concentrations, and in health-related quality of life. No serious or severe adverse events were reported for elagolix, compared with 7.1% of participants in the placebo group having serious adverse events (coronavirus disease 2019 [COVID-19] n=1, enlarged uvula n=1). Three patients (5.6%) discontinued elagolix due to adverse events. CONCLUSION: Elagolix 150 mg once-daily monotherapy significantly improved heavy menstrual bleeding associated with uterine leiomyomas compared with placebo in premenopausal patients. Treatment with elagolix 150 mg once daily was generally well-tolerated in this study, with no new safety signals. FUNDING SOURCE: AbbVie Inc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03886220.

BACKGROUND:Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations.AIM:To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD.METHODS:In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software.OUTCOMES:Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations.RESULTS:The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence.CLINICAL IMPLICATIONS:Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population.STRENGTHS AND LIMITATIONS:This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States.CONCLUSION:The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

BackgroundThe 52-mg levonorgestrel-releasing intrauterine system is an established, long-acting contraceptive option with approved use for up to 7 years.ObjectiveThe Mirena Extension Trial evaluated the efficacy and safety of the 52-mg levonorgestrel-releasing intrauterine system during extended use beyond 5 and up to 8 years.Study DesignThis was a multicenter, single-arm study in the United States, enrolling existing users of the 52-mg levonorgestrel-releasing intrauterine system, aged 18 to 35 years, who have had the system for 4.5 to 5 years. We assessed the contraceptive efficacy (Pearl Index) and cumulative failure rate (using the Kaplan–Meier method) of the 52-mg levonorgestrel-releasing intrauterine system during extended use. We also evaluated bleeding outcomes and adverse events.ResultsOf the 362 participants starting year 6, 243 entered and 223 completed 8 years of 52-mg levonorgestrel-releasing intrauterine system use. Just more than half the participants were parous. The mean (standard deviation) age was 29.2 (±2.9) years, and all participants were aged ≤36 years at the end of year 8. Two pregnancies occurred, both with the device in situ. The year 6 pregnancy was of undetermined location and resolved spontaneously. The pregnancy in year 7 was ectopic and resolved with methotrexate treatment. In both cases, the 52-mg levonorgestrel-releasing intrauterine system was removed and the participants left the trial. For years 6 to 8, the 3-year Pearl Index (95% confidence interval) was 0.28 (0.03–1.00) with a 3-year cumulative failure rate of 0.68% (0.17–2.71). Pearl Indexes for years 6, 7, and 8 were 0.34 (0.01–1.88), 0.40 (0.01–2.25), and 0.00 (0.00–1.90), respectively. The 3-year (years 6–8) ectopic pregnancy Pearl Index was 0.14 (0.00–0.77). We found treatment-emergent adverse events in 249 of 362 participants (68.8%), with 65 (18.0%) events considered to be related to the 52-mg levonorgestrel-releasing intrauterine system. The discontinuation rate was 38.4% (139/362), most commonly because of desire for pregnancy (12.2%, 44/362). During extended use beyond 5 years and up to 8 years, participants reported a decrease in the mean number of bleeding or spotting days with approximately half of the women experiencing amenorrhea or infrequent bleeding. We did not enroll a sufficient number of women using the 52-mg levonorgestrel-releasing intrauterine system for contraception and heavy menstrual bleeding to assess extended use for that indication. At the end of year 8, most (98.7%, 220/223) of the participants who completed the study remained satisfied with the continued use of the 52-mg levonorgestrel-releasing intrauterine system. Of the 31 women who discontinued early because of desire for pregnancy with evaluable data for return-to-fertility analysis, 24 reported a posttreatment pregnancy within 1 year, giving a 12-month return-to-fertility rate of 77.4%.ConclusionThe 52-mg levonorgestrel-releasing intrauterine system, initially approved for 5 years, maintains high contraceptive efficacy, user satisfaction, and a favorable safety profile through 8 years of use. Participants reported 26 posttreatment pregnancies in total, of which 24 occurred in women who had discontinued the 52-mg levonorgestrel-releasing intrauterine system because of a desire for pregnancy. Of note, among women who elected to continue use through 8 years, bleeding patterns remained highly favorable. These findings support continued 52-mg levonorgestrel-releasing intrauterine system use for up to 8 years in women who wish to continue treatment.

INTRODUCTION: TWIRLA is a low-dose contraceptive transdermal delivery system of 120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol (LNG/EE TDS) used in a 28-day cycle. It was approved by the US Food and Drug Administration in February 2020 as a method of contraception for use in women of reproductive potential with a body mass index (BMI) <30 kg/m2. The phase 3 SECURE study showed an acceptable safety profile for the LNG/EE TDS in a clinical trial setting. This assessment provides an update of LNG/EE TDS safety based on real-world postmarketing adverse event reporting. METHODS: Data collected from LNG/EE TDS standard postmarketing reporting during December 2020 through September 2021 were assessed and describe serious adverse events (SAEs) to date, including venous thromboembolism (VTE, an event of special interest), and the number of patients who received replacements in a patch-replacement program. RESULTS: Approximately 14,600 prescriptions for the LNG/EE TDS were dispensed during this postmarketing period, with additional patches dispensed as samples. No VTEs were reported. Two SAEs (one case each of suicidal ideation and loss of consciousness) were reported; based on spontaneous reporting, no new safety issues were identified. Reports of TDS adhesion issues were rare; only 11 individuals received a replacement over the 10-month period. CONCLUSION: In this assessment of real-world usage of the LNG/EE TDS, SAEs and TDS replacements were infrequent and no VTEs were reported. These findings are consistent with the safety profile reported in the SECURE study, where four patients with VTEs were identified, all in women with a BMI >30 kg/m2.

INTRODUCTION: Elagolix is an oral GnRH antagonist approved in combination with hormonal add back therapy (elagolix 300 mg BID+estradiol/norethindrone acetate QD) for the treatment of heavy menstrual bleeding (HMB) associated with uterine fibroids (UF) for up to 24 months (M). However, estradiol and/or norethindrone acetate may be contraindicated in some patients with UF and HMB. METHODS: This phase 4, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of elagolix 150 mg QD for UF-associated HMB. Premenopausal women with UF and HMB were randomized 2:1 to elagolix 150 mg QD or placebo for 6M. Assessments included the proportion of patients with menstrual blood loss (MBL) volume less than 80mL at the final month (FM) and greater than or equal to 50% reduction in MBL volume from baseline to FM, and evaluating adverse events (AEs). RESULTS: Eighty-two patients were randomized (54 elagolix, 28 placebo). Elagolix 150 mg QD reduced MBL volume to less than 80mL and by greater than or equal to 50% from baseline in a clinically meaningful and statistically significantly larger proportion of patients versus placebo at FM (49.4% versus 23.3%, respectively; difference of 26.1%; P < .05). The most common AEs were headache and hot flush (13.0% and 11.1%, respectively, with elagolix; both 3.6% placebo). The safety profile was consistent with previously established elagolix 150 mg monotherapy safety. CONCLUSION: Elagolix 150 mg QD alone significantly reduced HMB in patients with UF after 6M of treatment with no new safety signals and may be an effective therapeutic option for patients with contraindications to estradiol and/or norethindrone acetate.

We compared the pharmacokinetics and bioavailability of serum copper in women receiving either a novel low-dose nitinol frame copper IUD or the copper T380A IUD through the first 57 days of use. Two sites participated in this parallel -single-blind study that randomized reproductive age women 1:1 to an investigational low-dose copper IUD (with 175 mm2 of exposed copper) or the approved copper T380A (Paragard, 380 mm2) IUD. Participants provided two baseline total serum copper samples at least 24 hours apart within 28 days prior to IUD placement followed by seven samples following randomization on days 1, 3, 8, 15, 22, 29, and 57. We used a noncompartmental mixed-effects linear analysis of variance (ANOVA) model with treatment as a fixed effect and subject as a random effect to calculate uncorrected PK parameters Cmax, Cmean, and AUC0-56 days. We compared relative bioavailability between the two groups by geometric mean ratios and 90% confidence intervals. We hypothesized that the relative bioavailability of total serum copper for the low-dose device would not exceed established normal (490 to 1840 ng/ml) or levels seen in users of the copper T380A. Of the 41 participants enrolled, 39 had successful IUD placements (20 in the low-dose group and 19 in the T380A group) with 36 of those subjects completing the treatment comparison phase of the study (19 low-dose and 17 T380A). Participants reported a mean age of 28.4 years. The baseline mean serum copper concentrations for the low-dose group were 1220 ng/ml standard deviation (SD) ± 285 ng/ml vs. 1250 ng/ml ± 276 ng/ml for the T380A group. Observed copper concentrations in both groups remained in the normal range; with the relative mean Cmax, Cmean, and AUC 0-56 days of 1210 ng/ml, 1070 ng/ml, and 59,700 for the low-dose IUD group vs. 1300, 1150, and 63,600 for the T380A group. Post IUD placement values for both the low-dose group and the copper T380A group were slightly lower than baseline values over the seven timepoints from 0-56 days. Respective baseline-corrected mean values for the low-dose group were 7.8 to 29.8 ng/ml and for the T380A group were 14.9 to 34.3 ng/ml lower than baseline. Relative bioavailability by geometric mean copper exposure for all parameters ranged from 0.93-0.94 (90% CI for all values 0.85-1.02) with all mean values for the low-dose IUD lower than the T380A. Serum copper concentrations for the two IUDs remained within the normal range and trended toward lower values for participants assigned to the low-dose copper IUD relative to the T380A. Neither IUD generated clinically meaningful changes in total serum copper concentrations during the first 56 days after IUD placement.

Objective: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLA (R)) containing levonorgestrel (LNG) and ethinyl estradiol (EE). Study design: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women >= 18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days offtreatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used. Results: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI >= 30 kg/m(2) . In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m(2) and 8.6 (5.8-11.5) in women with BMI >= 30 kg/m(2) . Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs >= 30 kg/m(2)) reported thromboembolic events considered related to treatment. Conclusions: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI >= 30 kg/m(2). The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLA (R) for prevention of pregnancy in women with BMI <30 kg/m(2). (C) 2020 The Authors. Published by Elsevier Inc.

INTRODUCTION: The Mirena Extension Trial (MET) is a multicenter, open-label, single group study being conducted in the USA investigating contraceptive efficacy and safety of 52 mg LNG-IUS (Mirena®) during extended use for up to 8 years, with analyses planned at the end of Year 6, 7 and 8. METHODS: We recruited and screened current users of 52 mg LNG-IUS, ≤35 years of age, after a minimum of 4 years and 6 months of use. Eligible consenting participants underwent a baseline visit 0 to 14 days before the end of Year 5. Institutional review board approval was obtained for all centers. The primary aim was to assess contraceptive efficacy (Pearl Index, PI) for up to 8 years of use. We present the results of the Year 6 analysis. RESULTS: Most of the 362 participants starting Year 6 completed and entered Year 7; 14 were lost to follow up and 40 discontinued. At baseline, 11.3% of women were between 18 and 25 years of age (mean=29.4 years [±3.1]). Around half (47.2%) were nulliparous. During Year 6, one pregnancy occurred for a Year 6 PI of 0.35 (CI 95% 0.01, 1.95). This pregnancy was of undetermined location, occurred with 52 mg LNG-IUS in situ and resolved without intervention. Overall, participants reported high levels of satisfaction (92.6% very satisfied, 6.4% somewhat satisfied). Treatment-emergent adverse events were reported in 166 patients, with 27 considered related to 52 mg LNG-IUS. CONCLUSION: 52 mg LNG-IUS maintains high contraceptive efficacy during Year 6 with a favorable safety profile. Satisfaction also remains high.

Abstract Objective: Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. Methods: Menopausal women aged >40-65 years with moderate/severe VMS (≥50 episodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90 mg BID or 30, 60, 120 mg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS × 2] + [number of severe VMS × 3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (≥50% reduction in moderate/severe VMS frequency) was a key secondary outcome. Results: Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by −1.9 to −3.5/day at week 4 and −1.8 to −2.6/day at week 12 (all P < 0.05 vs placebo). Mean difference from placebo in VMS severity score was −0.4 to −1 at week 4 (all doses P < 0.05) and −0.2 to −0.6 at week 12 (P < 0.05 for 60 and 90 mg BID and 60 mg QD). Response (50% reduction) relative to placebo was achieved by 81.4% to 94.7% versus 58.5% of participants at end of treatment (all doses P < 0.05). Treatment-emergent adverse events were largely mild/moderate; no serious treatment-related treatment-emergent adverse events occurred. Conclusions: Fezolinetant is a well-tolerated, effective nonhormone therapy that rapidly reduces moderate/severe menopausal VMS. Video Summary:http://links.lww.com/MENO/A572; video script available at http://links.lww.com/MENO/A573.

This study aims to describe the short-term reactogenicity of the AS03-adjuvanted H5N1 vaccine expressed through adverse events (AEs) and quality-adjusted life-day (QALD) scores. The AEs are likely to be short-term and therefore the quality of life (QoL) questionnaire, SF-36v2, was administered daily to record changes over seven days. A more sensitive application of this instrument should allow for a better understanding of short-term tolerability of adjuvanted vaccines. Participants (N = 50) received a 2-dose vaccination schedule. Solicited (collected daily: days 0 to 7 [post dose 1] and 21 to 28 [post dose 2]) and unsolicited (collected weekly until day 21) AEs were collected via diary cards. The QoL questionnaires were completed daily (days 0–6) and weekly (days 0, 6, 21, 27) after dose one. Questionnaire data were transformed into SF-6D scores to report QALDs. It was hypothesized post-hoc that the QALD and daily AEs scores should correlate if discrete QoL-changes were captured. Pain (92%) and muscle ache (66%) were the most commonly reported solicited local and general AEs respectively, neither increased in intensity nor in frequency after dose 2. No safety concerns were identified during the study. A correlation between the daily AEs and QALD scores existed (correlation coefficient, − 0.97 (p < 0.001)). The impact of the AEs scores on the QALD was marginal (− 0.02 max for one day). Similarly with other H5N1 studies, no safety concern was identified throughout the study. Some time-limited variations in QALD-scores were reported. Our results imply that daily administration of the SF-36v2 captures changes in QALD-scores. ClinicalTrials.gov . NCT01788228. Registered 11 February 2013.

INTRODUCTION: AG200-15 (Twirla®) is an investigational transdermal contraceptive delivery system (TCDS), which delivers daily exposure of approximately 120 µg of levonorgestrel and 30Î1/4 g of ethinyl estradiol. We report the safety from three Phase 3 studies - the SECURE (ATI-CL23) study, ATI-CL12, and ATI-CL-13. METHODS: SECURE was a single-arm, 13-cycle, open-label study conducted in 2014-2016. ATI-CL12 (13-cycles) and ATI-CL13 (6-cycles) were conducted in 2010-2011 and were open-label, randomized, active-controlled (an approved oral contraceptive (OC)) safety and efficacy studies. Subjects reported all treatment emergent adverse events (TEAEs) and serious adverse events (SAEs). TEAEs were defined as adverse events with an onset date on or after the first patch application through Day 28 of the subject's final treatment cycle. The results reported represent combined safety data. RESULTS: For AG200-15 in all studies combined, 54% of 3,481 subjects had at least one TEAE, 26% had at least one study drug-related TEAE, 5% had TEAEs of severe intensity, and 11% had TEAEs resulting in study drug discontinuation. Fewer than 2 percent of subjects (n=56) had SAEs, and 0.5% (n=18) had study drug-related SAEs. The SAEs occurring in >2 subjects were cholelithiasis (n=4), deep vein thrombosis (3), pulmonary embolism (3), and depression (3). No deaths were reported. The most common TEAEs (≥-2%) included nasopharyngitis (5.7%), upper respiratory tract infection (4.5%), nausea (4.3%), headache (3.6%), and urinary tract infections (3.5%). CONCLUSION: The percentages of TEAEs and SAEs were generally similar across the Phase 3 studies. The adverse event profile of AG200-15 appears to be similar to approved OCs.

Objective: The aim of the study was to describe the effects of TX-001HR (17 beta-estradiol [E2] and natural progesterone [P4] in a single oral capsule) on menopause-specific quality of life in women with moderate to severe vasomotor symptoms (VMS). Methods: The REPLENISH study (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial which evaluated four E2/P4 doses in postmenopausal women with VMS and a uterus. Women with moderate to severe hot flushes (>= 7/d or >= 50/wk) were included in a VMS substudy. Participants self-administered the Menopause-Specific Quality of Life (MENQOL) questionnaire. Baseline changes in MENQOL overall and domains were determined as well as correlations between changes in MENQOL scores and VMS frequency or severity. Results: In the VMS substudy, women treated with E2/P4 had significantly greater improvements from baseline in their MENQOL overall score at week 12, and months 6 and 12, compared with placebo (all, P< 0.05, except the lowest E2/P4 dose at months 6 and 12). Improvements from baseline for the MENQOL vasomotor domain score were significantly greater with TX-001HR doses versus placebo at all time points (all, P< 0.01). Changes in MENQOL vasomotor scores moderately correlated with changes in VMS frequency (r = 0.56, P< 0.0001) and severity (r = 0.55, P< 0.0001). Conclusion: In the REPLENISH trial, women with moderate to severe VMS treated with most E2/P4 doses reported significant improvements in quality of life from baseline to 12 weeks compared with placebo, which were maintained up to 12 months. TX-001HR, if approved, may provide the first oral hormone therapy formulation in a single capsule containing E2 and P4 for the treatment of VMS in postmenopausal women with a uterus.

INTRODUCTION: AG200-15 (Twirla®) is an investigational transdermal contraceptive delivery system (TCDS), which delivers daily exposure of levonorgestrel (LNG) and ethinyl estradiol (EE) similar to oral doses of 120 μg LNG and 30 μg EE. We examine various aspects of patch adhesion and wearability with AG200-15 TCDS. METHODS: SECURE was a single-arm, open-label, Phase 3 study conducted in US women 18 years or older, with no restrictions on body mass index or weight (NCT02158572). Subjects recorded patch-related characteristics daily in electronic diaries; irritation/itching and patch adhesion were also evaluated by the investigator at each visit. Irritation/itching scores were rated from 0 (none) to 3 (severe). Patch adhesion scores were rated from 0 (no/small amount of lifting off skin) to 4 (entire patch falling off). RESULTS: In 2,031 women across 13 cycles, 6.2% reported a local site reaction. The subject-rated mean skin irritation/itching score was 1.31, and most women reported their worst skin irritation as none, mild, or moderate (26.2%, 32.0%, and 26.6%, respectively). The investigator-reported mean skin irritation score was 0.18, and most women were determined by the investigator to have none or mild skin irritation (85.0% and 12.6%, respectively). The mean subject- and investigator-rated patch adhesion scores were 0.52 and 0.04, respectively. Treatment discontinuation due to application site irritation/itching occurred in 1.9% of women. CONCLUSION: Overall, results of various subject- and investigator-rated patch characteristics provide favorable support for patch adhesion and wearability of the AG200-15 TCDS.

OBJECTIVE To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02147158.

OBJECTIVE: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18–50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3–51.1]) and 86 of 157 (54.8% [97.5% CI 45.5–63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0–3.8]) patients treated with placebo achieved amenorrhea ( P <.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P <.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P <.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147158.

Objective:Vulvovaginal atrophy (VVA) is characterized by vaginal changes, dyspareunia, and itching/irritation. Efficacy and safety of a lower-dose estradiol vaginal cream (0.003%) were evaluated in postmenopausal women with VVA-related dyspareunia.Methods:This was a phase 3, randomized, double-blind, placebo-controlled study. Sexually active postmenopausal women with moderate-severe dyspareunia as the most bothersome symptom, 5% vaginal superficial cells, and vaginal pH >5.0 were randomized (1:1) to 0.003% estradiol vaginal cream (15g estradiol; 0.5g cream) or placebo (0.5g cream) applied daily for 2 weeks followed by three applications/week for 10 weeks. Coprimary outcomes were changes in dyspareunia severity, vaginal cytology, and vaginal pH from baseline to final assessment. Additional efficacy outcomes and safety were assessed.Results:A total of 550 participants (average age, 58 y) were randomized. Compared with placebo, estradiol reduced dyspareunia severity (mean change from baselineSD: -1.5 +/- 1.0 estradiol vs -1.2 +/- 0.9 placebo), decreased vaginal pH (-1.36 +/- 0.89 vs -0.53 +/- 0.92), and improved vaginal cytology (percentage superficial and parabasal cells 10.1 +/- 16.7 vs 1.4 +/- 6.1 and -48.5 +/- 45.1 vs -14.6 +/- 39.6; P<0.001, all) at the final assessment. In addition, estradiol decreased dyspareunia severity at weeks 8 and 12, vaginal/vulvar irritation/itching at weeks 4 and 12, and dryness at week 12 versus placebo (P<0.01, all). VVA severity, pH, and cytology improved at week 12 with estradiol versus placebo (P<0.001, all). Vulvovaginal mycotic infections were more frequent with estradiol. One serious event leading to discontinuation occurred with estradiol. No deaths occurred.Conclusions:Lower-dose estradiol vaginal cream (0.003%) dosed three applications/week is an effective and well-tolerated treatment for VVA-related dyspareunia.