Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

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 co-primary 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 versus 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% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 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.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

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.

Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial.

BACKGROUND: The 52-mg levonorgestrel-releasing intrauterine system is an established, long-acting contraceptive option with approved use for up to 7 years. OBJECTIVE: The 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 DESIGN: This 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. RESULTS: Of 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%. CONCLUSION: The 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.

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

BACKGROUND: Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. METHODS: We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). RESULTS: All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. CONCLUSIONS: Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. CLINICAL TRIALS REGISTRATION: NCT01999842.

A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation.

OBJECTIVES: To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 µg/30 µg tablets plus seven days of EE 10 µg tablets in place of placebo. METHODS: This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. RESULTS: Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. CONCLUSIONS: The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC.

Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas: A Randomized Controlled Trial.

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.

Testosterone for low libido in postmenopausal women not taking estrogen.

BACKGROUND: The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS: We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS: At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS: In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Global cross-sectional survey of women with vasomotor symptoms associated with menopause: prevalence and quality of life burden.

OBJECTIVE: To determine prevalence and health-related quality of life (HRQOL) of moderate-to-severe vasomotor symptoms (VMS) in postmenopausal women in Europe, the US, and Japan, and among subgroups of women not taking hormone therapy (HT). METHODS: Screening surveys were sent to a random sample of women aged 40 to 65 years; full questionnaires followed to those who completed them and met inclusion criteria. Women with successfully treated VMS, breast cancer, or on HT for medical conditions were excluded. The Menopause-Specific QOL (MENQOL) and Work Productivity and Activity Impairment (WPAI) questionnaires were included in the questionnaire. RESULTS: Of 25,161 women completing the screening survey, 11,771 were postmenopausal and 3,460 met inclusion criteria and completed the full questionnaire. Prevalence of moderate-to-severe VMS was 40%, 34%, and 16% in Europe, the US, and Japan, respectively. A large proportion were HT averse, albeit eligible (Europe 56%, US 54%, Japan 79%). In total, 12%, 9%, and 8% in Europe, the US, and Japan, respectively, were HT-contraindicated. A high proportion were HT-cautious (Europe 70%, US 69%, Japan 52%). Most common menopausal symptoms reported in the MENQOL were feeling tired or worn out (Europe/US 74%, Japan 75%), aching in muscles and joints (Europe 69%, US 68%, Japan 61%), difficulty sleeping (Europe 69%, US 66%, Japan 60%), and hot flashes (Europe 67%, US 68%, Japan 62%). Overall, the most bothersome symptom was weight gain. As measured by the WPAI, hot flashes and night sweats had a greater impact on daily activities than on working activities. CONCLUSIONS: A high proportion of women experienced moderate-to-severe VMS, with associated symptoms impacting QOL.

Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.

OBJECTIVE: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLAⓇ) 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 off-treatment/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/m2. 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/m2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m2. 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/m2) 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/m2. 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Ⓡ for prevention of pregnancy in women with BMI <30 kg/m2. IMPLICATIONS: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA).

OBJECTIVE: In the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs). METHODS: In this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs). RESULTS: Of 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6). CONCLUSIONS: Oral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.

A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.

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.

Oral 17ß-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms.

OBJECTIVE: The aim of the study was to describe the effects of TX-001HR (17ß-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.

A randomized, multicenter, double-blind study to evaluate the safety and efficacy of estradiol vaginal cream 0.003% in postmenopausal women with dyspareunia as the most bothersome symptom.

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 (15 µg estradiol; 0.5 g cream) or placebo (0.5 g 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 baseline ±â€ŠSD: -1.5 ±â€Š1.0 estradiol vs -1.2 ±â€Š0.9 placebo), decreased vaginal pH (-1.36 ±â€Š0.89 vs -0.53 ±â€Š0.92), and improved vaginal cytology (percentage superficial and parabasal cells 10.1 ±â€Š16.7 vs 1.4 ±â€Š6.1 and -48.5 ±â€Š45.1 vs -14.6 ±â€Š39.6; 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.

Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

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.

Patient acceptability and satisfaction with a low-dose solubilized vaginal estradiol softgel capsule, TX-004HR.

OBJECTIVE: TX-004HR is an investigational, muco-adhesive, vaginal, softgel capsule containing low-dose, solubilized, 17ß-estradiol designed to treat postmenopausal vulvar and vaginal atrophy (VVA) and improve user experience without an applicator and less mess. METHODS: As part of the 12-week, placebo-controlled, double-blind, phase 3 REJOICE trial evaluating the efficacy/safety of 4-, 10-, and 25-µg TX-004HR in 764 postmenopausal women with VVA, a five-question product survey was administered. Pearson correlation coefficients were used to evaluate correlations between clinical endpoints (vaginal physiology, dyspareunia, and vaginal dryness) and patient acceptability and satisfaction. RESULTS: Majority of the women receiving TX-004HR or placebo reported that the product was easy to use (85.4%-92.1%) and rated ease of capsule insertion as "good" to "excellent" (75.0%-82.6%). A significantly greater percentage of women reported being "very satisfied" or "satisfied" with TX-004HR (68.6%-76.3%) than with placebo (56.8%, P < 0.05 for all). A greater percentage of women "somewhat" or "very much" preferred TX-004HR over their previous treatment versus those taking placebo (P < 0.05). Significantly more women receiving TX-004HR (72.8%-80.5%) versus placebo (62.5%, P < 0.05) would "probably" or "definitely" consider using the product again. Dyspareunia and vaginal dryness reductions were correlated with higher product satisfaction and the percentage of women who would consider re-using TX-004HR. CONCLUSIONS: TX-004HR had a high level of product acceptability, and more women were satisfied with TX-004HR, preferred it over their previous treatment, and would consider using it again versus placebo. Women may find TX-004HR to be a more acceptable product than current options to treat their dyspareunia associated with postmenopausal VVA.

Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study.

OBJECTIVE: To evaluate the efficacy and safety of a testosterone patch for the treatment of women with hypoactive sexual desire disorder after natural menopause. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in naturally menopausal women with hypoactive sexual desire disorder receiving a stable dose of oral estrogen with or without progestin (N = 549). Women were randomized to receive testosterone 300 microg/day or placebo patches twice weekly for 24 weeks. The primary efficacy measure was change from baseline in frequency of total satisfying sexual activity over a 4-week period (weeks 21-24). RESULTS: A total of 483 women (88%) were included in the primary analysis population (those with baseline sex hormone binding globulin levels < or = 160 nmol/L). The change from baseline in number of total satisfying sexual episodes was significantly greater for testosterone compared with placebo (participants with baseline sex hormone binding globulin levels < or = 160 nmol/L, mean change of 2.1 +/- 0.28 versus 0.5 +/- 0.23 episodes/4 weeks; P < 0.0001; intent-to-treat population, mean change from baseline of 1.9 +/- 0.26 versus 0.5 +/- 0.21 episodes/4 weeks, P < 0.0001). Testosterone also produced statistically significant improvements compared with placebo in all secondary efficacy measures, including sexual desire and personal distress. The testosterone patch was well tolerated. CONCLUSIONS: Testosterone patch treatment increased the frequency of satisfying sexual activity and sexual desire, decreased personal distress, and was well tolerated in naturally menopausal women with hypoactive sexual desire disorder.

Treatment of premenstrual disorders.

Premenstrual disorders are characterized by a wide variety of affective and somatic symptoms. This diversity of presenting symptoms has led to the use of many different types of treatment approaches, none of which has proven to be successful in all women with these disorders. Non-pharmacologic options include aerobic exercise, dietary changes and supplementation, and cognitive-behavioral therapy. Of the pharmacologic agents used to treat premenstrual symptoms, 3 selective serotonin reuptake inhibitors have received a Food and Drug Administration (FDA) indication for treating premenstrual dysphoric disorder (PMDD). Agents that are often used off label to treat premenstrual symptoms include spironolactone and oral contraceptives (OCs); gonadotropin-releasing hormone (GnRH) agonists and alprazolam are used less frequently in these patients. OCs have historically had little consistent data from controlled clinical trials to support their efficacy until a number of recent studies showed that an OC containing the novel progestin drospirenone is effective in reducing premenstrual symptoms in many women. A new drospirenone-containing OC formulation that is administered for 24 days in a 28-day cycle has been shown to be effective in treating PMDD.

Efficacy and safety of a 21/7-active combined oral contraceptive with continuous low-dose ethinyl estradiol.

OBJECTIVE: Substituting low-dose ethinyl estradiol (EE) for the hormone-free interval in combined oral contraceptives (COCs) may enhance ovarian suppression and improve tolerability. This noncomparative phase 3 study evaluated the efficacy and safety of a 21/7-active COC regimen including 21days of desogestrel (DSG)/EE followed by 7days of EE. STUDY DESIGN: This multicenter, open-label, phase 3, single-arm study enrolled sexually active women aged 18-40years at risk for pregnancy. Women received up to 1year, or 13 consecutive 28-day cycles, of DSG 150mcg/EE 20mcg for 21days and EE 10mcg alone for 7days. Participants kept diaries to record compliance, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index (PI) and life-table approach. Safety and tolerability were assessed primarily through reported adverse events (AEs). RESULTS: A total of 2858 women enrolled and 1680 completed the study. Forty-six pregnancies in 2401 women aged 18-35years occurred after COC initiation and up to 7days after last DSG/EE or EE-only tablet was taken. When cycles in which another contraceptive method was used were excluded, the PI was 2.68 [95% confidence interval (CI), 1.96-3.57]. The cumulative pregnancy rate after 1year of treatment was 2.47% (95% CI, 1.85-3.29) for all users aged 18-35years. When only cycles during which women considered compliant were included, the PI was 2.00 (95% CI, 1.39-2.80). AEs were similar to those seen with other oral contraceptives. CONCLUSIONS: This 21/7-active DSG/EE COC with 7days of low-dose EE was efficacious and well tolerated for pregnancy prevention. IMPLICATIONS STATEMENT: This phase 3 open-label study demonstrated that a 21/7-active COC regimen including 21days of DSG 150mcg/EE 20mcg and 7days of EE 10mcg was efficacious and well tolerated for pregnancy prevention.

Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial.

AIM: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women. METHODS: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm. RESULTS: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache. CONCLUSION: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

OBJECTIVE: This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN: The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS: Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17ß-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.