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SAT-237 Combined Bioidentical Estradiol and Progesterone Capsules Improved Quality of Sleep in Postmenopausal Women with Vasomotor Symptoms

ABSTRACT: Abstract Difficulty sleeping is a common complaint of postmenopausal women. In the REPLENISH trial, the oral 17?-estradiol/progesterone (E2/P4) softgel capsule (TX-001HR; 1 mg E2/100 mg P4 FDA approved as BIJUVATM; TherapeuticsMD, Boca Raton, FL), was shown to reduce moderate to severe hot flush frequency and severity and improve quality of life outcomes in menopausal women with a uterus, while protecting the endometrium. In this analysis, the effect of the E2/P4 capsules on “difficulty sleeping” in postmenopausal women experiencing hot flushes, was assessed by the menopause-specific quality of life (MENQOL) questionnaire and also analyzed by age. The phase 3 REPLENISH trial (NCT01942668), evaluated 4 daily doses of E2/P4 capsules in postmenopausal women (40-65 years, intact uterus) with vasomotor symptoms (VMS). Women with moderate to severe hot flushes (?7/day or ?50/week) were randomized to E2/P4 (mg/mg) 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo (VMS substudy); women with fewer/less severe VMS were randomized to active E2/P4 doses only for endometrial safety. MENQOL was administered at baseline, week 12, and months 6 and 12. The “difficulty sleeping” item was rated using a 7-item Likert scale ranging from “Not at all bothered” (analysis score of 2) to “Extremely bothered” (analysis score of 8) if difficulty sleeping was experienced, if not experienced, the score for the analysis was set to 1. Changes from baseline to week 12, and months 6 and 12 in all women (MITT population) were analyzed by ANCOVA between each E2/P4 groups vs placebo and stratified by age (pre-specified FDA subgroup; <55 and 55+). Treatment groups in the MITT population (n=1833) were E2/P4 1/100 (n=416), 0.5/100 (n=422), 0.5/50 (n=421), 0.25/50 (n=423) or placebo (n=151). The MITT population had a mean age of 55 years; in the <55-year group (n=927) mean age was 51.2 years and in the ?55-year group (n=906) mean age was 58.1 years. Mean baseline scores for the “difficulty sleeping” item ranged from 5.1 to 5.8 points. In the MITT population, difficulty sleeping significantly improved from baseline with the three highest E2/P4 doses (1/100, 0.5/100, 0.5/50) compared with placebo at all timepoints (all, P<0.05), except for 0.5/50 at month 6. In women <55 years, the sleep difficulty item significantly improved from baseline at all timepoints with two E2/P4 doses (1/100 and 0.5/50) vs placebo. In women 55+ years, significant improvements from baseline were observed at week 12 with three E2/P4 doses (1/100, 0.5/100, 0.5/50) vs placebo. In REPLENISH, women treated with E2/P4 capsules containing 1 or 0.5 mg E2 demonstrated significant and sustained improvements in the MENQOL difficulty sleeping assessment, especially those <55 years. These data warrant further evaluation.

SUBMITTER: Santoro N

PROVIDER: S-EPMC6551953 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:Abstract Vaginal bleeding associated with hormone therapy (HT) is the most common reason for treatment discontinuation. Cumulative amenorrhea rates (no bleeding or spotting for 13 cycles) ranging from 23% to 49% with current HT options1-3 are relatively lower than the 56% to 73% observed in the REPLENISH trial.4 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR (bioidentical 17β-estradiol and progesterone [E2/P4] combined in a single, oral softgel capsule; 1 mg E2/100 mg P4 FDA approved as BIJUVATM; TherapeuticsMD, Boca Raton, FL) vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). Overall, the proportion of women with no bleeding was high (74%-90%) with up to 1 year of TX-001HR. The objective of this analysis was to determine predictors of vaginal bleeding. Univariate analyses were used to assess the impact of age, race, BMI, smoking, time since last menstrual period (LMP), age at LMP, tubal ligation, parity, baseline E2 concentration, and baseline frequency and severity of VMS (mild=1 to severe=3) on the incidence of vaginal bleeding at any time during the study (cumulative incidence at cycle 13) and for bleeding that occurred in the first 3 months of the study (cumulative incidence at cycle 3). Predictors of vaginal bleeding with HT (at cycle 13) were age, time since LMP, E2 concentration, and severity of VMS. The likelihood of bleeding was reduced by 42% for every 5-year increase in age (P<0.0001) and by 39% for every 5-year increase in the time since LMP (P<0.0001). Incidence of bleeding significantly decreased by 54% with baseline E2 levels <10 pg/mL (P=0.0001), 59% with E2 levels <5 pg/mL (P<0.0001), and 47% for E2 levels 5 to <10 pg/mL (P=0.0040), when compared with E2 levels ≥10 pg/mL. There was 33% less bleeding reported for women with less severe VMS (<2.5 points). No statistically significant differences in reports of bleeding were noted for race, BMI, smoking, age at LMP, tubal ligation, parity, or baseline frequency of moderate to severe VMS. Similar predictors were noted for bleeding at cycle 3, except for baseline VMS severity, which was no longer a significant predictor. Cumulative amenorrhea was relatively high in TX-001HR users. Vaginal bleeding in women treated with TX-001HR increased in women who were younger, experienced their LMP more recently, and had higher baseline E2 concentrations. Even though the rate/amount of bleeding was relatively low overall,4 these data may help clinicians inform women who may be more likely to experience vaginal bleeding while taking combined E2/P4 for menopausal symptoms. 1. Prempro tablets PI. Wyeth Pharmaceuticals. 2. Activella tablets PI. Novo Nordisk FemCare AG. 3. Angeliq Tablets PI. Berlex. 4. Lobo RA, et al. Obstet Gynecol. 2018;132:161-170.

Project description:Abstract In the phase 3 REPLENISH trial of postmenopausal women with a uterus, TX-001HR (TherapeuticsMD, Boca Raton, FL), an oral 17β-estradiol-progesterone (E2/P4) softgel capsule, reduced moderate to severe hot flush frequency and severity and improved quality of life outcomes, while protecting the endometrium. The objective of this analysis was to further determine the effects of the E2/P4 capsules versus placebo on vasomotor symptoms (VMS) as assessed by the menopause-specific quality of life (MENQOL) questionnaire. In the REPLENISH trial (NCT01942668), women with moderate to severe hot flushes (≥7/day or ≥50/week) were randomized 1:1:1:1:1 to daily E2/P4 (mg/mg) of 1/100 (FDA approved as BIJUVATM), 0.5/100, 0.5/50, 0.25/50, or placebo (VMS substudy). Other women (with fewer VMS) were randomized 1:1:1:1 to active E2/P4 doses only. Three of the 29 items in the MENQOL questionnaire assess vasomotor symptoms: hot flushes, night sweats, and sweating. The symptoms, if experienced, were rated using a 7-item Likert scale ranging from “Not at all bothered” (score of 2) to “Extremely bothered” (score of 8); if not experienced, the score was 1. Changes from baseline to week 12, and months 6 and 12 in these 3 items were assessed in the overall efficacy population (MITT) and VMS (MITT-VMS) substudy population. Women were randomized to daily doses of E2/P4 (mg/mg) 1/100 (n=415), 0.5/100 (n=424), 0.5/50 (n=421), 0.25/50 (n=424) or placebo (n=151). Participants (mean age of 55 years and mean BMI of 27 kg/m2) were primarily white (65%) or black (32%). Mean baseline scores ranged from 6.7 to 7.4 for hot flushes, 6.1 to 7.1 for night sweats, and 6.0 to 6.9 for sweating. In the MITT population, women treated with all E2/P4 doses had significantly more favorable improvements from baseline in their hot flushes (range of significant mean changes with E2/P4 vs placebo, -2.9 to -4.3 vs -1.9 to -2.7), night sweats (-3.1 to -4.0 vs -2.4 to -3.0) and sweating (-2.8 to -3.6 vs -2.3 to -3.2) scores at week 12, and months 6 and 12 (all, P≤0.002). Similarly, significant improvements from baseline with E2/P4 vs placebo (all, P≤0.030) were observed in the MITT-VMS substudy population for hot flushes (-3.0 to -4.4 vs -1.9 to -2.7), night sweats (-3.3 to -4.4 vs -2.4 to -3.0), and sweating (-3.1 to -4.2 vs -2.3 to -3.2), except for those treated with the lowest E2/P4 dose (0.25 mg E2/50 mg P4) at months 6 and 12 for sweating. In the REPLENISH trial, compared with placebo, postmenopausal women treated with E2/P4 had significant improvements in their hot flushes, night sweats and sweating as assessed by MENQOL. Benefits continued for up to 12 months of treatment. These results with this first oral hormone therapy formulation combining bioidentical estradiol and progesterone in a single capsule are consistent with the primary REPLENISH results demonstrating efficacy for the treatment of moderate to severe vasomotor symptoms in menopausal women with a uterus.

Project description:ObjectivesTo compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology and total cancer incidence among healthy postmenopausal women.Study designThis study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17-beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo.Main outcome measuresParticipants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence.ResultsOver up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated.ConclusionOur results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women. ClinicalTrials.gov registration NCT00114517.

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SAT-237 Combined Bioidentical Estradiol and Progesterone Capsules Improved Quality of Sleep in Postmenopausal Women with Vasomotor Symptoms

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