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Improvement in sleep outcomes with a 17?-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women.

ABSTRACT: OBJECTIVE:The aim of the study was to evaluate the effects of TX-001HR, a single-capsule 17?-estradiol-progesterone on sleep parameters in postmenopausal women with vasomotor symptoms (VMS) using the Medical Outcomes Study (MOS)-Sleep scale questionnaire in the REPLENISH trial. METHODS:In the REPLENISH trial (NCT01942668), women were randomized to one of four doses of TX-001HR or placebo, and the 12-item MOS-Sleep questionnaire (secondary endpoint) was self-administered at baseline, week 12, and months 6 and 12. Changes from baseline in the MOS-Sleep total score and 7 subscale scores were analyzed for treatment groups versus placebo at all time points. Somnolence was also collected as an adverse event. RESULTS:Women (mean age 55 y) were randomized to TX-001HR (estradiol/ progesterone [E2/P4] [mg/mg]) doses: 1/100 (n?=?415), 0.5/100 (n?=?424), 0.5/50 (n?=?421), 0.25/50 (n?=?424), or placebo (n?=?151). TX-001HR significantly improved MOS-Sleep total score, Sleep Problems Index II subscale, and sleep disturbance subscale versus placebo at all time points, except with 0.25?mg E2/50?mg P4 at week 12. Differences in LS mean changes between TX-001HR and placebo for MOS-Sleep total scores ranged from -6.5 to -7.6 at 12 months (all; P ? 0.001). All doses of TX-001HR significantly improved the Sleep Problems Index I subscale at all time points. The sleep somnolence subscale significantly improved from baseline with 0.5?mg E2/100?mg P4 and 0.5?mg E2/50?mg P4 at month 12. The incidence of somnolence as a treatment-emergent adverse event ranged from 0.2% to 1.2% versus 0% with placebo. CONCLUSION:TX-001HR significantly improved MOS-Sleep parameters from baseline to week 12, which was sustained for up to 12 months, and was associated with a very low incidence of somnolence.

SUBMITTER: Kagan R

PROVIDER: S-EPMC6553506 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women.

Kagan Risa R Constantine Ginger G Kaunitz Andrew M AM Bernick Brian B Mirkin Sebastian S

Menopause (New York, N.Y.) 20181201 6

<h4>Objective</h4>The aim of the study was to evaluate the effects of TX-001HR, a single-capsule 17β-estradiol-progesterone on sleep parameters in postmenopausal women with vasomotor symptoms (VMS) using the Medical Outcomes Study (MOS)-Sleep scale questionnaire in the REPLENISH trial.<h4>Methods</h4>In the REPLENISH trial (NCT01942668), women were randomized to one of four doses of TX-001HR or placebo, and the 12-item MOS-Sleep questionnaire (secondary endpoint) was self-administered at baselin ...[more]

PMID: 30586005

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Project description:ObjectiveThe aim of the study was to evaluate the effect of a single-capsule 17β-estradiol/progesterone (E2/P4), TX-001HR, on endometrial safety, to report on amenorrhea and bleeding patterns of users, and to identify predictors of amenorrhea.MethodsThe REPLENISH trial (NCT01942668) evaluated use of TX-001HR in menopausal women (40-65 y) with vasomotor symptoms (VMS) and a uterus. Women were randomized to daily E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, or 0.25/50), or placebo for 12 months. Incidence rate of endometrial hyperplasia was calculated from endometrial biopsies conducted at screening and study completion. Women reported bleeding and spotting in daily diaries. The number of bleeding and/or spotting days and the proportion of women with no bleeding or amenorrhea were compared between treatment and placebo using the Fisher exact test. Predictors of cumulative amenorrhea were assessed by univariate analyses.ResultsWomen (n = 1,835) who took at least one study dose comprised the safety population; 1,255 had baseline and 12-month biopsies and comprised the endometrial safety population. Incidence of endometrial hyperplasia was ≤0.36% with any dose of TX-001HR after 1 year of use (one-sided upper 95% confidence interval ≤4%). Cumulative amenorrhea (no bleeding/spotting) rates increased over time and were relatively high from cycle 1 to 13 with TX-001HR (56%-73%; placebo 79%; P < 0.05 except with 0.25/50 dose). Few vaginal bleeding adverse events (1.0%-4.6% TX-001HR vs 0.7% placebo) were reported and discontinuations due to bleeding were low (0.4%-1.4% vs 0%). Cumulative amenorrhea was significantly more frequent in older women, those further from their last menstrual period, and those with lower baseline E2 concentrations (all; P < 0.01).ConclusionsAll doses of TX-001HR provided endometrial protection and were associated with an improved bleeding profile over time; older age, further last menstrual period, or lower baseline E2 may predict amenorrhea with TX-001HR.

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: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.

Dataset Information

Improvement in sleep outcomes with a 17?-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women.

Publications

Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women.

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