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17?-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

ABSTRACT: Objective: To examine responder rates and vasomotor symptom-free days with oral 17?-estradiol/progesterone (E2/P4; TX-001HR) versus placebo in the REPLENISH trial.

Methods: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluating single, oral, softgel E2/P4 capsules in postmenopausal women (40-65 y) with a uterus and vasomotor symptoms (VMS). Women with moderate to severe hot flushes (?7/d or ?50/wk) were randomized (VMS substudy) to daily E2/P4?(mg/mg) of 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo. Proportions of women with ?50% or ?75% reductions in moderate to severe VMS (responders), and those with no severe VMS as well as the weekly number of days without moderate to severe VMS with TX-001HR versus placebo were determined. Mixed model repeated measures was used to analyze data and Fisher exact test was employed to compare E2/P4 versus placebo.

Results: Seven hundred twenty-six women were eligible for the VMS efficacy analysis (E2/P4?1/100 [n?=?141], 0.5/100 [n?=?149], 0.5/50 [n?=?147], 0.25/50 [n?=?154], or placebo [n?=?135]). Significantly more women treated with all E2/P4 doses versus placebo were ?50% responders and ?75% responders at weeks 4 and 12 (P?
Conclusions: Women treated with E2/P4 had a greater response to treatment with more VMS-free days than with placebo. The E2/P4?1/100 dose (Bijuva [E2 and P4] capsules) represents an oral treatment option for postmenopausal women with moderate to severe VMS and a uterus.

SUBMITTER: Kaunitz AM

PROVIDER: S-EPMC7709918 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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17β-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

Kaunitz Andrew M AM Bitner Diana D Constantine Ginger D GD Bernick Brian B Graham Shelli S Mirkin Sebastian S

Menopause (New York, N.Y.) 20201201 12

<h4>Objective</h4>To examine responder rates and vasomotor symptom-free days with oral 17β-estradiol/progesterone (E2/P4; TX-001HR) versus placebo in the REPLENISH trial.<h4>Methods</h4>REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluating single, oral, softgel E2/P4 capsules in postmenopausal women (40-65 y) with a uterus and vasomotor symptoms (VMS). Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized (VMS subs ...[more]

PMID: 32740481

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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:Abstract Smoking has previously been reported to result in decreases in estradiol exogenous metabolism1,2,3 and may influence the efficacy of hormone therapy (HT) in postmenopausal women2,3. Importantly, differences in smoking rates among clinical trial populations may also contribute to differences in effects of HT observed across the trials.2 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated 4 doses of TX-001HR (17β-estradiol and progesterone [E2/P4]; 1/100, 0.5/100, 0.5/50, 0.25/50) combined in a single, oral softgel capsule vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). The 1 mg E2/100 mg P4 dose is FDA approved as BIJUVATM (TherapeuticsMD, Boca Raton, FL). In this trial, statistically significant improvements in the frequency and severity of moderate to severe VMS were observed for the two highest doses of TX-001HR (1/100 and 0.5/100) and is reported in detail elsewhere.4 The objective of this analysis was to assess the impact of smoking on estradiol metabolism by analyzing estradiol and estrone concentrations measured throughout the study and to assess the potential impact on efficacy. The overall percentage of current smokers was higher in the Replenish trial (26%) than in many other trials of HT, making analysis of the impact of smoking on estrogen levels and efficacy possible. Estradiol and estrone concentrations at baseline were similar between current smokers and nonsmokers (former/never smokers) for all treatment groups (active and placebo). However, at Weeks 4 and 12, Months 6, 9, and 12, estradiol (25%-32%) and estrone (30%-36%) concentrations were statistically significantly lower in smokers than in nonsmokers for all active estradiol/progesterone treatment groups (1/100, 0.5/100, 0.5/50, 0.25/50). There were no significant differences at any time point in the placebo group. Efficacy in reducing the frequency and severity of VMS was greater in nonsmokers. When evaluating nonsmokers, the 0.25/50 dose also demonstrated statistically significant improvements at Weeks 4 and 12, with a weekly reduction of greater than 14 hot flushes compared to placebo beginning at Week 4 and sustained through week 12. Results from this large Phase 3 clinical trial demonstrated a significant impact of current smoking on estradiol and estrone concentrations and indicate that non-smokers may benefit from lower doses of estradiol and progesterone than smokers. 1. Jensen J, et al. NEJM. 1985;313(16):973-975. 2.Tansavatdi B, et al. Minerva Ginecol. 2004;56:105-114. 3. Ruan X and Mueck AO. Climacteric. 2015;18:38-46. 4. Lobo RA, et al. Obstet Gynecol. 2018;132:161-170. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dataset Information

17?-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

Publications

17β-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

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