Oral 17?-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms.
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SUBMITTER: Simon JA
PROVIDER: S-EPMC6493699 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Oral 17β-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms.
Simon James A JA Kaunitz Andrew M AM Kroll Robin R Graham Shelli S Bernick Brian B Mirkin Sebastian S
Menopause (New York, N.Y.) 20190501 5
<h4>Objective</h4>The aim of the study was to describe the effects of TX-001HR (17β-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).<h4>Methods</h4>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 flushe ...[more]
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Project description:ObjectiveThe 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.MethodsIn 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.ResultsWomen (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.ConclusionTX-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.
| S-EPMC6553506 | biostudies-literature
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.
| S-EPMC7147409 | biostudies-literature
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.
| S-EPMC6551826 | biostudies-literature
Project description:ObjectiveTo examine responder rates and vasomotor symptom-free days with oral 17β-estradiol/progesterone (E2/P4; TX-001HR) versus placebo in the REPLENISH trial.MethodsREPLENISH (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.ResultsSeven 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 < 0.05) and also had significantly more days per week without moderate to severe VMS at week 12 (1.9-3.0 d for E2/P4 versus 1.3 d for placebo; P < 0.05). The proportion of women without severe hot flushes at week 12 was 43% to 56% for all E2/P4 doses versus 26% for placebo (P ≤ 0.01).ConclusionsWomen 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.
| S-EPMC7709918 | biostudies-literature
Project description:ObjectiveThe aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus.MethodsIn the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (≥7/d or ≥50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17β-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods.ResultsIn the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression-based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥25 moderate to severe VMS: 82-88% vs 69%; all, P < 0.05) and CID (weekly reduction of ≥39 VMS: 68%-73% vs 52%; all, P < 0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life-based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥34 VMS: 74%-81% vs 55%; all, P < 0.01) and CID (weekly reduction of ≥44 VMS: 61%-69% vs 42%; all, P < 0.01) at week 12.ConclusionsTX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.
| S-EPMC6493698 | biostudies-literature
Project description:OBJECTIVE:In the REPLENISH trial, women receiving TX-001HR-an oral, softgel capsule, combining 17β-estradiol (E2) and progesterone (E2 mg/P4 mg 1/100, 0.5/100), had significantly improved vasomotor symptoms, while having their endometrium protected from hyperplasia. The objective here was to describe P4 levels sufficient to counteract the potential endometrial effects of 1 or 0.5 mg oral E2 with TX-001HR. METHODS:In REPLENISH (phase 3; NCT01942668), serum P4, E2, and estrone (E1) levels were characterized in postmenopausal women treated with TX-001HR (E2 mg/P4 mg: 1/100, 0.5/100, [0.5/50, 0.25/50 and placebo not reported here]) at baseline, week 12, and month 12 for P4, and at baseline, weeks 4 and 12, and months 6, 9, and 12 for E2 and E1. In a phase 1 study, pharmacokinetic parameters were assessed after 7 daily doses of oral E2 mg/P4 mg (1/100 and 0.5/100). RESULTS:In REPLENISH (n = 1,835), mean P4 levels were 0.39 to 0.55 ng/mL with 100-mg P4 doses; E2 levels were 42.3 to 45.6 pg/mL and 23.0 to 27.4 pg/mL for the 1-mg and 0.5-mg E2 doses, respectively; E1 levels were 214 to 242 pg/mL and 114 to 129 pg/mL for the 1-mg and 0.5-mg E2 doses. In the phase 1 study (n = 40; day 7), mean Cavg for P4 was 0.66 ng/mL with 100-mg P4 doses; E2 was 38.1 pg/mL and 29.2 pg/mL for 1 mg and 0.5 mg E2, respectively; and E1 was 211 and 106 pg/mL for 1 mg and 0.5 mg E2. All three analytes reached steady state within 7 days; accumulation ratios were 1.36 to 1.94. CONCLUSIONS:P4 levels observed with TX-001HR were similar in the phase 1 and 3 studies, and were associated with no endometrial hyperplasia with either E2 daily dose over 1 year in the REPLENISH phase 3 study, which showed significant improvements in menopausal vasomotor symptoms.
| S-EPMC6636803 | biostudies-literature
Project description:ObjectiveTo characterize the impact of TX-001HR on the relationship between vasomotor symptom (VMS) improvement and quality of life and sleep.MethodsREPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, which evaluated four daily doses of 17β-estradiol and progesterone (E2/P4) combined in a single, oral, softgel capsule in postmenopausal women (40-65 years) with a uterus and moderate to severe VMS (≥7/day or ≥50/week). In post hoc analyses, growth models were used to examine relationships between linear changes in VMS frequency and severity over 12 weeks and changes from baseline in the Menopause-Specific Quality of Life (MENQOL; total score and VMS domain) and the Medical Outcomes Study-Sleep (total score, sleep problems indices I and II) questionnaire outcomes at 12 weeks with treatment compared with placebo.ResultsOutcomes with all four E2/P4 doses were combined (n = 591) and compared with placebo (n = 135). In all 5 growth models, the effects of TX-001HR on MENQOL total score and vasomotor domain were significantly associated with changes in VMS frequency and severity observed over 12 weeks (all, P < 0.001). Treatment-mediated effects on MENQOL via VMS frequency and severity models were significant. Similar results were found with Medical Outcomes Study-Sleep total score and sleep problems indices.ConclusionsTX-001HR improvements in quality of life and sleep outcomes are associated with and may be mediated through improvements in VMS frequency and severity.
| S-EPMC6553507 | biostudies-literature
Project description:Abstract Difficulty sleeping is a common complaint of postmenopausal women. In the REPLENISH trial, the oral 17β-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.
| S-EPMC6551953 | biostudies-literature
Project description:OBJECTIVE:The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17?-estradiol [E2]/progesterone [P4]) capsules on hot flushes severity (vasomotor symptoms [VMS] severity scale) using the patient-reported Clinical Global Impression (CGI). METHODS:REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR in postmenopausal women (40-65 y) with a uterus. Those with frequent moderate to severe hot flushes (?7/d or ?50/wk) were randomized in a VMS substudy to daily E2/P4 (1/100, 0.5/100, 0.5/50, or 0.25/50?mg/mg), or placebo. Patients rated VMS severity from 1 (mild) to 3 (severe) and symptom improvements with the CGI. CGI results were an anchor in a nonparametric discriminant analysis to define clinically important differences (CIDs) and minimal CID in VMS severity at weeks 4 and 12. RESULTS:In the VMS substudy (n?=?726), determined CID and minimal CID severity thresholds were reductions of 0.525 and 0.350 points at week 4, respectively, and 0.775 and 0.225 points at week 12. Significantly more women taking the two highest E2/P4 doses (1/100 and 0.5/100) versus placebo met CID severity thresholds at weeks 4 (40% and 44% vs 17%; P?<?0.05) and 12 (56% and 48% vs 29%; P?<?0.05). CONCLUSION:REPLENISH trial data demonstrated that E2/P4 1/100 and 0.5/100 provided clinically meaningful improvements in hot flushes severity in postmenopausal women. In conjunction with previously demonstrated clinically meaningful VMS frequency improvements, these data support oral E2/P4 1/100 and 0.5/100 for postmenopausal women with a uterus seeking treatment for moderate to severe VMS.
| S-EPMC7587237 | biostudies-literature
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.
| S-EPMC8571490 | biostudies-literature