17β-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 17β-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 < 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).

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.

Conflict of interest statement

Financial disclosure/conflicts of interest: Dr. Kaunitz has served as a consultant to or on the advisory board of AMAG, Mithra and Pfizer and has received research support (to University of FL) from Allergan, Bayer Healthcare, and TherapeuticsMD. Dr. Bitner is on the speaker's bureau of TherapeuticsMD. Dr. Constantine consults to multiple pharmaceutical companies including but not limited to TherapeuticsMD, and has stock options from TherapeuticsMD. Dr. Bernick, Dr. Graham and Dr. Mirkin are employees of TherapeuticsMD with stock/stock options.

Figures

FIG. 1

Disposition of participants in the modified intent-to-treat-vasomotor symptoms efficacy study. E2, 17β-estradiol; MITT, modified intent-to-treat; P4, progesterone, VMS, vasomotor symptoms.

FIG. 2

Treatment response rates (A) 50% and (B) 75% at weeks 4 and 12. Response rates were defined as the proportion of women with ≥50% and ≥75% reductions in frequency of moderate to severe vasomotor symptoms by treatment. aP < 0.05; bP < 0.01;cP ≤ 0.001 versus placebo (Fischer exact test). E2, 17β-estradiol; P4, progesterone.

FIG. 3

Number of days per week free of moderate to severe vasomotor symptoms up to week 12 by E2P4 dose versus placebo. P < 0.05 from aweeks 3-12; bweeks 4-12; cweeks 6-12 versus placebo (Fischer exact test). E2, 17β-estradiol; P4, progesterone.

FIG. 4

Proportion of women with no severe vasomotor symptoms at weeks 4 and 12 by treatment. Severe VMS was defined as sensation of heat with sweating that requires cessation of activity. aP ≤ 0.01; bP < 0.001 versus placebo (Fisher exact test). E2, 17β-estradiol; P4, progesterone; VMS, vasomotor symptoms.