REPLENISH Trial: Combination Capsule of Estradiol/Progesterone (TX-001HR) for Treating Hot Flushes [5M

Abstract

INTRODUCTION: Many FDA-approved hormone therapies (HTs) combining estrogens and progestins are currently available in the US for treating menopausal symptoms. The use of FDA-approved HT has recently declined, while that of custom-compounded hormone therapy (CHT) with estradiol and progesterone has increased. Current reports suggest that up to 3 million women 40 years and older are using CHT (30 million prescriptions/year). Compounded BHT may be associated with endometrial cancer. No single product combining natural 17β-estradiol and progesterone has been approved yet by the FDA. METHODS: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial (∼100 US sites) that evaluated the safety and efficacy of TX-001HR (a 17β-estradiol‒natural progesterone combination capsule) for treating moderate to severe hot flushes in postmenopausal women with an intact uterus. Of the total 1,847 women enrolled, 767 were randomly assigned to one of four TX-001HR daily doses (estradiol 1.0 mg/progesterone 100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg) or placebo for 12 months (vasomotor symptom substudy); the remaining 1,080 women were randomly assigned between the active treatments. The four co-primary efficacy endpoints were the mean change from baseline to weeks 4 and 12 in frequency and severity of moderate to severe vasomotor symptoms for active treatments vs placebo. The primary safety endpoint was the incidence of endometrial hyperplasia at 12 months. RESULTS: TX-001HR 1.0 mg/100 mg or 0.5 mg/100 mg met all 4 co-primary endpoints, with significant improvements from baseline in frequency and severity of moderate to severe hot flushes at weeks 4 (all, P< 0.05) and 12 (all, P< 0.001) compared with placebo. Women treated with TX-001HR 0.5 mg/50 mg had significant improvements in hot flush frequency and severity at week 12 (both, P< 0.05) vs placebo, while those taking 0.25 mg/50 mg had significant improvements in frequency, but not in severity, at weeks 4 and 12 (both, P≤ 0.001). The incidence of endometrial hyperplasia or malignancy was 0% (by consensus read) with all four TX-001HR doses and placebo after 12 months of therapy. A high incidence of amenorrhea was achieved with all TX-001HR doses. CONCLUSION: TX-001HR 1.0 mg/100 mg or 0.5 mg/100 mg effectively treated menopause-related moderate to severe hot flushes and had a safe endometrial safety profile. If approved, TX-001HR – the first combination HT product containing naturally occurring 17β-estradiol and progesterone – may provide an alternative option for the estimated 3 million of women currently using unregulated, unapproved, compounded bio-identical in the US.