Initial investigation into the optimal dose ratio of conjugated estrogens and bazedoxifene: a double-blind, randomized, placebo-controlled phase 2 dose-finding study

Objective: The aim of the study was to explore dose-related endometrial effects of conjugated estrogens/bazedoxifene (CE/BZA). Methods: In this randomized, double-blind, phase 2 study, 408 nonhysterectomized, symptomatic (with hot flushes [HFs]) postmenopausal women received >= 1 dose of CE 0.3 or 0.625 mg alone or with BZA 5, 10, or 20 mg/d; placebo; BZA 5 mg/d alone; or CE 0.625 mg with medroxyprogesterone acetate 2.5 mg/d for 84 days. The primary outcome was endometrial thickness on transvaginal ultrasound. HF frequency and severity based on diaries were key secondary outcomes. Results: CE 0.625 mg alone increased endometrial thickness compared with placebo (mean 5.5 vs 2.95 mm, P < 0.001); BZA countered this in a dose-related manner such that average thickness with the addition of BZA 5, 10, and 20 mg was 5.99, 4.33, and 3.54 mm, respectively. On average, endometrium was significantly less thick with CE 0.625 mg/BZA 20 mg than CE 0.625 mg (P < 0.001) and CE 0.3 mg/BZA 20 mg versus CE 0.3 mg (2.94 vs 3.92 mm, P < 0.05); endometrial thickness was similar to placebo with CE 0.625 mg/BZA 20 mg. Lower BZA doses failed to reduce endometrial thickness relative to the same dose of CE alone. Regimens containing CE 0.625 mg reduced HF frequency and severity versus placebo; CE 0.3 mg with BZA 10 or 20 mg was ineffective. Conclusions: BZA >= 20 mg is needed to counter endometrial growth resulting from treatment with CE 0.3 or 0.625 mg. CE 0.3 mg inadequately controls HFs if given with BZA 20 mg.