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Initial investigation into the optimal dose ratio of conjugated estrogens and bazedoxifene

a double-blind, randomized, placebo-controlled phase 2 dose-finding study

Pickar, James H. MD1; Lavenberg, Joanne BS2; Pan, Kaijie MS2; Komm, Barry S. PhD2

doi: 10.1097/GME.0000000000000992
Original Articles

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.

1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY

2Pfizer Inc, Collegeville, PA.

Address correspondence to: James H. Pickar, MD, P.O. Box 415, Bulger, PA 15019. E-mail:

Received 31 May, 2017

Revised 30 August, 2017

Accepted 30 August, 2017

Funding/support: The study was sponsored by Wyeth Research, which was acquired by Pfizer in October 2009. Medical writing support was provided by Lauren Cerruto and Diane M. Sloan, PharmD, at Peloton Advantage and was funded by Pfizer Inc.

Financial disclosure/conflicts of interest: JHP has received consultant fees from Wyeth/Pfizer, Shionogi Inc., Radius Health, and Therapeutics MD and has stock options in TherapeuticsMD. JL and KP are employees and shareholders of Pfizer. BSK is a former employee of Pfizer.

This study was conducted June 8, 1999, to April 26, 2000, before trial registration was required; it was not registered on

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© 2018 by The North American Menopause Society.