To evaluate efficacy, endometrial safety, and overall safety of a single-capsule 17β-estradiol–progesterone (TX-001HR) for treating menopausal moderate-to-severe vasomotor symptoms.
REPLENISH was a phase 3, 12-month, randomized, double-blind, placebo-controlled, multicenter trial. Women (aged 40–65 years) with vasomotor symptoms and a uterus were randomized to daily estradiol (mg)–progesterone (mg) (1/100, 0.5/100, 0.5/50, or 0.25/50), and women in the vasomotor symptoms substudy (women with moderate-to-severe hot flushes [seven or greater per day or 50 or greater per week]) to those estradiol–progesterone doses or placebo. The primary safety endpoint was endometrial hyperplasia incidence at 12 months in all women (the total population), and the primary efficacy endpoints were frequency and severity changes (from daily diaries) in moderate-to-severe vasomotor symptoms with estradiol–progesterone compared with placebo at weeks 4 and 12 in the vasomotor symptoms substudy. A sample size of 250 women in each active treatment arm with two or less endometrial hyperplasia cases would result in 1% or less annual incidence (upper bound 2.5% or less, one-sided 95% CI).
One thousand eight hundred forty-five women were enrolled and randomized from August 2013 to October 2015; 1,835 received medication (safety population); 1,255 were eligible for the endometrial safety population; 726 comprised the vasomotor symptoms substudy; their mean age and body mass index were 55 years and 27, respectively; one third were African American. No endometrial hyperplasia was found. Frequency and severity of vasomotor symptoms significantly decreased from baseline with 1 mg estradiol and 100 mg progesterone and 0.5 mg estradiol and 100 mg progesterone compared with placebo at week 4 (frequency: by 40.6 and 35.1 points [1 mg and 100 mg and 0.5 mg and 100 mg, respectively] vs 26.4 points [placebo]; severity: by 0.48 and 0.51 vs 0.34 points) and week 12 (by 55.1 and 53.7 vs 40.2; severity: by 1.12 and 0.90 vs 0.56); 0.5 mg estradiol and 50 mg progesterone improved (P<.05) frequency and severity at week 12, and 0.25 mg estradiol and 50 mg progesterone frequency but not severity at weeks 4 and 12.
No endometrial hyperplasia was observed while single-capsule estradiol–progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol–progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy.
Columbia University Medical Center, New York, New York; the Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia; the University of California, San Francisco, San Francisco, and Sutter East Bay Medical Foundation, Berkeley, California; the University of Florida College of Medicine-Jacksonville, Jacksonville, Florida; EndoRheum Consultants, LLC, Malvern, Pennsylvania; and TherapeuticsMD, Boca Raton, Florida.
Corresponding author: Rogerio A. Lobo, MD, Columbia University Medical Center, 622 W 168th Street, 16th Floor, New York, NY 10032; email: email@example.com.
TherapeuticsMD sponsored the study; was involved in the design, execution, analysis, and reporting of the study; and funded the medical writing support provided by Kathleen Ohleth, PhD, of Precise Publications, LLC.
Financial Disclosure Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant (in the last 3 years) to Allergan, AMAG, JDS Therapeutics, Mithra, Pfizer, Teva, and TherapeuticsMD. Dr. Archer (within the past 3 years) has received research support from Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Bayer Healthcare, Endoceutics, Glenmark, Merck (previously Schering Plough, Organon), Radius Health Inc, Shionogi Inc, and TherapeuticsMD; and has served as a consultant to AbbVie (previously Abbott Laboratories), Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Agile Therapeutics, Bayer Healthcare, Endoceutics, Exeltis (previously CHEMO), InnovaGyn, Merck (previously Schering Plough, Organon), Pfizer, Radius Health Inc, Sermonix Pharmaceuticals, Shionogi Inc, Teva, and TherapeuticsMD. Dr. Kagan (past 3 years) has received research grants and support from TherapeuticsMD (paid to Sutter Health) and has served as a consultant to Amgen, Noven, Novo Nordisk, Pfizer, Shionogi Inc, Sprout, JDS Therapeutics, Valeant, Merck, Palatin, AMAG, Allergan, Juniper, Azure, and Heptares. Dr. Kaunitz serves on Advisory Boards or consults for Allergan, AMAG, Bayer Healthcare, Mithra, Pfizer, Sebela, and Shionogi Inc; receives royalties from UpToDate; and the University of Florida College of Medicine–Jacksonville receives research funding from Allergan, Bayer Healthcare, Endoceutics, Millendo, Radius Health Inc, and TherapeuticsMD. Dr. Constantine consults to pharmaceutical companies, including but not limited to TherapeuticsMD, and has stock options with TherapeuticsMD. Dr. Pickar has received consultant fees from Pfizer, Shionogi Inc, and TherapeuticsMD; and has stock options with TherapeuticsMD. Dr. Bernick is a board member and an employee of TherapeuticsMD with stock and stock options. Drs. Graham and Mirkin are employees of TherapeuticsMD with stock and stock options.
Presented at the Endocrine Society's 99th annual meeting, April 1–4, 2017, Orlando, FL; the American College of Obstetricians and Gynecologists' Annual Clinical and Scientific Meeting, May 6–9, 2017, San Diego, CA; the 11th European Congress on Menopause and Andropause, May 22–24, 2017, Amsterdam, the Netherlands; and the North American Menopause Society annual meeting, October 11–14, 2017, Philadelphia, PA.
The authors thank all of the investigators of the REPLENISH study (Appendix 1, available online at http://links.lww.com/AOG/B98), as well as Chao Wang, PhD, of Pharma Data Associates, LLC for statistical analyses and Kathleen Ohleth, PhD, CMPP, of Precise Publications, LLC for manuscript writing assistance, both supported by TherapeuticsMD.
Each author has indicated that he or she has met the journal's requirements for authorship.
Received December 21, 2017. Received in revised form February 14, 2018. Accepted March 15, 2018.