A Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms

NCT ID: NCT01942668

Last Updated: 2019-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1845 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-05
• Study Completion Date: 2016-10-28

Brief Summary

This study will be a prospective, randomized, double-blind, placebo-controlled, parallel group, multicenter trial of postmenopausal subjects with an intact uterus.

Detailed Description

Postmenopausal subjects with an intact uterus who meet the study entry criteria will be randomized to one of five treatment arms (four active and one placebo) and followed for 12 months. During the Screening period all subjects will be provided with a diary to self-assess the frequency and severity of their vasomotor symptoms. Subjects experiencing a minimum daily frequency of ≥7 (or ≥50 per week) moderate to severe hot flushes will participate in a VMS Substudy during the first 12 weeks of treatment. The Substudy subjects will be stratified by treatment arm within the sites, and only Substudy subjects have the possibility of being randomized to placebo. Subjects who qualify for the study except for experiencing a minimum daily frequency of ≥7 (or ≥50 per week) moderate to severe hot flushes will be stratified within sites to one of the four active treatment arms and followed for 12 months, but will not participate in the VMS Substudy. (However, VMS information will be collected from all subjects during the first 12 weeks of treatment.) All Study Subjects: Postmenopausal women with an intact uterus who seek relief from hot flushes and meet all other inclusion/exclusion criteria are eligible for 12 months of study treatment.

VMS Substudy Subjects: A subset of All Study Subjects who have ≥7 per day or ≥50 per week moderate to severe hot flushes (as determined during Screening) are eligible for the 12-week VMS Substudy and for a total of 12 months of study treatment.

Clinical evaluations will be performed at the following time points:

• Screening Period (Week: - 8.5) (up to -60 Days)
• Visit 1 Randomization (Week 0) (Day 1)
• Visit 2 Interim (Week 4)
• Visit 3 Interim (Week 8)
• Visit 4 Interim (Week 12)
• Visit 5 Interim (Month 6)
• Visit 6 Interim (Month 9)
• Visit 7 End of Treatment (Month 12)

Conditions

Menopause

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Treatment 1

Combined Estradiol 1 mg / Progesterone 100 mg softgel capsule formulation and placebo taken orally once a day for twelve months.

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Progesterone

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Treatment 2

Combined Estradiol 0.5 mg / Progesterone 100 mg softgel capsule formulation and placebo taken orally once a day for twelve months.

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Progesterone

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Treatment 3

Combined Estradiol 0.5 mg / Progesterone 50 mg softgel capsule formulation and placebo, taken orally once a day for twelve months.

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Progesterone

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Treatment 4

Combined Estradiol 0.25 mg / Progesterone 50 mg softgel capsule formulation and placebo, taken orally once a day for twelve months.

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Progesterone

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Placebo

Two Placebo softgel capsules taken orally once a day for twelve months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Estradiol

Intervention Type: DRUG

Progesterone

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

17B-estradiol; Estrace; Prometrium

Eligibility Criteria

Inclusion Criteria

1. Be a female between the ages of 40 and 65 years (at the time of randomization) who is willing to participate in the study, as documented by signing the informed consent form.

2. Be a postmenopausal woman with an intact uterus and a Screening serum estradiol level of ≤50 pg/mL. Postmenopausal is defined herein as:

1. ≥ 12 months of spontaneous amenorrhea, or

2. at least 6 months of spontaneous amenorrhea with a Screening serum FSH level of >40 mIU/ml, or

3. ≥ 6 weeks postsurgical bilateral oophorectomy.

3. Be seeking treatment or relief for vasomotor symptoms associated with menopause.

4. To participate in the VMS Substudy, a subject must also report ≥7 moderate to severe hot flushes per day, or ≥50 per week, at the baseline assessment during Screening (subjects whose hot flushes are less frequent may still participate as non-Substudy subjects.

Note: A minimum of 14 consecutive days of complete hot flush diary data are required during the baseline assessment at Screening, and these consecutive days must occur within the last 14 days prior to the Randomization visit (not counting the Randomization visit day itself). The most recent 7 consecutive days of data prior to randomization (Day -7 to Day -1) will be used to determine the baseline number of mild, moderate and severe hot flushes for each subject.

5. Have a Body Mass Index (BMI) less than or equal to 34 kg/mP2P. (BMI values should be rounded to the nearest integer [e.g., 34.4 rounds down to 34, while 26.5 rounds up to 27]).

6. Be willing to abstain from using products (other than study medication) that contain estrogen, progestin, or progesterone throughout study participation.

7. Be judged by the principal or sub-investigator physician as being in otherwise generally good health based on a medical evaluation performed during the Screening period prior to the initial dose of study medication. The medical evaluation findings must include:

1. a normal or non-clinically significant physical examination, including vital signs (sitting blood pressure, heart rate, respiratory rate and temperature). Sitting systolic blood pressure is ≤140 mmHg and diastolic blood pressure ≤90 mmHg at Screening. A subject may be taking up to two antihypertensive medications.

2. a normal or non-clinically significant pelvic examination.

3. a mammogram that shows no sign of significant disease (can be performed within previous 6 months prior to initial dose of study medication). Subjects must have a BI-RADS 1 or 2 to enroll in the study. An incomplete mammogram result, i.e. BI-RADS 0, is not acceptable. The site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment.

4. a normal or non-clinically significant clinical breast examination. An acceptable breast examination is defined as no masses or other findings identified that are suspicious of malignancy.

5. a normal Screening Papanicolaou ("Pap") smear. (Subjects with findings of atypical glandular cells [AGC], AGUS, ASCUS with high risk HPV type upon reflex testing, LSIL, ASC-H, HSIL, dysplastic cells, or malignant cells must be excluded from randomization.)

6. an acceptable result from an evaluable Screening endometrial biopsy. The endometrial biopsy reports by the two central pathologists at Screening must each specify one of the following: proliferative endometrium; weakly proliferative endometrium; disordered proliferative pattern; secretory endometrium; endometrial tissue other (including benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc); endometrial tissue insufficient for diagnosis; no endometrium identified; or no tissue identified. However, at least one pathologist must identify sufficient tissue to evaluate the biopsy. Additionally, the endometrial biopsy reports by the two central pathologists of Other Findings at Screening must each specify one of the following: endometrial polyp not present; benign endometrial polyp; or polyp other. (See Exclusion criterion #27)

7. a normal or non-clinically significant 12-lead ECG.

Exclusion Criteria

• To participate in the study, a subject must NOT:

1. Be currently hospitalized.

2. Have a history of thrombosis of deep veins or arteries or a thromboembolic disorder.

3. Have a history of coronary artery or cerebrovascular disease (e.g., myocardial infarction, angina, stroke, TIA).

4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure).

5. Have a history of a malabsorption disorder (e.g., gastric bypass, Crohn's disease).

6. Have a history of gallbladder dysfunction/disorders (e.g., cholangitis, cholecystitis), unless gallbladder has been removed.

7. Have a history of diabetes, thyroid disease or any other endocrinological disease. (Subjects with diet-controlled diabetes or controlled hypothyroid disease at Screening are not excluded.)

8. Have a history of estrogen-dependent neoplasia.

9. Have a history of atypical ductal hyperplasia of the breast.

10. Have a finding of clinically significant uterine fibroids at Screening.

11. Have had a uterine ablation.

12. Have a history of undiagnosed vaginal bleeding.

13. Have any history of endometrial hyperplasia, melanoma, or uterine/endometrial, breast or ovarian cancer.

14. Have any history of other malignancy within the last 5 years, with the exception of basal cell (excluded if within 1 year) or non-invasive squamous cell (excluded if within 1 year) carcinoma of the skin.

15. Have a history of any other cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychological (e.g., bipolar disorder, schizophrenia, major depressive disorder), or musculoskeletal disease or disorder that is clinically significant in the opinion of the Principal Investigator or Medical Sub-Investigator.

16. Have any of the following clinical laboratory values at Screening:

1. fasting triglyceride of ≥300 mg/dL and/or total cholesterol of ≥300mg/dL

2. positive laboratory finding for Factor V Leiden mutation

3. AST or ALT ≥1.5 times the upper limit of normal (ULN)

4. fasting glucose >125 mg/dL

17. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.)

18. Have contraindication to estrogen and/or progestin therapy or allergy to the use of estradiol and/or progesterone or any components of the investigational drugs.

19. Use 15 or more cigarettes per day or currently use any electronic cigarettes.

20. Have a history of drug and/or alcohol abuse within one year of start of study.

21. Have used, within 28 days prior to the initial dose of study medication at Visit 1, any medication known to induce or inhibit CYP3A4 enzyme activity that may affect estrogen and/or progestin drug metabolism. (See 48TUSection 4.3U48T)

22. Have used, within 28 days prior to Screening, or plan to use during the study, any prescription or over-the-counter (OTC) medications (including herbal products, such as St. John's Wort) that would be expected to alter progesterone or estrogen activity or is being used to treat vasomotor symptoms. (See Section 4.3U48T)

23. Have used estrogen alone or estrogen/progestin, SERM (selective estrogen receptor modulator), testosterone, or estrogen/testosterone for any of the following time periods:

1. Vaginal nonsystemic hormonal products (rings, creams, gels) within 7 days prior to Screening, or vaginal systemic products (e.g., FemRing) within 28 days prior to Screening.

2. Transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening.

3. Oral estrogen and/or progestin and/or SERM therapy within 8 weeks prior to Screening.

4. Progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months prior to Screening.

5. Estrogen pellet therapy or progestational injectable drug therapy within 6 months prior to Screening.

6. Percutaneous estrogen lotions/gels within 8 weeks prior to Screening.

7. Oral, topical, vaginal, patch, implantable or injectable androgen therapy within 8 weeks prior to Screening.

24. Have used an intrauterine device (IUD) within the 12 weeks prior to Screening.

25. For subjects in the VMS Substudy only: use of medication that may affect the outcome of the vasomotor symptom endpoints within 28 days prior to Screening (e.g. SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin and norepinephrine reuptake inhibitors], aldomet, dopaminergic or antidopaminergic drugs, gabapentin, clonidine, or bellergal.)

26. Have any reason which, in the opinion of the Principal Investigator or Medical Sub-Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements.

27. Have a Screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the Screening endometrial biopsy may be repeated once.)

28. Endometrial polyps with atypical nuclei reported by at least 1 central pathologist.

29. Have contraindication to any planned study assessments (e.g., endometrial biopsy).

30. Have participated in another clinical trial within 30 days prior to Screening, have received an investigational drug within the three months prior to the initial dose of study medication, or be likely to participate in a clinical trial or receive another investigational medication during the study.

31. Currently use marijuana.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

TherapeuticsMD

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sebastian Mirkin, MD

Role: STUDY_DIRECTOR

TherapeuticsMD

Locations

Simon Williamson Clinic

Birmingham, Alabama, United States

Medical Affiliated Research Center

Huntsville, Alabama, United States

Coastal Clinical Research

Mobile, Alabama, United States

Mobile Ob-Gyn, P.C.

Mobile, Alabama, United States

Montgomery Women's Health

Montgomery, Alabama, United States

Advanced Research Associates

Glendale, Arizona, United States

Cactus Clinical Research

Mesa, Arizona, United States

Precision Trials

Phoenix, Arizona, United States

Radiant Research (Tucson)

Tucson, Arizona, United States

Visions Clinical Research Tucson

Tucson, Arizona, United States

Health Star Research, LLC

Hot Springs, Arkansas, United States

Sutter East Bay Medical Foundation

Berkeley, California, United States

Grossmont Center for Clinical Research

La Mesa, California, United States

Futura Research

Norwalk, California, United States

Medical Center for Clinical Research

San Diego, California, United States

Women's Health Care Research Corp.

San Diego, California, United States

Radiant Research, Inc.

Santa Rosa, California, United States

Diablo Clinical Research

Walnut Creek, California, United States

Downtown Women's Healthcare

Denver, Colorado, United States

Horizon's Clinical Research Center

Denver, Colorado, United States

Red Rocks OB/Gyn

Lakewood, Colorado, United States

Clinical Research Consulting

Milford, Connecticut, United States

Coastal Connecticut Research

New London, Connecticut, United States

South Florida Medical Research

Aventura, Florida, United States

Nature Coast Clinical Research

Crystal River, Florida, United States

Clinical Physiology Associates

Fort Myers, Florida, United States

Southeastern Integrated Medical, PL, d/b/a Florida Medical Research

Gainesville, Florida, United States

UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology

Jacksonville, Florida, United States

Suncoast Research

Margate, Florida, United States

Accelovance

Melbourne, Florida, United States

Suncoast Clinical Research, Inc

New Port Richey, Florida, United States

Segal Institute

North Miami, Florida, United States

Ideal Clinical Research

North Miami Beach, Florida, United States

Compass Research

Orlando, Florida, United States

Radiant Research (St. Petersburg)

Pinellas Park, Florida, United States

All Women's Healthcare of West Broward Discovery Clinical Research

Plantation, Florida, United States

Comprehensive Clinical Trials

West Palm Beach, Florida, United States

Radiant Research (Atlanta)

Atlanta, Georgia, United States

Women's Health Associates

Atlanta, Georgia, United States

Soapstone Center for Clinical Research

Decatur, Georgia, United States

Wake Research - Mount Vernon Clinical Research

Sandy Springs, Georgia, United States

Fellows Research Alliance

Savannah, Georgia, United States

Elite Clinical Trials

Blackfoot, Idaho, United States

Advanced Clinical Research

Meridian, Idaho, United States

Biofortis

Addison, Illinois, United States

Women's Health Practice

Champaign, Illinois, United States

Radiant Research (Chicago)

Chicago, Illinois, United States

The South Bend Clinic Granger

Granger, Indiana, United States

Davis Clinic

Indianapolis, Indiana, United States

Cypress Medical Research Center, LLC

Wichita, Kansas, United States

Central Kentucky Research Associates

Lexington, Kentucky, United States

Bluegrass Clinical Research

Louisville, Kentucky, United States

Horizon Research Group

Eunice, Louisiana, United States

Maryland Center for Sexual Health

Lutherville, Maryland, United States

Quest Research Institute

Bingham Farms, Michigan, United States

Female Pelvic Medicine & Urogynecology

Grand Rapids, Michigan, United States

Beyer Research

Kalamazoo, Michigan, United States

Saginaw Valley Medical Research Group

Saginaw, Michigan, United States

Radiant Research (St. Louis)

St Louis, Missouri, United States

Billings Clinical Research

Billings, Montana, United States

Montana Health

Billings, Montana, United States

Women's Clinic of Lincoln

Lincoln, Nebraska, United States

Affiliated Clinical Research INC

Las Vegas, Nevada, United States

Affiliated Clinical Research

Las Vegas, Nevada, United States

Lawrence OB-GYN Clinical Research

Lawrenceville, New Jersey, United States

Albuquerque Clinical Trials, Inc.

Albuquerque, New Mexico, United States

Bosque Women's Care

Albuquerque, New Mexico, United States

Southwest Clinical Research

Albuquerque, New Mexico, United States

Columbia University

New York, New York, United States

Suffolk OB/GYN

Port Jefferson, New York, United States

Upstate Clinical Research Associates

Williamsville, New York, United States

Women's Wellness Clinic

Durham, North Carolina, United States

Carolina Medical Trials

High Point, North Carolina, United States

Centre OBGYN

Raleigh, North Carolina, United States

Wake County Research

Raleigh, North Carolina, United States

Lyndhurst Clinical Research

Salem, North Carolina, United States

Carolina Medical Trials

Winston-Salem, North Carolina, United States

Hawthorne Research

Winston-Salem, North Carolina, United States

Triad Ob-Gyn

Winston-Salem, North Carolina, United States

Lillestol Research

Fargo, North Dakota, United States

Radiant Research (Akron)

Akron, Ohio, United States

University of Cincinnati Physicians Company

Cincinnati, Ohio, United States

Rapid Medical Research

Cleveland, Ohio, United States

Columbus Center for Women's Health Research

Columbus, Ohio, United States

HWC Women's Research Center

Englewood, Ohio, United States

Lynn Health Science Institute

Oklahoma City, Oklahoma, United States

Sunstone Medical Research

Medford, Oregon, United States

The Clinical Trial Center

Jenkintown, Pennsylvania, United States

Clinical Research of Philadelphia

Philadelphia, Pennsylvania, United States

Clinical Trials Research Services, LLC

Pittsburgh, Pennsylvania, United States

Omega Medical Research

Warwick, Rhode Island, United States

Fellows Research Group

Bluffton, South Carolina, United States

Vista Clinical Research

Columbia, South Carolina, United States

Upstate Pharmaceutical Research

Greenville, South Carolina, United States

Coastal Carolina Research Center

Mt. Pleasant, South Carolina, United States

Chattanooga Medical Research

Chattanooga, Tennessee, United States

Volunteer Research Group/NOCCR

Knoxville, Tennessee, United States

DiscoveResearch, Inc.

Bryan, Texas, United States

Advanced Research Associates

Corpus Christi, Texas, United States

Research Across America

Dallas, Texas, United States

Brownstone Clinical Trials

Fort Worth, Texas, United States

Advances in Health

Houston, Texas, United States

The Women's Hospital of Texas

Houston, Texas, United States

TMC Life Research

Houston, Texas, United States

Protenium Clinical Research

Hurst, Texas, United States

MacArthur OB/GYN

Irving, Texas, United States

Clinical Trials of Texas

San Antonio, Texas, United States

Stone Oak, LLC dba Discovery Clinical Trials

San Antonio, Texas, United States

NECRSA

Schertz, Texas, United States

PRO/ Salt Lake Women's Center

Draper, Utah, United States

Wasatch Clinical Research, LLC

Salt Lake City, Utah, United States

Jean Brown Research

Salt Lake City, Utah, United States

UVA/Midlife Health at North Ridge

Charlottesville, Virginia, United States

Clinical Research Center Eastern Virginia Medical School

Norfolk, Virginia, United States

Virginia Women's Center

Richmond, Virginia, United States

National Clinical Research-Richmond, Inc

Richmond, Virginia, United States

Tidewater Clinical Research

Virginia Beach, Virginia, United States

Seattle Women's Health Research, Gynecology

Seattle, Washington, United States

North Spokane Women's Health

Spokane, Washington, United States

Countries

United States

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Other Identifiers

REPLENISH Trial

Identifier Type: OTHER

Identifier Source: secondary_id

TXC12-05

Identifier Type: -

Identifier Source: org_study_id