Kronos Early Estrogen Prevention Study (KEEPS)

Phase 4

• Conditions: Menopause; Arteriosclerosis
• Interventions: Drug: Conjugated equine estrogens 0.45 mg/day; Drug: CEE , progesterone, estradiol patch or placebo for each; Drug: Transdermal estradiol, 50 mcg/day; Drug: Micronized progesterone, 200 mg/day x 12 d/month; Drug: CEE, progesterone, transdermal patch or the placebo

• Registration Number: NCT00154180
• Lead Sponsor: Kronos Longevity Research Institute

Brief Summary

The study will examine the effects of estrogen and progesterone on the development of atherosclerosis in menopausal women when hormone treatment is initiated within 3 years of the menopausal transition.

Detailed Description

The KEEPS is designed to explore the hypothesis that early initiation of hormone therapy, in women who are at the inception of their menopause, will decrease the rate of accumulation of atherosclerotic plaque, indicating a likely delay in the onset of clinical cardiovascular disease. The study is designed as a multicenter, 4 year randomized clinical trial. It will evaluate the effectiveness of of 0.45 mg/day of oral conjugated equine estrogens or 50 mcg/day of transdermal estradiol via skin patch changed weekly (each in combination with cyclic oral, micronized progesterone, 200 mg daily for 12 days per month), versus placebo in preventing progression of carotid intimal medial thickness by sonogram and the accrual of coronary calcium in women aged 42-58 who are within 36 months of their final menstrual period at initiation of treatment. A number of secondary endpoints including biochemical and genetic risk factors for cardiovascular and thrombotic disease, and effects on cognition will also be studied. The study will enroll a total of 720 women in 2005-6, with an anticipated completion of the trial in 2010.

Study Timeline

• Study Start: 2005-09
• Study First Submitted: 2005-09-07
• Study First Submitted QC: 2005-09-09
• Study First Posted: 2005-09-12
• Status Verified: 2009-09
• Last Update Submitted: 2009-09-10
• Last Update Posted: 2009-09-14
• Primary Completion: 2012-05
• Study Completion: 2012-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 728

Inclusion Criteria

• menses absent for at least 6 months and no more than 36 months
• good general health
• plasma FSH level greater than or equal to 35 mIU/ml
• estradiol levels < 40 pg/ml
• normal mammogram within 1 year of randomization

Exclusion Criteria

• use of hormone replacement or supplement within 3 months of randomization
• endometrial thickness >5 mm by vaginal ultrasound
• in utero exposure to diethylstilbestrol (DES)
• current smoking > 10 cigarettes/day
• obesity-body mass index > 35
• history of clinical cardiovascular disease
• history of cerebrovascular disease
• history of thromboembolic disease
• coronary calcium score ≥ 50 units
• dyslipidemia-LDL cholesterol >190 mg/dl
• hypertriglyceridemia-triglycerides >400 mg/dl
• lipid lowering medication (statin, fibrate,or > 500 mg/day of niacin)
• nut allergy (Prometrium includes peanut oil)
• uncontrolled hypertension-systolic BP >150 and/or diastolic BP > 95
• hysterectomy
• history of, or prevalent, chronic diseases including any cancer (other than basal cell skin cancers), renal failure, cirrhosis, diabetes mellitus, and endocrinopathies other than adequately treated thyroid disease
• known HIV infection and/or medications for HIV infection
• results of any safety laboratory test chemistries, (TSH, CBC, U/A) more than 20% abnormal

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	Conjugated equine estrogens 0.45 mg/day	CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Arm 1	Transdermal estradiol, 50 mcg/day	CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Arm 1	Micronized progesterone, 200 mg/day x 12 d/month	CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Arm 1	CEE, progesterone, transdermal patch or the placebo	CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Arm 2	CEE , progesterone, estradiol patch or placebo for each	Placebo patch, placebo CEE, placebo Prometrium
Arm 2	CEE, progesterone, transdermal patch or the placebo	Placebo patch, placebo CEE, placebo Prometrium

Primary Outcome Measures

Name	Time	Method
Rate of change of carotid intimal medial thickness by ultrasound	Measured at screening, 12, 24, 36, and 48 months

Secondary Outcome Measures

Name	Time	Method
Change in coronary calcium score by X-ray tomography	Meassured at screening and at 48 months
Plasma lipid profiles	Samples taken at screening , 12, 36, and 48 months
Blood clotting factors	Samples taken at screening, 12, 36 and 48 months
Serum inflammatory factors	Samples taken at screening, 12, 36 and 48 months
Hormone levels	Samples taken at screening, 12, 36 and 48 months
Cognitive and Affective scores on standard psychometric tests	Testing is conducted at Baseline, 18, 36 and 48 months
Quality of life	Measured at Baseline, 18, 36 and 48 months

Trial Locations

Locations (9)

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Albert Einstein College of Medicine; 🇺🇸 Bronx, New York, United States

Columbia Presbyterian Hospital; 🇺🇸 New York, New York, United States

Kronos Longevity Research Institute; 🇺🇸 Phoenix, Arizona, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

University of Washington/VA Puget Sound, HCS; 🇺🇸 Seattle/Tacoma, Washington, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Yale University Medical Center; 🇺🇸 New Haven, Connecticut, United States