Kronos Early Estrogen Prevention Study (KEEPS)

Sponsor

Kronos Longevity Research Institute (Other)

Overall Status

Unknown status

CT.gov ID

NCT00154180

Collaborator

Albert Einstein College of Medicine (Other), Brigham and Women's Hospital (Other), Columbia University (Other), Mayo Clinic (Other), University of California, San Francisco (Other), University of Utah (Other), University of Washington (Other), Yale University (Other)

728

Enrollment

Locations

Arms

Duration (Months)

80.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Menopause Arteriosclerosis	Drug: Conjugated equine estrogens 0.45 mg/day Drug: Transdermal estradiol, 50 mcg/day Drug: Micronized progesterone, 200 mg/day x 12 d/month Drug: CEE , progesterone, estradiol patch or placebo for each Drug: CEE, progesterone, transdermal patch or the placebo	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

728 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

Official Title:

Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women

Study Start Date :

Sep 1, 2005

Anticipated Primary Completion Date :

May 1, 2012

Anticipated Study Completion Date :

Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1 CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg	Drug: Conjugated equine estrogens 0.45 mg/day Pill, 1 pill taken daily each month for the study duration Other Names: Premarin or placebo Drug: Transdermal estradiol, 50 mcg/day Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis. Other Names: Climara 50 mcg/day or placebo Drug: Micronized progesterone, 200 mg/day x 12 d/month capsule, 1 capsule taken daily for the first 12 days of each month for the study duration Other Names: Prometrium or placebo Drug: CEE, progesterone, transdermal patch or the placebo CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent Other Names: Premarin Prometrium Climara
Placebo Comparator: Arm 2 Placebo patch, placebo CEE, placebo Prometrium	Drug: CEE , progesterone, estradiol patch or placebo for each CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week Other Names: Premarin Prometrium Climara Patch Drug: CEE, progesterone, transdermal patch or the placebo CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent Other Names: Premarin Prometrium Climara

Arm

Intervention/Treatment

Active Comparator: Arm 1

CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg

Drug: Conjugated equine estrogens 0.45 mg/day

Pill, 1 pill taken daily each month for the study duration

Other Names:

Premarin or placebo

Drug: Transdermal estradiol, 50 mcg/day

Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis.

Other Names:

Climara 50 mcg/day or placebo

Drug: Micronized progesterone, 200 mg/day x 12 d/month

capsule, 1 capsule taken daily for the first 12 days of each month for the study duration

Other Names:

Prometrium or placebo

Drug: CEE, progesterone, transdermal patch or the placebo

CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent

Other Names:

Premarin

Prometrium

Climara

Placebo Comparator: Arm 2

Placebo patch, placebo CEE, placebo Prometrium

Drug: CEE , progesterone, estradiol patch or placebo for each

CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week

Other Names:

Premarin

Prometrium

Climara Patch

Drug: CEE, progesterone, transdermal patch or the placebo

CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent

Other Names:

Premarin

Prometrium

Climara

Outcome Measures

Primary Outcome Measures

Rate of change of carotid intimal medial thickness by ultrasound [Measured at screening, 12, 24, 36, and 48 months]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

42 Years to 58 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kronos Longevity Research Institute	Phoenix	Arizona	United States	85016-3452
2	University of California, San Francisco	San Francisco	California	United States	94115
3	Yale University Medical Center	New Haven	Connecticut	United States	06519
4	Brigham and Women's Hospital	Boston	Massachusetts	United States	02215
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Albert Einstein College of Medicine	Bronx	New York	United States	10461
7	Columbia Presbyterian Hospital	New York	New York	United States	10032
8	University of Utah	Salt Lake City	Utah	United States	84108
9	University of Washington/VA Puget Sound, HCS	Seattle/Tacoma	Washington	United States	98493

Investigators

Study Director: S Mitchell Harman, MD, PhD, Kronos Longevity Research Institute
Study Director: Frederick Naftolin, MD, PhD, Kronos Longevity Research Institute
Principal Investigator: Michael Mendelsohn, MD, Tufts Medical Center
Principal Investigator: Howard Hodis, MD, University of Southern California
Principal Investigator: Matthew Budoff, MD, University of California, Los Angeles
Principal Investigator: Sanjay Asthana, MD, University of Wisconsin, Madison
Principal Investigator: Dennis M Black, PhD, University of California, San Francisco