Kronos Early Estrogen Prevention Study (KEEPS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women

Conditions
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Menopause, Arteriosclerosis

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 42 Years
Maximum Age: 58 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change of carotid intimal medial thickness by ultrasound |  | Measured at screening, 12, 24, 36, and 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perimenopause, Coronary Disease, Estrogen Replacement Therapy, Hormone Replacement Therapy