ELITE: Early Versus Late Intervention Trial With Estradiol

Study Overview
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Brief Summary
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The purpose of this study is to examine the effects of oral 17B-estradiol (estrogen) on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women.

Detailed Description
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The primary hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium (lining of blood vessels) is relatively healthy versus later when the endothelium has lost its responsiveness to estrogen. Ultrasonography will be used to measure the rate of change in the thickness of the carotid artery and cardiac computed tomography (CT) will be used to measure coronary artery calcium and coronary artery lesions. The second hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of cognitive decline if initiated soon after menopause when healthy brain tissue remains responsive to estrogen versus later when brain tissue has lost its responsiveness to estrogen. A total of 643 (actual; 504 initially proposed) postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral 17B-estradiol 1 mg daily or matching placebo. Women with a uterus will also use vaginal progesterone gel 4% (or placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blinded fashion along with the randomized treatment so that only women exposed to active treatment will receive active progesterone. As initially proposed, participants will undergo ultrasonography at baseline and every 6 months throughout the 2 to 5 years (average 3 years) of randomized treatment. Participants will also undergo cognitive testing at baseline and after 3 years of randomized treatment. The trial has been extended for an additional 2 to 2.5 years of randomized treatment (overall average randomized treatment of 5 years and range of 2 to 8.5 years). Ultrasonography will continue to be collected every 6 months and upon completion of randomized treatment, participants will undergo cardiac CT for coronary artery calcium and coronary artery lesion measurements. Participants will also undergo a third cognitive testing at the completion of randomized treatment.

Official Title
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Biologic Response of Menopausal Women to 17B-Estradiol

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: 17B-estradiol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with a serum estradiol level 25 pg/ml or less No period for 6 months or more Postmenopausal less than 6 years, OR 10 years or longer Exclusion Criteria: Clinical signs, symptoms, or personal history of cardiovascular disease Women who have had a hysterectomy only and no oophorectomy (since time from menopause cannot be determined) Diabetes mellitus or fasting serum glucose 140 mg/dL or greater Uncontrolled hypertension (diastolic blood pressure 110 mmHg or greater) Thyroid disease (untreated) Serum creatinine greater than 2.0 mg/dL Plasma triglyceride levels greater than 500 mg/dL Life threatening disease with prognosis less than 5 years Cirrhosis or liver disease History of deep vein thrombosis or pulmonary embolism History of breast cancer Current hormone replacement therapy (HRT)
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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 17B-estradiol<br>Oral 17B-estradiol 1 mg daily | Drug: 17B-estradiol<br>* Oral 17B-estradiol 1 mg daily<br>* Other names: Menopausal hormone replacement therapy;|
| Placebo Comparator: Placebo<br>Matching oral 17B-estradiol placebo daily | Other: Placebo<br>* Matching oral 17B-estradiol placebo daily<br>* Other names: Matching placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of Subclinical Atherosclerosis | Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up. | Baseline x 2 and then every 6 months up to 6.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Neurocognitive Function (Global Cognition) | All neuropsychological test scores at baseline and follow-up assessments were standardized ([raw score - mean score]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes. | Baseline and at 2.5 years and 5 years | 
| Coronary Artery Calcium | Number of participants with coronary artery calcium measured by cardiac computed tomography | End of randomized treatment, up to 6.7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prevention, atherosclerosis, CAD, cardiac computed tomography, cardiovascular disease, carotid artery intima-media thickness, cognitive function, computed tomography, coronary artery calcium, coronary artery disease, coronary artery lesions, CVD, estrogen, estrogen therapy, hormone therapy, postmenopausal, subclinical vascular disease, timing hypothesis, ultrasonography, menopausal hormone replacement therapy, menopause, intervention