ELITE: Early Versus Late Intervention Trial With Estradiol

Phase 2

Completed

Conditions: Atherosclerosis

Interventions: Drug: 17B-estradiol
Other: Placebo

Registration Number: NCT00114517

Lead Sponsor: University of Southern California

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 643

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
17B-estradiol	17B-estradiol	Oral 17B-estradiol 1 mg daily
Placebo	Placebo	Matching oral 17B-estradiol placebo daily

Primary Outcome Measures

Name	Time	Method
Progression of Subclinical Atherosclerosis	Baseline x 2 and then every 6 months up to 6.7 years	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.

Secondary Outcome Measures

Name	Time	Method
Change in Neurocognitive Function (Global Cognition)	Baseline and at 2.5 years and 5 years	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.
Coronary Artery Calcium	End of randomized treatment, up to 6.7 years	Number of participants with coronary artery calcium measured by cardiac computed tomography