ELITE: Early Versus Late Intervention Trial With Estradiol

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT00114517
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 643
• Location: 1
• Arms: 2
• Duration (Months): 104.1
• Patients Per Site Per Month: 6.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerosis	Drug: Oral 17B-estradiol; Drug: Placebo	Phase 2/Phase 3

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 a placebo. Women with a uterus will also use vaginal progesterone gel 4% (or a placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blind 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 643 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Biologic Response of Menopausal Women to 17B-Estradiol
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Feb 12, 2013
• Actual Study Completion Date: Mar 5, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 17B-estradiol Oral 17B-estradiol 1 mg daily	Drug: Oral 17B-estradiol; Oral 17B-estradiol 1 mg daily; Other Names: Estrace Estrogen replacement therapy Estrogen
Placebo Comparator: Placebo Matched placebo oral 17B-estradiol daily	Drug: Placebo; Matched placebo oral 17B-estradiol

Outcome Measures

Primary Outcome Measures

1. Rate of Change of Distal Common Carotid Artery (CCA) Far Wall Intima-media Thickness (IMT) [Twice at baseline and then every 6 months on trial]

Secondary Outcome Measures

1. 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.

2. Number of Participants With Coronary Artery Calcium Measured by Cardiac Computed Tomography [End of randomized treatment]

   measurement of coronary artery calcium at end of study

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine	Los Angeles	California	United States	90033

Sponsors and Collaborators

• University of Southern California
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Howard N. Hodis, MD, University of Southern California, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Howard Hodis, Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine and Preventive Medicine, Professor of Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit, University of Southern California
• ClinicalTrials.gov Identifier: NCT00114517
• Other Study ID Numbers: AG0025; R01AG024154
• First Posted: Jun 16, 2005
• Last Update Posted: Jun 8, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Howard Hodis, Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine and Preventive Medicine, Professor of Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit, University of Southern California: 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
• Additional relevant MeSH terms: Atherosclerosis; Estradiol; Estrogens

Study Results

Participant Flow

Arm/Group Title	Early Postmenopause 17B-estradiol	Early Postmenopause Placebo	Late Postmenopause 17B-estradiol	Late Postmenopause Placebo
Arm/Group Description	Early postmenopause, <6 years-since-menopause oral 17B-estradiol 1 mg daily	Early postmenopause <6 years-since-menopause	Late postmenopause >10 years-since-menopause oral 17B-estradiol 1 mg daily	Late postmenopause >10 years-since-menopause
Period Title: Overall Study
STARTED	137	134	186	186
COMPLETED	125	123	172	176
NOT COMPLETED	12	11	14	10

Baseline Characteristics

Arm/Group Title	Early Postmenopause 17B-estradiol	Early Postmenopause Placebo	Late Postmenopause 17B-estradiol	Late Postmenopause Placebo	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	125	123	172	176	596
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	55.4	55.4	64.3	63.0	60.0
Sex: Female, Male (Count of Participants)
Female	125 100%	123 100%	172 100%	176 100%	596 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White, non-hispanic	88 70.4%	73 59.3%	127 73.8%	127 72.2%	415 69.6%
Black, non-hispanic	7 5.6%	14 11.4%	17 9.9%	14 8%	52 8.7%
Hispanic	16 12.8%	20 16.3%	20 11.6%	23 13.1%	79 13.3%
Asian	14 11.2%	16 13%	8 4.7%	12 6.8%	50 8.4%

Outcome Measures

1. Primary Outcome

Title	Rate of Change of Distal Common Carotid Artery (CCA) Far Wall Intima-media Thickness (IMT)
Time Frame	Twice at baseline and then every 6 months on trial

Outcome Measure Data

Analysis Population Description

Early postmenopause group (<6 years since menopause) at baseline and late postmenopause group (>10 years since menopause) at baseline.

Arm/Group Title	17B-estradiol	Placebo
Arm/Group Description	Oral 17B-estradiol 1 mg daily Oral 17B-estradiol: Oral 17B-estradiol 1 mg daily	Matched placebo oral 17B-estradiol daily Placebo: Matched placebo oral 17B-estradiol
Measure Participants	297	299
Early postmenopause group	0.0044	0.0078
Late postmenopause group	0.0100	0.0088

2. Secondary Outcome

Title	Change in Neurocognitive Function (Global Cognition)
Description	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.
Time Frame	Baseline and at 2.5 years and 5 years

Outcome Measure Data

Analysis Population Description

Early postmenopause group (<6 years since menopause) at baseline and late postmenopause group (>10 years since menopause) at baseline. Sample size represents the number of participants with analyzable data collected at baseline, 2.5 years and 5.0 years.

Arm/Group Title	17B-estradiol	Placebo
Arm/Group Description	Oral 17B-estradiol 1 mg daily Oral 17B-estradiol: Oral 17B-estradiol 1 mg daily	Matched placebo oral 17B-estradiol daily Placebo: Matched placebo oral 17B-estradiol
Measure Participants	284	283
Early postmenopause group	0.42	0.40
Late postmenopause group	0.29	0.36

3. Secondary Outcome

Title	Number of Participants With Coronary Artery Calcium Measured by Cardiac Computed Tomography
Description	measurement of coronary artery calcium at end of study
Time Frame	End of randomized treatment

Outcome Measure Data

Analysis Population Description

CAC data was obtained in 380 participants. Participants who were not taking the study agents at the last follow-up visit, who had adherence to the study regimen that was lower than 80% or who had a CAC scan more than 6 months after the final study visit were not included in the analysis.

Arm/Group Title	17B-estradiol	Placebo
Arm/Group Description	Oral 17B-estradiol 1 mg daily Oral 17B-estradiol: Oral 17B-estradiol 1 mg daily	Matched placebo oral 17B-estradiol daily Placebo: Matched placebo oral 17B-estradiol
Measure Participants	188	192
Early postmenopause group	34 27.2%	24 19.5%
Late postmenopause gorup	57 45.6%	65 52.8%

Adverse Events

Adverse Event Reporting Description	Adverse events collected per intervention
Arm/Group Title	17B-estradiol		Placebo
Arm/Group Description	Oral 17B-estradiol 1 mg daily Oral 17B-estradiol: Oral 17B-estradiol 1 mg daily		Matched placebo oral 17B-estradiol daily Placebo: Matched placebo oral 17B-estradiol
All Cause Mortality
	17B-estradiol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/323 (0.3%)		1/320 (0.3%)
Serious Adverse Events
	17B-estradiol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/323 (13.3%)		45/320 (14.1%)
Blood and lymphatic system disorders
aplastic anemia	1/323 (0.3%)	1	0/320 (0%)	0
Cardiac disorders
unstable angina	2/323 (0.6%)	2	0/320 (0%)	0
atrial fibrillation	1/323 (0.3%)	1	1/320 (0.3%)	1
pleuropericarditis	0/323 (0%)	0	1/320 (0.3%)	1
myocardial infarction	1/323 (0.3%)	1	3/320 (0.9%)	3
Ear and labyrinth disorders
veritgo	1/323 (0.3%)	1	0/320 (0%)	0
Gastrointestinal disorders
ischemic colitis	1/323 (0.3%)	1	0/320 (0%)	0
gastroesophageal reflux disease	1/323 (0.3%)	1	0/320 (0%)	0
illeitis	1/323 (0.3%)	1	0/320 (0%)	0
gastrointestinal hemorrhage	1/323 (0.3%)	1	1/320 (0.3%)	1
pancreatitis	1/323 (0.3%)	1	0/320 (0%)	0
ulcerative colitis	0/323 (0%)	0	1/320 (0.3%)	1
General disorders
death	1/323 (0.3%)	1	1/320 (0.3%)	1
non-cardiac chest pain	2/323 (0.6%)	2	1/320 (0.3%)	1
Immune system disorders
drug hypersensitivity	1/323 (0.3%)	1	0/320 (0%)	0
Infections and infestations
cellulitis	0/323 (0%)	0	2/320 (0.6%)	2
lobar pneumonia	0/323 (0%)	0	1/320 (0.3%)	1
pelvic abscess	1/323 (0.3%)	1	0/320 (0%)	0
pneumonia	1/323 (0.3%)	1	1/320 (0.3%)	1
Injury, poisoning and procedural complications
cervical vertebral fracture	0/323 (0%)	0	1/320 (0.3%)	1
femoral neck fracture	1/323 (0.3%)	1	3/320 (0.9%)	3
foot fracture	0/323 (0%)	0	1/320 (0.3%)	1
fracture	0/323 (0%)	0	1/320 (0.3%)	1
Musculoskeletal and connective tissue disorders
systemic lupus erythematosus	1/323 (0.3%)	1	0/320 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	0/323 (0%)	0	1/320 (0.3%)	1
breast cancer	5/323 (1.5%)	5	4/320 (1.3%)	4
breast cancer in situ	5/323 (1.5%)	5	4/320 (1.3%)	4
colon adenoma	0/323 (0%)	0	1/320 (0.3%)	1
colorectal cancer	3/323 (0.9%)	3	2/320 (0.6%)	2
gastric cancer	0/323 (0%)	0	1/320 (0.3%)	1
glioblastoma	1/323 (0.3%)	1	0/320 (0%)	0
malignant peritoneal neoplasm	0/323 (0%)	0	1/320 (0.3%)	1
mycosis fungoides	1/323 (0.3%)	1	0/320 (0%)	0
ovarian epithelial cancer	0/323 (0%)	0	1/320 (0.3%)	1
pancreatic carcinoma	0/323 (0%)	0	1/320 (0.3%)	1
polycythemia vera	0/323 (0%)	0	1/320 (0.3%)	1
uterine cancer	2/323 (0.6%)	2	1/320 (0.3%)	1
Nervous system disorders
amnesia	0/323 (0%)	0	1/320 (0.3%)	1
dizziness	1/323 (0.3%)	1	0/320 (0%)	0
syncope	1/323 (0.3%)	1	1/320 (0.3%)	1
transient ischemic attack	1/323 (0.3%)	1	2/320 (0.6%)	2
Psychiatric disorders
Suicide ideation	0/323 (0%)	0	1/320 (0.3%)	1
psychotic disorder	1/323 (0.3%)	1	0/320 (0%)	0
Respiratory, thoracic and mediastinal disorders
pulmonary embolism	2/323 (0.6%)	2	0/320 (0%)	0
Surgical and medical procedures
spinal laminectomy	0/323 (0%)	0	1/320 (0.3%)	1
Vascular disorders
deep vein thrombosis	1/323 (0.3%)	1	2/320 (0.6%)	2
Other (Not Including Serious) Adverse Events
	17B-estradiol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	216/323 (66.9%)		226/320 (70.6%)
General disorders
chest discomfort	23/323 (7.1%)	23	22/320 (6.9%)	22
non-cardiac chest pain	18/323 (5.6%)	18	12/320 (3.8%)	12
Immune system disorders
drug hypersensitivity	26/323 (8%)	26	25/320 (7.8%)	25
Infections and infestations
bronchitis	19/323 (5.9%)	19	22/320 (6.9%)	22
influenza	44/323 (13.6%)	44	52/320 (16.3%)	52
sinusitis	24/323 (7.4%)	24	24/320 (7.5%)	24
urinary tract infection	63/323 (19.5%)	63	64/320 (20%)	64
Injury, poisoning and procedural complications
contusion	17/323 (5.3%)	17	12/320 (3.8%)	12
fall	37/323 (11.5%)	37	36/320 (11.3%)	36
road traffic accident	19/323 (5.9%)	19	13/320 (4.1%)	13
Musculoskeletal and connective tissue disorders
arthralgia	47/323 (14.6%)	47	53/320 (16.6%)	53
back pain	35/323 (10.8%)	35	32/320 (10%)	32
pain in extremity	10/323 (3.1%)	10	18/320 (5.6%)	18
Psychiatric disorders
depression	17/323 (5.3%)	17	20/320 (6.3%)	20
Reproductive system and breast disorders
cervical dysplasia	48/323 (14.9%)	48	42/320 (13.1%)	42
vaginal discharge	17/323 (5.3%)	17	8/320 (2.5%)	8
vulvovaginal pruritis	19/323 (5.9%)	19	11/320 (3.4%)	11
Respiratory, thoracic and mediastinal disorders
cough	25/323 (7.7%)	25	19/320 (5.9%)	19
Skin and subcutaneous tissue disorders
rash	16/323 (5%)	16	22/320 (6.9%)	22

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.