Clinical trial NCT00114517: ELITE: Early Versus Late Intervention Trial With Estradiol
Official title: Biologic Response of Menopausal Women to 17B-Estradiol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atherosclerosis
Keywords: 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
prevention
intervention
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2005-06-16
Enrollment: 643
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Progression of Subclinical Atherosclerosis
timeFrame: Baseline x 2 and then every 6 months up to 6.7 years
Secondary outcomes:
measure: Change in Neurocognitive Function (Global Cognition)
timeFrame: Baseline and at 2.5 years and 5 years
measure: Coronary Artery Calcium
timeFrame: End of randomized treatment, up to 6.7 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Atherosclerosis Research Unit, University of Southern California
state: California
Study officials:
affiliation: Atherosclerosis Research Unit, University of Southern California
name: Howard N. Hodis, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, Budoff MJ, Henderson VW. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2015 Apr;22(4):391-401. doi: 10.1097/GME.0000000000000343.
citation: Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241.
citation: Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016 Aug 16;87(7):699-708. doi: 10.1212/WNL.0000000000002980. Epub 2016 Jul 15.
citation: Lin F, Pa J, Karim R, Hodis HN, Han SD, Henderson VW, St John JA, Mack WJ. Subclinical carotid artery atherosclerosis and cognitive function in older adults. Alzheimers Res Ther. 2022 May 7;14(1):63. doi: 10.1186/s13195-022-00997-7.
citation: Sriprasert I, Mert M, Mack WJ, Hodis HN, Shoupe D. Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women. Maturitas. 2021 Dec;154:13-19. doi: 10.1016/j.maturitas.2021.09.002. Epub 2021 Sep 5.
citation: Sriprasert I, Kono N, Karim R, Hodis HN, Stanczyk FZ, Shoupe D, Mack WJ. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol. 2020 Oct;136(4):675-684. doi: 10.1097/AOG.0000000000004006.
citation: Sriprasert I, Mack WJ, Hodis HN, Allayee H, Brinton RD, Karim R. Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women. Am J Cardiol. 2019 Oct 1;124(7):1031-1037. doi: 10.1016/j.amjcard.2019.06.022. Epub 2019 Jul 15.
citation: Sriprasert I, Hodis HN, Karim R, Stanczyk FZ, Shoupe D, Henderson VW, Mack WJ. Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause. J Clin Endocrinol Metab. 2019 Feb 1;104(2):293-300. doi: 10.1210/jc.2018-01600.
citation: Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2015 Feb;100(2):508-15. doi: 10.1210/jc.2014-2834. Epub 2014 Nov 18.
citation: Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14. doi: 10.1097/WNN.0b013e3181a74ce7.