Biologic Response of Menopausal Women to 17B-Estradiol

描述（由申请人提供）：雌二醇早期与晚期干预试验（ELITE）是一项随机、双盲、安慰剂对照、连续动脉成像（颈动脉内膜-中膜厚度）试验，旨在检验“时间假说”，该假说认为激素治疗（HT）对动脉粥样硬化进展的不同影响取决于激素治疗何时开始与绝经有关。ELITE是一项2 × 2因子试验，在该试验中，没有心血管疾病的健康绝经后妇女根据绝经时间（<6年或≤10年）随机接受172-雌二醇或安慰剂治疗。自从6年前首次提出时间假说以来，科学证据已经大大增加。ELITE提前随机化，辍学率低于最初预期，研究干预依从性仍为0.94%，不良反应较低。本次更新申请有两个特定目的：1)通过对比和非对比心脏计算机断层扫描将试验成像终点扩大到冠状动脉亚临床动脉粥样硬化，以验证和扩展最近的发现，即HT可能减少年轻绝经后妇女的冠状动脉疾病；2)延长ELITE的干预期，以充分增加力量，以检测绝经后各阶段之间的治疗相互作用比最初设计的要小，因为ELITE仍然是唯一专门设计来检验时间假设的随机对照试验。确定年轻和老年绝经后妇女（定义为绝经后的时间）对172-雌二醇的生物学反应是否不同，仍然是本试验的长期和主要目标。

DESCRIPTION (provided by applicant): The Early versus Later Intervention Trial with Estradiol (ELITE) is a randomized, double-blind, placebo- controlled, serial arterial imaging (carotid artery intima-media thickness) trial designed to test the "timing hypothesis" which posits that there is a differential effect of hormone therapy (HT) on atherosclerosis progression according to when HT is initiated in relation to menopause. ELITE is a 2x2 factorial trial in which healthy postmenopausal women without pre-existing cardiovascular disease were randomized to 172-estradiol or placebo according to their time since menopause, <6 years or >10 years. Since initially proposed 6 years ago, the scientific evidence for the timing hypothesis has grown substantially. ELITE was randomized ahead of schedule, the dropout rate is lower than initially projected, compliance with the study intervention remains >94% and adverse effects are low. This Renewal Application is submitted for 2 specific purposes: 1) to broaden the trial imaging end point to subclinical atherosclerosis of the coronary arteries through contrast and non-contrast cardiac computed tomography to validate and extend recent findings that HT potentially reduces coronary artery disease in young postmenopausal women; and, 2) to extend the intervention period of ELITE to sufficiently increase power to detect a smaller treatment interaction between time since menopause strata than originally designed since ELITE remains the only randomized controlled trial specifically designed to test the timing hypothesis. To determine whether the biologic response to 172-estradiol is different in younger versus older postmenopausal women (defined as time since menopause) remains the long-term and primary goal of this trial. PUBLIC HEALTH RELEVANCE: With the growing number of women entering menopause (approximately 50% of U.S. women will be >45 years old by 2015) and with the introduction of new hormonal products into the marketplace, use of postmenopausal hormone therapy (HT) will continue. Therefore, understanding the effect of HT on the progression of subclinical atherosclerosis, especially in young postmenopausal women who are likely to initiate these products for menopausal symptoms (primarily for flushing since there are no comparably effective alternatives) continues to be an important and timely public health issue.