Atherosclerosis Intervention with Novel Tissue Selective Estrogen Complex Therapy

项目概要/摘要 这项拟议中的试验的临床和公共卫生影响是深远的，因为科学在过去的 十年来已经证实，雌激素提供了实质性的好处与低风险的妇女，特别是当 开始于围绝经期或绝经后早期。然而，大多数女性进入 绝经后子宫需要与孕激素共同治疗以对抗雌激素诱导的子宫内膜 增生与孕激素联合治疗是绝经后激素治疗的限制因素 (HT)因为相对于单独的雌激素，传统的含孕激素的HT方案具有最大的健康 女性的风险，包括静脉血栓栓塞（VTE）和乳腺癌。然而，作为 组织选择性雌激素复合物（TSEC），一类新的药物，雌激素现在可以在 无孕激素方案，无孕激素暴露风险。作为一种新型的创新药物， TSEC疗法通过与选择性的抗肿瘤药物结合，为治疗更年期症状提供了一种新的方法。 雌激素受体调节剂（SERM）与雌激素，以达到最佳的临床效果的基础上，混合 组织选择性活性谱。联合巴多昔芬（BZA），第三代SERM与 结合雌激素（CE）对乳腺、子宫内膜、骨、脂质生物合成和静脉血栓形成的影响， 独特的安全性和有效性优化。一系列3期随机对照试验显示， BZA/CE（FDA批准）可有效预防骨质疏松症并缓解血管扩张， 阴道症状，同时确保子宫内膜的安全。BZA/CE不刺激子宫内膜组织， BZA/CE的累积闭经率与安慰剂相当，子宫内膜异位症的发生率也是如此。 增生（<1%）。此外，BZA/CE不会刺激乳腺组织，不会增加乳房X线检查 相对于安慰剂的密度; VTE（深静脉血栓形成和肺栓塞）和卒中的发生率 与安慰剂相似。到目前为止，已经用传统的孕激素进行了随机对照试验， 基于HT采用创新的无孕激素配方BZA/CE保护女性子宫 不进行子宫切除术是传统HT（孕激素对抗雌激素治疗）的下一步， 为使用新型TSEC类药物的女性提供安全有效的治疗， 动脉粥样硬化进展是未知的。这项建议旨在填补我们知识上的这一重大空白， 停止这一独特的公共卫生机会。我们建议的具体目的是进行一项 在360例健康绝经后子宫切除妇女中进行的随机、双盲、安慰剂对照试验 绝经6年内且年龄小于60岁，无临床心血管疾病， 糖尿病患者随机接受BZA 20 mg/CE 0.45 mg或安慰剂治疗2 - 4.5年， 确定TSEC治疗对亚临床动脉粥样硬化进展的影响， 颈动脉内膜中层厚度和颈动脉硬度作为试验终点。

PROJECT SUMMARY/ABSTRACT The clinical and public health implications of this proposed trial are far-reaching as the science over the last decade has confirmed that estrogen provides substantial benefits with low risk to women especially when initiated in the perimenopausal or early postmenopausal period. However, the majority of women entering menopause have a uterus requiring co-treatment with progestogen to counter estrogen-induced endometrial hyperplasia. Co-treatment with progestogen creates a limiting factor for postmenopausal hormone therapy (HT) since relative to estrogen alone, traditional progestogen-containing HT regimens carry the greatest health risks for women, including venous thromboembolism (VTE) and breast cancer. However, as a component of tissue selective estrogen complex (TSEC), a new class of agents, estrogen can now be delivered in a progestogen-free regimen without risks from progestogen exposure. As a new class of innovative medications, TSEC therapy provides a novel approach for the treatment of menopausal symptoms by partnering a selective estrogen receptor modulator (SERM) with estrogen to achieve optimal clinical results based on the blended tissue-selective activity profile. The effect of combined bazedoxifene (BZA), a third generation SERM with conjugated estrogens (CE) on breast, endometrium, bone, lipid biosynthesis and venous thrombosis are unique with optimization of safety and efficacy. A series of phase 3 randomized controlled trials have shown that BZA/CE (FDA approved) is effective in preventing osteoporosis and providing relief of vasomotor and vaginal symptoms while ensuring endometrial safety. BZA/CE does not stimulate endometrial tissue and the rate of cumulative amenorrhea with BZA/CE is comparable with placebo as is the incidence of endometrial hyperplasia (<1%). In addition, BZA/CE does not stimulate breast tissue and does not increase mammographic density relative to placebo; the incidences of VTE (deep vein thrombosis and pulmonary embolism) and stroke are similar to placebo. To date, randomized controlled trials have been conducted with traditional progestogen- based HT. Deploying the innovative progestogen-free formulation of BZA/CE to protect the uterus in women without a hysterectomy is the next step beyond traditional HT (progestogen opposed estrogen therapy) in providing safe and effective therapy for women with the new TSEC class of agents, the effects of which on atherosclerosis progression are unknown. This proposal seeks to address this major gap in our knowledge and to cease upon this unique public health opportunity. The specific aim of our proposal is to conduct a randomized, double-blinded, placebo-controlled trial in 360 healthy postmenopausal women with a uterus within 6 years of menopause and less than 60 years of age without clinical cardiovascular disease and diabetes mellitus randomized to BZA 20 mg/CE 0.45 mg or placebo for a treatment period of 2 to 4.5 years to determine the effects of TSEC therapy on the progression of subclinical atherosclerosis measured as change in carotid artery intima-media thickness and carotid arterial stiffness as trial end-points.