Atherosclerosis Intervention with Novel Tissue Selective Estrogen Complex Therapy

采用新型组织选择性雌激素复合物疗法干预动脉粥样硬化

基本信息

批准号：
10250300
负责人：
Howard Neil Hodis
金额：
$ 283.79万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250300
关键词：
Address Affect Age-Years Amenorrhea Atherosclerosis Breast Cardiovascular Diseases Carotid Arteries Cause of Death Cessation of life Clinical Complex Confidence Intervals Conjugated Estrogens Coronary heart disease Data Deep Vein Thrombosis Diabetes Mellitus Endometrial Endometrial Hyperplasia Endometrium Ensure Estradiol Estrogen Therapy Estrogens Event FDA approved Formulation Generations Health Hysterectomy Incidence Intervention Intervention Trial Knowledge Life Mammary Gland Parenchyma Mammographic Density Measures Menopausal Symptom Menopause Meta-Analysis Osteoporosis prevention Perimenopause Pharmaceutical Preparations Phase Placebos Postmenopause Process Progesterone Progestins Public Health Pulmonary Embolism Randomized Randomized Controlled Trials Regimen Relative Risks Risk Safety Science Selective Estrogen Receptor Modulators Series Stroke Symptoms Testing Tissues Uterus Vagina Vasomotor Venous Thrombosis Woman age related arterial stiffness base bone double-blind placebo controlled trial drug discovery effective therapy hormone therapy innovation intimal medial thickening lipid biosynthesis malignant breast neoplasm men mortality novel novel strategies novel therapeutics stroke risk treatment duration venous thromboembolism

项目摘要

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.

项目概要/摘要正如过去的科学结果一样，这项拟议试验的临床和公共卫生影响是深远的十年来已经证实，雌激素可以为女性提供实质性益处，且风险较低，尤其是在以下情况下：开始于围绝经期或绝经后早期。然而，大多数进入的女性更年期子宫需要与孕激素联合治疗，以对抗雌激素引起的子宫内膜异位症增生。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 疗法具有最大的健康价值女性面临的风险包括静脉血栓栓塞 (VTE) 和乳腺癌。然而，作为一个组成部分组织选择性雌激素复合物（TSEC）是一类新型药物，雌激素现在可以通过无孕激素治疗方案，没有孕激素暴露的风险。作为一类新型创新药物， TSEC 疗法通过与选择性的药物合作，为治疗更年期症状提供了一种新方法。雌激素受体调节剂（SERM）与雌激素混合以达到最佳临床效果组织选择性活性概况。联合巴多昔芬 (BZA)（第三代 SERM）的效果结合雌激素（CE）对乳房、子宫内膜、骨骼、脂质生物合成和静脉血栓形成的影响具有独特的安全性和有效性的优化。一系列 3 期随机对照试验表明 BZA/CE（FDA 批准）可有效预防骨质疏松症并缓解血管舒缩和阴道症状，同时确保子宫内膜安全。 BZA/CE 不刺激子宫内膜组织， BZA/CE 组的累积闭经率与安慰剂组相当，子宫内膜异位症的发生率也与安慰剂组相当。增生（<1%）。此外，BZA/CE不会刺激乳腺组织，不会增加乳腺X光检查的强度。相对于安慰剂的密度； VTE（深静脉血栓形成和肺栓塞）和中风的发生率与安慰剂相似。迄今为止，已经用传统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 来保护女性子宫不进行子宫切除术是传统 HT（孕激素对抗雌激素疗法）的下一步使用新的 TSEC 类药物为女性提供安全有效的治疗，其效果动脉粥样硬化的进展尚不清楚。该提案旨在解决我们知识和经验方面的这一重大差距停止利用这个独特的公共卫生机会。我们建议的具体目标是开展对 360 名有子宫的健康绝经后妇女进行的随机、双盲、安慰剂对照试验绝经后 6 年内且年龄小于 60 岁，无临床心血管疾病，并且糖尿病患者随机接受 BZA 20 mg/CE 0.45 mg 或安慰剂治疗，治疗期为 2 至 4.5 年确定 TSEC 治疗对亚临床动脉粥样硬化进展的影响（以变化衡量）以颈动脉内膜中层厚度和颈动脉僵硬度作为试验终点。