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

• 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
• 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

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.

项目摘要/摘要 这项拟议试验对临床和公共卫生的影响是在最后的科学方面深远的。 十年已经证实，雌激素为女性提供了较低风险的可观利益，尤其是 在绝经期或绝经后早期开始。但是，大多数妇女进入 更年期的子宫需要与孕激素共同治疗以对抗雌激素引起的子宫内膜 增生。与孕激素共同治疗为绝经后激素治疗创造了一个限制因素 （HT）由于仅相对于雌激素，传统的含孕激素的HT方案具有最大的健康状况 女性的风险，包括静脉血栓栓塞（VTE）和乳腺癌。但是，作为 组织选择性雌激素复合物（TSEC），一种新类型的雌激素，现在可以在A中递送 无孕激素方案没有孕激素暴露的风险。作为新的创新药物， TSEC疗法通过合作有选择性，为治疗更年期症状提供了一种新颖的方法 雌激素受体调节剂（SERM）与雌激素，以基于混合的方式获得最佳的临床结果 组织选择性活动曲线。联合Bazedoxifene（BZA）的效果，这是第三代Serm 乳房，子宫内膜，骨，脂质生物合成和静脉血栓形成的共轭雌激素（CE）是 独特的安全性和功效。一系列3期随机对照试验已显示 BZA/CE（FDA批准）可有效预防骨质疏松症，并减轻血管舒适和 阴道症状，同时确保子宫内膜安全性。 BZA/CE不会刺激子宫内膜组织和 BZA/CE的累积闭经率与安慰剂相当，子宫内膜的发生率也是如此 增生（<1％）。此外，BZA/CE不会刺激乳房组织，也不会增加乳房X线摄影 密度相对于安慰剂； VTE（深静脉血栓形成和肺栓塞）和中风的发生率 类似于安慰剂。迄今为止，已经通过传统的孕激素进行了随机对照试验 基于HT。部署BZA/CE的无孕激素配方以保护女性的子宫 没有子宫切除术是超出传统HT（孕激素相反的雌激素治疗）的下一步 为新的TSEC类代理商提供安全有效的疗法，其影响 动脉粥样硬化进展未知。该建议旨在解决我们所知的这一主要差距， 停止这种独特的公共健康机会。我们建议的具体目的是进行 随机，双盲，安慰剂对照试验在360个健康的绝经后妇女中 在更年期的6年内，不到60岁，没有临床心血管疾病和 糖尿病在2至4.5岁的治疗期间随机分为BZA 20 mg/ce 0.45 mg或安慰剂 确定TSEC治疗对以变化为变化的亚临床动脉粥样硬化进展的影响 在颈动脉内膜中，厚度和颈动脉刚度作为试验终点。