PhytoSERM Efficacy to Prevent Menopause Associated Decline in Brain Metabolism and Cognition: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial

项目摘要/摘要 女性一生中患阿尔茨海默病(AD)的风险更大。一个有助于更美好生活的潜在因素-- AD的时间风险是中年更年期内分泌老化过渡，此时可能出现多种AD风险状况 并且与疾病的前驱症状/临床前特征相一致。而雌激素或激素治疗 在更年期妇女有症状时使用可以降低患AD的风险，对乳腺癌的恐惧导致 许多女性放弃了这一做法。雌激素治疗的一种创新选择是靶向雌激素作用 同时避免乳房组织中雌激素相关的增殖。为了实现这一目标，我们提出了阶段 2“PhytoSERM”的临床开发，它是一种选择性雌激素受体β(ER？)调节剂，促进 雌激素样作用在大脑中是通过ER？，而在生殖组织中则是抑制作用。PhytoSERM是一种设计合理的 3种植物雌激素的配方(每种都被FDA普遍认为是安全的)。我们早先的NIA支持 PhytoSERM 1b/2a期临床试验确定，PhytoSERM是安全和耐受性良好的，展示了 围绝经期和绝经后妇女的预测药代动力学和确定的应答者表型 (https://clinicaltrials.gov/ct2/show/NCT01723917).在此提出的是阶段2，双盲，随机， 安慰剂对照、平行分组临床试验，以确定PhytoSERM对有症状的围产期和非症状期患者的疗效 绝经后的女性。主要目标是确定PhytoSERM维持大脑的安全性和有效性 18F-FDG-PET测定的葡萄糖代谢，因为绝经过渡伴随着 大脑葡萄糖代谢率降低，这与更年期症状和糖尿病的进展有关 AD生物标记物在生命后期。次要目标将决定PhytoSERM在以下方面的疗效：1)认知功能， 2)血管运动症状的频率和严重程度；3)睡眠质量和情绪症状的变化。三级 目的是确定PhytoSERM对探索性MRI结果的影响，包括：1)灰质体积 在AD易损区，2)扩散张量成像显示白质纤维完整性，(3)固有连通性 静息状态功能磁共振测量，4)动脉自旋标记(ASL)测定脑血流量 5)与AD风险相关的血液生物标志物。2期PhytoSERM临床试验解决了多个战略 美国国家老龄问题研究所2020-2025年的发展方向：21世纪的良好老龄化 C-3至：“制定有效的干预措施，以维持健康、福祉和功能，并预防或减少 年龄相关疾病的负担“和”进行临床研究/将新的干预措施转化为临床 设置。“目标D-4：将基本发现转化为AD/ADRD的有效治疗和/或预防战略 以及“目标F-4：支持有关妇女健康的研究。”PhytoSERM临床试验也有助于实现 《国家阿尔茨海默病项目法案》(NAPA)旨在到2025年有效预防和治疗阿尔茨海默病目标1B。 PhytoSERM解决了女性健康中一个关键的未得到满足的需求，以降低晚年患阿尔茨海默氏症的风险。

PROJECT SUMMARY/ABSTRACT Women are at greater life-time risk for Alzheimer’s disease (AD). One potential factor contributing to greater life- time risk of AD is the midlife menopausal endocrine aging transition when multiple AD risk conditions can emerge and which are consistent with prodromal / preclinical features of the disease. While estrogen or hormone therapy administered when menopausal women are symptomatic could reduce risk of AD, the fear of breast cancer leads many women to forego this approach. An innovative alternative to estrogen therapy is to target estrogen action in brain while avoiding estrogen-associated proliferation in breast tissue. To achieve that goal, we propose Phase 2 clinical development of “PhytoSERM”, a selective estrogen receptor beta (ERß) modulator that promotes estrogenic action through ERß in brain while inhibitory in reproductive tissue. PhytoSERM is a rationally designed formulation of 3 phytoestrogens (each are Generally Recognized as Safe by the FDA). Our earlier NIA supported PhytoSERM Phase 1b/2a clinical trial determined that PhytoSERM was safe and well-tolerated, exhibited predictive pharmacokinetics in peri- and postmenopausal women and identified responder phenotype (https://clinicaltrials.gov/ct2/show/NCT01723917). Proposed herein is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group, clinical trial to determine efficacy of PhytoSERM in symptomatic peri- and post-menopausal women. Primary objectives are to determine safety and efficacy of PhytoSERM to sustain brain glucose metabolism as determined by 18F-FDG- PET because the menopausal transition is accompanied by reduction in cerebral metabolic rate of glucose, which correlates with menopausal symptoms and progression of AD biomarkers later in life. Secondary objectives will determine efficacy of PhytoSERM on: 1) cognitive function, 2) frequency and severity of vasomotor symptoms and 3) changes in sleep quality and mood symptoms. Tertiary objectives are to determine impact of PhytoSERM on exploratory MRI outcomes including 1) gray matter volume in AD-vulnerable regions, 2) white matter fiber integrity by diffusion tensor imaging, (3) intrinsic connectivity measured by resting state functional MRI, 4) cerebral blood flow determined by arterial spin labeling (ASL) and 5) blood-based biomarkers relevant to AD risk. The Phase 2 PhytoSERM clinical trial addresses multiple strategic directions of the National Institutes on Aging’s 2020-2025: Aging Well in the 21st Century ref Specifically, Goal C-3 to: “Develop effective interventions to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases” and “Conduct clinical studies / translation of new interventions to the clinical setting.” Goal D-4: Translate basic discovery into effective treatment and/or prevention strategies for AD/ADRD and” Goal F-4: Support research on women’s health.” PhytoSERM clinical trial also contributes to achieving the National Alzheimer’s Disease Project Act (NAPA) to effectively prevent and treat AD by 2025 Goal 1B. PhytoSERM addresses a critical unmet need in women’s health to reduce risk of Alzheimer’s in later life.