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

项目概要/摘要 女性一生中患阿尔茨海默病（AD）的风险更大。一个潜在的因素有助于更大的生活- AD的时间风险是中年绝经期内分泌衰老过渡，此时可能出现多种AD风险状况 并且与疾病的前驱/临床前特征一致。虽然雌激素或激素治疗 当绝经期妇女有症状时服用可以降低AD的风险，对乳腺癌的恐惧导致 许多女性放弃了这种做法。一个创新的替代雌激素治疗是针对雌激素的作用 同时避免乳腺组织中雌激素相关的增殖。为了实现这一目标，我们提出阶段 2“PhytoSERM”的临床开发，一种选择性雌激素受体β（ERP 4）调节剂， 在脑内通过ER β发挥雌激素作用，而在生殖组织中则具有抑制作用。PhytoSERM是一个合理设计的 3种植物雌激素的配方（每种都被FDA公认为安全）。我们早期的NIA支持 PhytoSERM 1b/2a期临床试验确定PhytoSERM是安全的，耐受性良好， 绝经期和绝经后妇女中的预测药代动力学和确定的应答者表型 （https：//clinicaltrials.gov/ct2/show/NCT01723917）。本文提出的是一项2期、双盲、随机、 安慰剂对照，平行组，临床试验，以确定PhytoSERM的疗效在有症状的乳腺癌， 绝经后妇女。主要目的是确定PhytoSERM的安全性和有效性，以维持大脑 通过18F-FDG- PET测定的葡萄糖代谢，因为绝经过渡期伴随着 脑葡萄糖代谢率降低，这与绝经期症状和 生命后期的AD生物标志物。次要目的将确定PhytoSERM对以下方面的功效：1）认知功能， 2)血管痉挛症状的频率和严重程度，以及3）睡眠质量和情绪症状的变化。叔 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易感区域，2）通过扩散张量成像检测白色纤维完整性，（3）内在连接性 通过静息状态功能MRI测量，4）通过动脉自旋标记（ASL）确定的脑血流量，以及 5)与AD风险相关的血液生物标志物。PhytoSERM的第二阶段临床试验解决了多个战略 国家老龄研究所的方向2020-2025：老龄化以及在21世纪世纪参考具体来说，目标 C-3改为：“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 年龄相关疾病负担”和“开展临床研究/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/或预防策略 和”目标F-4：支持妇女健康研究”。PhytoSERM临床试验也有助于实现 国家阿尔茨海默病项目法案（NAPA）到2025年有效预防和治疗AD目标1B。 PhytoSERM解决了女性健康中一个关键的未满足的需求，以减少老年痴呆症的风险。

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.