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

PhytoSERM 预防更年期相关脑代谢和认知能力下降的功效：双盲、随机、安慰剂对照 2 期临床试验

• 批准号: 10344556
• 负责人: ROBERTA EILEEN BRINTON
• 金额: $ 212.12万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344556
• 关键词: 3 year old; Address; Age; Aging; Alternative Health; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Brain; Breast; Cells; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Research; Clinical Trials; Clinical Trials Cooperative Group; Cognition; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Double-Blind Method; Drug Kinetics; Elderly; Endocrine; Estrogen Receptor beta; Estrogen Therapy; Estrogens; Exhibits; Female; Fiber; Formulation; Frequencies; Fright; Functional Magnetic Resonance Imaging; Genistein; Glucose; Goals; Health; Hormones; Hot flushes; Image; Inflammatory; Intervention; Label; Legal patent; Life; Magnetic Resonance Imaging; Mammary Gland Parenchyma; Measures; Memory; Menopausal Symptom; Menopause; Menstruation; Metabolic; National Institute on Aging; Neurologic; Neurologic Symptoms; Neurosecretory Systems; Outcome; Participant; Perimenopause; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Phytoestrogens; Placebo Control; Placebos; Postmenopause; Prevention strategy; Process; Quality Control; Randomized; Research Support; Rest; Risk; Safety; Severities; Symptoms; Tissues; Translating; Translations; Uterus; Vasomotor; Woman; Women' s Health; age related; aged; arterial spin labeling; blood-based biomarker; brain metabolism; brain volume; clinical development; clinical efficacy; cognitive function; critical period; daidzein; disability; effective intervention; effective therapy; equol; estrogenic; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; gray matter; hormone therapy; innovation; lifetime risk; malignant breast neoplasm; metabolic rate; middle age; mood symptom; pre-clinical; preclinical development; prevent; rational design; reproductive; sleep quality; stability testing; treatment strategy; white matter

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.

项目概要/摘要 女性一生中罹患阿尔茨海默病 (AD) 的风险更大，这是导致寿命延长的一个潜在因素。 AD 的时间风险是中年更年期内分泌老化转变，此时可能会出现多种 AD 风险状况 并且与雌激素或激素治疗时疾病的前驱/临床前特征一致。 当更年期妇女有症状时服用可以降低患 AD 的风险，而对乳腺癌的恐惧导致 许多女性放弃了这种雌激素治疗的创新替代方法是针对雌激素的作用。 为了实现这一目标，我们提出了阶段。 2 “PhytoSERM”的临床开发，这是一种选择性雌激素受体β (ERß) 调节剂，可促进 PhytoSERM 通过 ERß 在大脑中发挥雌激素作用，同时在生殖组织中发挥抑制作用。 3 种植物雌激素的配方（每种都被 FDA 认定为安全）。 PhytoSERM 1b/2a 期临床试验确定 PhytoSERM 安全且耐受性良好，表明 围绝经期和绝经后妇女的预测药代动力学和确定的反应者表型 （https://clinicaltrials.gov/ct2/show/NCT01723917）本文提出的是第 2 阶段、双盲、随机、 安慰剂对照、平行组临床试验，以确定 PhytoSERM 对有症状的围产期和围产期患者的疗效 主要目标是确定 PhytoSERM 维持大脑功能的安全性和有效性。 通过 18F-FDG-PET 测定葡萄糖代谢，因为绝经过渡伴随着 葡萄糖的大脑代谢率降低，这与更年期症状和进展相关 AD 生物标志物在以后的生活中将决定 PhytoSERM 在以下方面的功效：1) 认知功能， 2) 血管舒缩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。 目标是确定 PhytoSERM 对探索性 MRI 结果的影响，包括 1) 灰质体积 在 AD 脆弱区域，2) 通过扩散张量成像观察白质纤维完整性，(3) 内在连接 通过静息状态功能 MRI 测量，4) 通过动脉自旋标记 (ASL) 确定脑血流量，以及 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问题。 美国国家老龄化研究所的 2020-2025 年方向：21 世纪的良好老龄化具体参考目标 C-3：“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 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：支持女性健康研究”。 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 解决了女性健康中未得到满足的关键需求，以降低晚年患阿尔茨海默病的风险。