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: 10560591
• 负责人: ROBERTA EILEEN BRINTON
• 金额: $ 154.45万
• 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/10560591
• 关键词: 3 year old; Address; Age; Age Years; Aging; Alternative Health; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Brain; Brain region; Breast; Breast Cancer Risk Factor; Cell Proliferation; 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; Proliferating; Quality Control; Randomized; Research Support; Rest; Risk; Risk Reduction; Safety; Severities; Tissues; Translating; Translations; Uterus; 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; efficacy evaluation; equol; estrogenic; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; gray matter; hormone therapy; innovation; lifetime risk; malignant breast neoplasm; manufacture; manufacturing quality; menopausal aging; metabolic rate; middle age; mood symptom; pre-clinical; preclinical development; prevent; rational design; reproductive; sleep quality; stability testing; treatment strategy; vasomotor symptoms; 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.

项目摘要/摘要 妇女患阿尔茨海默氏病（AD）的终身风险更大。有助于更大生活的一个潜在因素 - 广告的时间风险是当多个AD风险条件出现时中期的绝经内分泌老化过渡过渡 并且与该疾病的前奏 /临床前特征一致。而雌激素或马酮治疗 当绝经妇女症状时，进行管理可以降低AD的风险，害怕乳腺癌的铅 许多妇女放弃这种方法。雌激素疗法的创新替代方案是靶向雌激素作用 在大脑中，同时避免了乳腺组织中与雌激素相关的增殖。为了实现这一目标，我们提出了阶段 2临床开发“ Phytoserm”，一种促进的选择性雌激素受体β（ERß）调节剂 雌激素通过ERß在脑中的雌激素作用，而在生殖组织中的抑制作用。 Phytoserm是一个理性设计的 形成了3种植物雌激素（每种植物雌激素通常被FDA确定为安全）。我们较早的NIA支持 Phytoserm期1b/2a临床试验确定植物酶是安全且耐受性良好的 预测性药代动力学在绝经后妇女和后妇女中识别出响应者表型 （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，以确定颗粒性植物度的效率 绝经后妇女。主要目标是确定植物剂的安全性和效率以维持大脑 由18F-FDG-PET确定的葡萄糖代谢，因为更年期过渡是通过 葡萄糖的脑代谢率降低，这与更年期症状和进展相关 AD生物标志物以后。次要对象将确定植物剂的效率：1）认知函数， 2）血管舒缩症状的频率和严重程度和3）睡眠质量和情绪症状的变化。第三 目的是确定植物类剂对探索性MRI结果的影响，包括1）灰质体积 在可广泛的区域中，2）扩散张量成像的白质纤维完整性，（3）固有连接性 通过静止状态功能MRI测量，4）由动脉自旋标记（ASL）确定的脑血流和 5）与AD风险相关的基于血液的生物标志物。第2阶段植物血临床试验解决了多重策略 美国国立衰老2020-2025机构的指示：在21世纪涉及的老龄化，特别是目标 C-3 TO：“制定有效的干预措施以维持健康，福祉和运作，并预防或减少 与年龄相关疾病的负担”和“对临床新干预措施进行临床研究 /翻译 设置。”目标D-4：将基本发现转化为有效的治疗和/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 国家阿尔茨海默氏病项目法（NAPA），以在2025年目标1B之前有效预防和治疗AD。 Phytoserm解决了妇女健康的至关重要的需求，以降低后来的阿尔茨海默氏症风险。