IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia

新型 Mas 受体激动剂的 IND 使研究能够治疗有阿尔茨海默病相关痴呆风险的患者的认知障碍

• 批准号: 10373528
• 负责人: Meredith Hay
• 金额: $ 38.02万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373528
• 关键词: Administrative Supplement; Agonist; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensins; Biological Assay; Biological Markers; Blood; Brain; Cardiovascular Diseases; Cerebral small vessel disease; Cerebrospinal Fluid; Chronic; Clinic; Clinical; Clinical Data; Clinical Trials; Cognitive; Coronary Artery Bypass; Coronary heart disease; Critical Illness; Data; Dementia; Development; Diagnosis; Disease; EFRAC; Early Intervention; Elderly; Eligibility Determination; Encephalitis; Enrollment; Goals; Heart Diseases; Heart failure; Hypoxic Brain Damage; Impaired cognition; Individual; Inflammatory; Lead; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Medical; Microvascular Dysfunction; Modeling; Monitor; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Neuropsychological Tests; Operative Surgical Procedures; Parents; Patients; Peptides; Perfusion; Phase; Population; Positioning Attribute; Prognostic Marker; Reproducibility; Risk; Sampling; Serum; Testing; Therapeutic; Traumatic Brain Injury; Validation; Vision; White Matter Hyperintensity; angiotensin I (1-7); axon injury; biobank; chronic inflammatory disease; clinical development; clinical predictors; clinically significant; cognitive function; dementia risk; mild cognitive impairment; neurofilament; neurofilament protein L; novel; patient population; prevent; prognostic; rate of change; receptor; recruit; systemic inflammatory response; tool; vascular cognitive impairment and dementia

PROJECT SUMMARY The proposed supplement is directly related to the parent U01 and will provide the exploratory clinical evidence needed for a larger fully powered study to determine if blood Nfl values might serve as a prognostic biomarker and as a clinical trial enrichment tool in our post U01 planned clinical trials to treat and hopefully prevent the development of VCID in at-risk heart failure (HF) patients. In our U01 TPP, we planned our first patient population to include an at-risk VCID population that include Heart Failure Class II/IV patients with decreased ejection fraction and evidence of mild cognitive impairment. We believe that NfL may serve as a clinical trial enrichment tool in our planned Phase 1b/2a clinical trial to treat and hopefully prevent the development of VCID in ADRD at-risk HF patients. The timing of proposed study in this administrative supplement will position our team in an excellent position to deploy Nfl as a biomarker for enrollment enrichment for clinical trial eligibility criteria to identify which HF patients who are more likely to develop VCID/ ADRD. In the clinic, VCID diagnosis and disease monitoring is generally achieved by magnetic resonance imaging (MRI) scans and the presence of white matter hyperintensities (WMH) that are typically interpreted as a surrogate of cerebral small vessel disease (SVD). However, the assessment and diagnosis of VCID using MRI most often occurs after the development of significant clinically measured cognitive dysfunction. Neurofilament light protein (NfL), a neurofilament found in blood and cerebral spinal fluid, has been shown to increase following axonal damage and neurodegeneration and is tightly correlated with increased cognitive impairment and has been observed to be elevated in subjects with neurodegenerative diseases, hypoxic brain injury, and cardiac disease and related surgeries. It is unclear if NfL can be used to detect neuronal damage in individuals at risk for VCID such as those withs chronic inflammatory disease such as coronary heart disease or HF. Ideally, if we can predict the presence of neurological and cognitive complications in individuals with heart disease, we will be able to identify those at-risk VCID patients who would benefit from therapeutic treatment. Our proposed Context of Use is that NfL might serve as a Prognostic Biomarker in blood that can help predict clinical progression in early at-risk VCID with stage II/IV heart failure (HF). Our ultimate goal will be to use levels of Nfl in blood as an enrollment enrichment factor for our planned post U01 clinical trial to identify individuals with HF who are more likely to develop VCID or ADRD. Specific Aim: Establish a baseline and 12-month longitudinal Nfl values in HF patients at risk for VCID and determine the association between absolute levels of Nfl with measures cognitive function and MRI in subjects with stage I/II and III-IV HF patients.

项目总结 建议的补充与亲本U01直接相关，并将提供探索性的临床证据 需要一项更大的全功率研究来确定血液NFL值是否可能作为预后的生物标志物 作为我们U01后计划的临床试验的丰富工具，用于治疗并有望预防 VCID在高危心力衰竭患者中的发展。 在我们的U01 TPP中，我们计划我们的第一个患者群体包括高危VCID人群，包括心脏 II/IV级衰竭患者，射血分数降低，有轻度认知障碍的证据。我们 相信NFL可以作为我们计划的1b/2a期临床试验的临床试验丰富工具，用于治疗和 希望能预防ADRD高危心力衰竭患者发生VCID。建议在这方面进行研究的时间 行政补充将使我们的团队处于有利地位，可以将NFL作为生物标志物部署到 临床试验资格标准的登记充实，以确定哪些心衰患者更有可能 开发VCID/ADRD。 在临床上，VCID的诊断和疾病监测通常是通过磁共振成像(MRI)来实现的 扫描和白质高信号(WMH)的存在通常被解释为 脑部小血管病(SVD)。然而，VCID的评估和诊断最常用的是MRI 发生在出现显著的临床测量的认知功能障碍之后。神经丝轻蛋白 在血液和脑脊液中发现的一种神经丝(NFL)，已被证明随着轴突的增加而增加 损伤和神经退行性变与认知障碍的增加密切相关，一直以来 在神经退行性疾病、缺氧性脑损伤和心脏病患者中观察到升高 以及相关的手术。目前尚不清楚NFL能否用于检测有VCID风险的个体的神经元损伤 例如患有慢性炎症性疾病的人，如冠心病或心力衰竭。理想情况下，如果我们可以 预测心脏病患者的神经和认知并发症的存在，我们将能够 确定哪些高危VCID患者将从治疗中受益。 我们提出的使用背景是NFL可能作为血液中的一个预测生物标记物，可以帮助预测 早期高危VCID伴II/IV期心力衰竭(HF)的临床进展。我们的最终目标将是使用 血液中NFL水平作为我们计划的U01后临床试验的登记浓缩因子以确定 更有可能发展为VCID或ADRD的心力衰竭患者。 具体目标：建立心力衰竭患者VCID和VCID的基线和12个月纵向NFL值 确定受试者NFL绝对水平与认知功能和磁共振之间的关系 对于I/II期和III-IV期心衰患者。