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.

项目概要 拟议的补充品与母体 U01 直接相关，并将提供探索性临床证据 需要进行更大规模的全功效研究来确定血液 Nfl 值是否可以作为预后生物标志物 作为我们 U01 后计划的临床试验中的临床试验丰富工具，以治疗并希望预防 高危心力衰竭 (HF) 患者发生 VCID。 在我们的 U01 TPP 中，我们计划将第一批患者群体纳入高危 VCID 群体，其中包括心脏疾病 射血分数降低且有轻度认知障碍证据的 II/IV 级失败患者。我们 相信 NfL 可以作为我们计划的 1b/2a 期临床试验中的临床试验丰富工具，以治疗和治疗 希望能够预防 ADRD 高危心力衰竭患者发生 VCID。本研究中拟议研究的时间安排 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 丰富临床试验资格标准的入组，以确定哪些心力衰竭患者更有可能 开发 VCID/ADRD。 临床上，VCID诊断和疾病监测一般通过磁共振成像（MRI）来实现 扫描和白质高信号 (WMH) 的存在通常被解释为 脑小血管疾病（SVD）。然而，最常使用 MRI 来评估和诊断 VCID 发生在临床测量的显着认知功能障碍的发展之后。神经丝轻蛋白 (NfL) 是一种在血液和脑脊液中发现的神经丝，已被证明在轴突 损伤和神经退行性变，与认知障碍的增加密切相关，并且已被证实 在患有神经退行性疾病、缺氧性脑损伤和心脏病的受试者中观察到升高 及相关手术。目前尚不清楚 NfL 是否可用于检测有 VCID 风险的个体的神经元损伤 例如患有冠心病或心力衰竭等慢性炎症疾病的人。理想情况下，如果我们可以 预测心脏病患者是否存在神经和认知并发症，我们将能够 识别那些可从治疗中受益的高危 VCID 患者。 我们建议的使用背景是 NfL 可以作为血液中的预后生物标志物，帮助预测 伴有 II/IV 期心力衰竭 (HF) 的早期高危 VCID 的临床进展。我们的最终目标是使用 血液中的 Nfl 水平作为我们计划的 U01 后临床试验的招募丰富因素，以确定 患有 HF 的个体更有可能出现 VCID 或 ADRD。 具体目标：为有 VCID 风险的 HF 患者建立基线和 12 个月纵向 Nfl 值 确定 Nfl 绝对水平与受试者认知功能测量和 MRI 之间的关联 I/II 期和 III-IV 期心力衰竭患者。