Phase 3 trial of inosine for Parkinson's disease CCC

肌苷治疗帕金森病 CCC 的 3 期试验

• 批准号: 9258571
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 9.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258571
• 关键词: Accounting; Animal Model; Antioxidants; Bioavailable; Cell model; Cerebrospinal Fluid; Clinical; Clinical Data; Clinical Management; Clinical Trials; Cognition; Computer software; Data; Data Coordinating Center; Databases; Development; Development Plans; Disease; Disease Progression; Dopamine; Dose; Double-Blind Method; Enrollment; Epidemiologic Studies; Epidemiology; Family; Foundations; Future; Goals; Gout; Government; Health; Healthcare; Human; Individual; Inosine; Investments; Laboratories; Leadership; Letters; Mammals; Measures; Methods; Molecular; Moods; Motor; Movement Disorders; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroprotective Agents; Oral; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Play; Population; Predisposition; Primates; Prognostic Marker; Property; Purines; Quality of life; Randomized; Reporting; Research Personnel; Risk; Risk Factors; Role; Safety; Serum; Services; Societies; Solubility; Symptoms; Training; Training Activity; Urate; Urate Oxidase; arm; base; blind; clinical biomarkers; clinical material; clinical research site; cost; data management; design; disability; dopamine transporter; efficacy trial; functional disability; improved; innovation; modifiable risk; nervous system disorder; neuroimaging; neuroprotection; novel; open source; oxidative damage; phase 2 study; primary outcome; purine metabolism; randomized trial; rate of change; trial design

DESCRIPTION (provided by applicant): Convergent laboratory, epidemiological and clinical observations have identified urate - the end product of purine metabolism in humans - as a neuroprotectant and the first molecular predictor of both reduced risk and slower progression of typical Parkinson's disease (PD). Urate is also a potent antioxidant and confers protection in cellular and animal models of PD. Epidemiological studies of prospectively followed healthy populations have repeatedly demonstrated serum urate to be an inverse risk factor for PD. These findings led to the discovery that among people with early PD serum and CSF urate levels are predictors of slower progression, assessed clinically or by neuroimaging of dopamine transporter (DAT) loss over years. Phase 2 Progress: Based on urate's properties as a neuroprotectant and favorable prognostic biomarker in PD, urate elevation was proposed as a candidate disease-modifying strategy. Inosine, an orally bioavailable precursor of urate, was investigated in a phase 2 study, the Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial. It demonstrated that inosine can safely produce well-tolerated elevations of serum and CSF urate for months or years in early PD. Secondary analyses of long-term clinical data support advancing to a pivotal efficacy trial. Results also suggested refinements in dosing and other design features. Phase 3 Aims: The primary aim of the study is to determine whether oral inosine dosed to persistently elevate serum urate (from =5.7 mg/dL to 7.1-8.0 mg/dL) slows clinical progression over two years in early PD. Secondary aims include assessing long-term safety and effects on a) the development of disability warranting dopaminergic medication, b) short-term changes in parkinsonian symptoms, c) changes in functional disability and quality of life, and d) non-motor measures of cognition, mood and autonomic function. The operational aim of the Clinical Coordinating Center (CCC) is to safely, effectively and efficiently manage all study activities and training of ~60 participating Parkinson Study Group (PSG) clinical sites and to integrate clinical management by the CCC with data and drug management by the partnered Data Coordinating Center (DCC). Methods: A placebo-controlled, double-blind randomized trial of inosine will enroll 270 subjects with early PD, lower serum urate and DAT deficiency by neuroimaging and will randomize them 1:1 to treatment with placebo or inosine dosed to elevate urate for 2 years with a 3-month wash-out. Our primary outcome of change in the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) total score will be assessed quarterly to measure patient- and investigator-reported and motor and non-motor features of the disease. Significance: Slowing the progressive clinical decline of PD remains a critical unmet goal of neurotherapeutics development. If the established association between higher urate and favorable outcomes in PD patients are due to neuroprotective properties, then this study is designed to provide direct evidence that urate-elevating inosine treatment slows clinical progression of the disease.

描述（由申请人提供）：收敛的实验室，流行病学和临床观察结果已经确定了尿酸盐 - 嘌呤代谢在人类中的最终产物 - 作为神经保护剂，是典型帕金森氏病（PD）的风险降低和降低风险降低的第一个分子预测因子。尿酸盐也是一种有效的抗氧化剂，并且赋予了PD细胞和动物模型中的保护。前瞻性遵循的流行病学研究反复证明血清尿酸盐是PD的逆危险因素。这些发现导致发现，在早期PD血清和CSF水平的人中，在临床或多年多年多巴胺转运蛋白（DAT）损失多年的神经影像学评估中是较慢的进展预测指标。第2阶段的进展：基于乌拉特作为神经保护剂和PD的预后生物标志物的特性，提出了尿酸盐升高作为候选疾病改良策略。肌苷是尿酸盐的口服生物利用前体，在第二阶段的研究中研究了帕金森氏病（Sure-PD）试验中尿酸盐升高的安全性。它表明，在PD早期，肌苷可以安全地产生良好的血清和CSF尿酸盐升高数月或几年。长期临床数据的次要分析支持前进到关键疗效试验。结果还提出了剂量和其他设计功能的改进。第三阶段的目的：研究的主要目的是确定口服肌苷是否持续升高血清尿酸含量（从= 5.7 mg/dl到7.1-8.0 mg/dl）在PD早期的两年内会在两年内放慢临床进展。次要目的包括评估长期安全性以及对a）残疾的发展保证多巴胺能药物的发展，b）帕金森氏症状的短期变化，c）功能障碍和生活质量的变化，以及d）非动力的认知，情绪，情绪和自治功能。临床协调中心（CCC）的运营目的是安全，有效，有效地管理所有研究活动，并培训约60个参与的帕金森研究小组（PSG）临床站点，并将CCC与合作数据协调中心（DCC）（DCC）的数据和药物管理相结合。方法：通过神经影像学通过神经影像学来，一项安慰剂对照的双盲随机试验将招募270名患者，血清尿酸盐和DAT较低的受试者，并将其1：1随机使其以安慰剂或inosine的治疗，以升高尿酸盐，以升高尿酸盐2年，并清洗了3个月。我们将每季度评估运动障碍社会统一PD评级量表（MDS-UPDRS）的主要结果，以衡量疾病的患者和研究者报告，运动和非运动特征。意义：放缓PD的渐进临床下降仍然是神经疗法发展的关键未得到的目标。如果在PD患者中较高的尿酸盐和有利结果之间建立的关联是由于神经保护特性引起的，那么本研究旨在提供直接的证据表明，尿酸氨酸肌苷治疗减慢了疾病的临床进展。