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: 9292399
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 338.88万
• 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/9292399
• 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; Epidemiology; Family; Foundations; Future; Goals; Gout; Government; 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; Pathogenicity; 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; Prospective Studies; Purines; Quality of life; Randomized; Recruitment Activity; Reporting; Research Personnel; Risk; Risk Factors; Role; Safety; Serum; Services; Societies; Solubility; Symptoms; Training; Urate; Urate Oxidase; arm; base; blind; clinical biomarkers; clinical material; clinical research site; cost; data management; design; disability; dopamine transporter; efficacy trial; epidemiology study; functional disability; improved; innovation; modifiable risk; nervous system disorder; neuroimaging; neuroprotection; novel; open source; oxidative damage; phase 2 study; primary outcome; public health relevance; purine metabolism; randomized trial; rate of change; secondary analysis; trial design; urate transporter

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）：综合实验室、流行病学和临床观察已确定尿酸盐（人类嘌呤代谢的最终产物）作为一种神经保护剂，并且是降低典型帕金森病 (PD) 风险和减缓进展的第一个分子预测因子。尿酸盐也是一种有效的抗氧化剂，可为帕金森病的细胞和动物模型提供保护。对健康人群进行前瞻性随访的流行病学研究一再证明血清尿酸是帕金森病的反向危险因素。这些发现导致发现，在早期帕金森病患者中，血清和脑脊液尿酸水平是进展缓慢的预测因素，通过临床或通过多年来多巴胺转运蛋白 (DAT) 损失的神经影像学评估进行评估。第二阶段进展：基于尿酸盐作为神经保护剂和PD有利预后生物标志物的特性，尿酸盐升高被提议作为候选疾病缓解策略。肌苷是一种口服生物可利用的尿酸盐前体，在一项 2 期研究中进行了研究，即帕金森病尿酸盐升高的安全性 (SURE-PD) 试验。它证明肌苷可以在帕金森病早期安全地使血清和脑脊液尿酸升高数月或数年，且耐受性良好。对长期临床数据的二次分析支持推进关键疗效试验。结果还建议对剂量和其他设计特征进行改进。第 3 期目标：该研究的主要目的是确定口服肌苷是否会持续升高血清尿酸（从 = 5.7 mg/dL 至 7.1-8.0 mg/dL），从而减缓早期 PD 两年内的临床进展。次要目标包括评估长期安全性和对 a) 需要多巴胺能药物治疗的残疾的发展，b) 帕金森症状的短期变化，c) 功能性残疾和生活质量的变化，以及 d) 认知、情绪和自主功能的非运动测量的影响。临床协调中心 (CCC) 的运营目标是安全、有效和高效地管理约 60 个参与帕金森研究组 (PSG) 临床中心的所有研究活动和培训，并将 CCC 的临床管理与合作数据协调中心 (DCC) 的数据和药物管理相结合。方法：一项肌苷安慰剂对照、双盲随机试验将招募 270 名患有早期 PD、血清尿酸降低和 DAT 缺乏（通过神经影像学检查）的受试者，并将他们以 1:1 的比例随机分配到安慰剂或肌苷治疗组，以提高尿酸水平，治疗 2 年，并有 3 个月的清除期。我们将每季度评估一次运动障碍协会统一 PD 评定量表 (MDS-UPDRS) 总分变化的主要结果，以衡量患者和研究者报告的疾病的运动和非运动特征。意义：减缓帕金森病临床进展的进展仍然是神经治疗药物开发中尚未实现的一个关键目标。如果高尿酸与帕金森病患者良好结局之间已建立的关联是由于神经保护特性，那么本研究旨在提供直接证据，证明升高尿酸的肌苷治疗可减缓疾病的临床进展。