Phase 3 trial of inosine for Parkinson's disease - DCC

肌苷治疗帕金森病的 3 期试验 - DCC

• 批准号: 9292389
• 负责人: David Oakes
• 金额: $ 119.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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/9292389
• 关键词: Accountability; Address; Algorithms; Animal Model; Antioxidants; Bioavailable; Biometry; Blinded; Cell model; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Cognition; Companions; Complement; Computational Biology; Critiques; Data; Data Aggregation; Data Coordinating Center; Databases; Development; Disclosure; Disease; Disease Progression; Doctor of Philosophy; Dose; Double-Blind Method; Emergency treatment; Enrollment; Ensure; Environment; Epidemiology; Event; Faculty; Futility; General Hospitals; Generations; Goals; Human; Individual; Inosine; Internet; Investigational Drugs; Investigational Therapies; Iowa; Joints; Label; Laboratories; Leadership; Maintenance; Masks; Massachusetts; Measures; Medical center; Methods; Molecular; Monitor; Moods; Motor; Movement Disorders; Neuroprotective Agents; Oral; Outcome; Outcome Measure; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Placebo Control; Placebos; Population; Prognostic Marker; Property; Prospective Studies; Publications; Quality of life; Randomized; Recruitment Activity; Reporting; Research; Research Infrastructure; Research Personnel; Resolution; Risk; Risk Factors; Safety; Scheme; Secure; Serious Adverse Event; Serum; Services; Site; Societies; Statistical Data Interpretation; Suspensions; Symptoms; Titrations; Training; Universities; Update; Urate; Withdrawal; base; capsule; clinical material; clinical research site; data management; design; disability; dopamine transporter; dosage; efficacy trial; epidemiology study; functional disability; meetings; neuroimaging; operation; phase 2 study; premature; primary outcome; public health relevance; purine metabolism; randomized trial; relational database; retention rate; secondary analysis; trend; 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，可在帕金森病的细胞和动物模型中提供保护，对健康人群的前瞻性流行病学研究多次证明血清尿酸盐是帕金森病的反向危险因素。发现在早期 PD 患者中，血清和脑脊液尿酸水平是进展缓慢的预测因素，经过临床评估或通过多年来多巴胺转运蛋白 (DAT) 损失的神经影像学评估，第 2 阶段进展：基于尿酸作为神经保护剂和有利的预后生物标志物的特性。在帕金森病中，尿酸盐升高被提议作为一种候选疾病缓解策略，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“尿酸盐的安全性”中进行了研究。帕金森病升高 (SURE-PD) 试验表明，肌苷可以在早期帕金森病中安全地产生数月或数年的血清和脑脊液尿酸升高，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：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）可减缓早期 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) 帕金森病的短期变化的影响。症状，c) 功能障碍和生活质量的变化，以及 d) 认知、情绪和自主功能的非运动测量 临床协调中心 (CCC) 的运营目标是安全、有效地进行治疗。有效管理约 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。肌苷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 的比例随机分配至安慰剂或肌苷以升高尿酸的治疗组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，为期 2 年，并进行 3 个月的清除。意义：减缓帕金森病的进展性临床衰退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的良好结果之间已建立的联系是由于神经保护特性。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。