Phase 3 trial of inosine for Parkinson's disease CCC

描述（由申请人提供）：实验室、流行病学和临床观察结果一致，已确定尿酸盐（人体嘌呤代谢的终产物）是一种神经保护剂，是降低典型帕金森病（PD）风险和减缓其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，并在PD的细胞和动物模型中提供保护。前瞻性随访健康人群的流行病学研究反复证明血清尿酸盐是PD的反向危险因素。这些研究结果导致发现，在早期PD患者中，血清和CSF尿酸盐水平是进展较慢的预测因素，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。第二阶段进展：基于尿酸盐作为神经保护剂和PD中有利的预后生物标志物的特性，提出尿酸盐升高作为候选疾病改善策略。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（SURE-PD）试验中尿酸盐升高的安全性。这表明，肌苷可以安全地产生耐受良好的血清和CSF尿酸升高数月或数年的早期PD。长期临床数据的次要分析支持推进关键疗效试验。结果还表明，在剂量和其他设计特点的完善。第3阶段目标：该研究的主要目的是确定口服肌苷持续升高血清尿酸盐（从=5.7 mg/dL至7.1-8.0 mg/dL）是否会减缓早期PD患者两年的临床进展。次要目的包括评估长期安全性和对以下方面的影响：a）阻止多巴胺能药物失能的发展，B）帕金森症状的短期变化，c）功能性失能和生活质量的变化，d）认知、情绪和自主神经功能的非运动测量。临床协调中心（CCC）的运营目标是安全、有效和高效地管理约60个参与帕金森研究组（PSG）临床研究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。研究方法：一项关于肌苷的安慰剂对照、双盲随机试验将招募270例早期PD、血清尿酸盐较低和DAT缺乏（通过神经影像学检查）的受试者，并将他们1：1随机分配至安慰剂或肌苷治疗组，以提高尿酸盐水平，持续2年，洗脱期为3个月。我们将每季度评估运动障碍协会统一PD评定量表（MDS-PDRS）总评分变化的主要结局，以衡量患者和患者报告的疾病运动和非运动特征。意义：减缓PD的进行性临床下降仍然是神经治疗学发展的一个关键未满足的目标。如果高尿酸盐与PD患者良好结局之间的既定关联是由于神经保护特性，那么本研究旨在提供直接证据，证明尿酸盐升高肌苷治疗可减缓疾病的临床进展。

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.