Phase 3 trial of inosine for Parkinson's disease CCC

描述（由申请人提供）：综合实验室、流行病学和临床观察已经确定尿酸盐——人类嘌呤代谢的最终产物——是一种神经保护剂，也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，在细胞和动物模型中具有保护作用。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一个反向危险因素。这些发现表明，在早期PD患者中，血清和脑脊液尿酸水平是进展较慢的预测因素，可通过临床评估或多年来多巴胺转运体（DAT）损失的神经影像学评估。2期进展：基于尿酸盐作为神经保护剂和PD预后良好的生物标志物的特性，尿酸盐升高被提出作为一种候选的疾病改善策略。肌苷是一种口服可利用的尿酸盐前体，在一项名为帕金森病尿酸盐升高的安全性（SURE-PD）试验的2期研究中进行了研究。研究表明，肌苷可以在早期PD患者数月或数年内安全地产生耐受性良好的血清和脑脊液尿酸升高。长期临床数据的二次分析支持推进关键疗效试验。结果还建议改进剂量和其他设计特征。3期目的：该研究的主要目的是确定口服肌苷持续提高血清尿酸（从=5.7 mg/dL到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a)需要多巴胺能药物治疗的残疾发展的影响，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、情绪和自主神经功能的非运动测量。临床协调中心（CCC）的运作目标是安全、有效和高效地管理约60个参与帕金森研究小组（PSG）临床站点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：一项肌苷的安慰剂对照双盲随机试验将招募270名早期PD、低血清尿酸和DAT缺乏的受试者，并将他们1:1随机分配到安慰剂或肌苷剂量以提高尿酸治疗2年，3个月洗脱期。我们的主要结局是运动障碍学会统一PD评定量表（MDS-UPDRS）总分的变化，将每季度评估一次，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：减缓帕金森病的进行性临床衰退仍然是神经治疗学发展的一个关键目标。如果PD患者高尿酸与良好预后之间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，证明尿酸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.