Phase 3 trial of inosine for Parkinson's disease CCC

描述(申请人提供)：汇聚的实验室、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，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指标。尿酸盐也是一种有效的抗氧化剂，在帕金森病的细胞和动物模型中具有保护作用。对前瞻性跟踪的健康人群的流行病学研究一再证明，血清尿酸盐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较慢的预测指标，临床或通过多年来多巴胺转运体(DAT)丢失的神经成像进行评估。第二阶段进展：基于尿酸盐作为帕金森病患者的神经保护剂和良好的预后生物标志物的特性，尿酸盐升高被认为是一种候选的疾病改善策略。肌苷是一种口服生物可利用的尿酸盐前体，在帕金森病尿酸盐升高的安全性(SURE-PD)试验的第2阶段研究中进行了研究。结果表明，肌苷可以安全地使早期帕金森病患者的血清和脑脊液尿酸在数月或数年内维持在可耐受的水平。对长期临床数据的二次分析支持进入关键的疗效试验。结果还表明，在剂量和其他设计特征方面有所改进。第三阶段的目标：这项研究的主要目标是确定口服肌苷持续升高血尿酸(从5.7 mg/dL到7.1-8.0 mg/dL)是否会在两年内减缓早期帕金森病的临床进展。次要目标包括评估长期安全性和对以下方面的影响：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性测量。临床协调中心(CCC)的业务目标是安全、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纳入270名早期帕金森病、血尿酸降低、神经影像显示DAT缺乏的受试者，他们将以1：1的比例随机接受安慰剂或肌苷剂量升高尿酸的治疗，为期2年，为期3个月。我们的运动障碍协会统一PD评定量表(MDS-UPDRS)总分变化的主要结果将按季度进行评估，以衡量患者和研究人员报告的疾病以及运动和非运动特征。意义：减缓帕金森病的进行性临床下降仍然是神经治疗学发展中一个关键的未实现的目标。如果PD患者较高的尿酸和良好的预后之间建立的联系是由于神经保护特性，那么这项研究旨在提供直接证据，证明提高尿酸肌苷治疗减缓了疾病的临床进展。

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.