Clinical Coordination Center for STEADY-PD3

描述（由申请方提供）：研究目的是确定伊拉地平每日10 mg减缓帕金森病（PD）残疾进展的疗效。这是来自罗切斯特大学的Kevin Biglan博士的配套应用程序，名为“STEADY-PD 3数据协调中心”。 PD是第二常见的神经退行性疾病，影响65岁以上人群的1%。PD的主要运动症状可归因于黑质延髓部多巴胺能神经元的优先损失。最近的数据表明，这些神经元的选择性脆弱性可能是由于这些神经元对L型Cav1.3钙通道的依赖，更重要的是，对于PD，用二氢吡啶钙通道拮抗剂israpadine阻断这些通道，在帕金森病的体外和体内模型中保护这些神经元。最近的流行病学数据也指出，长期使用二氢吡啶类药物可降低PD风险。 伊拉地平是批准用于治疗高血压的药剂。我们的II期临床研究发现，伊拉地平在早期PD参与者中的每日剂量为10 mg或以下是安全和耐受的。伊拉地平可穿透血脑屏障，10 mg每日剂量达到PD动物模型中神经保护范围内的血清浓度。 基于这些观察结果，我们建议进行一项为期36个月的3期平行组安慰剂对照研究，研究伊拉地平每日10 mg与安慰剂相比在336名早期PD参与者中减缓PD残疾进展的疗效。本研究将包括中期无效性分析，因此无需完成独立的无效性研究。拟议的研究旨在解决两个具体目标。首先，通过36个月内统一帕金森病评定量表（Unified Parkinson Disease Rating Scale，I-III部分）评分的变化来确定伊拉地平每日10 mg减缓PD残疾进展的疗效。第二，确定伊拉地平10 mg每日一次在36个月内对PD进展的影响，如通过许多临床上有意义的和广泛接受的早期PD残疾进展的测量所测量的，包括：1）多巴胺能治疗开始和剂量利用的时间; 2）多巴胺能运动并发症发作的时间; 3）非运动残疾的变化;探索性指标将包括功能性残疾、生活质量、步行能力变化（5个CRISPR项目之和：跌倒、冻结、行走、步态、姿势稳定性）和认知功能的总体指标。 拟定的研究设计代表了一个独特的机会，可以评价一种新型疗法对减缓PD残疾进展的影响，并确定疗效（如果存在）是否与有临床意义的获益相关。简单的研究设计反映了“真实的生活”场景和低成本的非专利伊拉地平的可用性，如果研究结果是阳性的，将有助于将其转化为有意义的临床应用。

DESCRIPTION (provided by applicant): The study objective is to establish the efficacy of isradipine 10 mg daily to slow the progression of Parkinson's disease (PD) disability. This is a companion application to that of Kevin Biglan, MD, from the University of Rochester entitled "Data Coordination Center for STEADY-PD3". PD is the second most common neurodegenerative disease that affects 1% of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta. Recent data demonstrated that the selective vulnerability of these neurons may be due to the reliance of these neurons on L-type Cav1.3 Ca2+ channels and, more importantly for PD, that blocking these channels with israpadine, a dihydropyridine Ca2+ channel antagonist, protects these neurons in in vitro and in vivo models of Parkinsonism. Recent epidemiological data also points to a reduced risk of PD with chronic use of dihydropyridines. Isradipine is an approved agent for the treatment of hypertension. Our Phase II clinical studies have found that isradipine is safe and tolerable at the daily dose of 10 mg or below in participants with early PD. Isradipine penetrates the blood brain barrier and 10 mg daily dose achieves serum concentrations within the range found to be neuroprotective in animal models of PD. Based on these observations we propose to conduct a 36 month Phase 3 parallel group placebo controlled study of efficacy of isradipine 10mg daily versus placebo to slow the progression of PD disability in 336 participants with early PD. The study will include interim futility analysis thus eliminating the need to complete a standalone futility study. The proposed study is designed to address two specific aims. First, to establish the efficacy of isradipine 10 mg daily to slow the progression of PD disability as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score over 36 months. Second, to ascertain effect of isradipine 10 mg daily on the progression of PD over 36 months as measured by a number of clinically meaningful and widely accepted measures of progression of disability in early PD including:1) Time to initiation and dose utilization of dopaminergic therapy; 2) Time to onset of dopaminergic motor complications; 3) Change in non-motor disability; Exploratory measures will include global measures of functional disability, quality of life, the change in the ambulatory capacity (sum of 5 UPDRS items: falling, freezing, walking, gait, postural stability) and cognitive function. The proposed study design represents a unique opportunity to evaluate the impact of a novel therapy to slow progression of PD disability and to determine if efficacy if such exists is associated with clinically meaningful benefits. The simple study design reflecting "real life" scenario and availability of low cost generic isradipine will facilitate the translatio of the study results, if positive, into a meaningful clinical application.