Clinical Coordination Center for STEADY-PD3

描述（由申请人提供）：研究目的是确定isradipine 10mg / d对减缓帕金森病（PD）残疾进展的疗效。这是罗彻斯特大学凯文·比格兰博士的一个配套应用程序，名为“STEADY-PD3数据协调中心”。PD是第二常见的神经退行性疾病，影响了1%的65岁以上人群。PD的主要运动症状可归因于黑质致密部多巴胺能神经元的优先丧失。最近的数据表明，这些神经元的选择性易感性可能是由于这些神经元依赖于l型Cav1.3 Ca2+通道，更重要的是，对于PD，用israpadine阻断这些通道，二氢吡啶Ca2+通道拮抗剂，在体外和体内帕金森模型中保护这些神经元。最近的流行病学数据也指出，长期使用二氢吡啶可降低患PD的风险。以色列地平是一种被批准用于治疗高血压的药物。我们的II期临床研究发现，在早期PD患者中，日剂量为10mg或以下的isradipine是安全且耐受的。以斯拉地平可穿透血脑屏障，每日10mg剂量可达到PD动物模型中发现的具有神经保护作用的血清浓度范围。基于这些观察结果，我们建议对336名早期PD患者进行为期36个月的平行组安慰剂对照研究，比较每天10mg的isradipine与安慰剂对减缓PD残疾进展的疗效。该研究将包括中期的无效性分析，从而消除了完成独立的无效性研究的需要。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（UPDRS）第I-III部分评分的变化来确定isradipine每日10mg减缓PD残疾进展的疗效。第二，通过一系列具有临床意义且被广泛接受的早期PD残疾进展指标，确定isradipine 10mg /天对PD进展超过36个月的影响，包括：1)开始多巴胺能治疗的时间和剂量利用；2)多巴胺能运动并发症发生时间；3)非运动障碍的变化；探索性测量将包括功能性残疾、生活质量、行动能力变化（UPDRS 5项的总和：跌倒、冻结、行走、步态、姿势稳定性）和认知功能的总体测量。拟议的研究设计提供了一个独特的机会来评估一种新疗法对减缓PD残疾进展的影响，并确定这种疗法的有效性是否与临床有意义的益处相关。简单的研究设计反映了“真实生活”场景和低成本仿制isradipine的可用性，如果研究结果是积极的，将有助于将研究结果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.