Data Coordination Center for STEADY-PD3

描述(由申请人提供)：该研究的目标是确定伊拉地平每天10毫克延缓帕金森病(PD)残疾进展的疗效。这是罗切斯特大学医学博士Kevin Biglan的一个配套应用程序，标题为“稳定数据协调中心-pd3”。帕金森病是第二种最常见的神经退行性疾病，65岁以上人口中有1%受到影响。帕金森病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丢失。最近的数据表明，这些神经元的选择性易损性可能是由于这些神经元对L类Cav1.3钙通道的依赖，更重要的是，对于PD，二氢吡啶钙通道拮抗剂伊拉帕定在体外和体内帕金森病模型中对这些神经元具有保护作用。最近的流行病学数据还表明，长期使用二氢吡啶可降低帕金森病的风险。伊拉地平是一种被批准用于治疗高血压的药物。我们的第二阶段临床研究发现，对于早期帕金森病患者，伊拉地平每天10毫克或以下的剂量是安全和耐受的。伊拉地平通过血脑屏障，每天10毫克的剂量达到在帕金森病动物模型中发现的神经保护范围内的血清浓度。基于这些观察，我们建议进行一项为期36个月的3期平行安慰剂对照研究，比较每日服用10毫克伊拉地平与服用安慰剂对336名早期帕金森病患者延缓帕金森病残疾进展的效果。这项研究将包括临时无效性分析，从而消除了完成独立无效性研究的必要性。拟议的研究旨在解决两个具体目标。首先，通过36个月来统一帕金森病评定量表(UPDRS)第I-III部分评分的变化来衡量伊拉地平每天10毫克对延缓帕金森病残疾进展的疗效。第二，为了确定每日10毫克伊拉地平对帕金森病患者36个月的进展的影响，通过一些临床上有意义和被广泛接受的衡量早期帕金森病患者残疾进展的指标来衡量，这些指标包括：1)开始接受多巴胺能治疗的时间；2)开始使用多巴胺能运动并发症的时间；3)非运动障碍的变化；探索性措施将包括功能残疾、生活质量、活动能力的变化(总共5项UPDRS项目：跌倒、冻结、行走、步态、姿势稳定性)和认知功能。拟议的研究设计代表了一个独特的机会，可以评估一种新的治疗方法对减缓帕金森病残疾进展的影响，并确定是否存在这种有效性与临床上有意义的好处相关。简单的研究设计反映了“现实生活”的情景和低成本仿制药伊拉地平的可用性，如果阳性，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.