Clinical Coordination Center for STEADY-PD3

STEADY-PD3临床协调中心

• 批准号: 8629209
• 负责人: Tanya Simuni
• 金额: $ 273.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629209
• 关键词: Address; Affect; Age; Animal Model; Antihypertensive Agents; Biological Markers; Biometry; Blood - brain barrier anatomy; Calcium; Calcium Channel; Chronic; Climacteric; Clinical; Clinical Research; Companions; Cytoplasm; Data; Data Coordinating Center; Development; Dihydropyridines; Disease; Disease Progression; Dopamine; Dose; Early treatment; Epidemiologic Studies; Epidemiology; FDA approved; Foundations; Freezing; Futility; Gait; Generic Drugs; Grant; Health Care Costs; In Vitro; Isradipine; L-Type Calcium Channels; Life; Measures; Medical center; Mitochondria; Motor; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinsonian Disorders; Participant; Pathogenesis; Patients; Phase; Phenotype; Physiological; Placebos; Population; Protocols documentation; Public Health; Quality of life; Randomized; Reliance; Research; Research Design; Risk; Role; Serum; Solid; Substantia nigra structure; Sum; Symptoms; Testing; Therapeutic; Time; Translations; Universities; Walking; Work; base; clinical application; cognitive function; cost; data management; design; dihydropyridine; disability; dopaminergic neuron; double-blind placebo controlled trial; economic impact; falls; follow up assessment; functional disability; health economics; human data; hypertension treatment; in vivo Model; novel; oxidant stress; pars compacta; phase 2 study; phase 3 study; placebo controlled study; pre-clinical; public health relevance; translational study

PROJECT SUMMARY/ABSTRACT 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 translation of the study results, if positive, into a meaningful clinical application.

项目概要/摘要 该研究的目的是确定每日 10 毫克伊拉地平对于减缓病情进展的功效 帕金森病（PD）残疾。这是凯文·比格兰（Kevin Biglan）医学博士的配套应用程序，来自 罗切斯特大学题为“STEADY-PD3 数据协调中心”。 PD 是第二常见的神经退行性疾病，影响 1% 以上的人口 65 岁。PD 的主要运动症状可归因于多巴胺能神经元的优先丧失 在黑质致密部。最近的数据表明，这些的选择性脆弱性 神经元可能是由于这些神经元对 L 型 Cav1.3 Ca2+ 通道的依赖，更重要的是 PD，用二氢吡啶 Ca2+ 通道拮抗剂 Israpadine 阻断这些通道，从而保护这些通道 帕金森病体外和体内模型中的神经元。最近的流行病学数据也表明， 长期使用二氢吡啶类药物有患帕金森病的风险。 伊拉地平是一种批准用于治疗高血压的药物。我们的 II 期临床研究 发现伊拉地平对于早期帕金森病患者来说，日剂量 10 毫克或以下是安全且可耐受的。 伊拉地平可穿透血脑屏障，每日 10 mg 剂量可达到血清浓度 在 PD 动物模型中发现具有神经保护作用。 根据这些观察结果，我们建议进行为期 36 个月的第 3 阶段平行组安慰剂治疗 每日 10 毫克伊拉地平与安慰剂相比，减缓帕金森病残疾进展的对照研究 336 名患有早期 PD 的参与者。该研究将包括临时无效分析，从而无需 完成一项独立的徒劳研究。拟议的研究旨在解决两个具体目标。首先，要 确定伊拉地平每日 10 mg 减缓帕金森病残疾进展的功效（通过测量） 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。其次，为了 确定每天 10 mg 伊拉地平对 36 个月内帕金森病进展的影响（通过数字测量） 早期 PD 残疾进展的具有临床意义和广泛接受的测量方法，包括：1). 时间 多巴胺能治疗的启动和剂量利用； 2）。多巴胺能运动开始的时间 并发症； 3）。非运动障碍的变化；探索性措施将包括全球措施 功能障碍、生活质量、行走能力的变化（5 个 UPDRS 项目的总和：跌倒、 冻结、行走、步态、姿势稳定性）和认知功能。 拟议的研究设计提供了一个独特的机会来评估新疗法的影响 减缓帕金森病残疾的进展，并确定疗效（如果存在）是否与临床相关 有意义的好处。简单的研究设计反映了“现实生活”场景和低成本仿制药的可用性 如果研究结果呈阳性，伊拉地平将有助于将其转化为有意义的临床应用。