Phase II Safety, Tolerability, and Dose Selection Study of Isradipine as a Potential Disease-Modifying Intervention in Early Parkinson's Disease (STEADY-PD)
Phase II Safety, Tolerability, and Dose Selection Study of Isradipine as a Potential Disease-Modifying Intervention in Early Parkinson's Disease (STEADY-PD)
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DOI：
10.1002/mds.25639
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发表时间：
2013-11-01
影响因子：
8.6
通讯作者：
Simuni, Tanya
中科院分区：
文献类型：
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作者：
Simuni, Tanya
Isradipine是一种二氢吡啶钙通道拮抗剂，在帕金森病（PD）动物模型中显示出神经保护作用。为了确定可耐受的isradipine控释（CR）剂量，并显示其在未来关键疗效试验中的初步疗效，在不需要多巴胺能治疗（多巴胺激动剂或左旋多巴）的早期PD患者中进行了2期随机、双盲、平行组试验（Dynacirc CR在帕金森病中的安全性、耐受性和疗效评估[STEADY-PD]），随机比例为1:1:1:1至5,10。或每天20mg的isradipine CR或匹配的安慰剂。主要结局是耐受性，定义为活性组和安慰剂组在最初指定剂量下完成研究的患者比例差异不超过30%。如果一个以上的isradipine剂量是可耐受的，那么从基线到第52周（或达到足够残疾需要多巴胺能治疗的时间），统一帕金森病评定量表（UPDRS）总变化的3点差异被作为选择未来研究最理想剂量的标准。STEADY-PD招募了99名受试者。isradipine的耐受性是剂量依赖性的：26例患者中有25例（96%）为安慰剂；5mg， 23例患者中19例（83%）；26例患者中19例（73%）为10 mg；24例患者中有9例为20mg（37%）。不同剂量间UPDRS变化无差异。最常见的不良事件是外周水肿（30例）和头晕（24例）。在本研究中，每日10毫克的以色列地平是早期帕金森病的最大耐受剂量。有必要进行一项大型安慰剂对照试验，并计划评估每天10mg伊拉西平对减缓PD残疾进展的疗效。(c) 2013年国际帕金森和运动障碍学会。
Isradipine, a dihydropyridine calcium channel antagonist, has been shown to be neuroprotective in animal models of Parkinson's disease (PD). To establish a dosage of isradipine controlled-release (CR) that is tolerable and demonstrates preliminary efficacy for use in a future pivotal efficacy trial a Phase 2, randomized, double-blind, parallel group trial (Safety, Tolerability and Efficacy Assessment of Dynacirc CR in Parkinson Disease [STEADY-PD]) was undertaken in subjects with early PD not requiring dopaminergic therapy (dopamine agonists or levodopa) randomized 1:1:1:1 to 5, 10, or 20 mg of isradipine CR or matching placebo daily. The primary outcome was tolerability defined as no more than a 30% difference in the proportion of patients completing the study on the originally assigned dosage between an active and placebo group. If more than one isradipine dosage was tolerable, then a 3-point difference in total Unified Parkinson's Disease Rating Scale (UPDRS) change between baseline and week 52 (or time to sufficient disability to require dopaminergic therapy) was taken as a criterion for selection of the most desirable dosage for future study. STEADY-PD enrolled 99 subjects. The tolerability of isradipine was dose dependent: placebo, 25 of 26 patients (96%); 5 mg, 19 of 23 patients (83%); 10 mg 19 of 26 patients (73%); and 20 mg 9 of 24 patients (37%). There was no difference in change in UPDRS among dosages. The most common adverse events were peripheral edema (30) and dizziness (24). Isradipine 10 mg daily was the maximal tolerable dosage in this study of early PD. A large placebo-controlled trial will be necessary and is planned to assess efficacy of isradipine 10 mg daily to slow progression of PD disability. (c) 2013 International Parkinson and Movement Disorder Society.