Phase 2 Study of 4-Aminopyridine for the Treatment of Episodic Ataxia Type 2

描述(由申请人提供)： 家族性发作性共济失调(EA)综合征是一种罕见的异质性单基因疾病，其特征是剧烈发作的不平衡和不协调。发作性共济失调2型(EA2)是所有EA综合征中最常见和最具特征的。由CACNA1A(一种神经元钙通道基因)突变引起的EA2通常表现为早发性衰弱共济失调发作，与眼球震颤、头痛和波动性虚弱相关。自从发现EA2对乙酰唑胺的显著反应以来，乙酰唑胺一直是EA2的一线治疗药物。然而，一些患者对乙酰唑胺没有反应，不能耐受副作用，或者对乙酰唑胺过敏。对于这些患者(大约三分之一的人目前正在参与加州大学洛杉矶分校正在进行的发作性共济失调研究以及与罗切斯特大学的合作研究)，没有替代治疗方法。4-氨基吡啶(4AP)在欧洲被发现对少数EA2患者有效，Acorda Treeutics公司的4AP缓释制剂刚刚于2010年1月被FDA批准用于多发性硬化症患者。在Acorda保证提供4AP和安慰剂的情况下，建议进行一项随机试验，以测试4AP在减少EA2患者共济失调发作频率方面的有效性，其次评估其耐受性及其对治疗满意度和与健康相关的生活质量的影响。建议招募20名受试者参加这项为期3年的4AP双盲、双交叉、随机试验。

DESCRIPTION (provided by applicant): Familial episodic ataxia (EA) syndromes are rare and heterogeneous monogenic disorders characterized by dramatic episodes of imbalance and uncoordination. Episodic ataxia type 2 (EA2) is the most common and the best characterized of all the EA syndromes. EA2 caused by mutations in CACNA1A (a neuronal calcium channel gene) typically presents with early onset debilitating ataxia episodes variably associated with nystagmus, headaches, and fluctuating weakness. Since the discovery of dramatic response of EA2 to acetazolamide, acetazolamide has been the first-line treatment for EA2. Yet, some patients are not responsive to acetazolamide, cannot tolerate the side effects, or are allergic to acetazolamide. For these patients (roughly a third of individuals who are currently participating in an ongoing UCLA Episodic Ataxia study as well a collaborative study with the University of Rochester), there are no alternative treatments. 4-Aminopyridine (4AP) was found in Europe to be effective in a few patients with EA2, and an extended release formulation of 4AP by Acorda Therapeutics has just been approved by the FDA in January 2010 for use in patients with multiple sclerosis. With assurance from Acorda to supply 4AP and placebo, a randomized trial is proposed to test the efficacy of 4AP in reducing ataxia episode frequency and secondarily to evaluate its tolerability and its impact on treatment satisfaction and health-related quality of life in patients with EA2. Recruitment of 20 subjects for this 3-year, double-blind, two-crossover, randomized trial of 4AP is proposed.