Phase 3 Trial of DCA in PDC Deficiency IND 028,625 (02/04/2015)

摘要 先天性丙酮酸脱氢酶复合物（PDC）缺乏症（PDCD）是一种危及生命的疾病， 代谢整合的线粒体疾病，其中碳水化合物燃料有效转化为 能量受到干扰。对于PDCD，目前还没有成熟的治疗方法。然而，二氯乙酸盐（DCA）代表 通过刺激残留PDC活性，降低高乳酸血症， 和改善线粒体能量。这一背景和我们的初步数据表明，DCA可能 有利于PDCD患儿的临床状况。我们与FDA密切合作， 组织制定适当的研究设计并确定前瞻性受试者。我们现建议 进行为期4年的3期临床试验，以测试口服DCA将改善家庭状况的假设 与安慰剂相比，受影响儿童的功能性将得到改善，并且长期使用将耐受良好且安全。 我们的主要终点将基于临床状态的改善，由一个新的观察者确定， 报告结局（ObsRO）指标。我们的次要终点将包括：1）证实 生活中儿童家庭功能的Karnofsky/Lansky表现量表的临床结局- 威胁性疾病;和2）降低的乳酸血症。

Abstract Congenital pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a life-threatening mitochondrial disease of metabolic integration in which the efficient conversion of carbohydrate fuel into energy is perturbed. There are no proven therapies for PDCD. However, dichloroacetate (DCA) represents targeted potential therapy for this disease by stimulating residual PDC activity, decreasing hyperlactatemia and improving mitochondrial energetics. This background and our preliminary data suggest that DCA may benefit the clinical status of PDCD children. We have worked closely with the FDA and a parent-driven organization to develop an appropriate study design and identify prospective subjects. We now propose to undertake a 4 year phase 3 clinical trial to test the hypotheses that oral DCA will improve at-home functionality of affected children compared to placebo and will be well-tolerated and safe for chronic use. Our primary endpoint will be based on an improved clinical status, as determined by a novel, Observer Reported Outcome (ObsRO) measure. Our secondary endpoints will include 1) confirmation of better clinical outcome by the Karnofsky/Lansky performance scale of home functionality in children with life- threatening disease; and 2) decreased lactatemia.