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体缺乏症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地转化为 能量被扰乱了。目前还没有针对PDCD的有效治疗方法。然而，二氯乙酸酯(DCA)代表 通过刺激残留的PDC活性、降低高乳酸血症来靶向治疗这种疾病 以及改善线粒体能量学。这一背景和我们的初步数据表明，DCA可能 有利于改善PDCD患儿的临床状况。我们与FDA和一家由家长驱动的 组织制定适当的研究设计并确定预期的受试者。我们现在建议 进行为期4年的第三阶段临床试验，以检验口服DCA将在家中改善的假设 与安慰剂相比，该药改善了受影响儿童的功能，且耐受性良好，长期使用安全。 我们的主要终点将基于临床状况的改善，这是由一个新的观察者确定的 报告结果(ObsRO)测量。我们的次要终端将包括1)确认更好 卡诺夫斯基/兰斯基家庭功能量表对有生活障碍儿童的临床结果 危险疾病；2)乳酸血症减少。

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.