Planning Grant for Phase 3 Trial of Dichloroacetate in PDH Deficiency

二氯乙酸治疗 PDH 缺乏症第三阶段试验的规划拨款

• 批准号: 7976507
• 负责人: Peter Wallace Stacpoole
• 金额: $ 12.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976507
• 关键词: Address; Adherence; Agreement; Applications Grants; Case Report Form; Child; Clinical Practice Guideline; Clinical Trials; Data; Development; Dichloroacetate; Ensure; Environment; Evaluation; FDA approved; Future; Good Clinical Practice; Grant; Healthcare; Hereditary Disease; Interdisciplinary Study; International; Investigation; Investigational Drugs; Laboratories; Lactic Acidosis; Manuals; Methodology; Methods; Monitor; Multienzyme Complexes; Neurologic; North America; Orphan; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Procedures; Progressive Disease; Pyruvate Dehydrogenase Complex; Pyruvate Dehydrogenase Complex Deficiency Disease; Randomized Clinical Trials; Randomized Controlled Trials; Reporting; Research Design; Research Infrastructure; Research Personnel; Resources; Safety; Science; Scientist; Specific qualifier value; Staging; Structure; Technology; United States Food and Drug Administration; United States National Institutes of Health; neuromuscular; novel; open label; originality; public health relevance; pyruvate dehydrogenase; tool

DESCRIPTION (provided by applicant): The primary objectives of this R34 proposal are to: 1) establish the scientific rationale; and 2) develop the operational infrastructure to conduct a pivotal phase III trial of the investigational drug dichloroacetate (DCA) in young children with biochemically and genetically proven deficiency of the pyruvate dehydrogenase (PDH) complex. PDH deficiency is one of the most common causes of congenital lactic acidosis; it is a uniformly fatal disease of progressive neurological and neuromuscular degeneration for which no proven treatment exists. DCA represents targeted potential therapy for PDH deficiency because of its ability to increase both the catalytic activity and stability of the enzyme complex. The conclusions of numerous laboratory investigations and open label clinical trials are consistent with this postulate and have led to the designation of DCA as an Orphan Product for congenital lactic acidosis by the Food and Drug Administration. The ability to accomplish our primary objectives requires that we successfully address the following specific aims: For the Future Randomized Clinical Trial (RCT). Aim 1: Provide a rationale for the trial, including its impact on the science, health care and practice relevant to PDH deficiency. Aim 2: Provide information on how the trial will be conducted, including the study design, methods and analysis and an appreciation of potential limitations, bottlenecks and alternative approaches. Aim 3: Ensure the innovativeness and originality of the RCT, particularly regarding the development and application of novel concepts and assessment tools. Aim 4: Establish an investigative team and an environment conducive to multidisciplinary collaboration that provides complimentary expertise relevant to the evaluation and treatment of patients, the development and implementation of appropriate study methodologies, technologies and analyses and the adherence to local, national and international regulatory issues and compliance with Good Clinical Practice guidelines. For the Planning Period. Aim 1P: Justify the need for the Planning Grant prior to embarking on a RCT, including how it will address potential major barriers to the future trial. Aim 2P: Establish the appropriateness of the investigators, environments, organizational and reporting structures, information flow and specific research resources to be assembled for the RCT, including development of a Manual of Procedures (MOP), Case Report Forms (CRFs), multi-institutional collaborative agreements, regulatory issues and data safety and monitoring plans. Aim 3P: Specify how the planning period will be used in terms of how and when specific scientific and operational objectives will be accomplished to set the stage for implementing the RCT. PUBLIC HEALTH RELEVANCE: This Planning Grant application will provide support to bring together investigators from across North America to develop a randomized controlled trial of the drug dichloroacetate (DCA) for treating young children born with pyruvate dehydrogenase (PDH) deficiency. This is a rare and so far fatal genetic disease for which there is no proven therapy. The Planning Grant will allow scientists and clinicians to submit to the NIH a 5-year clinical trial that, if successful, will establish DCA as the first FDA-approved treatment of PDH-deficiency.

描述(由申请人提供)：这项R34提案的主要目标是：1)建立科学理论基础；以及2)发展操作基础设施，以进行研究药物二氯乙酸酯(DCA)的关键III期试验，用于患有生化和遗传证明的丙酮酸脱氢酶(PDH)复合体缺陷的幼儿。PDH缺乏是先天性乳酸酸中毒最常见的原因之一；它是一种进行性神经和神经肌肉变性的致命疾病，目前还没有得到证实的治疗方法。DCA代表了PDH缺乏症的靶向治疗，因为它能够提高酶复合体的催化活性和稳定性。大量实验室研究和开放标签临床试验的结论与这一假设一致，并导致食品和药物管理局将DCA指定为治疗先天性乳酸酸中毒的孤儿产品。要实现我们的主要目标，我们需要成功地实现以下具体目标：未来随机临床试验(RCT)。目的1：提供试验的理由，包括它对与PDH缺乏症相关的科学、保健和实践的影响。目的2：提供将如何进行试验的信息，包括研究设计、方法和分析，以及对潜在限制、瓶颈和替代方法的评价。目标3：确保区域工作队的创新性和原创性，特别是在开发和应用新概念和评估工具方面。目标4：建立一支调查团队和一个有利于多学科合作的环境，提供与患者评估和治疗相关的免费专业知识，开发和实施适当的研究方法、技术和分析，遵守当地、国家和国际监管问题，并遵守良好临床实践指南。在规划期内。目标1P：在开始进行随机对照试验之前，证明需要规划补助金，包括它将如何解决未来试验的潜在主要障碍。目标2P：确定为区域工作队收集的调查员、环境、组织和报告结构、信息流和具体研究资源的适当性，包括制定程序手册、案例报告表、多机构协作协定、监管问题和数据安全及监测计划。目标3P：具体说明如何利用规划期实现具体的科学和业务目标，以及何时实现具体的科学和业务目标，为实施区域技术合作奠定基础。 公共卫生相关性：这项计划拨款申请将提供支持，将来自北美各地的研究人员聚集在一起，开发一项治疗出生时患有丙酮酸脱氢酶(PDH)缺陷的幼儿的药物二氯乙酸酯(DCA)的随机对照试验。这是一种罕见的、迄今致命的遗传病，目前还没有得到证实的治疗方法。规划拨款将允许科学家和临床医生向NIH提交一项为期5年的临床试验，如果成功，将建立DCA作为FDA批准的第一种治疗PDH缺乏症的方法。

项目成果

The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients.

• DOI: 10.1016/j.ymgme.2011.09.032
• 发表时间: 2012-01
• 期刊: MOLECULAR GENETICS AND METABOLISM
• 影响因子: 3.8
• 作者: Patel, Kavi P.;O'Brien, Thomas W.;Subramony, Sankarasubramon H.;Shuster, Jonathan;Stacpoole, Peter W.
• 通讯作者: Stacpoole, Peter W.