Planning Grant for Phase 3 Trial of Dichloroacetate in PDH Deficiency

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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.