Trial of DCA in PDCD

The objective of this research study is to conduct a pivotal phase 3 trial of treatment with the investigational drug dichloroacetate (DCA) in young children with deficiency of the pyruvate dehydrogenase complex (PDC). PDC deficiency (PDCD) is the most common cause of congenital lactic acidosis and is a frequently fatal metabolic disease of childhood for which no proven treatment exists. The investigators predict that DCA represents targeted potential therapy for PDCD because of its ability to increase both the catalytic activity and stability of the enzyme complex. The conclusions of numerous laboratory and clinical investigations 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.

A novel Observer reported outcome (ObsRO) survey that is completed by study participant's parent/caregiver, is the efficacy outcome measure.

Funding Source * FDA OOPD

Clinical sites will be established across the United States for study participation. The investigators will conduct a randomized, placebo-controlled, double-blind trial of 24 children, aged 6 months through 17 years, with confirmed diagnosis of PDC Deficiency.

Study participants complete Screening procedures at Visit 1 to confirm eligibility for study participation. Screening study procedures include medical history review and physical exam; blood and urine collection, and collection of cheek (buccal) cells; training to complete the ObsRO daily survey. The ObsRO is a survey developed for this study to evaluate how study participants are feeling and functioning in the home setting. The ObsRO survey is completed by the study participant parent/caregiver every day during both treatment periods (study medication and placebo) of study participation (approximately 9 months). During treatment period 1 and 2 (4 months of study medication and 5 months of placebo), the study participant will communicate with the study team at least 2 times per month to evaluate the child's level of health, and compliance with daily survey completion and taking the study medication.

Study participants complete Baseline study procedures at Visit 2 prior to randomization to treatment. Baseline study procedures include, medical history review and physical exam; blood and urine collection; 3 day food record. The study medication will be shipped to the study participants home each month of study participation.

Safety labs are completed during each randomization period (month 3 and month 5). The safety labs can be completed at the clinical trial site, or at any standard clinical laboratory.

Study participants will complete a study visit after each randomization period (month 5 and

1. to complete study assessments at the same clinical site. Visit study procedures include medical history review and physical exam; blood and urine collection; 3 day food record. Study participants who complete both treatment periods and did not sustain serious adverse events attributable to DCA, will be offered continued access to investigational medication DCA through an open-label access program until the study concludes. Study participants must sign a separate consent form for participation in the open-label access phase of this clinical trial and must complete a study visit every 6 months at the same clinical site for study assessments that include medical history review and physical exam, blood and urine collection. The study medication will continue to be mailed to the study participant during the open-label phase at the same dose received during the blinded phase of the study. Study participants will be stratified according to their predicted rate of DCA metabolism and clearance, based on genotyping prior to randomization (completed at visit 1 buccal cell collection). Study participants will continue whatever diet and other "standard of care" is deemed appropriate by their local expert clinicians.

Inclusion Criteria:

• Age 6 m through 17 y

• Presence of characteristic clinical or metabolic features of pyruvate dehydrogenase complex deficiency (PDCD) and

• Presence of a known pathogenic mutation of a gene that is specifically associated with PDCD.

Exclusion Criteria:

A genetic mitochondrial disease other than those stipulated under inclusion criteria

Primary disorders of amino acid metabolism; primary disorders of fatty acid oxidation

Secondary lactic acidosis due to impaired oxygenation or circulation (cardiomyopathy or

congenital heart defect) Renal insufficiency (defined as: requires chronic dialysis or

serum creatinine ≥ 1.2 mg/dl; creatinine clearance