Principal Investigator: Nicola Longo
Keywords: DCA , dichloroacetate , PDCD , pyruvate dehydrogenase complex Deficiency Department: Pediatric Genetics
IRB Number: 00106354
Specialty: Pediatric Genetics
Sub Specialties: Medical Genetics
Recruitment Status: Recruiting

Contact Information

Jenny  Billy

Brief Summary

A randomized, placebo-controlled, double-blind trial of at least 24 evaluable children (30 randomized), aged 6 months through 17 years, with proven deficiency of the PDC. The study will begin with a 1 month lead-in period/no treatments for screening and baseline clinical data collection and subjects will then be entered in a crossover design in which each subject receives DCA or placebo by enteral administration for 4 months. This period will be followed by a 1 month washout period, during which all subjects will receive placebo, followed by crossover to the alternate treatment for 4 months. Following the conclusion of this crossover period, and providing the patient has not sustained serious adverse events attributable to DCA, the patient (if capable) or the parent/guardian of the patient will be offered the opportunity to receive open label DCA at the same dose he or she was receiving during the blinded portion of the trial, in order to monitor chronic safety of the drug. This phase of the trial addresses a specific request by FDA to include an open-label period to better assess chronic DCA safety. Patients will be stratified according to their predicted rate of DCA metabolism and clearance, based on genotyping prior to randomization. Patients will be provided whatever diet and other “standard of care” is deemed appropriate by local primary medical clinicians of the study participant.

The hypothesis, stated as the null, is that the two treatment groups do not differ, vs. the alternate conclusion that there is a difference between DCA and Placebo.
This postulate will be tested by accomplishing the following specific aims:
Specific Aim 1: to determine the efficacy of DCA based on one major clinical outcome measure:
Efficacy Aim 1: Determine the efficacy of DCA in improving clinical signs associated with PDCD. This outcome will be determined by applying a novel Observer Reported Outcome (ObsRO) measure of health.
Efficacy Hypothesis 1 (as Null): DCA is equivalent to P in affecting the health of patients.
Specific Aim 2: to evaluate the safety and tolerability of DCA by comparing the 1) number and 2) severity of Adverse Events during both the double-blind and open label treatment phases.
Safety Hypothesis (as Null): DCA is less safe than P.
Specific Aim 3: address the following secondary questions:
For efficacy, does DCA differ from P in affecting:
a. Clinical well-being, as quantified by the Karnofsky/Lansky Performance Status, which is an age-appropriate tool applicable to children with life-threatening diseases?
b. Plasma lactate levels?
c. Plasma β-hydroxybutyrate (β-OHB) concentrations?
In addition, we will conduct secondary analyses to determine the safety and efficacy of DCA vs. P as functions of 1) genetic-based dosing; 2) age at randomization; and 3) dietary fat intake.

Inclusion Criteria

Age 6 m through 17 y
• Presence of characteristic clinical or metabolic features of PDCD (3, 15) and
• Presence of a known pathogenic mutation of a gene that is specifically associated with PDC (PDHA1, PDHB, DLAT, PDHX)
• Presence of ObsRO signs
• No evidence of other primary mitochondrial dysfunction and

Females of reproductive age must be willing to use an effective method of barrier contraception for the duration of the study.

Exclusion Criteria

A genetic mitochondrial disease other than those stipulated under inclusion criteria
• Primary, defined organic acidurias other than lactic acidosis (e.g., propionic aciduria)
• Primary disorders of amino acid metabolism
• Primary disorders of fatty acid oxidation
• Secondary lactic acidosis due to impaired oxygenation or circulation (e.g., due to severe cardiomyopathy or congenital heart defects)
• Malabsorption syndromes associated with D-lactic acidosis
• Renal insufficiency, defined as 1) a requirement for chronic dialysis or 2) serum creatinine ≥ 1.2 mg/dl or creatinine clearance <60 ml/min
• Primary hepatic disease unrelated to PDCD
• Pregnancy or breast feeding
• Requires respiratory assistance by continuous or bi-level positive airway pressure (CPAP or BiPAP) or mechanical ventilation by face mask or tracheal intubation.