Published online May 1, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1519-1531 (doi:10.1542/peds.2005-1226)
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Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

Peter W. Stacpoole, MD, PhDa,b,c, Douglas S. Kerr, MD, PhDd, Carie Barnes, RNa, S. Terri Bunch, MDe, Paul R. Carney, MDe, Eileen M. Fennell, PhDf, Natalia M. Felitsyn, PhDa, Robin L. Gilmore, MDg, Melvin Greer, MDg, George N. Henderson, PhDa,c, Alan D. Hutson, PhDc,h, Richard E. Neiberger, MD, PhDe, Ralph G. O'Brien, PhDc,h, Leigh Ann Perkins, RNa, Ronald G. Quisling, MDi, Albert L. Shroads, MSa, Jonathan J. Shuster, PhDc,h, Janet H. Silverstein, MDe, Douglas W. Theriaque, MSc and Edward Valenstein, MDg

a Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida
b Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida
c General Clinical Research Center, University of Florida, Gainesville, Florida
d Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio
e Department of Pediatrics, University of Florida, Gainesville, Florida
f College of Public Health and Health Professions, the Department of Clinical Health Psychology, University of Florida, Gainesville, Florida
g Department of Neurology, University of Florida, Gainesville, Florida
h Department of Statistics, University of Florida, Gainesville, Florida
i Department of Radiology, University of Florida, Gainesville, Florida

OBJECTIVE. Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease.

METHODS. Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function.

OUTCOME. There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor {delta}-aminolevulinate.

CONCLUSIONS. In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.

Key Words: dichloroacetate • congenital lactic acidosis • mitochondria • clinical trial • pyruvate dehydrogenase • respiratory chain • peripheral neuropathy

Abbreviations: PDC—pyruvate dehydrogenase complex • mtDNA—mitochondrial DNA • MELAS—mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes • CSF—cerebrospinal fluid • DCA—dichloroacetate • TCA—tricarboxylic acid • GCRC—General Clinical Research Center • DSMB—Data Safety Monitoring Board • EEG—electroencephalogram • GATE—Global Assessment of Treatment Efficacy • GOR—generalized odds ratio

Accepted Oct 24, 2005.




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