DOI: 10.1542/peds.2005-1226. Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

10.1542/peds.2005-1226

Crossref journal-article

American Academy of Pediatrics (AAP)

Pediatrics (417)

Abstract

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 δ-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.

Bibliography

Stacpoole, P. W., Kerr, D. S., Barnes, C., Bunch, S. T., Carney, P. R., Fennell, E. M., Felitsyn, N. M., Gilmore, R. L., Greer, M., Henderson, G. N., Hutson, A. D., Neiberger, R. E., OâBrien, R. G., Perkins, L. A., Quisling, R. G., Shroads, A. L., Shuster, J. J., Silverstein, J. H., Theriaque, D. W., & Valenstein, E. (2006). Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children. Pediatrics, 117(5), 1519â1531.

Authors 20

Peter W. Stacpoole (first)
Douglas S. Kerr (additional)
Carie Barnes (additional)
S. Terri Bunch (additional)
Paul R. Carney (additional)
Eileen M. Fennell (additional)
Natalia M. Felitsyn (additional)
Robin L. Gilmore (additional)
Melvin Greer (additional)
George N. Henderson (additional)
Alan D. Hutson (additional)
Richard E. Neiberger (additional)
Ralph G. O'Brien (additional)
Leigh Ann Perkins (additional)
Ronald G. Quisling (additional)
Albert L. Shroads (additional)
Jonathan J. Shuster (additional)
Janet H. Silverstein (additional)
Douglas W. Theriaque (additional)
Edward Valenstein (additional)

References 37 Referenced 214

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Stacpoole PW, Gilbert LR: Pyruvate dehydrogenase complex deficiency. In: Glew RH, Rosenthal MD, eds. Clinical Cases in Medical Biochemistry. Oxford, United Kingdom: Oxford University Press; 2006; In press (10.1093/oso/9780195176872.003.0007)
Munnich A, Rötig A, Cormier-Daire V, Rustin P: Clinical presentation of respiratory chain deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 9th ed. New York, NY: McGraw-Hill; 200:2261–2274
DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656–2668 (10.1056/NEJMra022567)
Kerr DS. Treatment of congenital lactic acidosis: a review. Int Pediatr. 1995;10:75–81
Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989;38:1124–1144 (10.1016/0026-0495(89)90051-6)
Fouque F, Brivet M, Boutron A, et al. Differential effect of DCA treatment on the pyruvate dehydrogenase complex in patients with severe PDHC deficiency. Pediatr Res. 2003;53:793–799 (10.1203/01.PDR.0000057987.46622.64)
Morten KJ, Beattie P, Brown GK, Matthews PM. Dichloroacetate stabilizes the mutant E1α subunit in pyruvate dehydrogenase deficiency. Neurology. 1999;53:612–616 (10.1212/WNL.53.3.612)
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Stacpoole PW, Henderson GN, Yan Z, Cornett R, James MO. Pharmacokinetics, metabolism and toxicology of dichloroacetate. Drug Metab Rev. 1998;30:499–539 (10.3109/03602539808996323)
Ammini CV, Stacpoole PW. Biotransformation, toxicology and pharmacogenomics of dichloroacetate. In: Gribble GW, ed. Natural Production of Organohalogen Compounds. Vol 3/P in the series: The Handbook of Environmental Chemistry. Berlin, Germany: Springer-Verlag; 2003:215–234 (10.1007/b10453)
Stacpoole PW. Lactic acidosis. Endocrinol Metab Clin North Am. 1993;22:221–245 (10.1016/S0889-8529(18)30163-4)
Bonnefont JP, Specola NB, Vassault A, et al. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Paediatr. 1990;150:80–85 (10.1007/BF02072043)
Henderson GH, Darr RA, Whalen PO, Curry SH, Stacpoole PW. Development of an oral drug formulation for dichloroacetate and thiamine. Drug Dev Indust Pharm. 1994;20:2425–2437 (10.3109/03639049409042647)
Stacpoole PW, Harwood HJ, Cameron DF, et al. Chronic toxicology of dichloroacetate: possible relation to thiamine deficiency in rats. Fundam Appl Toxicol. 1990;14:327–337 (10.1016/0272-0590(90)90212-3)
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Dates

Type	When
Created	19 years, 4 months ago (May 1, 2006, 1:22 p.m.)
Deposited	1 year, 7 months ago (Feb. 3, 2024, 11:58 p.m.)
Indexed	3 weeks, 5 days ago (Aug. 12, 2025, 5:39 p.m.)
Issued	19 years, 4 months ago (May 1, 2006)
Published	19 years, 4 months ago (May 1, 2006)
Published Online	19 years, 4 months ago (May 1, 2006)
Published Print	19 years, 4 months ago (May 1, 2006)

Funders 0

None

BibTeX

@article{Stacpoole_2006, title={Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children}, volume={117}, ISSN={1098-4275}, url={http://dx.doi.org/10.1542/peds.2005-1226}, DOI={10.1542/peds.2005-1226}, number={5}, journal={Pediatrics}, publisher={American Academy of Pediatrics (AAP)}, author={Stacpoole, Peter W. and Kerr, Douglas S. and Barnes, Carie and Bunch, S. Terri and Carney, Paul R. and Fennell, Eileen M. and Felitsyn, Natalia M. and Gilmore, Robin L. and Greer, Melvin and Henderson, George N. and Hutson, Alan D. and Neiberger, Richard E. and O’Brien, Ralph G. and Perkins, Leigh Ann and Quisling, Ronald G. and Shroads, Albert L. and Shuster, Jonathan J. and Silverstein, Janet H. and Theriaque, Douglas W. and Valenstein, Edward}, year={2006}, month=may, pages={1519–1531} }

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  "abstract": "<jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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 \u03b4-aminolevulinate.</jats:p><jats:p>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.</jats:p>",
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