Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.
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.


RESULTS
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.
Stacpoole
Peter W
PW
Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida, USA. stacpool@gcrc.ufl.edu
Kerr
Douglas S
DS
Barnes
Carie
C
Bunch
S Terri
ST
Carney
Paul R
PR
Fennell
Eileen M
EM
Felitsyn
Natalia M
NM
Gilmore
Robin L
RL
Greer
Melvin
M
Henderson
George N
GN
Hutson
Alan D
AD
Neiberger
Richard E
RE
O'Brien
Ralph G
RG
Perkins
Leigh Ann
LA
Quisling
Ronald G
RG
Shroads
Albert L
AL
Shuster
Jonathan J
JJ
Silverstein
Janet H
JH
Theriaque
Douglas W
DW
Valenstein
Edward
E
D000140:Acidosis, Lactic / Q000151:congenital* / Q000188:drug therapy* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003999:Dichloroacetic Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007223:Infant; D007773:Lactates / Q000378:metabolism; D008297:Male; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000378:metabolism; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000188:drug therapy / Q000378:metabolism; D011788:Quality of Life
D007773:Lactates; D003999:Dichloroacetic Acid