Phase III trial of sodium dichloroacetate for pyruvate dehydrogenase complex deficiency in children.

BACKGROUNDDichloroacetate (DCA) is an orally administered structural analog of pyruvate, an endogenous pyruvate dehydrogenase kinase inhibitor.METHODSWe conducted a phase III multicenter trial in 34 children with pyruvate dehydrogenase complex deficiency (PDCD). Participants were randomly allocated to 4 months of treatment with DCA or a placebo, followed by a 1-month washout period and crossover to the alternate arm, and could continue into an open-label extension period. DCA dosing was predetermined by pharmacogenomic analysis of GSTZ1, which modulates DCA metabolism. The primary endpoint was the observer-reported outcomes motor domain (ObsROmotor) score. Additional assessments evaluated motor function, plasma lactate levels, and survival.RESULTSChronic DCA was well tolerated and safe. The primary endpoint, ObsROmotor, was not statistically significantly different between the treatment and placebo groups (P = 0.512). However, longer-term treatment, including the open-label extension, showed a statistically significant treatment effect (P = 0.002), especially in participants with higher baseline motor impairment (ObsROmotor ≥ 8; P = 0.001). DCA decreased plasma lactate -0.48 (0.82) mmol/L (-20%; P = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank P = 0.027).CONCLUSIONLonger-term treatment with DCA, dosed based on GSTZ1 haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.FUNDINGNIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics.