Dichloroacetate for PDC deficiency missed its primary end point

Design

Phase III randomised, placebo-controlled crossover with open-label extension

Population

34 children with pyruvate dehydrogenase complex deficiency

Primary outcome

Observer-reported motor domain score

Effect

No difference vs placebo (P = 0.512); lactate −20% (P = 0.006)

This phase III multicentre crossover trial randomised 34 children with pyruvate dehydrogenase complex deficiency to four months of dichloroacetate or placebo, with dosing set by GSTZ1 genotype, followed by crossover and an optional open-label extension. It was published in JCI Insight on 22 September.

The primary motor end point did not differ between dichloroacetate and placebo (P = 0.512). With longer open-label treatment, motor scores improved (P = 0.002), particularly in more impaired children, and plasma lactate fell by about 20%. Survival was better than a historical natural-history cohort. The drug was well tolerated.

The randomised comparison was negative; the positive signals come from uncontrolled extension data and historical comparison. This does not yet establish benefit.

• Discuss dichloroacetate only within specialist metabolic care.
• Genotype-guided dosing is part of the regimen studied.
• Explain that the randomised result was negative.

Why it matters

For a rare, severe disease, promising extension data can be mistaken for proof.

Don't overread it

The primary randomised end point was negative; the benefits reported come from uncontrolled data.

The statistics, in plain English

With 34 children, the trial could only detect large effects. Open-label extension results lack a control group, and comparison with a historical cohort is vulnerable to differences in care over time.

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