SL1009-01

29 evidence topics · 10 sources

Objective

Pivotal evaluation of dichloroacetate

“conduct a pivotal phase 3 trial of treatment with the investigational drug dichloroacetate (DCA)” (opens the source at this quote in a new tab)

Location and study date

Multicenter trial initiation

“In 2018, we began a multicenter phase 3 trial of DCA in PDCD” (opens the source at this quote in a new tab)

Participating centers

“The study was conducted by nine academic health centers across the United States” (opens the source at this quote in a new tab)

Study design

Randomized population and masking

“randomized, placebo-controlled, double-blind trial of 34 children, aged 6 months through 17 years, with confirmed diagnosis of PDC Deficiency.” (opens the source at this quote in a new tab)

Crossover and extension design

“Thirty-four subjects, aged 6 months to 17 years, were randomized to DCA or placebo in a 9-month crossover study, followed by open label DCA of indefinite duration.” (opens the source at this quote in a new tab)

Eligibility criteria

Age, molecular diagnosis, and phenotype

“Eligible children (6m-17y at entry) have a proven pathological mutation in any PDC component (except DLD) or in a pyruvate dehydrogenase phosphatase isoform, and a clinical phenotype consistent with PDCD.” (opens the source at this quote in a new tab)

Treatment

Treatment periods and washout

“Each treatment arm lasts four months, separated by a one-month washout (w/o).” (opens the source at this quote in a new tab)

Genotype-directed investigational doses

“subjects are genotyped to determine whether they are a “fast” (12.5mg/kg/12h) or “slow” (6.25mg/kg/12h) DCA metabolizer” (opens the source at this quote in a new tab)

Background treatment

“Enrolled subjects continued their ketogenic diets and other supplements.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using ObsRO motor function as the primary endpoint

Daily parent or caregiver reporting

“requires less than five minutes for a parent/caregiver to complete daily.” (opens the source at this quote in a new tab)

At-home function and symptom domains

“at-home level of functionality” (opens the source at this quote in a new tab)
“motor; breathing; seizures; eating; fatigue; sleep; and general health.” (opens the source at this quote in a new tab)

Original scoring specification

“The ObsRO scoring analysis includes 11 equally-weighted items reflecting at-home functionality.” (opens the source at this quote in a new tab)
“A negative slope indicates functional improvement” (opens the source at this quote in a new tab)

FDA assessment of plasma lactate as a surrogate

“did not support the observed reduction in plasma lactate as a surrogate endpoint that predicts clinical benefit in PDCD.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Original evaluable sample-size target

“We took advantage of the rapid pharmacodynamics effects of DCA to construct a double-blind, placebo-controlled, crossover trial of 24 evaluable children, aged 6 months through 17 years, with genetically proven PDCD.” (opens the source at this quote in a new tab)

Original recruitment goal

“exceeding our original statistically based goal of 30 subjects.” (opens the source at this quote in a new tab)

Randomized sample

“Thirty-four subjects” (opens the source at this quote in a new tab)

Description of analysis sets

Original analysis strategy and missing-data plan

“an intent-to-treat strategy” (opens the source at this quote in a new tab)
“an appropriate imputation scheme for missing data” (opens the source at this quote in a new tab)

Results

Participant disposition

Interim disposition at the conference reporting cutoff

“23 patients have completed the double-blind period as of March 15, 2023, and 22 patients are now in the open-label phase.” (opens the source at this quote in a new tab)

Final randomized-period disposition by treatment sequence

No evidence found.

Baseline characteristics

Baseline demographics

“34 children (8 males, 26 females), median age at entry 2 ½ yrs” (opens the source at this quote in a new tab)

Genetic diagnoses

“33 patients have a mutation in PDHA1 and one patient has a mutation in PDHX.” (opens the source at this quote in a new tab)

Efficacy results

Original primary endpoint

“The original primary efficacy endpoint, a novel Observer Reported Outcome (ObsRO) survey, was not met.” (opens the source at this quote in a new tab)

FDA primary-analysis treatment difference

“treatment difference 0.29 [95% CI: -0.62, 1.21; p=0.52] favoring placebo arm” (opens the source at this quote in a new tab)

Plasma lactate

“DCA also significantly (p=0.006) decreased plasma lactate concentrations” (opens the source at this quote in a new tab)

Additional motor-function analysis in more seriously affected participants

“Additional analysis suggested by the FDA showed a clinically meaningful, but not statistically significant (p=0.66), improvement in motor function among the most seriously affected subjects, based on ObsRO data.” (opens the source at this quote in a new tab)

Longer-duration treatment, including the open-label extension

“Longer duration of therapy, including the open label extension (OLE), demonstrated a statistically significant improvement in motor function in the ITT population (p=0.002).” (opens the source at this quote in a new tab)

FDA assessment of post hoc subgroup analyses

“The proposed post hoc analyses for the subgroup of subjects with Period 1 baseline ObsRO motor score ≥ 8 were deemed inappropriate to determine the presence of a DCA treatment effect.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Most commonly reported adverse reaction occurring in more than 5% of participants

“gastrointestinal disorders (n=2, 5.9%).” (opens the source at this quote in a new tab)

Study limitations

Summary

The trial enrolled 34 participants and did not meet its original primary endpoint. The FDA did not accept the proposed post hoc subgroup analyses or plasma lactate reduction as evidence establishing clinical benefit. The reported p=0.002 motor-function finding included longer treatment and the open-label extension, rather than demonstrating success on the randomized primary comparison. The p=0.66 analysis in more seriously affected participants was also not statistically significant. The report provides an interim disposition update, but not final participant disposition by randomized sequence. The original design publication describes an intention-to-treat strategy and planned imputation, but is not a complete account of the final analysis implementation.

Manuscript listing status

“Phase 3 Trial of Sodium Dichloroacetate for Pyruvate Dehydrogenase Complex Deficiency (PDCD) in Children. JCI Insight In Revision 2026.” (opens the source at this quote in a new tab)