Phase 3 Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
Trial Snapshot
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- Saol Therapeutics Inc
- Enrollment
- 34
- Locations
- 10
- Primary Endpoint
- The efficacy will be measured between the groups by using the Observer Reported Outcome (ObsRO) measure of health.
Study Overview
Brief Summary
The objective of this research study is to conduct a pivotal phase 3 trial of treatment with the investigational drug dichloroacetate (DCA) in young children with deficiency of the pyruvate dehydrogenase complex (PDC). PDC deficiency (PDCD) is the most common cause of congenital lactic acidosis and is a frequently fatal metabolic disease of childhood for which no proven treatment exists. The investigators predict that DCA represents targeted potential therapy for PDCD because of its ability to increase both the catalytic activity and stability of the enzyme complex. The conclusions of numerous laboratory and clinical investigations are consistent with this postulate and have led to the designation of DCA as an Orphan Product for congenital lactic acidosis by the Food and Drug Administration.
A novel Observer reported outcome (ObsRO) survey that is completed by study participant's parent/caregiver, is the efficacy outcome measure.
Funding Source - FDA OOPD
Detailed Description
Clinical sites will be established across the United States for study participation. The investigators will conduct a randomized, placebo-controlled, double-blind trial of 24 evaluable children (30 randomized), aged 6 months through 17 years, with confirmed diagnosis of PDC Deficiency.
Study participants complete Screening procedures at Visit 1 to confirm eligibility for study participation. Screening study procedures include medical history review and physical exam; blood and urine collection, and collection of cheek (buccal) cells; training to complete the ObsRO daily survey. The ObsRO is a survey developed for this study to evaluate how study participants are feeling and functioning in the home setting. The ObsRO survey is completed by the study participant parent/caregiver every day during both treatment periods (study medication and placebo) of study participation (approximately 9 months). During treatment period 1 and 2 (4 months of study medication and 5 months of placebo), the study participant will communicate with the study team at least 2 times per month to evaluate the child's level of health, and compliance with daily survey completion and taking the study medication.
Study participants complete Baseline study procedures at Visit 2 prior to randomization to treatment. Baseline study procedures include, medical history review and physical exam; blood and urine collection; 3 day food record. The study medication will be shipped to the study participants home each month of study participation.
Safety labs are completed during each randomization period (month 3 and month 5). The safety labs can be completed at the clinical trial site, or at any standard clinical laboratory.
Study participants will complete a study visit after each randomization period (month 5 and 9) to complete study assessments at the same clinical site. Visit study procedures include medical history review and physical exam; blood and urine collection; 3 day food record.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 6 Months to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 6 m through 17 y
- •Presence of characteristic clinical or metabolic features of pyruvate dehydrogenase complex deficiency (PDCD) and
- •Presence of a known pathogenic mutation of a gene that is specifically associated with PDCD.
Exclusion Criteria
- •A genetic mitochondrial disease other than those stipulated under inclusion criteria Primary disorders of amino acid metabolism; primary disorders of fatty acid oxidation Secondary lactic acidosis due to impaired oxygenation or circulation (cardiomyopathy or congenital heart defect) Renal insufficiency (defined as: requires chronic dialysis or serum creatinine ≥ 1.2 mg/dl; creatinine clearance <60 ml/min Primary hepatic disease unrelated to PDCD Pregnancy or breast feeding
Arms & Interventions
Dichloroacetate, then Placebo
This group will start on the Dichloroacetate (DCA) treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the placebo treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Dichloroacetate (DCA) (Drug)
Dichloroacetate, then Placebo
This group will start on the Dichloroacetate (DCA) treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the placebo treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Placebo (Other)
Dichloroacetate, then Placebo
This group will start on the Dichloroacetate (DCA) treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the placebo treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Genotype (Genetic)
Placebo, then Dichloroacetate
This group will start on the placebo treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the Dichloroacetate (DCA) treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Dichloroacetate (DCA) (Drug)
Placebo, then Dichloroacetate
This group will start on the placebo treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the Dichloroacetate (DCA) treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Placebo (Other)
Placebo, then Dichloroacetate
This group will start on the placebo treatment which will last for 4 months. After 4 months a 1 month washout period will occur. After the 1 month the group will crossover to the Dichloroacetate (DCA) treatment for 4 months.
Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens
Intervention: Genotype (Genetic)
Outcomes
Primary Outcomes
The efficacy will be measured between the groups by using the Observer Reported Outcome (ObsRO) measure of health.
Time Frame: 9 months
The efficacy of dichloroacetate will be determined by applying a novel Observer Reported Outcome (ObsRO) measure of health. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).
The number of participants with adverse events will be compared between the groups.
Time Frame: 9 months
This is to evaluate the safety and tolerability of dichloroacetate by comparing the 1) number and 2) severity of adverse events during both the double-blind and open label treatment phases.
Secondary Outcomes
- Plasma β-hydroxybutyrate (β-OHB) concentrations between the groups.(9 months)
- Blood lactate levels between the groups.(9 months)
- Karnofsky/Lansky Performance Status(9 months)