DCA for Pyruvate Dehydrogenase Deficiency

(DCA/PDCD Trial)

Recruiting at 9 trial locations

Overseen By Breeana Usher, BS

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Saol Therapeutics Inc

Disqualifiers: Mitochondrial disease, Amino acid disorders, Fatty acid disorders, Renal insufficiency, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

34 Participants Needed

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug dichloroacetate (DCA) for pyruvate dehydrogenase deficiency?

Research shows that DCA can activate the pyruvate dehydrogenase complex, which helps lower lactate levels in the blood and cerebrospinal fluid, improving energy metabolism. It has been effective in increasing enzyme activity in patients with certain genetic mutations related to pyruvate dehydrogenase deficiency, leading to clinical improvements. ^{1 2 3 4 5}

Is DCA generally safe for humans?

Dichloroacetate (DCA) has been used in various conditions and is generally well-tolerated in humans, though it can cause reversible peripheral neuropathy (nerve damage). Long-term studies show stable health markers in patients, but some experienced mild nerve issues, leading to dose adjustments. ^{2 4 6 7 8}

How is the drug DCA unique in treating pyruvate dehydrogenase deficiency?

DCA is unique because it helps activate the pyruvate dehydrogenase complex, which is crucial for energy production, by inhibiting an enzyme that inactivates it. This can lead to increased enzyme activity and reduced lactate levels in the blood, making it potentially effective for patients with specific genetic mutations causing pyruvate dehydrogenase deficiency. ^{1 2 5 9 10}

Research Team

Richard Neibeger, MD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for children aged 6 months to 17 years with Pyruvate Dehydrogenase Complex Deficiency (PDCD), evidenced by a known pathogenic gene mutation and clinical or metabolic features of PDCD. It excludes those with unrelated liver disease, amino acid metabolism disorders, pregnancy, fatty acid oxidation disorders, other genetic mitochondrial diseases besides PDCD, renal insufficiency, or secondary lactic acidosis.

Inclusion Criteria

I have a genetic mutation linked to programmed cell death.

I am between 6 months and 17 years old.

You show signs of pyruvate dehydrogenase complex deficiency (PDCD) in your health or metabolism.

Exclusion Criteria

My condition is not one of the specified mitochondrial diseases.

I have a disorder that affects how my body breaks down fats.

I have high lactic acid levels due to heart issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline

Baseline study procedures including medical history review, physical exam, and sample collection prior to randomization

1 week

1 visit (in-person)

Treatment Period 1

Participants receive either placebo or dichloroacetate for 4 months, with monthly communication and safety labs

4 months

2 visits (in-person), monthly communication

Washout

1 month washout period between treatment phases

1 month

Treatment Period 2

Participants crossover to the alternate treatment (placebo or dichloroacetate) for 4 months, with monthly communication and safety labs

4 months

2 visits (in-person), monthly communication

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month

1 visit (in-person)

Open-label extension (optional)

Participants may opt into continued access to dichloroacetate with biannual visits for assessments

Long-term

1 visit every 6 months (in-person)

Treatment Details

Interventions

• Dichloroacetate (DCA)

Trial Overview The study tests Dichloroacetate (DCA) against a placebo in young children with PDCD. DCA could potentially stabilize the enzyme complex affected by this condition. The trial's effectiveness will be measured using an Observer reported outcome survey completed by the child's parent or caregiver.

Participant Groups

Group I: Dichloroacetate, then Placebo Active Control 3 Interventions

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

Group II: Placebo, then Dichloroacetate Placebo Group 3 Interventions

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

Dichloroacetate (DCA) is already approved in Canada for the following indications:

Approved in Canada as Dichloroacetic acid for:

• Topical treatment of warts
• Cauterization and removal of skin and tissue lesions

Who Is Running the Clinical Trial?

Saol Therapeutics Inc

Lead Sponsor

Trials

3

Recruited

200+

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Medosome Biotec LLC

Industry Sponsor

Trials

2

Recruited

80+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

Chronic administration of dichloroacetate (DCA) for 9.7 to 16.5 years in 8 patients with metabolic deficiencies was generally well-tolerated and effectively maintained normal blood lactate levels, even in children not on strict ketogenic diets.

Despite some modest changes in nerve conduction in a few patients, there were no significant symptoms of peripheral neuropathy, indicating that DCA can be a safe long-term treatment for congenital lactic acidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of dichloroacetate in congenital lactic acidosis. Abdelmalak, M., Lew, A., Ramezani, R., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Congenital lactic acidosis. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Differential effect of DCA treatment on the pyruvate dehydrogenase complex in patients with severe PDHC deficiency. [2014]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical and radiologic improvements in mitochondrial encephalomyelopathy following sodium dichloroacetate therapy. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Role of dichloroacetate in the treatment of genetic mitochondrial diseases. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Long-term safety of dichloroacetate in congenital lactic acidosis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

The effects of dichloroacetate in a rabbit model of acute hind-limb ischemia and reperfusion. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of sodium dichloroacetate on human pyruvate metabolism. [2019]