Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency: (DCA/PDCD)

• ClinicalTrials.gov Identifier: NCT02616484
• Recruitment Status: Active, not recruiting
• First Posted: November 30, 2015
• Last Update Posted: September 15, 2022
• Sponsor: University of Florida
• Collaborators: Medosome Biotec LLC; Saol Therapeutics Inc; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Food and Drug Administration (FDA)
• Information provided by (Responsible Party): University of Florida

Study Description

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

Condition or disease	Intervention/treatment	Phase
Pyruvate Dehydrogenase Complex Deficiency	Drug: Dichloroacetate (DCA); Other: Placebo; Genetic: Genotype	Phase 3

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 children, 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 participants who complete both treatment periods and did not sustain serious adverse events attributable to DCA, will be offered continued access to investigational medication DCA through an open-label access program until the study concludes. Study participants must sign a separate consent form for participation in the open-label access phase of this clinical trial and must complete a study visit every 6 months at the same clinical site for study assessments that include medical history review and physical exam, blood and urine collection. The study medication will continue to be mailed to the study participant during the open-label phase at the same dose received during the blinded phase of the study.

Study participants will be stratified according to their predicted rate of DCA metabolism and clearance, based on genotyping prior to randomization (completed at visit 1 buccal cell collection).

Study participants will continue whatever diet and other "standard of care" is deemed appropriate by their local expert clinicians.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3 Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
• Actual Study Start Date: July 14, 2020
• Estimated Primary Completion Date: April 30, 2023
• Estimated Study Completion Date: May 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 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	Drug: Dichloroacetate (DCA); Study medication DCA is a liquid formulation mixed with an artificial sweetener containing aspartame and strawberry extract (50mg/mL) 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: EGT carriers will receive 12-14 mg/kg/12hr DCA. EGT non-carriers will receive 6-7 mg/kg/12 hr.; Other Name: Sodium Dichloroacetate; Other: Placebo; Participants will receive the same volume of placebo in liquid form given during DCA treatment arm. Liquid will be an exact replication of DCA formulation with no DCA added.; Genetic: Genotype; Participants will be genotyped to determine GSTZ1 haplotype status.
Placebo Comparator: 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	Drug: Dichloroacetate (DCA); Study medication DCA is a liquid formulation mixed with an artificial sweetener containing aspartame and strawberry extract (50mg/mL) 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: EGT carriers will receive 12-14 mg/kg/12hr DCA. EGT non-carriers will receive 6-7 mg/kg/12 hr.; Other Name: Sodium Dichloroacetate; Other: Placebo; Participants will receive the same volume of placebo in liquid form given during DCA treatment arm. Liquid will be an exact replication of DCA formulation with no DCA added.; Genetic: Genotype; Participants will be genotyped to determine GSTZ1 haplotype status.

Outcome Measures

Primary Outcome Measures :

1. 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).
2. 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 Outcome Measures :

1. Karnofsky/Lansky Performance Status [ Time Frame: 9 months ]

   The Karnofsky/Lansky performance Scale is completed by the study team. It is a measure of the study participants functional ability to carry on activities of daily living.

   The Karnofsky Scale is used for study participants age greater than 16 years. The Lansky Scale is used for study participants age less than 16 years.

2. Blood lactate levels between the groups. [ Time Frame: 9 months ]
   The measurement of blood lactate level will be performed.
3. Plasma β-hydroxybutyrate (β-OHB) concentrations between the groups. [ Time Frame: 9 months ]
   The measurement of plasma β-hydroxybutyrate (β-OHB) concentrations will be performed.

Other Outcome Measures:

1. The number of participants with adverse events based on the age at randomization between the groups. [ Time Frame: 9 months ]
   The number of participants with adverse events based on the age at randomization will be measured between the groups.
2. The number of participants with adverse events based on dietary fat intake between the groups. [ Time Frame: 9 months ]
   The number of participants with adverse events based on dietary fat intake will be measured between the groups.
3. The efficacy will be measured using the Observer Reported Outcome (ObsRO) scale of health based on the genetic-based dosing between the groups. [ Time Frame: 9 months ]
   The efficacy of dichloroacetate will be determined by using the Observer Reported Outcome (ObsRO) measure of health based on the GSTZ1 haplotype status, genetic-based dosing. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).
4. The efficacy will be measured using the Observer Reported Outcome (ObsRO) scale of health based on the age at randomization between the groups [ Time Frame: 9 months ]
   The efficacy of dichloroacetate will be determined by using the Observer Reported Outcome (ObsRO) measure of health based on the age at randomization. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).
5. The efficacy will be measured using the Observer Reported Outcome (ObsRO) scale of health based on the dietary fat intake between the groups [ Time Frame: 9 months ]
   The efficacy of dichloroacetate will be determined by using the Observer Reported Outcome (ObsRO) measure of health based on the dietary fat intake. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Children's Hospital of Orange County

Orange, California, United States, 92868

Stanford University

Stanford, California, United States, 94305

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Florida

University of Florida

Gainesville, Florida, United States, 32611

United States, Ohio

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States, 44106

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 15224

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84113

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Sponsors and Collaborators

University of Florida

Medosome Biotec LLC

Saol Therapeutics Inc

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

Food and Drug Administration (FDA)

Investigators

• Principal Investigator: Richard Neibeger, MD; University of Florida

More Information

Publications:

Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012 Jul;106(3):385-94. doi: 10.1016/j.ymgme.2012.03.017.

DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab. 2012 Nov;107(3):394-402. doi: 10.1016/j.ymgme.2012.09.001. Epub 2012 Sep 7.

Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.

Stacpoole PW. The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither? Environ Health Perspect. 2011 Feb;119(2):155-8. doi: 10.1289/ehp.1002554. Epub 2010 Oct 4.

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Han Z, Berendzen K, Zhong L, Surolia I, Chouthai N, Zhao W, Maina N, Srivastava A, Stacpoole PW. A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate. Mol Genet Metab. 2008 Apr;93(4):381-7. doi: 10.1016/j.ymgme.2007.10.131. Epub 2008 Feb 21.

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Chu PI, Curry SH, Baumgartner TG, Henderson GN, Stacpoole PW. Preparation and stability of intravenous solutions of sodium dichloroacetate (DCA). J Parenter Sci Technol. 1992 Jan-Feb;46(1):16-8.

Berendzen K, Theriaque DW, Shuster J, Stacpoole PW. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion. 2006 Jun;6(3):126-35. doi: 10.1016/j.mito.2006.04.001. Epub 2006 May 3.

Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O'Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW, Valenstein E. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006 May;117(5):1519-31. doi: 10.1542/peds.2005-1226.

Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW, Shuster JJ. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics. 2008 May;121(5):e1223-8. doi: 10.1542/peds.2007-2062. Epub 2008 Apr 14.

Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony SH, Stacpoole PW. Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab. 2013 Jun;109(2):139-43. doi: 10.1016/j.ymgme.2013.03.019. Epub 2013 Apr 6.

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Shroads AL, Langaee T, Coats BS, Kurtz TL, Bullock JR, Weithorn D, Gong Y, Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW. Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. J Clin Pharmacol. 2012 Jun;52(6):837-49. doi: 10.1177/0091270011405664. Epub 2011 Jun 3.

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• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02616484
• Other Study ID Numbers: IRB201500698 - A - N; R01FD005407 ( U.S. FDA Grant/Contract ); FD-R-05407-01 ( Other Grant/Funding Number: Orphan Products Development ); OCR17309 ( Other Identifier: OnCore ); 2R42HD089804 ( U.S. NIH Grant/Contract ); IRB201602089 ( Other Identifier: UF IRB )
• First Posted: November 30, 2015
• Last Update Posted: September 15, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Florida:

Sodium Dichloroacetate; Treatment of PDCD with Dichloroacetate

Additional relevant MeSH terms:

Pyruvate Dehydrogenase Complex Deficiency Disease; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Mitochondrial Diseases