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

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ClinicalTrials.gov Identifier: NCT02616484
Recruitment Status : Recruiting
First Posted : November 30, 2015
Last Update Posted : August 29, 2019
Sponsor:
Collaborators:
Columbia University
Medosome Biotec LLC
Saol Therapeutics
Information provided by (Responsible Party):
University of Florida

Tracking Information
First Submitted Date  ICMJE November 17, 2015
First Posted Date  ICMJE November 30, 2015
Last Update Posted Date August 29, 2019
Estimated Study Start Date  ICMJE October 1, 2019
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 24, 2015)
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02616484 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2017)
  • 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.
  • Blood lactate levels between the groups. [ Time Frame: 9 months ]
    The measurement of blood lactate level will be performed.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 24, 2015)
  • Karnofsky/Lansky Performance Status between the groups [ Time Frame: 9 months ]
    The Karnofsky score runs from 100 to 0, where 100 is "perfect" health and 0 is death. 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead
  • Blood lactate levels between the groups. [ Time Frame: 9 months ]
    The measurement of blood lactate level will be performed.
  • 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.
Current Other Pre-specified Outcome Measures
 (submitted: February 21, 2017)
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
Original Other Pre-specified Outcome Measures
 (submitted: November 24, 2015)
  • The number of participants with adverse events based on genetic-based dosing between the groups. [ Time Frame: 9 months ]
    The number of participants with adverse events of genetic-based dosing will be measured by using the GSTZ1 haplotype status between the groups.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
 
Descriptive Information
Brief Title  ICMJE Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
Official Title  ICMJE Phase 3 Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
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 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pyruvate Dehydrogenase Complex Deficiency
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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

    Interventions:
    • Drug: Dichloroacetate (DCA)
    • Other: Placebo
    • Genetic: Genotype
  • 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

    Interventions:
    • Drug: Dichloroacetate (DCA)
    • Other: Placebo
    • Genetic: Genotype
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2019)
9
Original Estimated Enrollment  ICMJE
 (submitted: November 24, 2015)
24
Estimated Study Completion Date  ICMJE March 30, 2023
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Peter W Stacpoole, PhD, MD 352-273-9023 pws@ufl.edu
Contact: Tracie Kurtz, RN 352-273-9014 tlkurtz@ufl.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02616484
Other Study ID Numbers  ICMJE IRB201500698 - A - N
R01FD005407 ( U.S. FDA Grant/Contract )
FD-R-05407-01 ( Other Grant/Funding Number: Orphan Products Development )
OCR17309 ( Other Identifier: OnCore )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Florida
Study Sponsor  ICMJE University of Florida
Collaborators  ICMJE
  • Columbia University
  • Medosome Biotec LLC
  • Saol Therapeutics
Investigators  ICMJE
Principal Investigator: Richard Neibeger, MD University of Florida
PRS Account University of Florida
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP