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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 : February 15, 2019
Sponsor:
Collaborators:
Columbia University
Medosome Biotec LLC
Saol Therapeutics
Information provided by (Responsible Party):
University of Florida

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 in June 2020. 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 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 : October 1, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : March 30, 2022


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.




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).



Information from the National Library of Medicine

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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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02616484


Contacts
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Contact: Peter W Stacpoole, PhD, MD 352-273-9023 pws@ufl.edu
Contact: Tracie Kurtz, RN 352-273-9014 tlkurtz@ufl.edu

Locations
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United States, California
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Jose E Abdenur, MD    888-770-2462    jabdenur@choc.org   
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Gregory M Enns, M.B., Ch.B.    650-498-5798    greg.enns@stanford.edu   
Contact: Thu Quan, MBA/HCM CCRC    650-736-8166    tquan@stanford.edu   
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Andrea L Gropman, MD    202-476-6230    agropman@cnmc.org   
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Contact: Richard Neiberger, MD    352-273-9014    neibere@peds.ufl.edu   
Contact: Tracie Kurtz, RN    352-273-9014    tlkurtz@ufl.edu   
United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Jirair Bedoayn, MD    215-844-3936    Jirair.Bedoyan@UHhospitals.org   
Contact: Audrey Lynn, PhD    216-844-7124    audrey.lynn@uhhospitals.org   
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 15224
Contact: Marni J Falk, MD    215-590-4564    falkm@email.chop.edu   
Contact: Laura Dennis    267-426-0229    DENNISL@email.chop.edu   
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Gerard Vockley, MD    412-692-5070    gerard.vockley@chp.edu   
Contact: Jennifer Baker    412-692-6378    jennifer.baker@chp.edu   
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84113
Contact: Nicola Longo, MD, PhD    801-585-2457    NICOLA.LONGO@HSC.UTAH.EDU   
Contact: Margaret Kuenzi, BS CCRC    801-585-9183    Margaret.Kuenzi@hsc.utah.edu   
United States, Washington
Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98105
Contact: Russell P Saneto, DO, PhD    206-987-2078    russ.saneto@seattlechildrens.org   
Sponsors and Collaborators
University of Florida
Columbia University
Medosome Biotec LLC
Saol Therapeutics
Investigators
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Principal Investigator: Richard Neibeger, MD University of Florida

Publications:
Henderson GH, Whalen PO, Darr RA, Curry SH, Derendorf H, Baumgartner TG, Stacpoole PW: Development of an oral drug formulation for dichloroacetate and thiamine. Drug Devel Indust Pharm, 20:2425-2437, 1994.
Robinson BH. Lactic academia (disorders of pyruvate carboxylase, pyruvate dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D. (Eds.). The metabolic and molecular bases of inherited disease, seventh ed. McGraw-Hill, New York, pp. 1479-1499, 1995.
Papadopoulos EJ, Patrick DL, Tassinari MS, Mulberg AE, Epps C, Pariser AR, Burke LB. Clinical outcome assessments for clinical trials in children. In Pediatric Drug Development: Concepts and Applications (Eds. AE Mulberg, D Murphy, J Dunne and LL Mathis. John Wiley & Sons, Ltd, Hoboken, NJ, pp. 539-548.
Lehman, EL. Nonparametrics: Statistical methods Based on Ranks. (Page 173). Holden-Day, San Francisco, 1975.

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02616484     History of Changes
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 )
First Posted: November 30, 2015    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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