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A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT02690285
Recruitment Status : Completed
First Posted : February 24, 2016
Last Update Posted : December 31, 2018
Sponsor:
Collaborators:
Medosome Biotec LLC
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
University of Florida

Tracking Information
First Submitted Date  ICMJE February 9, 2016
First Posted Date  ICMJE February 24, 2016
Last Update Posted Date December 31, 2018
Actual Study Start Date  ICMJE March 1, 2016
Actual Primary Completion Date May 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 19, 2016)
GSTZ1 haplotype frequency [ Time Frame: Baseline Visit ]
The TagMan-based genotyping technology will be used for GSTZ1 haplotype analysis from both blood and cheek samples. Haplotype variations in GSTZ1 influence the kinetics of chronically administered investigational medication DCA. The coding region of the GSTZ1 gene contains three functionally important non-synonymous single nucleotide polymorphisms (SNPs) that give rise to five major GSTZ1 haplotypes: KRT (Z1A), KGT (Z1B), EGT (Z1C), EGM (Z1D), and KGM (Z1F).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02690285 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2016)
Peak Plasma Concentration (Cmax) of Dichloroacetate (DCA) [ Time Frame: -10, 0, 5, 10, 20, 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 30 hours post dose ]
After 5 days of oral DCA administration, blood samples will be collected at the specified times for Peak Plasma Concentration (Cmax) analysis.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers
Official Title  ICMJE A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers Part 1: Rapid Haplotyping Procedure for Determining the Response of Patients to DCA. Part 2: Personalized Dosing of Dichloroacetate for the Treatment of Rare and Common Diseases
Brief Summary

The purpose of this study is to identify and analyze the frequency of GSTZ1 haplotypes in a healthy adult population and determine the pharmacokinetics of Dichloroacetate (DCA) metabolism based on haplotype analysis.

The DCA drug is the first targeted treatment for Pyruvate Dehydrogenase Complex Deficiency (PDCD).

This pilot study, focuses on developing a high throughput, sensitive and accurate screening test for determining glutathione transferase zeta 1 (GSTZ1) haplotype status in individuals who would be treated with DCA.

Detailed Description Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure with the life of expectancy of affected children severely truncated. Treatment of PDCD remains a serious, unmet challenge. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity. Cumulative experience with DCA has revealed dose accumulation in a subset of the population. This can be abated through personalized dosing of DCA, assigned by haplotype variation in the gene encoding glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate. Haplotype variations in GSTZ1 influence the kinetics and dynamics of chronically administered DCA. A single dose of DCA has a bioavailability approaching unity and is widely distributed throughout the body. The plasma half-life (t ½) is ~1 hr in drug-naïve subjects. Gender does not influence DCA kinetics or metabolism. The major route of biotransformation is via dehalogenation to glyoxylate by glutathione transferase zeta 1 (GSTZ1). DCA is a mechanism-based inhibitor of GSTZ1, so repeated administration results in increased plasma t ½ and decreased clearance.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Dichloroacetate (DCA)
    Dichloroacetate (DCA) 25 mg/kg oral solution will be administered daily for 5 days.
  • Other: GSTZ1 haplotyping
    One teaspoon of blood is collected by standard phlebotomy. Cheek cells are collected by standard brushing. Samples will be analyzed at two independent laboratories to validate methods for GSTZ1 haplotype analysis.
    Other Names:
    • Blood collection
    • Cheek cell collection
Study Arms  ICMJE
  • Part 1: glutathione transferase zeta 1 (GSTZ1) haplotyping
    The participants will have blood collection and cheek cell collection after signing the informed consent, to determine GSTZ1 haplotype.
    Intervention: Other: GSTZ1 haplotyping
  • Experimental: Part 2: Dichloroacetate (DCA) Kinetics
    Eight study participants will be administered oral Dichloroacetate (DCA) 25 mg/kg daily for 5 days. On the fifth day frequent blood samples will be obtain over the following 24 hours. Study participants will complete a DCA kinetic study on day 5, at the Clinical Research Clinic (CRC).
    Interventions:
    • Drug: Dichloroacetate (DCA)
    • Other: GSTZ1 haplotyping
Publications * Not Provided

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: December 12, 2017)
45
Original Estimated Enrollment  ICMJE
 (submitted: February 19, 2016)
30
Actual Study Completion Date  ICMJE November 1, 2017
Actual Primary Completion Date May 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy as outline in the physical exam and blood tests
  • Non smoker

Exclusion Criteria:

  • Cannot comprehend or refuse to sign the informed consent form;
  • Febrile or have other clinical signs of infection;
  • Pregnant or are nursing;
  • In females, cannot or refuse to use contraception or avoid unprotected intercourse during the study;
  • Uncontrolled hypertension (BPs > 160 mmHg or BPd > 100 mmHg) on conventional medication;
  • Anemic (hematocrit < 35% in males; < 35% in females;
  • Serum creatinine ≥ 1.3 mg/dl, TSH > 4.5 mIU/ml; a transaminase (ALT or AST) > 2 x ULN, total bilirubin > 1.2 mg/dl or fasting glucose ≥ 110 mg/dl.
  • History of psychosis, seizures or diabetes mellitus or be receiving anti-psychotic, anti-epileptic or blood glucose-lowering medication.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02690285
Other Study ID Numbers  ICMJE IRB201500995 - N
R43FD005349 ( U.S. FDA Grant/Contract )
OCR15997 ( Other Identifier: Universiy of Florida )
Has Data Monitoring Committee No
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
  • Medosome Biotec LLC
  • Food and Drug Administration (FDA)
Investigators  ICMJE
Principal Investigator: Peter W Stacpoole, PhD, MD University of Florida
PRS Account University of Florida
Verification Date December 2018

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