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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

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.


Condition or disease Intervention/treatment Phase
Healthy Drug: Dichloroacetate (DCA) Other: GSTZ1 haplotyping Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Official Title: 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
Actual Study Start Date : March 1, 2016
Actual Primary Completion Date : May 30, 2017
Actual Study Completion Date : November 1, 2017

Arm Intervention/treatment
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.
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

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).
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




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

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): NCT02690285


Locations
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United States, Florida
UF Health: Clinical Research Center
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Medosome Biotec LLC
Food and Drug Administration (FDA)
Investigators
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Principal Investigator: Peter W Stacpoole, PhD, MD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02690285     History of Changes
Other Study ID Numbers: IRB201500995 - N
R43FD005349 ( U.S. FDA Grant/Contract )
OCR15997 ( Other Identifier: Universiy of Florida )
First Posted: February 24, 2016    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 2018
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