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

NCT ID: NCT02690285

Last Updated: 2018-12-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-01
• Study Completion Date: 2017-11-01

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.

Conditions

Healthy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

GSTZ1 haplotyping

Intervention Type: OTHER

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.

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).

Group Type: EXPERIMENTAL

Dichloroacetate (DCA)

Intervention Type: DRUG

Dichloroacetate (DCA) 25 mg/kg oral solution will be administered daily for 5 days.

GSTZ1 haplotyping

Intervention Type: OTHER

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.

Interventions

Dichloroacetate (DCA)

Dichloroacetate (DCA) 25 mg/kg oral solution will be administered daily for 5 days.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Blood collection; Cheek cell collection

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Medosome Biotec LLC

INDUSTRY

Sponsor Role: collaborator

Food and Drug Administration (FDA)

FED

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter W Stacpoole, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Health: Clinical Research Center

Gainesville, Florida, United States

Countries

United States

Other Identifiers

R43FD005349

Identifier Type: FDA

Identifier Source: secondary_id

View Link

OCR15997

Identifier Type: OTHER

Identifier Source: secondary_id

IRB201500995 - N

Identifier Type: -

Identifier Source: org_study_id