Prevention of Dichloroacetate Toxicity

This is a study to determine the safety of dichloroacetate (DCA) with a low-tyrosine diet given with or without nitisinone (NTBC) in children with chronic lactic acidosis (CLA).

Study Overview

• Status: Completed
• Conditions: Chronic Disease; Acidosis, Lactic
• Intervention / Treatment: Drug: Dichloroacetate; Drug: Nitisinone (NTBC); Behavioral: Low-tyrosin diet

Detailed Description

DCA is being studied for the treatment of patients with CLA, which is a rare collection of mitochondrial metabolism errors causing cellular energy failure and early death. DCA causes reversible liver and peripheral nerve toxicity and it interrupts both tyrosine and heme metabolism. The inhibitory effect of DCA on mammalian tyrosine metabolism elicits biochemical changes similar to those observed in hereditary tyrosinemia type I (HT). However, some reports and studies indicate substantial reduction in the biochemical and clinical consequences of HT may occur when patients are treated concomitantly with a low-tyrosine diet (LTD) and the chemical NTBC, which inhibits an early step in tyrosine catabolism. Possibly, the same dietary and pharmacologic interventions may mitigate or prevent toxicity associated with chronic DCA exposure.

Patients visit the Center 5 times over a 1-year period, usually for 2 to 3 days per visit, for an extensive series of clinical and biochemical tests. Visit 1 is for baseline examinations and blood and urine chemistries and to educate the patient on an LTD. This visit lasts approximately 7 days to determine acceptable circulating tyrosine concentrations for LTD formula at discharge. Patients are provided with tubes to take to local laboratories every 2 weeks for blood work. Patients are readmitted in 1 month to determine adherence to diet and serum tyrosine levels. Patients who evidence dietary compliance, no adverse effects, and a willingness to continue are placed in 1 of 2 treatment arms: DCA plus an LTD plus placebo or DCA plus an LTD plus NTBC. Thereafter, patients return during Months 5, 9, and 13, which completes their 1-year treatment phase.

Completion date provided represents the completion date of the grant per OOPD records

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Biochemical or molecular genetic proof of a defect in mitochondrial enzyme of glucose metabolism or oxidative phosphorylation.
• Clinical history consistent with CLA (e.g., basal hyperlactatemia, stroke-like episodes, neuromuscular degeneration, and seizures).
• Ability to withstand an 8-hour fast (if 2 years old or younger) or a 12-hour fast without developing hypoglycemia (blood glucose greater than or equal to 50 mg/dL).

Exclusion criteria:

• Secondary lactic acidosis due to impaired oxygenation or circulation.
• Hyperlactatemia associated with proven biotinidase deficiency or with enzyme deficiencies of gluconeogenesis.
• Primary, defined organic acidurias other than lactic acidosis for which effective therapy is available (e.g., propionic aciduria).
• Primary disorders of amino acid metabolism.
• Primary disorders of fatty acid oxidation.
• Malabsorption syndromes associated with D-lactic acidosis.
• Renal insufficiency.
• Serum creatinine greater than 1.2 mg/g.
• Creatinine clearance less than or equal to 60 mL/min.
• Primary hepatic disease unrelated to chronic lactic acidosis.
• In patients with pyruvate dehydrogenase enzyme complex deficiency, an inability to maintain a diet greater than 50% calories from fat without biological and/or neurological deterioration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Masking: Double

Collaborators and Investigators

• Sponsor: University of Florida

Study record dates

Study Major Dates

• Study Start: September 1, 2001
• Study Completion: September 1, 2005

Study Registration Dates

• First Submitted: February 26, 2002
• First Submitted That Met QC Criteria: February 26, 2002
• First Posted (Estimate): February 27, 2002

Study Record Updates

• Last Update Posted (Estimate): March 25, 2015
• Last Update Submitted That Met QC Criteria: March 24, 2015
• Last Verified: January 1, 2002

More Information

Terms related to this study

• Keywords: Diet; Enzyme Inhibitors; Tyrosine; 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione; 4-Hydroxyphenylpyruvate Dioxygenase
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease Attributes; Acid-Base Imbalance; Chronic Disease; Acidosis; Acidosis, Lactic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nitisinone
• Other Study ID Numbers: FD-R-2013-01; FD-R-002013-01