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Prevention of Dichloroacetate Toxicity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00031161
Recruitment Status : Completed
First Posted : February 27, 2002
Last Update Posted : March 25, 2015
Information provided by:
FDA Office of Orphan Products Development

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acidosis, Lactic Chronic Disease Drug: Nitisinone (NTBC) Drug: Dichloroacetate Behavioral: Low-tyrosin diet Not Applicable

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Masking: Double
Primary Purpose: Prevention
Official Title: Prevention of Dichloroacetate Toxicity
Study Start Date : September 2001
Study Completion Date : September 2005

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

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 identifier (NCT number): NCT00031161

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United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Layout table for additonal information Identifier: NCT00031161    
Other Study ID Numbers: FD-R-2013-01
First Posted: February 27, 2002    Key Record Dates
Last Update Posted: March 25, 2015
Last Verified: January 2002
Keywords provided by FDA Office of Orphan Products Development:
4-Hydroxyphenylpyruvate Dioxygenase
Enzyme Inhibitors
Additional relevant MeSH terms:
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Acidosis, Lactic
Chronic Disease
Disease Attributes
Pathologic Processes
Acid-Base Imbalance
Metabolic Diseases
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action