Prevention of Dichloroacetate Toxicity

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2002 by FDA Office of Orphan Products Development.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
FDA Office of Orphan Products Development
ClinicalTrials.gov Identifier:
NCT00031161
First received: February 26, 2002
Last updated: June 23, 2005
Last verified: January 2002
  Purpose

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 Intervention
Acidosis, Lactic
Chronic Disease
Drug: Nitisinone (NTBC)
Drug: Dichloroacetate
Behavioral: Low-tyrosin diet

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Masking: Double-Blind
Primary Purpose: Prevention
Official Title: Prevention of Dichloroacetate Toxicity

Resource links provided by NLM:


Further study details as provided by FDA Office of Orphan Products Development:

Estimated Enrollment: 30
Study Start Date: September 2001
Estimated Study Completion Date: August 2004
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.

  Eligibility

Ages Eligible for Study:   3 Months to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00031161

Locations
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Peter W. Stacpoole, M.D., Ph.D.    352-392-2321    stacpool@gcrc.ufl.edu   
Sponsors and Collaborators
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00031161     History of Changes
Other Study ID Numbers: FD-R-2013-01, FD-R-002013-01
Study First Received: February 26, 2002
Last Updated: June 23, 2005
Health Authority: United States: Food and Drug Administration

Keywords provided by FDA Office of Orphan Products Development:
Tyrosine
Diet
2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
4-Hydroxyphenylpyruvate Dioxygenase
Enzyme Inhibitors

Additional relevant MeSH terms:
Acidosis
Acidosis, Lactic
Chronic Disease
Acid-Base Imbalance
Metabolic Diseases
Disease Attributes
Pathologic Processes
Nitisinone
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 21, 2014