Clinical Trial: Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
Brief Summary:
Nitisinone is a potent inhibitor of the enzyme that catalyzes the formation of homogentisic acid, and should be an even more logical treatment for alkaptonuria than for tyrosinemia, for which it has been approved by the FDA.The objective of this research is to explore reported age related differences in toxicity of nitisinone and its pharmacokinetic underpinnings and to develop an optimal therapeutic requirement for a targeted population of presymptomatic patients. The additional effect of mixtures of amino acids excluding tyrosine will be explored to take advantage of protein synthesis to avoid elevations of tyrosine that would otherwise limit the optimal dosage of nitisinone. The study is designed to treat patients and find the optimal dosage of nitisinone to obtain maximal reduction in levels of homogentisic acid and maintain safe levels of tyrosine.
The long term objective in the target population of pre-symptomatic patients is the prevention of the characteristic effects on joint cartilage and tendons.
Detailed Summary:
Study procedures are designed to:
- Develop a method for nitisinone measurement via tandem mass spectrometry (MS/MS).
- Determine whether differences between adult and children could be erased by employing a dosage regimen based on m2 of body surface area as opposed to per kg of body weight, as we have found in a recent study of dichloroacetate
- Determine optimal dosage for reduction of urinary levels of homogentisic acid and minimal elevation of plasma levels of tyrosine in the target population of pre-symptomatic patients.
- Determine optimal doses of Tyrex to prevent hypertyrosinemia and allow maximal reduction in homogentisic acid.
Baseline studies will include ophthalmologic examinations, echocardiogram, X-rays of all joints, MRI of selected joints when financially plausible; history and physical examinations with emphasis on joints and tendons. Ideally MRI will be repeated at 12 month intervals thereafter. Ophthalmologic exam, x-rays of the kidneys and prostate, and echocardiogram will be repeated approximately every 12 months, depending on the age of the subject and the nitisinone dose. Patients will be seen every 3 months for the first year, then at 6 month intervals to month 36. The timing of the visits may be altered in response to modifications of nitisinone and/or Tyrex doses.
Complete or near complete elimination of homogentisic acid excretion will be sought. Optimal NTBC dosage would be judged to yield plasma concentration of tyrosine less than 1000 mmol/L with the concomitant use of tyrosine free amino acid supplement. Dosage will be escalated or reduced dependent on evidence of accumulation of nitisinone and urinary levels
Sponsor: University of California, San Diego
Current Primary Outcome: Elimination or near elimination of homogentisic acid excretion [ Time Frame: 3-6 months ]
Original Primary Outcome: Decrease in homogentisic acid excretion [ Time Frame: 3-6 months ]
Current Secondary Outcome: Tyrosine levels [ Time Frame: three-six months ]
Original Secondary Outcome: Tyrosine levels [ Time Frame: 6 months ]
Information By: University of California, San Diego
Dates:
Date Received: July 5, 2011
Date Started: January 2011
Date Completion: July 2016
Last Updated: May 12, 2016
Last Verified: May 2016
