Clinical Trial: Long-Term Study of Nitisinone to Treat Alkaptonuria

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Long-Term Clinical Trial of Nitisinone in Alkaptonuria

Brief Summary:

This 3-year study will examine the safety and effectiveness of long-term use of nitisinone (Orfadin) for treating joint problems in patients with alkaptonuria, an inherited disease in which a compound called homogentisic acid accumulates. The excess homogentisic acid causes arthritis and limited joint movement. It can also cause heart valve damage and kidney stones.

Patients between 30 and 80 years of age with alkaptonuria may be eligible for this study. Patients must have hip involvement, but at least one remaining hip joint. Candidates are recruited from among patients enrolled in protocol 00-HG-0141, "Clinical, Biochemical, and Molecular Investigations into Alkaptonuria." Participants may enter both protocols simultaneously.

Participants are randomly assigned to one of two treatment groups: one group takes their regular medicines plus a 2-mg nitisinone capsule daily; the other group takes only their regular medicines. Patients taking nitisinone have blood tests to measure liver function 2 weeks and 6 weeks after starting treatment. Before starting therapy, all patients are admitted to the NIH Clinical Center for 4-5 days to undergo the following procedures:

  • Medical history and physical examination
  • 24-hour urine collection to test for sugar, protein, and other molecules
  • Blood tests for liver and thyroid function, blood counts, and blood chemistries
  • Blood and urine tests to measure tyrosine and other amino acids and homogentisic acid
  • Bone x-rays
  • Spiral CT (computed tomography) of the abdomen to detect kidney stones
  • Eye examin

    Detailed Summary: Alkaptonuria is a rare metabolic disease in which homogentisic acid (HGA), an intermediary metabolite in tyrosine catabolism, accumulates due to deficiency of the enzyme homogentisic acid oxidase. Patients with alkaptonuria exhibit homogentisic aciduria and ochronosis, or dark pigmentation of various tissues due to binding of HGA and its oxidized metabolites. The ochronosis results in debilitating destruction of cartilage, arthritis, lumbosacral ankylosis, limitation of motion, and bone deterioration in later life. No effective therapy exists for alkaptonuria. However, a compound named 2-(2-nitro-4-trifluoromethylbenzoyl) - 1, 3-cyclohexanedione (nitisinone, NTBC, Orfadin) inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone, at doses of approximately 1 mg/kg/day, has proven safe and effective in tyrosinemia type I, which causes fatal liver disease in infants and children. Under protocol 97-HG-0201, we treated 9 alkaptonuria patients with nitisinone; for the 7 who received 1.05 mg twice daily, the HA fell from 4.0 plus or minus 1.8 g/24h to 0.2 plus or minus 0.2 g/24h (normal 0.028 plus or minus 0.015 g/24h, n=10). Plasma tyrosine levels rose from 67 plus or minus 18 micro M to 760 plus or minus 181 micro M. The current protocol (05-HG-0076) is a randomized, controlled clinical trial to determine if nitisinone (2 mg daily) is beneficial for the joint symptoms of alkaptonuira. Patients are examined at the NIH Clinical Research Center every 4 months for 3 years. Hip joint range of motion serves as the primary outcome parameter, and nitisinone (Orfadin) is provided by Swedish Orphan International through an IND obtained by William A. Gahl. Forty patients (20 with nitisinone treatment and 20 untreated) have been enrolled for at least 16 months, and an interim analysis shows promising results. Serious adverse events in patients on nitisinone have included a death from myocardial infarction, keratopathy, and elevated liver function tests
    Sponsor: National Human Genome Research Institute (NHGRI)

    Current Primary Outcome: Change in Total ROM Worse Hip. [ Time Frame: Measured at baseline and at 36 months ]

    Change from baseline in the total (external + internal) hip range of motion (ROM) in the worse hip at 36 months.


    Original Primary Outcome:

    Current Secondary Outcome:

    • Change in Schober's Test [ Time Frame: Measured at baseline and at 36 months ]
      Change from baseline of Schober's test at 36 months. Schober's test measures a patient's ability to flex his/her lower back. The examiner makes a mark at L5 (fifth lumbar vertebra) and places one finger 5 cm below and another finger 10 cm above this mark. The patient is asked to touch his/her toes. The examiner measures the increase in distance between the two fingers.
    • Change in Functional Reach Assessment [ Time Frame: Measured at baseline and at 36 months ]
      Change from baseline of functional reach assessment at 36 months. Functional reach assessment measures the difference between the length of a person's outstretched arm and their maximal reach forward, while maintaining balance.
    • Change in Timed Get up and go [ Time Frame: Measured at baseline and at 36 months ]
      Change from baseline of timed get up and go at 36 months. In timed get up and go, the patient is asked to stand up from a standard chair and walk a distance of 3 meters, turn around and walk back to the chair and sit down. The examiner measures the time it takes for the patient to perform this series of tasks.
    • Change in 6 Minute Walk Test (6MWT) [ Time Frame: Measured at baseline and at 36 months ]
      Change from baseline of the 6MWT at 36 months. The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.


    Original Secondary Outcome:

    Information By: National Institutes of Health Clinical Center (CC)

    Dates:
    Date Received: April 7, 2005
    Date Started: January 2005
    Date Completion:
    Last Updated: December 20, 2010
    Last Verified: December 2010