Long-Term Study of Nitisinone to Treat Alkaptonuria
Condition: Alkaptonuria
MeSH terms: Alkaptonuria; Ochronosis
Study type: Interventional
Phase: Phase 2

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 examination and evaluations by specialists in rehabilitation medicine and pain, plus
           other consults in skin, brain, lung, heart, and kidney, as needed

      All patients, whether or not they receive nitisinone, return to the Clinical Center for a 2-3
      day follow-up admission every 4 months for a history and physical examination, blood tests,
      and two 24-hour urine collections. Every 12 months (12, 24 and 36 months after starting the
      study), patients also have repeat bone x-rays, spiral CT, kidney ultrasound, echocardiogram,
      and electrocardiogram. An Magnetic Resonance Imaging (MRI) of the brain is done at the end of
      the study.

      Sixteen months after the end of the study enrollment period, the treated and non-treated
      groups are evaluated. If nitisinone has delayed the progression of joint disease in the
      treated group, the study continues and all patients receive the drug for the remainder of the
      study. If not, the study continues for another 20 months, at which time the study ends and
      the evaluation process is repeated.

      Patients who develop symptoms such as corneal crystals, pain, or severe liver or nervous
      system toxicity may be taken off the study.
    

Detailed description: 
      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 (ROM)
      serves as the primary outcome parameter, and nitisinone (Orfadin) is provided by Swedish
      Orphan International through an Investigational New Drug Application (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 related to gallstones.
    

Intervention name(s): Nitisinone (NTBC)
Intervention type(s): Drug
Intervention description(s): Treatment
Other intervention name(s): Orfadin
Intervention MeSH terms: Nitisinone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Arthritis; Homogentisic Acid; Corneal Damage; Tyrosine; Alkaptonuria; Photophobia; Nitisinone