Long-Term Study of Nitisinone to Treat Alkaptonuria
Condition: Alkaptonuria
MeSH terms: Alkaptonuria; Ochronosis
Intervention: Nitisinone (NTBC)
Intervention description: Treatment
Intervention MeSH terms: Nitisinone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 40.0
Sex: All
Minimum age: 30 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Arthritis; Homogentisic Acid; Corneal Damage; Tyrosine; Alkaptonuria; Photophobia; Nitisinone

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Age 30-80 years, either gender

          -  Diagnosis of alkaptonuria based upon urinary HGA excretion greater than 0.4 g/24h

          -  At least one hip joint remaining

          -  Some evidence of hip involvement, e.g., pain or decreased range of motion

          -  Ability to travel to the NIH Clinical Research Center for admissions

          -  Ability to consent

          -  Availability of local medical follow-up

        EXCLUSION CRITERIA:

          -  Age less than 30 or greater than 80

          -  Non-alkaptonuria causes of ochronosis

          -  Bilateral hip joint replacement

          -  Keratopathy

          -  Contact lenses

          -  Uncontrolled glaucoma

          -  History of myocardial infarction

          -  History of emphysema or pulmonary insufficiency (Forced vital capacity less than 70%)

          -  Psychiatric illness or neurological disease that interferes with compliance or
             communication with health care personnel

          -  Current malignancy

          -  Open skin lesions

          -  Dietary habits or use of homeopathic therapies that interfere with tyrosine
             catabolism. The diet must be reasonably balanced, as determined by a dietician.

          -  Uncontrolled hypertension (blood pressure greater than 180 systolic or greater than 95
             diastolic)

          -  History of extreme alcohol abuse or sever liver disease

          -  Liver greater than 3 cm below the right costal margin

          -  Electrocardiogram changes indicative of myocardial infarction, arrhythmia,
             tachycardia, bradycardia, left bundle branch block

          -  Chest radiographic abnormalities, including an infiltrate, mass, congestive heart
             failure, embolism, atelectasis

          -  Serum postassium less than 3. 0 mEq/L

          -  Serum creatinine greater than 2.0 mg/dL

          -  Serum glutamic-pyruvic transaminase (SGPT) greater than 41 U/L or Serum
             glutamic-oxaloacetic transaminase (SGOT) greater than 34 U/L

          -  Creatine kinase (CK) greater than 500 U/L

          -  Hemoglobin less than 10.0 g/dL

          -  Platelets less than 100 k/mm(3)

          -  White blood cells (WBCs) less than 3.0 k/microL

          -  Free thyroxine (T4) greater than 15 microg/dL

          -  T4 less than 4 microg/dL

          -  Erythrocyte sedimentation rate (ESR) greater than 100 mm/h

          -  Plasma tyrosine greater than 150 microM