Long-Term Study of Nitisinone to Treat Alkaptonuria

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.

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.

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