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 investigated the safety of administering a dose of nitisinone necessary to lower HGA excretion to 0.5 grams/day. We We treated 9 alkaptonturia 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 + 0.015 g/24h, n=10). This reduction in HGA production can be expected to retard the progression of joint disease in alkaptonuria. Plasma tyrosine levels rose from 67 + 18 microliter M to 760 plus or minus 181 microliter M, but no patient experienced ophthalmologic complications during the 3-4 month study. Therefore, westudy intend to perform a randomized, controlled clinical trial of nitisinone (2 mg daily) to determine if this treatment proves beneficial for the joint symptoms of alkaptonuria. Patients will be examined at the NIH Clinical Research Center every 4 months for 3 years. Hip joint range of motion will serve as the primary outcome parameter, and nitisinone (Orfadin) will be provided by Swedish Orphan International through an IND obtained by William A. Gahl.

Treatment or Intervention	Phase
Drug: Nitisinone (NTBC)	Phase II

Further Study Details: 

Expected Total Enrollment:  40

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 investigated the safety of administering a dose of nitisinone necessary to lower HGA excretion to 0.5 grams/day. We We treated 9 alkaptonturia 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 + 0.015 g/24h, n=10). This reduction in HGA production can be expected to retard the progression of joint disease in alkaptonuria. Plasma tyrosine levels rose from 67 + 18 microliter M to 760 plus or minus 181 microliter M, but no patient experienced ophthalmologic complications during the 3-4 month study. Therefore, westudy intend to perform a randomized, controlled clinical trial of nitisinone (2 mg daily) to determine if this treatment proves beneficial for the joint symptoms of alkaptonuria. Patients will be examined at the NIH Clinical Research Center every 4 months for 3 years. Hip joint range of motion will serve as the primary outcome parameter, and nitisinone (Orfadin) will be provided by Swedish Orphan International through an IND obtained by William A. Gahl.

Genders Eligible for Study:  Both

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

Maryland
      National Human Genome Research Institute (NHGRI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050076; 05-HG-0076
Record last reviewed:  December 28, 2004
Last Updated:  April 7, 2005
Record first received:  April 7, 2005
ClinicalTrials.gov Identifier:  NCT00107783
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08