Protocol Number: 05-HG-0076

Title:

Long-Term Clinical Trial of Nitisinone in Alkaptonuria

Number:

05-HG-0076

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 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.

Sponsoring Institute:

National Human Genome Research Institute (NHGRI)

Recruitment Detail

Type: No longer recruiting/follow-up only

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria: This study is not currently recruiting new subjects. If you have questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.

Special Instructions:

Currently Not Provided

Keyword(s):

Arthritis

Homogentisic Acid

Corneal Damage

Tyrosine

Alkaptonuria

Photophobia

Nitisinone

Recruitment Keyword(s):

None

Condition(s):

Alkaptonuria

Investigational Drug(s):

Nitisinone (NTBC)

Investigational Device(s):

None

Interventions:

Drug: Nitisinone (NTBC)

Supporting Site:

National Human Genome Research Institute

Contact(s):

This study is not currently recruiting new subjects. If you have questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.

Citation(s):

Introne WJ, Phornphutkul C, Bernardini I, McLaughlin K, Fitzpatrick D, Gahl WA. Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation. Mol Genet Metab. 2002 Sep-Oct;77(1-2):136-42. PMID: 12359141

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21. PMID: 12501223

Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, GuŽnet JL, Grimm T, Kress W, MŸller CR. The Human Gene for Alkaptonuria (AKU) Maps to Chromosome 3q. Genomics. 1994 Jan 1;19(1):5-8.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

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