Long-Term Study of Nitisinone to Treat Alkaptonuria
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ClinicalTrials.gov Identifier: NCT00107783 |
Recruitment Status :
Completed
First Posted : April 8, 2005
Results First Posted : January 19, 2011
Last Update Posted : August 26, 2021
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Tracking Information | |||
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First Submitted Date ICMJE | April 7, 2005 | ||
First Posted Date ICMJE | April 8, 2005 | ||
Results First Submitted Date ICMJE | December 20, 2010 | ||
Results First Posted Date ICMJE | January 19, 2011 | ||
Last Update Posted Date | August 26, 2021 | ||
Study Start Date ICMJE | January 2005 | ||
Actual Primary Completion Date | April 2009 (Final data collection date for primary outcome measure) | ||
Current Primary Outcome Measures ICMJE |
Change in Total ROM Worse Hip [ Time Frame: Measured at baseline and at 36 months ] Change from baseline in the total (external + internal) hip range of motion (ROM) in the worse hip at 36 months. The patient lies on exam table in the supine position. The patient flexes his/her hip and knee to 90 degrees. The examiner measures the patient's hip external rotation and hip internal rotation range of motion with a goniometer.
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Original Primary Outcome Measures ICMJE | Not Provided | ||
Change History | |||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Not Provided | ||
Current Other Pre-specified Outcome Measures | Not Provided | ||
Original Other Pre-specified Outcome Measures | Not Provided | ||
Descriptive Information | |||
Brief Title ICMJE | Long-Term Study of Nitisinone to Treat Alkaptonuria | ||
Official Title ICMJE | Long-Term Clinical Trial of Nitisinone in Alkaptonuria | ||
Brief 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:
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. |
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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. | ||
Study Type ICMJE | Interventional | ||
Study Phase ICMJE | Phase 2 | ||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Single (Outcomes Assessor) Primary Purpose: Treatment |
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Condition ICMJE | Alkaptonuria | ||
Intervention ICMJE | Drug: Nitisinone (NTBC)
Treatment
Other Name: Orfadin
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Study Arms ICMJE |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||
Recruitment Status ICMJE | Completed | ||
Actual Enrollment ICMJE |
40 | ||
Original Enrollment ICMJE | Same as current | ||
Actual Study Completion Date ICMJE | April 2009 | ||
Actual Primary Completion Date | April 2009 (Final data collection date for primary outcome measure) | ||
Eligibility Criteria ICMJE |
EXCLUSION CRITERIA:
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Sex/Gender ICMJE |
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Ages ICMJE | 30 Years to 80 Years (Adult, Older Adult) | ||
Accepts Healthy Volunteers ICMJE | No | ||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||
Listed Location Countries ICMJE | United States | ||
Removed Location Countries | |||
Administrative Information | |||
NCT Number ICMJE | NCT00107783 | ||
Other Study ID Numbers ICMJE | 050076 05-HG-0076 ( Other Identifier: NHGRI ) |
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Has Data Monitoring Committee | Yes | ||
U.S. FDA-regulated Product | Not Provided | ||
IPD Sharing Statement ICMJE | Not Provided | ||
Current Responsible Party | William A. Gahl, M.D./National Human Genome Research Institute, National Institutes of Health | ||
Original Responsible Party | Not Provided | ||
Current Study Sponsor ICMJE | National Human Genome Research Institute (NHGRI) | ||
Original Study Sponsor ICMJE | Same as current | ||
Collaborators ICMJE | Not Provided | ||
Investigators ICMJE | Not Provided | ||
PRS Account | National Institutes of Health Clinical Center (CC) | ||
Verification Date | December 2010 | ||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |