Ignite Creation Date:
2024-05-05 @ 11:39 AM
Last Modification Date:
2024-10-26 @ 9:11 AM
Study NCT ID:
NCT00107783
Status:
COMPLETED
Last Update Posted:
2021-08-26
First Post:
2005-04-07
Brief Title:
Long-Term Study of Nitisinone to Treat Alkaptonuria
Sponsor:
National Human Genome Research Institute NHGRI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Long-Term Clinical Trial of Nitisinone in Alkaptonuria
Status:
COMPLETED
Status Verified Date:
2010-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
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
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 mgkgday 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 105 mg twice daily the HA fell from 40 plus or minus 18 g24h to 02 plus or minus 02 g24h normal 0028 plus or minus 0015 g24h n10 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-HG-0076 | OTHER | NHGRI | None |