History of Changes for Study: NCT00107783

Long-Term Study of Nitisinone to Treat Alkaptonuria

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Study Record Versions

Version	Submitted Date	Changes
1	June 23, 2005	None (earliest Version on record)
2	June 19, 2006	Eligibility, Study Status, References, Contacts/Locations, Study Design, Study Description, Oversight and Study Identification
3	August 23, 2006	Contacts/Locations and Study Status
4	October 26, 2006	Study Status
5	December 2, 2006	Recruitment Status, Study Status, Contacts/Locations and References
6	December 8, 2006	Study Status
7	December 12, 2006	Study Status and Contacts/Locations
8	February 24, 2007	Study Status
9	November 22, 2007	Conditions and Study Status
10	November 28, 2007	References, Eligibility, Study Description and Study Status
11	November 29, 2007	Study Status
12	December 21, 2007	Study Design, Outcome Measures and Study Status
13	March 22, 2008	Eligibility, Study Description and Study Status
14	April 15, 2008	Outcome Measures and Study Status
15	July 16, 2008	References and Study Status
16	July 22, 2008	Outcome Measures, Study Design, Arms and Interventions and Study Status
17	October 6, 2008	Sponsor/Collaborators and Study Status
18	November 7, 2008	Study Status
19	June 9, 2009	Study Status
20	August 27, 2009	Study Status
21	October 30, 2009	Recruitment Status and Study Status
22	November 25, 2009	Study Design and Study Status
23	June 16, 2010	Study Status
24	July 7, 2010	Study Status
25	September 10, 2010	Study Status
26	September 17, 2010	References and Study Status
27	October 9, 2010	Study Status
28	December 2, 2010	Outcome Measures, Arms and Interventions, Study Design, Oversight, Study Status and Study Identification
29	December 20, 2010	Outcome Measures, Study Status and Results
30	August 3, 2021	Outcome Measures, Study Description, Study Status, Baseline Characteristics and Eligibility

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	050076
Brief Title:	Long-Term Study of Nitisinone to Treat Alkaptonuria
Official Title:	Long-Term Clinical Trial of Nitisinone in Alkaptonuria
Secondary IDs:	05-HG-0076

Study Status


Record Verification:	November 29, 2005
Overall Status:	Recruiting
Study Start:	January 19, 2005
Primary Completion:
Study Completion:

First Submitted:	April 7, 2005
First Submitted that Met QC Criteria:	April 7, 2005
First Posted:	April 8, 2005 [Estimate]

Last Update Submitted that Met QC Criteria:	June 23, 2005
Last Update Posted:	June 24, 2005 [Estimate]

Sponsor/Collaborators


Sponsor:	National Human Genome Research Institute (NHGRI)
Responsible Party:
Collaborators:

Oversight


U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring:

Study Description

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 neededAll 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.

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 investigated the safety of administering a dose of nitisinone necessary to lower HGA excretion to 0.5 grams/day. 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, we 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.

Conditions


Conditions:	Alkaptonuria
Keywords:	Arthritis Ochronosis Homogentisic Joint Replacement Vertebral Disc Deterioration Corneal Damage Tyrosine Alkaptonuria Photophobia Nitisinone

Study Design


Study Type:	Interventional
Primary Purpose:	Other
Study Phase:	Phase 2
Interventional Study Model:
Number of Arms:
Masking:	(masked roles unspecified)
Enrollment:	40

Arms and Interventions


Intervention Details:
	Drug: Nitisinone (NTBC)

Eligibility


Minimum Age:
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
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-upEXCLUSION 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

Contacts/Locations


Locations:	United States, Maryland
	National Human Genome Research Institute (NHGRI) [Recruiting] Bethesda, Maryland, United States, 20892 Contact:Contact: Patient Recruitment and Public Liaison Office 8004111222 prpl@mail.cc.nih.gov Contact:Contact: TTY 1-866-411-1010

IPDSharing


Plan to Share IPD:

References


Citations:	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. doi: 10.1016/s1096-7192(02)00121-x. PubMed 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. doi: 10.1056/NEJMoa021736. PubMed 12501223
Links:	URL: http://clinicalstudies.info.nih.gov/detail/A_2005-HG-0076.html Description: Detailed Web Page
Available IPD/Information: