Long-Term Study of Nitisinone to Treat Alkaptonuria

NCT00107783 | Completed Phase 2 Results DMC

• 2 other identifiers: 05007605-HG-0076
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Alkaptonuria

Keywords

Arthritis; Homogentisic Acid; Corneal Damage; Tyrosine; Alkaptonuria; Photophobia; Nitisinone

Outcome Measures

Primary Outcomes (1)

• Change in Total ROM Worse Hip

  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.

  Measured at baseline and at 36 months

Secondary Outcomes (4)

• Change in Schober's Test

  Measured at baseline and at 36 months

• Change in Functional Reach Assessment

  Measured at baseline and at 36 months

• Change in Timed Get up and go

  Measured at baseline and at 36 months

• Change in 6 Minute Walk Test (6MWT)

  Measured at baseline and at 36 months

Study Arms (2)

Control

NO INTERVENTION

No treatment

Nitisinone-treated

EXPERIMENTAL

Subjects received nitisinone 2 mg orally, once daily.

Drug: Nitisinone (NTBC)

Interventions

Nitisinone (NTBC) DRUG

Treatment

Also known as: Orfadin

Nitisinone-treated

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Dietary habits or use of homeopathic therapies that interfere with tyrosine catabolism. The diet must be reasonably balanced, as determined by a dietician.
• Uncontrolled hypertension (blood pressure greater than 180 systolic or greater than 95 diastolic)
• History of extreme alcohol abuse or sever liver disease
• Liver greater than 3 cm below the right costal margin

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 12359141 BACKGROUND

• 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.

  PMID: 12501223 BACKGROUND

• Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, Guenet JL, Grimm T, Kress W, Muller CR. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics. 1994 Jan 1;19(1):5-8. doi: 10.1006/geno.1994.1003.

  PMID: 8188241 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Alkaptonuria; Arthritis; Corneal Injuries; Photophobia

Interventions

nitisinone

Condition Hierarchy (Ancestors)

Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Joint Diseases; Musculoskeletal Diseases; Eye Injuries; Facial Injuries; Craniocerebral Trauma; Trauma, Nervous System; Nervous System Diseases; Corneal Diseases; Eye Diseases; Wounds and Injuries; Vision Disorders; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Small number of patients involved in study and several patients dropped out; primary outcome parameter selection possibly inappropriate because hip joint damage that is already present may be irreversible.

Results Point of Contact

• Title: William Gahl, MD/Clinical Director
• Organization: NHGRI

gahlw@mail.nih.gov

301-402-2739

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH

Study Record Dates

• First Submitted: April 7, 2005
• First Posted: April 8, 2005
• Study Start: January 1, 2005
• Primary Completion: April 1, 2009
• Study Completion: April 1, 2009
• Last Updated: August 26, 2021
• Results First Posted: January 19, 2011

Record last verified: 2010-12

Locations

US (1)