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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 : January 19, 2011
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)

Tracking Information
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 January 19, 2011
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
 (submitted: December 20, 2010)
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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00107783 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2010)
  • Change in Schober's Test [ Time Frame: Measured at baseline and at 36 months ]
    Change from baseline of Schober's test at 36 months. Schober's test measures a patient's ability to flex his/her lower back. The examiner makes a mark at L5 (fifth lumbar vertebra) and places one finger 5 cm below and another finger 10 cm above this mark. The patient is asked to touch his/her toes. The examiner measures the increase in distance between the two fingers.
  • Change in Functional Reach Assessment [ Time Frame: Measured at baseline and at 36 months ]
    Change from baseline of functional reach assessment at 36 months. Functional reach assessment measures the difference between the length of a person's outstretched arm and their maximal reach forward, while maintaining balance.
  • Change in Timed Get up and go [ Time Frame: Measured at baseline and at 36 months ]
    Change from baseline of timed get up and go at 36 months. In timed get up and go, the patient is asked to stand up from a standard chair and walk a distance of 3 meters, turn around and walk back to the chair and sit down. The examiner measures the time it takes for the patient to perform this series of tasks.
  • Change in 6 Minute Walk Test (6MWT) [ Time Frame: Measured at baseline and at 36 months ]
    Change from baseline of the 6MWT at 36 months. The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.
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:

  • 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.

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 serves as the primary outcome parameter, and nitisinone (Orfadin) is provided by Swedish Orphan International through an 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
Condition  ICMJE Alkaptonuria
Intervention  ICMJE Drug: Nitisinone (NTBC)
Treatment
Other Name: Orfadin
Study Arms  ICMJE
  • No Intervention: Control
    No treatment
  • Experimental: Nitisinone-treated
    Subjects received nitisinone 2 mg orally, once daily.
    Intervention: Drug: Nitisinone (NTBC)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2005)
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
  • 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-up

EXCLUSION 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
  • 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
  • Electrocardiogram changes indicative of myocardial infarction, arrhythmia, tachycardia, bradycardia, left bundle branch block
  • Chest radiographic abnormalities, including an infiltrate, mass, congestive heart failure, embolism, atelectasis
  • Serum postassium less than 3. 0 mEq/L
  • Serum creatinine greater than 2.0 mg/dL
  • SGPT greater than 41 U/L or SGOT greater than 34 U/L
  • CK greater than 500 U/L
  • Hemoglobin less than 10.0 g/dL
  • Platelets less than 100 k/mm(3)
  • WBC less than 3.0 k/microL
  • T4 greater than 15 microg/dL
  • T4 less than 4 microg/dL
  • ESR greater than 100 mm/h
  • Plasma tyrosine greater than 150 microM
Sex/Gender  ICMJE
Sexes Eligible for Study: All
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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party William A. Gahl, M.D./National Human Genome Research Institute, National Institutes of Health
Study Sponsor  ICMJE National Human Genome Research Institute (NHGRI)
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