AlkaptonuriaPhase 2NCT00107783
Long-Term Study of Nitisinone to Treat Alkaptonuria
A Phase 2 study testing Nitisinone (NTBC) in people with Alkaptonuria, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 to 80 years
- Conditions the study is for
- Alkaptonuria
- What is being tested?
- Nitisinone (NTBC)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2005to Apr 2009
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Age less than 30 or greater than 80
- Non-alkaptonuria causes of ochronosis
- Bilateral hip joint replacement
- Keratopathy
- Contact lenses
- Uncontrolled glaucoma
Show all 28Show fewer
- 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
- Serum glutamic-pyruvic transaminase (SGPT) greater than 41 U/L or Serum glutamic-oxaloacetic transaminase (SGOT) greater than 34 U/L
- Creatine kinase (CK) greater than 500 U/L
- Hemoglobin less than 10.0 g/dL
- Platelets less than 100 k/mm(3)
- White blood cells (WBCs) less than 3.0 k/microL
- Free thyroxine (T4) greater than 15 microg/dL
- T4 less than 4 microg/dL
- Erythrocyte sedimentation rate (ESR) greater than 100 mm/h
- Plasma tyrosine greater than 150 microM
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Long-Term Clinical Trial of Nitisinone in Alkaptonuria
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.
Read more
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.
Read the 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.
- Conditions
- Alkaptonuria
- Being tested
- Nitisinone (NTBC)
- Keywords
- Arthritis, Homogentisic Acid, Corneal Damage, Tyrosine, Alkaptonuria, Photophobia, Nitisinone
- Medical subject headings
- Alkaptonuria, Arthritis, Corneal Injuries, Photophobia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitisinone (NTBC)Drug
Also called Orfadin
Treatment
| Study group | Role | What they receive |
|---|---|---|
| Control | No intervention | No treatment |
| Nitisinone-treated | Experimental | Subjects received nitisinone 2 mg orally, once daily. Receives: Drug: Nitisinone (NTBC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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: Measured at baseline and at 36 months
Secondary outcomes (4)
Change in Schober's Test
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.
Measured: Measured at baseline and at 36 months
Change in Functional Reach Assessment
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.
Measured: Measured at baseline and at 36 months
Change in Timed Get up and go
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.
Measured: Measured at baseline and at 36 months
Change in 6 Minute Walk Test (6MWT)
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.
Measured: Measured at baseline and at 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Apr 2005 (estimated)
- Study startJan 2005
- Primary completionApr 2009
- Study completionApr 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for AlkaptonuriaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00107783
- Sponsor's protocol ID
- 050076
- Other IDs
- 05-HG-0076
- Status last verified
- Dec 2010
- First submitted
- 7 Apr 2005
- Last updated
- 26 Aug 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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 12359141Phornphutkul 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 12501223Janocha 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.
PubMed 8188241
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long-Term Clinical Trial of Nitisinone in Alkaptonuria
- ClinicalTrials.gov ID
- NCT00107783
- Acronym / sponsor ID
- 050076
- Conditions
- Alkaptonuria
- Keywords
- Arthritis, Homogentisic Acid, Corneal Damage, Tyrosine, Alkaptonuria, Photophobia, Nitisinone
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- Jan 2005
- Primary completion
- Apr 2009 (actual)
- Study completion
- Apr 2009 (actual)
- First posted
- 8 Apr 2005 (estimated)
- Results
- Posted 19 Jan 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –No treatment |
| Nitisinone-treated | Experimental | Drug: Nitisinone (NTBC)Subjects received nitisinone 2 mg orally, once daily. |
Who may qualify
- Ages
- 30 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (28 listed)
- Age less than 30 or greater than 80
- Non-alkaptonuria causes of ochronosis
- Bilateral hip joint replacement
- Keratopathy
- Contact lenses
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitisinone (NTBC)Also: OrfadinTreatment | Drug | Nitisinone-treated |
Primary outcome
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.
4 secondary outcomes
Change in Schober's Test
Time frame: Measured at baseline and at 36 months
Change in Functional Reach Assessment
Time frame: Measured at baseline and at 36 months
Change in Timed Get up and go
Time frame: Measured at baseline and at 36 months
Change in 6 Minute Walk Test (6MWT)
Time frame: Measured at baseline and at 36 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 12359141Introne 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.
- Background: PubMed 12501223Phornphutkul 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.
- Background: PubMed 8188241Janocha 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitisinone (NTBC) in people with Alkaptonuria, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Jan 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Total ROM Worse Hip (time frame: Measured at baseline and at 36 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00107783, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2021.