AlkaptonuriaPhase 2/3NCT01390077
Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
A Phase 2/3 study testing Nitisinone in people with Alkaptonuria, run by University of California, San Diego at 1 site in United States.
Trial summary
Nitisinone is a potent inhibitor of the enzyme that catalyzes the formation of homogentisic acid, and should be an even more logical treatment for alkaptonuria than for tyrosinemia, for which it has been approved by the FDA.The objective of this research is to explore reported age related differences in toxicity of… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Alkaptonuria
- What is being tested?
- Nitisinone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2011to Jul 2016
- Phase
- Phase 2/3
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Diagnosis of alkaptonuria with documented increased excretion of homogentisic acid
- Willing and able to provide written, signed informed consent, or age appropriate written assent and written informed consent by a legally authorized representative after the study has been explained, prior to any research-related procedures.
- Willing and able to be seen in the UCSD Clinical Center for Research or a satellite site for the study visits
- Possession of insurance coverage for standard of care procedures, clearly stated in the consent forms
Who cannot join
- Baseline tyrosine level above 250 mmol/mL
- Baseline serum creatinine, creatine kinase, or transaminases 2x upper limit of normal
- Baseline anemia or thrombocytopenia
- Current participation in another investigational medication trial.
- Pregnant or lactating women
- Current keratopathy, contact use or uncontrolled glaucoma
Show all 10Show fewer
- History myocardial infarction or arrhythmia
- History of pulmonary insufficiency
- Psychiatric illness that may interfere with compliance or communication
- Current malignancy or hypertension
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California San Diego
La Jolla, California, 92093
About this study
Nitisinone is a potent inhibitor of the enzyme that catalyzes the formation of homogentisic acid, and should be an even more logical treatment for alkaptonuria than for tyrosinemia, for which it has been approved by the FDA.The objective of this research is to explore reported age related differences in toxicity of nitisinone and its pharmacokinetic underpinnings and to develop an optimal therapeutic requirement for a targeted population of presymptomatic patients. The additional effect of mixtures of amino acids excluding tyrosine will be explored to take advantage of protein synthesis to avoid elevations of tyrosine that would otherwise limit the optimal dosage of nitisinone. The study is designed to treat patients and find the optimal dosage of nitisinone to obtain maximal reduction in levels of homogentisic acid and maintain safe levels of tyrosine.
The long term objective in the target population of pre-symptomatic patients is the prevention of the characteristic effects on joint cartilage and tendons.
Read the detailed description
Study procedures are designed to:
- Develop a method for nitisinone measurement via tandem mass spectrometry (MS/MS).
- Determine whether differences between adult and children could be erased by employing a dosage regimen based on m2 of body surface area as opposed to per kg of body weight, as we have found in a recent study of dichloroacetate
- Determine optimal dosage for reduction of urinary levels of homogentisic acid and minimal elevation of plasma levels of tyrosine in the target population of pre-symptomatic patients.
- Determine optimal doses of Tyrex to prevent hypertyrosinemia and allow maximal reduction in homogentisic acid.
Baseline studies will include ophthalmologic examinations, echocardiogram, X-rays of all joints, MRI of selected joints when financially plausible; history and physical examinations with emphasis on joints and tendons. Ideally MRI will be repeated at 12 month intervals thereafter. Ophthalmologic exam, x-rays of the kidneys and prostate, and echocardiogram will be repeated approximately every 12 months, depending on the age of the subject and the nitisinone dose. Patients will be seen every 3 months for the first year, then at 6 month intervals to month 36. The timing of the visits may be altered in response to modifications of nitisinone and/or Tyrex doses.
Complete or near complete elimination of homogentisic acid excretion will be sought. Optimal NTBC dosage would be judged to yield plasma concentration of tyrosine less than 1000 mmol/L with the concomitant use of tyrosine free amino acid supplement. Dosage will be escalated or reduced dependent on evidence of accumulation of nitisinone and urinary levels of HGA. The maximum initial dose of nitisinone for adult and adolescent patients will be 0.2/mg/kg/day, younger patients may require a larger dose; the standard dose in hypertyrosinemia is 1mg/kg/day, which will be tentatively used as the maximum dose for all populations.
Patients will be asked to collect first morning or 12 hour urine collections for homogentisic acid and p-hydroxyphenyllactic acids and to monitor levels of tyrosine. Accumulation will be tested for by repeated studies after 3 months of treatment. Trough levels for nitisinone will be collected prior to and 5-7 days after dose increases and/or at months 6, 12, 18, 24 and every 12 months.
The SF-36 Health Status Survey, a two page quality of life questionnaire which asks about ADLs and emotional/social impacts of disease, will be completed by the patient or patient's parent at baseline and every six months.
At any point during the study if the plasma tyrosine level is greater than 900umol/L the amount of Tyrex or dietary protein intake may be modified, or the nitisinone dose may be decreased. Protein Saver blood spot cards, which can be done in the patient's home and mailed to our lab, will be given to the patients with instructions on blood collection to check the tyrosine level after 5-7 days of the drug/dietary modifications. These steps-the dietary modification with diet records if needed, addition or adjustment of Tyrex, adjustment of the nitisinone dose, and repeat tyrosine analysis-will be repeated as necessary.
- Conditions
- Alkaptonuria
- Being tested
- Nitisinone
- Keywords
- homogentisic acid
- Medical subject headings
- Alkaptonuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitisinoneDrug
Also called Orfadin®,, NTBC
Taken orally. Supplied as a 2mg tablet. The starting dose is 2 mg once daily.
| Study group | Role | What they receive |
|---|---|---|
| Nitisinone | Experimental | all subjects will receive open-label nitisinone Receives: Drug: Nitisinone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Homogentisic Acid Excretion
Urine homogentisic acid (umol/mmol creatinine)
Measured: 3-6 months
Secondary outcomes (1)
Tyrosine Levels
Plasma tyrosine (uM)
Measured: 3-6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jul 2011 (estimated)
- Study startJan 2011
- Primary completionJun 2016
- Study completionJul 2016
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 (5)Papers the sponsor has linked to this study.
- Other trials for AlkaptonuriaStudies of the same condition, open and under way.
- More trials run by University of California, San DiegoThe sponsor's other registered studies.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Diego
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- William L Nyhan, MD, PhD, Principal investigator, University of California, San Diego
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01390077
- Sponsor's protocol ID
- WLN02
- Status last verified
- Mar 2021
- First submitted
- 5 Jul 2011
- Last updated
- 22 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun;54(6):719-28. doi: 10.1016/j.metabol.2004.12.017.
PubMed 15931605Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011 Aug;103(4):307-14. doi: 10.1016/j.ymgme.2011.04.016. Epub 2011 May 6.
PubMed 21620748Phornphutkul 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 12501223Gertsman I, Gangoiti JA, Nyhan WL, Barshop BA. Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome. Mol Genet Metab. 2015 Mar;114(3):431-7. doi: 10.1016/j.ymgme.2015.01.005. Epub 2015 Jan 29.
PubMed 25680927Gertsman I, Barshop BA, Panyard-Davis J, Gangoiti JA, Nyhan WL. Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria. JIMD Rep. 2015;24:13-20. doi: 10.1007/8904_2014_403. Epub 2015 Feb 10.
PubMed 25665838
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
- ClinicalTrials.gov ID
- NCT01390077
- Acronym / sponsor ID
- WLN02
- Conditions
- Alkaptonuria
- Keywords
- homogentisic acid
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University of California, San DiegoUniversity, hospital or other
- Study start
- Jan 2011
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jul 2016 (actual)
- First posted
- 8 Jul 2011 (estimated)
- Results
- Posted 22 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Nitisinone is a potent inhibitor of the enzyme that catalyzes the formation of homogentisic acid, and should be an even more logical treatment for alkaptonuria than for tyrosinemia, for which it has been approved by the FDA.The objective of this research is to explore reported age related differences in toxicity of nitisinone and its pharmacokinetic underpinnings and to develop an optimal therapeutic requirement for a targeted population of presymptomatic patients. The additional effect of mixtures of amino acids excluding tyrosine will be explored to take advantage of protein synthesis to avoid elevations of tyrosine that would otherwise limit the optimal dosage of nitisinone. The study is designed to treat patients and find the optimal dosage of nitisinone to obtain maximal reduction in levels of homogentisic acid and maintain safe levels of tyrosine.
The long term objective in the target population of pre-symptomatic patients is the prevention of the characteristic effects on joint cartilage and tendons.
Detailed description
Study procedures are designed to:
- Develop a method for nitisinone measurement via tandem mass spectrometry (MS/MS).
- Determine whether differences between adult and children could be erased by employing a dosage regimen based on m2 of body surface area as opposed to per kg of body weight, as we have found in a recent study of dichloroacetate
- Determine optimal dosage for reduction of urinary levels of homogentisic acid and minimal elevation of plasma levels of tyrosine in the target population of pre-symptomatic patients.
- Determine optimal doses of Tyrex to prevent hypertyrosinemia and allow maximal reduction in homogentisic acid.
Baseline studies will include ophthalmologic examinations, echocardiogram, X-rays of all joints, MRI of selected joints when financially plausible; history and physical examinations with emphasis on joints and tendons. Ideally MRI will be repeated at 12 month intervals thereafter. Ophthalmologic exam, x-rays of the kidneys and prostate, and echocardiogram will be repeated approximately every 12 months, depending on the age of the subject and the nitisinone dose. Patients will be seen every 3 months for the first year, then at 6 month intervals to month 36. The timing of the visits may be altered in response to modifications of nitisinone and/or Tyrex doses.
Complete or near complete elimination of homogentisic acid excretion will be sought. Optimal NTBC dosage would be judged to yield plasma concentration of tyrosine less than 1000 mmol/L with the concomitant use of tyrosine free amino acid supplement. Dosage will be escalated or reduced dependent on evidence of accumulation of nitisinone and urinary levels of HGA. The maximum initial dose of nitisinone for adult and adolescent patients will be 0.2/mg/kg/day, younger patients may require a larger dose; the standard dose in hypertyrosinemia is 1mg/kg/day, which will be tentatively used as the maximum dose for all populations.
Patients will be asked to collect first morning or 12 hour urine collections for homogentisic acid and p-hydroxyphenyllactic acids and to monitor levels of tyrosine. Accumulation will be tested for by repeated studies after 3 months of treatment. Trough levels for nitisinone will be collected prior to and 5-7 days after dose increases and/or at months 6, 12, 18, 24 and every 12 months.
The SF-36 Health Status Survey, a two page quality of life questionnaire which asks about ADLs and emotional/social impacts of disease, will be completed by the patient or patient's parent at baseline and every six months.
At any point during the study if the plasma tyrosine level is greater than 900umol/L the amount of Tyrex or dietary protein intake may be modified, or the nitisinone dose may be decreased. Protein Saver blood spot cards, which can be done in the patient's home and mailed to our lab, will be given to the patients with instructions on blood collection to check the tyrosine level after 5-7 days of the drug/dietary modifications. These steps-the dietary modification with diet records if needed, addition or adjustment of Tyrex, adjustment of the nitisinone dose, and repeat tyrosine analysis-will be repeated as necessary.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nitisinone | Experimental | Drug: Nitisinoneall subjects will receive open-label nitisinone |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of alkaptonuria with documented increased excretion of homogentisic acid
- Willing and able to provide written, signed informed consent, or age appropriate written assent and written informed consent by a legally authorized representative after the study has been explained, prior to any research-related procedures.
- Willing and able to be seen in the UCSD Clinical Center for Research or a satellite site for the study visits
- Possession of insurance coverage for standard of care procedures, clearly stated in the consent forms
Key exclusion criteria (10 listed)
- Baseline tyrosine level above 250 mmol/mL
- Baseline serum creatinine, creatine kinase, or transaminases 2x upper limit of normal
- Baseline anemia or thrombocytopenia
- Current participation in another investigational medication trial.
- Pregnant or lactating women
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 |
|---|---|---|
| NitisinoneAlso: Orfadin®,, NTBCTaken orally. Supplied as a 2mg tablet. The starting dose is 2 mg once daily. | Drug | Nitisinone |
Primary outcome
Homogentisic Acid Excretion
Time frame: 3-6 months
Urine homogentisic acid (umol/mmol creatinine)
1 secondary outcome
Tyrosine Levels
Time frame: 3-6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 15931605Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun;54(6):719-28. doi: 10.1016/j.metabol.2004.12.017.
- Background: PubMed 21620748Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011 Aug;103(4):307-14. doi: 10.1016/j.ymgme.2011.04.016. Epub 2011 May 6.
- 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 25680927Gertsman I, Gangoiti JA, Nyhan WL, Barshop BA. Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome. Mol Genet Metab. 2015 Mar;114(3):431-7. doi: 10.1016/j.ymgme.2015.01.005. Epub 2015 Jan 29.
- Results publication: PubMed 25665838Gertsman I, Barshop BA, Panyard-Davis J, Gangoiti JA, Nyhan WL. Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria. JIMD Rep. 2015;24:13-20. doi: 10.1007/8904_2014_403. Epub 2015 Feb 10.
Related trials for Alkaptonuria
RecruitingObservational study
Study of Alkaptonuria
Alkaptonuria
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.
William L Nyhan, MD, PhD principal investigator
University of California, San Diego
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Nitisinone in people with Alkaptonuria, run by University of California, San Diego 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 4 inclusion and 10 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 22 Apr 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 combined 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.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 22 Apr 2021). 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?
Homogentisic Acid Excretion (time frame: 3-6 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 NCT01390077, which also lists 5 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 22 Apr 2021.