Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria

NCT01390077 | Completed Phase 2 Results

• 1 other identifier: WLN02
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Alkaptonuria

Keywords

homogentisic acid

Outcome Measures

Primary Outcomes (1)

• Homogentisic Acid Excretion

  Urine homogentisic acid (umol/mmol creatinine)

  3-6 months

Secondary Outcomes (1)

• Tyrosine Levels

  3-6 months

Study Arms (1)

Nitisinone

EXPERIMENTAL

all subjects will receive open-label nitisinone

Drug: Nitisinone

Interventions

Nitisinone DRUG

Taken orally. Supplied as a 2mg tablet. The starting dose is 2 mg once daily.

Also known as: Orfadin®,, NTBC

Nitisinone

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• History myocardial infarction or arrhythmia
• History of pulmonary insufficiency
• Psychiatric illness that may interfere with compliance or communication
• Current malignancy or hypertension

Sponsors & Collaborators

• University of California, San Diego: lead

Study Sites (1)

University of California San Diego

La Jolla, California, 92093, United States

Location

Related Publications (5)

• 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.

  PMID: 15931605 BACKGROUND

• Introne 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.

  PMID: 21620748 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

• Gertsman 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.

  PMID: 25680927 BACKGROUND

• Gertsman 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.

  PMID: 25665838 RESULT

MeSH Terms

Conditions

Alkaptonuria

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

Results Point of Contact

• Title: William Leo Nyhan, M.D., Ph.D.
• Organization: University of California, San Diego

wnyhan@ucsd.edu

(619)543-5337

Study Officials

• William L Nyhan, MD, PhD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 5, 2011
• First Posted: July 8, 2011
• Study Start: January 1, 2011
• Primary Completion: June 1, 2016
• Study Completion: July 1, 2016
• Last Updated: April 22, 2021
• Results First Posted: April 22, 2021

Record last verified: 2021-03

Locations

US (1)