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Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

Ranganath, LR and Milan, AM and Hughes, AT and Dutton, JJ and Fitzgerald, R and Briggs, MC and Bygott, H and Psarelli, EE and Cox, TF and Gallagher, JA and Jarvis, JC and van Kan, C and Hall, AK and Laan, D and Olsson, B and Szamosi, J and Rudebeck, M and Kullenberg, T and Cronlund, A and Svensson, L and Junestrand, C and Ayoob, H and Timmis, OG and Sireau, N and Le Quan Sang, KH and Genovese, F and Braconi, D and Santucci, A and Nemethova, M and Zatkova, A and McCaffrey, J and Christensen, P and Ross, G and Imrich, R and Rovensky, J (2014) Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Annals of the Rheumatic Diseases. ISSN 1468-2060

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Abstract

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

Item Type: Article
Uncontrolled Keywords: 1103 Clinical Sciences, 1107 Immunology, 1117 Public Health And Health Services
Subjects: R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions: Sport & Exercise Sciences
Publisher: BMJ PUBLISHING GROUP
Related URLs:
Date Deposited: 28 Oct 2015 10:40
Last Modified: 28 Oct 2015 10:40
DOI or Identification number: 10.1136/annrheumdis-2014-206033
URI: http://researchonline.ljmu.ac.uk/id/eprint/2261

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