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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, Milan, AM, Hughes, AT, Dutton, JJ, Fitzgerald, R, Briggs, MC, Bygott, H, Psarelli, EE, Cox, TF, Gallagher, JA, Jarvis, JC, van Kan, C, Hall, AK, Laan, D, Olsson, B, Szamosi, J, Rudebeck, M, Kullenberg, T, Cronlund, A, Svensson, L , Junestrand, C, Ayoob, H, Timmis, OG, Sireau, N, Le Quan Sang, KH, Genovese, F, Braconi, D, Santucci, A, Nemethova, M, Zatkova, A, McCaffrey, J, Christensen, P, Ross, G, 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: 14 Sep 2018 09:37
DOI or Identification number: 10.1136/annrheumdis-2014-206033
URI: http://researchonline.ljmu.ac.uk/id/eprint/2261

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