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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 |
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| 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: | 04 Sep 2021 13:51 |
| DOI or ID number: | 10.1136/annrheumdis-2014-206033 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/2261 |
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