Lakshminarayan R Ranganath1, Anna M Milan1, Andrew T Hughes1, John J Dutton2, Richard Fitzgerald3, Michael C Briggs4, Helen Bygott2, Eftychia E Psarelli5, Trevor F Cox5, James A Gallagher6, Jonathan C Jarvis7, Christa van Kan8, Anthony K Hall9, Dinny Laan8, Birgitta Olsson10, Johan Szamosi10, Mattias Rudebeck10, Torbjörn Kullenberg10, Arvid Cronlund10, Lennart Svensson10, Carin Junestrand10, Hana Ayoob11, Oliver G Timmis11, Nicolas Sireau11, Kim-Hanh Le Quan Sang12, Federica Genovese13, Daniela Braconi14, Annalisa Santucci14, Martina Nemethova15, Andrea Zatkova15, Judith McCaffrey16, Peter Christensen17, Gordon Ross17, Richard Imrich18, Jozef Rovensky19. 1. Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK. 2. Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK. 3. Department of Clinical Pharmacology, Royal Liverpool University Hospital, Liverpool, UK. 4. Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK. 5. Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. 6. Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK. 7. School of Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK. 8. PSR group B.V., Hoofddorp, Netherlands. 9. Cudos BV, Hoofddorp, Netherlands. 10. Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden. 11. AKU Society, Cambridge, UK. 12. Hôpital Necker-Enfants Malades, Paris Cedex 15, France. 13. Nordic Bioscience, Herlev, Denmark. 14. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy. 15. Laboratory of Genetics, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia. 16. Agilent Technologies Ireland, Cork, Ireland. 17. Agilent Technologies, Stockport, UK. 18. Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia. 19. National Institute of Rheumatic Diseases, Piešťany, Slovakia.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
RCT Entities:
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: F Genovese; A S Siebuhr; K Musa; J A Gallagher; A M Milan; M A Karsdal; J Rovensky; A C Bay-Jensen; L R Ranganath Journal: JIMD Rep Date: 2015-03-19
Authors: A S Davison; B P Norman; E A Smith; J Devine; J Usher; A T Hughes; M Khedr; A M Milan; J A Gallagher; L R Ranganath Journal: JIMD Rep Date: 2018-05-13