title: 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.
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.
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.
authors.affiliation: Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath
authors.affiliation: Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Milan
authors.affiliation: Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hughes
authors.affiliation: Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dutton
authors.affiliation: Department of Clinical Pharmacology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Fitzgerald
authors.affiliation: Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Briggs
authors.affiliation: Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Bygott
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Eftychia E
authors.initials: EE
authors.lastname: Psarelli
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Cox
authors.affiliation: Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
authors.affiliation: School of Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jarvis
authors.affiliation: PSR group B.V., Hoofddorp, Netherlands.
authors.forename: Christa
authors.initials: C
authors.lastname: van Kan
authors.affiliation: Cudos BV, Hoofddorp, Netherlands.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Hall
authors.affiliation: PSR group B.V., Hoofddorp, Netherlands.
authors.forename: Dinny
authors.initials: D
authors.lastname: Laan
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Olsson
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Szamosi
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rudebeck
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Kullenberg
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Arvid
authors.initials: A
authors.lastname: Cronlund
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.affiliation: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
authors.forename: Carin
authors.initials: C
authors.lastname: Junestrand
authors.affiliation: AKU Society, Cambridge, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Ayoob
authors.affiliation: AKU Society, Cambridge, UK.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Timmis
authors.affiliation: AKU Society, Cambridge, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sireau
authors.affiliation: Hôpital Necker-Enfants Malades, Paris Cedex 15, France.
authors.forename: Kim-Hanh
authors.initials: KH
authors.lastname: Le Quan Sang
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Federica
authors.initials: F
authors.lastname: Genovese
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braconi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Santucci
authors.affiliation: Laboratory of Genetics, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Nemethova
authors.affiliation: Laboratory of Genetics, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zatkova
authors.affiliation: Agilent Technologies Ireland, Cork, Ireland.
authors.forename: Judith
authors.initials: J
authors.lastname: McCaffrey
authors.affiliation: Agilent Technologies, Stockport, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Christensen
authors.affiliation: Agilent Technologies, Stockport, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Ross
authors.affiliation: Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Richard
authors.initials: R
authors.lastname: Imrich
authors.affiliation: National Institute of Rheumatic Diseases, Piešťany, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Rovensky
mesh_terms: D000328:Adult; D000474:Alkaptonuria / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003512:Cyclohexanones / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006713:Homogentisic Acid / Q000097:blood / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009579:Nitrobenzoates / Q000008:administration & dosage*; D012107:Research Design; D014443:Tyrosine / Q000097:blood
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; C077073:nitisinone; D006713:Homogentisic Acid
keywords: Arthritis; Osteoarthritis; Spondyloarthritis