Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

Lakshminarayan R. Ranganath, Eftychia Eirini Psarelli, Jean Baptiste Arnoux, Daniela Braconi, Michael Briggs, Anders Bröijersén, Nadia Loftus, Helen Bygott, Trevor F. Cox, Andrew S. Davison, Jane P. Dillon, Michael Fisher, Richard FitzGerald, Federica Genovese, Helena Glasova, Anthony K. Hall, Andrew T. Hughes, Juliette H. Hughes, Richard Imrich, Jonathan C. JarvisMilad Khedr, Dinny Laan, Kim Hanh Le Quan Sang, Emily Luangrath, Ol'ga Lukáčová, Anna M. Milan, Alpesh Mistry, Vanda Mlynáriková, Brendan P. Norman, Birgitta Olsson, Nicholas P. Rhodes, Jozef Rovenský, Mattias Rudebeck, Annalisa Santucci, Ella Shweihdi, Ciarán Scott, Jana Sedláková, Nicolas Sireau, Roman Stančík, Johan Szamosi, Sophie Taylor, Christa van Kan, Sobhan Vinjamuri, Eva Vrtíková, Chris Webb, Elizabeth West, Elizabeth Záňová, Andrea Zatkova, James A. Gallagher

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.

METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA 24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA 24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382).

FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA 24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred.

INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.

FUNDING: European Commission Seventh Framework Programme.

Original languageEnglish
Pages (from-to)762-772
Number of pages11
JournalThe Lancet Diabetes and Endocrinology
Volume8
Issue number9
Early online date18 Aug 2020
DOIs
Publication statusPublished - 1 Sep 2020
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Alkaptonuria/diagnosis
  • Cyclohexanones/administration & dosage
  • Drug Administration Schedule
  • Enzyme Inhibitors/administration & dosage
  • Female
  • Homogentisic Acid/metabolism
  • Humans
  • Internationality
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Nitrobenzoates/administration & dosage
  • Single-Blind Method
  • Treatment Outcome

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