Article Text

Original research
Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study
  1. Douglas L Arnold1,2,
  2. Brenda Banwell3,
  3. Amit Bar-Or4,5,
  4. Angelo Ghezzi6,
  5. Benjamin M Greenberg7,
  6. Emmanuelle Waubant8,
  7. Gavin Giovannoni9,
  8. Jerry S Wolinsky10,
  9. Jutta Gärtner11,
  10. Kevin Rostásy12,
  11. Lauren Krupp13,
  12. Marc Tardieu14,
  13. Wolfgang Brück15,
  14. Tracy E Stites16,
  15. Gregory L Pearce17,
  16. Dieter A Häring18,
  17. Martin Merschhemke18,
  18. Tanuja Chitnis19
  19. On behalf of the PARADIGMS Study Investigators
  1. 1 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
  2. 2 NeuroRx Research, Montreal, Quebec, Canada
  3. 3 The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4 Perelman School of Medicine, University of Pennsylvania, Philadephia, Pennsylvania, USA, Montreal, Quebec, Canada
  5. 5 Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada, Philadephia, Pennsylvania, USA
  6. 6 Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate, Italy
  7. 7 Department of Neurology and Neurotherapeutics, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  8. 8 Department of Neurology, University of California, San Francisco, California, USA
  9. 9 Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UK
  10. 10 McGovern Medical School, Department of Neurology, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA, Houston, Texas, USA
  11. 11 Department of Paediatrics and Adolescent Medicine, German Centre for Multiple Sclerosis in Childhood and Adolescence, University Medical Centre, Göttingen, Germany
  12. 12 Division of Paediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany
  13. 13 Department of Neurology; Pediatric MS Center, NYU Langone Health, New York, NY USA, USA, New York, USA
  14. 14 Hôpitaux universitaires Paris Sud, Paediatric Neurology Department, Assistance Publique-Hôpitaux de Paris, Paris France, Paris, France
  15. 15 Department of Neuropathology, University Medical Centre, Göttingen, Germany
  16. 16 Neuroscience TA, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
  17. 17 GCE Solutions, Bloomington, Illinois, USA
  18. 18 Neuroscience TA, Novartis Pharma AG, Basel, Switzerland
  19. 19 Partners Pediatric Multiple Sclerosis Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Douglas L Arnold, Montreal Neurological Institute, McGill University, Montreal, H3A 0G4, Canada; douglas.arnold{at}mcgill.ca

Abstract

Objective PARADIGMS demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study.

Methods Patients with multiple sclerosis (MS) (aged 10–<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA).

Results Of the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (–72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (–0.48% vs −0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group.

Conclusion Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

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Footnotes

  • Contributors DLA contributed to the study design, data acquisition, data analysis and interpretation outline review and critical revision of the manuscript. BB contributed to the interpretation of study data and critical revision of the manuscript. ABO contributed to the study concept, design, data analysis and interpretation, outline review, critical revision of the manuscript and supervision of the research. AG was involved in study execution, acquisition, data interpretation and critical revision of the manuscript. BG contributed to the study concept, data analysis and critical revision of the manuscript. EW contributed to the study design, execution, acquisition, data interpretation, outline review and critical revision of the manuscript. GG contributed to the study concept, design, execution and critical revision of the manuscript. JW contributed to the study concept, design, execution, data interpretation, outline review and critical revision of the manuscript. JG contributed to the study concept, design, acquisition, data interpretation and critical revision of the manuscript. KR contributed to data interpretation and critical revision of the manuscript. LK contributed to the study concept, design, critical revision of the manuscript and supervision of the research. MT contributed to the study execution, acquisition and critical revision of the manuscript. WB contributed to the data interpretation, outline review and critical revision of the manuscript. TS contributed to the study design, execution, acquisition, data analysis and interpretation, critical revision of the manuscript and supervision of the research. GLP contributed to the statistical analysis and data analysis. DAH contributed to the study design, execution, acquisition, statistical analysis, data analysis and interpretation, outline review and critical revision of the manuscript. MM contributed to the study concept, design, execution, acquisition, statistical analysis, data analysis and interpretation, outline review, critical revision of the manuscript and supervision of the research. TC contributed to the study concept, design, execution, data interpretation, outline review and critical revision of the manuscript.

  • Funding This work was supported by Novartis Pharma AG, Basel, Switzerland.

  • Competing interests DLA receives grant support and consultant fees from Novartis, which manufactures the drug that is tested in this study. He also has an equity interest in NeuroRx Research, which performed the MRI analyses for the study. BB reports consultant fees and personal fees during the study conduct from Novartis, which manufactures the drug that is tested in this study. ABO reports personal fees from Novartis, which manufactures the drug that is tested in this study. AG reports personal fees during the study conduct from Novartis, which manufactures the drug that is tested in this study. BG reports personal fees from Novartis during the study conduct from Novartis, which manufactures the drug that is tested in this study. EW has nothing to disclose. GG reports consultant fees for steering committee and advisory board activities during the study conduct from Novartis, which manufactures the drug that is tested in this study. JW reports consultation fees for on a data monitoring committee (not this study) and during this study for steering committee participation from Novartis, which manufactures the drug that is tested in this study. JG reports consultant fees for research, lectures and advisory boards from Novartis, which manufactures the drug that is tested in this study. KR reports consultant fees for an advisory board from Novartis, which manufactures the drug that is tested in this study. LK reports personal fees personal fees during the study conduct from Novartis, which manufactures the drug that is tested in this study. MT reports personal fees for an advisory board during the study conduct from Novartis, which manufactures the drug that is tested in this study. WB reports grant support and personal fees during the study conduct from Novartis, which manufactures the drug that is tested in this study. TS is an employee of Novartis and holds some stocks and restricted stocks of the company. GLP has nothing to disclose. DAH is an employee of Novartis. MM is an employee of Novartis and holds some stocks and restricted stocks of the company. TC reports consultant fees for steering committee and advisory board activities during the study conduct from Novartis, which manufactures the drug that is tested in this study.

  • Patient consent for publication Obtained.

  • Ethics approval The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines. The study protocol and amendments were reviewed and approved by the Independent Ethics Committees and Institutional Review Boards for each centre as per local regulations. All patients or legal guardians of paediatric patients provided written informed consent before study entry.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. Once the 5-year open-label extension has been completed, the reader will be able to request the raw data (anonymised) and related documents (eg, protocol, reporting and analysis plan, clinical study report) that underlie the results reported in this article by connecting to https://www.clinicalstudydatarequest.com and signing a Data Sharing Agreement with Novartis. These will be made available to qualified external researchers, with requests reviewed and approved by an independent review panel on the basis of scientific merit.

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