title: Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation.
abstract: OBJECTIVE
  To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period.
  
  
  BACKGROUND
  Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study.
  
  
  METHODS
  A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion.
  
  
  RESULTS
  A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6-12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0-12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG.
  
  
  CONCLUSIONS
  Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA Department of Neurology, State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Weinstock-Guttman
authors.affiliation: Department of Neurology, Buffalo Neuroimaging Analysis Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Jesper
authors.initials: J
authors.lastname: Hagemeier
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA.
authors.forename: Katelyn S
authors.initials: KS
authors.lastname: Kavak
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA.
authors.forename: Vasu
authors.identifier: http://orcid.org/0000-0002-6796-5881
authors.initials: V
authors.lastname: Saini
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Patrick
authors.affiliation: Department of Neurology, Buffalo Neuroimaging Analysis Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Deepa P
authors.initials: DP
authors.lastname: Ramasamy
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Nadeem
authors.affiliation: Department of Neurology, Buffalo Neuroimaging Analysis Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Carl
authors.affiliation: Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hojnacki
authors.affiliation: Department of Neurology, State University of New York at Buffalo, Buffalo, New York, USA Department of Neurology, Buffalo Neuroimaging Analysis Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Zivadinov
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000473:pathology*; D000069442:Natalizumab / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D016899:Interferon-beta