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Background and Objectives: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID., Methods: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated., Results: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms., Discussion: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations., Competing Interests: Declaration of competing interest A.A. Toorop: nothing to disclose. M.H.J. Wessels: nothing to disclose. L.M.Y. Gelissen: nothing to disclose. E. Hoitsma: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche, and Sanofi Genzyme. E.M.P.E. Zeinstra: reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C. van Rooij: nothing to disclose. C.E.P. van Munster: nothing to disclose. A. Vennegoor: nothing to disclose. J.P. Mostert: nothing to disclose. B.H.A. Wokke: nothing to disclose. N.F. Kalkers: nothing to disclose. E.L.J. Hoogervorst: nothing to disclose. J.J.J. van Eijk: reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M. Roosendaal: nothing to disclose. J.J. Kragt: nothing to disclose. M. Eurelings: nothing to disclose. J. Nielsen: nothing to disclose. J. van Genugten: nothing to disclose. L.G.F. Sinnige: nothing to disclose. M.E. Kloosterziel: nothing to disclose. E.P.J. Arnoldus: nothing to disclose. G.W. van Dijk: nothing to disclose. W.H. Bouvy: nothing to disclose. E.M.M. Strijbis: nothing to disclose. B.W. van Oosten: nothing to disclose. B.A. de Jong: nothing to disclose. B.I. Lissenberg-Witte: nothing to disclose. T. Rispens received funding for research from Genmab and consultancy fees from Novartis. B.M.J. Uitdehaag: reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche, and Immunic Therapeutics. J. Killestein: received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd., Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd., Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E. van Kempen: nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: This was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase., Results: Sixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%-7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%-7.4%) or relapses (95% CI 0%-7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0-5.0) and after follow-up (3.0, IQR 2.0-5.0)., Conclusion: Personalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations., Classification of Evidence: This study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS., (© 2020 American Academy of Neurology.)