Background Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals.
Methods The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID).
Results Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI −4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy.
Conclusions MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks.
Trial registration number NCT04225312.
- multiple sclerosis
Data availability statement
Data are available upon request.
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Contributors Study design: AAT, ZLEvK and JK. Study investigators: AAT, ZYGvL, EH, EMPEZ, LCvR, CEPvM, AV, JM, BW, NFK, ELJH, JvE, CMR, JJK, ME, JvG, JN, LGFS, MEK, EPJA, GvD, WHB, LB, CET, TR, JK and ZLEvK. Data analyses: AAT and BIL-W. Data verification: AAT, BIL-W. Manuscript preparation: AAT, ZLEvK and JK. Data interpretation, reviewed and revised the manuscript: all authors. Guarantor: AAT.
Funding This study was kindly funded by the Dutch MS Research Foundation (18-1030), the Brain Foundation Netherlands (HA2015.01.05), and Innovation Fund Healthcare insurers (B 18-313/ File 3.798).
Disclaimer The funding sources had no involvement in the execution of the study.
Competing interests EH: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche and Sanofi Genzyme. EMPEZ: reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. JvE: reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. FB: Steering committee and iDMC for Biogen, Merck, Roche, EISAI. Consultant to Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder of Queen Square Analytics. Funding by NIHR-UCLH-BRC, Novartis, GE, UKMSS, MAGNIMS-ECTRIMS, EC-H2020, EC-JU (IMI), EPSRC. Editorial board member for Brain, MSJ, Neurology, Radiology and Neuroradiology (section editor). CET: reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology and Neuroinflammation, and is editor of a Neuromethods book Springer. TR received funding for research from Genmab and consultancy fees from Novartis. BMJU: reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche, and Immunic Therapeutics. JK: 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, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only).
Provenance and peer review Not commissioned; externally peer reviewed.
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