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Multiple sclerosis
Original research
Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS)
  1. Alyssa A Toorop1,
  2. Zoë YGJ van Lierop1,
  3. Liza MY Gelissen1,
  4. Elske Hoitsma2,
  5. Esther MPE Zeinstra3,
  6. Luuk C van Rooij4,
  7. Caspar EP van Munster5,
  8. Anke Vennegoor6,
  9. Jop P Mostert7,
  10. Beatrijs HA Wokke8,
  11. Nynke F Kalkers9,
  12. Erwin LJ Hoogervorst10,
  13. Jeroen JJ van Eijk11,
  14. Christiaan M Roosendaal12,
  15. Jolijn J Kragt13,
  16. Marijke Eurelings14,
  17. Jessie van Genugten15,
  18. Jessica Nielsen16,
  19. LGF Sinnige17,
  20. Mark E Kloosterziel18,
  21. Edo PJ Arnoldus19,
  22. Gert W van Dijk20,
  23. Willem H Bouvy21,
  24. Mark HJ Wessels1,
  25. Lynn Boonkamp22,
  26. Eva MM Strijbis1,
  27. Bob W van Oosten1,
  28. Brigit A De Jong1,
  29. Birgit I Lissenberg-Witte23,
  30. Frederik Barkhof24,25,
  31. Bastiaan Moraal24,
  32. Charlotte E Teunissen22,
  33. Theo Rispens26,27,
  34. Bernard MJ Uitdehaag1,
  35. Joep Killestein1,
  36. Zoé LE van Kempen1
  1. 1MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
  2. 2Department of Neurology, MS Center, Alrijne Hospital, Leiden, The Netherlands
  3. 3Department of Neurology, Isala, Meppel, The Netherlands
  4. 4Department of Neurology, Maasstad Hospital, Rotterdam, The Netherlands
  5. 5Department of Neurology, Amphia Hospital, Breda, The Netherlands
  6. 6Department of Neurology, Flevoziekenhuis, Almere, The Netherlands
  7. 7Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands
  8. 8Department of Neurology, ErasMS, Erasmus Medical Center, Rotterdam, The Netherlands
  9. 9Department of Neurology, OLVG Hospital, Amsterdam, The Netherlands
  10. 10Department of Neurology, St Antonius Hospital, Utrecht, Netherlands
  11. 11Department of Neurology, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
  12. 12Department of Neurology, Slingeland Hospital, Doetinchem, The Netherlands
  13. 13Department of Neurology, Reinier de Graaf Hospital, Delft, The Netherlands
  14. 14Department of Neurology, Spaarne Gasthuis, Haarlem, The Netherlands
  15. 15Department of Neurology, Ziekenhuisgroep Twente, Almelo, The Netherlands
  16. 16Department of Neurology, Ommelander Hospital Groningen, Scheemda, The Netherlands
  17. 17Department of Neurology, Medical Center Leeuwarden, Leeuwarden, The Netherlands
  18. 18Department of Neurology, Wilhelmina Hospital Assen, Assen, The Netherlands
  19. 19Department of Neurology, Elisabeth TweeSteden Hospital, Tilburg, The Netherlands
  20. 20Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
  21. 21Department of Neurology, Diakonessenhuis Hospital, Utrecht, The Netherlands
  22. 22Neurochemistry Laboratory, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
  23. 23Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
  24. 24Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
  25. 25Queen Square MS Centre, Department of Neuroinflammation, Faculty of Brain Sciences, University College London Hospitals and National Institute for Health Research, London, UK
  26. 26Diagnostic Services and Immunopathology, Sanquin Research, Amsterdam, The Netherlands
  27. 27Department of Immunopathology, Landsteiner Laboratory, University of Amsterdam, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
  1. Correspondence to Alyssa A Toorop, Neurology, Amsterdam UMC Location VUmc, Amsterdam, Noord-Holland, The Netherlands; a.toorop{at}amsterdamumc.nl

Abstract

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.

http://dx.doi.org/10.1136/jnnp-2023-332119

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    Data availability statement

    Data are available upon request.

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    Footnotes

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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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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