Natalizumab for the treatment of relapsing-remitting multiple sclerosis Systematic review Endbericht Project Report No.: 112 ISSN: 1992-0488 ISSN-online: 1992-0496 Natalizumab for the treatment of relapsing-remitting multiple sclerosis Systematic Review Endbericht Vienna, Februar 2019 Project team Projectleader: Mag. Dr. Eva Fuchs Author: Mag. Dr. Eva Fuchs Project support Systematic literature search: Mag. Dr. Eva Fuchs External review: Ao Univ. Prof. PD Dr. Siegrid Fuchs OA Dr. Sabine Urbanits, MSc, MA Internal review: Dr. Ingrid Zechmeister-Koss, MA Correspondence: Mag. Dr. Eva Fuchs, [email protected] This report should be referenced as follows: Fuchs E. Natalizumab for the treatment of relapsing-remitting multiple sclerosis. LBI-HTA Projektbericht Nr.: 112; Jahr 2019. Wien: Ludwig Boltzmann Institut für Health Technology Assessment. Conflict of interest All authors and the reviewers involved in the production of this report have declared they have no conflicts of interest in relation to the technology assessed according to the Uniform Requirements of Manuscripts Statement of Medical Journal Editors (www.icmje.org). Disclaimer The external reviewers did not co-author the scientific report and do not necessarily all agree with its content. Only the LBI-HTA is responsible for errors or omissions that could persist. The final version and the policy recommendations are under the full responsibility of the LBI-HTA. CONTENT INFORMATION Publisher: Ludwig Boltzmann Gesellschaft GmbH Nußdorferstr. 64, 6 Stock, A-1090 Wien https://hta.lbg.ac.at/page/imprint Responsible for content: Ludwig Boltzmann Institute for Health Technology Assessment (LBI-HTA) Garnisongasse 7/20, A-1090 Vienna https://hta.lbg.ac.at/ Project reports of the LBI-HTA do not appear on a regular basis and serve to publicise the research results of the Ludwig Boltzmann Institute of Health Technology Assessments. Project reports of the LBI-HTA are only available to the public via the Internet at http://eprints.hta.lbg.ac.at HTA-Project report No.: 112 ISSN: 1992-0488 ISSN-online: 1992-0496 © 2019 LBI-HTA – All rights reserved Content Zusammenfassung ............................................................................................................................................... 5 Summary ................................................................................................................................................................ 8 1 Introduction ........................................................................................................................................................ 11 1.1 Description of the condition ...................................................................................................................... 11 1.2 Description of the intervention ................................................................................................................. 13 1.3 Research objectives ..................................................................................................................................... 14 1.4 Research question ....................................................................................................................................... 14 2 Methods ............................................................................................................................................................... 15 2.1 Criteria for considering studies for this review ........................................................................................ 15 2.2 Search methods for identification of studies ............................................................................................ 17 2.3 Data collection and analysis ...................................................................................................................... 17 2.4 Assessment of risk of bias in included studies ........................................................................................ 17 2.5 Data synthesis ............................................................................................................................................. 18 3 Results .................................................................................................................................................................. 19 3.1 Efficacy/Effectiveness ................................................................................................................................ 20 3.2 Safety ........................................................................................................................................................... 22 4 Grading of evidence ........................................................................................................................................... 25 5 Discussion ........................................................................................................................................................... 27 6 Conclusion ........................................................................................................................................................... 31 7 References ............................................................................................................................................................ 33 8 Appendices .......................................................................................................................................................... 37 8.1 Evidence tables of individual studies included for clinical effectiveness and safety ............................ 37 8.2 Risk of bias tables ....................................................................................................................................... 44 8.3 GRADE Evidence profile tables ................................................................................................................ 46 8.4 Applicability table ...................................................................................................................................... 47 8.5 List of ongoing randomised controlled trials and observational studies ............................................... 47 8.6 List of excluded studies .............................................................................................................................. 49 8.7 Literature search strategies ........................................................................................................................ 51 LBI-HTA | 2019 3 Natalizumab for the treatment of relapsing-remitting multiple sclerosis List of figures Figure 3-1: Flow chart of the study selection. ....................................................................................................... 19 List of tables Table 2.1-1: Inclusion criteria .................................................................................................................................. 15 Table 3.1-1: Overview of the main study characteristics ....................................................................................... 20 Table 4-1: Summary of findings table .................................................................................................................. 26 Table 8.1-1: Evidence table – RCT .......................................................................................................................... 37 Table 8.1-2: Evidence table – non-randomised controlled trials .......................................................................... 39 Table 8.1-3: Evidence table – single-arm studies ................................................................................................... 41 Table 8.2-1: Risk of bias table – RCT ..................................................................................................................... 44 Table 8.2-2: Risk of bias table – non-randomised controlled trials ...................................................................... 44 Table 8.2-3: Risk of bias – single-arm studies ........................................................................................................ 45 Table 8.3-1: Grade evidence table ........................................................................................................................... 46 Table 8.4-1: Summary table characterising the applicability of a body of studies .............................................. 47 Table 8.5-1: List of ongoing randomised controlled trials and observational studies ......................................... 47 Table 8.6-1: Table of excluded studies .................................................................................................................... 49 List of abbreviations AE .................. Adverse Event MRI .............. Magnetic Resonance Imaging ARR ............... Annualized Relapse Rate MS................. Multiple Sclerosis CG ................. Control Group PPMS ............ Primary Progressive Multiple CI ................... Confidence Interval Sclerosis CIS................. Clinically Isolated Syndrome QALY ........... Quality Adjusted Life Year CNS ............... Central Nervous System RCT .............. Randomised Controlled Trial EDSS ............. Expanded Disability Status Score RoB ............... Risk of Bias FDA............... Food and Drug Administration ROBINS-I…. Risk of Bias in Non-Randomized Studies of Interventions GRADE ......... Grading of Recommendations, Assessment, Development and RRMS