Abstract

BackgroundNatalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. MethodsBy re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs.We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. ResultsThe pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. ConclusionThe results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Highlights

  • Evidence-based 2018 guidelines (Montalban et al, 2018) for the use of disease modifying drugs (DMDs) in multiple sclerosis (MS) suggest that in patients with relapsing-remitting MS (RRMS) the choice of DMD should be based upon patient characteristics and comorbidities, disease severity, drug safety profile and accessibility of the drug

  • Data in MSBase and Danish Multiple Sclerosis Registry (DMSR) had been updated with more patients and longer follow-up presented in this study, whereas the data provided from Observatoire Français de la Sclerose en Plaques (OFSEP) for this study was the same as used in the original study

  • The weighting improved the balance between the natalizumab and the fingolimod treated groups which is demonstrated by the reduced standardized mean differences (SMD)

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Summary

Introduction

Evidence-based 2018 guidelines (Montalban et al, 2018) for the use of disease modifying drugs (DMDs) in multiple sclerosis (MS) suggest that in patients with relapsing-remitting MS (RRMS) the choice of DMD should be based upon patient characteristics and comorbidities, disease severity, drug safety profile and accessibility of the drug. This study is based on three published studies from The Danish Multiple Sclerosis Treatment Register (Koch-Henriksen et al, 2017), the French MS Registry (Observatoire Français de la Sclerose en Plaques) OFSEP (Kalincik et al, 2015) and MSBase (Barbin et al, 2016) which led to seemingly discordant results. We hypothesize that these differences are primarily driven by differ­ ences in the studied populations rather than the used analytical meth­ odology.

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