Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts

Sharmin, Sifat; Lefort, Mathilde; Andersen, Johanna Balslev; Leray, Emmanuelle; Horáková, Dana; Havrdová, Eva; Alroughani, Raed; Izquierdo, Guillermo; Özakbaş, Serkan; Patti, Francesco; Onofrj, Marco; Terzı, Murat; Grammond, Pierre; Grand’Maison, François; Yamout, Bassem; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Boz, Cavit; Trojano, María; McCombe, Pamela A.; Slee, Mark; Lechner‐Scott, Jeannette; Türkoğlu, Recai; Sola, Patrizia; Ferraro, Diana; Granella, Franco; Prevost, Julie; Maimone, Davide; Skibina, Olga; Buzzard, Katherine; Walt, Anneke van der; Wijmeersch, Bart Van; Csépány, Tünde; Spitaleri, Daniele; Vucic, Steve; Casey, Romain; Debouverie, Marc; Edan, Gilles; Ciron, Jonathan; Ruet, Aurélie; Sèze, Jérôme De; Maillart, Élisabeth; Zephir, Hélène; Labauge, Pierre; Defer, Gilles; Lebrun-Frénay, Christine; Moreau, Thibault; Berger, Ėric; Clavelou, Pierre; Pelletier, Jean; Stankoff, Bruno; Gout, Olivier; Thouvenot, Éric; Heinzlef, Olivier; Al-Khedr, A.; Bourre, Bertrand; Casez, Olivier; Cabre, Philippe; Montcuquet, Alexis; Wahab, Abir; Camdessanché, Jean‐Philippe; Maurousset, Aude; Patry, I.; Hankiewicz, Karolina; Pottier, Corinne; Maubeuge, Nicolas; Labeyrie, Céline; Nifle, Chantal; Laplaud, David; Koch-Henriksen, Niels; Sellebjerg, Finn; Soerensen, Per Soelberg; Pfleger, Claudia; Rasmussen, Peter Vestergaard; Mb, Jensen; Frederiksen, Jette Lautrup; Bramow, Stephan; Mathiesen, Henrik Kahr; Schreiber, Karen; Magyari, Melinda; Vukusic, Sandra; Butzkueven, Helmut; Kalinčík, Tomáš

doi:10.1007/s40263-021-00860-7

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…Overall, 5,148 patients were included in this study [ 10 ]; 1,989 (39%) were treated with natalizumab and 3,159 (61%) with fingolimod. Patient’s characteristics are described in Table 2 (overall median age at baseline: 37.7 years; median MS duration at baseline: 6.9 years).…”

Section: Resultsmentioning

confidence: 99%

“…This study is a result of a collaborative project [ 11 , 17 ]. Longitudinal demographic and clinical data were extracted from MSBase on 15 th of May 2018 [ 18 , 19 ].…”

Section: Methodsmentioning

confidence: 99%

“…In particular, we focus on three studies which used data from three multiple sclerosis (MS) registries, with differences in methods and conclusions [ 5 – 7 ]. We have already shown that some of this variability can be attributed to differences between the study populations [ 10 , 11 ] . In the present work, we focus on the impact of methodological choices on the results—in particular, the methods used to control treatment indication bias and to manage censoring in time-to-event analysis.…”

Section: Introductionmentioning

confidence: 97%

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Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

Lefort

Sharmin

Andersen

et al. 2022

BMC Med Res Methodol

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Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

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Section: Resultsmentioning

confidence: 99%

“…This study is a result of a collaborative project [ 11 , 17 ]. Longitudinal demographic and clinical data were extracted from MSBase on 15 th of May 2018 [ 18 , 19 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

Lefort

Sharmin

Andersen

et al. 2022

BMC Med Res Methodol

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“…In summary, it is now well understood that differences in demographic and clinical characteristics at treatment initiation can drive heterogeneity in treatment response . Our recent study shows that the effectiveness of rituximab and ocrelizumab cannot be considered equal among patients with moderately advanced, active relapsing disease.…”

mentioning

confidence: 91%

Comparative Efficacy of Disease-Modifying Treatments for Relapsing Multiple Sclerosis—Variations in Real-World Experience—Reply

Roos,

Kalincik

2024

JAMA Neurol

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“…Natalizumab (TYSABRI ® ) is a high-efficacy DMT approved for the treatment of relapsing forms of MS on the basis of randomized clinical trials 27 , 28 and real-world studies. 29 – 39 Natalizumab has shown a high degree of disease control in patients as an early treatment option. 23 , 40 – 42 However, outcome data on long-term clinical benefits of natalizumab as a first-line therapy in comparison with lower-efficacy DMTs are still limited.…”

Section: Introductionmentioning

confidence: 99%

Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies

Butzkueven,

Kalincik,

Patti

et al. 2024

Ther Adv Neurol Disord

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Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070–0.092) for natalizumab patients and 0.191 (0.178–0.205) for BRACETD patients ( p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42–0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

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Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts

Cited by 9 publications

References 28 publications

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

Comparative Efficacy of Disease-Modifying Treatments for Relapsing Multiple Sclerosis—Variations in Real-World Experience—Reply

Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies

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