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Disease-Modifying Therapies in Amyotrophic Lateral Sclerosis: A Network Meta-Analysis of Randomized Clinical Trials
Published online by Cambridge University Press: 19 September 2025
Abstract
Background:
Currently, there are no head-to-head studies to compare the efficacy of riluzole, edaravone, sodium phenylbutyrate and taurursodiol (SPT) and tofersen. This study aims to compare all possible interventions for amyotrophic lateral sclerosis (ALS) using network meta-analysis (NMA) methods.
Methods:
A conventional meta-analysis was done if at least two studies with the same intervention, control and outcomes were present. Since all studies included were randomized clinical trials, a NMA comparing five interventions was done, especially when similarity and consistency were assured. Both riluzole and edaravone had three clinical trials included, while SPT and tofersen each had one.
Results:
A total of 1601 ALS patients were included in this review, 1185 in the intervention group and 416 in the control group. Compared to placebo, ALS patients taking riluzole had 36% higher probability of surviving (OR: 1.36, I2 = 4%, p = 0.03, FEML) while those in the edaravone group had 1.44 point lower ALSFRS-R score (SMD: 1.44, p = 0.19, I2 = 98%, REML) at study end. Comparing all interventions in terms of mortality, all no interventions were significantly different to placebo. Moreover, compared to one another, no statistically significant differences were noted.
Conclusion:
Despite the benefit of riluzole in terms of survival in conventional meta-analysis, non-significant findings and the lack of comparison of ALSFRS-R to placebo, edaravone, SPT and tofersen in NMA may preclude any strong recommendation for its use. Moreover, the difference in outcome measures limits important comparison between interventions, and while global consistency in NMA was satisfied, the heterogeneity of patient population limits the interpretability of our results.
Résumé
Les traitements modificateurs de la maladie dans la sclérose latérale amyotrophique : résultats d’une méta-analyse en réseau d’essais cliniques à répartition aléatoire.
Il n’existe à l’heure actuelle aucune étude comparative directe sur l’efficacité du riluzole, de l’édaravone, de l’association de phénylbutyrate de sodium et de taurursodiol (PST) ainsi que du tofersen. L’étude visait donc à comparer toutes les interventions thérapeutiques possibles de la sclérose latérale amyotrophique (SLA) à l’aide des techniques de méta-analyse en réseau (MAR).
Une méta-analyse usuelle était réalisée s’il existait au moins deux études qui portaient sur la même intervention, comptaient des témoins et présentaient les critères d’évaluation. Comme il s’agissait, dans tous les cas, d’essais cliniques à répartition aléatoire, l’équipe de recherche a effectué une MAR dans laquelle étaient comparées cinq interventions, tout particulièrement si la similarité et la cohérence étaient sûres. Ainsi, le riluzole et l’édaravone comptaient trois essais chacun dans la méta-analyse, tandis que le PST et le tofersen n’en comptaient qu’un chacun.
Au total, 1601 sujets atteints de SLA ont été retenus dans la méta-analyse : 1185 appartenaient au groupe expérimental et 416, au groupe témoin. Les patients atteints de SLA traités par le riluzole, comparativement à un placébo, avaient 36 % plus de chances de survivre à la maladie (modèle à effets fixes; risque relatif approché : 1,36; I2 = 4 %; p = 0,03), tandis que la cote de stadification selon l’ALSFRS R de ceux traités par l’édaravone était inférieure de 1,44 point (modèle à effets aléatoires; différence moyenne standardisée : 1,44; p = 0,19; I2 = 98 %) à la fin de l’étude. Sur le plan de la mortalité, le résultat des interventions retenues différait peu de celui produit par les placébos. De plus, aucune différence statistique ne s’est dégagée des comparaisons entre les médicaments.
Malgré les avantages du riluzole quant à la survie dans l’autophagie médiée par les chaperonnes, l’existence de données non significatives et l’absence de comparaison de la cote selon l’ALSFRS R par rapport aux placébos, à l’édaravone, au PST et au tofersen dans la MAR peuvent empêcher la formulation de recommandations solides quant à son emploi. En outre, les différences de critères d’évaluation limitent des comparaisons importantes entre les interventions et, bien que le degré de cohérence générale fût satisfaisant dans la MAR, l’hétérogénéité de la population étudiée limite l’interprétabilité des résultats.
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- © The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation
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