Disease-Modifying Therapies in Amyotrophic Lateral Sclerosis: A Network Meta-Analysis of Randomized Clinical Trials

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, I 2 = 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, I 2 = 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.