Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

中文翻译：

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马赛替尼作为利鲁唑的附加疗法治疗肌萎缩侧索硬化症患者：一项随机临床试验。


目的：评估马赛替尼治疗 ALS 的效果。方法：双盲研究，随机分配 394 名患者 (1:1:1) 接受利鲁唑 (100 mg/d) 加安慰剂或马赛替尼 (4.5 或 3.0 mg/kg/d)。从第 2 期到第 2/3 期的盲法过渡之后，根据 ALSFRS-R 从疾病发作到基线的进展率 (ΔFS) 实施了前瞻性定义的两层设计。该方法选择更同质的主要疗效人群（“正常进展者”，ΔFS < 1.1 点/月），同时允许对更广泛的人群进行二次评估。主要终点是第 48 周时 ALSFRS-R 的下降 (ΔALSFRS-R)，其中高剂量“正常进展者”队列是前瞻性宣布的主要疗效人群。缺失数据通过最后观察结转（LOCF）方法进行估算，并进行敏感性分析以测试稳健性。结果：对于主要疗效人群，马赛替尼 (n = 99) 显示出明显优于安慰剂 (n = 102) 的益处，ΔALSFRS-R 组间差异 (ΔLSM) 为 3.4 (95% CI 0.65-6.13；p = 0.016) ，相当于功能衰退速度减缓 27%（LOCF 方法）。敏感性分析全部收敛，包括 FCS-REGPMM 的保守多重插补技术，ΔLSM 为 3.4（95% CI 0.53-6.33；p = 0.020）。次要终点（ALSAQ-40、FVC 和事件时间分析）也很重要。相反，对于更广泛的“正常和快速进展者”马赛替尼 4.5 mg/kg/d 队列或任一低剂量（马赛替尼 3.0 mg/kg/d）队列，没有观察到根据 ΔALSFRS-R 的显着治疗效果。治疗中出现的不良事件 (AE)（无论因果关系或发病后 ΔFS）的发生率，马赛替尼 4.5 mg/kg/d 组为 88%，3 组为 85%。0 mg/kg/d，安慰剂组为 79%。同样，严重 AE 的发生率分别为 31%、23% 和 18%。没有明显的事件导致马赛替尼观察到的较高发病率，也没有与马赛替尼相关的死亡。结论：结果显示 4.5 mg/kg/d 的马赛替尼可使 ALS 患者受益。将启动验证性第三阶段研究来证实这些数据。