Jesus S Mora1, Angela Genge2, Adriano Chio3, Conrado J Estol4, Delia Chaverri5, Maria Hernández5, Saúl Marín5, Javier Mascias5, Gabriel E Rodriguez6, Monica Povedano7, Andrés Paipa7, Raul Dominguez7, Josep Gamez8, Maria Salvado8, Christian Lunetta9, Carlos Ballario10, Nilo Riva11, Jessica Mandrioli12, Alain Moussy13, Jean-Pierre Kinet13,14, Christian Auclair13,15, Patrice Dubreuil13,16, Vincent Arnold13, Colin D Mansfield13, Olivier Hermine13,17. 1. ALS Unit, Hospital San Rafael, Madrid, Spain. 2. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada. 3. Department of Neuroscience, University of Turin, Turin, Italy. 4. Neurological Center for Treatment and Rehabilitation, Buenos Aires, Argentina. 5. Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain. 6. Neurology Department, Neuron Motor Disease Clinic, Hospital JM Ramos, Buenos Aires, Argentina. 7. Neurology Department, Bellvitge Hospital-IDIBELL, Barcelona, Spain. 8. Neurology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain. 9. NEMO Clinical Centre, Serena Onlus Foundation, Milan, Italy. 10. Neurorosario, Rosario, Argentina. 11. Department of Neurology-INSPE, San Raffaele Scientific Institute, Milan, Italy. 12. Department of Neurosciences, St. Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy. 13. AB Science, Paris, France. 14. Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA. 15. Department of Biology, Université Paris Sud Université Paris-Saclay CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Cachan, France. 16. INSERM, CNRS, Institut Paoli-Calmettes, CRCM, Centre de Référence des Mastocytoses, Equipe Labelisée Ligue Nationale Contre le Cancer, Aix-Marseille University, Marseille, France; and. 17. Imagine Institute, INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France.
Abstract
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.
RCT Entities:
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.
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