1. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial
- Author
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Mora, Jesús S., Genge, Angela, Chio, Adriano, Estol, Conrado J., Chaverri, Delia, Hernández, María, Marín, Saúl, Mascias, Javier, Rodríguez, Gabriel E., Povedano, Mònica, Paipa, Andres Julian, Domínguez, Raúl, Gamez, Josep, Salvado, Maria, Lunetta, Christian, Ballario, Carlos, Riva, Nilo, Mandrioli, Jessica, Moussy, Alain, Kinet, Jean-Pierre, Auclair, Christian, Dubreuil, Patrice, Arnold, Vincent, Mansfield, Colin D., Hermine, Olivier, The Ab10015 Study Group, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Università degli studi di Torino (UNITO), Neurological Center for Treatment and Research, Universidade da Coruña, DFKI Bremen (DFKI), Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Vall d'Hebron University Hospital [Barcelona], AB Science, Harvard Medical School [Boston] (HMS), Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Oncology ,Pyridines ,[SDV]Life Sciences [q-bio] ,Tyrosine kinase inhibitor ,masitinib ,Tyrosine-kinase inhibitor ,law.invention ,chemistry.chemical_compound ,tyrosine kinase inhibitor ,0302 clinical medicine ,Clinical trials ,Piperidines ,Randomized controlled trial ,law ,Protein kinases ,therapy ,Young adult ,Amyotrophic lateral sclerosis ,Riluzole ,Masitinib ,Middle Aged ,3. Good health ,Treatment Outcome ,Neurology ,Benzamides ,Disease Progression ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Therapeutics ,Placebo ,Young Adult ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,medicine ,Aged ,Amyotrophic Lateral Sclerosis ,Humans ,Thiazoles ,business.industry ,medicine.disease ,Terapèutica ,Clinical trial ,Proteïnes quinases ,chemistry ,Therapy ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Assaigs clínics - Abstract
Financial support for medical editorial assistance was provided by AB Science. We thank the study participants, their families, and caregivers. We also thank the AB10015 Study Group collaborators (Supplementary eTable 1). The Spanish ALS Research Foundation, FUNDELA, contributed to Dr. Mora's group support. 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.
- Published
- 2019