| Title: |
Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial |
| Authors: |
Mora J. S.; Genge A.; Chio A.; Estol C. J.; Chaverri D.; Hernandez M.; Marin S.; Mascias J.; Rodriguez G. E.; Povedano M.; Paipa A.; Dominguez R.; Gamez J.; Salvado M.; Lunetta C.; Ballario C.; Riva N.; Mandrioli J.; Moussy A.; Kinet J. -P.; Auclair C.; Dubreuil P.; Arnold V.; Mansfield C. D.; Hermine O. |
| Contributors: |
Mora J.S.; Genge A.; Chio A.; Estol C.J.; Chaverri D.; Hernandez M.; Marin S.; Mascias J.; Rodriguez G.E.; Povedano M.; Paipa A.; Dominguez R.; Gamez J.; Salvado M.; Lunetta C.; Ballario C.; Riva N.; Mandrioli J.; Moussy A.; Kinet J.-P.; Auclair C.; Dubreuil P.; Arnold V.; Mansfield C.D.; Hermine O. |
| Publication Year: |
2020 |
| Collection: |
Università degli studi di Torino: AperTo (Archivio Istituzionale ad Accesso Aperto) |
| Subject Terms: |
Clinical trial; masitinib; therapy; tyrosine kinase inhibitor |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/31280619; info:eu-repo/semantics/altIdentifier/wos/WOS:000474402000001; volume:21; issue:1-2; firstpage:5; lastpage:14; numberofpages:10; journal:AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION; http://hdl.handle.net/2318/1776273; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85068572784; http://www.tandfonline.com/loi/iafd20 |
| DOI: |
10.1080/21678421.2019.1632346 |
| Availability: |
http://hdl.handle.net/2318/1776273; https://doi.org/10.1080/21678421.2019.1632346; http://www.tandfonline.com/loi/iafd20 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.D724DCF5 |
| Database: |
BASE |