PMID- 31280619
OWN - NLM
STAT- MEDLINE
DCOM- 20210303
LR  - 20240123
IS  - 2167-9223 (Electronic)
IS  - 2167-8421 (Linking)
VI  - 21
IP  - 1-2
DP  - 2020 Feb
TI  - Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral 
      sclerosis: a randomized clinical trial.
PG  - 5-14
LID - 10.1080/21678421.2019.1632346 [doi]
AB  - 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 
      (DeltaFS). This approach selects a more homogeneous primary efficacy population 
      ("Normal Progressors", DeltaFS < 1.1 points/month) while concurrently permitting 
      secondary assessment of the broader population. Primary endpoint was decline in 
      ALSFRS-R at week-48 (DeltaALSFRS-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 DeltaALSFRS-R between-group difference (DeltaLSM) 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 DeltaLSM 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 DeltaALSFRS-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 DeltaFS) 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.
FAU - Mora, Jesus S
AU  - Mora JS
AD  - ALS Unit, Hospital San Rafael, Madrid, Spain.
FAU - Genge, Angela
AU  - Genge A
AD  - Department of Neurology and Neurosurgery, Montreal Neurological Institute and 
      Hospital, McGill University, Montreal, Canada.
FAU - Chio, Adriano
AU  - Chio A
AUID- ORCID: 0000-0001-9579-5341
AD  - Department of Neuroscience, University of Turin, Turin, Italy.
FAU - Estol, Conrado J
AU  - Estol CJ
AD  - Neurological Center for Treatment and Rehabilitation, Buenos Aires, Argentina.
FAU - Chaverri, Delia
AU  - Chaverri D
AD  - Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain.
FAU - Hernandez, Maria
AU  - Hernandez M
AD  - Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain.
FAU - Marin, Saul
AU  - Marin S
AD  - Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain.
FAU - Mascias, Javier
AU  - Mascias J
AD  - Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain.
FAU - Rodriguez, Gabriel E
AU  - Rodriguez GE
AD  - Neurology Department, Neuron Motor Disease Clinic, Hospital JM Ramos, Buenos 
      Aires, Argentina.
FAU - Povedano, Monica
AU  - Povedano M
AD  - Neurology Department, Bellvitge Hospital-IDIBELL, Barcelona, Spain.
FAU - Paipa, Andres
AU  - Paipa A
AD  - Neurology Department, Bellvitge Hospital-IDIBELL, Barcelona, Spain.
FAU - Dominguez, Raul
AU  - Dominguez R
AD  - Neurology Department, Bellvitge Hospital-IDIBELL, Barcelona, Spain.
FAU - Gamez, Josep
AU  - Gamez J
AUID- ORCID: 0000-0003-3127-7486
AD  - Neurology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research 
      Institute, Autonomous University of Barcelona, Barcelona, Spain.
FAU - Salvado, Maria
AU  - Salvado M
AD  - Neurology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research 
      Institute, Autonomous University of Barcelona, Barcelona, Spain.
FAU - Lunetta, Christian
AU  - Lunetta C
AD  - NEMO Clinical Centre, Serena Onlus Foundation, Milan, Italy.
FAU - Ballario, Carlos
AU  - Ballario C
AD  - Neurorosario, Rosario, Argentina.
FAU - Riva, Nilo
AU  - Riva N
AD  - Department of Neurology-INSPE, San Raffaele Scientific Institute, Milan, Italy.
FAU - Mandrioli, Jessica
AU  - Mandrioli J
AD  - Department of Neurosciences, St. Agostino-Estense Hospital, Azienda Ospedaliero 
      Universitaria di Modena, Modena, Italy.
FAU - Moussy, Alain
AU  - Moussy A
AD  - AB Science, Paris, France.
FAU - Kinet, Jean-Pierre
AU  - Kinet JP
AD  - AB Science, Paris, France.
AD  - Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical 
      Center, Boston, MA, USA.
FAU - Auclair, Christian
AU  - Auclair C
AD  - AB Science, Paris, France.
AD  - Department of Biology, Universite Paris Sud Universite Paris-Saclay CNRS UMR 
      8113, Ecole Normale Superieure de Cachan, Cachan, France.
FAU - Dubreuil, Patrice
AU  - Dubreuil P
AD  - AB Science, Paris, France.
AD  - INSERM, CNRS, Institut Paoli-Calmettes, CRCM, Centre de Reference des 
      Mastocytoses, Equipe Labelisee Ligue Nationale Contre le Cancer, Aix-Marseille 
      University, Marseille, France; and.
FAU - Arnold, Vincent
AU  - Arnold V
AD  - AB Science, Paris, France.
FAU - Mansfield, Colin D
AU  - Mansfield CD
AD  - AB Science, Paris, France.
FAU - Hermine, Olivier
AU  - Hermine O
AD  - AB Science, Paris, France.
AD  - Imagine Institute, INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and 
      Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, 
      Hopital Necker, Paris, France.
CN  - AB10015 STUDY GROUP
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190707
PL  - England
TA  - Amyotroph Lateral Scler Frontotemporal Degener
JT  - Amyotrophic lateral sclerosis & frontotemporal degeneration
JID - 101587185
RN  - 0 (Benzamides)
RN  - 0 (Piperidines)
RN  - 0 (Pyridines)
RN  - 0 (Thiazoles)
RN  - 7LJ087RS6F (Riluzole)
RN  - M59NC4E26P (masitinib)
SB  - IM
CIN - Amyotroph Lateral Scler Frontotemporal Degener. 2020 Feb;21(1-2):1-2. PMID: 
      31603357
EIN - Amyotroph Lateral Scler Frontotemporal Degener. 2024 Feb;25(1-2):223. PMID: 
      37861274
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Amyotrophic Lateral Sclerosis/*drug therapy
MH  - Benzamides
MH  - Disease Progression
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Piperidines
MH  - Pyridines
MH  - Riluzole/*therapeutic use
MH  - Thiazoles/*therapeutic use
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - Clinical trials
OT  - masitinib
OT  - therapy
OT  - tyrosine kinase inhibitor
EDAT- 2019/07/10 06:00
MHDA- 2021/03/04 06:00
CRDT- 2019/07/09 06:00
PHST- 2019/07/10 06:00 [pubmed]
PHST- 2021/03/04 06:00 [medline]
PHST- 2019/07/09 06:00 [entrez]
AID - 10.1080/21678421.2019.1632346 [doi]
PST - ppublish
SO  - Amyotroph Lateral Scler Frontotemporal Degener. 2020 Feb;21(1-2):5-14. doi: 
      10.1080/21678421.2019.1632346. Epub 2019 Jul 7.