Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients

Official title

Phase 3 Study to Compare the Efficacy and Safety of Masitinib in Combination With Riluzole Versus Placebo in Combination With Riluzole in the Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS)

Overview

The objective is to compare the efficacy and safety of masitinib in combination with riluzole versus matched placebo in combination with riluzole for the treatment of Amyotrophic Lateral Sclerosis (ALS).

Detailed description

Masitinib is a selective, oral tyrosine kinase inhibitor with neuroprotective capability demonstrated via numerous preclinical studies. Two of masitinib's main cellular targets are the mast cell and microglia cell. It is well-established that mast cells play a prominent role in neuroinflammatory processes. Microglia, resident immune cells of the central nervous system (CNS), also constitute an important source of neuroinflammatory mediators and may have fundamental roles in numerous neurodegenerative disorders. The development of masitinib in ALS is therefore based on the pharmacological action of masitinib in microglia cells and mast cells, thereby slowing microglial-related disease progression, reducing neuro-inflammation, and modulating the neuronal microenvironment in both central and peripheral nervous systems. This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group (two ascending dose titrations of masitinib and matching placebo), comparative study of oral masitinib in the treatment of patients with amyotrophic lateral sclerosis (ALS).

Interventions

• Drug Masitinib (6.0)
  Masitinib (titration to 6.0 mg/kg/day)
• Drug Riluzole
  Riluzole 50 mg tablet, treatment per os
• Drug Placebo
  treatment per os
• Drug Masitinib (4.5)
  Masitinib (titration to 4.5 mg/kg/day)

Primary outcome measures

• ALSFRS-R [Time frame: 48 weeks]

Secondary outcome measures (5)

• ALSAQ-40 [Time frame: 48 weeks]
• PFS [Time frame: From day of randomization to disease progression or death, assessed for a maximum of 36 months]
• FVC [Time frame: 48 weeks]
• HHD [Time frame: 48 weeks]
• Change in the Combined Assessment of Function and Survival (CAFS) score from baseline to week 48 [Time frame: 48 weeks]

Eligibility criteria

Main inclusion criteria include:

• Patients diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria
• Patient with a familial or sporadic ALS
• ALS disease duration from diagnosis no longer than 24 months at the screening visit
• Patient treated with a stable dose of riluzole (100 mg/day) for at least 12 weeks days prior to the baseline visit
• Patient with an ALSFRS-R score progression between onset of the disease and screening of > 0.3 per month, confirmed with an ALSFRS-R score progression of ≥ 1 point during a 12-week run-in period between screening and randomization.
• Patient with a score, at screening, of at least 26 overall, including a score of at least 3 on item #3 and at least 2 on each of the 12 ALSFRS-R individual component items and with a score, at randomization, of at least 2 on each of the 12 ALSFRS-R individual component items

Main exclusion criteria include:

• Patient with dementia or significant neurological, psychiatric, systemic or organic disease, uncontrolled or that may interfere with the conduct of the trial or its results
• Patient with a FVC < 60% predicted normal value for gender, height, and age at screening and baseline
• Pregnant, or nursing female patient

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

France · 11 centers

• CHU de Angers — Angers
• Groupe Hospitalier Pellegrin Tripode — Bordeaux
• Hôpital neurologique Pierre Wertheimer — Bron
• CHU Gabriel Montpied — Clermont-Ferrand
• CHU de Lille - Hopital Roger Salengro — Lille
• CHU de Limoges - Hôpital Dupuytren — Limoges
• CHU de Marseille - Hôpital de la Timone — Marseille
• CHRU de Montpellier - Gui de Chauliac — Montpellier
• … and 3 more centers

Italy · 11 centers

• Ospedale Civile Sant'Agostino - Estense — Baggiovara
• ASST degli Spedali Civili di Brescia — Brescia
• Centro Clinico NeMO Fondazione Serena Onlus — Gussago
• Clinico Nemo Center (Centro Clinico NeMO Milano) — Milan
• IRCCS Istituto Auxologico Italiano — Milan
• Istituti Clinici Scientifici Maugeri IRCCS — Milan
• San Raffaele Hospital (Ospedale San Raffaele) — Milan
• University Hospital Maggiore della Carita — Novara
• … and 3 more centers

United States · 6 centers

• University of Alabama at Birmingham — Birmingham
• University of Southern California — Los Angeles
• University of Kentucky — Lexington
• Johns Hopkins Medicine Brain Science Institute — Baltimore
• Lahey Hospital and Medical Center — Burlington
• University of Virginia Health System — Charlottesville

Spain · 6 centers

• Hospital General Universitario de Alicante — Alicante
• Hospital Universitari de Bellvitge — Barcelona
• Hospital Carlos III — Madrid
• Hospital San Rafael — Madrid
• Clinical Hospital Santiago de Compostela — Santiago de Compostela
• Hospital Universitario y Politecnico La Fe — Valencia

Greece · 4 centers

• Athens Naval Hospital — Athens
• Eginition Hospital — Athens
• University General Hospital of Larissa — Larissa
• General University Hospital of Patras — Rio

Sweden · 3 centers

• Centralsjukhuset Karlstad (Central Hospital Karlstad) — Karlstad
• Skåne University Hospital — Malmö
• Norrlands universitetssjukhus — Umeå

Ukraine · 3 centers

• The State Institution of Neurology, Psychiatry and Narcology of NAMS of Ukraine — Kharkiv
• Medical Center of LLC Medical Center Dopomoga Plus — Kyiv
• Communal Non-Profit Enterprise of Lviv Regional Council, Lviv Regional Clinical Hospital, — Lviv

Israel · 2 centers

• Hadassah University Hospital — Jerusalem
• Tel-Aviv Medical Center Hôpital Sourasky (ICHILOV) — Tel Aviv

Russia · 2 centers

• Moscow city clinical Hospital after V.M. Buyanov — Moscow
• Scientific Practical Medical Center "Innovation and Health" — Novosibirsk

Belgium · 1 center

• University Hospital Leuven (UZ Leuven) — Leuven

Denmark · 1 center

• Bispebjerg Hospital — Copenhagen

Germany · 1 center

• Department of Neurology, University of Ulm — Ulm

Norway · 1 center

• Oslo University Hospital HF Ullevål — Oslo

Poland · 1 center

• Centrum Medyczne Neuromed — Bydgoszcz

Portugal · 1 center

• Hospital de Santa Maria — Lisbon

Serbia · 1 center

• Clinical Centre of Serbia — Belgrade

Slovenia · 1 center

• Klinicni center Ljubljana — Ljubljana

Publications

• Latham BD, Oskin DS, Crouch RD, Vergne MJ, Jackson KD. Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib. Chem Res Toxicol. 2022 Sep 19;35(9):1467-1481. doi: 10.1021/acs.chemrestox.2c00057. Epub 2022 Sep 1. PMID 36048877

Identifiers

NCT: NCT03127267 · AB19001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗