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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Masitinib (6.0)
* Drug: Riluzole
* Drug: Placebo
* Drug: Masitinib (4.5)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 81 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Masitinib (4.5) & Riluzole<br>Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d | Drug: Riluzole<br>* Riluzole 50 mg tablet, treatment per os<br>* Other names: Rilutek;Drug: Masitinib (4.5)<br>* Masitinib (titration to 4.5 mg/kg/day)<br>* Other names: AB1010;|
| Experimental: Masitinib (6.0) & Riluzole<br>Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment, followed by dose escalation to 6.0 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d. | Drug: Masitinib (6.0)<br>* Masitinib (titration to 6.0 mg/kg/day)<br>* Other names: AB1010;Drug: Riluzole<br>* Riluzole 50 mg tablet, treatment per os<br>* Other names: Rilutek;|
| Placebo Comparator: Placebo & Riluzole<br>Participants receive a matched dose placebo, given orally twice daily, in combination with riluzole at 50 mg b.i.d. | Drug: Riluzole<br>* Riluzole 50 mg tablet, treatment per os<br>* Other names: Rilutek;Drug: Placebo<br>* treatment per os<br>* Other names: Placebo Oral Tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALSFRS-R | Change in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALSAQ-40 | Change in ALS quality of life patient questionnaire (ALSAQ-40) | 48 weeks | 
| PFS | Progression free survival (PFS) is defined as the time from randomization to progression (decline of more than 9 points in ALSFRS-R score from baseline) or death | From day of randomization to disease progression or death, assessed for a maximum of 36 months | 
| FVC | Change in Forced Vital Capacity (FVC) | 48 weeks | 
| HHD | Change in evaluation of upper- and lower-limb muscle strength using hand-held dynamometry (HHD) | 48 weeks | 
| Change in the Combined Assessment of Function and Survival (CAFS) score from baseline to week 48 | CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MND, Amyotrophic Lateral Sclerosis, ALS, Tyrosine kinase inhibitor, Lou Gehrig's disease, Charcot's disease, Motor Neuron disease