Masitinib in Patients With Mild to Moderate Alzheimer's Disease

Study Overview
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Brief Summary
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Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB21004 will evaluate masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate Alzheimer's disease.

Detailed Description
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Masitinib is an oral tyrosine kinase inhibitor that has demonstrated neuroprotective action in neurodegenerative diseases via inhibition of mast cell and microglia/macrophage activity, and which is capable of accumulating within the central nervous system (CNS) at a therapeutically relevant concentration. There is a growing body of evidence implicating mast cells and microglia (types of innate immune cells that are present in the CNS), with the pathophysiology of Alzheimer's disease. Masitinib has been shown to restore normal spatial learning performance and promote recovery of synaptic markers in a mouse model of Alzheimer's disease, with its synapto-protective action being directly linked to mast cell inhibition. The potential benefit of masitinib in the treatment of patients with mild to moderate Alzheimer's disease has been previously demonstrated in a phase 2 study (AB04024; NCT00976118) and a positive phase 2B/3 study (AB09004; NCT01872598) that showed masitinib (4.5 mg/kg/day) was associated with a statistically significant slowing of cognitive deterioration. The objective of study AB21004 is to confirm treatment effect with masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate Alzheimer's disease.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 3 Study of Masitinib as add-on Therapy in Patients With Mild to Moderate Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: Masitinib (4.5)
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria include: Patient with clinical diagnosis of Alzheimer's disease based on the International Working Group criteria according to the European Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease (CPMP/EWP/553/95 Rev.2 - 2018) at screening visit Patient with MMSE ≥ 14 and ≤ 25 at screening visit and baseline visit Patient with Alzheimer's disease biomarker profile at screening visit Patients treated for a minimum of 6 months with a stable dose of cholinesterase inhibitors (donepezil, rivastigmine or galantamine) at baseline visit, and/or a stable dose of memantine for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the study If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) must be taking a stable dose for at least 4 months prior to screening visit Main exclusion criteria include: Patients with any other cause of dementia shown by MRI findings and neurological examination in the last 12 months prior to screening visit Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit Patients with substance-induced dementia at screening visit Patients with Alzheimer's disease with delirium at screening visit Patients with severe forms of delusions (e.g, NPI-12 delusion score of 4 or more) at screening visit Patients with evidence of psychosis and/or use of antipsychotic drugs at screening, or history of significant psychiatric disorder at screening visit

Ages Eligible for Study
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Minimum Age: 50 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
Interventional Model Description: Randomized, Double-blind, Placebo-controlled, Parallel group (1:1), Multicenter, Comparative study over 24 weeks with a 24-week extension period (all patients can enter the extension phase until week 48).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Masitinib (4.5) & SOC<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. Dose up-titration is subjected to a safety control. Masitinib will be administered as an add-on to cholinesterase inhibitor and/or memantine standard of care (SOC). | Drug: Masitinib (4.5)<br>* Masitinib (titration to 4.5 mg/kg/day)<br>* Other names: AB1010;Drug: Standard of care<br>* Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine<br>|
| Placebo Comparator: Placebo & SOC<br>Participants receive a matched dose placebo, given orally twice daily. Placebo will be administered as an add-on to cholinesterase inhibitor and/or memantine standard of care (SOC). | Drug: Placebo<br>* treatment per os<br>* Other names: Placebo Oral Tablet;Drug: Standard of care<br>* Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in ADAS-Cog-11 score | Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) (scores range from 0 to 70, with higher scores indicating worse dementia) | 24 weeks | 
| Absolute change from baseline in ADCS-ADL score | Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) (scores from 0 to 78, with lower scores indicating worse function) | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to severe dementia (MMSE<10) | Mini-Mental State Examination (MMSE) (scores from 0 to 30, with lower scores indicating poorer cognitive performance) | 48 weeks | 
| Absolute change from baseline in ADAS-Cog-11 score | Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) (scores range from 0 to 70, with higher scores indicating worse dementia) | 48 weeks | 
| Absolute change from baseline in ADCS-ADL score | Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) (scores from 0 to 78, with lower scores indicating worse function) | 48 weeks | 
| Clinical Responder rate | Clinical response defined as decrease from baseline at week 24 in ADAS-cog of ≥4, without deterioration in ADCS-ADL (ADCS-ADL change ≥ 0 between baseline and timepoint) or worsening in the CIBIC-plus scale (response CIBIC in 1-3] or no change [CIBIC in 4]). | 24 weeks | 
| CIBIC-plus | Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), a seven-point categorical rating scale ranging from 1 (marked improved) to 7 (markedly worse) compared with baseline. | 24 weeks | 
| Absolute change from baseline in CDR | Clinical Dementia Rating (CDR), scores from 0 to 18, with higher scores indicating worse dementia | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Mast Cells, Microglia, Tyrosine kinase inhibitor