Masitinib in Patients With Mild to Moderate Alzheimer's Disease

Sponsor

AB Science (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05564169

Collaborator

(none)

600

Enrollment

Location

Arms

Anticipated Duration (Months)

16.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: Placebo Drug: Masitinib (4.5) Drug: Standard of care	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

600 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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).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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Computerized central randomization system using an external provider.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Nov 15, 2022

Anticipated Primary Completion Date :

Nov 15, 2025

Anticipated Study Completion Date :

Dec 15, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Masitinib (4.5) & SOC 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) Masitinib (titration to 4.5 mg/kg/day) Other Names: AB1010 Drug: Standard of care Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine
Placebo Comparator: Placebo & SOC 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 treatment per os Other Names: Placebo Oral Tablet Drug: Standard of care Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine

Arm

Intervention/Treatment

Experimental: Masitinib (4.5) & SOC

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)

Masitinib (titration to 4.5 mg/kg/day)

Other Names:

AB1010

Drug: Standard of care

Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine

Placebo Comparator: Placebo & SOC

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

treatment per os

Other Names:

Placebo Oral Tablet

Drug: Standard of care

Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Time to severe dementia (MMSE<10) [48 weeks]
Mini-Mental State Examination (MMSE) (scores from 0 to 30, with lower scores indicating poorer cognitive performance)
Absolute change from baseline in ADAS-Cog-11 score [48 weeks]
Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) (scores range from 0 to 70, with higher scores indicating worse dementia)
Absolute change from baseline in ADCS-ADL score [48 weeks]
Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) (scores from 0 to 78, with lower scores indicating worse function)
Clinical Responder rate [24 weeks]
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]).
CIBIC-plus [24 weeks]
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.
Absolute change from baseline in CDR [24 weeks]
Clinical Dementia Rating (CDR), scores from 0 to 18, with higher scores indicating worse dementia

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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