Alzheimer Disease
Conditions
Keywords
Alzheimer's Disease, Mast Cells, Microglia, Tyrosine kinase inhibitor
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.
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.
Interventions
DRUGPlacebo
treatment per os
DRUGMasitinib (4.5)
Masitinib (titration to 4.5 mg/kg/day)
DRUGStandard of care
Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine
Sponsors
AB Science
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Computerized central randomization system using an external provider.
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).
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main inclusion criteria include: 1. Patient with clinical diagnosis of Alzheimer's disease based on criteria defined by IWG (International Working Group on Alzheimer's disease) at screening visit. 2. Patients with ADCS-ADL score at screening visit and baseline visit \< 73 3. Patient with MMSE ≥ 21 and ≤ 25 at screening visit and baseline visit. 4. Patient with Alzheimer's Disease biomarker profile at screening visit: * A positive amyloid PET scan * Alternatively, positive a-beta AND p-tau results OR an abnormal p-tau/a-beta ratio in CSF analysis. Before randomization, the results will be verified centrally. 5. If patients are treated with cholinesterase inhibitors (donepezil, rivastigmine or galantamine), and/or memantine. They should have been at stable dose for a minimum of 6 months at baseline visit, with no changes foreseen in therapy throughout the trial. 6. If receiving a supplement for cognition (eg, gingko biloba, omega-3 polyunsaturated fatty acid, vitamin E, curcumin, souvenaid) patients must have been taking it at stable dose for at least 4 months prior to screening visit. 7. Patients with a caregiver who, at screening and baseline visits, agrees to accompany the participant to all trial visits, supervise compliance with procedures, provide detailed information, has sufficient contact (≥1 hour/day for ≥3 days/week or as deemed sufficient by the Investigator), can read, understand, and speak the designated language, and is cognitively capable of fulfilling trial requirements. Main
Exclusion criteria
include: Related to disease 1. Patients with any other cause of dementia shown by MRI findings and neurological examination 2. Systemic conditions known to cause dementia, e.g., hypothyroidism, untreated vitamin B12 or folic acid deficiency, niacin deficiency, neurosyphilis, HIV infection at screening visit. 3. Patients with substance-induced dementia, Alzheimer's disease with delirium, severe delusions (e.g., NPI delusion score ≥ 4), psychosis or antipsychotic use, or a history of significant psychiatric disorders at the screening visit. 4. Patients with a significant unexplained improvement or decline in overall status on ADAS-Cog and ADCS-ADL at screening and baseline compared to previous assessments, and those whose scores are not in line with their medical history.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute change from baseline in iADRS score at week 24 | 24 weeks | The iADRS is a linear combination of its two components: the ADAS-Cog11 and the ADCS-iADL. The iADRS is calculated as follows: iADRS = ADCS-iADL + (70 - ADAS-Cog11). Lower scores on the iADRS indicate greater impairment; iADRS scores range from 0 to 129. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute change from baseline in ADAS-Cog11 score at week 24 | 24 weeks | The global score, which is the sum of the 11 items, ranges from 0 to 70, with higher scores indicating greater cognitive impairment. |
| 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 Mini-Mental State Examination (MMSE) at week 24 | 24 weeks | Mini-Mental State Examination (MMSE) (scores from 0 to 30, with lower scores indicating poorer cognitive performance) |
| Time to severe dementia (MMSE<10) | 24 weeks | Mini-Mental State Examination (MMSE) (scores from 0 to 30, with lower scores indicating poorer cognitive performance) |
| Absolute change from baseline in ADAS-Cog11 score at week 48 | 48 weeks | The global score, which is the sum of the 11 items, ranges from 0 to 70, with higher scores indicating greater cognitive impairment. |
| Absolute change from baseline in ADCS-ADL score at week 24 | 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) |
| Absolute change from baseline in Neuropsychiatric Inventory (NPI) at week 24 | 24 weeks | Total NPI-12 score ranges from 0 to 144 (higher = more severe symptoms) |
| Absolute change from baseline in CDR | 24 weeks | Clinical Dementia Rating (CDR), scores from 0 to 18, with higher scores indicating worse dementia |
Countries
France, Spain
Contacts
Primary ContactClinical Study Coordinator
Outcome results
None listed