Clinical trial NCT05564169: Masitinib in Patients With Mild to Moderate Alzheimer's Disease
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Alzheimer Disease
Keywords: Alzheimer's Disease
Mast Cells
Microglia
Tyrosine kinase inhibitor
Lead sponsor: AB Science
Sponsor class: INDUSTRY
First posted: 2022-10-03
Enrollment: 600
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Absolute change from baseline in ADAS-Cog-11 score
timeFrame: 24 weeks
measure: Absolute change from baseline in ADCS-ADL score
timeFrame: 24 weeks
Secondary outcomes:
measure: Time to severe dementia (MMSE<10)
timeFrame: 48 weeks
measure: Absolute change from baseline in ADAS-Cog-11 score
timeFrame: 48 weeks
measure: Absolute change from baseline in ADCS-ADL score
timeFrame: 48 weeks
measure: Clinical Responder rate
timeFrame: 24 weeks
measure: CIBIC-plus
timeFrame: 24 weeks
measure: Absolute change from baseline in CDR
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut de la mémoire et Maladie d'Alzheimer, Hôpitaux Universitaires Pitié-Salpêtrière
city: Albacete
country: Spain
facility: Hospital Universitario Nuestra Señora del Perpetuo Socorro de Albacete (Hospital Universitario Nuestra Señora del Perpétuo Socorro)
city: Barcelona
country: Spain
facility: Ace Alzheimer Center Barcelona (Fundació ACE)
city: Donostia-San Sebastian
country: Spain
facility: Hospital Policlínico de Gipuzkoa
city: Granada
country: Spain
facility: Virgen de las Nieves University Hospital (Hospital Universitario Virgen de las Nieves)
city: Madrid
country: Spain
facility: La Paz University Hospital (Hospital Universitario La Paz)
city: Murcia
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
city: Pamplona
country: Spain
facility: Hospital Universitario de Navarra
city: Zamora
country: Spain
facility: Complejo Asistencial de Zamora. Hospital Provincial de Zamora
Study officials:
affiliation: Hôpital Universitaire Pitié-Salpêtrière, Paris, France
name: Bruno Dubois, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet JP, Dubreuil P, Moussy A, Hermine O. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011 Apr 19;3(2):16. doi: 10.1186/alzrt75.
citation: Dubois B, Lopez-Arrieta J, Lipschitz S, Doskas T, Spiru L, Moroz S, Venger O, Vermersch P, Moussy A, Mansfield CD, Hermine O, Tsolaki M; AB09004 Study Group Investigators. Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial. Alzheimers Res Ther. 2023 Feb 28;15(1):39. doi: 10.1186/s13195-023-01169-x.
citation: Li T, Martin E, Abada YS, Boucher C, Ces A, Youssef I, Fenaux G, Forand Y, Legrand A, Nachiket N, Dhenain M, Hermine O, Dubreuil P, Delarasse C, Delatour B. Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease. J Alzheimers Dis. 2020;76(4):1339-1345. doi: 10.3233/JAD-200466.