Masitinib in Patients With Mild Alzheimer's Disease

Official title

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Masitinib as add-on Therapy in Patients With Mild Alzheimer's Disease, Treated With Standard of Care

Overview

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

• Drug Placebo
  treatment per os
• Drug Masitinib (4.5)
  Masitinib (titration to 4.5 mg/kg/day)
• Drug Standard of care
  Cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine

Primary outcome measures

• Absolute change from baseline in iADRS score at week 24 [Time frame: 24 weeks]

Secondary outcome measures (10)

• Absolute change from baseline in Mini-Mental State Examination (MMSE) at week 24 [Time frame: 24 weeks]
• Absolute change from baseline in ADAS-Cog11 score at week 24 [Time frame: 24 weeks]
• Absolute change from baseline in ADCS-ADL score [Time frame: 48 weeks]
• Clinical Responder rate [Time frame: 24 weeks]
• CIBIC-plus [Time frame: 24 weeks]
• Absolute change from baseline in CDR [Time frame: 24 weeks]
• Time to severe dementia (MMSE<10) [Time frame: 24 weeks]
• Absolute change from baseline in ADAS-Cog11 score at week 48 [Time frame: 48 weeks]
• Absolute change from baseline in ADCS-ADL score at week 24 [Time frame: 24 weeks]
• Absolute change from baseline in Neuropsychiatric Inventory (NPI) at week 24 [Time frame: 24 weeks]

Eligibility criteria

Main inclusion criteria include:

• Patient with clinical diagnosis of Alzheimer's disease based on criteria defined by IWG (International Working Group on Alzheimer's disease) at screening visit.
• Patients with ADCS-ADL score at screening visit and baseline visit < 73
• Patient with MMSE ≥ 21 and ≤ 25 at screening visit and baseline visit.
• 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.
• 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.
• 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.
• 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

• Patients with any other cause of dementia shown by MRI findings and neurological examination
• 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, 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Spain · 8 centers

• Hospital Universitario Nuestra Señora del Perpetuo Socorro de Albacete (Hospital Universit — Albacete
• Ace Alzheimer Center Barcelona (Fundació ACE) — Barcelona
• Hospital Policlínico de Gipuzkoa — Donostia / San Sebastian
• Virgen de las Nieves University Hospital (Hospital Universitario Virgen de las Nieves) — Granada
• La Paz University Hospital (Hospital Universitario La Paz) — Madrid
• Hospital Clinico Universitario Virgen de la Arrixaca — Murcia
• Hospital Universitario de Navarra — Pamplona
• Complejo Asistencial de Zamora. Hospital Provincial de Zamora — Zamora

France · 1 center

• Institut de la mémoire et Maladie d'Alzheimer, Hôpitaux Universitaires Pitié-Salpêtrière — Paris

Publications

• 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. PMID 21504563
• 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. PMID 36849969
• 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. PMID 32623401

Identifiers

NCT: NCT05564169 · AB21004

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗