The investigators hypothesize that Nilotinib will be safe in individuals with mild to moderate AD. Specifically, investigators hypothesize that low daily oral doses of Nilotinib will lead to CSF penetration, CNS Abl inhibition, and stabilization of CSF total Tau and p-Tau231/181 and Abeta42/40 levels. The investigators hypothesize that Nilotinib will decrease brain load of amyloid using amyloid positron emission tomography (PET). The investigators also predict that Nilotinib will reduce CSF markers of cell death, including neuron specific enolase (NSE) and S100B.
The investigators propose a novel treatment strategy that involves Abl inhibition to alter Abeta40/42, total Tau and p-Tau231/181 in subjects with mild to moderate dementia due to AD. The goal of this study is to evaluate the impact of low dose Nilotinib on safety, biomarkers and clinical symptoms in patients with mild to moderate AD. Forty two (42) participants with mild to moderate and their study partners will be recruited and randomly assigned 1:1 to group 1 (placebo) for one year or group 2 treated with 150mg Nilotinib for 6 months followed by dose escalation to 300mg once for 12 months. Primary outcomes, we will evaluate the effects of Nilotinib on: Safety and tolerability: Safety will be measured using the occurrence of adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug. Tolerability for a given participant will be defined as the ability of participants to remain on treatment. Overall tolerability of the drug will be defined as less than 25% discontinuations due to drug-related AEs and SAEs. Secondary outcomes, we will determine the effects of Nilotinib treatment on measurement of Nilotinib in the CSF and Abl inhibition to demonstrate CNS target engagement and changes of AD related CSF and plasma levels of Abeta42/40, total Tau and p-Tau231/181. Exploratory outcomes will include assessment of: Cognitive function via MMSE, AD Assessment Scale-Cognitive subscale (ADAS-cog), AD Cooperative Study-Activity of Daily Living (ADCS-ADL), Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB), and Neuropsychiatric Inventory (NPI).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
37
1 capsule of Placebo once a day for 6 months followed by 2 capsules of Placebo for another 6 months
1 capsule of Nilotinib 150 mg once a day for 6 months followed by 2 capsules of Nilotinib (150 mg each capsule = 300 mb total) for the subsequent 6 months
Georgetown University Medical Center
Washington D.C., District of Columbia, United States
Safety Will be Measured by Number of Participants Experiencing the Occurrence of Adverse Events and/or Abnormal Laboratory Values
Safety will be measured by assessing number of participants with abnormal laboratory values, as well as adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug.
Time frame: 12 months
Pharmacokinetics of Nilotinib in Individuals With Alzheimer's Disease
To determine the Cmax (ng/ml), we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 months
Pharmacokinetics of Nilotinib in Individuals With Alzheimer's Disease
To determine the Tmax, we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 months
Pharmacokinetics of Nilotinib in Individuals With Alzheimer's Disease
To determine the AUC (ng/ml\*h) , we will measure Bosutinib in both the CSF and Plasma and perform population pharmacokinetics using Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Time frame: 12 months
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