- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02947893
Impact of Nilotinib on Safety, Biomarkers and Clinical Outcomes in Mild to Moderate Alzheimer's Disease (AD)
March 12, 2019 updated by: R. Scott Turner, Georgetown University
A Randomized, Double Blind, Placebo-controlled Study to Evaluate the Impact of Low Doses of Nilotinib (Tasigna®) on Safety, Biomarkers and Clinical Outcomes in Subjects With Mild to Moderate Alzheimer's Disease
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.
Study Overview
Status
Unknown
Conditions
Intervention / Treatment
Detailed Description
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 investigators pre-clinical studies show that Nilotinib inhibits brain Abl, decreases Abeta and p-Tau, modulates brain and peripheral immune profiles and reverses cognitive decline in AD models.
Taken together, these data support the hypothesis that Nilotinib is a viable therapeutic candidate - via Abl inhibition - in subjects with AD.
Based on strong pre-clinical evidence about the effects of Nilotinib on neurodegenerative pathologies, including autophagic clearance of neurotoxic proteins, immunity and behavior, the investigators conducted an open label pilot clinical trial in advanced (stage 3-5) PD with dementia (PDD) and Lewy Body Dementia (LBD) patients.
Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months.
The investigators showed that Nilotinib penetrates the blood brain barrier (BBB), in agreement with pre-clinical data.
Several studies show that Abeta42 is decreased and CSF total Tau and p-Tau are increased in PD and LBD.
Investigators data show that Nilotinib reverses loss of CSF Abeta40/42 and significantly reduces (N=5, P<0.05) CSF total Tau and p-Tau between baseline and 6 months treatment.
These biomarker changes are consistent with cognitive improvement (3.5-3.85 points) using Mini-Mental Status Exam (MMSE) and the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) between baseline and 6 months.
These data are very compelling to evaluate the effects of Nilotinib in a phase II, randomized, double-blind, placebo-controlled trial in patients with mild to moderate AD.
Study Type
Interventional
Enrollment (Anticipated)
42
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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District of Columbia
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Washington, District of Columbia, United States, 20007
- Georgetown University Medical Center
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
50 years to 85 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Age ≥ 50
- Fluent in English
- Biomarker confirmed AD with CSF level of Abeta42 <600ng/mL
- Able to ingest oral medications
- Diagnosis of mild to moderate AD according to dementia criteria outlined by McKhann et al.
- Neuroimaging (MRI or CT) consistent with the diagnosis of AD within the past year
- MMSE between 17 and 24 (inclusive) at screening
- Modified Hachinski score ≤ 4
- QTc interval 350-460ms, inclusive
- Caregiver/study partner to accompany participant to all visits and have direct contact with the participant > 2 days/week
- Written informed consent
- Capability and willingness to comply with all study criteria
- Supervision available for study medication
- Stable medical conditions for 3 months prior to screening visit
- Stable medications for 4 weeks prior to screening visit
- Able to complete baseline assessments
- Minimum of 6 years of education, or work history sufficient to exclude mental retardation
- Stable use of cholinesterase inhibitors and memantine (U.S. FDA-approved medications for patients with probable AD), vitamin E (up to 400 IU daily), estrogens, aspirin (81-300 mg daily), and cholesterol-lowering agents for 3 months prior to screening is allowed.
- Clinical laboratory values within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator
Exclusion Criteria:
- Non-AD dementia, probable AD with Down syndrome, APP, PS-1, or PS-2 mutations (known familial AD), LBD and Fronto-temporal dementia (FTD)
- History of clinically significant stroke
- Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
- Sensory impairment that would preclude participation/cooperation with the protocol
- Patients with hypokalemia, hypomagnesaemia, or long QTc syndrome.
- Concomitant drugs known to prolong the QTc interval (>461ms) and history of cardiovascular disease, including myocardial infarction or cardiac failure, angina, arrhythmia
- Prescribed strong CYP3A4 inhibitors or a medical history of liver or pancreatic disease
- Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality
- Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history of treated basal or squamous skin cancer, or stable prostate cancer are not exclusionary)
- Pregnancy or possible pregnancy
- Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, or history of a bleeding disorder
- Contraindication to MRI
- Evidence of more than 4 micro hemorrhages and/or hemosiderosis by a recent (12 months) and/or the screening MRI.
- A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
- Enrolled in another active trial investigating an experimental drug or therapy for AD
- HIV positive
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Group 1 (placebo)
Out of 42 total participants with mild to moderate AD (MMSE=17-24 inclusive) and their study partners that will be recruited and 1:1 randomized, 21 (twenty-one) will be assigned to group 1 and given 1 capsule of a placebo drug by mouth every day for the first 6 months followed by 2 capsules once daily for the subsequent 6 months, every time taken without a meal, for the total duration of the study for 12 months.
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1 capsule of Placebo once a day for 6 months followed by 2 capsules of Placebo for another 6 months
Other Names:
|
Active Comparator: Group 2 (treated)
Out of 42 total participants with mild to moderate AD (MMSE=17-24 inclusive) and their study partners that will be recruited and 1:1 randomized, 21 (twenty-one) will be assigned to group 2 treated with 1 capsule (150mg Nilotinib) once a day by mouth for the first 6 months followed by dose escalation to 2 capsules (300mg Nilotinib) once daily by mouth for the subsequent 6 months, every time taken without a meal, for the total study duration of 12 months.
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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
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety will be measured by number of participants experiencing the occurrence of adverse events and/or abnormal laboratory values
Time Frame: 12 months
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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.
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12 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Effects of Nilotinib treatment on measurement of Nilotinib in the CSF
Time Frame: 12 months
|
The investigators will determine the effects of Nilotinib treatment on Abl inhibition to demonstrate CNS target engagement
|
12 months
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Raymond S. Turner, MD, PhD, Georgetown University
- Study Director: Charbel E Moussa, MD, PhD, Georgetown University
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
January 1, 2017
Primary Completion (Anticipated)
December 1, 2019
Study Completion (Anticipated)
February 1, 2020
Study Registration Dates
First Submitted
October 21, 2016
First Submitted That Met QC Criteria
October 27, 2016
First Posted (Estimate)
October 28, 2016
Study Record Updates
Last Update Posted (Actual)
March 13, 2019
Last Update Submitted That Met QC Criteria
March 12, 2019
Last Verified
March 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2016-0315
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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