Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Dementia With Lewy Bodies

A Randomized, Double Blind, Placebo-controlled Study to Evaluate the Impact of Nilotinib Treatment on Safety, Tolerability, Pharmacokinetics and Biomarkers in Dementia With Lewy Bodies (DLB)

Dementia with Lewy Bodies (DLB) is an alphasynucleinopathy and the second most common form of dementia in the elderly. DLB shares striking neuropathological and clinical similarities with both Parkinson's disease (PD) and Alzheimer's disease (AD). Nilotinib (Tasigna®, AMN107, Novartis, Switzerland) is approved by the FDA and is well tolerated for CML treatment at oral doses of 600-800mg daily. The Investigators propose to perform a phase II randomized, double blinded, placebo controlled study to evaluate the impact of Nilotinib in patients with DLB.

Study Overview

• Status: Completed
• Conditions: Dementia With Lewy Bodies
• Intervention / Treatment: Drug: Placebo oral capsule; Drug: Nilotinib Oral Capsule

Detailed Description

A phase II randomized, double blinded, placebo controlled study will be performed to evaluate the impact of Nilotinib (Tasigna®, AMN107, Novartis, Switzerland) on safety, tolerability, pharmacokinetics, pharmacodynamics and clinical outcomes in patients with Dementia with Lewy Bodies. Sixty ( 60) participants will be recruited and randomly assigned 1:1 to placebo (arm 1) or 200 mg Nilotinib (arm 2).This study will be conducted in DLB patients with 2.5≥Hoehn & Yahr≤3 and UPDRS I-III ≤50 and 15≥UPDRS III (motor) ≥40 (Unified Parkinson's Disease Rating Score)and MoCA≥18(Montreal Cognitive Assessment). Eligible participants must be stable on MAO-B inhibitors (Rasageline or Selegeline) for 4 weeks and must not be on ≥800mg Levodopa daily. Participants must be stable on acetylcholinesterase inhibitors and other medications for at least 6 weeks. Participants will be treated for 6 months and monitored every month ( 4 weeks) in a total of 9 visits that include screening , baseline, 1, 2, 3, 4, 5, 6 months follow up and 7 month washout. Blood and cerebrospinal fluid (CSF) will be collected at baseline and at 6 months to determine Nilotinib effects on CSF biomarkers.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent
2. Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR).
3. Clinical diagnosis of DLB according to McKeith et al (7) with both dementia MoCA≥18 and Parkinsonian defined as bradykinesia in combination with rest tremor, rigidity or both UPDRS I-III is less than 50 and/or UPDRS-III between 15 -40 on-state. Dementia and Parkinsonism must be present with at least one other symptom such as fluctuation, visual hallucinations or REM sleep behavioral disorder (RBD)
4. 2.5 ≥Hoehn and Yahr stage ≤3
5. MDS-UPDRS-III 15-40 on-state (or up to 70 on the off state)
6. Abnormal DaTScan
7. Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI
8. Patients between the age of 25-90 years, medically stable
9. Must NOT be stable on mono-amine oxidase (MAO)-B inhibitors (Selegeline or rasagiline) for at least 4 weeks before enrollment and during Nilotinib treatment.
10. Must be medically stable on less than or equal to 800mg Levodopa daily for at least 4 weeks
11. QTc interval 350-460 ms, inclusive
12. Participants must be willing to undergo LP at baseline and 6 months after treatment

Exclusion Criteria:

1. Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms
2. Concomitant drugs known to prolong the QTc interval and history of any cardiovascular disease, including myocardial infraction or cardiac failure, angina, arrhythmia

3. History or presence of cardiac conditions including:

   1. Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke)
   2. Congestive heart failure
   3. First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
   4. Any history of Torsade de Pointes

4. Treatment with any of the following drugs at the time of screening or the preceding 30 days, and/or planned use over the course of the trial:

   1. Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)
   2. Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Paxil, Zoloft, Cymbalta, Sertraline, etc...)
   3. Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) must be avoided. Grapefruit products may also increase serum concentrations of Nilotinib. Should treatment with any of these agents be required, therapy with Nilotinib should be interrupted.
   4. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xarelto, etc.
   5. St. John's Wort and the concomitant use of strong other CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) must be avoided since these agents may reduce the concentration of Nilotinib.
5. Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal
6. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal
7. History of HIV, clinically significant chronic hepatitis, or other active infection
8. Females must not be lactating, pregnant or with possible pregnancy
9. Medical history of liver or pancreatic disease
10. Clinical signs indicating syndromes other than DLB, including, PD, PD with Dementia (PDD), corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, Babinski sign
11. 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
12. 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
13. Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history of skin melanoma or stable prostate cancer are not exclusionary)
14. 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
15. Must not be on any immunosuppressant medications or IVIG
16. Must not be enrolled as an active participant in another clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Sixty (60) participants will be recruited and randomized into 2 arms (1:1). Thirty (30) patients in arm 1 will receive the matching placebo ("sugar pill") one (1) capsule orally (without food) once daily for 6 months (180 days).	Drug: Placebo oral capsule; Thirty (30) patients in arm 1 will receive the matching placebo ("sugar pill") one (1) capsule orally (without food) once daily for 6 months (180 days).; Other Names: Placebo
Active Comparator: 200 mg Nilotinib; Sixty (60) participants will be recruited and randomized into 2 arms (1:1). Thirty (30) patients in arm 2 will receive the 200 mg of Nilotinib one (1) capsule orally (without food) once daily for 6 months (180 days).	Drug: Nilotinib Oral Capsule; Thirty (30) patients in arm 2 will receive the 200 mg of Nilotinib one (1) capsule orally (without food) once daily for 6 months (180 days).; Other Names: Tasigna

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability: Occurrence of Adverse Events (AEs)	The Investigators will determine safety and tolerability using the occurrence of adverse events (AEs) of interest as per Nilotinib Investigator Brochure (IB).	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLB Related CSF Biomarkers	Pharmacodynamics: Determine the effects of Nilotinib on primary biomarkers	6 Months
The Investigators Will Quantify Amyloid Burden Via Florbetaben PET Scan	Quantification of brain amyloid burden via Florbetaben PET at baseline and 6 months (end of treatment)	6 Months
DLB Related CSF Biomarkers	Pharmacodynamics: Determine the effects of Nilotinib on CSF levels of Homavanillic Acid (HVA) between baseline and 6 months.	Changes from Baseline to 6 months
DLB Related CSF Biomarkers	Pharmacodynamics: Determine the effects of Nilotinib on the ratio change of phospho-Tau(181)/Abeta42 (pTau(181)/Ab42) in DLB patients	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure the Effects of Nilotinib on Cognition Using the Montreal Cognitive Assessment (MoCA)	The MoCA is designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains, including attention and concentration, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations and orientation. Scores range between 0 and 30; a score of 26 or higher is generally considered normal, while lower scores indicate impairment.	Change from Baseline in the Montreal Cognitive Assessment at 6 months
Measure the Effects of Nilotinib on Cognition Using the Trail Making Test (TMT)	The Trail Making Test (TMT) is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. The time to complete the test is measured in seconds. Lower times indicate better executive function, while higher scores suggest impairment.	Change from Baseline in the Trail Making Test at 6 months
Measure the Effects of NIlotinib on Cognition Using the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog14).	The 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog14) measures cognitive impairment, with higher scores (0-90) indicating greater disability.	Change from Baseline in the Alzheimer's Disease Assessment Scale - cognitive at 6 months
Measure the Effects of Nilotinib on Behavior Using the Alzheimer's Disease Cooperative Study-Activity of Daily Living Scale (ADCS-ADL)	ADCS-ADL is an activity of daily living inventory to assess functional performance. Using a structured interview format, study partners are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The ADCS-ADL includes some items from traditional basic ADL tests as well as instrumental (complex) activities of daily living. It is a 23 item scale that provide a total score from 0-78 with a lower score indicating greater severity.	Change from Baseline in the Alzheimer's Disease Cooperative Study-Activity of Daily Living Scale at 6 months
Measure the Effects of Nilotinib on Behavior Using the Neuropsychiatric Inventory (NPI)	The Neuropsychiatric Inventory (NPI) is a test widely used, clinician-administered tool that evaluates 12 behavioral domains in dementia patients (e.g., agitation, depression, delusions). Each item is scored by multiplying frequency (1-4) by severity (1-3), resulting in a maximum total score of 144, with higher scores indicating greater neuropsychiatric symptoms, often aligning with disease progression. Minimum Score is 0 (no behavioral symptoms present); maximum Score is 144 (highest severity and frequency across all 12 domains). Higher scores indicate a higher frequency and greater severity of neuropsychiatric symptoms (such as delusions, agitation, or apathy) while lower scores indicate few or no behavioral and psychiatric symptoms.	Change from Baseline in Neuropsychiatric Inventory at 6 months
Measure the Effects of Nilotinib on Behavior Using the Clinical Assessment of Fluctuation (CAF)	The CAF consists of seven items of confusional behavior (falls, fluctuation, drowsiness, attention, disorganized thinking, altered level of consciousness, communication), scores for which are summed to provide a severity score for fluctuating confusion ranging from 0 to 21. Higher scores indicate more severe fluctuations while lower scores indicate less severe fluctuations.	Change from Baseline in Clinical Assessment of Fluctuation at 6 months
Measure the Effects of Nilotinib on Behavior Using the Irritability-Apathy Scale (IAS)	The IAS measures apathy and irritability in patients with dementia. The IAS is a 14-item self-administered questionnaire collecting information about different aspects of irritability and apathy utilizing a 0-3 scale for each item to indicate severity (0 (absent) to 3 (maximum intensity) per question). Total Range is 0-42; a higher total score indicates more severe symptoms, which are often associated with greater morbidity and worse functional outcomes while a lower score indicates lower severity.	Change from Baseline in Irritability-Apathy Scale at 6 months
Measure the Effects of Nilotinib on Behavior Using the Problem Behaviors Assessment Short Form (PBA-s)	PBA-s is a structured interview in which a trained interviewer rates the frequency and severity of neuropsychiatric symptoms through observation and the reporting of the Subject and Study Partner. Symptoms rated include depressed mood, suicidal ideation, anxiety, irritability, angry or aggressive behavior, apathy, perseverative thinking or behavior, obsessive-compulsive behaviors, delusional or paranoid thinking, hallucinations, and disoriented behavior. Each behavioral problem is rated for both severity and frequency on a 0-4- point scale; severity and frequency ratings are then multiplied to provide an overall score for each symptom. Minimum score is 0 (symptom is absent); maximum score is 176 (11 items × maximum severity 4 × maximum frequency 4). Higher scores indicate increased frequency or severity of behavioral issues while lower scores indicate decreased severity and frequency.	Change from Baseline in Problem Behaviors Assessment short form at 6 months
Measure the Effects of Nilotinib on Motor Function by Using the Unified Parkinson's Disease Rating Scale (UPDRS)-I-III.	UPDRS-I-III is used to follow the longitudinal course of Parkinson's disease. The UPDRS is made up of these sections: Part I: evaluation of mentation, behavior, and mood. Part II: self-evaluation of the activities of daily life (ADLs) Part III: clinician-scored monitored motor evaluation. Part IV: complications of therapy. Part V: Hoehn and Yahr staging of severity of Parkinson's disease. The minimum possible score on the UPDRS is 0, which indicates no disability or no symptoms of Parkinson's disease. The scale, used to assess severity, typically ranges from 0 to 199 (total) (199 being the maximum) or 0 to 108 (motor section, Part III) (108 being maximum). Higher scores on the Unified Parkinson's Disease Rating Scale (UPDRS) Parts I-III indicate increased severity of disease, greater disability, and more significant impairment, while lower scores signify better function.	Change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS)-I-III at 6 months
Measure the Effects of Nilotinib on Motor Function by Using the Timed-Up-And-Go (TUG).	Timed Up and Go (TUG) is an assessment of mobility, balance, walking ability, and fall risk. It measures the time that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. This assessment is measured in seconds. A score of less than 10 seconds is normal, 14-20 seconds indicates a high fall risk or frailty, and over 30 seconds suggests significant mobility impairment.	Change from Baseline in Timed-Up-And-Go at 6 months

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Fernando L Pagan, MD, Georgetown University

Publications and helpful links

General Publications

• Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum Mol Genet. 2013 Aug 15;22(16):3315-28. doi: 10.1093/hmg/ddt192. Epub 2013 May 10.

Helpful Links

• https://sites.google.com/a/georgetown.edu/moussa-lab/lab-members

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): April 30, 2025
• Study Completion (Actual): April 30, 2025

Study Registration Dates

• First Submitted: April 8, 2019
• First Submitted That Met QC Criteria: June 27, 2019
• First Posted (Actual): June 28, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Lewy Body Disease; nilotinib
• Other Study ID Numbers: STUDY00000122 (University of Texas Health Science Center at San Antonio)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No