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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Dementia With Lewy Bodies

Intervention / Treatment
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* Drug: Placebo oral capsule
* Drug: Nilotinib Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR). 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) 2.5 ≥Hoehn and Yahr stage ≤3 MDS-UPDRS-III 15-40 on-state (or up to 70 on the off state) Abnormal DaTScan Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI Patients between the age of 25-90 years, medically stable 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. Must be medically stable on less than or equal to 800mg Levodopa daily for at least 4 weeks QTc interval 350-460 ms, inclusive Participants must be willing to undergo LP at baseline and 6 months after treatment Exclusion Criteria: Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms Concomitant drugs known to prolong the QTc interval and history of any cardiovascular disease, including myocardial infraction or cardiac failure, angina, arrhythmia History or presence of cardiac conditions including: Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke) Congestive heart failure First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances Any history of Torsade de Pointes 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: Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine) Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Paxil, Zoloft, Cymbalta, Sertraline, etc...) 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. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xarelto, etc. 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. Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal History of HIV, clinically significant chronic hepatitis, or other active infection Females must not be lactating, pregnant or with possible pregnancy Medical history of liver or pancreatic disease 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 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 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 skin melanoma or stable prostate cancer are not exclusionary) 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 Must not be on any immunosuppressant medications or IVIG Must not be enrolled as an active participant in another clinical study

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigators will evaluate the effects of 200 mg of Nilotinib versus matching Placebo taken daily by mouth for 6 Months, followed by 1 Month wash-out period in individuals with DLB. Sixty (60) participants will be recruited and randomly assigned 1:1 to placebo (arm 1) or 200 mg Nilotinib (arm 2). 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* 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).<br>* Other names: Placebo;|
| Active Comparator: 200 mg Nilotinib<br>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<br>* 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).<br>* Other names: Tasigna;|

What is the study measuring?
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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 |
| --- | --- | --- |
| The Investigator will determine Nilotinib levels in CSF and plasma. | Pharmacokinetics: Measure the CSF concentration of Nilotinib | 6 Months | 
| The Investigators will determine changes in DLB related CSF and plasma biomarkers | Pharmacodynamics: Determine the effects of Nilotinib on primary biomarkers, including changes of CSF levels of HVA between baseline and 6 months.Furthermore, measure the CSF concentration of surrogate/exploratory 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 |