Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Dementia With Lewy Bodies
Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Dementia With Lewy Bodies
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.
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.
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 UPDRS-III between 15-40. 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

 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. 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