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

Last updated: May 11, 2023
Sponsor: Georgetown University
Overall Status: Active - Recruiting

Phase

2

Condition

Parkinson's Disease

Dementia

Lewy Body Dementia

Treatment

Nilotinib Oral Capsule

Placebo oral capsule

Clinical Study ID

NCT04002674
STUDY00000122
  • Ages 25-90
  • All Genders

Study Summary

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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Written informed consent
  2. Capable of providing informed consent and complying with study procedures. Subjectswho 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≥18and Parkinsonian defined as bradykinesia in combination with rest tremor, rigidity orboth UPDRS I-III is less than 50 and/or UPDRS-III between 15 -40 on-state. Dementiaand 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 4weeks
  11. QTc interval 350-460 ms, inclusive
  12. Participants must be willing to undergo LP at baseline and 6 months after treatment

Exclusion

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 cardiovasculardisease, including myocardial infraction or cardiac failure, angina, arrhythmia
  3. History or presence of cardiac conditions including:
  4. Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstableangina, or stroke)
  5. Congestive heart failure
  6. First, second- or third-degree atrioventricular block, sick sinus syndrome, orother serious cardiac rhythm disturbances
  7. Any history of Torsade de Pointes
  8. Treatment with any of the following drugs at the time of screening or the preceding 30days, and/or planned use over the course of the trial:
  9. Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)
  10. Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding SelectiveSerotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Paxil, Zoloft, Cymbalta,Sertraline, etc...)
  11. Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use ofstrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,telithromycin, voriconazole) must be avoided. Grapefruit products may alsoincrease serum concentrations of Nilotinib. Should treatment with any of theseagents be required, therapy with Nilotinib should be interrupted.
  12. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin,xarelto, etc.
  13. 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 ofNilotinib.
  14. Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal
  15. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit ofnormal
  16. History of HIV, clinically significant chronic hepatitis, or other active infection
  17. Females must not be lactating, pregnant or with possible pregnancy
  18. Medical history of liver or pancreatic disease
  19. 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, headinjury or encephalitis, cerebellar signs, early severe autonomic involvement, Babinskisign
  20. Current evidence or history in past two years of epilepsy, focal brain lesion, headinjury with loss of consciousness or DSM-IV criteria for any major psychiatricdisorder including psychosis, major depression, bipolar disorder, alcohol or substanceabuse
  21. Evidence of any significant clinical disorder or laboratory finding that renders theparticipant unsuitable for receiving an investigational drug including clinicallysignificant or unstable hematologic, hepatic, cardiovascular, pulmonary,gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratoryabnormality
  22. Active neoplastic disease, history of cancer five years prior to screening, includingbreast cancer (history of skin melanoma or stable prostate cancer are notexclusionary)
  23. Contraindications to LP: prior lumbosacral spine surgery, severe degenerative jointdisease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, orhistory of a bleeding disorder
  24. Must not be on any immunosuppressant medications or IVIG
  25. Must not be enrolled as an active participant in another clinical study

Study Design

Total Participants: 60
Treatment Group(s): 2
Primary Treatment: Nilotinib Oral Capsule
Phase: 2
Study Start date:
July 01, 2019
Estimated Completion Date:
December 30, 2023

Study 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.

Connect with a study center

  • MedStar Georgetown University Hospital

    Washington, District of Columbia 20007
    United States

    Active - Recruiting

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