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

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ClinicalTrials.gov Identifier: NCT04002674
Recruitment Status : Recruiting
First Posted : June 28, 2019
Last Update Posted : March 25, 2020
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Fernando Pagan MD, Georgetown University

Tracking Information
First Submitted Date  ICMJE April 8, 2019
First Posted Date  ICMJE June 28, 2019
Last Update Posted Date March 25, 2020
Actual Study Start Date  ICMJE January 14, 2019
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
Safety and tolerability: occurrence of adverse events (AEs) [ Time Frame: 6 Months ]
The Investigators will determine safety and tolerability using the occurrence of adverse events (AEs) of interest as per Nilotinib Investigator Brochure (IB).
Original Primary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
Safety and tolerability: occurrence of adverse events (AEs) [ Time Frame: 6 Months ]
We will determine safety and tolerability using the occurrence of adverse events (AEs) of interest as per Nilotinib Investigator Brochure (IB).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • The Investigator will determine Nilotinib levels in CSF and plasma. [ Time Frame: 6 Months ]
    Pharmacokinetics: Measure the CSF concentration of Nilotinib
  • The Investigators will determine changes in DLB related CSF and plasma biomarkers [ Time Frame: 6 Months ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 28, 2019)
  • Measurement of the effects of Nilotinib on Cognition using the Montreal Cognitive Assessment (MoCA) [ Time Frame: 6 Months ]
    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 where 30 is the highest score and 0 is the lowest score.
  • Measurement of the effects of Nilotinib on Cognition using the Trail Making Test (TMT) [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of NIlotinib on Cognition using the Alzheimer's Disease Assessment Scale - cognitive (ADAS-cog). [ Time Frame: 6 Months ]
    ADAS-cog aims to evaluate cognitive impairment in Alzheimer's disease. ADAS-cog was included in this LBD study to better capture potential changes in activities of daily living (ADL) and non-ADLs and severity of cognitive impairment. Points for errors in each task are added up and the greater the dysfunction, the greater the total score. The lower the dysfunction the lower the total score .
  • Measuring the effects of Nilotinib on Behavior using the Alzheimer's disease Cooperative Study-Activity of Daily Living scale [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of Nilotinib on Behavior using the Neuropsychiatric Inventory (NPI) [ Time Frame: 6 Months ]
    The NPI is a multi-item instrument to assess psychopathology in Azheimer's disease based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency.
  • Measuring the effects of Nilotinib on Behavior using the Clinical Assessment of Fluctuation (CAF) [ Time Frame: 6 Months ]
    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
  • Measuring the effects of Nilotinib on Behavior using the Irritability-Apathy Scale (IAS) [ Time Frame: 6 Months ]
    The IAS measures apathy and irritability in patients with dementia. The IAS is a 28-item self-administered questionnaire collecting information about different aspects of irritability and apathy utilizing a 0-3 scale for each item to indicate severity. Both a patient and a study partner version can be administered. The IAS will be completed separately by Subjects and Study Partners. A higher total score indicates higher severity , a lower one indicated lower severity.
  • Measuring the effects of Nilotinib on Behavior using the Problem Behaviors Assessment short form (PBA-s) [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of Nilotinib on Motor Function by using the Unified Parkinson's Disease Rating Scale (UPDRS)-I-III. [ Time Frame: 6 Months ]
    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. Part VI: Schwab and England ADL scale. The greater the score the higher the severity, the lower the score the lower the severity. The maximum possible UPDRS score is 199.
  • Measuring the effects of Nilotinib on Motor Function by using the Timed-Up-And-Go (TUG). [ Time Frame: 6 Months ]
    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.
Original Other Pre-specified Outcome Measures
 (submitted: June 27, 2019)
  • Measurement of the effects of Nilotinib on Cognition using the Montreal Cognitive Assessment (MoCA) [ Time Frame: 6 Months ]
    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 where 30 is the highest score and 0 is the lowest score.
  • Measurement of the effects of Nilotinib on Cognition using the Trail Making Test (TMT) [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of NIlotinib on Cognition using the Alzheimer's Disease Assessment Scale - cognitive (ADAS-cog). [ Time Frame: 6 Months ]
    ADAS-cog aims to evaluate cognitive impairment in Alzheimer's disease. ADAS-cog was included in this LBD study to better capture potential changes in activities of daily living (ADL) and non-ADLs and severity of cognitive impairment. Points for errors in each task are added up and the greater the dysfunction, the greater the score
  • Measuring the effects of Nilotinib on Behavior using the Alzheimer's disease Cooperative Study-Activity of Daily Living scale [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of Nilotinib on Behavior using the Neuropsychiatric Inventory (NPI) [ Time Frame: 6 Months ]
    The NPI is a multi-item instrument to assess psychopathology in Azheimer's disease based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency.
  • Measuring the effects of Nilotinib on Behavior using the Clinical Assessment of Fluctuation (CAF) [ Time Frame: 6 Months ]
    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
  • Measuring the effects of Nilotinib on Behavior using the Irritability-Apathy Scale (IAS) [ Time Frame: 6 Months ]
    The IAS measures apathy and irritability in patients with dementia. The IAS is a 28-item self-administered questionnaire collecting information about different aspects of irritability and apathy utilizing a 0-3 scale for each item to indicate severity. Both a patient and a study partner version can be administered. The IAS will be completed separately by Subjects and Study Partners. A higher total score indicates higher severity.
  • Measuring the effects of Nilotinib on Behavior using the Problem Behaviors Assessment short form (PBA-s) [ Time Frame: 6 Months ]
    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.
  • Measuring the effects of Nilotinib on Motor Function by using the Unified Parkinson's Disease Rating Scale (UPDRS)-I-III. [ Time Frame: 6 Months ]
    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. Part VI: Schwab and England ADL scale.
  • Measuring the effects of Nilotinib on Motor Function by using the Timed-Up-And-Go (TUG). [ Time Frame: 6 Months ]
    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
 
Descriptive Information
Brief Title  ICMJE Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Dementia With Lewy Bodies
Official Title  ICMJE 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)
Brief 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Participants will be randomized by a Biostatistician by an internet based randomization module into two groups. The researchers include : Primary investigator , Sub-Investigators ,Clinical Coordinators, Nurse Practitioners , and Clinical Reseach unit staff.
Primary Purpose: Treatment
Condition  ICMJE Dementia With Lewy Bodies
Intervention  ICMJE
  • 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 Name: Placebo
  • 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 Name: Tasigna
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Placebo oral capsule
  • 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).
    Intervention: Drug: Nilotinib Oral Capsule
Publications * Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 27, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2023
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Myrna J Arellano, RN (202)-444-7273 mja6@gunet.georgetown.edu
Contact: Sara Matar, BS 5715283575 sm3469@georgetown.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04002674
Other Study ID Numbers  ICMJE STUDY00000122
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fernando Pagan MD, Georgetown University
Study Sponsor  ICMJE Georgetown University
Collaborators  ICMJE National Institutes of Health (NIH)
Investigators  ICMJE
Principal Investigator: Fernando L Pagan, MD Georgetown University
PRS Account Georgetown University
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP