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Nilotinib in Cognitively Impaired Parkinson Disease Patients 001

Primary Purpose

Parkinson's Disease, Parkinson's Disease Dementia, Diffuse Lewy Body Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Nilotinib
Sponsored by
Georgetown University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Parkinson's Disease

Eligibility Criteria

40 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

1. Patients aged 40 to 90 with Idiopathic Parkinson's Disease (Significant Sinemet response) on a stable medication drug regimen L-dopa and/or Dopamine agonist (at least 1 month before enrollment with no new medication change) and with moderate to severe cognitive impairment (MOCA ≤24).

Inclusions criteria:

  1. Written informed consent
  2. Capability and willingness to comply with the study related criteria
  3. Patients between the age of 40-90 y
  4. Diagnosis of PD according to the UK Brain Bank Diagnostic Criteria
  5. Early PD subjects with MMSE between 23-30.
  6. Hoehn and Yahr stage <2
  7. Stable treatment (>4 weeks) with MAO-B inhibitor (Selegeline up to 10mg/d or rasagiline up to 1 mg/d) allowable
  8. Patients not needing dopamine agonist or levodopa therapy presently or at least for the next 6 months
  9. Idiopathic PD with NO genetic mutations (autosomal recessive or dominant)
  10. Detectable levels of CSF for blood and CSF Alpha-Synuclein

Exclusion Criteria:

  1. Patients with a known genetic form of PD that does not involve alpha-synuclein.
  2. Unwillingness to undergo lumbar punctures
  3. Immeasurable CSF α-synuclein.
  4. Presence of dementia or severe cognitive impairment that would not permit the patient to give adequate feedback for potential side effects.
  5. Unwilling to be in an off state for UPDRS assessment.
  6. Pre-menopausal women
  7. Patients with autosomal recessive (PARKIN, PINK1 or DJ1) or dominant mutations (LRRK2)
  8. Patients with hypokalemia, hypomagnesaemia, or long QT syndrome.
  9. Concomitant drugs known to prolong the QT interval
  10. Strong CYP3A4 inhibitors
  11. Any drugs or foods that may interact with Nilotinib as stated in the Package Insert (PI).
  12. Medical history of liver and pancreatic diseases.
  13. Clinical signs indicating syndromes other than idiopathic PD, including supranucelar gaze palsy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar sings, early severe autonomic involvement, Babinski's signs.
  14. History of any cardiovascular disease, including hypertension, myocardial infraction or cardiac failure, angina, arrhythmia.

Sites / Locations

  • MedStar Georgetown University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

150mg dosing

300mg dosing

Arm Description

This arm will take 150mg of Nilotinib by mouth daily for the 6 month drug period to establish a safe and efficacious dose.

This arm will take 300mg of Nilotinib by mouth daily for the 6 month drug period to establish a safe and efficacious dose.

Outcomes

Primary Outcome Measures

Change in α-synuclein and Tau concentrations in the CSF and serum of patients
Working Hypothesis: PD patients have been shown to have elevated levels of α-synuclein in their CSF. Nilotinib has been shown to reduce α-synuclein and Tau in the gastrointestinal tract and central nervous system in animal models, and similarly, we propose will show changes in CSF and serum α-synuclein concentrations in nilotinib treated PD patients.

Secondary Outcome Measures

Determine nilotinib's efficacy by improvement in motor and non-motor symptoms
Working Hypothesis: By following strict safety guidelines, monitoring patients through physical examinations, self-examinations, laboratory and neurological examinations, nilotinib will be a safe drug to use in patients with PD and PD related patients. Determine if any clinical benefit is observed in this small, short, limited clinical trial. Working Hypothesis: In cell culture and animal models of PD, dopaminergic neurons have shown increased cell death with accumulating α-synuclein. Therefore, PD patients treated with nilotinib, which lowers α-synuclein and Tau in vivo and in vitro studies, will have improvement or stabilization of their motor UPDRS and cognition.
Safety and tolerability, as measured by number of Participants with Adverse Events
Working Hypothesis: By following strict safety guidelines, monitoring patients through physical examinations, self-examinations, laboratory and neurological examinations, nilotinib will be a safe drug to use in patients with PD and PD related patients. Determine if any clinical benefit is observed in this small, short, limited clinical trial. Working Hypothesis: In cell culture and animal models of PD, dopaminergic neurons have shown increased cell death with accumulating α-synuclein. Therefore, PD patients treated with nilotinib, which lowers α-synuclein and Tau in vivo and in vitro studies, will have improvement or stabilization of their motor UPDRS and cognition.

Full Information

First Posted
October 27, 2014
Last Updated
December 15, 2015
Sponsor
Georgetown University
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1. Study Identification

Unique Protocol Identification Number
NCT02281474
Brief Title
Nilotinib in Cognitively Impaired Parkinson Disease Patients 001
Official Title
Open Label Dose Escalation of Nilotinib in Cognitively Impaired Parkinson Disease Patients With Elevated Cerebrospinal Fluid and Blood α-Synuclein
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Completed
Study Start Date
November 2014 (undefined)
Primary Completion Date
May 2015 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Georgetown University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot study will test Nilotinib's ability to alter the abnormal protein build up in Parkinson disease and Diffuse Lewey Body Disease patients . Patients will receive Nilotinib at different doses for 6 months. Patients will then be tested to see if there is change in three areas: 1) has the disease symptoms changed. 2) has levels of a specific misfolded protein changed in the fluid around their brain and spine. 3) Have inflammatory markers changed in the patient's blood and fluid around their brain and spine. If successful, this drug could be used to slow down or stop the progression of disorders that involve abnormal collection of misfolded proteins. However, the main purpose of this pilot study is to check for the safety of using this medication at this level.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Parkinson's Disease, Parkinson's Disease Dementia, Diffuse Lewy Body Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
150mg dosing
Arm Type
Active Comparator
Arm Description
This arm will take 150mg of Nilotinib by mouth daily for the 6 month drug period to establish a safe and efficacious dose.
Arm Title
300mg dosing
Arm Type
Active Comparator
Arm Description
This arm will take 300mg of Nilotinib by mouth daily for the 6 month drug period to establish a safe and efficacious dose.
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Other Intervention Name(s)
Tasigna
Primary Outcome Measure Information:
Title
Change in α-synuclein and Tau concentrations in the CSF and serum of patients
Description
Working Hypothesis: PD patients have been shown to have elevated levels of α-synuclein in their CSF. Nilotinib has been shown to reduce α-synuclein and Tau in the gastrointestinal tract and central nervous system in animal models, and similarly, we propose will show changes in CSF and serum α-synuclein concentrations in nilotinib treated PD patients.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Determine nilotinib's efficacy by improvement in motor and non-motor symptoms
Description
Working Hypothesis: By following strict safety guidelines, monitoring patients through physical examinations, self-examinations, laboratory and neurological examinations, nilotinib will be a safe drug to use in patients with PD and PD related patients. Determine if any clinical benefit is observed in this small, short, limited clinical trial. Working Hypothesis: In cell culture and animal models of PD, dopaminergic neurons have shown increased cell death with accumulating α-synuclein. Therefore, PD patients treated with nilotinib, which lowers α-synuclein and Tau in vivo and in vitro studies, will have improvement or stabilization of their motor UPDRS and cognition.
Time Frame
6 months
Title
Safety and tolerability, as measured by number of Participants with Adverse Events
Description
Working Hypothesis: By following strict safety guidelines, monitoring patients through physical examinations, self-examinations, laboratory and neurological examinations, nilotinib will be a safe drug to use in patients with PD and PD related patients. Determine if any clinical benefit is observed in this small, short, limited clinical trial. Working Hypothesis: In cell culture and animal models of PD, dopaminergic neurons have shown increased cell death with accumulating α-synuclein. Therefore, PD patients treated with nilotinib, which lowers α-synuclein and Tau in vivo and in vitro studies, will have improvement or stabilization of their motor UPDRS and cognition.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 1. Patients aged 40 to 90 with Idiopathic Parkinson's Disease (Significant Sinemet response) on a stable medication drug regimen L-dopa and/or Dopamine agonist (at least 1 month before enrollment with no new medication change) and with moderate to severe cognitive impairment (MOCA ≤24). Inclusions criteria: Written informed consent Capability and willingness to comply with the study related criteria Patients between the age of 40-90 y Diagnosis of PD according to the UK Brain Bank Diagnostic Criteria Early PD subjects with MMSE between 23-30. Hoehn and Yahr stage <2 Stable treatment (>4 weeks) with MAO-B inhibitor (Selegeline up to 10mg/d or rasagiline up to 1 mg/d) allowable Patients not needing dopamine agonist or levodopa therapy presently or at least for the next 6 months Idiopathic PD with NO genetic mutations (autosomal recessive or dominant) Detectable levels of CSF for blood and CSF Alpha-Synuclein Exclusion Criteria: Patients with a known genetic form of PD that does not involve alpha-synuclein. Unwillingness to undergo lumbar punctures Immeasurable CSF α-synuclein. Presence of dementia or severe cognitive impairment that would not permit the patient to give adequate feedback for potential side effects. Unwilling to be in an off state for UPDRS assessment. Pre-menopausal women Patients with autosomal recessive (PARKIN, PINK1 or DJ1) or dominant mutations (LRRK2) Patients with hypokalemia, hypomagnesaemia, or long QT syndrome. Concomitant drugs known to prolong the QT interval Strong CYP3A4 inhibitors Any drugs or foods that may interact with Nilotinib as stated in the Package Insert (PI). Medical history of liver and pancreatic diseases. Clinical signs indicating syndromes other than idiopathic PD, including supranucelar gaze palsy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar sings, early severe autonomic involvement, Babinski's signs. History of any cardiovascular disease, including hypertension, myocardial infraction or cardiac failure, angina, arrhythmia.
Facility Information:
Facility Name
MedStar Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States

12. IPD Sharing Statement

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