Clinical trial NCT03205488: Nilotinib in Parkinson's Disease
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase IIa, Parallel Group, Two Cohort Study to Define the Safety, Tolerability, Clinical and Exploratory Biological Activity of the Chronic Administration of Nilotinib in Participants With Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Northwestern
Nilotinib
USA
NILO-PD
Parkinson Disease
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: University of Rochester
name: University of Iowa
name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2017-07-02
Enrollment: 76
Sex: ALL
Minimum age (years): 40
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the safety and tolerability of daily oral administration of nilotinib (150-300mg once daily) in Parkinson's Disease.

Detailed description: The purpose of this study is to determine if nilotinib is safe, if it can be tolerated by patients with Parkinson's disease (PD) and to learn if nilotinib has the possibility of effectively treating PD symptoms. Nilotinib has been approved by the Food and Drug Administration (FDA) to treat certain types of cancer (leukemia) but is considered investigational in this study because it has not been approved for treating PD. Twenty-five sites will enroll participants into 2 cohorts,approximately 75 in Cohort 1 and 60 in Cohort 2. Participants with moderate to advanced PD symptoms will be enrolled in Cohort 1, randomly assigned to take nilotinib (150 mg or 300mg) or placebo, and will complete 13 in-person study visits over 8.5 months.

The results from Cohort 1 will determine if either dose of nilotinib (150mg or 300 mg) is safe and tolerable enough to move forward and evaluate in Cohort 2. If either dose is found to be safe and tolerable, participants with early PD will be enrolled into Cohort 2.

Participants in Cohort 2 will be randomly assigned to either nilotinib (dose to be determined from Cohort 1 results) or placebo and will complete 17 in-person visits over 14.5 months. For both cohorts, the study visits will include clinical assessment of motor, neuropsychiatric and cognitive testing as well as collection of blood and cerebral spinal fluid, collected by lumbar puncture.

This study will also evaluate if nilotinib can help improve motor symptoms associated with PD. All participants in Cohort 1 and participants in Cohort 2 who have started PD medications will have an assessment of the motor exam (Part III) in a practically defined OFF state (12 hours post dose) and ON state (at least one-hour post dose).

Eligibility criteria: Inclusion Criteria; Cohort 1 and 2:

1. Idiopathic PD based on the UK Brain Bank diagnostic criteria.
2. Any race and either gender, age 40-79
3. Able to read and understand English with the capacity to provide voluntary informed consent by signing the informed consent form (ICF)
4. Willing to comply with all study procedures including multiple lumbar punctures (LP)
5. Must be on a stable regimen of central nervous system acting medications (if applicable) for at least 30 days prior to the baseline visit (e.g., benzodiazepines, antidepressants, hypnotics)

Inclusion criteria specific for Cohort 1:

6a. Diagnosis of PD duration \> 5 year 7a. Hoehn \& Yahr scale (H\&Y) stage \> 2 and \< 4 in the ON state 8a. Must be on a stable regimen of PD medications, that includes levodopa, for at least 30 days prior to the screening visit

a. Treatment with monoamine oxidase B (MAO-B) inhibitors will be allowed provided the dose has been stable for 60 days prior to baseline

Inclusion criteria specific for Cohort 2:

6b. Diagnosis of PD duration \< 3 years 7b. H\&Y stage ≤ 2 8b. Participants who are currently NOT receiving symptomatic therapy (ST) (levodopa,dopamine agonists and monoamine oxidase B (MAO-B) inhibitors) and NOT projected to require ST for at least 3 months from enrollment.

a. Treatment with amantadine or an anticholinergic agent will be allowed provided the dose has been stable for 30 days prior to screening and will remain stable for the duration of the study

Exclusion Criteria; Cohorts 1 and 2:

1. Diagnosis of atypical parkinsonism
2. History of bipolar disorder or major depression, or presence of active depression defined as a Beck Depression Inventory II (BDI-II) score \>17
3. History of a suicide attempt within the last 5 years or active suicidal ideations
4. History of schizophrenia or schizophrenia spectrum disorders
5. History of uncontrolled hypokalemia or hypomagnesaemia, or laboratory evidence of such on screening
6. History of cardiac arrhythmia, long QT syndrome, or a corrected QT interval (QTcF) ≥450ms at screening visit 1
7. Treated within 30 days prior to randomization, or planned use during the trial with any of the following classes of Concomitant drugs:

   1. Class IA or III antiarrhythmic drugs
   2. QT prolonging drugs
   3. Strong CYP3A4 inhibitors or inducers
   4. Anticoagulants
   5. Proton pump inhibitors
8. A clinical history, or the active presence of a cardiovascular condition including:

   1. Myocardial infarction, known cardiac ischemia, or angina
   2. Cerebrovascular event (e.g. embolic stroke)
   3. Congestive heart failure, symptomatic first degree atrioventricular (AV) block or PR interval \> 220msec and all second and third degree AV block, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
   4. History of Torsade de Pointes
   5. Other cardiovascular history that, in the opinion of the Site Investigator, will preclude study participation
9. History of hepatic disease, including abnormal liver function defined as Total Bilirubin \> 1.5 times upper limit, Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) \> 2 times the upper limit of the normal, or coagulopathy with INR \> 1.4
10. History of epilepsy or a seizure within the last 6 months
11. Active malignancy, or history of a neoplasm in the prior 5 years (excluding basal/squamous cell carcinoma)
12. Prior history of pancreatitis or total gastrectomy or evidence of abnormal pancreatic function defined as elevated amylase and/or lipase \> 2 times upper limit of normal
13. Diagnosis of human immunodeficiency virus (HIV), clinically significant chronic hepatitis such as hepatitis B (HBV) or hepatitis C (HCV), or clinical history or signs of an active infection
14. History of drug or alcohol abuse ≤ 5 years
15. Active medical or psychiatric condition that in the opinion of the Site Investigator should preclude study participation
16. Previous surgical management for PD
17. Participants participating in any drug or device clinical investigation concurrently or within 30 days prior to screening for this study
18. Severe lactose and galactose intolerance
19. Participants with evidence of other significant laboratory abnormalities which in the opinion of the site investigator or clinical monitor should preclude study participation
20. Known hypersensitivity or contraindication to study drugs (nilotinib or matching placebo) or their components.
21. Female participants of child-bearing potential. Female participants must be post-menopausal, post-hysterectomy, or have a documented infertility based on a known medical or surgical condition
22. Participants with a history of bone marrow suppression or evidence of persistent myelosuppression defined as absolute neutrophil count \<1.8 X 109/L, significant anemia, or thrombocytopenia defined as platelet count \< 100 X 109/L

Exclusion criteria specific for Cohort 1:

22a. Diagnosis of dementia based on the clinician's assessment, or a Montreal Cognitive Assessment (MoCA) score \< 21 at baseline

Exclusion criteria specific for Cohort 2:

22b.MoCA score \< 26 at baseline 23b. Treated within 60 days prior to randomization or expected to require treatment within 3 months from randomization with any ST (including levodopa and dopamine agonists )

a. Treatment with amantadine or an anticholinergic agent will be allowed provided the dose has been stable for 30 days prior to screening and will remain stable for the duration of the study

Primary outcomes:
measure: Tolerability of Nilotinib Over Placebo
timeFrame: 6 months
measure: Safety of Nilotinib
timeFrame: We assessed adverse events that were collected from the first dose of study drug until 60 days after the participant's last dose.
Secondary outcomes:
measure: Change in MDS-UPDRS Part III
timeFrame: The MDS-UPDRS Part III ON state was collected at baseline, day 14, day 30, month 3, month 6, 30 and 60 days post treatment. The OFF state was collected at baseline, month 3, month 6, 30 and 60 days post treatment.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Sun City
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: Aurora
country: United States
facility: University of Colorado at Denver
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Las Vegas
country: United States
facility: Cleveland Clinic - Las Vegas
state: Nevada
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Northwestern University
name: Tanya Simuni, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Simuni T, Fiske B, Merchant K, Coffey CS, Klingner E, Caspell-Garcia C, Lafontant DE, Matthews H, Wyse RK, Brundin P, Simon DK, Schwarzschild M, Weiner D, Adams J, Venuto C, Dawson TM, Baker L, Kostrzebski M, Ward T, Rafaloff G; Parkinson Study Group NILO-PD Investigators and Collaborators. Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):312-320. doi: 10.1001/jamaneurol.2020.4725.