Nilotinib in Parkinson's Disease

Parkinson Disease Clinical Trial

— NILO-PD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03205488
• Other study ID #: NILO-PD
• Status: Completed
• Phase: Phase 2
• Start date: October 16, 2017
• Est. completion date: September 28, 2019

Study information

• Verified date: July 2020
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: September 28, 2019
• Est. primary completion date: August 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 79 Years

Eligibility

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

Related Conditions & MeSH terms

• Parkinson Disease

Intervention

Drug:
• Cohort 1:Nilotinib Oral Capsules (150mg or 300mg)
2 capsules taken once daily
• Cohort 2: Nilotinib Oral Capsules (dose to be determined from Cohort 1)
2 capsules taken once daily
• Placebo
2 capsules taken once daily

Locations

Country	Name	City	State
United States	Albany Medical College	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado at Denver	Aurora	Colorado
United States	John Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University	East Lansing	Michigan
United States	University of Florida	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Cleveland Clinic - Las Vegas	Las Vegas	Nevada
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Beth Israel Medical Center	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	University of California Davis	Sacramento	California
United States	Inland Northwest Research	Spokane	Washington
United States	Barrow Neurological Institute	Sun City	Arizona
United States	University of South Florida	Tampa	Florida

Sponsors (4)

Lead Sponsor	Collaborator
Northwestern University	Michael J. Fox Foundation for Parkinson's Research, University of Iowa, University of Rochester

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tolerability of Nilotinib Over Placebo	The count of study participants who completed the 6-month study treatment period while active on their original assigned dose	6 months
Primary	Safety of Nilotinib	The count of study participants who experienced any treatment-related SAE in each treatment group	We assessed adverse events that were collected from the first dose of study drug until 60 days after the participant's last dose.
Secondary	Change in MDS-UPDRS Part III	The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III is a motor examination in both practically defined medications OFF state (12 hrs post dose) and ON state (based on the participant/site investigator defined best ON and/or approximately 1 hour post dose). Measure Description: The part III subscale score ranges from 0-165. The Larger the value stands for more disability from PD.	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.