NILO-PD: Nilotinib in Parkinson's Disease

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03205488
• Collaborator: University of Rochester (Other), University of Iowa (Other), Michael J. Fox Foundation for Parkinson's Research (Other)
• Enrollment: 76
• Locations: 24
• Arms: 2
• Actual Duration (Months): 23.4
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	Drug: Cohort 1:Nilotinib Oral Capsules (150mg or 300mg); Drug: Cohort 2: Nilotinib Oral Capsules (dose to be determined from Cohort 1); Drug: Placebo	Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Oct 16, 2017
• Actual Primary Completion Date: Aug 26, 2019
• Actual Study Completion Date: Sep 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cohort 1 Moderate to Advanced PD Population Randomized 1:1:1	Drug: Cohort 1:Nilotinib Oral Capsules (150mg or 300mg); 2 capsules taken once daily; Drug: Placebo; 2 capsules taken once daily
Active Comparator: Cohort 2 Early/de novo Randomized 2:1	Drug: Cohort 2: Nilotinib Oral Capsules (dose to be determined from Cohort 1); 2 capsules taken once daily; Drug: Placebo; 2 capsules taken once daily

Outcome Measures

Primary Outcome Measures

1. Tolerability of Nilotinib Over Placebo [6 months]

   The count of study participants who completed the 6-month study treatment period while active on their original assigned dose

2. Safety of Nilotinib [We assessed adverse events that were collected from the first dose of study drug until 60 days after the participant's last dose.]

   The count of study participants who experienced any treatment-related SAE in each treatment group

Secondary Outcome Measures

1. Change in MDS-UPDRS Part III [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.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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.

1. 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:

8. Class IA or III antiarrhythmic drugs

9. QT prolonging drugs

10. Strong CYP3A4 inhibitors or inducers

11. Anticoagulants

12. Proton pump inhibitors

13. A clinical history, or the active presence of a cardiovascular condition including:

14. Myocardial infarction, known cardiac ischemia, or angina

15. Cerebrovascular event (e.g. embolic stroke)

16. 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

17. History of Torsade de Pointes

18. Other cardiovascular history that, in the opinion of the Site Investigator, will preclude study participation

19. 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

20. History of epilepsy or a seizure within the last 6 months

21. Active malignancy, or history of a neoplasm in the prior 5 years (excluding basal/squamous cell carcinoma)

22. 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

23. 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

24. History of drug or alcohol abuse ≤ 5 years

25. Active medical or psychiatric condition that in the opinion of the Site Investigator should preclude study participation

26. Previous surgical management for PD

27. Participants participating in any drug or device clinical investigation concurrently or within 30 days prior to screening for this study

28. Severe lactose and galactose intolerance

29. Participants with evidence of other significant laboratory abnormalities which in the opinion of the site investigator or clinical monitor should preclude study participation

30. Known hypersensitivity or contraindication to study drugs (nilotinib or matching placebo) or their components.

31. 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

32. 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 )

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-0017
2	Barrow Neurological Institute	Sun City	Arizona	United States	85013
3	University of California Davis	Sacramento	California	United States	95817
4	University of Colorado at Denver	Aurora	Colorado	United States	80045
5	University of Florida	Gainesville	Florida	United States	32607
6	University of South Florida	Tampa	Florida	United States	33620
7	Rush University Medical Center	Chicago	Illinois	United States	60612
8	John Hopkins University	Baltimore	Maryland	United States	21093
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	University of Michigan	Ann Arbor	Michigan	United States	48109
11	Michigan State University	East Lansing	Michigan	United States	48824
12	Cleveland Clinic - Las Vegas	Las Vegas	Nevada	United States	89106
13	Albany Medical College	Albany	New York	United States	12208
14	Beth Israel Medical Center	New York	New York	United States	10003
15	Duke University Medical Center	Durham	North Carolina	United States	27705
16	University of Cincinnati	Cincinnati	Ohio	United States	45219
17	Cleveland Clinic	Cleveland	Ohio	United States	44195
18	Oregon Health and Science University	Portland	Oregon	United States	97239
19	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19107
20	Medical University of South Carolina	Charleston	South Carolina	United States	29425
21	Baylor College of Medicine	Houston	Texas	United States	77030
22	University of Virginia	Charlottesville	Virginia	United States	22903
23	Inland Northwest Research	Spokane	Washington	United States	99202
24	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Northwestern University
• University of Rochester
• University of Iowa
• Michael J. Fox Foundation for Parkinson's Research

Investigators

• Principal Investigator: Tanya Simuni, MD, Northwestern University

Study Documents (Full-Text)

• Study Protocol - Feb 21, 2018
• Statistical Analysis Plan - Sep 24, 2019

More Information

Publications

None provided.

• Responsible Party: Tanya Simuni, Director, Parkinson's disease and Movement Disorders Center Northwestern University Feinberg School of Medicine, Northwestern University
• ClinicalTrials.gov Identifier: NCT03205488
• Other Study ID Numbers: NILO-PD
• First Posted: Jul 2, 2017
• Last Update Posted: Jul 22, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tanya Simuni, Director, Parkinson's disease and Movement Disorders Center Northwestern University Feinberg School of Medicine, Northwestern University: Northwestern; Nilotinib; USA; NILO-PD; Parkinson Disease
• Additional relevant MeSH terms: Parkinson Disease

Study Results

Participant Flow

Recruitment Details	From November 2017 to December 2018, 125 patients were assessed for eligibility. Of those screened, 76 participants were enrolled in the trial.
Pre-assignment Detail	Of the patients assessed for eligibility, 49 (39%) were excluded. 42 patients did not meet inclusion criteria and 7 declined study participation.

Arm/Group Title	Placebo	Nilotinib 150	Nilotinib 300
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally once per day over the course of 6 months.	Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo each day over the course of 6 months.	Patients were administered 2 capsules of 150 mg Nilotinib each day over the course of 6 months.
Period Title: Overall Study
STARTED	25	25	26
COMPLETED	24	23	21
NOT COMPLETED	1	2	5

Baseline Characteristics

Arm/Group Title	Placebo	Nilotinib 150	Nilotinib 300	Total
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally once per day over the course of 6 months.	Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo each day over the course of 6 months.	Patients were administered 2 capsules of 150 mg Nilotinib each day over the course of 6 months.	Total of all reporting groups
Overall Participants	25	25	26	76
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	13 52%	16 64%	9 34.6%	38 50%
>=65 years	12 48%	9 36%	17 65.4%	38 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.5 (6.8)	61.2 (7.4)	66.9 (7.3)	64.6 (7.5)
Sex: Female, Male (Count of Participants)
Female	9 36%	10 40%	5 19.2%	24 31.6%
Male	16 64%	15 60%	21 80.8%	52 68.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4%	0 0%	1 3.8%	2 2.6%
Not Hispanic or Latino	24 96%	25 100%	25 96.2%	74 97.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	24 96%	23 92%	25 96.2%	72 94.7%
More than one race	1 4%	1 4%	0 0%	2 2.6%
Unknown or Not Reported	0 0%	1 4%	1 3.8%	2 2.6%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	26 100%	76 100%
Parkinson's Disease History (years) [Mean (Standard Deviation) ]
Parkinson's Disease Duration	9.4 (4.9)	8.5 (3.2)	11.7 (5.2)	9.9 (4.7)
Age at Diagnosis	56.2 (6.8)	52.7 (7.6)	55.2 (9.3)	54.7 (8.0)
MDS-UPDRS Total Score (units on a scale) [Mean (Standard Deviation) ]
MDS-UPDRS Total OFF Score	63.8 (21.3)	65.0 (16.0)	70.2 (20.2)	66.4 (19.3)
MDS-UPDRS Total ON Score	46.2 (17.8)	46.9 (15.1)	51.9 (15.7)	48.4 (16.2)
Parkinson's Disease Classifications (Count of Participants)
Hoehn and Yahr Stage 0-2	4 16%	5 20%	1 3.8%	10 13.2%
Hoehn and Yahr Stage 3	21 84%	20 80%	25 96.2%	66 86.8%
Class of Symptomatic Therapy, MAOB Inhibitors	11 44%	8 32%	12 46.2%	31 40.8%
Levodopa Equivalent Daily Dose (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	1066.5 (519.7)	971.8 (251.4)	1012.5 (390.5)	1016.9 (398.7)
Education Adjusted MoCA Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26.9 (2.4)	27.4 (1.9)	27.0 (2.4)	27.1 (2.2)
DRS-2 (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	138.1 (5.7)	137.8 (7.8)	137.7 (6.3)	137.9 (6.6)
BDI-II (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.6 (4.9)	7.3 (5.4)	6.6 (4.3)	6.8 (4.8)
PDSS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	106.6 (21.8)	115.3 (11.6)	103.2 (18.6)	108.3 (18.3)
Modified S/E ADL (units on a scale) [Mean (Standard Deviation) ]
Modified S/E ADL OFF	73.2 (16.5)	77.3 (17.8)	77.0 (14.9)	75.8 (16.8)
Modified S/E ADL ON	86.8 (8.7)	92.2 (5.8)	87.0 (17.9)	88.6 (12.2)
PDQ-39 (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	19.0 (12.7)	19.0 (9.4)	18.4 (10.3)	18.8 (10.8)
EQ-5D (units on a scale) [Mean (Standard Deviation) ]
EQ-5D Summary Index	0.79 (0.14)	0.83 (0.13)	0.78 (0.15)	0.80 (0.14)
EQ-5D Health Score	70.6 (25.1)	71.5 (23.3)	76.0 (15.9)	72.8 (21.5)

Outcome Measures

1. Primary Outcome

Title	Tolerability of Nilotinib Over Placebo
Description	The count of study participants who completed the 6-month study treatment period while active on their original assigned dose
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population, all randomized subjects per arm. The Count of participants below are the number of participants that met the criteria for analysis of tolerability.

Arm/Group Title	Placebo	Nilotinib 150 mg	Nilotinib 300 mg
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally once per day over the course of 6 months	Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo each day over the course of 6 months.	Patients were administered 2 capsules of 150 mg Nilotinib each day over the course of 6 months.
Measure Participants	25	25	26
Count of Participants [Participants]	21 84%	19 76%	20 76.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3626
	Comments
	Method	Fisher Exact
	Comments	One-sided Fisher's Exact tested the proportion of participants who met tolerability between the Nilotinib 150 group to the Placebo group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3895
	Comments
	Method	Fisher Exact
	Comments	One-sided Fisher's Exact tested the proportion of participants who met tolerability between the Nilotinib 300 group to the Placebo group.

2. Primary Outcome

Title	Safety of Nilotinib
Description	The count of study participants who experienced any treatment-related SAE in each treatment group
Time Frame	We assessed adverse events that were collected from the first dose of study drug until 60 days after the participant's last dose.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population, all randomized subjects. The counts refer to the number of participants that experienced an SAE in each treatment arm.

Arm/Group Title	Placebo	Nilotinib 150	Nilotinib 300
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally once per day over the course of 6 months.	Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo each day over the course of 6 months.	Patients were administered 2 capsules of 150 mg Nilotinib each day over the course of 6 months.
Measure Participants	25	25	26
Count of Participants [Participants]	2 8%	1 4%	1 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	H0 : p1 = p2, where p represents the proportion of SAEs for each group. HA : p1 ≠ p2
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments	Fisher's Exact test compared a proportion of participants who experienced any serious adverse event in the Nilotinib 150 group and the Placebo group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	H0 : λ1 = λ2, where λ represents the rate of SAEs for each group. HA : λ1 ≠ λ2
Statistical Test of Hypothesis	p-Value	0.5689
	Comments
	Method	Regression, Poisson
	Comments	Rates of serious adverse event between the Nilotinib 150 group and the placebo were also compared using a Poisson regression model
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.4977
	Confidence Interval	(2-Sided) 95%; 0.0451 to 5.489
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 300 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	H0 : p1 = p3, where p represents the proportion of SAEs for each group. HA : p1 ≠ p3
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	Fisher Exact
	Comments	Fisher's Exact test compared a proportion of participants who experienced any serious adverse event in the Nilotinib 300 group and the Placebo group.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 300 mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	H0 : λ1 = λ3, where λ represents the rate of SAEs for each group. HA : λ1 ≠ λ3
Statistical Test of Hypothesis	p-Value	0.5940
	Comments
	Method	Regression, Poisson
	Comments	Rates of serious adverse event between the Nilotinib 300 group and the placebo were also compared using a Poisson regression model
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.5206
	Confidence Interval	(2-Sided) 95%; 0.0472 to 5.7409
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in MDS-UPDRS Part III
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nilotinib 150	Nilotinib 300
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally twice per day over the course of 6 months.	Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo each day over the course of 6 months.	Patients were administered 2 capsules of 150 mg Nilotinib each day over the course of 6 months.
Measure Participants	25	25	26
Baseline MDS-UPDRS Part III (ON)	22.80 (8.85)	24.76 (11.62)	25.15 (8.17)
Day 14 MDS-UPDRS Part III (ON)	23.13 (11.29)	27.58 (13.53)	29.33 (9.77)
Day 30 MDS-UPDRS Part III (ON)	22.36 (10.00)	26.84 (13.08)	29.73 (10.83)
Month 3 MDS-UPDRS Part III (ON)	19.83 (9.23)	24.88 (13.70)	25.76 (8.71)
Month 6 MDS-UPDRS Part III (ON)	19.63 (9.86)	24.43 (11.50)	25.61 (8.93)
30 Day Post MDS-UPDRS Part III (ON)	20.52 (8.82)	25.13 (12.26)	26.79 (9.10)
60 Day Post MDS-UPDRS Part III (ON)	20.88 (10.88)	23.91 (12.93)	26.42 (10.58)
Baseline MDS-UPDRS Part III (OFF)	40.36 (13.51)	42.84 (12.53)	43.50 (14.01)
Month 3 MDS-UPDRS Part III (OFF)	37.92 (14.46)	39.92 (12.41)	41.04 (13.38)
Month 6 MDS-UPDRS Part III (OFF)	36.21 (14.91)	41.91 (13.40)	43.96 (11.62)
30 Day Post MDS-UPDRS Part III (OFF)	38.92 (14.15)	41.48 (12.19)	45.26 (14.13)
60 Day Post MDS-UPDRS Part III (OFF)	37.36 (14.20)	40.27 (11.33)	43.00 (13.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg
	Comments	The key secondary objective is to conduct a futility analysis within each treatment group which examines the observed change in the MDS-UPDRS Part III ON within the two dose groups compared to previously reported changes from the Pagan et al (2016) study (NCT02281474).
	Type of Statistical Test	Non-Inferiority
	Comments	The hypotheses of interest (H0: δ ≤ -9.8 (7 x 1.4) vs. HA: δ > -9.8) where δ represents the change from baseline to 6 months using the MDS-UPDRS Part III ON in the Nilotinib 150 mg treatment group. The hypotheses of interest were evaluated based on an assessment of parameter estimates from a non-linear mixed effects model, adjusted for a participant's Levodopa Equivalent Daily Dose (LEDD) at each time point.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.05
	Confidence Interval	(1-Sided) 90%; -0.78 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 300 mg
	Comments	The key secondary objective is to conduct a futility analysis within each treatment group which examines the observed change in the MDS-UPDRS Part III ON within the two dose groups compared to previously reported changes from the Pagan et al (2016) study (NCT02281474).
	Type of Statistical Test	Non-Inferiority
	Comments	The hypotheses of interest (H0: δ ≤ -9.8 (7 x 1.4) vs. HA: δ > -9.8) where δ represents the change from baseline to 6 months using the MDS-UPDRS Part III ON in the Nilotinib 300 mg treatment group. The hypotheses of interest were evaluated based on an assessment of parameter estimates from a non-linear mixed effects model, adjusted for a participant's Levodopa Equivalent Daily Dose (LEDD) at each time point.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.93
	Confidence Interval	(1-Sided) 90%; -0.89 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg, Nilotinib 300 mg
	Comments	Additional secondary objective #1 is to establish the degree of symptomatic effect of Nilotinib as measured by the change in the MDS_UPDRS Part III ON score between baseline and 1 month.
	Type of Statistical Test	Equivalence
	Comments	H0 : β1 = β 2 = β 3, where β represents the slope for each group. HA : at least one β i ≠ β j. Using the same LMM as in the key secondary analysis, a two degree of freedom test was used to test for any differences in the slopes from baseline to 1 month for the three treatment groups.
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Mixed Models Analysis
	Comments
Other Statistical Analysis		In order to assess which group may be driving these findings, pairwise comparisons were also utilized (Nilotinib 150 vs PBO at 1 Month, Nilotinib 300 vs PBO at 1 month, Nilotinib 300 vs Nilotinib 150 at 1 month).

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg, Nilotinib 300 mg
	Comments	Additional secondary objective #2 is to establish the degree of symptomatic effect of Nilotinib as measured by the change in the MDS_UPDRS Part III ON score between the final visit on study drug and 30 days off study drug.
	Type of Statistical Test	Equivalence
	Comments	H0 : β1 = β 2 = β 3, where β represents the slope for each group. HA : at least one β i ≠ β j. For this analysis, a separate LMM was constructed, modeling the change from final visit on study drug to the 30 and 60 day follow up visits, while adjusting for the MDS-UPDRS Part III ON scores at the final visit on study drug as well as the Levodopa Equivalent Daily Dose (LEDD) at each visit.
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg, Nilotinib 300 mg
	Comments	Additional secondary objective #3 is to assess the impact of Nilotinib on the progression of PD disability as measured by the change in the MDS_UPDRS Part III ON score between baseline and 6 months.
	Type of Statistical Test	Equivalence
	Comments	H0 : β1 = β 2 = β 3, where β represents the slope for each group. HA : at least one β i ≠ β j. Using the same LMM as in the key secondary analysis, a two degree of freedom test was used to test for any differences in the slopes from baseline to 6 months for the three treatment groups.
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	Mixed Models Analysis
	Comments
Other Statistical Analysis		Pairwise comparisons were also examined for trends (Active 150 vs PBO at 6 Months, Active 300 vs PBO at 6 months).

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nilotinib 150 mg, Nilotinib 300 mg
	Comments	Additional secondary objective #3 is to assess the impact of Nilotinib on the progression of PD disability as measured by the change in the MDS_UPDRS Part III OFF score between baseline and 6 months.
	Type of Statistical Test	Equivalence
	Comments	H0 : β1 = β 2 = β 3, where β represents the slope for each group. HA : at least one β i ≠ β j. Using a similar LMM as in the key secondary analysis, except simplified to only include baseline, month 3 and month 6, a two degree of freedom test was used to test for any differences in the slopes from baseline to 6 months for the three treatment groups.
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Treatment emergent adverse events were collected following the first dose of study drug until 30 days after the participant's last dose of study drug.
Arm/Group Title	Placebo		Nilotinib 150		Nilotinib 300
Arm/Group Description	Placebo enclosed in capsules to maintain the blind was administered orally once per day over the course of 6 months.		Patients were administered 1 capsule of 150 mg Nilotinib and 1 capsule of matching placebo once per day over the course of 6 months.		Patients were administered 2 capsules of 150 mg Nilotinib once per day over the course of 6 months.
All Cause Mortality
	Placebo		Nilotinib 150		Nilotinib 300
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)		0/26 (0%)
Serious Adverse Events
	Placebo		Nilotinib 150		Nilotinib 300
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/25 (8%)		1/25 (4%)		1/26 (3.8%)
Cardiac disorders
Arrhythmia	0/25 (0%)	0	0/25 (0%)	0	1/26 (3.8%)	1
Gastrointestinal disorders
Abdominal Pain	1/25 (4%)	1	0/25 (0%)	0	0/26 (0%)	0
Gastrooesophageal reflux disease	1/25 (4%)	1	0/25 (0%)	0	0/26 (0%)	0
Psychiatric disorders
Suicidal ideation	0/25 (0%)	0	1/25 (4%)	1	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Nilotinib 150		Nilotinib 300
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/25 (88%)		23/25 (92%)		23/26 (88.5%)
Gastrointestinal disorders
Abdominal pain upper	2/25 (8%)	2	0/25 (0%)	0	0/26 (0%)	0
Constipation	1/25 (4%)	1	2/25 (8%)	2	1/26 (3.8%)	1
Diarrhoea	0/25 (0%)	0	2/25 (8%)	2	2/26 (7.7%)	2
Gastrooesophageal reflux disease	3/25 (12%)	4	0/25 (0%)	0	0/26 (0%)	0
Nausea	0/25 (0%)	0	2/25 (8%)	2	4/26 (15.4%)	5
General disorders
Fatigue	4/25 (16%)	5	4/25 (16%)	4	0/26 (0%)	0
Infections and infestations
Nasopharyngitis	5/25 (20%)	5	2/25 (8%)	2	2/26 (7.7%)	3
Urinary tract infection	2/25 (8%)	3	1/25 (4%)	1	0/26 (0%)	0
Injury, poisoning and procedural complications
Fall	5/25 (20%)	11	4/25 (16%)	4	0/26 (0%)	0
Skin abrasion	3/25 (12%)	4	0/25 (0%)	0	0/26 (0%)	0
Investigations
Alanine aminotransferase increased	2/25 (8%)	2	1/25 (4%)	1	0/26 (0%)	0
Amylase Increased	2/25 (8%)	2	4/25 (16%)	4	4/26 (15.4%)	6
Blood bilirubin increased	0/25 (0%)	0	0/25 (0%)	0	2/26 (7.7%)	2
CSF protein increased	0/25 (0%)	0	0/25 (0%)	0	2/26 (7.7%)	2
Lipase increased	4/25 (16%)	5	7/25 (28%)	11	6/26 (23.1%)	9
Musculoskeletal and connective tissue disorders
Muscle spasms	2/25 (8%)	2	2/25 (8%)	2	2/26 (7.7%)	2
Musculoskeletal stiffness	0/25 (0%)	0	2/25 (8%)	2	0/26 (0%)	0
Myalgia	3/25 (12%)	3	0/25 (0%)	0	0/26 (0%)	0
Pain in extremity	1/25 (4%)	1	2/25 (8%)	2	0/26 (0%)	0
Nervous system disorders
Dizziness	1/25 (4%)	1	4/25 (16%)	4	0/26 (0%)	0
Dyskinesia	1/25 (4%)	1	2/25 (8%)	2	0/26 (0%)	0
Headache	2/25 (8%)	2	1/25 (4%)	1	3/26 (11.5%)	3
Tremor	1/25 (4%)	2	2/25 (8%)	2	1/26 (3.8%)	1
Psychiatric disorders
Anxiety	0/25 (0%)	0	3/25 (12%)	3	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/25 (4%)	1	2/25 (8%)	2	0/26 (0%)	0
Vascular disorders
Hypertension	1/25 (4%)	1	2/25 (8%)	2	1/26 (3.8%)	1
Orthostatic hypotension	0/25 (0%)	0	1/25 (4%)	1	2/26 (7.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.