Clinical trial NCT03205488
Conditions: Parkinson Disease
Keywords: Northwestern Nilotinib USA NILO-PD Parkinson Disease
Sponsor: Northwestern University
Start date: 2017-10-16; Completion date: 2019-09-28
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: Moderate to Advanced PD Population Randomized 1:1:1 arm 2: Early/de novo Randomized 2:1
Interventions: intervention 1: Cohort 1:Nilotinib Oral Capsules (150mg or 300mg) intervention 2: Cohort 2: Nilotinib Oral Capsules (dose to be determined from Cohort 1) intervention 3: Placebo
Intervention descriptions: intervention 1: 2 capsules taken once daily intervention 2: 2 capsules taken once daily intervention 3: 2 capsules taken once daily

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
CONFIDENTIAL 
This document is a confidential communication. The recipient agrees that no information contained herein will be 
published or disclosed without written approval. This document may be disclosed to appropriate institutional review 
boards, independent ethics committees, or duly authorized representatives of the U.S. Food & Drug Administration or 
other regulatory authorities as appropriate; under the condition that confidentiality is requested. 
 
 
 
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 (PD) 
 
 
 
 
 
 
Acronym: 
 
 
NILO-PD 
 
IND#: 
 
134973 
 
Version: 
 
4 
 
Clinical Phase: 
 
 IIa 
 
Sponsor: 
 
 Northwestern University Feinberg School of Medicine  
 
 
  
 
Principal Investigator: 
 Tanya Simuni, MD 
 
 Professor of Neurology  
             Director, Parkinson's Disease and Movement Disorders Center  
 
 
             Northwestern University Feinberg School of Medicine  
             Department of Neurology, Abbott Hall, 11th Floor  
             710 North Lake Shore Drive  
             Chicago, Illinois 60611  
 
 
  
Funding: 
 
 
 
Michael J. Fox Foundation for Parkinson’s Research 
 
Supported by: 
 
 
 
Parkinson Study Group 
  
 
 
Clinical Coordination Center: 
 
Clinical Trials Coordinating Center, Rochester, NY 
Data Coordination Center:  
 
Clinical Trials Coordinating Center, Rochester, NY 
Biostatistics Coordination Center: 
Clinical Trials Statistical & Data Management Center, 
 
 
 
 
 
Iowa City, Iowa 
 
 
 
 
 
 
 
  
 
 


Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase ha, 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 (PD)
PROTOCOL APPROVAL
Amendment 1
STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Phase ha, Parallel Group,
Two-Cohort Study to Define the Safety, Tolerability, Clinical and Exploratory Biological Activity
of the Chronic Administration ofNilotinib in Participants with Parkinson’s Disease (PD)
STUDY ACRONYM: N1LO-PD
Tanya Simuni, MD
Principal Investigator
Cynthiçasaceli, MB
ClinicaJria1s Coordinat on Center Administrative Principal Investigator
\)
-tf’-2ë
Date
Page 2 of 198
Version 4
Date: 21 feb2018
Christopher S. Coffey, PhD
Date
Biostatistician
-
\
Date
3/14/18


Protocol 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 (PD) 
 
 
Page 3 of 198 
Version  4 
Date: 21 Feb 2018 
 
INVESTIGATOR AGREEMENT 
 
Amendment 1 
 
 
STUDY ACRONYM: NILO-PD 
IND# 134973 
Protocol Version: 4 
 
I have carefully read this protocol, including all appendices, and the nilotinib package insert, and 
agree that it contains all the necessary information for conducting the study safely. 
 
I will conduct this study in strict accordance with this protocol and according to the current Good 
Clinical Practice (GCP) regulations and guidelines [21 CFR (Code of Federal Regulations) Parts 11, 
50, 54 and 56 and ICH (International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use) Topic E6 (R2)], and local regulatory requirements.  
Any changes in procedure will only be made if necessary to eliminate immediate hazards and/or to 
protect the safety, rights or welfare of participants.   
 
I will provide copies of the protocol and all other information relating to the pre-clinical and prior 
clinical experience, which were furnished to me, to all physicians and other study personnel 
responsible to me who participate in this study.  I will discuss this information with them to assure 
that they are adequately informed regarding the study drug and conduct of the study. 
 
I will ensure that the drugs supplied to me for this study will be used only for administration to 
participants enrolled in this study protocol and for no other purpose. 
 
I agree to keep records on all participant information (case report forms, informed consent 
statements, drug shipment, drug return forms, and all other information collected during the study) 
in accordance with the current GCP, local and national regulations. 
 
 
 
 
Site Number 
 
Printed Site Name 
 
 
 
 
 
 
Printed Site Investigator Name 
 
 
 
 
 
 
Site Investigator Signature 
 
Date 


Protocol 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 (PD) 
 
 
Page 4 of 198 
Version  4 
Date: 21 Feb 2018 
                                                    DOCUMENT HISTORY 
Document 
Version 
Date of 
Issue 
Summary of Changes 
1.0 
05 May 2017 
n/a 
2.0 
15 Jun 2017 
 Remove renal impairment as exclusion criteria  
 Addition of tobacco and caffine exposure questionnaire at 
baseline visit 
  Treatment expectation questionnaire added to SV1 
 Editorial updates 
3.0 
14 Jul 2017 
 Move Diagnostic Features assessment from Baseline to 
Screening Visit 1 
 Move C-SSRS from Baseline to Screening Visit 1 
 Clarify MDS-UPDRS OFF assessment in SOA (Cohort 1 and 
Cohort 2) 
 Editorial Changes 
 
4.0 
21 Feb 2018 
Section 4.2 Inclusion Criteria 
 Cohort 1 inclusion criteria 8a revised to allow treatment with 
monoamine oxidase B (MAO-B) inhibitors provided the 
dose has been stable for 60 days prior to baseline. 
Section 4.3 Exclusion Criteria 
 Added time frame (5yrs) for suicidal history and active 
suicidal ideations. 
 Excluded participants with history uncontrolled electrolytes 
(hypokalemia or hypomagnesaemia) and significant lab 
abnormalities. Clarification added to the exclusion criteia on 
lab abnormalities (to align with dose reduction rules (table 
2).   


Protocol 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 (PD) 
 
 
Page 5 of 198 
Version  4 
Date: 21 Feb 2018 
 Exclusion Criteria #9 clarified to include specific parameters 
for exclusion of first degree AV block. 
 History of bone marrow suppression or evidence of 
persistent myelosuppression added to exclusion criteria to 
align the protocol language with the Dose Adjustment Table. 
 Definition of abnormal pancreatic funciton added- exclusion 
criteria 14. 
 Added time frame ( ≤ 5 years) for history of alcohol abuse 
 Patients treated with MAO-Bs removed from exclusion 
criteria. 
Section 4.4.1 Warnings/Precautions 
 Musculoskeletal Symptoms after Discontinuation added 
based on revised Tasigna Package Insert (12/2017). 
Section 5.1   Recruitment 
 Previous screen failures under protocol version 14Jul2017 
allowed to rescreen if deemed eligbile based on Amendment 
1 inclusion/exclusion criteria.  
Section 6.  Schedule of Activities 
 Clarification provided - if PD medication is increased, MDS-
UPDRS ON assessment is required at next study visit, even 
if not required per visit SOA. 
 Section 9 moved up and combined with Section 6 to contain 
all protocol details related to the schedule of activities (all 
now contained in section 6). The changes/new language is 
highlighted in new section 6 of the revised protocol. 
 Rescreening visit (section 6.2.2): +/- 7 day window added to 
rescreening visit. 
 Added a 10 day window around the coagulation parameters 
for V03 and PW.  Use of local labs allowed (STAT results) 


Protocol 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 (PD) 
 
 
Page 6 of 198 
Version  4 
Date: 21 Feb 2018 
for coagulation parameters, to accomodate for patrticipants 
who are unable to return to clinic 10 days prior to visit. 
 Table 2 – dose reduction/suspension revised: reference 
ranges have been added/revised. 
Appendix 1 
 December 2017 Tasigna Package Inserted 
Editorial Revisions Throughout 
 
 
 
 


Protocol 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 (PD) 
Page 7 of 198 
Version4 
Date:   
PROTOCOL SYNOPSIS 
 
Protocol 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 (PD) 
Acronym/Title 
NILO-PD 
Clinical Phase 
Phase Iia 
Site Investigators 
PSG Site Investigators 
Study Centers 
25 sites located in the US 
Study Period 
Planned enrollment duration: approximately six (6) months for each cohort. 
Duration of post randomization follow up: 
 Cohort 1 (moderate to advanced PD): Six (6) months  
 Cohort 2 (early/de novo PD): Twelve (12) months  
N Participants 
 Cohort 1: N=75 randomized 1:1:1 to once daily dose of nilotinib or 
placebo (150mg: 300mg : placebo) 
 Cohort 2: N=60 randomized 2:1 to once daily dose of nilotinib or placebo 
(the selected dose from cohort 1: placebo). Randomization in this cohort 
will not commence unless a safe & tolerable dose is determined from 
Cohort 1. 
Study Rationale 
A small number of cell and animal models suggest that nilotinib may 
positively affect the alpha (α) -synuclein pathology observed in PD1-8. A 
small open-label clinical study that lacked a placebo control group tested 
the safety and tolerability of nilotinib in PD and dementia with Lewy body 
(DLB) patients for the first time and explored its efficacy 9. Although 
preliminary data appear promising, the study design precludes firm 
conclusions about safety, tolerability, optimal dose or efficacy10. Nilotinib 
is approved by the Food and Drug Administration (FDA) for certain types 
of leukemia but not for PD. An opportunity exists to rigorously establish 
the safety, tolerability as well as optimal dose, of nilotinib to enable 
future definitive efficacy studies in PD patients. 
Primary Study Objective 
To assess the safety and tolerability of the daily oral administration of 
nilotinib (150-300mg once daily) in moderate/advanced and early/de novo 
PD participants. 
Key Secondary 
Objective 
(Moderate/Advanced 
Cohort) 
To conduct a futility analysis within each treated group in Cohort I. This 
futility analysis will compare the observed change in MDS-UPDRS part III 
between baseline and 6 months to the observed change from the 
clintrials.gov NCT02281474 nilotinib study in order to determine whether 
we can rule out the large change previously reported – i.e., declare 
“futility”. 
Secondary Objectives 
 To establish the degree of symptomatic effect of nilotinib as measured 
by the change in MDS-UPDRS part III between 1) baseline and Visit 2 
(1 month) and 2) final visit on study drug and 30 days off study drug in 
cohorts 1 and 2.  


Protocol 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 (PD) 
 
 
Page 8 of 198 
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Date: 21 Feb 2018 
 To explore the impact of nilotinib on progression of PD disability as 
measured by the change in the MDS-UPDRS Part III in the defined 
medications OFF state in cohort 1 (moderate/advanced PD) between 
baseline and 6 months. 
 To establish the impact of nilotinib on progression of PD disability as 
measured by the change in the MDS-UPDRS Part III score in Cohort 
2 (early/de novo PD) between baseline and 12 months or time of 
initiation of symptomatic therapy (ST), whichever comes first. 
Exploratory  
Clinical Measures 
The change in the following measures of disability, quality of life and 
functional status from baseline to final visit will be analyzed: 
Motor disability 
 The change in MDS-UPDRS total score. For participants on ST, MDS-
UPDRS part III assessments will be collected in the defined medications 
OFF (approximately 12 hours post dose) and ON (based on the 
participant/site investigator defined best ON and/or approximately 1 
hour after dose of ST) state 
 The change in the ambulatory capacity (sum of 5 MDS-UPDRS 
questions:(falling, freezing, walking, gait, postural stability) 
 Analysis of ST utilization as measured by levodopa equivalence 
dose 
 Severity of motor complications as measured by MDS-UPDRS IV 
subscale (complications of therapy) 
 
Cognitive disability 
 
The change in the cognitive function as measured by the change in 
Mattis Dementia Rating Scale – 2 (DRS-2)  
 
Sleep function  
 The change in sleep quality as measured by the Parkinson’s Disease 
Sleep Scale (PDSS)  
 
Measures of global disability 
 Clinician and Participant Global Impression of Change Score (CGI) 
 
Measures of functional status and quality of life 
 The change in the MDS-UPDRS Motor and Non-Motor 
Experiences of Daily Living subscores 
 The change in the modified Schwab and England scale (S&E) 
 The change in Parkinson Disease Quality of Life Questionnaire 39 
(PDQ-39) 
 The change in European Quality of Life Scale (EQ-5D) 


Protocol 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 (PD) 
 
 
Page 9 of 198 
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Date: 21 Feb 2018 
 
Blindedness and Treatment Expectations assessments  
 Questionnaires completed by the Site Investigator and Participant  
 
Pharmacology and Biomarkers  
Pharmacokinetics (PK) and Pharmacodynamics: 
o To determine the serum PK of nilotinib in patients with PD. 
o To investigate the ability of nilotinib to cross the blood brain barrier 
in patients at a dose(s) that is tolerable and safe as measured by 
dose-dependent increases in unbound nilotinib concentrations in the 
cerebrospinal fluid (CSF). 
o To investigate factors that could affect the PK of nilotinib such as 
age, sex, PD severity, race/ethnicity. 
o To investigate the ability of nilotinib to engage its known molecular 
target(s) at a dose that is tolerable and safe as measured by 
biomarkers of pathway inhibition in the serum and CSF (including 
but not limited to reduction in phospho-cAbl tyrosine kinase). 
o To investigate the relationship between nilotinib exposures in serum 
and CSF with its ability to engage known molecular target(s) 
[measured by biomarkers of pathway inhibition in the serum and CSF 
(including but not limited to reduction in phosphor-cAbl).  
To explore impact of nilotinib on: 
o Dopaminergic system as measured by an increase in dopamine 
and its metabolites in CSF (e.g., homovanilic acid (HVA) level) 
o Other biomarkers linked to potential mechanism of 
neuroprotection (including but not limited to CSF α -synuclein, 
total tau, phosphorylated -tau, etc.) 
Store additional blood/serum/plasma/DNA/CSF samples for future research. 
Study Population 
Cohort 1: Participants with moderate/advanced PD (see inclusion and 
exclusion criteria) 
Cohort 2: Participants with early untreated PD (see inclusion and 
exclusion criteria) 
Study Design 
This is a Phase IIa, multicenter, randomized, double-blind, placebo-
controlled, parallel group study of nilotinib in participants with moderate to 
advanced (Cohort 1) and early/de novo (Cohort 2) PD.  The study will 
define the safety, tolerability, and exploratory clinical and biological 
activity of the chronic administration of nilotinib in participants with PD.   
 
Cohort 1 will treat participants with moderate/advanced PD. Participants 
will be randomized in a 1:1:1 ratio into one of the following treatment 
arms: 
 nilotinib 150mg  
 nilotinib 300mg  
 matching placebo 


Protocol 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 (PD) 
 
 
Page 10 of 198 
Version  4 
Date: 21 Feb 2018 
 
Study duration will be approximately 8.5 months from screening to post 
drug evaluation; treatment period from randomization to final on treatment 
visit will be 6 months.  
 
A primary outcome analysis for safety and tolerability will be conducted 
after 6 months of treatment. The results will determine whether either of 
the doses are sufficiently safe and tolerated to justify moving forward with 
Cohort 2. 
 
Cohort 2 will treat early/de novo PD participants.  Participants will be 
randomized in a 2:1 ratio as follows: 
 nilotinib – selected dose, based on safety and tolerability in Cohort 1. 
or 
 matching placebo  
 
Study duration will be approximately 14.5 months from screening to post 
drug evaluation; treatment period from randomization to final on study 
drug visit will be 12 months. 
 
Participants in both Cohorts will be dosed orally once daily (QD) in a 
fasted state (no food consumed for at least 2 hours before and at least one 
hour after dosing). 
Number of Participants 
The combined two cohorts will screen approximately one hundred eighty 
(180) participants in order to randomize a total of approximately one 
hundred thirty-five (135) participants.  Approximately seventy-five (75) 
participants will be randomized into Cohort 1 and approximately sixty (60) 
participants will be randomized into Cohort 2. 
Main Inclusion Criteria 
Cohort 1 and 2 
1. Participants with idiopathic PD based on the UK Brain Bank diagnostic 
criteria. 
2. Participants of any race and either gender, age 40-79 on the date the 
informed consent form (ICF) is signed and with the capacity to provide 
voluntary informed consent. 
3. Participants able to read and understand English and the ICF and are 
willing to comply with all study procedures, treatment and follow-up. 
4. Participants must be willing to undergo multiple lumbar punctures (LP) 
as outlined in the schedule of activities. 
5. Participants who are taking any central nervous system acting 
medications (e.g., benzodiazepines, antidepressants, hypnotics) must be 
on a stable regimen for at  l east  30 days prior to the baseline visit. 
 
Inclusion criteria specific for Cohort 1 
6a.  Participants with a diagnosis of PD duration > 5 years. 


Protocol 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 (PD) 
 
 
Page 11 of 198 
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Date: 21 Feb 2018 
7a.  Participants with Hoehn & Yahr scale (H&Y) stage > 2 and < 4 in the 
ON state. 
8a.  Participants 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.  Participants with a diagnosis of PD duration < 3 years. 
7b.  Participants with H&Y stage < 2. 
8b.  Participants who are currently NOT receiving 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. 
Main Exclusion Criteria 
Cohorts 1 and 2  
1. Participants with a diagnosis of atypical parkinsonism. 
2. Participants with a history of bipolar disorder or major depression, or 
the presence of active depression defined as a Beck Depression 
Inventory II (BDI-II) score >17. 
3. Participants with a history of a suicide attempt within the last 5 years 
or active suicidal ideations  
4. Participants with a history of schizophrenia or schizophrenia spectrum 
disorders  
5. Participants with a history of uncontrolled hypokalemia or 
hypomagnesaemia, or laboratory evidence of such on screening 
6. Participants with evidence of other significant laboratory abnormalities 
which in the opinion of the site investigator or clinical monitor should 
preclude study participation 
7. Participants with history of cardiac arrhythmia, long QT 
syndrome, or a corrected QT interval (QTcF) ≥450ms at screening    
visit 1 
8. Participants treated within 30 days prior to randomization, or planned 
use during the trial with any of the following classes of Concomitant 
drugs (see full lise in Appendix 2): 
a. Class IA or III antiarrhythmic drugs  
b. QT prolonging drugs  
c. Strong CYP3A4 inhibitors or inducers  
d. Anticoagulants 
e. Proton pump inhibitors 
9. Participants with a clinical history, or the active presence of a 


Protocol 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 (PD) 
 
 
Page 12 of 198 
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Date: 21 Feb 2018 
cardiovascular condition including: 
a.  Myocardial infarction, known cardiac ischemia, or angina 
b.  Cerebrovascular event (e.g. embolic stroke) 
c.  Congestive heart failure, symptomatic first degree 
atrioventricular (AV) block  or  PR interval >220msec and all 
second and third degree AV block, sick sinus syndrome, or other 
serious cardiac rhythm disturbances 
d.  Any history of Torsade de Pointes 
e.  Any other cardiovascular history that, in the opinion of the Site 
Investigator, will preclude study participation 
10. Participants with a history of hepatic disease, including abnormal liver 
function defined as Total Bilirubin > 1.5 times upper limit of normal,  
Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase 
(ALT) > 2 times the upper limit of the normal, or coagulopathy with 
INR > 1.4 
11. 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 
12. Participants with a prior history of epilepsy or a seizure within the last 
6 months 
13. Participants with an active malignancy, or history of a neoplasm in the 
prior 5 years (excluding basal/squamous cell carcinoma) 
14. Participants with a prior history of pancreatitis, total gastrectomy or 
evidence of abnormal pancreatic function defined as elevated amylase 
and/or lipase > 2 times upper limit of normal  
15. Participants diagnosed with 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 
16. Participants with a history of drug or alcohol abuse ≤ 5 years  
17. Participants who have an active medical or psychiatric condition that in 
the opinion of the Site Investigator should preclude study participation 
18. Participants with previous surgical management for Parkinson’s 
19. Participants participating in any drug or device clinical investigation 
concurrently or within 30 days prior to screening for this study 
20. Participants with severe lactose and galactose intolerance 
21. Participants with a known hypersensitivity or contraindication to study 
drugs (nilotinib or matching placebo) or their components. 
22. 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  
 


Protocol 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 (PD) 
 
 
Page 13 of 198 
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Date: 21 Feb 2018 
Exclusion criteria specific for Cohort 1 
23a. Participants with a 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 
23b. Participants with a MoCA score < 26 at baseline 
24b. Participants treated within 60 days prior to randomization or expected 
to require treatment within 3 months from randomization with any ST 
(including levodopa, dopamine agonists and MAO-B inhibitors) 
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 
Route and Dosage Form 
Nilotinib versus matching placebo administered orally QD 
Dosage 
Nilotinib 150mg, 300mg and matching placebo 
Duration of Treatment 
Cohort 1 = 6 months 
Cohort 2 = 12 months 
Primary Outcome 
Measure(s) 
 
 
To establish the safety and tolerability of nilotinib (150mg and 300mg 
orally QD) versus placebo in PD patients (moderate/advanced & early/de 
novo) 
 Tolerability will be judged by the proportion of participants enrolled in 
a dosage group able to complete the study on their originally assigned 
dosage. Tolerability of each active arm will be compared to placebo 
group. 
Safety will be primarily assessed based on a direct comparison of 
treatment-related serious adverse events across the treatment groups.   
Sample Size 
Considerations 
We assumed at least 90% of participants on placebo will meet definition of 
“tolerability” and determined required sample size to detect an absolute 
difference of 30% with respect to tolerability for active treatment arms 
versus placebo (in other words if 60% or fewer participants on an active 
treatment arm meet the stated definition of tolerability). Under this 
assumption and considering a one-sided test with alpha = 0.05, a total of 25 
participants per group provides 80% power for the moderate/advanced 
cohort.  Similarly, a sample size of 40 participants on the selected dose and 
20 participants on placebo for the early/de novo second cohort provides 
similar power. With three groups in the moderate/advanced initial cohort, 
and two groups in the early/de novo second cohort, this leads to a total 
sample size of 135 participants. 
 
For the major secondary objective, based on results from Table 2 in the 
Pagan et al9  publication, the mean change over 6 months in the 150mg 


Protocol 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 (PD) 
 
 
Page 14 of 198 
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Date: 21 Feb 2018 
group was 7.0 – with a standard deviation of 12.9.  Using these estimates, 
we computed the power of the currently proposed study to detect “futility” 
based on comparisons of the change within the dosage groups themselves.  
Converting from the UPDRS used in the Pagan et al study9, to the MDS-
UPDRS proposed for this study, we will test the following hypothesis in 
the 150mg group: 
H0: δ ≤ -9.8 (7 x 1.4) vs. HA: δ > -9.8 
Since this is an early phase exploratory study, we assume an alpha level of 
0.10 for this one-sided hypothesis test.  Based on these assumptions, if the 
observed reduction is half that observed in the prior study (-3.5), then the 
study has marginal power (52%) to declare futility.  If there is no observed 
reduction associated with treatment, the study has 92% power to declare 
futility.  Thus, this test of futility will have adequate power mainly if the 
direction of effect is in the opposite direction from that observed in the 
previous study (i.e., if there is no reduction, only a potentially smaller 
increase in MDS-UPDRS compared to placebo).  Since bigger effects were 
observed over 6 months for the 300mg group, the study has adequate 
power for addressing futility in the 300mg group in a similar manner. 
 
 
 


Protocol 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 
(PD) 
Page 15 of 198 
Version4 
Date:   
 
 
SCHEDULE OF ACTIVITIES - Cohort 1 
Cohort 1 
 
 
Screening 
 
 
Baseline 
Titration Phase 
Maintenance Period 
Final 
visit 
On drug 
Post-Drug Evaluation 
 
Unsched 
Visit 
 
 
Premature 
W/Db 
 
 
SC 1 
 
Day 
-30-14d 
SC 2 
 
Day 
-14-7d 
Visit BL 
 
Day 
0 
SV 1 
 
Day 
7+3d 
V01 
 
Day 
14+3d 
V02 
 
Day 
30+3d 
SV 2 
 
Day 
60+7d 
V03 
3mo 
Day 
90+7d 
SV 3 
 
Day 
120+7d 
SV 4 
 
Day 
150+ 7d 
V04 
6mo 
Day 
180+7d 
V05 
1 mo post 
+30 +7d 
post 
V06 
(FNL) 
2 mo 
 post 
+60 +7d 
post 
(U01, U02, 
etc.) 
 
PW 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Entry Numbers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-economic form  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Neuro History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck Depression Inventory 
(BDI) – II 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
Physical Exam 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
Neurological exam  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Fundoscopy  exam  
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 Hoehn & Yahr Scale 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
X 
MDS-UPDRS I-IV ON # 
 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
MDS-UPDRS III OFF  
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
X 
Modified Schwab & England 
scale  
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
PD diagnostic features  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Primary Dx form  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Mattis Dementia Scale - 2  
 
 
X 
 
 
 
 
Xd 
 
 
X 
 
 
 
Xd 
PDQ-39 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
EQ-5D 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
CGI I and P 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
C-SSRS 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
PDSS  
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 


Protocol 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 (PD) 
 
 
Page 16 of 198 
Version  4 
Date: 21 Feb 2018 
Cohort 1 
 
 
Screening 
 
 
Baseline 
Titration Phase 
Maintenance Period 
Final 
visit 
On drug 
Post-Drug Evaluation 
 
Unsched 
Visit 
 
 
Premature 
W/Db 
 
 
SC 1 
 
Day 
-30-14d 
SC 2 
 
Day 
-14-7d 
Visit BL 
 
Day 
0 
SV 1 
 
Day 
7+3d 
V01 
 
Day 
14+3d 
V02 
 
Day 
30+3d 
SV 2 
 
Day 
60+7d 
V03 
3mo 
Day 
90+7d 
SV 3 
 
Day 
120+7d 
SV 4 
 
Day 
150+ 7d 
V04 
6mo 
Day 
180+7d 
V05 
1 mo post 
+30 +7d 
post 
V06 
(FNL) 
2 mo 
 post 
+60 +7d 
post 
(U01, U02, 
etc.) 
 
PW 
Visit 
Tobacco & Caffeine Q 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blindedness Q 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Tx expectation Q 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
ECG-12 LEAD 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CBC 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comp chem panel 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameters 
X 
 
 
 
 
 
 
Xc 
 
 
X 
 
 
 
XC 
Lipid panel 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum lipase and amylase  
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Lumbar puncture a 
 
X 
 
 
 
 
 
X 
 
 
 
X* 
 
 
X 
CSF PK 
 
 
 
 
 
 
 
2hr 
 
 
 
 
 
 
 
Serum PK 
 
 
 
 
 
trough 
(1) 
trough 
(1) 
Random 
(1) 
trough 
and 
2hr(2) 
Random 
(1) 
Random 
(1) 
2-5 hr 
(1) 
 
 
 
Random 
(1) 
HIV/HBV/HCV Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA Sample* 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Blood Biomarker panel 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
CSF Biomarker panel 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Adverse Events  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Drug Therapy 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Dose titration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dose management log 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Check drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
a Initial LP will be performed 7 to 14 days prior to the Baseline visit -  after coagulation parameters, other safety labs and fundus exam results have been reviewed, considered normal and participant 
continues to qualify for the study. Subsequent LPs can be performed within the visit window prior to or after the scheduled visit (except V03) - after coagulation parameters and other safety lab results 
from previous visit have been reviewed and are normal. Fundoscopy must be completed prior to LP.  LP for Visit 3 must be conducted on the same day all other assessments. 


Protocol 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 (PD) 
 
 
Page 17 of 198 
Version  4 
Date: 21 Feb 2018 
bParticipants permanently discontinued from study drug after suspension or  intolerance must complete the Premature Withdrawal (PW) visit on return to clinic.  Participants will be encouraged to 
complete the 30d and 60d post drug evaluation visits V05 and V06. 
cParticipants must have coagulation parameters drawn  within 10 days of their V03 and/or PW Lumbar Puncture. The results must be made available to the site investigator prior to performing the 
lumbar puncture.   
d Alternate form 
* Optional 
#      MDS-UPDRS ON required if participant increases PD medications -  even if not part of SOA for visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 18 of 198 
Version  4 
Date: 21 Feb 2018 
.SCHEDULE OF ACTIVITIES  -  Cohort 2  
Cohort 2 
Screening 
Base
-line 
Titration Phase 
Maintenance Period 
Final 
visit 
On 
drugc 
Sympto-
matic 
Therapyd 
Post-Drug 
 Eval 
Un- 
Sched 
Visit 
Pre-
mature 
W/Dc 
 
SC 1 
 
 
Day 
-30  
-14d 
SC 2 
 
 
Day 
-14 
-7d 
BL 
 
 
Day 
0 
SV1 
 
 
Day 
7 
+3d 
 
V01 
 
 
Day 
14 
+3d 
V02 
 
 
Day 
30 
+3d 
SV2 
 
 
Day 
60 
+7d 
 
V03 
3Mo 
 
Day 
90 
+7d 
SV3 
 
 
Day 
120 
+7d 
 
SV4 
 
 
Day 
150 
+7d 
 
V04 
6Mo 
 
Day 
180 
+7d 
SV5 
 
 
Day 
210 
+7d 
 
SV6 
 
 
Day 
240 
+7d 
 
V05 
9Mo 
 
Day 
270 
+7d 
 
V06 
12Mo 
 
Day 
365 
+7d 
As  
Needed 
V07 
 
 
1 mo post 
+30d 
+7d post 
V08  
(FNL) 
 
2mo post 
+60 d 
+7d post 
(U01, 
U02, 
etc.) 
 
PW 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Entry 
Numbers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-economics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Neuro History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck Depression 
Inventory (BDI)- II 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
Physical exam 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
Neurological exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
Fundoscopy exam 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Xe 
X 
 
 
X 
 Hoehn & Yahr 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
MDS-UPDRS I-IV 
ONa# 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
X 
MDS-UPDRS III OFF 
 
 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Assess need for 
symptomatic therapy 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Modified Schwab & 
England scale 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
PD diagnostic features 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
Primary Dx form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
Mattis Dementia Scale-2 
 
 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
X 
Xg 
 
 
 
Xg 
PDQ-39 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
EQ-5D 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
CGI I and P 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
C-SSRS 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
PDSS 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 


Protocol 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 (PD) 
 
 
Page 19 of 198 
Version  4 
Date: 21 Feb 2018 
Cohort 2 
Screening 
Base
-line 
Titration Phase 
Maintenance Period 
Final 
visit 
On 
drugc 
Sympto-
matic 
Therapyd 
Post-Drug 
 Eval 
Un- 
Sched 
Visit 
Pre-
mature 
W/Dc 
 
SC 1 
 
 
Day 
-30  
-14d 
SC 2 
 
 
Day 
-14 
-7d 
BL 
 
 
Day 
0 
SV1 
 
 
Day 
7 
+3d 
 
V01 
 
 
Day 
14 
+3d 
V02 
 
 
Day 
30 
+3d 
SV2 
 
 
Day 
60 
+7d 
 
V03 
3Mo 
 
Day 
90 
+7d 
SV3 
 
 
Day 
120 
+7d 
 
SV4 
 
 
Day 
150 
+7d 
 
V04 
6Mo 
 
Day 
180 
+7d 
SV5 
 
 
Day 
210 
+7d 
 
SV6 
 
 
Day 
240 
+7d 
 
V05 
9Mo 
 
Day 
270 
+7d 
 
V06 
12Mo 
 
Day 
365 
+7d 
As  
Needed 
V07 
 
 
1 mo post 
+30d 
+7d post 
V08  
(FNL) 
 
2mo post 
+60 d 
+7d post 
(U01, 
U02, 
etc.) 
 
PW 
Visit 
Tobacco & Caffeine Q 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blindedness Q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xhi 
X 
 
 
X 
Tx expectation Q 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Xij 
X 
X 
 
X 
ECG-12 LEAD 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CBC 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comp chem  panel 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameters 
X 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
X 
Xfh 
 
 
 
X C 
Lipid panel 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum Lipase and 
amylase  
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Lumbar puncture b 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
LP per 
SOA of 
visit 
replacing 
X* 
 
 
X 
CSF PK 
 
 
 
 
 
 
 
2 hr 
 
 
 
 
 
 
 
 
 
 
 
 
Serum PK 
 
 
 
 
trough  
(1) 
troug
h   
(1) 
Rando
m (1) 
trough 
and 
2hr(2) 
Rando
m (1) 
Rando
m (1) 
2-5hr 
(1) 
Rando
m (1) 
Rando
m  (1) 
trough 
(1) 
trough 
(1) 
PK per 
SOA of 
visit 
replacing 
 
 
 
Rando
m (1) 
HIV/HBV/HCV Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA Sample* 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
 
X 
 
X 
Blood Biomarker panel 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Xhi 
X 
 
 
X 
CSF Biomarker panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Xe 
X 
 
 
X 
Adverse Events  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Drug Tx 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Xefg 
 
 
 
 
Dose Titration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose management log 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 20 of 198 
Version  4 
Date: 21 Feb 2018 
Cohort 2 
Screening 
Base
-line 
Titration Phase 
Maintenance Period 
Final 
visit 
On 
drugc 
Sympto-
matic 
Therapyd 
Post-Drug 
 Eval 
Un- 
Sched 
Visit 
Pre-
mature 
W/Dc 
 
SC 1 
 
 
Day 
-30  
-14d 
SC 2 
 
 
Day 
-14 
-7d 
BL 
 
 
Day 
0 
SV1 
 
 
Day 
7 
+3d 
 
V01 
 
 
Day 
14 
+3d 
V02 
 
 
Day 
30 
+3d 
SV2 
 
 
Day 
60 
+7d 
 
V03 
3Mo 
 
Day 
90 
+7d 
SV3 
 
 
Day 
120 
+7d 
 
SV4 
 
 
Day 
150 
+7d 
 
V04 
6Mo 
 
Day 
180 
+7d 
SV5 
 
 
Day 
210 
+7d 
 
SV6 
 
 
Day 
240 
+7d 
 
V05 
9Mo 
 
Day 
270 
+7d 
 
V06 
12Mo 
 
Day 
365 
+7d 
As  
Needed 
V07 
 
 
1 mo post 
+30d 
+7d post 
V08  
(FNL) 
 
2mo post 
+60 d 
+7d post 
(U01, 
U02, 
etc.) 
 
PW 
Visit 
Check drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
a MDS-UPDRS ON to be completed once the participants start symptomatic therapy during the visits where it is included in the SOA. Initiation of any PD medication will warrant OFF/ON assessment   
b Initial LP will be performed 7 to 14 days prior to the Baseline visit -  after coagulation parameters, other safety labs and fundus exam results have been reviewed, considered normal and participant 
continues to qualify for the study. Subsequent LPs can be performed within the visit window prior to or after the scheduled visit (except V03) - after coagulation parameters and other safety lab results 
from previous visit have been reviewed and are normal. Fundoscopy must be completed prior to LP.  LP for Visit 3 must be conducted on the same day all other assessments. 
c Participants permanently discontinued from study drug after suspension or intolerance must complete the Premature Withdrawal (PW) visit on return to clinic. Participants will be encouraged to 
complete the 30d and 60d  post drug evaluation visits V07 and V08. 
d Symptomatic Therapy (ST) visits should be performed prior to initiation of ST and ideally should replace the regularly scheduled clinic visits using the designated schedule of activities. 
e  If ST visit is replacing V03; f If ST visit is replacing V04; g If replacing V05; h If replacing V06; iIf replacing V07; j If replacing V08 
f Participants must have coagulation parameters drawn  within 10 days of their V03 and/or PW Lumbar Puncture. The results must be made available to the site investigator prior to perfoming the lumbar 


Protocol 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 (PD) 
Page 21 of 198 
Version4 
Date:   
puncture.   
g     Alternate form (as applicable) 
*  Optional  
#      MDS-UPDRS ON required if participant increases PD medications -  even if not part of SOA for visit. 
 
 
 
 
Protocol Synopsis ........................................................................................................... 7 
Table 1. List of abbreviations and definition of terms ................................................... 28 
1. INTRODUCTION ....................................................................................................... 32 
1.1 
Background ........................................................................................................ 32 
1.2 
Clinical Experience ............................................................................................. 33 
2. STUDY OBJECTIVES ............................................................................................... 34 
2.1 Primary Objective ................................................................................................... 34 
2.2 
Key Secondary Objective ..................................................................................... 35 
2.3 
Additional Secondary Objectives ......................................................................... 35 
2.4 
Exploratory Objectives ........................................................................................ 35 
2.4.1 Clinical Measures ............................................................................................... 35 
2.4.2 Pharmacology and biomarkers objectives ............................................................ 36 
3. STUDY DESIGN ....................................................................................................... 37 
3.1      Overview ........................................................................................................... 37 
3.2      Discussion of Study Design ............................................................................... 39 
3.2.1   Rationale for Study ........................................................................................... 39 
3.2.2 Rationale for the study design ............................................................................. 39 
3.2.3 Nilotinib .............................................................................................................. 40 
3.2.4 Rationale for Dosage ........................................................................................... 41 
4. STUDY POPULATION ............................................................................................... 42 
4.1 
Participant Numbers ........................................................................................... 42 
4.2     Inclusion Criteria ............................................................................................... 42 
4.3     Exclusion Criteria .............................................................................................. 43 
4.4     Discussion of Participant Characteristics ........................................................... 45 
4.4.1  Warnings/Precautions ....................................................................................... 45 
5. STUDY PROCEDURES ............................................................................................. 51 
5.1    Recruitment ........................................................................................................ 51 
6. SCHEDULE OF ACTIVITIES ..................................................................................... 52 
6.1 
Participant Identification (ID) Number ................................................................. 53 
6.2 
Screening Visits (SC1/SC2): Cohort 1 ................................................................. 53 


Protocol 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 (PD) 
 
 
Page 22 of 198 
Version  4 
Date: 21 Feb 2018 
6.2.1 Screening Visit 1 -  SC1: Cohort 1 ....................................................................... 54 
6.2.2  Rescreening ....................................................................................................... 55 
6.2.3  Screening Visit 2- SC2: Cohort 1 ........................................................................ 55 
6.3     Baseline Visit – BL (Day 0) – Cohort 1 ................................................................ 56 
6.4     Safety Visits SV1 through SV4 – cohort 1 ........................................................... 58 
6.5     Visit 01 (Day 14 + 3d) – V01 – Cohort 1 .............................................................. 59 
          Visit 02 (Day 30 + 3d) – V02 – cohort 1 .............................................................. 59 
6.6     Visit 03 (Day 90 + 7d) – V03 – cohort 1 .............................................................. 60 
6.7     Visit 04 (Day 180+7d) – V04 – Cohort 1 (Final “On Drug” Visit) .......................... 63 
6.8     Visit 05 (30 Days post-treatment ± 7 d) – V05 – Cohort 1 ................................... 64 
          Visit 06 (60 Days post-treatment ± 7d) – V06 – End of Study ............................. 64 
6.9     Unscheduled Visits – Visit U01, U02, etc. – Cohort 1 ......................................... 66 
6.10   Premature Withdrawal Visit - Visit PW – Cohort 1 .............................................. 67 
6.11   Procedures for the participants who Discontinue the study drug for safety and 
intolerability  reasons ........................................................................................ 70 
6.12   Screening Visit 1 (Visit SC 1) – Cohort 2 (EARLY/de novo PD) ............................ 70 
6.12.1 Rescreening ...................................................................................................... 72 
6.13   Screening Visit 2 ................................................................................................ 72 
6.14   Baseline Visit – BL (Day 0) – Cohort 2 ................................................................ 73 
6.15   Safety VISITS - SV 1 through Sv 6 – Cohort 2 .................................................... 75 
6.16   Visit 01 (Day 14 + 3d) – V01 – Cohort 2 .............................................................. 76 
          Visit 02 (Day 30 + 3d) – V02 – Cohort 2 ............................................................. 76 
6.17   Visit 03 (Day 90 +7d) – V03 – Cohort 2 ............................................................... 77 
6.18   Visit 04 (Day 180 ±7d) – V04 – Cohort 2 ............................................................. 79 
6.19   Visit 05 (Day 270 ± 7d) – V05 – Cohort 2 ............................................................ 82 
6.20   Visit 06 (Day 365 ± 7d) – V06 – Cohort 2 (Final “On Drug” Visit) ........................ 84 
6.21   Visit 07 (30 Days post-treatment ± 7 d) – V07 – Cohort 2 ................................... 86 
          Visit 08 (60 days post-treatment + 7d) – V08 – COHORT 2 End of Study............ 86 
6.22   Unscheduled Visits – Visit U01, U02, etc. – Cohort2 .......................................... 88 
6.23   Premature Withdrawal Visit - Visit PW – Cohort 2 .............................................. 89 
6.24   Symptomatic therapy Visit ................................................................................. 92 


Protocol 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 (PD) 
 
 
Page 23 of 198 
Version  4 
Date: 21 Feb 2018 
6.25   Procedures for participants who Discontinue study drug for safety and 
intolerability reasons ......................................................................................... 94 
7. STUDY DRUG ADMINISTRATION/ASSIGNMENT ..................................................... 95 
7.1 
Study Drug ......................................................................................................... 95 
7.2 
Labeling .............................................................................................................. 95 
7.3 
PHARMACIST/Site Drug Handling Instructions .................................................. 96 
7.4 
Storage ............................................................................................................... 97 
7.5 
Accountability of Study Drug Supplies ................................................................ 97 
7.6 
participant Number Assignment/Enrollment ...................................................... 97 
7.7 
Coding/Emergency Drug Disclosure ................................................................... 98 
7.8 
Dosage of Study Drug ......................................................................................... 99 
7.8.1  Rules for Study Drug Administration ............................................................... 101 
7.9 
Rules for Dose Reduction .................................................................................. 102 
7.9.1   Rules for Dose Reduction for Intolerability ...................................................... 102 
7.9.2   Rules for Dose Reduction/ Suspension for Safety Reasons ............................. 102 
7.10  Rules for Study Drug Re-challenge ................................................................... 104 
7.10.1 Rules for Dose Re-challenge in Case of Intolerability ....................................... 104 
7.10.2.Rules for Dose Suspension and Re- challenge for Safety Reasons ................... 105 
7.10.3 Rules for Dose Re-challenge in Cases not Related to Safety or Tolerability ...... 105 
8. CONCOMITANT MEDICATIONS ............................................................................. 106 
8.1 
Allowed Concomitant Medications ..................................................................... 106 
8.2 
Cautionary and Exclusionary Medications with Nilotinib .................................. 107 
9. ASSESSMENTS ...................................................................................................... 109 
9.1     Primary Variables ............................................................................................ 109 
9.2     Documentation of Parkinson Disease ............................................................... 109 
9.3     Safety Assessments .......................................................................................... 109 
9.3.1  Clinical Variables ............................................................................................. 109 
9.3.2  Medical History ................................................................................................ 110 
9.3.3  Physical Examination ....................................................................................... 110 
9.3.4  Neurological Examination ................................................................................ 110 
9.3.5  Vital Signs, Weight, Height ............................................................................... 110 


Protocol 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 (PD) 
 
 
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9.3.6  Clinical Laboratory Tests .................................................................................. 110 
9.3.7  Fundoscopy Exam ............................................................................................ 111 
9.3.8   Lumbar puncture (LP) ..................................................................................... 111 
9.3.9  Electrocardiogram (ECG) .................................................................................. 112 
10. CLINICAL ASSESSMENTS .................................................................................... 112 
10.1.  Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS)................ 112 
10.2   Modified Schwab & England Activities of Daily Living    Scale .......................... 113 
10.3   Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) scale ............... 114 
10.4   Hoehn and Yahr Scale ...................................................................................... 114 
10.5   Montreal Cognitive Assessment (MoCA) ............................................................ 114 
10.6   Primary Diagnosis Assessment ......................................................................... 114 
10.7   PD Features ..................................................................................................... 115 
10.8   Beck Depression Inventory-II (BDI-II) ............................................................... 115 
10.9   Parkinson’s Disease Sleep Scale (PDSS) ........................................................... 115 
10.10 European Quality of Life Scale (EQ-5D) ............................................................ 115 
10.11 Blindedness Evaluation .................................................................................... 115 
10.12 C-SSRS (baseline and since last visit) ............................................................... 116 
10.13 Mattis Dementia Rating Scale (DRS-2) ............................................................. 116 
10.14 Clinical Global Impression scale ....................................................................... 116 
10.15 PD – Study Treatment Expectancy Questionnaire ............................................ 116 
10.16 Additional Assessments ................................................................................... 117 
10.16.1 Assessment of Participant Compliance .......................................................... 117 
10.16.2 Assess need for Symptomatic Therapy (Cohort 2) .......................................... 117 
10.16.3 Pharmacokinetic Assessments ...................................................................... 117 
10.16.4 Biomarkers Assessments .............................................................................. 118 
11. INTERCURRENT ILLNESS .................................................................................... 119 
12.  PREMATURE WITHDRAWALS/DROPOUTS ......................................................... 120 
13. ADVERSE EVENTS .............................................................................................. 122 
13.1 Adverse Event (AE) Definition ............................................................................ 122 
13.2  Serious Adverse Events (SAE) ........................................................................... 123 
13.3  Adverse Event Definitions ................................................................................. 124 


Protocol 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 (PD) 
 
 
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13.4  Identifying and Recording of Adverse Events ..................................................... 124 
13.5  Adverse Event Causality Definitions .................................................................. 125 
13.6  Adverse Event Severity Definitions .................................................................... 126 
13.7   Reporting Serious Adverse Events .................................................................... 126 
13.8 SERIOUS ADVERSE EVENTS EXPECTEDNESS TO THE STUDY       
INTERVENTION ............................................................................................... 127 
13.9 Review of Adverse Events ................................................................................... 128 
13.10   Follow-Up of Unresolved Events ..................................................................... 128 
13.11   Reporting of Pregnancy .................................................................................. 129 
13.12   Reportable Events .......................................................................................... 129 
14. STATISTICAL CONSIDERATIONS ......................................................................... 130 
14.1     General Design Issues .................................................................................... 130 
14.1.1  Summary of Study Design – Cohort 1 ............................................................ 130 
14.1.2  Summary of Study Design – Cohort 2 ............................................................ 131 
14.1.3  Randomization ............................................................................................... 132 
14.2     Outcomes ....................................................................................................... 132 
14.2.1  Primary Outcome ........................................................................................... 132 
14.2.2  Secondary Outcome ....................................................................................... 132 
14.3     Analysis Plan – Cohort 1 ................................................................................ 133 
14.3.1  Primary Hypotheses ....................................................................................... 133 
14.3.2  Decision Algorithm Based on Primary Hypotheses ......................................... 134 
14.3.3  Key Secondary Objective ................................................................................ 135 
14.3.4  Other Secondary Objectives ........................................................................... 136 
14.3.5  Exploratory Objectives ................................................................................... 137 
14.4     Analysis Plan – Cohort 2 ................................................................................ 137 
14.4.1  Primary Hypotheses ....................................................................................... 137 
14.4.2  Secondary Objectives ..................................................................................... 138 
14.4.3  Exploratory Objectives ................................................................................... 139 
14.5     Sample Size Justification ............................................................................... 139 
14.5.1  Sample Size – Cohort 1 .................................................................................. 139 
14.5.2  Sample Size – Cohort 2 .................................................................................. 141 


Protocol 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 (PD) 
 
 
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14.6     Impact of Missing Data .................................................................................. 141 
15. PHARMACOLOGY ................................................................................................ 142 
15.1     Pharmacology Plan ......................................................................................... 142 
15.2     Pharmacokinetic Analysis .............................................................................. 142 
16. REGULATORY/ETHICS ........................................................................................ 143 
16.1     Compliance Statement ................................................................................... 143 
16.2     Informed Consent .......................................................................................... 143 
16.3     Institutional Review Board ............................................................................. 143 
16.4     Protocol Amendments .................................................................................... 144 
16.5     Participant Confidentiality ............................................................................. 144 
17. DOCUMENTATION ............................................................................................... 145 
17.1     Investigator Site File....................................................................................... 145 
17.2     Maintenance and Retention of Records .......................................................... 146 
17.3     Quality Assurance (QA) Audits/Site Visits ...................................................... 146 
17.4     Regulatory Inspections ................................................................................... 147 
17.5     Data Management .......................................................................................... 147 
18. SITE INVESTIGATOR/SITE .................................................................................. 148 
19. CLINICAL SAFETY MONITORING ......................................................................... 148 
19.1     Clinical Monitor ............................................................................................. 148 
19.2     Independent Medical Monitor ......................................................................... 148 
19.3     Study Committees .......................................................................................... 149 
19.3.1  Steering Committee ........................................................................................ 149 
19.3.2  Data and Safety Monitoring Board (DSMB)..................................................... 149 
19.4     Case Report Forms ......................................................................................... 149 
19.5     Site Monitoring .............................................................................................. 150 
19.6     Primary Source Documents ............................................................................ 151 
19.7     Closeout Plan ................................................................................................. 151 
20.       Publication of Research Findings ................................................................... 152 
21.       Data Sharing.................................................................................................. 152 
22. REFERENCES ...................................................................................................... 153 
APPENDIX 1: Tasigna Package Insert ......................................................................... 156 


Protocol 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 (PD) 
 
 
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APPENDIX 2: Exclusionary and Precautionary Medications ....................................... 191 
APPENDIX 3: Steering Committee .............................................................................. 198 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
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Table 1. List of abbreviations and definition of terms 
 
Abbreviation 
or specialist 
term 
Definition 
ADL 
Activities of Daily Living 
AE 
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
AUC 
Area under the concentration-time curve 
AV 
Atrioventricular 
BCC 
Biostatistics Coordination Core 
BDI-II 
Beck Depression Inventory-II 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CAPA 
Corrective and Preventive Action Plan 
CBC 
Complete Blood Count 
CDE 
Common Data Elements 
CFR 
Code of Federal Regulations 
CML 
Chronic Myelogenous Leukemia 
CMSU 
Clinical Materials Services Unit 
CGI 
CNS 
Clinical Global Impression Scale 
Central Nervous System 
CPK 
Creatinine Phosphokinase 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 


Protocol 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 (PD) 
 
 
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Abbreviation 
or specialist 
term 
Definition 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCC 
Clinical Trials Coordination Center 
DCC 
Data Coordination Core 
DBP 
Diastolic Blood Pressure 
DLB 
Dementia with Lewy Body 
DRS-2 
DSMB 
Mattis Dementia Rating Scale 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EQ-5D 
 
European Quality of Life Scale 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
HCV 
Hepatitis B virus 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HSPP 
Human Subjects Protection Program 
H&Y 
Hoehn and Yahr Scale 
HVA 
Homovanilic Acid 
ICD 
ICF 
International Classification of Diseases 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IP 
Investigational Product 
IRB 
Institutional Review Board 


Protocol 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 (PD) 
 
 
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Abbreviation 
or specialist 
term 
Definition 
ITT 
Intent-to-treat 
LDE 
Levodopa Dose Equivalence 
LFT 
Liver Function Tests 
LMM 
Linear Mixed Effects Model 
LP 
Lumbar Puncture 
MAO-B 
Monoamine Oxidase B 
MDS-UPDRS 
MedDRA 
Movement Disorders Society Unified PD Rating Scale 
Medical dictionary for Regulatory Activities 
MJFF 
MRI 
Michael J. Fox Foundation 
Magnetic Resonance Imaging 
MMSE 
Mini Mental Status Exams 
MoCA© 
Montreal Cognitive Assessment 
NDA 
New Drug Application 
NCI 
National Cancer Institute 
NINDS 
National Institute of Neurological Disorders and Stroke 
OTC 
Over the Counter 
PBMC  
Peripheral Blood Mononuclear Cell 
PD 
Parkinson’s Disease 
PDD 
Parkinson’s Disease Dementia 
PDQ-39 
PDSS 
PI 
Parkinson’s Disease Questionnaire – 39 Item Version Scale 
Parkinson’s Disease Sleep Scale 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
PSG 
Parkinson Study Group 
PT 
Preferred Term 
PW 
Premature Withdrawal 


Protocol 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 (PD) 
 
 
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Abbreviation 
or specialist 
term 
Definition 
QD 
Daily 
QTc 
Corrected QT Interval 
QTcF 
Fridericia’s correction for QT interval 
ULN 
Upper Limit of Normal 
RBC 
Red Blood Cell 
S&E 
SAE 
Modified Schwab and England Scale 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SCOPA-Cog 
Scales for Outcomes in Parkinson’s Disease-Cognition 
SD 
Standard Deviation 
SOA 
Schedule of Activities 
SOC 
System Order Class 
SOP 
Standard Operating Procedure 
ST 
Symptomatic Therapy 
TEAE 
Treatment Emergent Adverse Event 
T1/2 
Terminal half-life 
Tmax 
Time at which Cmax (serum concentration) was obtained 
Vss 
Steady state volume of distribution 
Vz 
Volume of distribution 
WBC 
White Blood Cell 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
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1. INTRODUCTION 
1.1  BACKGROUND 
 
 
Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects 1% 
of the population above the age 65 11. The prevalence of PD will increase substantially in the next 
20 years due to the aging of the population and age-related increase of the incidence of the disease 
12,13.  PD is characterized by progressive motor disability that includes bradykinesia, rigidity, 
resting tremor and gait dysfunction. PD is associated with a spectrum of non-motor symptoms 
including autonomic, cognitive, mood, sleep dysfunction and sensory abnormalities which are 
intrinsically related to the widespread PD neuropathological process and can in part precede the 
onset of motor manifestations 14. The economic burden of PD is estimated to be $23 billion 
annually in US and projected to increase to $50 billion by year 2040 15. Most of the cost is due to 
lost productivity and correlates with more advanced stages of the disease signifying the 
importance of developing  treatment strategies that slow progression of accumulating  disability 
16. 
 
Treatment options for PD are limited to symptomatic therapy (ST) geared towards replacement 
of dopamine deficiency 17. Despite a wide armamentarium of effective ST for early PD, 
management of advanced disease is limited. Availability of an effective disease modifying 
intervention that will slow the progression of the disease will have a substantial impact on the 
patients’ quality of life and the economic burden of disease. 
 
As of today there is no single proven neuroprotective agent in PD 18. Tested agents targeted 
various potential mechanisms of PD pathogenesis including oxidative stress (rasagiline, 
selegiline, Vitamin E), mitochondrial dysfunction (Coenzyme Q10, creatine), apoptotic 
mechanism of cell death (caspase inhibitors) and others 19-27. 
 
The defining pathological features of PD include the progressive loss of dopaminergic neurons 
in the substantia nigra-pars compacta and intra-neuronal accumulation of misfolded proteins to 
form Lewy bodies and Lewy neurites, where α -synuclein is the major component 28,29. 
Mutations in the gene encoding alpha (α) -synuclein, SNCA, lead to autosomal dominant PD 
while polymorphisms constitute risk factors for non-familial PD (reviewed by Mullin and 
Schapira30). Thus α -synuclein represents a convergent point between genetic etiology and 
pathology of PD and as such is an attractive target for therapeutic interventions.  
 
Recent genetic, biochemical and pharmacological studies indicate that deficits in the cellular 
pathways involved in autophagy underlie inadequate clearance of misfolded α -synuclein and 
contribute to PD pathogenesis (reviewed by Brundin et al.; Xilouri et al.,31,32). A class of 
enzymes termed tyrosine kinases and exemplified by the non-receptor tyrosine kinase Abelson 
(c-Abl) are known to induce autophagy33.  In fact, inhibitors of c-Abl have emerged as key 
therapies of certain tumors such as chronic myeloid leukemia (reviewed by Turcotte and 
Giaccia, 201034) .  


Protocol 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 (PD) 
 
 
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Recent analyses of autopsied tissues from PD patients and animal models of PD show an 
increase in the level of c-Abl as well as increases in the phosphorylation of its protein 
substrates, α-synuclein and parkin in dopaminergic neurons1,3,7,35-37. Interestingly, parkin is an 
E3 ubiquitin ligase, an enzyme critical for proteasome-mediated protein clearance. Like α -
synuclein, mutations and polymorphisms in the parkin gene also lead to familial PD and 
represent risk factors of sporadic PD, respectively38. More importantly, inhibition of c-Abl by 
nilotinib, a drug used for the treatment of Chronic Myelogenous Leukemia (CML), ameliorated 
α -synuclein pathology and rescued dopamine neuronal loss in mouse models of PD1,3. Further 
support for a critical role of c-Abl in inducing α -synuclein-mediated PD pathogenesis was 
recently provided by Brahmachari et al. 39. Using mouse genetic models they demonstrated that 
deletion of the gene encoding c-Abl reduced α-synuclein aggregation and neurobehavioral 
deficits whereas overexpression of the constitutively active c-Abl accelerated α-synuclein 
aggregation, neuropathology, and neurobehavioral deficits. Thus the first steps towards the 
development of c-Abl targeted cancer therapies for PD was undertaken and reported by Pagan 
et al9.  
 
1.2 CLINICAL EXPERIENCE 
Nilotinib experience in PD population  
To date, the safety and tolerability of nilotinib in PD and Dementia with Lewy Bodies (DLB) 
population have only been studied in a single small open label clinical study 9. The primary 
objective of the study was safety and tolerability with the secondary objectives of target 
engagement and pharmacokinetics (PK) and exploratory clinical outcomes. The study recruited 
12 participants with advanced PD, PD dementia (PDD) and Lewy body dementia who were 
randomized to nilotinib 150mg versus 300mg once daily in an open label fashion and were 
followed for 6 months. 
 
Thirty patients were screened and twelve late stage (Hoehn and Yahr 3-5) PD, PDD or DLB 
participants were randomized into 150mg (N=5) or 300mg  (N=7) groups and received oral 
daily doses of nilotinib for 24 weeks with 3 months follow up. Eighteen patients failed 
screening due to cardiovascular disease, infarcts, corrected QT (QTc) interval >450ms or 
excluded medications (i.e. warfarin). One participant was withdrawn from the study due to 
serious adverse events (SAEs) and another discontinued at 5 months due to increased caregiver 
burden. Ten participants completed the 24-week study and returned for a follow up visit (week 
36). One participant did not follow up at week 36. 
 
Clinical outcomes included Unified Parkinson’s Disease Rating Scale (UPDRS) and Mini Mental 
Status Exams (MMSE). Motor symptoms were monitored with UPDRS. The UPDRS scores were 
obtained at 1-4 hours after dosing with nilotinib. An average decrease of 3.4 points and 
3.6 points in UPDRS-III (motor) was observed at six months (week 24) compared to baseline 
with 150mg and 300mg nilotinib, respectively. These effects were reversed at 36-week 


Protocol 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 (PD) 
 
 
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follow up visit. An average decrease of 7 points and 11.1 points in UPRDS I-IV was also 
observed at 6 months in the 150mg and 300mg groups, respectively. The change in UPDRS was 
progressive throughout the 6 months (24 weeks) trial, and was reversed in participants in the 
follow up visit at 36 weeks. Most participants experienced increased psychotic symptoms 
(hallucination, paranoia, agitation, etc.) and some dyskinesia.  
 
Cognitive performance was monitored with MMSE throughout all visits. An average increase 
of 3.85 and 3.5 points in MMSE was observed at six months (24 weeks) compared to 
baseline with 150mg and 300mg nilotinib, respectively. The increase in MMSE scores was 
incremental throughout the 24-week treatment, and returned to baseline at the 36-week follow 
up visit. The Scales for Outcomes in Parkinson’s Disease-Cognition (SCOPA-Cog) test also 
showed an average increase of 1.85 and 2 points at six months compared to baseline with 
150mg and 300mg nilotinib, respectively. 
 
While the investigators concluded that nilotinib at tested doses was safe and tolerable in PD 
population, one participant had a serious cardiac event during the study and two others had QT 
prolongation (both are within the spectrum of the known nilotinib related adverse events and 
QT prolongation is reflected in the drug black box warning). The authors reported central 
nervous system penetration of unbound nilotinib, with the Cerebral Spinal Fluid (CSF):plasma 
ratio of 12% and 5 % with 300mg and 150mg dose respectively at 2 hours post dose 
administration and non-detectable CSF levels at 3 hours.  With regard to the secondary 
outcomes of target engagement, the authors reported reduction of phosphorylated Abl by 30 % 
with both doses of nilotinib. In addition, the authors reported significant increase in CSF 
dopamine metabolite, homovanilic acid (HVA) in both treatment groups and interpreted it as 
potentially reflection of nilotinib induced up regulation and protection of dopamine neurons. 
The authors also reported significant symptomatic benefit of nilotinib with improvement of 
motor disability and cognitive performance both of which subsided 3 months after 
discontinuation of treatment. Although the preliminary data appear promising, the study design 
precludes firm conclusions about safety, tolerability, optimal dose or efficacy. In addition, the 
data on the PK profile and target engagement have to be validated and replicated10.  Nilotinib is 
approved by the Food and Drug Administration (FDA) for certain types of leukemia but not PD.   
 
An opportunity exists to establish rigorously the safety, tolerability and optimal dosing of 
nilotinib for future efficacy studies in PD patients. 
 
 
2. STUDY OBJECTIVES 
 2.1 PRIMARY OBJECTIVE  
 
 
The primary objective of this two-cohort study is to assess the safety and tolerability of the daily 
oral administration of nilotinib or placebo in Participants with moderate to advanced PD (Cohort 


Protocol 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 (PD) 
 
 
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1) and in Participants with early/de novo PD (Cohort 2). Participants in Cohort 1 will be treated 
with nilotinib 150mg, 300mg or matching placebo. If at least one dose is shown to be safe and 
tolerable in cohort 1, the study steering committee will select a dose for consideration in cohort 
2. Participants in Cohort 2 will be treated with the selected dose determined in Cohort 1 or 
matching placebo. 
 
2.2 KEY SECONDARY OBJECTIVE  
To conduct a futility analysis within each treated group in Cohort I. This futility analysis will 
compare the observed change in the Movement Disorder Society Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) part III between baseline and 6 months to the observed change 
from the clintrials.gov NCT02281474 nilotinib study in order to determine whether we can rule 
out the large change previously reported – i.e., declare “futility”. 
 
 
2.3 ADDITIONAL SECONDARY OBJECTIVES  
      To establish the degree of symptomatic effect of nilotinib as measured by: 
 
1) The change in MDS-UPDRS part III between baseline and Visit 2 (1 month)  
2) Final visit on study drug and 30 days off study drug in cohorts 1 and 2.  
 
 To explore the impact of nilotinib on progression of PD disability as measured by the change in 
the MDS-UPDRS Part III score in the defined medications OFF state in Cohort 1 
(moderate/advanced) between baseline and 6 months. 
 
 To establish the impact of nilotinib on progression of PD disability as measured by the change 
in the MDS-UPDRS Part III score in Cohort 2 (early/de novo) between baseline and 12 months 
or time to initiation of ST whichever comes first. 
 
2.4 EXPLORATORY OBJECTIVES  
2.4.1 
CLINICAL MEASURES 
The change in the following measures of disability, quality of life and functional status 
from baseline to final visit will be analyzed: 
 
 
 
Motor disability 
 The change in MDS-UPDRS total score. For participants on ST, MDS-UPDRS part 
III assessments will be collected in the defined medications OFF (approximately 12 
hours post dose) and ON (based on the participant/site investigator defined best ON 
and/or approximately 1 hour after dose of ST) state 
 The change in the ambulatory capacity (sum of 5 MDS-UPDRS questions: (falling, 


Protocol 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 (PD) 
 
 
Page 36 of 198 
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freezing, walking, gait, postural stability) 
 Analysis of ST utilization as measured by levodopa equivalence dose 
 Severity of motor complications as measured by MDS-UPDRS IV subscale 
(complications of therapy) 
 
 
  Cognitive disability 
 The change in the cognitive function as measured by the change in Mattis 
dementia     rating scale - 2 (DRS-2)  
 
 
Sleep function  
 The change in sleep quality as measured by the Parkinson’s disease sleep scale 
(PDSS)  
 
 
   Measures of global disability 
 Clinician and Participant Global Impression of Change Score (CGI) 
 
 
Measures of functional status and quality of life 
 The change in the MDS-UPDRS Motor and Non-Motor Experiences of Daily 
Living subscores 
 The change in the modified Schwab and England scale (S&E) 
 The change in Parkinson Disease Quality of Life Questionnaire 39 (PDQ-39) 
 The change in European Quality of Life Scale (EQ-5D) 
 
       Blindedness and Treatment Expectations assessments  
 Questionnaires completed by the Site Investigator and Participant  
 
2.4.2 PHARMACOLOGY AND BIOMARKERS OBJECTIVES 
 
1. Pharmacokinetics and pharmacodynamics 
a. To determine the serum PK of nilotinib in patients with PD. 
b. To investigate the ability of nilotinib to cross the blood brain barrier in PD patients 
at a dose(s) that is tolerable and safe as measured by dose-dependent increases in 
unbound nilotinib levels in the CSF. 
c. To investigate factors that could affect the PK of nilotinib such as age, sex, PD 
severity, race/ethnicity. 
d. To investigate the ability of nilotinib to engage its known molecular target(s) at a 
dose that is tolerable and safe as measured by biomarkers of pathway inhibition in 
the serum and CSF (including but not limited to reduction in phospho-cAbl tyrosine 
kinase). 


Protocol 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 (PD) 
 
 
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e. To investigate the relationship between nilotinib exposures in serum and CSF with its 
ability to engage known molecular target(s) (measured by biomarkers of pathway 
inhibition in the serum and CSF (including but not limited to reduction in phospho-
cAbl)).  
 
2. To explore impact of nilotinib on: 
a. Dopaminergic system as measured by an increase in dopamine and its 
metabolites in CSF (e.g., homovanilic acid (HVA) level) 
b. Other biomarkers linked to potential mechanism of neuroprotection (including 
but not limited to CSF α -synuclein, total tau, phospho-tau, etc.) 
 
3.    Store additional blood/serum/ plasma/DNA/CSF samples for future research 
 
 
3. STUDY DESIGN 
 
 
 
 
 
3.1 OVERVIEW 
 
 
This is a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study of nilotinib in participants with moderate to advanced (Cohort 1) and early/de novo (Cohort 
2) PD.  The study will define the safety, tolerability, and exploratory clinical and biological 
activity of the chronic administration of nilotinib in participants with PD.   
 
Participants in Cohort 1 (moderate/advanced PD) will be randomized in a 1:1:1 ratio to a once 
daily dose of either 150mg or 300mg of nilotinib or matching placebo.  The duration of Cohort 1 
study is expected to be approximately 8.5 months from screening to post drug evaluation; whereas 
treatment period from randomization to final “On Treatment” visit will be 6 months.  The analysis 
for safety and tolerability will be conducted after all participants in Cohort 1 have completed 6 
months of their randomized treatment assignment. These results will be analyzed to inform the 
dose chosen for evaluation in Cohort 2. 
 
Cohort 2 will treat early/de novo PD participants.  Participants will be randomized in a 2:1 ratio 
to: 
 
•   nilotinib – selected dose, based on safety and tolerability data in  Cohort 1.   
  
            or 
•    matching placebo 
 
The duration of Cohort 2 study is expected to be approximately 14.5 months from screening to 
post drug evaluation; whereas the treatment period from randomization to final “On Treatment” 
visit will be 12 months.   
 


Protocol 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 (PD) 
 
 
Page 38 of 198 
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All participants in both Cohorts will be dosed once daily (QD) in a fasted state (no food consumed 
for at least 2 hours before and at least one hour after dosing).   
 
Sparse PK sampling will be conducted to assess serum and CSF concentrations of nilotinib 
throughout the duration of the study in both Cohorts (see section 11.3).   
 
The study design is displayed diagrammatically below: 
 
 
 
 
 
Note:  Cohort 2 dose will be determined based on safety and tolerability in Cohort 1. 


Protocol 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 (PD) 
 
 
Page 39 of 198 
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3.2 DISCUSSION OF STUDY DESIGN 
3.2.1      RATIONALE FOR STUDY  
A small number of cell and animal models suggest that nilotinib may positively affect the α -
synuclein pathology observed in PD1-3,7,31,35,36,39.   A small clinical study, that lacked a placebo 
control group and blinding, tested the safety and tolerability of nilotinib in PD patients for the 
first time and also explored its efficacy9. Although the preliminary data appear promising, the 
study design precludes firm conclusions about safety, tolerability, optimal dose or efficacy9. 
Nilotinib is approved by the FDA for certain types of leukemia but not for PD.  An opportunity 
exists to rigorously establish the safety, tolerability as well as optimal dose of nilotinib to enable 
future definitive efficacy studies in PD patients. 
 
 
 
 
 
 
3.2.2 
 RATIONALE FOR THE STUDY DESIGN 
The study is planned as a two-cohort study. Based on the fact that `the data on the safety profile 
of the drug and prior clinical experience with nilotinib were limited to an advanced PD population 
with cognitive deficits, PDD a or DLB, it was felt prudent to validate and expand the data on 
nilotinib safety and tolerability in the moderately advanced PD population.  It is expected that 
tolerability of nilotinib in Cohort 1 will be lower than in Cohort 2 (early/de novo PD population).  
Such data are important to establish, provided that nilotinib, if shown to have disease modifying 
benefit, will be administered long-term to PD patients across all disease stages. Another important 
objective of the study is to establish the magnitude of potential symptomatic effect of nilotinib 
and dopaminergic therapy interaction. These data will be essential for the design of future disease 
modifying trials.   
 
If shown to be safe and well tolerable, future development of nilotinib will target disease 
modification objectives. Disease modification has historically been tested in cohorts of de novo 
PD population. To pursue future disease modification trials, safety and tolerability of nilotinib 
has to be established in the de novo PD population as well. While we do not expect that the de 
novo population will have a lower tolerability and safety threshold, this hypothesis must be tested. 
In addition, a key piece of information to be collected in Cohort 2 is the presence and degree of 
symptomatic effect of nilotinib, if such exists.  These data will be essential for the design of the 
future disease modifying trials.  Lastly, while the study is not powered to test efficacy of nilotinib 
as a putative disease modifying intervention, the data on the magnitude of the effect of nilotinib 
versus placebo on the rate of progression in PD disability will be collected.  These data will guide 
the decision to pursue future clinical evaluation for that indication as well as provide essential 
data for the power calculations and sample size estimation for future disease modifying trials.  
 
 


Protocol 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 (PD) 
 
 
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3.2.3  NILOTINIB 
Nilotinib mechanism of action and pharmacokinetic data  
Nilotinib (Tasigna®, AMN107, Novartis, Switzerland) is a kinase inhibitor approved by the 
FDA for the treatment of adult patients with the newly diagnosed Philadelphia chromosome 
positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) 
Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib.  
Nilotinib is available in 150mg and 200mg capsules. The recommended dose of nilotinib for 
CML ranges from 300 to 400mg orally twice-daily (600-800mg/day).  
Please use the following link to view the package insert 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf 
Nilotinib is an inhibitor of the breakpoint cluster region protein (BCR)-Abl kinase. Nilotinib 
binds to and stabilizes the inactive conformation of the kinase domain of Abl protein.  
Tasigna (nilotinib) capsules, for oral use, contain 150mg or 200mg nilotinib base, anhydrous 
(as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon 
dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188. The 
capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and 
titanium dioxide.  Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions 
permitted between 15° to 30°C (59° to 86°F) 
 
 Pharmacokinetics of Nilotinib 
 The absolute bioavailability of nilotinib has not been determined.  As compared to an oral drink 
solution (pH of 1.2 to 1.3); relative bioavailability of nilotinib capsule is approximately 50%.  
Peak serum concentrations of nilotinib are reached 3 hours after oral administration.  Steady-
state nilotinib exposure was dose-dependent with less than dose-proportional increases in 
systemic exposure at dose levels higher than 400mg given as once-daily dosing. Steady state 
exposure area under the concentration-time curve (AUC) of nilotinib with 400mg twice-daily 
dosing was 13% higher than with 300mg twice-daily dosing. The average steady state nilotinib 
trough and peak concentrations did not change over 12 months. There was no relevant increase 
in exposure to nilotinib when the dose was increased from 400 mg twice-daily to 600mg twice-
daily. 
 
 The bioavailability of nilotinib is increased with food, thus nilotinib must not be taken with 
food. No food should be consumed for at least 2 hours before and for at least 1 hour after 
the dose is taken. Also avoid grapefruit products and other foods that are known to inhibit 
CYP3A4 [see Cautionary and Exclusionary Medications in Appendix 2] 
 
 The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% 
based on in vitro experiments. 
 


Protocol 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 (PD) 
 
 
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The apparent elimination half-life estimated from the multiple dose PK studies with daily 
dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 
64%. Steady state conditions were achieved by Day 8. An increase in serum exposure to 
nilotinib between the first dose and steady state was approximately 2-fold for daily dosing 
and 3.8-fold for twice-daily dosing. 
 
Main metabolic pathways identified in healthy participants are oxidation and hydroxylation. 
CYP3A4 is expected to be the main contributor to oxidative metabolism with CYP2C8 also 
making contribution.  In vitro studies show nilotinib to be a competitive inhibitor of 
CYP3A4/5, 2C8, 2C9, 2D6, and UGT1A1.  Additionally, in vitro studies demonstrate possible 
induction of CYP2B6, 2C8, and 2C9.  Nilotinib is the main circulating component in the 
serum. None of the metabolites contribute significantly to the pharmacological activity of 
nilotinib. 
 
After a single dose of radiolabeled nilotinib in healthy participants, more than 90% of the 
administered dose was eliminated within 7 days: mainly in feces (93% of the dose). Parent 
drug accounted for 69% of the dose. Age, body weight, gender, or ethnic origin did not 
significantly affect the PK of nilotinib. 
 
3.2.4 
RATIONALE FOR DOSAGE 
 
The FDA approved dose of nilotinib for CML ranges from 300 to 400mg orally twice-daily. The 
study will test two doses of nilotinib 150mg and 300mg administered once daily. We have chosen 
to target the lowest dosing range for this study based on the concerns regarding the safety profile 
of the tested agent and preliminary data from Pagan et al9 demonstrating CNS penetration at these 
doses which would require confirmation in the current study. For the same reasons we have 
chosen once daily schedule of administration.   
 
To minimize bias on the part of participants, Site Investigators, and analysts, the study is to be 
conducted as a randomized, double-blind, placebo-controlled, parallel group study. To maintain 
the blind, study drug and placebo will be manufactured as matching capsules, packaged and 
provided in matching containers. 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
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4. STUDY POPULATION 
 
 
 
 
 
4.1  PARTICIPANT NUMBERS  
 
 
This study will enroll a total of approximately one hundred eighty (180) participants with the goal 
of randomizing one hundred thirty-five (135) participants in two cohorts at approximately 25 sites 
in the United States (US).  Enrollment will be conducted in two cohorts: 
 
 Cohort 1: Approximately seventy-five (75) participants with moderate to advanced PD will 
be randomized 1:1:1 to a once daily dose of nilotinib or placebo (150mg; 300mg; placebo) 
 Cohort 2:  Approximately sixty (60) participants with early/de novo PD will be randomized 
to a once daily dose of nilotinib or placebo (the selected dose from Cohort 1, based on 
safety and tolerability).  Randomization in this cohort will not commence until/if a dose is 
determined from Cohort 1.  
 
Refer to Section 15 Statistical Considerations for justification of the selected sample sizes and 
the process for selecting the dose from cohort 1 for consideration in cohort 2. 
 
  4.2 INCLUSION CRITERIA 
 
 
Both Cohorts 1 and 2 will include participants who meet the following criteria: 
 
1. Participants with idiopathic PD based on the UK Brain Bank diagnostic criteria. 
2. Participants of any race and either gender, age 40-79 on the date the informed consent 
form (ICF) is signed and with the capacity to provide voluntary informed consent. 
3. Participants able to read and understand English and the ICF and are willing to comply 
with all study procedures, treatment and follow-up. 
4. Participants must be willing to undergo multiple lumbar punctures (LP) as outlined in 
the schedule of activities. 
5. Participants who are taking any central nervous system acting medications (e.g.,      
benzodiazepines, antidepressants, hypnotics) must be on a stable regimen for at least 30 
days prior to the baseline visit. 
 
Inclusion criteria specific for Cohort 1: 
 
6a. Participants with a diagnosis of PD duration > 5 years. 
7a. Participants with H&Y stage > 2 and < 4 in the ON state.  
8a. Participants 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. 
  


Protocol 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 (PD) 
 
 
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Inclusion criteria specific for Cohort 2: 
 
6b. Participants with a diagnosis of PD duration < 3 years.    
7b. Participants with H&Y stage < 2. 
8b. Participants who are currently NOT receiving 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. 
 
 
 
 
 
4.3 EXCLUSION CRITERIA 
 
 
 
 
 
Both Cohorts 1 and 2 will exclude participants who meet the following criteria: 
 
1. Participants with a diagnosis of atypical parkinsonism. 
2. Participants with a history of bipolar disorder or major depression, or the presence of   
active depression defined as a Beck Depression Inventory II (BDI-II) score >17. 
3. Participants with a history of a suicide attempt within the last 5 years or active suicidal 
ideations  
4. Participants with a history of schizophrenia or schizophrenia spectrum disorders  
5. Participants with a history of uncontrolled hypokalemia or hypomagnesaemia, or 
laboratory evidence of such on screening 
6. Pariticipants with evidence of other significant laboratory abnormalities which in the 
opinion of the site investigator or clinical monitor should preclude study participation 
7. Participants with history of a cardiac arrhythmia, long QT syndrome, or a QTcF 
≥450ms at screening visit 1 
8. Participants treated within 30 days prior to randomization, or planned use during the 
trial with any of the following classes of Concomitant drugs (see full list in Appendix 
2): 
a. Class IA or III antiarrhythmic drugs  
b. QT prolonging drugs  
c. Strong CYP3A4 inhibitors or inducers  
d. Anticoagulants 
e. Proton pump inhibitors 
9. Participants with a clinical history, or the active presence of a cardiovascular condition 
including: 
a. Myocardial infarction, known cardiac ischemia, or angina 
b.   Cerebrovascular event (e.g. embolic stroke) 
c.  Congestive heart failure, symptomatic first degree atrioventricular (AV) 
block  or  PR interval >220msec and all second and third degree AV 
block, sick sinus syndrome, or other serious cardiac rhythm disturbances 


Protocol 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 (PD) 
 
 
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d.  Any history of Torsade de Pointes 
e.   Any other cardiovascular history that in the opinion of the Site 
Investigator will preclude study participation  
10. Participants with a history of hepatic disease, including abnormal liver function 
defined Total Bilirubin > 1.5 times upper limit of normal,   Aspartate Aminotransferase 
(AST) and/or Alanine Aminotransferase (ALT) > 2 times the  upper limit of normal, 
or coagulopathy with INR > 4 
11. Participants with a history of bone marrow suppression or evidence of persistent 
myelosuppression defined as absolute neutrophyl count <1.8 X 109/L, significant 
anemia, or thrombocytopenia defined as platelet count < 100 X 109/L  
12. Participants with a prior history of epilepsy or a seizure within the last 6 months 
13. Participants with an active malignancy, or history of a neoplasm in the prior 5 years 
(excluding basal/squamous cell carcinoma) 
14. Participants with a prior history of pancreatitis, total gastrectomy or evidence of 
abnormal pancreatic function defined as elevated amylase and/or lipase > 2 times upper 
limit of normal  
15. Participants diagnosed with 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 
16. Participants with a history of drug or alcohol abuse ≤ 5 years  
17. Participants who have an active medical or psychiatric condition that in the opinion of 
the Site Investigator should preclude study participation 
18. Participants with previous surgical management for Parkinson’s disease 
19. Participants participating in any drug or device clinical investigation concurrently or 
within 30 days prior to screening for this study 
20. Participants with severe lactose and galactose intolerance 
21. Participants with a known hypersensitivity or contraindication to study drugs (nilotinib 
or matching placebo) or their components. 
22. 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  
 
 
 
 
Exclusion criteria specific for Cohort 1: 
23a. Participants with a diagnosis of dementia based on the clinician’s assessment, or a    
MoCA score < 21 at baseline 
 
 
     
Exclusion criteria specific for Cohort 2: 
23b. Participants with a MoCA score < 26 at baseline 
24b. Participants treated within 60 days prior to randomization or expected to require 
treatment within 3 months from randomization with any ST (including levodopa, 
dopamine agonists and MAO-B inhibitors) 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
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 
 
 
 
4.4 DISCUSSION OF PARTICIPANT CHARACTERISTICS 
 
 
 
 
The inclusion criteria were developed to select a study population that will optimally address 
the study specific objectives. The exclusion criteria were selected to further define the study 
population and to minimize putting the Participant’s safety at risk. Exclusion criteria include all 
the warnings and precautions as guided by the nilotinib package insert Nilotinib (Tasigna®, 
AMN107, Novartis, Switzerland) revised 12/2017.  See Appendix 1 and 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf 
 
 
 
 
 
 
4.4.1 WARNINGS/PRECAUTIONS  
Refer to the Tasigna package insert for the detailed discussion of the safety profile, warnings 
and precautions (revised 12/2017).  See Appendix 1 and 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf 
 
The following serious adverse reactions can occur with nilotinib (discussed in detail in the 
Package Insert) 
 
QT prolongation 
 
Myelosuppression  
 
Sudden Deaths  
 
Cardiac and Arterial Vascular Occlusive Events  
 
Pancreatitis and Elevated Serum Lipase  
 
Hepatotoxicity  
 
Electrolyte Abnormalities  
 
Hemorrhage  
 
Fluid Retention  
 Embryo-fetal toxicity   
 
 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
Warnings and Precautions [from Tasigna® (nilotinib) package insert (revised 12/2017)].  See 
Appendix 1 and 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf   
 
Nilotinib WARNING: QT Prolongation and Sudden Deaths:  
 
Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, 
monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain 
electrocardiograms (ECGs) to monitor the QTc at baseline, 7 days after initiation, 
and periodically thereafter, and following any dose adjustments.  
 
Sudden deaths have been reported in patients receiving nilotinib. Do not use 
nilotinib in patients with hypokalemia, hypomagnesemia, or long QT syndrome.  
 
Avoid use of concomitant drugs known to prolong the QT interval and strong 
CYP3A4 inhibitors. Patient should avoid food 2 hours before and 1 hour after taking 
a nilotinib dose. 
QT Prolongation 
Nilotinib has been shown to prolong cardiac ventricular repolarization as measured by the QT 
interval on the surface ECG in a concentration-dependent manner. Prolongation of the QT 
interval can result in a type of ventricular tachycardia called torsade de pointes, which may 
result in syncope, seizure, and/or death. ECGs should be performed at baseline, 7 days after 
initiation of nilotinib, and periodically as clinically indicated and following dose adjustments 
[see SOA]. 
Nilotinib should not be used in patients who have hypokalemia, hypomagnesemia or long QT 
syndrome. Before initiating nilotinib and periodically, test electrolyte, calcium and 
magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to 
initiating nilotinib and these electrolytes should be monitored periodically during therapy 
[see SOA]. 
Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken 
with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential 
to prolong QT. Therefore, co-administration with food must be avoided and concomitant use 
with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong 
QT should be avoided [see appendix )]. The presence of hypokalemia and hypomagnesemia 
may further prolong the QT interval [see Exclusion criteria]. 
Sudden Deaths 
Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in 
clinical studies of 5,661 patients. The relative early occurrence of some of these deaths 


Protocol 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 (PD) 
 
 
Page 47 of 198 
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Date: 21 Feb 2018 
relative to the initiation of nilotinib suggests the possibility that ventricular repolarization 
abnormalities may have contributed to their occurrence. 
Cardiac and Arterial Vascular Occlusive Events 
Cardiovascular events, including arterial vascular occlusive events, were reported in a 
randomized, clinical trial in newly diagnosed CML patients and observed in the post-
marketing reports of patients receiving nilotinib therapy. With a median time on therapy of 60 
months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, 
occurred in 9.3% and 15.2% of patients in the nilotinib 300 and 400mg bid arms, 
respectively. These included cases of cardiovascular events including ischemic heart disease-
related cardiac events (5.0% and 9.4% in the nilotinib 300mg and 400mg bid arms 
respectively, peripheral arterial occlusive disease (3.6% and 2.9% in the nilotinib 300mg and 
400mg bid arms respectively, and ischemic cerebrovascular events (1.4% and 3.2% in the 
nilotinib 300mg and 400mg bid arms respectively. If acute signs or symptoms of 
cardiovascular events occur, advise patients to seek immediate medical attention. The 
cardiovascular status of patients should be evaluated and cardiovascular risk factors should be 
monitored and actively managed during nilotinib therapy according to standard guidelines 
[see Exclusion criteria and SOA]. 
Myelosuppression 
Treatment with nilotinib can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. 
Perform complete blood counts every 2 weeks for the first 2 months and then monthly 
thereafter, or as clinically indicated [see SOA]. Myelosuppression was generally reversible 
and usually managed by withholding nilotinib temporarily or dose reduction.  
Pancreatitis and Elevated Serum Lipase 
Nilotinib can cause increases in serum lipase. Patients with a previous history of pancreatitis 
may be at greater risk of elevated serum lipase. [See Exclusion criteria]   
Hepatotoxicity 
Nilotinib may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and 
alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated [see 
SOA]. 
Electrolyte Abnormalities 
The use of nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, 
hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating 
nilotinib and during therapy. Monitor these electrolytes periodically during therapy [see 
Exclusion criteria and SOA]. 
Hepatic Impairment 
Nilotinib exposure is increased in patients with impaired hepatic function [see Exclusion 
criteria and SOA]. 
 


Protocol 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 (PD) 
 
 
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Hemorrhage 
In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing 
nilotinib and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the nilotinib 
300mg bid arm, in 1.8% patients in the nilotinib 400mg bid arm, and 0.4% of patients in the 
imatinib arm. GI hemorrhage occurred in 2.9% and 5.1% of patients in the nilotinib 300mg bid 
and 400mg bid arms and in 1.4% of patients in the imatinib arm, respectively. Grade 3 or 4 
events occurred in 0.7% and 1.4% of patients in the nilotinib 300mg bid and 400mg bid arms, 
respectively, and in no patients in the imatinib arm. 
Monitoring Laboratory Tests 
Complete blood counts should be performed every 2 weeks for the first 2 months and then 
monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, 
liver enzymes, lipid profile, and glucose prior to therapy and periodically. ECGs should be 
obtained at baseline, 7 days after initiation and periodically thereafter, as well as following 
dose adjustments [see Warnings and Precautions (5.2)]. Monitor lipid profiles and glucose 
periodically during the first year of nilotinib therapy and at least yearly during chronic therapy. 
Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to 
treat lipid elevations, evaluate the potential for a drug-drug interaction before initiating therapy 
as certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway [see 
Precautionary/Exclusionary Drugs Appendix 2]. Assess glucose levels before initiating 
treatment with nilotinib and monitor during treatment as clinically indicated. If test results 
warrant therapy, physician should follow their local standards of practice and treatment 
guidelines. 
Embryo-Fetal Toxicity 
There are no adequate and well controlled studies of nilotinib in pregnant women. Therefore, 
women of child-bearing potential will be excluded from the study [see Exclusion criteria]. 
Fluid Retention 
In the randomized trial in patients with newly diagnosed Ph+ CML in chronic phase, severe 
(Grade 3 or 4) fluid retention occurred in 3.9% and 2.9% of patients receiving nilotinib, 
300mg bid and 400mg bid, respectively, and in 2.5% of patients receiving imatinib. Monitor 
patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) 
and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during 
nilotinib treatment; evaluate etiology and treat patients accordingly. 
 
Other warnings and precautions (discussed in detail in the Package Insert) 
 
Total gastrectomy 
Since the exposure of nilotinib is reduced in patients with total gastrectomy, participants with 
gastrectomy will be excluded [see Exclusion criteria)]. 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
Lactose Intolerance  
Since the capsules contain lactose, nilotinib is not recommended for patients with rare 
hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree 
of intolerance to lactose-containing products, or of glucose-galactose malabsorption [see 
Exclusion criteria]. 
Musculoskeletal Symptoms after Discontinuation 
Patients taking nilotinib reported more frequent musculoskeletal symptoms (e.g., myalgia, 
pain in extremity, arthralgia, bone pain or musculoskeletal pain during the first year of 
discontinuation of treatment than before discontinuation. 
Adverse events: Clinical trial experiences in CML population  
The data below reflect exposure to nilotinib from a randomized trial in patients with newly 
diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300mg twice-daily 
(n=279). The median time on treatment in the nilotinib 300mg twice-daily group was 61 
months (range 0.1 to 71 months). The median actual dose intensity was 593mg/day in the 
nilotinib 300mg twice-daily group. 
The most common (>10%) non-hematologic adverse drug reactions were rash, pruritis, 
headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, 
dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia 
were observed less commonly (≤10% and>5%) and have been of mild to moderate severity, 
manageable and generally did not require dose reduction. 
Increase in Fridericia’s correction for QT interval (QTcF) >60 msec from baseline was 
observed in 1 patient (0.4%) in the 300mg twice-daily treatment group. No patient had an 
absolute QTcF of >500 msec while on study drug.  
The most common hematologic adverse drug reactions (all grades) were myelosuppression 
including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%). Discontinuation 
due to adverse reactions, regardless of relationship to study drug, was observed in 10% of 
patients. 
In patients with CML-AP, the most commonly reported non-hematologic adverse drug 
reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions 
(≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, 
leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. 
Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from 
baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed 
in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) 
 
 
 


Protocol 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 (PD) 
 
 
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Nilotinib safety profile in PD population9 
The safety profile of nilotinib in a PD population is limited, and is based on a single, small, 
open label study where 12 patients were treated for 24 weeks9.  There were three SAEs. One 
participant in the 300mg nilotinib group was withdrawn at week 4 and diagnosed with 
myocardial infarct and left bundle block. One participant in the 300mg nilotinib group was 
hospitalized with urinary tract infection (UTI) and one participant in the 150mg group 
was hospitalized with pneumonia and UTI 9. 
The spectrum of adverse events (AEs) reported in this small PD population included cases of 
mild confusion and hallucinations as well as anxiety and agitation, not reported in CML 
cohorts. Non-serious AEs included transient QTc prolongation>450ms but they returned to 
normal QTc range in subsequent visits (one participant in 150mg and one in 300mg group). 
Participants in the 150mg group reported three UTIs, two cases of pneumonia, one cold 
virus, one mild back pain, one mild headache, one mild dysgraphia, one mild left foot drag, 
one mild confusion, one mild hallucination, one mild paranoia, one mild agitation, one 
moderate anxiety, one mild incontinence, one moderate itching and one skin irritation. 
Participants in the 300mg group reported one incident of blurry vision, one diarrhea, one 
nausea, one mild fatigue, two generalized weakness, three UTIs, one pneumonia, one 
weight loss, one tooth extraction, one dizziness, two mild hallucinations, one mild 
paranoia, one mild crying episode, one mild urinary urgency, one mild cough and one 
eczematous lesion. With regard to the laboratory parameters, a total of three AEs below 
normal range of ALT level (<100%) were observed in the 150mg group nilotinib. Two AEs 
above normal range (>100%), including one ALT and one bilirubin elevations observed 
in the 150mg group nilotinib. Two AEs with transient increase of ALT and one AST above 
normal range (>100%) were observed in the 300mg group nilotinib but returned to normal 
by end of the study. 
 
Contraindicated Medications (see Section 8.2 and Appendix 2 for the full list of 
contraindicated medications and potential drug interactions)  
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 
in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In 
vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and 
decrease the concentrations of drugs which are eliminated by these enzymes. 
Avoid administration of nilotinib with agents that may increase nilotinib exposure (e.g., strong 
CYP3A4 inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, 
disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT 
interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, 
moxifloxacin and pimozide).  
 
 


Protocol 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 (PD) 
 
 
Page 51 of 198 
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Drugs that affect gastric pH 
Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as 
proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may 
decrease the solubility of nilotinib and reduce its bioavailability. The concomitant use of 
proton pump inhibitors with nilotinib is not recommended and is prohibited in this study. 
In healthy participants, no significant change in nilotinib PK was observed when a single 
400mg dose of nilotinib was administered 10 hours after and 2 hours before famotidine (an 
H2 blocker). Therefore, when the concurrent use of a H2 blocker is necessary, it may be 
administered approximately 10 hours before and approximately 2 hours after the dose of 
nilotinib. 
Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to 
healthy participants, 2 hours before or 2 hours after a single 400mg dose of nilotinib did not 
alter nilotinib PK . Therefore, if necessary, an antacid may be administered approximately 2 
hours before or approximately 2 hours after the dose of nilotinib. 
Food effects  
The bioavailability of nilotinib is increased with food; high fat meals increase Cmax and AUC 
by 112% and 82%, respectively, while a light meal increases Cmax by 33 – 55% and increase 
AUC by 15-29%.  Thus, nilotinib must not be taken with food. No food should be consumed 
for at least 2 hours before and for at least 1 hour after the dose is taken. Also, avoid grapefruit 
products and other products that are known to inhibit CYP3A4. 
 
 
 
 
 
5. STUDY PROCEDURES 
 
 
5.1    RECRUITMENT 
The study will be conducted at approximately 25 clinical sites in US. Each site should have a 
qualified Site Investigator and a Study Coordinator. Each site is required to have an individual 
Institutional Review Board (IRB) approval. All Site Investigators should be trained and 
qualified in the administration of the MDS-UPDRS and will be required to provide certification 
of training on the MDS-UPDRS within the last 2 years. Training sessions will be performed at 
the Investigator’s meeting with special emphasis on the primary outcome measures. New sites 
and/or new Site Investigators identified after the Investigator’s meeting will be trained 
individually. Enrollment will be closed as soon as the target number of participants are enrolled. 
Information regarding the clinical trial will be posted on multiple websites including 
clinicaltrials.gov and the Michael J. Fox Foundation (MJFF) website, Fox Trial Finder. A 
detailed recruitment plan will be provided. 
 
Once a study site has obtained IRB approval, they can start identifying potential participants for 
the study.  Participants should be community dwelling.  All participants asked to participate in 
this trial will be tracked on a Confidential Participant Log, which is to be kept in a secure 


Protocol 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 (PD) 
 
 
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location by the site study staff. This information is necessary to establish that the patient 
population was selected without bias.  Information regarding how participants learned about the 
trial, referral sources will be tracked in source documents.   
 
Only participants who meet all the inclusion and none of the exclusion criteria will be eligible 
to participate in the study.  Reasons for ineligibility and reasons for non- participation for 
eligible participants will be tracked in both source documents and Electronic Case Report Form 
(eCRF) for all participants who have signed a consent and are screened for the study. No 
protocol waivers will be granted for participants unable to meet eligibility criteria. However, a 
one-time rescreening may be allowed on a case-by-case basis when potential for an 
improvement or recovery of the criteria for ineligibility is possible and the participant could 
become eligible for enrollment in the study.  Participants may also rescreen if they were 
determined to be a screen failure prior to protocol Amendment 1 and are now deemed elegible 
based on Amendment 1 includsion/exclusion criteria.    
 
During or before a screening visit, the Participant will be thoroughly informed about all aspects 
of the study, including all scheduled visits and activities, and will be able to ask questions. The 
participant will be requested to sign and date the informed consent form prior to undergoing any 
study-specific procedures.  The original signed and dated informed consent form must be 
retained by the Site Investigator and a copy must be provided to the Participant. 
 
Refer to the study recruitment plan for central and site-specific strategies for effective 
recruitment. 
 
 
6.  SCHEDULE OF ACTIVITIES 
 
Throughout the study, it is highly recommended that assessments be performed in the same order 
as outlined in the Study Procedures section of this protocol at every visit and, if possible, at a 
similar time of day.  Site staff that have been trained and approved to administer these 
assessments for this study must perform them, per delegation of authority log. 
 
The Site Investigator is responsible for the overall conduct of the study and for conducting 
specific study assessments to ensure consistency in ratings and performance over the course of 
the study.  Sub-Investigators will be allowed, provided that there is consistency in the personnel 
performing the ratings over the course of the study (i.e., MDS-UPDRS is performed by the same 
investigator at each visit throughout the study). 
 
In this study, the Site Investigator will be responsible for the following:  
 Determining Participant eligibility 
 Conducting the physical (medical) and neurological examinations 
 Conducting the MDS-UPDRS Part IA, Part III and Part IV 


Protocol 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 (PD) 
 
 
Page 53 of 198 
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 Conducting fundoscopic exam prior to lumbar puncture  
 Assessing Hoehn and Yahr stage  
 Assessing Modified Schwab and England Activities of Daily Living 
 Assessing Clinical Global Impression scale  
 Determining need for ST (cohort 2) 
 Ensuring Participant safety 
 Assessing blindedness to treatment assignment and probability of PD as the accurate 
diagnosis, after a Participant discontinues study drug 
 
 
 
 
6.1  PARTICIPANT IDENTIFICATION (ID) NUMBER 
 
 
 
 
 
 
A participant ID Number will be assigned in sequential order by the site from a list provided to 
the site by the Clinical Trials Coordination Center (CTCC).  This 4-digit number will be used to 
identify the participant on all study forms and safety lab specimens (as appropriate). Research 
specimens will be labeled per protocol (alternate labeling without the participant ID number, 
such as barcode labels, may be required to protect confidentiality). 
 
Cohort 1 will enroll participants with moderate to advanced PD.   After all participants in 
Cohort 1 complete the treatment period (throughV04), a planned interim analysis will determine 
whether either of the doses are sufficiently safe and tolerated to justify further study.  If so, then 
the study steering committee will select one of the two doses for Cohort 2.  Cohort 2 will enroll 
early/de novo PD participants.  Enrollment into Cohort 2 will not begin until/if a dose is 
determined from Cohort 1.   
 
Sections 6.2 through 6.11 pertain to Cohort 1.  Sections 6.12 through 6.25 pertain to 
Cohort 2. 
 
Schedule of activities for Cohort 1  
 
6.2 SCREENING VISITS (SC1/SC2): COHORT 1 
Participants will be assessed for study eligibility by the Site Investigator.    
 
Prior to performing any study-specific procedures, the Site Investigator, designated Sub-
Investigator or Study Coordinator will thoroughly explain to the Participant all aspects of the 
study, including all scheduled visits, activities and procedures, potential risks involved and that 
their participation is voluntary.  Once the Participant has read and sign/dated the IRB-approved 
informed consent form, the procedures outlined below may begin.  All Participants will be given 
a photocopy of the signed consent form. 
 


Protocol 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 (PD) 
 
 
Page 54 of 198 
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Screening activities for this cohort will include two screening visits at the clinical site (Visit SC1 
and SC2):  
 Screening Visit 1 (SC1) which will take place within 14 to 28 days prior to the 
Baseline (BL) Visit.  
 Screening Visit 2 (SC2) which will take place within 7 to 14 days prior to the Baseline 
(BL) Visit. 
 
For the Participant to be randomized, all the inclusion criteria must be met and none of the 
exclusion criteria may apply. All results from the screening visit must be available and assessed 
before the final determination of a participant’s eligibility for the study, which will be made 
before the baseline visit (BL). 
 
Promptly after receipt of results from the screening activities, site staff will contact Participants 
to inform them either of exclusionary results that preclude their enrollment, or of their continued 
eligibility and to confirm their SC2 and BL visit appointment.  
 
6.2.1 
SCREENING VISIT 1 -  SC1: COHORT 1  
The following procedures and evaluations are to be performed at the Screening Visit (SC1): 
 
Note:  Assessments should be completed in the following order as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Obtain signed, written informed consent and permission to use Protected Health 
Information  
 Assign Participant Entry ID 
 Assign Unique Participant ID  
 Determine eligibility through an assessment of inclusion/exclusion criteria 
 Obtain demographic data and socio-economic information (highest level of 
education attained, marital status, handedness)  
  Obtain vital signs, including height, weight and orthostatic vital signs (blood 
pressure, heart rate after participant has been seated for 1-3 minutes). Orthostatic vital 
signs are serial measurements of blood pressure and pulse that will be taken  in 
supine position and standing position after 2 minutes  
 Obtain medical & neurological history: include diagnosis and history of PD with 
dates 
 Administer Beck Depression Inventory-II (BDI-II) 
 Administer Montreal Cognitive Assessment (MoCA) 
 Obtain list of concomitant medications; record: 


Protocol 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 (PD) 
 
 
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• 
Prescription and Over the Counter (OTC) medications  
• 
Vitamins and herbal supplements 
• 
Alcohol, tobacco and marijuana 
 Perform physical examination (by Site Investigator) 
 Perform neurological examination (by Site Investigator) 
 Perform fundoscopy exam (by Site Investigator)   
 Administer Hoehn and Yahr Scale 
 Complete primary diagnosis form 
 Perform 12-lead electrocardiogram (ECG) 
 Complete Treatment Expectation Questionnaire 
 Determine PD (diagnostic) features 
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) - ‘Baseline’ version 
 Collect blood for safety lab tests: Complete Blood Count (CBC), comprehensive 
chemistry panel, lipid panel, serum lipase and amylase 
 Collect blood for coagulation parameters 
 Collect blood  for pregnancy test (for all women unless they are surgically sterile) 
 Collect blood for HIV/HBV/HCV testing 
 
The SC 1 visit will be approximately 4 hours in duration. 
 
 6.2.2 RESCREENING  
Rescreening will be permitted for the following reasons: 
 
1. At the discretion of the Clinical Monitor 30 days (+/- 7days) of Screening Visit 1 for 
laboratory and other reversible variables.  
 
2. If a participant screen fails prior to protocol Amendment 1 and is determined to be 
eligible based on Amendment 1 inclusion/exclusion criteria.  This visit may occur 
any time after the intial Screening Visit 1. 
 
 
6.2.3 SCREENING VISIT 2- SC2: COHORT 1 
 Participant will return to clinic between 7 and 14 days prior to the Baseline Visit for an 
initial lumbar puncture.  The procedure can be performed once coagulation parameters, other 
safety labs from Screening Visit 1 and fundus exam results have been reviewed, are 
determined to be within normal limits and participant continues to qualify for the study.  
Perform lumbar puncture to collect CSF for biomarker panel.    


Protocol 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 (PD) 
 
 
Page 56 of 198 
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• CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count;  
• CSF samples will be processed by specialty lab for biomarker panel  
 
The SC2 visit will be approximately 45 minutes in duration 
 
6.3 BASELINE VISIT – BL (DAY 0) – COHORT 1 
Participant will return to clinic for BL assessments, randomization and first dose of study drug.  
Participants should be instructed to NOT take their PD medications at home on the morning of 
the study visit and bring their PD medication to clinic.  
 
Participant should have abstained from PD medication(s) for approximately 12 hours prior to 
visit.  Participants should be examined in the medications OFF and ON state. PD medications 
should be taken after completion of MDS-UPDRS OFF exam. 
MDS- UPDRS Part III assessment should be completed in the defined medications OFF state 
(approximately 12 hours after the last dose of ST) and in medications ON state (based on the 
participant/ Site Investigator defined BEST ON and/or approximately 1 hour after dose of ST). 
MDS-UPDRS Parts I and II are to be completed in the ON state.  Part IV is historical 
information. 
 
Assessments should be completed in the order presented below as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Review of inclusion/exclusion criteria to ensure Participant remains eligible  
 Administer Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) Part III OFF (approximately 12 hours after the last dose of ST) 
 Allow the Participant to take their regular dose of PD medications  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Obtain vital signs, including orthostatic vital signs (blood pressure, heart rate after 
participant has been seated for 1-3 minutes) 


Protocol 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 (PD) 
 
 
Page 57 of 198 
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Date: 21 Feb 2018 
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ Site Investigator 
defined BEST ON and/or approximately 1 hour after dose of ST).   
 Administer MDS-UPDRS Part IV (historical information)   
 Perform physical examination (by Site Investigator) 
 Perform 12-lead electrocardiogram (ECG) 
 Administer Modified Schwab & England Activities of Daily Living  
 Perform Clinical Global Impression of severity (CGI) (Site Investigator and Participant)  
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self- administered 
by Participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by Participant) 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Complete Caffeine and Tobacco Exposure questionnaires 
 Complete Treatment Expectation Questionnaire 
 Collect blood for biomarker panel 
 
 Randomize participant:  If the participant continues to meet all eligibility requirements per 
the Site Investigator’s final assessment, the participant may be randomized to treatment.  
Upon successful completion of randomization, the EDC system will generate the Participant’s 
5-digit enrollment/randomization number, which will be used to identify the Participant’s 
appropriate drug kit. 
Under no circumstances may study drug be pulled from storage and given to a 
Participant unless that drug kit has been assigned to that Participant via the enrollment 
process.  
 
The coordinator will record the Participant’s initials and Participant ID Number on 
the drug kit when it is taken from storage. 
 Dispense one (1) bottle A and one (1) bottle B from the kit assigned to the Participant, which 
is a 3-month supply of study drug. Observe participant for approximately 30 minutes after 
taking first dose of study drug.  
 Record initial dose on the Dose Management Log 
 Educate Participant regarding dosing restrictions.  
 Provide instructions regarding study drug covering: 
 Storage requirements  
 Importance of any specific Participant instructions 
 Study drug should be taken at the same time every day in the morning unless otherwise 
instructed. Study drug should be taken on empty stomach. No food should be consumed 
for at least 2 hours before and for at least 1 hour after the dose is taken.   


Protocol 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 (PD) 
 
 
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 Always take capsules with a glass of water or unsweetened, non-alcoholic beverage;  
 Participant should avoid grapefruit, including beverages or any supplements 
containing grapefruit for the duration of the study. 
 Ensure if participant takes antacids, they are not taken sooner than 2 hours before 
taking study drug and not for at least 2 hours afterwards 
 Return of all study drug bottles at each visit (whether empty, partially used, or unused) 
 When applicable, importance of not taking any study medication on designated study 
visit days until after assessments or blood draw. 
 Stress to Participant the importance of calling site to report any AEs or for any study 
questions 
 
BL visit will be approximately 4-6 hours in duration  
 
 
6.4 SAFETY VISITS SV1 THROUGH SV4 – COHORT 1 
Safety Visit 1 (Day 7 +3d) – SV1   
Safety Visit 2 ((Day 60 + 7d) – SV2  
Safety Visit 3 ((Day 120 + 7d) – SV3  
Safety Visit 4 ((Day 150 + 7d) – SV4  
 
Additional assessments for individual visits are listed below.  
Note:  Blood collection parameters vary for each Safety visit.  
 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 PD Medications – if dose increased, MDS-UPDRS ON required 
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Complete study drug accountability and compliance check on all returned study drug 
bottles (empty, partially used or unused); clarify issues with Participant during visit; re-
train participant if necessary. 
 Obtain vital signs, including orthostatic vital signs (blood pressure, heart rate after 
participant has been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG)  
 


Protocol 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 (PD) 
 
 
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Additional assessments 
Safety Visit 2 (Day 60 + 7d)   
Safety Visit 3 (Day 120 + 7d) 
Safety Visit 4 (Day 150 + 7d) 
 Collect blood for sparse PK analysis – post-dose random sample to be collected at any 
time relative to last dose of study drug- SV2, SV3 and SV4 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase. - SV2, SV3 and SV4 
 
The safety visits will be approximately 1 hour each in duration   
 
6.5 VISIT 01 (DAY 14 + 3D) – V01 – COHORT 1 
      VISIT 02 (DAY 30 + 3D) – V02 – COHORT 1 
 
Participant will return to clinic abstaining from taking study drug for 24 + 2 hours in anticipation 
of sparse PK blood draw.  Participant can take their regular dose of PD medication(s) the morning 
of their visit.  Participant must bring both PD medication(s) and study drug to the visit.   
 
Assessments should be completed in the order presented below as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel 
 Collect blood for sparse PK analysis – pre-dose trough sample to be collected 24 + 2 hours 
post last dose of study drug.  
 Allow the participant to take their study drug  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Obtain vital signs, including orthostatic vital signs (blood pressure, heart rate after 
participant has been seated for 1-3 minutes) 


Protocol 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 (PD) 
 
 
Page 60 of 198 
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 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially used or unused); clarify issues with participant during visit; re-train 
participant if necessary.   
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/site investigator 
defined best ON and/or approximately 1 hour after dose of ST) 
 Administer MDS-UPDRS Part IV (historical information)  
 
Additional assessment – V1 only 
Visit 01 (Day 14 + 3d) 
 Determine dose titration  
 
Additional assessment – V2 only 
Visit 02 (Day 30 + 3d) 
 Collect blood for safety lab tests: lipid panel, serum lipase and amylase 
 Perform 12-lead electrocardiogram (ECG)  
 
Visits 01 and 02 will be approximately 2 hours in duration. 
 
 
6.6   VISIT 03 (DAY 90 + 7D) – V03 – COHORT 1 
 
Participant should be instructed to NOT take their PD medication(s) or their study drug at home 
on the morning of Visit 3 and bring their PD medication(s) and study drug to clinic.  
 
Participant will return to clinic, abstaining from study drug for 24 + 2 hours in anticipation of 
sparse PK blood draw. 
 
Participant should bring study drug to the visit as CSF and corresponding serum PK will be 
collected 2 + 0.5 hours post observed dose.   Lumbar puncture must be conducted on the same 
day as the rest of the assessments for Visit 3.  Coagulation parameters, collected within 10 days 
prior to the study visit, must be reviewed by the site investigator prior to performing the LP.   
 
Participants should be examined in the medications OFF and ON state. PD medications should 
be taken after completion of MDS-UPDRS OFF exam.  MDS-UPDRS Part III assessment should 
be completed in the defined medications OFF state (approximately 12 hours after the last dose of 


Protocol 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 (PD) 
 
 
Page 61 of 198 
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Date: 21 Feb 2018 
ST) and in medications ON state (based on the participant/ Site Investigator defined BEST ON 
and/or approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed 
in the ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last dose of ST).  
 Collect blood for coagulation parameters for a stat read if the participant did not have their 
blood drawn and coagulation parameters tested in the last 10 days.  
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase. 
 Collect blood for biomarker panel 
 Collect blood for sparse PK analysis at 2 time points:  
 Sample 1:  pre-dose trough sample must be collected 24 + 2 hours post last 
dose of study drug.  
 Sample 2:  must be collected 2 + 0.5 hours post observed dose at the time of 
the collection of the CSF sample 
 Allow the participant to take their study drug and regular dose of PD medications  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination (by Site Investigator) 
 Perform fundoscopy exam (to be performed by the PI prior to the LP)  
 Perform Clinical Global Impression of Change (CGI) (Site Investigator and participant) 
 Administer Hoehn and Yahr Scale 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered by 
participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 


Protocol 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 (PD) 
 
 
Page 62 of 198 
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Date: 21 Feb 2018 
 Perform 12-lead electrocardiogram (ECG) 
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ Site Investigator 
defined BEST ON and/or approximately 1 hour after dose of ST) 
 Administer MDS-UPDRS Part IV (historical information)  
 Perform lumbar puncture to collect spinal fluid samples (note: all samples collected on same 
day):  
 PK sample must be collected 2 + 0.5 hours post observed dose of study drug - note: a 
corresponding blood sample must also be collected.   
 Biomarker sample  
 LP may be performed only after results of the coagulation lab parameters 
(collected at SV2 visit) and fundoscopic exam (performed by PI) have been 
reviewed and documented  
 CSF sample will be processed by the site’s local lab facility (unless the lab is 
not able to process the CSF within 4 hours) to evaluate protein and glucose 
levels (routine chemistry) and cell count; 
 CSF samples will be process by specialty lab for biomarker panel.  Refer to 
NILO-PD Lab Manual for specific instructions.  
 LP must be performed on the same day as the rest of the assessments for Visit 
3. 
 Complete IP accountability and compliance check on all returned IP bottles (empty, partially 
used, or unused) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Dispense one (1) bottle A and one (1) bottle B from the original kit assigned to the 
participant, which is a 3-month supply of study drug. Under no circumstances may study 
drug be pulled from storage and given to a participant unless that drug kit has been 
assigned to that participant via the enrollment process.  
 
The coordinator will record the participant’s initials and participant ID Number on the 
drug kit when it is taken from storage. 
 
V03 will be approximately 2 hours in duration. 
 
 
 
 


Protocol 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 (PD) 
 
 
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6.7  VISIT 04 (DAY 180+7D) – V04 – COHORT 1 (FINAL “ON DRUG” VISIT) 
This is the Participant’s final visit on study drug, therefore all unused, empty and partially used 
bottles should be returned for final accountability at this visit. 
 
Participant should be instructed to NOT take their PD medication(s) at home on the morning of 
Visit 4 and bring their PD medication(s) to clinic.  Additionally, Participant should adjust the 
time in which they take their study drug to ensure a 2 to 5 hour period prior to sparse PK blood 
draw.   
 
Participant must abstain from taking PD medication(s) for approximately 12 hours prior to their 
clinic visit. Participant should be examined in the medications OFF and ON state.   PD 
medication(s) should be taken after completion of MDS-UPDRS OFF exam. 
MDS-UPDRS Part III assessment should be completed in the defined medications OFF state 
(approximately 12 hours after the last dose of ST) and in medications ON state (based on the 
participant/ Site Investigator defined BEST ON and/or approximately 1 hour after dose of ST). 
MDS-UPDRS Parts I and II are to be completed in the ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Allow Participant to take their study drug, if they haven’t previously taken their daily dose, 
ensuring a 2 to 5 hour period prior to PK blood collection,  
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last dose of ST) 
 Allow Participant to take their regular dose of PD medications  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination by Site Investigator 
 Perform neurological examination by Site Investigator 
 Administer Clinical Global Impression of Change (CGI) (Site Investigator and Participant)  
 Determine PD diagnostic features 
 Complete primary diagnosis form 
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ Site Investigator 
defined BEST ON and/or approximately 1 hour after dose of ST) 
 Administer MDS-UPDRS Part IV (historical information)  


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered 
by participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
  Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Administer Treatment expectation questionnaire (self-administered by participant) 
 Collect blood for PK;  
 Sample must be collected 2-5 hours post-dose of study drug 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase 
 Collect blood for coagulation parameters 
 Collect blood for biomarker samples 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Hoehn and Yahr Scale  
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 
 Perform a 12-lead electrocardiogram (ECG) 
 Complete a final study drug accountability and compliance check on all returned 
study drug bottles (empty, partially used or unused) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit. 
 
V04 will be approximately 3 hours in duration. 
 
6.8  VISIT 05 (30 DAYS POST-TREATMENT ± 7 D) – V05 – COHORT 1 
 
VISIT 06 (60 DAYS POST-TREATMENT ± 7D) – V06 – END OF STUDY  
 
Participant should be instructed to NOT take their PD medication(s) at home on the morning of 
Visit 4 and bring their PD medication(s) to clinic. 
 
Participant will return to clinic abstaining from PD medications for approximately 12 hours. 
Participants should be examined in the PD medications OFF and ON state. PD medication should 
be taken after completion of MDS-UPDRS OFF exam. 


Protocol 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 (PD) 
 
 
Page 65 of 198 
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Date: 21 Feb 2018 
MDS-UPDRS Part III assessment should be completed in the defined medications OFF state 
(approximately 12 hours after the last dose of ST) and in medications ON state (based on the 
participant/ Site Investigator defined BEST ON and/or approximately 1 hour after dose of ST). 
MDS-UPDRS Parts I and II are to be completed in the ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 MDS-UPDRS Part III OFF (approximately 12 hours after the last dose of ST) 
 Allow the participant to take their regular dose of PD medications  
 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
    Prescription and OTC medications  
 
Vitamins and herbal supplements 
 
Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Administer Hoehn and Yahr Scale 
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ Site Investigator    
defined BEST ON and/or approximately 1 hour after dose of ST) 
 Administer MDS-UPDRS Part IV (historical information) 
 Administer Treatment expectation questionnaire (participant) 
 Obtain vital signs and orthostatic vital signs (blood pressure, heart rate after participant has 
been seated for 1-3 minutes) 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel serum 
lipase and amylase  
 
Additional assessments 
 
Visit 05 (30 days post-treatment + 7 d)   
 Perform physical examination (by Site Investigator) 
 Height and weight 
 Perform a 12-lead electrocardiogram (ECG) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Perform fundoscopy exam (to be performed by the PI prior to the LP)   
 
 
 Perform lumbar puncture. (Lumbar puncture for this visit is strongly encouraged but not 
required)  


Protocol 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 (PD) 
 
 
Page 66 of 198 
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 
LP may be performed only after results of the coagulation lab parameters (collected 
at V04 visit) and fundoscopic exam (performed by PI) have been reviewed and 
documented  
 
CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count; 
 
CSF samples will be process by specialty lab for biomarker panel;  
 
LP may be performed on a separate day within the visit window, if necessary 
 Collect blood for biomarker panel  
 
V05 will be approximately 1.5 hours in duration. 
 
Additional assessments 
Visit 06 (60 Days post-treatment + 7d)  
 
Columbia Suicide Severity Rating Scale (C-SSRS) - ‘Since Last Visit’ Version – only 
 
 Collect blood for pregnancy test (for all women unless surgically sterile) 
 
V06 will be approximately 2.5 hours in duration. 
 
6.9 UNSCHEDULED VISITS – VISIT U01, U02, ETC. – COHORT 1   
 
 
 
An unscheduled visit may be performed at any time during the study at the participant’s request 
or as deemed necessary by the Site Investigator.  The date and reason for the unscheduled visit 
or telephone contact will be recorded in the source documentation. Reasons for unscheduled 
visits may include, but are not limited to, a potential severe side effect, worsening of symptoms, 
multiple missed doses of medication.  
 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 PD Medications – if dose increased, MDS-UPDRS ON required 
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  


Protocol 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 (PD) 
 
 
Page 67 of 198 
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 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Obtain vital signs, including orthostatic vital signs (blood pressure, heart rate after 
participant has been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG)  
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel  
 Complete study drug accountability and compliance check on all returned study drug 
bottles (empty, partially used or unused) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 
An unscheduled visit may vary in duration. 
 
6.10 PREMATURE WITHDRAWAL VISIT - VISIT PW – COHORT 1  
 
 
 
 
 
Participants have the right to withdraw from the study at any time without prejudice.  The Site 
Investigator may withdraw study drug from a participant in the study in the event of intercurrent 
illness, adverse events, other reasons concerning the health or well-being of the participant, or in 
the case of lack of cooperation, non-compliance, protocol violation or other administrative 
reasons. Premature withdrawal will be implemented in the case of emergency disclosure of drug 
treatment.   
 
In the event of premature withdrawal from the study, the Premature Withdrawal (PW) Visit 
procedures and evaluations should be completed whether or not the withdrawal is determined at 
a regularly scheduled study visit or at an unscheduled visit. In instances where the participant 
refuses or cannot to return for a PW visit, it is acceptable to attempt to obtain data by telephone 
and arrange for return of study drug.  It is important to collect the final date and time of day the 
last dose of study drug was taken. 
 
Reasons for withdrawal of the Participant prior to completion of the study must be stated in the 
eCRF and in the site source documentation for all study participants who were enrolled in the 
study.  The Participant will be encouraged to remain in the study and return for the 1 month and 
2 month post drug evaluations (V05 and V06) as a safety follow up.  
 
Adverse events will be followed for 30 days after a Participant’s last dose of study drug.  AEs, 
abnormal laboratory results and abnormal ECG values will be followed to resolution or 
stabilization, whichever occurs first, but no new AEs will be recorded. 
 


Protocol 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 (PD) 
 
 
Page 68 of 198 
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Date: 21 Feb 2018 
The CTCC must be informed within 24 hours of all study Participants who prematurely 
withdraw from the study.    
 
Participant should be instructed to bring both study drug and PD medications to the PW visit.  It 
is important to collect the final date and time of day the last dose of study drug was taken. 
Participants should be instructed to NOT take their PD medications at home on the morning of 
their PW visit and to bring their PD medication(s) the study visit. Participant must return to clinic 
abstaining from PD medications for approximately 12 hours. Participants should be examined in 
the medications OFF and ON state. Medication should be taken after completion of MDS-UPDRS 
OFF exam. 
Lumbar puncture must be conducted on the same day as the rest of the PW visit assessments.  
Coagulation parameters, collected within 10 days prior to the study visit, must be reviewed by 
the site investigator prior to performing the LP.   
 
MDS- UPDRS Part III assessment should be completed in the defined medications OFF state 
(approximately 12 hours after the last dose of ST) and in medications ON state (based on the 
participant/ Site Investigator defined BEST ON and/or approximately 1 hour after dose of ST). 
MDS-UPDRS Parts I and II are to be completed in the ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 MDS-UPDRS Parts III OFF (approximately 12 hours after the last dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ Site Investigator 
defined BEST ON and/or approximately 1 hour after dose of ST) 
 Administer MDS-UPDRS Part IV (historical information) 
 Collect blood for PK only if the participants remained on the study drug or discontinued 
within the last 3 days;  
 If study drug was taken within past 3 days, collection of one random sample 
at any time relative to post-dose at each visit.   
 The date and time of day of the last dose of the study drug has to be 
documented in the eCRF 
 Collect blood for pregnancy test (for all women unless surgically sterile) 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel and lipid panel. 
 Collect blood for coagulation parameters (results must be reviewed and documented prior to 
performing lumbar puncture) 
 Collect blood for biomarker samples 


Protocol 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 (PD) 
 
 
Page 69 of 198 
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Date: 21 Feb 2018 
 Review concomitant medication use since last visit.  Record changes and additions as     
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination by Site Investigator 
 Perform neurological examination by Site Investigator 
 Perform fundoscopy exam (to be performed by the PI prior to the LP)  
 Administer Clinical Global Impression of Change (CGI) (Site Investigator and participant) –  
 Determine PD diagnostic features 
 Complete primary diagnosis form 
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered 
by participant) 
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version-
only 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Administer Treatment expectation questionnaire (self-administered by participant) 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Hoehn and Yahr Scale  
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 
 Perform a 12-lead electrocardiogram (ECG) 
 Perform lumbar puncture. (Lumbar puncture for this visit is strongly encouraged but not 
required)  
 
LP may be performed only after results of the coagulation lab parameters and 
fundoscopic exam have been reviewed and documented  
 
CSF sample will be processed by the site’s local lab facility (unless the lab is 
not able to process the CSF within 4 hours) to evaluate protein and glucose 
levels (routine chemistry) and cell count; 
 
CSF samples will be process by specialty lab for biomarker panel;  
 
LP may be performed on a separate day within the visit window, if necessary 


Protocol 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 (PD) 
 
 
Page 70 of 198 
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Date: 21 Feb 2018 
 Complete a final study drug accountability and compliance check on all returned 
study drug bottles (empty, partially used or unused.) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit. 
 
PW will be approximately 3 hours in duration. 
 
6.11  PROCEDURES FOR THE PARTICIPANTS WHO DISCONTINUE THE STUDY DRUG FOR 
SAFETY AND INTOLERABILITY  REASONS  
 
If a participant needs to discontinue study drug for safety reasons, the site should complete a 
Premature Withdrawal visit (section 6.10) either while still taking the study drug or as soon as 
possible after drug discontinuation.  AEs will be followed for 30 days after a Participant’s last 
dose of study drug.  AEs, abnormal laboratory results and abnormal ECG values will be 
followed to resolution or stabilization, whichever occurs first, but no new AEs will be recorded. 
The participant will be encouraged to return for the 30 and 60 days post drug evaluations (V05 
and V06) as per schedule of activities.  
 
In case the study drug has been discontinued for safety laboratory values or ECG abnormalities 
reasons, ECG and abnormal laboratories values must be repeated in 2 weeks and at 30 days.  
Schedule of activities for Cohort 2  
 
NOTE: Cohort 2 will not start enrollment until/when a safe and tolerable dose of study drug is 
determined from Cohort 1 and study materials for Cohort 2 are available for distribution to sites.  
 
 
 
 
6.12 SCREENING VISIT 1 (VISIT SC 1) – COHORT 2 (EARLY/DE NOVO PD) 
Participants will be assessed for study eligibility by the Site Investigator.    
 
Prior to performing any study-specific procedures, the Site Investigator or designated sub-
investigator or study coordinator will thoroughly explain to the Participant all aspects of the study, 
including all scheduled visits, activities and procedures, potential risks involved and that their 
participation is voluntary.  Once the Participant has read and sign/dated the IRB-approved 
informed consent form, the procedures outlined below may begin.  All participants will be given 
a photocopy of the signed consent form. 
 
Screening activities for this cohort will include one screening visit at the clinical site (Visit SC), 
which will take place within 28 to 14 days prior to the Baseline (BL) Visit.  
 


Protocol 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 (PD) 
 
 
Page 71 of 198 
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For the Participant to be randomized, all the inclusion criteria must be met and none of the 
exclusion criteria may apply. All results from the screening visit must be available and assessed 
before the final determination of a participant’s eligibility for the study, which will be made 
before the baseline visit (BL). 
 
Promptly after receipt of results from the screening activities, site staff will contact participants 
to inform them either of exclusionary results that preclude their enrollment, or of their continued 
eligibility and to confirm their BL visit appointment.  
 
The following procedures and evaluations are to be performed at the Screening Visit (SC1): 
 
Note:  Assessments should be completed in the following order as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Obtain signed, written informed consent and permission to use Protected Health Information  
 Assign participant Entry ID 
 Assign Unique participant ID  
 Determine eligibility through an assessment of inclusion/exclusion criteria 
 Obtain demographic data and socio-economic information (highest level of education 
attained, marital status, handedness)  
 Administer Beck Depression Inventory-II (BDI-II) 
 Administer Montreal Cognitive Assessment (MoCA©) 
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart    
rate after participant has been seated for 1-3 minutes) 
 Obtain medical & neurological history: include diagnosis and history of PD with dates 
 Obtain list of concomitant medications; record: 
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Perform physical examination (by Site Investigator) 
 Perform neurological examination (by Site Investigator) 
 Perform fundoscopy exam (by Site Investigator)   
 Administer Hoehn and Yahr Scale 
 Assess need for ST  
 Complete primary diagnosis form 
 Determine PD (diagnostic) features 
  Administer Columbia Suicide Severity Rating Scale (C-SSRS) -‘Baseline’ version 


Protocol 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 (PD) 
 
 
Page 72 of 198 
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Date: 21 Feb 2018 
 Perform 12-lead electrocardiogram (ECG) 
 Complete Treatment Expectation Questionnaire 
 
 Collect blood  for safety lab tests: CBC, comprehensive chemistry panel,  lipid panel, serum 
lipase and amylase 
 Collect blood for coagulation parameters 
 Collect blood for pregnancy test (for all women unless they are at least two years 
postmenopausal,   or surgically sterile) 
 Collect blood for HIV, HBV, HCV testing 
 
The SC 1 visit will be approximately 2 to 3 hours in duration. 
 
 
 
6.12.1 RESCREENING  
 
Rescreening will be permitted at the discretion of the Clinical Monitor within 30 days (+/- 7 
days) of the original screening visit for the laboratory and other reversible variables. Only out of 
range parameters will have to be repeated. 
 
Participants may also rescreen if they were determined to be a screen failure prior to protocol 
Amendment 1 and are now deemed elegible based on Amendment 1 includsion/exclusion 
criteria.   
 
 
 
6.13   SCREENING VISIT 2 
Participant will return to clinic between 7 to 14 days prior to the Baseline Visit for an initial 
lumbar puncture.  The procedure can be performed once coagulation parameters, other safety 
labs from Screening Visit 1 and fundus exam results have been reviewed and are normal and 
participant continues to qualify for the study. 
 
 Perform lumbar puncture to collect CSF  for biomarker panel.    
 
CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count;  
 
CSF samples will be process by specialty lab for biomarker panel  
 
The SC 2 visit will be approximately 45 minutes in duration 


Protocol 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 (PD) 
 
 
Page 73 of 198 
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Date: 21 Feb 2018 
 
6.14   BASELINE VISIT – BL (DAY 0) – COHORT 2 
Participant will return to clinic for BL assessments, randomization and first dose of study drug.  
Assessments should be performed in the order presented below if possible.     
 
Assessments should be completed in the order presented below as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Review of inclusion/exclusion criteria to ensure participant remains eligible  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Obtain vital signs and orthostatic vital signs (blood pressure, heart rate after participant has 
been seated for 1-3 minutes) 
 Perform physical examination (by Site Investigator) 
 Perform 12-lead electrocardiogram (ECG) 
 Administer Modified Schwab & England Activities of Daily Living  
 Perform Clinical Global Impression of Severity(CGI) (Site Investigator and participant)  
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self- administered 
by participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Complete Treatment Expectation Questionnaire 
 Complete Environmental Questionnaire 
 Administer MDS-UPDRS Parts I-III  
 Collect blood for biomarker panel 
 Randomize participant:  If the participant continues to meet all eligibility requirements per 
the Site Investigator’s final assessment, the participant will be randomized to treatment via 
the web-based enrollment module (see Section 6.1 for information regarding enrollment 
procedures). Upon successful completion of randomization, the EDC system will generate 


Protocol 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 (PD) 
 
 
Page 74 of 198 
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Date: 21 Feb 2018 
the participant’s 4-digit enrollment/randomization number, which will be used to identify 
the participant’s appropriate drug kit. 
Under no circumstances may study drug be pulled from storage and given to a 
participant unless that drug kit has been assigned to that participant via the enrollment 
process.  
The coordinator will record the participant’s initials and participant ID Number on the 
drug kit when it is taken from storage. 
 Dispense a 3-month supply of study drug as outlined in Section 7.8. Observe 
participant for approximately 30 minutes after taking first dose of study drug.  
 Record initial dose on the Dose Management Log 
 Educate Participant regarding dosing restrictions.  
 Provide instructions regarding study drug covering: 
 Storage requirements  
 Importance of any specific patient instructions,  
 Study drug should be taken at the same time every day in the morning 
unless otherwise instructed.  Participants should avoid eating food for at 
least 2 hours before the dose is taken and avoid eating food for at least 1 
hour after the dose is taken.   
 Always take capsules with a glass of water or unsweetened, non-alcoholic 
beverage;  
 Participant should avoid grapefruit, including beverages or any supplements 
containing grapefruit for the duration of the study. Ensure if participant 
takesH2 blockers, they are not taken sooner than 10 hours before taking study 
drug and not for at least 2 hours afterwards. 
 Ensure if participant takes an antacid, they are not taking these medications for 
about 2 hours before the study drug is taken or for at least 2 hours after study 
drug is taken. 
 Return of all study drug bottles at each visit (whether empty, partially used, or 
unused) 
 When applicable, importance of not taking any study medication on designated 
study visit days until after assessments or blood draw. 
 Stress to participant the importance of calling site to report any AEs or for any study                      
questions 
 
BL visit will be approximately 2-4 hours in duration (timing dependent on when lumbar puncture 
is performed).  
 
 
 


Protocol 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 (PD) 
 
 
Page 75 of 198 
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Date: 21 Feb 2018 
6.15   SAFETY VISITS - SV 1 THROUGH SV 6 – COHORT 2  
Safety Visit 1 (Day 7 + 3d) – SV1 
Safety Visit 2 (Day 60 + 7d) – SV2   
Safety Visit 3 (Day 120 + 7d) – SV3  
Safety Visit 4 (Day 150 + 7d) – SV4  
Safety Visit 5 (Day 210 + 7d) - SV5 
Safety Visit 6 (Day 240 + 7d) – SV6 
 
Additional assessments for individual visit are listed below. 
 
 
Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 
Prescription and OTC medications  
 
PD Medications – if dose increased, MDS-UPDRS ON required – SV03, 
SV04, SV05, SV06 
 
Vitamins and herbal supplements 
 
Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train participant if necessary. 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially or unused); clarify issues with participant during visit; re-train participant if 
necessary. 
 Vital signs and orthostatic vital signs (blood pressure, heart rate after participant has been 
seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG)  
 
Additional assessments 
Safety Visit 2 (Day 60 + 7d)    
Safety Visit 3 (Day 120 + 7d) 
Safety Visit 4 (Day 150 + 7d) 
Safety Visit 5 (Day 210 + 7d) 
Safety Visit 6 (Day 240 + 7d) 
 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase  
 Collect blood for sparse PK analysis – post-dose random sample to be collected at any time 
relative to last dose of study drug. 
 


Protocol 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 (PD) 
 
 
Page 76 of 198 
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Date: 21 Feb 2018 
The safety visits will be approximately 1 hour each in duration 
 
6.16   VISIT 01 (DAY 14 + 3D) – V01 – COHORT 2 
           VISIT 02 (DAY 30 + 3D) – V02 – COHORT 2 
 
Participant will return to clinic abstaining from taking study drug for 24 + 2 hours in anticipation 
of the sparse PK blood draw.  Participant must bring study drug to the visit.   
 
Assessments should be completed in the order presented below as closely as possible to ensure 
that the neurological tests are performed at approximately the same time (mornings) on each 
testing day: 
 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase  
 Collect blood for sparse PK analysis – pre-dose trough sample to be collected 24 + 2 hours 
post last dose of study drug.  
 Allow the participant to take their study drug  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Obtain vital signs, and orthostatic vital signs (blood pressure, heart rate after participant has 
been seated for 1-3 minutes) 
 Determine dose titration (Visit 1 only – if applicable) 
 Maintain dose management log 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially or unused); clarify issues with participant during visit; re-train participant 
if necessary.   
 Administer MDS-UPDRS Parts I-III 
 
Additional assessments 
Visit 02 (Day 30 + 3d) 
 Perform 12-lead electrocardiogram (ECG)  
 


Protocol 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 (PD) 
 
 
Page 77 of 198 
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Date: 21 Feb 2018 
Visits 01 and 02 will be approximately 2 hours in duration. 
 
  
6.17 VISIT 03 (DAY 90 +7D) – V03 – COHORT 2 
 
Participant will return to clinic, abstaining from study drug for 24 + 2 hours in anticipation of 
sparse PK blood draw.   
 
Participant should bring study drug to the visit as CSF and corresponding serum PK will be 
collected 2 + 0.5 hours post observed dose.  Lumbar puncture must be conducted on the same day 
as the rest of the assessments for Visit 3.  Coagulation parameters, collected within 10 days prior 
to the study visit, must be reviewed by the site investigator prior to performing the LP.   
 
The Site Investigator should assess the participants need for ST at the beginning of the visit.  If 
ST is required, V03 will be abandoned and replaced by the ST visit. The Site Investigator and 
Coordinator should refer to the ST visit description in section 6.24 and follow the ST visit SOA 
(NOTE: expected assessments for the visit being replaced will be provided in section 6.24 as well 
as the ST visit SOA). 
Once ST is initiated, participants should be examined in the medications OFF and ON state.  
Participants should be instructed to NOT take PD medications prior to the study visit.  
Participants must bring both PD medication(s) and study drug to the visit.  PD Medication 
should be taken after completion of MDS-UPDRS Part III OFF exam.  
 
Once ST is initiated, MDS- UPDRS Part III assessment should be completed in the defined 
medications OFF state (approximately 12 hours after the last dose of ST) and in medications ON 
state (based on the participant/ Site Investigator defined BEST ON and/or approximately 1 hour 
after dose of ST). MDS-UPDRS Parts I and II are to be completed in the ON state.  Part IV is 
historical information. 
 
Initiation of ST is a reportable event and CTCC must be notified.  
Assessments should be performed in the order presented below, if possible: 
 
Participant must bring study drug to visit. Assessments should be performed in the order 
presented below, if possible: 
 
 
Administer MDS-UPDRS 
 If ST has been initiated: 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the 


Protocol 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 (PD) 
 
 
Page 78 of 198 
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Date: 21 Feb 2018 
last dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-III in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose 
of ST) 
 Administer MDS-UPDRS Part IV (historical information) - if applicable  
 
 If no therapy has been initiated at this time:  
 Administer MDS-UPDRS Parts I-III   
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see 
SOA). 
 Assessments specifically required at this visit must be completed as well 
as assessments required for the ST visit (see SOA)     
 Collect blood for sparse PK analysis at 2 time points:  
 Sample 1:  pre-dose trough sample must be collected 24 + 2 hours post last 
dose of study drug.  
 Sample 2:  must be collected 2 + 0.5 hours post observed dose at the time 
of the collection of the CSF sample 
 LP must be conducted on the same day as the rest of the assessments for 
Visit 3. 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination (by Site Investigator) 
 Perform fundoscopy exam (to be performed by the Site Investigator prior to the LP)  
 Administer Hoehn and Yahr Scale 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Obtain Vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG) 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase  


Protocol 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 (PD) 
 
 
Page 79 of 198 
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Date: 21 Feb 2018 
 Collect blood for biomarker panel 
 Collect blood for coagulation parameters for a stat read if the participant did not have their 
blood drawn and coagulation parameters tested in the last10 days.  
 Perform lumbar puncture to collect spinal fluid samples:  
 PK sample must be collected 2 + 0.5 hours post observed dose of study drug - note: a 
corresponding blood sample must also will also be collected at the same time.   
 CSF Biomarker sample  
 LP may be performed only after results of the coagulation lab parameters (collected 
at SV02 visit) and fundoscopic exam have been reviewed and documented  
 CSF samples will be process by specialty lab for biomarker panel 
 CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count;  
 LP must be conducted on the same day as the rest of the assessments for Visit 3. 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially used or unused) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Dispense a 3-month resupply of study drug as outlined in Section 7.8.  
Under no circumstances may study drug be pulled from storage and given to a 
participant unless that drug kit has been assigned to that participant via the enrollment 
process.  
The coordinator will record the participant’s initials and participant ID Number on the 
drug kit when it is taken from storage. 
 
V03 will be approximately 4 hours in duration. 
 
6.18 VISIT 04 (DAY 180 ±7D) – V04 – COHORT 2 
 
Participants should be instructed to adjust the time they take their study medication so that PK 
blood collect may occur 2 to 5 hours post-dose. 
 
The Site Investigator should assess the Participants need for ST at the beginning of the visit.  If 
ST is required, V04 will be abandoned and replaced by the ST visit. The Site Investigator and 
Coordinator should refer to the ST visit description in section 6.24 and follow the ST visit SOA 
(NOTE: expected assessments for the visit being replaced will be provided in section 6.24 as 
well as the ST visit SOA). 


Protocol 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 (PD) 
 
 
Page 80 of 198 
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Date: 21 Feb 2018 
 
If ST has already been initiated, Participant should be instructed to NOT take their PD 
medication(s) at home on the morning of V04 and bring their PD medication(s) to clinic.  
Participant must abstain from taking PD medication(s) for approximately 12 hours prior to their 
clinic visit. Participant must bring both PD medication(s) and study drug to visit.   
Once ST has been initiated, Participants should be examined in the medications OFF and ON 
state.  MDS- UPDRS Part III assessment should be completed in the defined medications OFF 
state (approximately 12 hours after the last dose of ST).   PD Medication should be taken after 
completion of MDS-UPDRS Part III OFF exam.  
In medications ON state (based on the participant/ Site Investigator defined BEST ON and/or 
approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed in the 
ON state.  Part IV is historical information. 
 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 
Administer MDS-UPDRS 
 If ST has been initiated: 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last 
dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-IV in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose of 
ST) 
 Administer MDS-UPDRS Part IV (historical information) - if applicable  
 
 If no ST has been initiated at this time:  
 Administer MDS-UPDRS Parts I-III   
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see 
SOA). 
 Assessments specifically required at this visit must be completed as well as 
assessments required for the ST visit (see SOA) 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 


Protocol 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 (PD) 
 
 
Page 81 of 198 
Version  4 
Date: 21 Feb 2018 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination (by Site Investigator) 
 Perform Clinical Global Impression of Change (CGI) (Site Investigator and participant) 
 Administer Hoehn and Yahr Scale 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered by   
participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Administer Parkinson Disease Sleep Scale (PDSS)  
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG) 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, including lipid 
panel, serum lipase and amylase  
 Collect blood for biomarker panel 
 Collect blood for sparse PK analysis:  
 Sample must be collected 2 – 5 hours post dose of study drug. 
 Dispense a 3-month resupply of study drug as outlined in Section 7.8  
Under no circumstances may study drug be pulled from storage and given to a 
participant unless that drug kit has been assigned to that participant via the 
enrollment process.  
The coordinator will record the participant’s initials and participant ID Number on 
the drug kit when it is taken from storage. 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Complete IP accountability and compliance check on all returned IP bottles (empty, 
partially used or unused) 
 
V04 will be approximately 2 - 3 hours in duration. 
 
 
 


Protocol 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 (PD) 
 
 
Page 82 of 198 
Version  4 
Date: 21 Feb 2018 
 6.19 VISIT 05 (DAY 270 ± 7D) – V05 – COHORT 2 
 
Participant should return to clinic, abstaining from study drug for 24 + 2 hours in anticipation of 
sparse PK blood draw; participant should bring study drug and PD medication (if applicable) to 
visit. 
 
 The Site Investigator should assess the participants need for ST at the beginning of the visit.  If 
ST is required, V05 will be abandoned and replaced by the ST visit. The Site Investigator and 
Coordinator should refer to the ST visit description in section 6.24 and follow the ST visit SOA 
(NOTE: expected assessments for the visit being replaced will be provided in section 6.24 as well 
as the ST visit SOA). 
 
If ST has already been initiated, Participant should be instructed to NOT take their PD 
medication(s) at home on the morning of V04 and bring their PD medication(s) to clinic.  
Participant must abstain from taking PD medication(s) for approximately 12 hours prior to their 
clinic visit. Participant must bring both PD medication(s) and study drug to visit.   
 
Once ST has been initiated, Participants should be examined in the medications OFF and ON 
state.  MDS- UPDRS Part III assessment should be completed in the defined medications OFF 
state (approximately 12 hours after the last dose of ST).   PD Medication should be taken after 
completion of MDS-UPDRS Part III OFF exam.  
In medications ON state (based on the participant/ Site Investigator defined BEST ON and/or 
approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed in the 
ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Administer MDS-UPDRS 
 If ST has been initiated: 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last 
dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-IV in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose of 
ST) 
 Administer MDS-UPDRS Part IV (historical information) - if applicable  
 


Protocol 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 (PD) 
 
 
Page 83 of 198 
Version  4 
Date: 21 Feb 2018 
 If no therapy has been initiated at this time:  
 Administer MDS-UPDRS Parts I-III   
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see 
SOA). 
 Assessments specifically required at this visit must be completed as well as 
assessments required for the ST visit (see SOA)   
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase  
 Collect blood for sparse PK analysis – pre-dose trough sample to be collected 24 + 2 hours 
post last dose of study drug.  
 Allow the participant to take their study drug  
 Review concomitant medication use since last visit.  Record changes and additions as follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical exam (by Site Investigator) 
 Administer Hoehn and Yahr Scale 
 Assess need for ST 
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 Dispense a 3-month resupply of study drug as outlined in Section 7.8. Under no 
circumstances may study drug be pulled from storage and given to a participant unless 
that drug kit has been assigned to that participant via the enrollment process.  
The coordinator will record the participant’s initials and participant ID Number on 
the drug kit when it is taken from storage. 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially used or unused); clarify issues with participant during visit; re-train 
participant if necessary.   
 
Visits 05 will be approximately 2 hours in duration. 


Protocol 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 (PD) 
 
 
Page 84 of 198 
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Date: 21 Feb 2018 
6.20 VISIT 06 (DAY 365 ± 7D) – V06 – COHORT 2 (FINAL “ON DRUG” VISIT) 
 
Participant should return to clinic, abstaining from study drug for 24 + 2 hours in anticipation of 
sparse PK blood draw.  Participant should bring study drug and PD medication (if applicable) to 
visit. 
The Site Investigator should assess the participants need for ST at the beginning of the visit.  If 
ST is required, V06 will be abandoned and replaced by the ST visit. The Site Investigator and 
Coordinator should refer to the ST visit description in section 6.24 and follow the ST visit SOA 
(NOTE: expected assessments for the visit being replaced will be provided in section 6.24 as well 
as the ST visit SOA). 
If ST has already been initiated, Participant should be instructed to NOT take their PD 
medication(s) at home on the morning of V06 and bring their PD medication(s) to clinic.  
Participant must abstain from taking PD medication(s) for approximately 12 hours prior to their 
clinic visit. Participant must bring both PD medication(s) and study drug to visit.   
 
Once ST has been initiated, Participants should be examined in the medications OFF and ON 
state.  MDS- UPDRS Part III assessment should be completed in the defined medications OFF 
state (approximately 12 hours after the last dose of ST).   PD Medication should be taken after 
completion of MDS-UPDRS Part III OFF exam.  
In medications ON state (based on the participant/ Site Investigator defined BEST ON and/or 
approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed in the 
ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Administer MDS-UPDRS 
 If ST has been initiated: 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last 
dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-IV in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose of 
ST) 
 Administer MDS-UPDRS Part IV (historical information) - if applicable  
 
 If no therapy has been initiated at this time:  


Protocol 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 (PD) 
 
 
Page 85 of 198 
Version  4 
Date: 21 Feb 2018 
 Administer MDS-UPDRS Parts I-III   
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see 
SOA); if no need for ST, continue with visit schedule. 
 Assessments specifically required at this visit must be completed as well as 
assessments required for the ST visit (see SOA) 
 Collect blood for PK;  
 Pre-dose trough sample to be collected 24 + 2 hours post last dose of study drug.  
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel including lipid panel, 
serum lipase and amylase  
 Collect blood for coagulation parameters 
 Collect blood for biomarker samples 
 Allow the participant to take their study drug and PD medications (if applicable) 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
    Prescription and OTC medications  
 
Vitamins and herbal supplements 
 
Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination by Site Investigator 
 Perform neurological examination by Site Investigator 
 Administer Clinical Global Impression of Change (CGI) (Site Investigator and participant)  
 Determine PD diagnostic features 
 Complete primary diagnosis form 
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered by 
participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Administer Treatment expectation questionnaire (self-administered by participant) 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Hoehn and Yahr Scale  
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes 
 Perform a 12-lead electrocardiogram (ECG) 


Protocol 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 (PD) 
 
 
Page 86 of 198 
Version  4 
Date: 21 Feb 2018 
 Complete a final study drug accountability and compliance check on all returned study 
drug bottles (empty, partially used or unused) 
  Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 
V06 will be approximately 2 hours in duration. 
 
 6.21 VISIT 07 (30 DAYS POST-TREATMENT ± 7 D) – V07 – COHORT 2 
         VISIT 08 (60 DAYS POST-TREATMENT + 7D) – V08 – COHORT 2 END OF STUDY  
The Site Investigator should assess the participants need for ST at the beginning of the visit.  If 
ST is required, V07/V08 will be abandoned and replaced by the ST visit. The Site Investigator 
and Coordinator should refer to the ST visit description in section 6.24 and follow the ST visit 
SOA (NOTE: expected assessments for the visit being replaced will be provided in section 6.24 
as well as the ST visit SOA). 
Once ST has been initiated, Participants should be examined in the medications OFF and ON 
state.  MDS- UPDRS Part III assessment should be completed in the defined medications OFF 
state (approximately 12 hours after the last dose of ST).   PD Medication should be taken after 
completion of MDS-UPDRS Part III OFF exam.  
In medications ON state (based on the participant/ Site Investigator defined BEST ON and/or 
approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed in the 
ON state.  Part IV is historical information. 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Administer MDS-UPDRS 
 If ST has been initiated: 
 Administer MDS-UPDRS Part III OFF (approximately 12 hours after the last 
dose of ST) 
 Allow the participant to take their PD medications  
 Administer MDS-UPDRS Parts I-IV in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose of 
ST) 
 Administer MDS-UPDRS Part IV (historical information) - if applicable  
 
 If no ST has been initiated at this time:  
 Administer MDS-UPDRS Parts I-III   
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see 


Protocol 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 (PD) 
 
 
Page 87 of 198 
Version  4 
Date: 21 Feb 2018 
SOA). 
 Assessments specifically required at this visit must be completed as well as 
assessments required for the ST visit (see SOA)  
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Administer Hoehn and Yahr Scale 
 Administer Treatment expectation questionnaire (participant) 
 Obtain vital signs and orthostatic vital signs (blood pressure, heart rate after participant has 
been seated for 1-3 minutes) 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel,  serum 
lipase and amylase  
 
Additional assessments 
Visit 07 (30 days post-treatment + 7 d) 
 Perform physical examination (by Site Investigator) 
 Height and weight 
 Perform fundoscopy exam (to be performed by the Site Investigator prior to the LP)  
 Perform a 12-lead electrocardiogram (ECG) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Perform lumbar puncture (can be performed on a separate day within the visit window if 
necessary). Lumbar puncture for this visit is strongly encouraged but not required.  
CSF Biomarker panel:  
 LP may be performed only after results of the coagulation lab parameters (collected 
at V06 visit) and fundoscopic exam (performed by Site Investigator) have been 
reviewed and documented  
 CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count; 
 CSF samples will be process by specialty lab for biomarker panel;  
 LP may be performed on a separate day within the visit window, if necessary 
 Collect blood for biomarker panel  
 Complete IP accountability and compliance check on all returned IP bottles (empty, 
partially used or unused), if any were not returned in previous visits. 


Protocol 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 (PD) 
 
 
Page 88 of 198 
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Date: 21 Feb 2018 
 
V07 will be approximately 2 hours in duration. 
 
Additional assessments 
Visit 08 (60 days post-treatment + 7d)   
 Columbia Suicide Severity Rating Scale (C-SSRS) - ‘Since Last Visit’ Version – only  
 Collect blood for pregnancy test (for all women unless they are surgically sterile) 
 
V08 will be approximately 1.5 hours in duration. 
 
6.22 UNSCHEDULED VISITS – VISIT U01, U02, ETC. – COHORT2  
 
 
 
An unscheduled visit may be performed at any time during the study at the participant’s request 
or as deemed necessary by the Site Investigator.  The date and reason for the unscheduled visit 
or telephone contact will be recorded in the source documentation. Reasons for unscheduled 
visits may include, but are not limited to, a potential severe side effect, worsening of symptoms, 
multiple missed doses of medication.  
 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 PD Medications – if dose increased, MDS-UPDRS ON required 
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version 
 Obtain vital signs and orthostatic vital signs (blood pressure, heart rate after participant has 
been seated for 1-3 minutes) 
 Perform 12-lead electrocardiogram (ECG)  
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel. 
 Complete study drug accountability and compliance check on all returned study drug bottles 
(empty, partially or unused). 


Protocol 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 (PD) 
 
 
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 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 
Unscheduled visit durations may vary 
 
6.23 PREMATURE WITHDRAWAL VISIT - VISIT PW – COHORT 2 
 
 
 
 
 
Participants have the right to withdraw from the study at any time without prejudice.  The Site 
Investigator may withdraw study drug from a participant in the study in the event of intercurrent 
illness, adverse events, other reasons concerning the health or well-being of the participant, or in 
the case of lack of cooperation, non-compliance, protocol violation or other administrative 
reasons. Premature withdrawal will be implemented in the case of emergency disclosure of drug 
treatment.   
 
In the event of premature withdrawal from the study, the Premature Withdrawal (PW) Visit 
procedures and evaluations should be completed whether or not the withdrawal is determined at 
a regularly scheduled study visit or at an unscheduled visit.  In instances where the participant 
refuses or cannot to return for a PW visit, it is acceptable to attempt to obtain primary outcome 
data by telephone and arrange for return of study drug.  
 
If a participant will return to the study site for the PW visit and undergo LP, coagulation 
parameters must be reviewed by the site investigator prior to performing the LP.  The sample may 
be collected within 10 days of the PW visit. 
 
Reasons for withdrawal of the participant prior to completion of the study must be stated in the 
eCRF and in the site source documentation for all study participants who were enrolled in the 
study.  The participant will be encouraged to remain in the study and return for the 1 month and 
2 month post drug evaluations (V07 and V08) as a safety follow up. 
 
Adverse events will be followed for 30 days after a Participant’s last dose of study drug.  AEs, 
abnormal laboratory results and abnormal ECG values will be followed to resolution or 
stabilization, whichever occurs first, but no new AEs will be recorded. 
 
In case the study drug has been discontinued for safety laboratory values or ECG abnormalities 
reasons, ECG and abnormal laboratories must be repeated in 2 weeks and at 30 days.  
 
The CTCC must be informed within 24 hours of all subjects who Prematurely Withdrawal from 
study for any reason. 
 
Participant will return to clinic, abstaining from both PD medications (if applicable) for 12 hours; 
the participant should bring both PD medications and study drug to visit. 


Protocol 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 (PD) 
 
 
Page 90 of 198 
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Once ST is initiated, participants should be examined in the medications OFF and ON state.  
Participants should be instructed to NOT take PD medications at home on the morning of the 
study visit.   
 
Once ST is initiated, MDS- UPDRS Part III assessment should be completed in the defined 
medications OFF state (approximately 12 hours after the last dose of ST). PD Medication 
should be taken after completion of MDS-UPDRS Part III OFF exam.  
 
In medications ON state (based on the participant/ Site Investigator defined BEST ON and/or 
approximately 1 hour after dose of ST). MDS-UPDRS Parts I and II are to be completed in the 
ON state.  Part IV is historical information. 
 
Assessments should be completed in the following order as closely as possible to ensure that the 
neurological tests are performed at approximately the same time (mornings) on each testing day: 
 
 Administer MDS-UPDRS 
 
If ST has been initiated: 
• 
Administer MDS-UPDRS Part III OFF (approximately 12 hours after the 
last dose of ST) 
• 
Allow the participant to take their PD medications  
• 
Administer MDS-UPDRS Parts I-IV in ON state (based on the participant/ 
Site Investigator defined BEST ON and/or approximately 1 hour after dose 
of ST) 
• 
Administer MDS-UPDRS Part IV (historical information) - if applicable  
 
 
If no ST has been initiated at this time:  
• 
Administer MDS-UPDRS Parts I-III 
• 
Assess Need for ST  
• 
If participant requires initiation of ST, an ST visit should be   initiated 
(see SOA). 
Assessments specifically required at this visit must be completed as well as assessments 
required for the ST visit (see SOA)   
 Collect blood for PK only if the participants remained on the study drug or discontinued 
within last 3 days;  
 If study drug taken within past 3 days, collection of one random sample at any time   
relative to post-dose at each visit.    
 The time of the last dose of the study drug has to be documented in the eCRF 
 Collect blood for pregnancy test (for all women unless surgically sterile) 


Protocol 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 (PD) 
 
 
Page 91 of 198 
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Date: 21 Feb 2018 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel, lipid panel, serum 
lipase and amylase  
 Collect blood for biomarker samples 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Perform physical examination by Site Investigator 
 Perform neurological examination by Site Investigator 
 Perform fundoscopy exam (to be performed by the PI prior to the LP)  
 Administer Clinical Global Impression of Change (CGI) (Site Investigator and participant)  
 Determine PD diagnostic features 
 Complete primary diagnosis form 
 Administer Mattis Dementia Scale 
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered 
by participant) 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) - ‘Since Last Visit’ Version 
– only  
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant) 
 Administer Treatment expectation questionnaire (self-administered by participant) 
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Hoehn and Yahr Scale  
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes 
 Perform a 12-lead electrocardiogram (ECG) 
 Perform lumbar puncture. (Lumbar puncture for this visit is strongly encouraged but not 
required)  
 LP may be performed only after results of the coagulation lab parameters and 
fundoscopic exam have been reviewed and documented  
 CSF sample will be processed by the site’s local lab facility (unless the lab is not 
able to process the CSF within 4 hours) to evaluate protein and glucose levels 
(routine chemistry) and cell count; 


Protocol 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 (PD) 
 
 
Page 92 of 198 
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Date: 21 Feb 2018 
 CSF samples will be process by specialty lab for biomarker panel;  
 LP may be performed on a separate day within the visit window, if necessary 
 Complete a final study drug accountability and compliance check on all returned 
study drug bottles (empty, partially used or unused) 
 Ensure dose management log is maintained appropriately; clarify issues with participant 
during visit; re-train Participant if necessary. 
 
PW will be approximately 3 hours in duration.   
 
 
 
 
6.24   SYMPTOMATIC THERAPY VISIT 
 
 
If the Site Investigator determines that a participant needs PD ST, every attempt should be made 
to conduct an ST visit prior to initiation of ST.  An ST visit should only be conducted if the subject 
has NOT yet started ST. Initiation of ANY PD medications (amantadine, anticholinergics, 
dopamine agonists or levodopa compounds) OR increase in the dose of medications allowed at 
baseline (amantadine and/or anticholinergics) is considered initiation of ST. 
If the need for ST is determined by the Site Investigator during a regularly scheduled study 
visit or safety visit (per SOA), the ST visit should be initiated.  Additionally, assessments 
required at specified visits (e.g., PK assessment, lumbar puncture, coagulation parameters) 
must be completed as well as assessments required for the ST visit.  
 
If the need for ST is determined between scheduled study visits and the subject has NOT yet 
started taking PD medication(s), the ST visit should be initiated in place of the regularly scheduled 
visit (see SOA). Note: subjects will not be required to return for an additional visit to perform ST 
visit; ST will replace the next scheduled study visit, including safety visits. 
Participants who initiate ST will continue on study drug and will continue in the study until the 
Final Visit.  
Initiation of ST is a reportable event and CTCC must be notified. 
 
Assessments should be performed in the order presented below, if possible: 
  Administer MDS-UPDRS 
 Administer MDS-UPDRS Parts I-III 
 Assess Need for ST  
 If participant requires initiation of ST, an ST visit should be initiated (see SOA). 
 
Assessments specifically required at this scheduled visit must be completed as well as 
assessments required for the ST visit (see SOA)   
 


Protocol 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 (PD) 
 
 
Page 93 of 198 
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Date: 21 Feb 2018 
 Collect blood for PK – per SOA of visit replacing 
 Collect blood for safety lab tests: CBC, comprehensive chemistry panel including  lipid 
panel, serum lipase and amylase  
 Collect blood for coagulation parameters – if replacing V06 
 Collect blood for pregnancy test (for all women unless surgically sterile)- if replacing V06 
or V08 
 Collect blood for biomarker samples – if replacing V06 or V07  
 Perform lumbar puncture if replacing V03 or V07 (can be performed on a separate day 
within the visit window if necessary). Lumbar puncture for this visit is strongly encouraged 
but not required.  
 Perform fundoscopy exam (to be performed by the Site Investigator prior to the LP)  
 Lumbar Puncture for CSF Biomarker panel:  if replacing V03 or V07 
 LP may be performed only after results of the coagulation lab parameters and 
fundoscopic exam (performed by Site Investigator) have been reviewed and 
documented  
 CSF sample will be processed by the site’s local lab facility (unless the lab is 
not able to process the CSF within 4 hours) to evaluate protein and glucose 
levels (routine chemistry) and cell count; 
 CSF samples will be process by specialty lab for biomarker panel;  
 LP may be performed on a separate day within the visit window, if necessary 
 Review concomitant medication use since last visit.  Record changes and additions as 
follows:  
 Prescription and OTC medications  
 Vitamins and herbal supplements 
 Alcohol, tobacco and marijuana 
 Inquire and record information regarding adverse events (AEs)  
 Administer Columbia Suicide Severity Rating Scale (C-SSRS) – ‘Since Last Visit’ version  
 Perform physical examination by Site Investigator 
 Perform neurological examination by Site Investigator 
 Administer Clinical Global Impression of Change (CGI) (Site Investigator and participant)  
 Assess need for ST 
 Determine PD diagnostic features 
 Complete primary diagnosis form 
 Administer Mattis Dementia Scale  
 Administer Parkinson Disease Quality of Life Questionnaire (PDQ-39) (self-administered 
by participant) 


Protocol 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 (PD) 
 
 
Page 94 of 198 
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Date: 21 Feb 2018 
 Administer European Quality of Life Scale (EQ-5D) (self-administered by participant) 
 Administer Parkinson Disease Sleep Scale (PDSS) 
 Administer Blindedness questionnaires (Site Investigator, Coordinator and participant)- if 
replacing V06 or V07 
 Administer Treatment expectation questionnaire (self-administered by participant -  if 
replacing V05, V07 or V08  
 Administer Modified Schwab & England Activities of Daily Living  
 Administer Hoehn and Yahr Scale 
 Obtain vital signs, including height, weight and orthostatic vital signs (blood pressure, heart 
rate after participant has been seated for 1-3 minutes 
 Perform a 12-lead electrocardiogram (ECG) 
 Complete a final study drug accountability and compliance check on all returned study drug 
bottles (empty, partially used or unused) 
 Dispense a 3-month resupply of study drug as outlined in Section 7.8. – if replacing V03, 
V04 or V05 
 
Under no circumstances may study drug be pulled from storage and given to a participant 
unless that drug kit has been assigned to that participant via the enrollment process.  
 
The coordinator will record the participant’s initials and participant ID Number on the 
drug kit when it is taken from storage.  
 
6.25   PROCEDURES FOR PARTICIPANTS WHO DISCONTINUE STUDY DRUG FOR SAFETY AND 
INTOLERABILITY REASONS 
If a participant discontinues study drug for safety reasons, the participant should complete the 
Premature Withdrawal visit (section 6.23) either while the participant is still taking the study 
drug or as soon as possible after the drug discontinuation.  Adverse events will be followed for 
30 days after a Participant’s last dose of study drug.  AEs, abnormal laboratory results and 
abnormal ECG values will be followed to resolution or stabilization, whichever occurs first, but 
no new AEs will be recorded.  The Participants will be encouraged to return for the 30 and 60 
days post drug evaluations (V07 and V08) as per schedule of activities.  
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 95 of 198 
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Date: 21 Feb 2018 
 
 
 
 
 
7. STUDY DRUG ADMINISTRATION/ASSIGNMENT 
 
 
 
 This section will describe how the study drug will appear and how it will be administered. 
Additional details about study drug, supply, labeling, and distribution are provided in the NILO-
PD Operations Manual.  
 
 
7.1  STUDY DRUG 
   The study will use nilotinib 150mg oral capsules and matching placebo.  
Study drug will be supplied as identical appearing capsules (hard gelatin, size 1) for oral        
administration.  
 Active study drug capsules will contain: 150mg nilotinib and the following inactive 
ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium 
stearate and poloxamer 188. 
 Placebo will contain the inactive ingredients (colloidal silicon dioxide, crospovidone, 
lactose monohydrate, magnesium stearate and poloxamer 188) used in the active study 
drug.  
 
The Active and Placebo study drug will be provided by Novartis Pharmaceuticals Corporation 
in 120-count, appropriately sized white high-density polyethylene (HDPE) bottles with a 
standard lid closure. 
 
The CMSU will be responsible for the following: 
 Generation of the clinical labels 
 Labeling of the bottles and kits 
 Configuration of the bottles into 4-bottle kits that will support 6 months of dosing 
 Distribution of kits to the sites 
 
 
7.2 LABELING 
 
At a minimum, the following information will be included on each six (6) month kit box and 
each bottle:  
 
 Name and address of distribution center 
 Study number/Acronym 
 Enrollment ID (randomization number) 
 Description of the product (dosage form, strength, quantity per bottle) 
 Route of administration 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
 Directions for use  
 Storage conditions 
 Space for information to be completed by Site Investigator/designee: 
 Name and telephone number of Site Investigator 
 Dispensing date 
 Participant number 
 Statement “Caution: New Drug – Limited by United States law to investigational use” 
 Statement: “Keep out of reach of children” 
 Labeling will be in English text. 
 
Participants enrolled into Cohort 1 will require one 6-month kit and Participants enrolled into 
Cohort 2 will require two 6-month kits.  
 
 
 
7.3  PHARMACIST/SITE DRUG HANDLING INSTRUCTIONS  
 
 
 
 
 
 Upon receipt of a study drug shipment from the CMSU, the pharmacist or study 
coordinator should perform a complete inventory by comparing packing list to check the 
contents and condition of the shipment.  
 Discrepancies or damaged kits must be reported to CMSU for immediate replacement. 
 The pharmacist/study coordinator performing the inventory the signs, dates and returns a 
copy of the Packing List/Acknowledgement of Receipt to CMSU within 48 hours of 
receipt.  
 File the original Packing List/Acknowledgement of Receipt in the site’s regulatory 
binder. 
 Ensure drug is properly secured (locked area) and stored at 25°C (77°F); excursions 
permitted between 15° to 30°C (59° to 86°F). 
 
Cohort 1  
 
Study drug will be supplied in participant-specific kits that each contains four (4) bottles.  Each 
four (4) bottle kit is intended to support six months of dosing and contains two (2) bottle A’s and 
two (2) bottles B’s.  
 
Cohort 2  
 
300mg Option 
 
Study drug will be supplied in participant-specific kits that each contains four (4) bottles.  Each 
four (4) bottle kit is intended to support six months of dosing.   
 


Protocol 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 (PD) 
 
 
Page 97 of 198 
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Date: 21 Feb 2018 
 
150mg Option 
 
Study drug will be supplied in participant-specific kits that each contains two (2) bottles.  Each 
two (2) bottle kit is intended to support six months of dosing.   
 
 
 
 
 
7.4  STORAGE  
All study drug must be kept in a secure, safe area where temperature is controlled and monitored 
under recommended storage conditions as stated on the labeling (at 25°C (77°F); excursions 
permitted between 15° to 30°C (59° to 86°F) with access limited to persons directly 
involved in the study. 
  
  
 
 
7.5  ACCOUNTABILITY OF STUDY DRUG SUPPLIES          
 
In accordance with local regulatory requirements, the Site Investigator or designated site staff 
must document the amount of investigational product dispensed and/or administered to study 
participants, the amount received from the CMSU, and the amount destroyed upon completion of 
the study. Sites are expected to arrange for destruction any unused study drug at their site 
according to their institution’s policies.  Only if local environmental regulations prohibit the 
destruction of study drug at the site level will the CMSU accept a return of unused study drug 
from the site. 
 
The Site Investigator is responsible for keeping current and accurate records of study drug 
received, dispensed and its disposition.  The study drug must be stored under the appropriate 
conditions (described in Section 7.4) during the course of the study, the Site 
Investigator/designee must maintain an accurate inventory of all study drug dispensed to or 
returned by the Participant.  The reason for any unreturned study drug must be documented.    
 
The Site Investigator is responsible for ensuring product accountability records are maintained 
throughout the course of the study. The inventory will include details of the study drug and 
dispensed to participants, batch, and ID numbers. All unused capsules and bottles must be kept 
until reconciliation of delivery records with accountability logs by the study monitor.  
 
 
  
 
 
7.6   PARTICIPANT NUMBER ASSIGNMENT/ENROLLMENT           
 
 
The Biostatistics Coordination Center (BCC) will generate the randomization code that will 
identify the Enrollment ID/randomization numbers that the CMSU will include on the labels of 
the bottles/kits that will be supplied to sites.   
 


Protocol 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 (PD) 
 
 
Page 98 of 198 
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Date: 21 Feb 2018 
 A5-digit Enrollment ID Number will be assigned at the BL (randomization) visit to confirm 
enrollment and proper receipt of the randomized study drug assignment. The Enrollment ID 
Number will be correspondingly labeled on the respective study drug container 
 
 
 
 The treatment for each participant will be assigned by a randomized code. A blocked 
randomization scheme will be used to ensure approximately even distribution of participants 
in treatment groups.   
 
 As the participant qualifies for the randomized phase of the study, the Site Investigator or 
Study Coordinator completes the RANDOM process in the Internet accessible Electronic 
EDC system, which will assign to that participant an Enrollment ID (Randomization Kit) 
Number.  These numbers are assigned in a randomized order, rather than sequentially. 
 
 
The randomization algorithm and participant enrollment process will be implemented through 
the EDC system using authenticated, password-protected accounts for each study site.  The 
EDC system will check for participant eligibility based on inclusion/exclusion page entries.  
 
 Once a participant has been allocated an Enrollment ID Number, this number cannot be 
assigned to another participant. 
 
 
 
7.7 CODING/EMERGENCY DRUG DISCLOSURE  
 
 
 
The Site Investigator or Site Pharmacist (if applicable) will be provided with a sealed code 
envelope for each Enrollment ID (Randomized Kit Number) for all kits received from the 
CMSU.  With each supply of Cohort #1 kits and Cohort #2 baseline kits will be tamper evident 
envelopes that are labeled with a randomization number and contain a scratch-off (similar to a 
lottery ticket) treatment disclosure associated with a particular randomization number.  These 
envelopes contain the individual study treatment assignments associated with each kit.  All 
sealed code envelopes will be collected at the closeout monitoring visit (either on site or 
remotely) at the end of the study and returned to CMSU will be inspected to ensure that they 
have not been opened.   
 
Sealed code envelopes should only be opened in emergency situations for reasons of participant 
safety.  Whenever possible, the Site Investigator should consult with the Clinical Monitor   or 
another member of the study team prior to opening the sealed code envelope and “breaking the 
blind”. When the sealed code envelope for a Participant has been opened, the reason must be fully 
documented detailing the purpose, date and personnel involved in the source document and entered 
on the case report form. The participant will be withdrawn from further exposure to study drug.   
 


Protocol 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 (PD) 
 
 
Page 99 of 198 
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The disclosure envelope and contents should be sent to an unblinded designee at CMSU within 
48 hours of the disclosure. Assigned drug treatment must not be revealed to any other individual 
associated with the study unless disclosure to him/her is critical to the care of the participant.     
 
 
7.8 DOSAGE OF STUDY DRUG 
 
 
Cohort 1 
      Participants will be randomized in a 1:1:1 ratio into one of the following treatment arms: 
 nilotinib 150mg 
 nilotinib 300mg 
 placebo  
 
 
Rules for drug initiations and titration  
 
The double-blind dosing for the three treatment arms in Cohort 1 will be achieved using a two-
bottle type (Bottle A and Bottle B) approach.  During the two-week dose titration period, 
participants will take one capsule daily from Bottle A.  After two weeks of titration, participants 
will continue to take one capsule daily from Bottle A and add one capsule daily from Bottle B.  
The table below summarizes the contents of Bottles A and B for the 150mg, 300mg and Placebo 
treatment arms.  
 
Treatment Arm 
Bottle A 
Bottle B 
Nilotinib 150mg  
Nilotinib 150mg 
Capsules 
Matching Placebo 
Capsules 
Nilotinib 300mg 
Nilotinib 150mg 
Capsules 
Nilotinib 150mg Capsules 
Placebo 
Matching Placebo 
Capsules 
Matching Placebo 
Capsules 
 
At their baseline visit, participants will be dispensed one (1) bottle A and one (1) bottle B. 
Participants will initiate study drug at a dosage of 150mg daily or matching placebo (1 capsule 
once daily from bottle A) and titrate to either 150mg daily, 300mg daily or matching placebo (2 
capsules once daily) after the first 2 weeks.  To maintain the blind of the study, participants will 
take one (1) capsule from bottle A and one (1) capsule from bottle B once daily. 
 
Participants must remain on one capsule daily dosage level a  minimum of 14 days prior to upward 
titration to 2 capsules once daily.  Dose up-titration can be delayed at the discretion of the Site 
Investigator by 2 weeks but has to occur no later than V02 (1 month).  If the participant is 
unable to up-titrate the dose, this will be considered intolerability and they will remain on 
one capsule daily for the duration of the study.   


Protocol 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 (PD) 
 
 
Page 100 of 198 
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At their 3-month visit, participants will return their bottles A and B from the baseline visit and 
will be dispensed an additional one (1) bottle A and one (1) bottle B.  Participants will continue 
to take one (1) capsule from each bottle once daily for the remainder of the study. 
 
 
Cohort 2 
 
Participants will be randomized in a 2:1 ratio into one of the following treatment arms: 
 
Selected dose from Cohort 1 based on safety and tolerability (150mg or 300mg)  
 
Placebo  
 
 
150mg Dose Option 
 
The double-blind dosing for the two treatment arms in Cohort 2 will be achieved using a single 
bottle type approach.  If 150mg is selected as the dose for Cohort 2, there will be no titration 
period.  Participants will take one capsule daily for the duration of the study. Study drug will be 
supplied in participant-specific kits that each contains two (2) bottles.  Each two (2) bottle kit is 
intended to support six months of dosing.  Participants will be dispensed one (1) bottle at the 
baseline visit and will take one (1) capsule daily.  
 
The table below summarizes the bottle contents for the 150mg and Placebo treatment arms.  
 
Treatment Arm 
Bottle  
Nilotinib 150mg  
Nilotinib 150mg 
Capsules 
Placebo  
Matching Placebo 
Capsules  
 
Participants will be dispensed one bottle for three months of dosing at randomization and at 
Months 3, 6 and 9. At their 3, 6 and 9-month visits, participants will return their bottle from their 
previous visit and will be dispensed an additional one (1) bottle.  Participants will continue 
taking one capsule daily for the remainder of the study. The 60 participants will each require 4 
bottles of study drug.   
 
 
300mg Dose Option 
 
Double-blind dosing for the two treatment arms in Cohort 2 will be achieved using a single 
bottle type approach.  During the two-week dose titration period, participants will take one 
capsule daily.  After two weeks of titration, participants will begin taking two capsules daily.  
 


Protocol 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 (PD) 
 
 
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Dose up-titration can be delayed at the discretion of the Site Investigator by up to 2 weeks and 
must occur no later than V02 (month 1).  If the participant is unable to up-titrate prior to 
V02, this will be considered intolerability and the participant will remain at one capsule 
daily for the duration of the study. 
 
Study drug will be supplied in participant-specific kits that each contain four (4) bottles.  Each 
four (4) bottle kit is intended to support six months of dosing.  Participants will be dispensed two 
(2) bottles at the baseline visit and will take one (1) capsule daily for the first two (2) 
weeks.  After two (2) weeks participants will increase their dose to two (2) capsules daily.  
 
The table below summarizes the bottle contents for the 300mg and Placebo treatment arms.  
 
Treatment Arm 
Bottle  
Nilotinib 300mg  
Nilotinib 150mg Capsules 
Placebo  
Matching Placebo Capsules  
 
At their 3, 6 and 9-month visits, participants will return their bottles from their previous visit and 
will be dispensed an additional two (2) bottles.  Participants will continue taking two (2) 
capsules daily for the remainder of the study.  
 
7.8.1 RULES FOR STUDY DRUG ADMINISTRATION  
 
 Study drug must be taken on an empty stomach. 
 Participants should avoid eating food for at least 2 hours before the dose is taken, and 
avoid eating food for at least 1 hour after the dose is taken. 
 Participants should swallow study drug capsules whole with water. 
  Participants should not drink grapefruit juice, eat grapefruit, or take supplements containing 
grapefruit extract at any time during treatment.  
 Participants should take study medication at a regularly scheduled time daily in the morning 
(except  when scheduled for specific study visits). 
 
If a participant is late by 12 hours in taking their daily dose, it is considered a missed 
dose and should be instructed to take their next dose at their regularly scheduled time. 
 
Participants should not take 2 doses at the same time to make up for a missed dose. 
Participants should never take a double dose in the event of a missed dose. 
 Participants who take medication to block the production of stomach acid (H2 blocker, see 
Appendix  2), should avoid taking these medications for about 10 hours before study drug is 
taken or for at least 2  hours after study drug taken. 
 Participants who take antacids containing aluminum hydroxide, magnesium hydroxide or 
simethicone to reduce the amount of acid in their stomach, should avoid taking these 
medications for about 2 hours before the study drug is taken or for at least 2 hours after study 
drug is taken. 
 


Protocol 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 (PD) 
 
 
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7.9 RULES FOR DOSE REDUCTION 
7.9.1 RULES FOR DOSE REDUCTION FOR INTOLERABILITY   
Dosage reductions can occur at any time during the study.   
 
All study drug reductions must be called into the CTCC. 
 
In case of intolerability at two capsules daily dosage reduction to one capsule daily should be 
attempted prior to discontinuing study drug.  Instructions for dosage reduction may be given either 
over the phone after review of any adverse events, or at the corresponding in-person visit (either 
regularly scheduled or unscheduled visit depending on the timing of the dosage reduction). See 
below for dosage reduction directions.  
 
Cohort 1  
 
Following the 2 weeks of titration, dose reduction will be accomplished by eliminating the capsule 
taken daily from bottle A.  Participants will reduce their dosage in a blinded fashion by 1 capsule 
(equivalent to 150mg of nilotinib or placebo).  Participants unable to tolerate one capsule from 
Bottle B daily will be taken off the study drug and will not be allowed to continue in the study.  
 
Cohort 2 
 
150mg Option –study drug will be suspended (see rules for dose re challenge below, Section 7.10). 
 
300mg Option – Following two weeks of titration, dose reduction is accomplished by reducing 
quantity of capsules taken daily from two (2) to one (1).   
 
If a participant is not able to tolerate the lowest dose of study drug, one capsule daily (150mg or 
placebo), the participant will be taken off the study drug and followed until resolution of any 
adverse events.  The participant will be encouraged to complete the 30 and 60 day post drug 
evaluations as per schedule of activities.  See Section 7.10 for the specific visits instructions.  
 
7.9.2   RULES FOR DOSE REDUCTION/ SUSPENSION FOR SAFETY REASONS   
Dosage reductions can occur at any time during the study.  The following safety variables will 
trigger dose reduction/ suspension 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 103 of 198 
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Table 2. Dose adjustment for safety reasons 
Dose adjustment for QT prolongation 
 
ECG with QTc > 480 msec 
Symptomatic (Cardiac Event, Syncope) 
Terminate nilotinib dosing, treat accordingly, 
and obtain cardiology referral. 
 
Asymptomatic 
Withhold nilotinib 
Perform an analysis of serum potassium and 
magnesium and if abnormal, correct with 
supplements to within normal limits. 
Review concomitant medication usage. 
Repeat ECG in one week. 
Re-challenge allowed if QTcF returns to < 
480 msec and to within 20 msec of baseline 
Terminate dosing if QTcF returns to > 480 
msec after re-challenge 
Dose adjustment for myelosuppression 
 
 
Absolute Neutrophil count < 1.2 X 109/L 
 
Platelet count < 100 X 109/L 
 
Hemoglobin : 2 units drop in hemoglobin 
compared to baseline 
Symptomatic (Infection, Bleeding) 
Terminate nilotinib dosing, treat accordingly, 
and obtain hematology referral. 
Asymptomatic 
Withhold nilotinib and monitor blood counts  
every 2 weeks until normalization 
Re-challenge allowed if prior abnormalities 
fully resolve. Increase hematological 
monitoring to every 2 weeks. 
Terminate dosing if the participant develops 
any recurrent evidence of myelosuppression 
Dose adjustment for selected non –
hematologic laboratory abnormalities  
 
Elevated serum lipase or amylase > 2 X 
the ULN 
 
Elevated bilirubin > 1.5 X ULN 
 
Elevated ALT/AST> 2X the ULN 
 
 
 
 
 
Symptomatic (signs and symptoms of 
pancreatitis, hepatitis) 
Terminate nilotinib dosing, initiate work-up 
and treat accordingly, and obtain 
gastroenterology referral. 
 
Asymptomatic 
Withhold nilotinib and repeat serum 
analyses. 


Protocol 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 (PD) 
 
 
Page 104 of 198 
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Re-challenge if serum lipase, amylase, 
bilirubin, or liver function tests (LFTs) 
normalize. 
Magnesium ≤ 1.5 
 
Potassium ≤ 3.5 
 
Any out of range clinically significant 
electrolyte abnormalities  
 
Symptomatic (cardiac or other adverse 
events) 
Terminate nilotinib dosing, treat accordingly, 
and obtain internal medicine referral. 
 
Asymptomatic 
Correct electrolytes abnormalities, and 
monitor electrolytes every 2 weeks until 
normalization ( if clinically significant).  
Terminate dosing if the participant develops 
recurrent evidence of hypokalemia, 
hypomagnesemia or clinically significant 
electrolyte abnormalities despite appropriate 
supplementation. 
Dosage adjustment for new cardiac 
and vascular occlusive events  
 
New cardiovascular event  
 
 
 
Terminate nilotinib dosing, initiate work-up 
and treat accordingly, and obtain cardiology 
referral. 
 
 
 
See Section 6.11 (Cohort 1) and 9.25 (Cohort 2) for the instructions on the schedule of activities 
for the participants who discontinue the study drug for safety or tolerability reasons. 
 
7.10 
RULES FOR STUDY DRUG RE-CHALLENGE  
 
All attempts at re-titration of study drug must be called into the CTCC. 
 
7.10.1 RULES FOR DOSE RE-CHALLENGE IN CASE OF INTOLERABILITY  
Following dosage reductions for tolerability reasons, participants may be re- challenged 
once during the study titration phase at the discretion of the Site Investigator.   
Participants may resume titration to two capsules daily dosage at the discretion of the Site 
Investigator, provided the intolerability issues have resolved. Participants that are unable to 
tolerate the dose increase will be reduced to one capsule daily and enter the maintenance phase 
of the study. Participants unable to tolerate one capsule daily  will be taken off the study drug and 


Protocol 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 (PD) 
 
 
Page 105 of 198 
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will follow procedures outlined for study termination for intolerability (See Section 6.10- 
Premature Withdrawal).  
 
No re-challenges will be allowed after Safety Visit 02 (SV02), Day 60.  Visit 03, Day 90 will 
be the formal beginning of the maintenance phase of the study.  If intolerability symptoms do not 
resolve by SV02, and participant is not able to tolerate at least one capsule daily, the participant 
will not be allowed to continue in the study and a premature withdrawal visit should be conducted.  
The participant will be required to return to the study site for the 30 and 60 day safety follow-up 
visits (for Cohort 1 = Visit 05 and Visit 06; for Cohort 2 = Visit 07 and Visit 08). 
 
 
7.10.2. RULES FOR DOSE SUSPENSION AND RE- CHALLENGE FOR SAFETY REASONS  
Dosage suspension for safety reasons can occur at any time during the study.  Re-challenge will 
be allowed when abnormalities have resolved fully.  Please, refer to the Table 2 (above)  
 
See instructions for dose re challenges if dose reduction / suspension were triggered by safety reasons 
(Table 2 above).    
 
7.10.3  RULES FOR DOSE RE-CHALLENGE IN CASES NOT RELATED TO SAFETY OR 
TOLERABILITY  
If study drug is temporarily suspended for occurrences other than study drug related safety or 
tolerability issues, study drug may be resumed by the Site Investigator.  Drug suspensions 
lasting more than 7 days require re-titration.  If drug suspension is less than 7 days, the 
participant can restart study drug at prior dosing level. This occurrence must be carefully 
documented on the Dose Management Log. 
 
For drug suspensions lasting more than 7 days, participants need to be re-titrated: 
 
Cohort 1:  Participants will take one capsule once daily (150mg or matching placebo- Bottle A) 
and increase to 2 capsules once daily (one capsule from Bottle A and one capsule from Bottle B) 
in 7 days.  
 
Cohort 2:  If dose will be 150mg: Participants will resume one capsule once daily dose (either 
150mg or matching placebo).    
If dose will be 300mg:  Participants will take one capsule once daily (150mg or matching placebo) 
and increase the dose to 2 capsules once daily in 7 days. 
 
Participants will not be allowed to remain in the study if study drug is permanently discontinued.  
Once the decision to permanently discontinue study drug is made, a premature withdrawal visit 
should be conducted.  The participant will be encouraged return to the study site for the 30 and 


Protocol 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 (PD) 
 
 
Page 106 of 198 
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60 day safety follow-up visits (for Cohort 1 = Visit 05 and Visit 06; for Cohort 2 = Visit 07 and 
Visit 08). 
 
All study drug suspensions must be called into the CTCC. 
 
 
 
 
 
8. CONCOMITANT MEDICATIONS  
 
8.1 ALLOWED CONCOMITANT MEDICATIONS 
Cohort 1- Stable regimen of PD medications, that includes levodopa, will be allowed. The 
regimen needs to be stable for at least 30 days prior to the screening visit and for the duration 
of the study if feasible. Dose adjustment will be allowed at the discretion of the Site 
Investigator.  If PD medications are to be increased, participants should be seen at  regularly 
scheduled visit and MDS-UPDRS ON has to be completed even if not part of the SOA for that 
visit. Reduction of the dose of PD medications for side effects or intolerability can be done at 
any point and can be done either in person or over the phone. The Site Investigator will 
document any new medications or changes in medication at each study visit in source 
documents and on the Concomitant Medication Log in the eCRF. 
 
Cohort 2-Use of amantadine or anticholinergics will be allowed. The dosage needs to be stable 
for 30 days prior to baseline visit and for the duration of the study if feasible.  Initiation or an 
increase in dosage of these medications or the initiation of any new ST during the study will result 
in the participant reaching milestone of time for ST and all assessments as described in the ST 
visit will need to be completed.  
 
Any change in the dosage of these medications will require CTCC notification.  
 
It is anticipated that around 50% of participants recruited in Cohort 2, will require initiation of ST 
during the study.  As per inclusion criteria, Participants are not expected to start ST prior to 
Visit 3 (3 months).  Subsequent to Visit 3, ST may be initiated at any time at the discretion of the 
Site Investigator and /or treating physician. The Site Investigator will document any new 
medications or changes in medication at each study visit in the source documents and on the 
Concomitant Medication Log in the eCRF. 
Time to initiation of ST (for Cohort 2) or change in the dose of ST for Cohort 1 will be 
analyzed. ST dose will be calculated in levodopa dose equivalence (LDE)40.   
A stable regimen of central nervous system acting medications (benzodiazepines, antidepressants, 
hypnotics) is allowed. The dosage needs to be stable for 30 days prior to the baseline visit. The 
dosage can be adjusted during the study at the discretion of the Site Investigator.  Central nervous 
system acting medications can be initiated during the study, if needed, at the discretion of the Site 
Investigator. 


Protocol 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 (PD) 
 
 
Page 107 of 198 
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8.2 CAUTIONARY AND EXCLUSIONARY MEDICATIONS WITH NILOTINIB 
The general categories of exclusionary medications include: QT prolonging drugs, strong 
CYP3A4/5 inhibitors or inducers, anticoagulants and proton pump inhibitors. Detailed lists of 
exclusionary and precautionary medications are available in Appendix 2 and may be updated as 
new information is generated. Study site staff will be informed if any updates to the list(s) are 
made. 
 
Drugs that May Prolong the QT Interval  
Nilotinib may prolong the QT interval. The administration of nilotinib with agents that prolong 
the QT interval such as anti-arrhythmic medicines should be avoided.  See Appendix 2 for a list 
of drugs that can prolong the QT interval (see also the precautionary list of drugs with possible 
or conditional risk of Torsades de Pointes- Appendix 2). 
 
Concomitant Strong CYP3A4 Inhibitors and Inducers 
See Appendix 2 for a list of exclusionary medications: Strong CYP3A4 Inhibitors 
 
Nilotinib is predominantly metabolized by CYP3A4 and partially by CYP2C8.  Therefore, 
concomitant use of strong CYP3A4 inhibitors is prohibited to avoid undesirable increases in 
exposure to nilotinib.  For example, in a drug-drug interaction study of healthy individuals 
receiving the CYP3A4 inhibitor, ketoconazole (400mg once daily), the systemic exposure of 
nilotinib was increased ~ 3-fold.   Products containing grapefruit should also be avoided, as 
previous studies have reported increases in nilotinib Cmax and AUC by 60% and 29%, 
respectively (Yin et al. 201045).   
 
Concomitant use of strong inducers of CYP3A4 will also not be allowed, to avoid reducing 
nilotinib exposures to a clinically relevant extent. In a drug-drug interaction study of rifampicin, 
a potent CYP3A4 inducer, nilotinib AUC decreased by approximately 80%.  Should treatment 
with any potent CYP3A4 inhibitors or inducers be required, therapy with nilotinib should be 
interrupted. 
 
Nilotinib is a competitive inhibitor of CYP3A4, 2C8, 2C9, 2D6, and UGT1A1 in vitro, 
potentially increasing the concentrations of drugs eliminated by these enzymes.  In vitro studies 
also suggest that nilotinib may induce CYP2B6, 2C8, and 2C9, and decrease the concentration 
of drugs which are eliminated by these enzymes.  In human studies, nilotinib is considered a 
moderate inhibitor of CYP3A4.  It has been shown to increase the systemic exposure of oral 
midazolam (a CYP3A4 substrate) 2.6-fold.  As a result, the systemic exposure of drugs 
metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when 
co-administered with nilotinib. Dose adjustment may be necessary for drugs that are CYP3A4 
substrates, especially those that have narrow therapeutic indices when co-administered with 
nilotinib. Therefore, appropriate monitoring is needed for potential adverse effects related to 


Protocol 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 (PD) 
 
 
Page 108 of 198 
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Date: 21 Feb 2018 
concomitant medications that are substrates of CYP3A4 and the other CYP enzymes mentioned 
above with the initiation of nilotinib.  Also, precaution with the initiation of a new medication 
during the course of study should be taken if that agent is a substrate of any of the CYP 
enzymes mentioned above.   
 
Nilotinib inhibits the human drug efflux transporter, P-glycoprotein (P-gp).  If nilotinib is 
administered with drugs that are substrates of P-gp, increased concentrations of the substrate 
drug are likely, and cautions should be exercised. Nilotinib is also a substrate of P-gp, and if it 
is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely.  
Thus, caution should be exercised with concomitant use of P-gp inhibitors.  
 
See Appendix 2 for a list of exclusionary medications: Strong CYP3A4 Inducers. 
 
Drugs that Affect Gastric pH  
 
See Appendix 2 for a list of exclusionary medications: Proton Pump Inhibitors. 
 
Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as 
proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease 
the solubility of nilotinib and reduce its bioavailability. In healthy participants, coadministration 
of a single 400mg dose of nilotinib with multiple doses of esomeprazole (a proton pump 
inhibitor) at 40mg daily decreased the nilotinib AUC by 34%. Increasing the dose of nilotinib 
when coadministered with such agents is not likely to compensate for the loss of exposure. 
Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation 
of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with 
nilotinib is not recommended. 
 
Antacid that contains aluminum hydroxide, magnesium hydroxide, or simethicone are allowed. 
These medicines should be taken about 2 hours before or about 2 hours after they take study drug.  
 
 In healthy participants, no significant change in nilotinib PK was observed when a single 
400mg dose of nilotinib was administered 10 hours after and 2 hours before famotidine (an H2 
blocker). Therefore, when the concurrent use of an H2 blocker is necessary, it may be 
administered approximately 10 hours before and approximately 2 hours after the dose of 
nilotinib. Administration of an antacid (aluminum hydroxide/magnesium 
hydroxide/simethicone) to healthy participants, 2 hours before or 2 hours after a single 400mg 
dose of nilotinib did not alter nilotinib PK. Therefore, if necessary, an antacid may be 
administered approximately 2 hours before or approximately 2 hours after the dose of nilotinib. 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 109 of 198 
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Date: 21 Feb 2018 
9. ASSESSMENTS 
 
 
 
 
 
The timing of assessments described below will be per the protocol Schedule of Activities. 
 
9.1 PRIMARY VARIABLES 
Tolerability: will be defined based on ability to complete the study on the assigned dose. 
Tolerability will be judged by the proportion of participants enrolled in a dosage group able to 
complete the study on their originally assigned dosage. Tolerability of each active arm will be 
compared to group. 
 
Safety: Safety will be primarily assessed based on a direct comparison of treatment-related 
serious adverse events across the two treatment groups.  Additional safety assessments will 
involve further comparisons of adverse events, overall serious adverse events, and safety 
laboratory findings across the two groups. Summary tables will be tabulated and provided for 
review to the Independent Medical Monitor (IMM) and Data Safety Monitoring Board (DSMB) 
on an agreed upon time frequency.).  
 
Efficacy: will be assessed by the change of the MDS-UPDRS Part III over time. All participants 
in cohort 1 and participants in cohort 2 who have started ST will have an assessment of the 
motor exam (Part III) in a practically defined OFF state (approximately 12 hours after the last 
dose of ST) and ON state  (based on the participant/ Site Investigator defined BEST ON, 
approximately 1 hour after dose of ST). A number of other exploratory efficacy outcome 
measures will be collected as per SOA 
 
 
9.2   DOCUMENTATION OF PARKINSON DISEASE 
The diagnosis of idiopathic PD should be documented based on the UK Brain Bank diagnostic 
criteria41. The participants are expected to have at least two out of three cardinal manifestations 
of PD. If tremor is not present, participants must have unilateral onset and persistent asymmetry 
of the symptoms. 
 
 
 
 
9.3 SAFETY ASSESSMENTS 
  
9.3.1 CLINICAL VARIABLES 
In addition to the data from assessments listed below, participants will provide information 
on their demographics, past medical history, including PD, socio-economic history, smoking, 
alcohol and caffeine usage, as well as concomitant medication usage and compliance with 
study procedures. 
 


Protocol 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 (PD) 
 
 
Page 110 of 198 
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9.3.2   MEDICAL HISTORY  
Medical history (by body system with current-status) and detailed PD diagnosis and history 
will be obtained prior to randomization. Clinical evaluations at each subsequent in-person 
visit after randomization will review any changes over baseline and will involve clinical 
assessments including vital signs (blood pressure, heart rate, respiratory rate, temperature), 
weight, electrocardiogram, laboratory abnormalities, and adverse events. 
 
 
9.3.3 PHYSICAL EXAMINATION 
Physical examinations during the study will include assessment of skin, head, neck, 
lymphatic, eyes, ears, nose and throat, abdomen, and respiratory, cardiovascular/peripheral 
vascular and musculoskeletal systems. 
 
9.3.4  NEUROLOGICAL EXAMINATION 
A comprehensive neurological examination, including assessment of tremor and 
coordination, will be performed by the Site Investigator, who will conduct open and directed 
questioning to the participant followed by physical examination. 
 
9.3.5 VITAL SIGNS, WEIGHT, HEIGHT 
Vital signs will be assessed at every visit and will include blood pressure, pulse rate, 
respiratory rate and temperature. Blood pressure (BP) and pulse rate should be taken after 
participant has been seated for 1-3 minutes. Orthostatic vital signs are serial measurements 
of blood pressure and pulse that will be taken in supine position and standing position after 
2 minutes.  At Screening, if BP is “uncontrolled” (Systolic Blood pressure (SBP) greater 
than 180mmHg or Diastolic Blood Pressure (DBP) greater than 98mmHg) on the first 
reading, this can be repeated up to 2 more times to obtain a reading that is “controlled”. If 
the first reading is “controlled” (SBP less than 180mmHg or DBP less than 98mmHg) then 
no need for further measurements.  Measurement of height will be taken at Screening only 
and weight will be measured at all visits. 
 
 
 
 
9.3.6 CLINICAL LABORATORY TESTS 
 
 
 
Clinical laboratory tests will be performed by the laboratory(ies) specified in Section 4 of the 
Form FDA 1572 for the study and their reference ranges will be used. If a clinical laboratory 
not listed on the Form FDA 1572 is used, their reference ranges must be provided to the 
CTCC. 
 


Protocol 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 (PD) 
 
 
Page 111 of 198 
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Date: 21 Feb 2018 
All samples for laboratory analysis must be collected, prepared, labeled, and shipped 
according to the laboratory’s requirements as outlined in detail in the laboratory manual.  
 
 Complete blood count (CBC) with differential (hematocrit, hemoglobin, platelet 
count, RBC indices, Total RBC, Total WBC, and WBC & differential)  
 Comprehensive (metabolic) chemistry panel bicarbonate, blood urea nitrogen (BUN), 
chloride, creatinine, glucose, potassium, sodium glucose, calcium, albumin, total 
protein, electrolytes, alkaline phosphatase (ALP), alanine amino transferase 
(ALT), aspartate amino transferase (AST), bilirubin 
 Specialty blood chemistry- Lipid panel (Lipids comprise cholesterol, High-Density 
Lipoprotein, Low-Density Lipoprotein and triglycerides), serum lipase and 
amylase. 
 Serum pregnancy test for all women unless surgically sterile.  
 All participants will have safety laboratory tests at the designated visits outlined in the 
protocol. These samples will be analyzed at a central laboratory.  All samples for 
laboratory analysis must be collected, prepared, labeled, and shipped according to the 
laboratory’s requirements. There will be provisions for reflex testing in the event of 
an abnormal result requiring immediate retesting. 
 Coagulation Parameters- will be collected prior to performing Lumbar puncture. 
Results of the coagulation parameters should be available to the site Investigator prior 
to performing  Lumbar puncture as per section 6.0   
 
 
9.3.7 FUNDOSCOPY EXAM 
Fundoscopy will be performed by the Site Investigator to examine the disk margins prior to 
every lumbar puncture. If disk margins are not clearly visualized the Site Investigator can 
refer the participant to ophthalmology for the dilated eye exam  
 
 
9.3.8 LUMBAR PUNCTURE (LP) 
The LP will be performed by the Site Investigator or another qualified clinician appointed 
by the Site Investigator. 
A LP for the collection of approximately 15-20 mL of CSF will be conducted for all 
participants per the visit schedule unless there is evidence of clinically significant 
coagulopathy or thrombocytopenia that would interfere with the safe conduct of the 
procedure.  It is expected that all participants will undergo an LP prior to randomization. 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
The baseline LP should be scheduled as indicated in the SOA within 7 to 14 days prior to 
randomization.  Safety laboratory results have to be available prior to LP. The fundoscopic 
exam has to be documented. In case the clinician fails to perform routine LP, LP procedure 
can be scheduled under fluoroscopy – once that has been approved by the CTCC. 
The first 1-2 mL of CSF will be discarded; the subsequent 2-4 mL will be processed at the 
site’s local laboratory facility (unless the laboratory is not able to process the CSF within 
4 hours) to conduct standard analyses on cell count, including red blood cell counts. The 
remaining CSF will be processed and shipped to a central laboratory for biomarker and 
PK assessments (PK only at visit 3). Please refer to the laboratory manual provided by the 
central laboratory. 
The CSF samples will be sent to a central repository to be stored indefinitely for research 
purposes. The CSF samples will be made available to researchers to conduct analyses related 
to PD and other disorders. 
Participants will be closely monitored during the procedure and following the procedure.  
Further details can be found in the Operations Manual for this study. 
 
9.3.9   ELECTROCARDIOGRAM (ECG)  
 
 
 
 
 
Electrocardiogram (ECG) (12-lead) will be performed at designated visits per the Schedule 
of Activities and transmitted electronically to the central ECG laboratory which will 
determine the RR, PR, QRS and QTc (QTcF) intervals and provide a report back to the site. 
The ECGs will be recorded after the participant has been in the supine position for at least 5 
minutes and will be read centrally by qualified cardiologist(s). The ECG report must be 
reviewed by the Site Investigator and any new or worsening clinically significant 
abnormalities will be followed up with the participant and reported in the CRF as an AE. 
 
 
 
 
 
10. CLINICAL ASSESSMENTS  
 
10.1.  MOVEMENT DISORDERS SOCIETY UNIFIED PD RATING SCALE (MDS-UPDRS) 
The MDS-UPDRS will be conducted per the Schedule of Activities. The MDS-UPDRS was 
designed by movement disorders experts to address weaknesses of the original UPDRS (e.g., 
by adding questions on constipation and sialorrhea) while preserving its overall format. The 
MDS-UPDRS has four parts:  
 Part I (non-motor experiences of daily living), comprising 
 Part IA concerning behaviors that are assessed by the Site Investigator with all pertinent 
information from patients and caregivers 
 Part IB that is completed by the patient with or without the aid of the caregiver, but 
independently of the Site Investigator. 


Protocol 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 (PD) 
 
 
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 Part II (motor experiences of daily living), designed to be a self-administered questionnaire 
like Part IB, but similarly can be reviewed by the Site Investigator to ensure completeness 
and clarity. 
 
 Part III (motor examination) has instructions for the rater to give or demonstrate to the 
patient; it is completed by the clinician rater. Once the participant initiates ST MDS-
UPDRS part III will be collected in the defined medications OFF (approximately 12 hours 
after the last dose of ST) state at designated visits and cohorts and both OFF and ON (based 
on the participant/ Site Investigator defined BEST ON and/or approximately 1 hour after dose 
of ST) states for designated visit and cohorts per the schedule of activities. 
 Part IV (motor complications) with instructions for the rater and also instructions to be read 
to the patient. This part integrates patient-derived information with the rater's clinical 
observations and judgments and is completed by the rater. Complete Part IV only if ST has 
been initiated.  
  
Participants will self-administer Parts IB and II, but will review responses for accuracy and 
clarity with the Site Investigator or Coordinator.  Parts IA, III and IV must be conducted by 
the Site Investigator.  Parts I, II, and III will be conducted at study visits as indicated on the 
Schedule of Activities. For participants who have started ST, Part IV will be conducted at 
visits where MDS-UPDRS Parts I-III are conducted/collected.  Use of MDS-UPDRS is 
responsive to core instrument recommendations for the Quality of Life subdomain of the 
National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements 
(CDEs) for PD, and to FDA guidance encouraging use of patient-reported outcomes (PROs) 
as a substantial portion of the responses are patient-reported. Ideally, the same Site 
Investigator should assess all participants on parts IA and III of the MDS-UPDRS at all 
study visits. 
 
10.2   MODIFIED SCHWAB & ENGLAND ACTIVITIES OF DAILY LIVING    SCALE  
 
The Modified Schwab & England scale is a Site Investigator and participant assessment of 
the participant’s level of independence. The participant will be scored on a percentage scale 
reflective of his/her ability to perform acts of daily living. Printed scores with associated 
descriptors range from 100% to 0% in increments of 10%, where 100% is “participant has 
full ability and is completely independent; essentially normal” and 0% is “vegetative 
functions such as swallowing, bladder and bowel functions are not functioning; bedridden”. 
Scores should be coded in increments of 5, (i.e. 095, 090, 085).  This assessment will be 
completed jointly by the participant and Site Investigator.  
 


Protocol 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 (PD) 
 
 
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10.3   PARKINSON’S DISEASE QUESTIONNAIRE - 39 ITEM VERSION (PDQ-39) SCALE 
The PDQ-39 is a disease-specific quality of life questionnaire containing 39 questions 
organized over eight domains: mobility (10 items), activities of daily living (6 items), 
emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), 
communication (3 items), and bodily discomfort (3 items). The PDQ-39 is the most widely 
used health related-QoL instrument in PD, and is considered to have generally good 
psychometric properties and content validity. Use of PDQ-39 is responsive to core instrument 
recommendations for the Quality of Life subdomain of the NINDS CDEs for PD, and to FDA 
guidance encouraging use of patient reported outcomes (PROs). This assessment will be 
collected from participants. 
 
10.4 HOEHN AND YAHR SCALE 
The Hoehn and Yahr is a commonly used scale for describing how the symptoms of PD 
progress. The scale allocates stages from 0 to 5 to indicate the relative level of disability.  This 
scale is included within the MDS-UPDRS and will be completed for all subjects. 
 
 Stage zero: No symptoms. 
 Stage one: Symptoms on one side of the body only. 
 Stage two: Symptoms on both sides of the body. No impairment of balance. 
 Stage three: Balance impairment. Mild to moderate disease. Physically 
independent. 
 Stage four: Severe disability, but still able to walk or stand unassisted. 
 Stage five: Wheelchair-bound or bedridden unless assisted. 
 
10.5  MONTREAL COGNITIVE ASSESSMENT (MOCA) 
In early PD, when cognitive deficits occur, they are subtle and mild and the participants 
usually perform in the normal range of the widely used Mini-Mental State Exam (MMSE). 
The Montreal Cognitive Assessment is a rapid screening instrument like the MMSE, but was 
developed to be more sensitive to patients presenting with mild cognitive complaints. It is 
designated an NINDS CDE for PD. Compared to the MMSE the MoCA may be more 
sensitive to mild cognitive deficits in PD.188 The MoCA assesses short term and working 
memory, visual-spatial abilities, executive function, attention, concentration, language and 
orientation.  The total score ranges from 0 to 30 (highest function).   
 
10.6 PRIMARY DIAGNOSIS ASSESSMENT 
The Primary Diagnosis form captures, in the Site Investigator’s opinion, a current percentile 
probability the participant has idiopathic Parkinson disease as well as meets current diagnostic 
criteria for the study based on available information. Ranges include: 90-100%; 50-89%, 10-
49% and 0-9%. In addition, the Site Investigator selects the most likely primary diagnosis 


Protocol 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 (PD) 
 
 
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from a listing that includes idiopathic PD, many other neurological disorders, and the option 
of no neurological disorder nor other neurological disorder, or other neurological disorder.  
 
10.7 PD FEATURES 
The PD Features assessment captures participant reported first PD symptom onset and actual 
or estimated date of PD diagnosis and symptoms that were present at the time of diagnosis, if 
known. 
 
10.8    BECK DEPRESSION INVENTORY-II (BDI-II) 
The Beck Depression Inventory-II (BDI-II). The BDI-II is a 21-item self-reporting inventory 
covering cognitive, behavioral and somatic aspects of depression.  Each item consists of four 
statements ordered for severity and the participant selects the statement that best describes 
how he or she felt over the past week.  Total scores range from 0 to 63; higher scores indicate 
higher severity. 
   
10.9  PARKINSON’S DISEASE SLEEP SCALE (PDSS) 
The change in sleep function will be assessed via the Parkinson’s disease sleep scale (PDSS).  
The PDSS consists of 15 questions that the person with Parkinson’s rates by marking along 
a line that represents a continuum from worst (0) to best (10). The clinician or scorer then 
measures the marks and assigns values to them. The PDSS asks about movement during the 
night, awkward positions or difficulty in changing positions, nocturia, nightmares, and other 
factors that interrupt sleep. The PDSS is primarily useful for physicians in trying to assess 
the need for nighttime anti-parkinson’s medications.  
 
10.10 EUROPEAN QUALITY OF LIFE SCALE (EQ-5D) 
The EQ-5D is a measure of self-reported health outcomes that is applicable to a wide range 
of health conditions and treatments. It consists of two parts: a descriptive system (Part I) and 
a visual analogue scale (Part II). Part I of the scale consists of 5 single-item dimensions 
including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has a 3-point response scale designed to indicate the level of the problem. Part II 
uses a vertical graduated VAS (thermometer) to measure health status, ranging from worst 
imaginable health state to best imaginable health state. The extended version of the EQ-5D 
includes a valuation task which is used only for valuation studies. There is also an optional 
set of demographic questions (EuroQol Group; McDowell & Newell, 1996; Bowling, 2005). 
 
10.11 BLINDEDNESS EVALUATION 
Per the schedule of activities, the Site Investigator, Coordinator, and participant will complete 
a blindedness evaluation in which each is asked to give his/her independent impression of the 


Protocol 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 (PD) 
 
 
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participant’s treatment assignment and the primary and secondary reasons for this opinion. 
Participants’ responses will not be available to the Site Investigator or Coordinator when they 
make their assessments. 
10.12 C-SSRS (BASELINE AND SINCE LAST VISIT) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an FDA endorsed questionnaire to 
screen for suicidality in trials of central nervous system (CNS) active compounds.42,43  The C-
SSRS is an interview by trained study personnel that should be done at Screening and during 
the study as outlined in the Schedule of Activities. The form called “Baseline” provided at 
Screening collects the history of suicide and a form called “Since the Last Visit” collects data 
at subsequent visits. 
 
10.13 MATTIS DEMENTIA RATING SCALE (DRS-2)  
The Mattis dementia rating scale is a psychometric Instrument designed to assess the extent 
and nature of dementia. The scale consists of content that covers: attention, 
initiation/perseveration, construction, conceptualization, and memory (Monsch et al., 1995). 
The scale has been used extensively in studies assessing cognitive function pertaining to 
neurodegenerative disorders like Alzheimer’s disease (Monsch et al., 1995) and PD (Brown 
et al., 1999). The DRS -2 is responsive to change over time in early and more advanced PD 
and has been validated as a screening test to detect dementia in PD (Llebaria, Mov dis 
2008).   DRS-2 alternate forms will be used at V03 and PW (as applicable) during cohort 1 
and at V03, ST and PW (as applicable) to avoid practice bias.  
 
10.14 CLINICAL GLOBAL IMPRESSION SCALE 
The CGI is a 3-item observer-rated scale that measures illness severity (CGIS), global 
improvement or change (CGIC), and therapeutic response. Each component of the CGI is 
rated separately; the instrument does not yield a global score.  
 
The CGIS is rated on a 7-point scale, with the severity of illness scale using a range of 
responses from 1 (normal) through to 7 (amongst the most severely ill patients). CGIC 
scores range from1 (very much improved) through to 7 (very much worse). Treatment 
response ratings should take account of both therapeutic efficacy and treatment-related AEs 
and range from 0 (marked improvement and no side-effects), and 4 (unchanged or worse 
and side-effects outweigh the therapeutic effects). 
 
10.15  PD – STUDY TREATMENT EXPECTANCY QUESTIONNAIRE 
A self-administered questionnaire assessing expectations of study drug effect will be collected at 
the selected visits as specified in the SOA 


Protocol 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 (PD) 
 
 
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10.16 ADDITIONAL ASSESSMENTS  
 
 10.16.1 ASSESSMENT OF PARTICIPANT COMPLIANCE   
At each study visit, the Site Investigator and/or Study Coordinator will assess the participant’s 
compliance with the study requirements. This will include checks of protocol compliance, 
including use of study drug and concomitant medications, if applicable in order to assess the 
reliability of participant-generated data. (If applicable, note that participants who fail to 
comply with the study requirements may be withdrawn from the study.) 
 
10.16.2 ASSESS NEED FOR SYMPTOMATIC THERAPY (COHORT 2) 
Beginning at Visit 3, the Site Investigator will assess the participant’s need for ST. A 
questionnaire will be used to facilitate the Site Investigator’s decision.  This decision will be 
based on PD disability posing a threat to the participant’s current occupational status, current 
abilities (potential capacities) related to occupational matters, to handle routine personal 
finances and domestic responsibilities, and activities of daily living.   
 
10.16.3 PHARMACOKINETIC ASSESSMENTS 
PK samples will be collected to determine the serum PK  of nilotinib in patients with PD. 
PK analysis will use serum and CSF sample from Visit 3.  
 To investigate the ability of nilotinib to cross the blood brain barrier in PD patients at a 
dose(s) that is tolerable and safe as measured by dose-dependent increases in unbound 
nilotinib levels in the CSF 
 To investigate the relationship between nilotinib exposures in serum and CSF with its 
ability to engage known molecular target(s) (measured by biomarkers of pathway 
inhibition in the serum and CSF (e.g., reduction in phosphor-cAbl)).  
 To investigate factors that could affect the PK of nilotinib such as age, sex, PD severity, 
race/ethnicity. 
 
Serum and CSF PK samples will be collected at the specified visits as outlined in the Schedule 
of activities and summarized below  
 Cohort 1 
 Serum PK samples will be collected  
 Visit 1 (Day 14): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose).  
 Visit 2 (Day 30): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose).   


Protocol 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 (PD) 
 
 
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 Visit 3 (Day 90): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose).  A cerebrospinal fluid (CSF) sample will be collected via lumbar 
puncture 2 + 0.5 hours post-observed dose, and a corresponding serum 
sample will also be collected.   
 Visit 4 (Day 180): Collection of a sample 2 – 5 hours post-dose.   
 Safety Visits 2, 3, 4: Collection of one random sample at any time relative 
to post-dose at each visit. 
 Pre-Mature Withdrawal Visits: If study drug taken within past 3 days, 
collection of one random sample at any time relative to post-dose at each 
visit.    
 
 Cohort 2 
 Visit 1 (Day 14): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose). 
 Visit 2 (Day 30): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose). 
 Visit 3 (Day 90): Collection of a pre-dose trough sample (24 + 2 hours since 
last dose).  A cerebrospinal fluid (CSF) sample will be collected via lumbar 
puncture 2 + 0.5 hours post-observed dose, and a corresponding serum 
sample will also be collected.   
 Visit 4 (Day 180): Collection of a sample 2 – 5 hours post-dose.   
 Visit 5 (Month 9): Collection of a pre-dose trough sample (24 + 2 hours 
since last dose). 
 Visit 6 (Month 12): Collection of a pre-dose trough sample (24 + 2 hours 
since last dose).   
 Safety Visits 2, 3, 4, 5, 6: Collection of one random sample at any time 
relative to post-dose at each visit.   
 Pre-Mature Withdrawal Visits: If study drug taken within past 3 days, 
collection of one random sample at any time relative to post-dose at each 
visit.    
PK samples will be collected and shipped according to the laboratory’s requirements.  
(Refer to instructions in the laboratory’s manual.) 
 
 
10.16.4   BIOMARKERS ASSESSMENTS  
Refer to the laboratory manual for the detailed description of the biomarkers panel.  


Protocol 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 (PD) 
 
 
Page 119 of 198 
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Blood, serum, plasma and spinal fluid samples collection aimed to explore the ability of 
nilotinib to engage its known and exploratory molecular target(s) by biomarkers of pathway 
inhibition in the serum and CSF. In addition, Peripheral blood mononuclear cell (PBMC) 
will be collected. . In addition, the biomarkers panel will explore impact of nilotinib on 
dopaminergic system as measured by the levels of dopamine and its metabolites in CSF and 
collect data on other biomarkers linked to potential mechanism of neuroprotection 
(including but not limited to  CSF alpha-synuclein, total tau, phospho-tau, etc.). Please, refer 
to the biomarkers analysis plan for the specific details on the data collection and to the labs 
operational manual for the instructions for the samples collection.  
 
The samples will be collected, at the visits indicated:   
 Blood for DNA [collected at BL] 
 Blood for  biomarkers [see SOA for the schedule of samples collection] 
 
 
*If the participant permanently discontinues study drug for any reason, before the final visit, 
the blood sample should be taken at an unscheduled study visit on the day participant plans 
to discontinue the study drug as outlined in the SOA for the Premature Withdrawal visit 
(Section 6.10- Cohort 1; Section 6.23- Cohort 2).  
 
DNA Sample Collection 
A blood sample will be collected from each participant at the Baseline visit. These samples 
will be used to extract DNA for storage and shared for future unspecified research.  
Participants will be given the option of refusing to have this sample collected or may request 
that their sample be destroyed at any time, without affecting their participation in the study. 
One of the rationales for the DNA sample collection is to assess if there is correlation of 
response to nilotinib with a particular genetic profile.  
 
 
  
 
 
 
11. INTERCURRENT ILLNESS 
 
 
 
 
 
In the event of an intercurrent illness, it is at the Site Investigator’s discretion to determine if 
the participant may continue in the study with study drug treatment. The clinical course of the 
intercurrent illness will be followed to its appropriate conclusion and full notation made in 
the appropriate source documentation.  All intercurrent illnesses must be recorded in the eCRF 
as adverse events. 
 


Protocol 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 (PD) 
 
 
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12.  PREMATURE WITHDRAWALS/DROPOUTS 
 
Participants will be advised in the written informed consent forms that they have the right to 
withdraw from the study at any time without prejudice, and may be withdrawn at the Site 
Investigator’s/Principal Investigator’s discretion at any time.  Reason for withdrawal from study 
will be documented in the source documents and captured in the eCRF as appropriate.  
 
If a participant who has started study drug terminates the study prematurely, every effort should 
be made to obtain final laboratory tests and evaluations of clinical status, especially those 
pertaining to the study’s primary outcome measure.  Reasonable effort should be made to contact 
any participant lost to follow up during the course of the study in order to complete study related 
assessments and retrieve any outstanding data, drugs or clinical supplies.  Following unsuccessful 
telephone contact, an effort to contact the participant by mail using a method that provides proof 
of receipt should be attempted.  A Participant may be deemed lost to follow up if all efforts have 
failed after one month. Such efforts should be documented in the source documents. Participants 
withdrawn from the study will not be replaced. Such efforts should be documented in the source 
documents. 
 
A Participant may withdraw or be withdrawn from the study for the following reasons: 
 
 Adverse Event  
 Refer to Section 14 
 
 Administrative 
 Withdrawal of consent 
 Request of Study Sponsor or Steering Committee (SC) 
 Request of primary care physician 
 Participant non-compliance with protocol  
 Failure to meet entry criteria 
 Pregnancy 
 Protocol deviation 
 Participant deemed lost to follow up/failure to return 
 Early termination of study 
 Other 
 
All patients who prematurely and permanently discontinue study medication prior to (Visit 
04) in Cohort 1, or (Visit 06) in Cohort 2 will be asked to complete Premature Withdrawal 
visit and Post Drug Evaluation Visits  V05/V06 for Cohort 1 and V07/V08 for Cohort 2, if possible. 
 
Participant early discontinuation of study drug and premature withdrawal (including 
participants who are lost to follow up) should be reported to the CTCC Project Manager within 
24 hours of the site’s knowledge of the event. 


Protocol 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 (PD) 
 
 
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The Screening/Demographic form must be completed for all study participants who sign informed 
consent. This includes participants who completed the study or withdrew/were withdrawn from 
study treatment or were screened and signed a consent form but did not start treatment.   
 
The End of Study/Conclusion of Study Participation form should be completed for all participants 
who have been randomized. If a participant withdraws due to an adverse event, the site must 
ensure that the event is captured on the eCRF Adverse Event form. 
 
 
List of criteria for permanent treatment discontinuation 
 
The following may be justifiable reasons for the Site Investigator to discontinue a participant 
from treatment. 
Participant specific criteria: 
• 
Participant experiences two similar SAEs or one life-threatening SAE 
(assessed as related by the Independent Medical Monitor and/or site 
investigator) 
• 
Participant becomes pregnant 
 
Trial specific criteria: 
• 
Any AEs, per Site Investigator judgment, that may jeopardize the 
participant's safety 
• 
Participant develops any ECG, laboratory or clinical events as outlined in 
Table 2, Section 7.9.2 
• 
Any unblinding of the study treatment by the Site Investigator 
• 
Any use of prohibited concomitant treatment (see Appendix 2) 
• 
At participant’s request, i.e., withdrawal of the consent for treatment 
 
 
Any abnormal laboratory or ECG value will be rechecked by the  Clinical Monitor and the 
central reader, respectively, for confirmation before making a decision of permanent 
discontinuation of the study drug for the concerned participant. 
 
If a participant decides to discontinue participation in the study, he/she should be contacted by 
the Site Investigator in order to obtain information about the reason(s) for discontinuation and 
collection of any potential AEs. 


Protocol 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 (PD) 
 
 
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If possible, and after the permanent discontinuation of study drug treatment, the participant 
will be assessed using the Premature Withdrawal Visit.  
All cases of permanent treatment discontinuation should be recorded by the Site Investigator in 
the source documents and appropriate pages of the eCRF when considered as confirmed. 
Participants who permanently discontinue treatment will be withdrawn from the study.  Please 
refer to section 6.10 (cohort 1) and section 6.23 (cohort 2) for specific instructions for 
premature withdrawal.   
Circumstances for permanent discontinuation and premature withdrawal must be clearly 
documented in source documents. 
 
 
13. ADVERSE EVENTS 
 
 Refer to the Safety Management Plan for a detailed description of adverse events 
assessment.  
 
 
 
 
13.1 ADVERSE EVENT (AE) DEFINITION  
 
 
 
 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
An adverse event can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a drug, and does not imply 
any judgment about causality.  An adverse event can arise with any use of the drug (e.g., off-
label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
 
Some examples of adverse events are: 
 
 
A change, excluding minor fluctuations, in the nature, severity, frequency, or duration of a 
pre-existing condition. 
 
A deterioration in the participant’s condition due to the participant’s primary disease or a 
pre-existing condition. 
 
Development of an intercurrent illness during the study. 
 
Development of symptoms which may or may not be related to the use of a concomitant 
medication or study drug. 
 
Appearance of abnormal laboratory results or significant shifts from baseline, but still within 
the reference ranges, which the Investigator considers clinically important. 
 
 
 
 
 


Protocol 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 (PD) 
 
 
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When possible, AEs should be reported as diagnoses rather than individual signs and symptoms 
or procedures. The AE description must include start and stop dates (when available), intensity, 
causality and outcome, as well as any actions taken. 
 
13.2  SERIOUS ADVERSE EVENTS (SAE) 
 
 
An SAE is an AE or suspected adverse reaction occurring at any dose of the investigational 
product (including placebo) and is considered “serious” if, in the view of either the investigator 
or IMM, it results in any of the following outcomes: 
 Death 
 Report if you suspect that the death was an outcome of the adverse event, and include the 
date if known; 
 Life-threatening adverse event 
 Report if suspected that the patient was at substantial risk of dying at the time of 
the adverse event, or use or continued use of the device or other medical product 
might have resulted in the death of the patient. 
 This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death; 
 Inpatient hospitalization (initial or prolonged) 
 Report if admission to the hospital or prolongation of hospitalization was a 
result of the adverse event. 
 Emergency room visits that do not result in admission to the hospital should be 
evaluated for one of the other serious outcomes (e.g., life-threatening; required 
intervention to prevent permanent impairment or damage; other serious 
medically important event). 
 This does not include hospitalization for: 
• Elective or pre-planned treatment for a pre-existing condition which has not 
worsened since signing the informed consent 
• Social reasons and/or respite care in the absence of any deterioration of the 
participant’s general condition.   
• Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. 
 Disability or Permanent Damage 
 Report if the adverse event resulted in a substantial disruption of a person's 
ability to conduct normal life functions, i.e., the adverse event resulted in a 
significant, persistent or permanent change, impairment, damage or disruption 
in the patient's body function/structure, physical activities and/or quality of 
life; 
 Congenital Anomaly Birth Defect 


Protocol 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 (PD) 
 
 
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 Report if you suspect that exposure to a medical product prior to conception 
or during pregnancy may have resulted in an adverse outcome in the child. 
 Other Serious (Important Medical Events) 
 Report when the event does not fit the other outcomes, but the event may 
jeopardize the participant and may require medical or surgical intervention 
(treatment) to prevent one of the other outcomes. Examples include allergic 
bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency 
room, 
serious 
blood 
dyscrasias 
(blood 
disorders) 
or 
seizures/convulsions that do not result in hospitalization. The development of 
drug dependence or drug abuse would also be examples of important medical 
events. 
 This category also includes any event the Site Investigator or the Clinical 
Monitor judges to be serious or which would suggest a significant hazard, 
contraindication, side effect or precaution. It can also involve the withdrawal 
of a participant from a study due to abnormal lab values, excluding screening 
labs. 
 
Reports of serious adverse events, as defined above, require immediate notification (within 24 
hours of the site’s awareness) to the CTCC Project Manager or Clinical Monitor whether or not 
the Investigator believes that the experience is related to study drug or expected.   
 
Novartis Drug Safety & Epidemiology will also be notified if any of the events above occur.  
Reporting will occur according to the Safety Management Plan. 
  
 
 
13.3 ADVERSE EVENT DEFINITIONS  
1. Adverse events that present after a participant signs the informed consent but prior to the 
initiation of study drug are considered non-treatment emergent adverse events and will be coded 
separately. 
2. Treatment Emergent AES (TEAE): Adverse events that present, or worsen in intensity or 
frequency, following the first dose of study drug will be categorized as treatment emergent 
adverse events.  
 
13.4  IDENTIFYING AND RECORDING OF ADVERSE EVENTS  
At each visit, the site study staff will assess adverse events by recording all voluntary complaints 
of the participant and by assessment of clinical and laboratory features. At each study visit, the 
occurrence of AEs should be sought by non-leading questioning of the participant and caregiver 
during the study and may also be identified when the participant and/or caregiver spontaneously 
volunteered them. Open-ended, non-leading questioning of the participant is the preferred 
method to detect AEs.  
 


Protocol 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 (PD) 
 
 
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Suitable non-leading questions include:   
“How are you feeling?”  
“How have you been doing since your last evaluation?” 
“Have you taken any new medicines since your last evaluation? If so, why?” 
 
Collection of AEs will begin immediately following signing of the ICF through the final study 
visit. All AEs will be recorded into the adverse events eCRF in EDC within 5 business days. AEs 
should be recorded by diagnosis (if known) rather than individual signs and symptoms. Each 
individual event should be recorded in the eCRF.  The Site Investigator will monitor each 
participant closely and record all observed or volunteered AEs. Adverse findings detected at the 
Screening visit (e.g., abnormalities on clinical laboratory testing, ECGs, physical/neuro 
examination) will be recorded as Medical History and adverse events occurring after the 
Screening visit but before starting study treatment will be recorded on the AE log and considered 
non-treatment emergent.  Participants will be contacted by the site to follow up on any 
outstanding AE at the end of the study. 
 
AEs will be followed: 
 until resolution;   
 stabilization; 
 for 30 days after the participant’s last dose of study drug; 
Whichever occurs first. 
 
 
 
 
 
 
 
 
13.5  ADVERSE EVENT CAUSALITY DEFINITIONS 
For each adverse event, the causality (i.e., their relationship to the study treatment) must be 
assessed by the Investigator and recorded on the Adverse Event Log according to the 
classifications in the table below. Ambiguous cases should be considered as having a reasonable 
possibility of a causal relationship unless further evidence becomes available to refute this. 
 
 
 
 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated 
No possible 
relationship  
The 
temporal 
relationship 
between 
drug 
exposure and the adverse event onset/course is 
unreasonable or incompatible, or a causal 
relationship to study drug is implausible. 
Unlikely 
Not reasonably related, 
although a causal 
relationship cannot be 
ruled out 
While the temporal relationship between drug 
exposure and the adverse event onset/course does 
not preclude causality, there is a clear alternate 
cause that is more likely to have caused the 
adverse event than the study drug. 
Possible 
Causal relationship is 
uncertain 
The 
temporal 
relationship 
between 
drug 
exposure and the adverse event onset/course is 
reasonable 
or 
unknown, 
dechallenge 
or 


Protocol 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 (PD) 
 
 
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TERM 
DEFINITION 
CLARIFICATION 
rechallenge information is either unknown or 
equivocal, and while other potential causes may 
not exist, a causal relationship to the study drug 
does not appear probable. 
Probable 
High degree of 
certainty for causal 
relationship 
The 
temporal 
relationship 
between 
drug 
exposure and the adverse event onset/course is 
reasonable.  There is a clinically compatible 
response to dechallenge (rechallenge is not 
required), and other causes have been eliminated 
or are unlikely. 
Definite 
Causal relationship is 
certain 
The 
temporal 
relationship 
between 
drug 
exposure and the adverse event onset/course is 
reasonable, there is a clinically compatible 
response to dechallenge, other causes have been 
eliminated, and the event must be definitive 
pharmacologically or phenomenologically, using 
a satisfactory rechallenge procedure if necessary. 
AE Causality Table adapted from the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), v. 4.03. 
 
 
13.6  ADVERSE EVENT SEVERITY DEFINITIONS  
 
 
 
The Site Investigator will make an assessment of severity (intensity) for each AE reported 
during the study. The assessment will be based on the Site Investigator’s clinical judgement. 
The intensity of each AE recorded in the CRF should be assigned to one of the following 
categories: 
 
 Mild: An event that causes no limitations of usual activities 
 Moderate: An event that causes some limitation of usual activities 
 Severe: An event that prevents carrying out usual activities 
 
 
 
 
 
13.7   REPORTING SERIOUS ADVERSE EVENTS  
 
Collection of SAEs will begin immediately following signing of the ICF through the final 
study visit.  The Site Investigator will monitor each participant closely and record all 
observed or volunteered SAEs.  Serious adverse events occurring after signing the 
informed consent form but before starting study treatment will be considered non-treatment 
emergent. The Site Investigator should record all serious adverse events that occur during 
the study period on the Adverse Event Log and in the appropriate source documents. 


Protocol 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 (PD) 
 
 
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 The Site Investigator and/or Coordinator should notify the CTCC Project Manager by 
phone or email (PM) within 24 hours of his/her becoming aware of the occurrence of a 
serious adverse event.  The PM will in turn notify the Clinical Monitor (CM) and 
Independent Medical Monitor (IMM).   Novartis Drug Safety & Epidemiology will also be 
notified as outlined in Safety Management Plan.   
  
 
The following information should be supplied if available at the time of the initial report: study 
identifier (acronym or short title), site number, participant number, date of onset of event, 
event description, criteria for a serious event that were met, hospital admission information (if 
applicable), and the Site Investigator’s current opinion of the causality/relationship between 
the event and the study drug. 
 
 
Upon completion of the initial report, the CTCC PM will enter the appropriate participant 
information into the EDC Incident Protocol.  
 
 
Within 24 hours of the initial report, the Site Coordinator will complete the MedWatch 3500A 
form and submit to the CTCC, following procedures outlined in the operations manual. The 
MedWatch 3500Aform must be completed for all Serious Adverse Events regardless of causality 
or expectedness. Additional supplementary information (e.g., hospital discharge summary with 
patient identifiers obliterated) should be obtained and forwarded to the CTCC Project Manager. 
 
 
The Site Investigator determines causality (as defined in Section 14.5) of the adverse event for 
the purposes of SAE reporting.  The Independent Medical Monitor (IMM) will make the final 
adjudication on causality.  
 
 
The IMM will review SAE reports to determine causality, severity and expectedness as outlined 
in the Safety Management Plan. 
 
 
IMM, with the assistance of the CTCC PM is responsible for identifying events requiring SAE 
reporting that are “Unexpected” and classified as “Suspected Adverse Reactions” (SUSARs) in 
an expedited manner.   
 
 
The Site Investigator will comply with his/her local IRB regulations regarding the reporting of 
AEs/SAEs.  
 
 
13.8 SERIOUS ADVERSE EVENTS EXPECTEDNESS TO THE STUDY INTERVENTION  
Expectedness will be determined for each SAE reported during the study. The assessment will 
be based on the IMM clinical judgement. The judgement will be based on the known spectrum 
of adverse events reported with the investigational drug nilotinib, as reported in the package 


Protocol 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 (PD) 
 
 
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insert 
(Tasigna®, 
AMN107, 
Novartis, 
Switzerland) 
revised 
12/2017.  
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf 
and limited data from the small study in PD population (see Section 1.1) 
Each SAE should be assigned to one of the following categories: 
• Expected   
• Unexpected  
 
13.9 REVIEW OF ADVERSE EVENTS 
  Adverse events will be presented in tabular form and given to the IMM and the DSMB on 
a periodic basis as agreed upon or as requested. Local Site Investigators are also required to 
fulfill all reporting requirements of their local institutions. 
 
The DCC/BCC will prepare aggregate reports of all adverse events (serious/not serious, 
expected/unexpected and relationship to study drug) for the IMM and the DSMB on an 
agreed upon basis or as requested. In addition, all adverse events will be coded using the 
MedDRA system. A report detailing protocol compliance will also be available from the 
DCC/BCC for DSMB and/or site review monthly or as requested. The research team will 
then evaluate whether the protocol or informed consent document requires revision based on 
the reports.  
 
13.10   FOLLOW-UP OF UNRESOLVED EVENTS 
 
SAEs that remain ongoing past the participant’s last protocol-specified visit will be 
evaluated by the Site Investigator.   
SAEs will be followed: 
 until resolution;   
 stabilization; 
 for 30 days after the Participant’s last dose of study drug; 
Whichever occurs first. 
 
The Site Investigator and CM will assist the IMM, as appropriate, by providing further 
information on the event especially if the event has not resolved or stabilized at the time of 
completion of the initial report. This may involve contacting other clinicians responsible for the 
participant’s care, with participant’s authorization for release of information, to obtain 
information on diagnoses, investigations performed and treatment given. 
 


Protocol 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 (PD) 
 
 
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13.11   REPORTING OF PREGNANCY  
 This study excludes women of child bearing potential. While unlikely, the study site must 
report all pregnancies in study participants or female partners of male participants to the 
CTCC PM within 24 hours from notification.   
 Any participant becoming pregnant during the study will be taken off study drug 
immediately and will have premature withdrawal visit.  
 All reported pregnancies must be followed to conclusion and outcome reported to the CTCC 
PM on the Pregnancy Outcome Form. If an SAE occurs during pregnancy (e.g., spontaneous 
abortion), if the offspring is born with a congenital anomaly or there is a neonatal death, the 
site has to inform the CTCC PM within 24 hours from notification. 
 Pregnancies in Female Partners of Male Participants: 
 Male participants will be instructed through the Informed Consent Form to 
immediately inform the Site Investigator if their partner becomes pregnant during 
the study or within 12 weeks after the last dose of study drug. The Site Investigator 
must notify the CTCC within 24 hours after learning of the pregnancy. Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. A Site 
Investigator who is contacted by the male participant or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
13.12   REPORTABLE EVENTS 
The following occurences will be considered reportable events and must be reported to the CTCC 
within 24 hours of the event, or the Site Investigator’s knowledge of the event.  The CTCC PM 
and Principal Investigator will notify FDA, Novartis and other appropriate entities as necessary 
as outlined in the Safety Management Plan: 
 
Temporary suspension of Study Drug; 
 
Study Drug reduction/rechallenge; 
 
Participant withdrawal; 
 
Early discontinuation of Study Drug; 
 
Serious adverse event (SAE); 
 
Death  
 
Emergency treatment disclosure; 
 
Overdosage, defined as is the accidental or intentional use of the drug in an 
amount higher than the dose being studied even if it did not result in AE; 
 
Pregnancy (including female partner of male participant);  


Protocol 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 (PD) 
 
 
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 
All reports of misuse and abuse of Nilotinib  
 
Other medication errors and uses outside of what is foreseen in the protocol 
(irrespective if a clinical event has occurred) 
 
14. STATISTICAL CONSIDERATIONS 
A brief description of the statistical analysis plan is provided below.  More details will be 
included in a formal statistical analysis plan, which will be developed by Clinical Trials 
Statistical Management Center at the University of Iowa in collaboration with the protocol PI, 
CTCC and NILO-PD Steering Committee (SC) 
Due to the exploratory nature of this study, we will not attempt to make any type of adjustment 
for multiple comparisons.  Correspondingly, unless specified differently, all hypotheses will be 
assessed at that 0.05 significance level. 
 
14.1 GENERAL DESIGN ISSUES 
14.1.1 SUMMARY OF STUDY DESIGN – COHORT 1 
Nilotinib is approved by the FDA for certain types of leukemia.  A small number of cell and 
animal models suggest that nilotinib may positively affect the α-synuclein pathology observed 
in PD1-3,7,31,36.  A small clinical study that lacked a placebo control group and blinding tested the 
safety/tolerability of nilotinib in PD patients for the first time, and also explored its efficacy9  
Although the preliminary data appear promising, the study design used in these prior studies 
precludes making firm conclusions about safety, tolerability, optimal dose, or efficacy10. Hence, 
an opportunity exists to rigorously establish the safety, tolerability, and optimal dose of nilotinib 
to enable and inform the conduct of future definitive efficacy studies in PD participants.   
To address these issues, we will conduct a multi-center, prospective, randomized, controlled, 
double-blinded phase IIa study intended to evaluate the safety, tolerability, and preliminary 
efficacy of nilotinib in participants with moderate to advanced PD.  The first stage of the study 
will enroll approximately 75 participants, randomized in a 1:1:1 manner to receive a once daily 
dose of either nilotinib (150mg), nilotinib (300mg), or placebo.  All Participants will be treated 
for 6 months.  The primary objective of the first stage of this study is to determine the most 
tolerated dose.  This objective will be accomplished by comparing the percentage of 
participants who complete the study on their assigned dose across the three arms.  Although the 
decision will be primarily based on tolerability, we will also compare the safety profiles across 
the three groups and utilize this safety information in making a final decision.  At the end of the 
first stage, we will make one of three decisions: 
 If the 300mg dose is tolerable, and has an acceptable safety profile, this dose will be 
chosen for inclusion in the second cohort. 
 If the 300mg dose is not tolerable, or if the 300mg dose is tolerable but has an 
unacceptable safety profile, then we will consider the 150mg dose.  If the 150mg dose is 


Protocol 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 (PD) 
 
 
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tolerable, and has an acceptable safety profile, this dose will be chosen for inclusion in 
the second cohort. 
 If neither dose is tolerable, or if all tolerable doses have unacceptable safety profiles, we 
will conclude that no dose appears suitably safe and tolerable for inclusion in the second 
cohort.  Under this scenario, the trial should be stopped without proceeding to a second 
cohort. 
A key secondary objective of the first cohort will be to conduct a single group futility 
hypothesis in each PD group comparing the observed change in MDS-UPDRS part III between 
baseline and month 6 in order to determine whether the study can rule out the large change 
previously reported in the prior clinical study9 .  Other secondary objectives will involve 
examining the degree of symptomatic effect of nilotinib as measured by the change in MDS-
UPDRS part III shortly after initiation of study drug (between baseline and 1 month), and after  
discontinuation of study drug [between month 6 (end of treatment)and month 7 (1 month after 
treatment)].  For all participants, assessment of the potential symptomatic effect will be done 
using the MDS-UPDRS part III collected in the ON (based on the participant/site investigator 
defined best ON and/or approximately 1 hour after dose of ST) state. 
 
14.1.2 SUMMARY OF STUDY DESIGN – COHORT 2 
The second cohort will involve a multi-center, prospective, randomized, controlled, double-
blind phase IIa study intended to evaluate the safety, tolerability, and preliminary efficacy of 
nilotinib in participants with early/de novo PD.  Based on the algorithm described in section 
14.1.1 above, the dose most tolerated and safe from cohort 1 will be selected for inclusion in 
cohort 2.  The second stage of the study will enroll approximately 60 participants, randomized 
in a 2:1 manner to receive a once daily dose of either nilotinib (at the dose chosen from the 
findings in cohort 1) or placebo.  All participants will be treated for 12 months.  The primary 
objective of the second stage is to determine whether the chosen dose of nilotinib appears to be 
sufficiently safe and tolerable to support further study in larger studies to further assess efficacy.  
A secondary objective will involve examining the degree of symptomatic effect of nilotinib as 
measured by the change in MDS-UPDRS part III shortly after initiation of study drug (between 
baseline and 1 month), and after  discontinuation of study drug (between month 12 (end of 
treatment) and month 13 (1 month after treatment).  For the participants treated with ST, 
assessment of the potential symptomatic effect will be done in the PD medications ON (based 
on the participant/site investigator defined best ON and/or approximately 1 hour after dose of 
ST) state. 
 
 
 


Protocol 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 (PD) 
 
 
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14.1.3 RANDOMIZATION 
Refer to Section 7.6 for details. 
 
The randomization process will be similar for both Cohort 1 and 2.  Participants will be assigned 
a Participant ID number at the time they sign/date the informed consent form.   The treatment for 
each participant will be assigned by a randomized code. A blocked randomization scheme will 
be used to ensure approximately even distribution of participants in treatment groups.  As the 
participant qualifies for the randomized phase of the study, the Site Investigator or Study 
Coordinator completes the randomization process in the EDC system, which will assign to that 
participant a unique Enrollment ID (Randomization Kit) Number.  These numbers are assigned 
in a randomized order, rather than sequentially. The randomization algorithm and participant 
enrollment process will be implemented through the EDC system using authenticated, password-
protected accounts for each study site.  The EDC system will check for participant eligibility 
based on inclusion/exclusion page entries 
 
14.2 OUTCOMES 
 
14.2.1 PRIMARY OUTCOME 
The specific primary aims of both stages of this study are to determine whether nilotinib is 
sufficiently safe and tolerable to warrant future study in a phase III efficacy trial. 
Tolerability: Tolerability will be defined based on the ability to complete the study (6 months 
for cohort 1; 12 months for cohort 2) on the assigned dose.  Any Participant who has to be 
removed from study drug, or fails to complete the study (for any reason) will be deemed not to 
have tolerated their assigned medication.  Tolerability will be assessed by comparing the 
percentage of Participants enrolled in each dosage group who are able to complete the study on 
their originally assigned dosage group across all groups within each cohort. 
Safety: Safety will be primarily assessed by examining the frequency of treatment- related 
serious adverse events across all groups within each cohort.  
 
14.2.2 SECONDARY OUTCOME 
A key secondary efficacy outcome for each cohort is to compare the MDS-UPDRS part III over 
time. 
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 
(approximately 12 hours after the last dose of ST) and ON state (at least one-hour post dose). 
 


Protocol 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 (PD) 
 
 
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14.3 ANALYSIS PLAN – COHORT 1 
 
14.3.1 PRIMARY HYPOTHESES 
Primary Tolerability Hypotheses: To assess whether either 150mg or 300mg once daily 
dosing of nilotinib is sufficiently tolerable, compared to placebo 
Below, we introduce some key notation that we use to describe the analysis plan for the 
proposed trial: 
 Let p150 represent the true (unknown) percentage of participants treated with 
nilotinib 150mg who will tolerate the assigned medication 
 Let p300 represent the true (unknown) percentage of participants treated with 
nilotinib 300mg who will tolerate the assigned medication 
 Let pp represent the true (unknown) percentage of participants treated with placebo 
who will tolerate the assigned medication 
 The primary tolerability hypotheses being tested in this trial are that participants treated with   
either dose of nilotinib will have similar tolerability to participants treated with placebo.  The 
primary hypotheses will compare the overall tolerability rates for each nilotinib arm vs. placebo 
participants.  Using the notation above, the two one-sided hypothesis tests below will be 
assessed: 
𝐻01: 𝑝150 = 𝑝𝑃     𝑣𝑠.     𝐻𝐴1: 𝑝150 < 𝑝𝑃 
AND 
𝐻02: 𝑝300 = 𝑝𝑃     𝑣𝑠.     𝐻𝐴2: 𝑝300 < 𝑝𝑃. 
Therefore, rejecting the null hypothesis suggests that the particular dose group of nilotinib shows 
significantly less tolerability relevant to the placebo group.  If we do not reject the null hypothesis, 
this would provide justification for proceeding with further study of that drug (pending the results 
of the safety assessment).  Each hypothesis will be assessed via a logistic regression model, 
adjusted for center (stratification variable).  Due to randomization, it is unlikely that important 
covariates will be imbalanced in this study.  However, given the small sample size, this cannot 
be dismissed.  We will assess for important baseline imbalances, and if any imbalances exist, the 
logistic regression model will also adjust for the relevant covariates with important imbalances 
present.    
Primary Safety Hypothesis:  To assess whether there are clinically important increases in 
treatment related adverse events for the nilotinib-treated vs. placebo participants. 
 
The set of primary safety hypotheses will involve separate comparisons of the safety profiles for 
each of the nilotinib groups vs. placebo.  As described elsewhere, general assessments of safety 
will occur throughout the trial in conjunction with reviews by the IMM and DSMB.  This specific 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
primary hypothesis will be assessed in two ways.  First, the percentage of participants who 
experience a treatment-related SAE, overall and by body system, will be compared across the two 
groups using standard chi-square tests.  Then, the rates of treatment-related SAE’s across the two 
groups will be compared using a Poisson regression model.  In order to provide an overall 
summary of the safety of each nilotinib dose, additional safety assessments will involve further 
comparisons of adverse events, serious adverse events, and safety laboratory findings across the 
two groups.  All of this information will be synthesized and reviewed by the Sponsor and steering 
committee at the end of each cohort.  Notably, this summary information will be critical for 
making the dosing decision for cohort 2 (or deciding not to proceed with cohort 2) at the 
conclusion of follow-up for cohort 1. 
 
 14.3.2  DECISION ALGORITHM BASED ON PRIMARY HYPOTHESES 
At the conclusion of these analyses, a decision rule will be invoked to make a determination 
regarding the “best” dose to move forward with in the second cohort of the study.  This decision 
will be based on a combination of the results from the tolerability and safety hypotheses.  In 
general, the decision algorithm will proceed as follows: 
 Did the 300mg nilotinib group show suitable tolerability? 
o If ‘Yes’, then did the 300mg nilotinib group show suitable safety? 
 If ‘Yes’, then recommend taking the 300mg nilotinib dose to the second 
cohort 
 If ‘No’ then did the 150mg nilotinib group show suitable tolerability? 
 If ‘Yes’, then did the 150mg nilotinib group show suitable safety? 
o If ‘Yes’, then recommend taking the 150mg nilotinib dose to 
the second cohort 
o If ‘No’ then recommend stopping the study and concluding 
that neither dose is sufficiently safe and tolerable to justify 
further exploration 
 If ‘No’ then recommend stopping the study and concluding that 
neither dose is sufficiently safe and tolerable to justify further 
exploration 
o If ‘No’, then did the 150mg nilotinib group show suitable tolerability? 
 If ‘Yes’, then did the 150mg nilotinib group show suitable safety? 
 If ‘Yes’ then recommend taking the 150mg nilotinib dose to the 
second cohort 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
 If ‘No’ then recommend stopping the study and concluding that 
neither dose is sufficiently safe and tolerable to justify further 
exploration 
 If ‘No’ then recommend stopping the study and concluding that neither 
dose is sufficiently safe and tolerable to justify further exploration 
 
14.3.3  KEY SECONDARY OBJECTIVE 
A key secondary objective of this study is to conduct a single group hypothesis within each PD 
group to assess “futility” for replicating the large difference observed in a previously published 
study9 .  This will be based on a single group hypothesis test comparing the observed change in 
the MDS-UPDRS part III scores collected ON (based on the participant/site investigator defined 
best ON and/or approximately 1 hour after dose of ST) between baseline and 6 months to the 
observed change reported from the Pagan et al9  study in order to determine whether we can rule 
out the large change previously reported.  Based on the results from the Pagan et al9 publication, 
which used the UPDRS: 
 Mean change over 6 months in the 150mg group = 7.0 reduction (std dev = 12.9) 
 Mean change over 6 months in the 300mg group = 10.8 reduction (std dev = 7.8) 
For consistency, we will test a similar hypothesis within each group using the smallest observed 
reduction. However, since we will be using the MDS-UPDRS, we include a correction factor of 
1.4 as specified in Goetz et al44.  In other words, the ‘futility’ test will be based on the following 
set of hypotheses: 
H0: δ ≤ -9.8 (7 x 1.4) vs. HA: δ > -9.8 
where δ represents the change from baseline to 6 months in the corresponding group being tested.  
Since this is an early phase exploratory study, and we want to ensure adequate power for ruling 
out the large effects previously observed, we assume an alpha level of 0.10 for each one-sided 
hypothesis of interest. 
To assess this hypothesis, the following linear mixed effects model (LMM) will be used.  Model 
parameters and variance components will be estimated using restricted maximum likelihood.  
Several potential covariance structures (unrestricted, independent, compound symmetry, 
autoregressive 1) will be considered, and the model with the lowest AIC value will be selected.  
The following model will be used:  
𝜇𝑖𝑗= 𝛽0 + 𝛽1𝑋1 + 𝛽2𝑋2 + 𝛽3𝑋3 + 𝛽4𝑋4 + 𝛽5𝑋5 + 𝛽6𝑋6 + 𝑒𝑖𝑗 
where 
 µij is the difference between the observed MDS-UPDRS part III score for the jth 
visit (day 14, day 30, month 3, month 6) and the MDS-UPDRS part III score 
observed at baseline for ith participant 


Protocol 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 (PD) 
 
 
Page 136 of 198 
Version  4 
Date: 21 Feb 2018 
 X1 represents the baseline MDS-UPDRS part III score for the ith participant 
 X2 is an indicator term representing the center for the ith participant 
 X3 = 1 the record is from a day 14 visit, and 0 otherwise 
 X4 = 1 the record is from a day 30 visit, and 0 otherwise 
 X5 = 1 the record is from a 3 month visit, and 0 otherwise 
 X6 = 1 the record is from a 6 month visit, and 0 otherwise 
 eij is random error for ith participant from jth visit 
The desired test of interest can be obtained by testing the null hypothesis of the following 
contrast: 
H0: β6 ≤ -9.8 vs. HA: β6 > -9.8 
Rejecting the null hypothesis implies that a future study is unlikely to observe the large effects 
reported in the Pagan et al (2016) study.  However, that would not rule out potentially meaningful 
effects on a smaller scale.  Furthermore, note that failure to reject the null hypothesis does not 
imply that a significant difference has been observed.  If the null hypothesis is not rejected, or if 
the hypothesis is rejected but the observed differences seem potentially meaningful, further study 
would be warranted. 
 
14.3.4 OTHER SECONDARY OBJECTIVES 
The study will also assess additional secondary objectives comparing the change in MDS-UPDRS 
scores over time between groups in order to establish both the potential degree of symptomatic 
effect of nilotinib and the impact of nilotinib on the progression of PD disability.  These analyses 
will be examined using a model similar to that described in section 15.3.3, with additional terms 
added to represent the treatment group, post-treatment visits, and potential interaction terms.  The 
interaction terms will be assessed initially.  If significant, then the specific terms will be extracted 
for each comparison: 
 To assess the impact of nilotinib on the progression of PD disability, we will examine 
the change in MDS-UPDRS from baseline to 6 months (evaluated for both the “OFF” 
and “ON” states 
 To assess the degree of symptomatic effect, we will compare both: 
o Change in MDS-UPDRS from baseline to 1 month (MDS-UPDRS ON state ) 
 Change in MDS-UPDRS from 6 months (end of treatment) to 7 months (1 month post 
treatment) (MDS-UPDRS ON state) 
 
If no significant interaction is observed, then it will be assumed that the effect of nilotinib is 
consistent over time and a single result will be provided. 
 


Protocol 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 (PD) 
 
 
Page 137 of 198 
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Date: 21 Feb 2018 
14.3.5  EXPLORATORY OBJECTIVES 
A number of additional exploratory objectives will be assessed in order to further examine the 
impact of nilotinib on disability, quality of life, and functional status.  These will include, but are 
not limited to: 
 Motor Disability 
o Change in MDS-UPDRS Total Score (Performed for ON and OFF scores) 
o Change in Ambulatory Capacity (sum of 5 MDS-UPDRS questions – falling, 
freezing, walking, gait, postural stability) 
o Analysis of ST utilization as measured by levodopa equivalence dose 
o Severity of motor complications as measured by MDS-UPDRS part IV 
subscale (complications of therapy) 
 Cognitive Disability – Change in cognitive function as measured by the change in 
DRS-2 (Mattis dementia rating scale) 
 Sleep Function – Change in sleep quality as measured by the Parkinson’s disease sleep 
scale (PDSS) 
o Measures of Global Disability – Clinician and patient global impression of change 
score (CGI) 
o Measures of Functional Status and Quality of Life 
 Change in the MDS-UPDRS Motor and Non-Motor Experiences of Daily 
Living subscores 
 Change in the modified Schwab and England scale 
 Change in Parkinson Disease Quality of Life Questionnaire 39 (PDQ-39) 
 Change in European Quality of Life Scale (EQ-5D) 
 
14.4 ANALYSIS PLAN – COHORT 2 
 
14.4.1 PRIMARY HYPOTHESES 
Primary Tolerability Hypotheses: To assess whether the dose selected from cohort 1 (either 
150mg or 300mg once daily dosing of nilotinib) is sufficiently tolerable, compared to placebo 
The primary tolerability hypothesis for cohort 2 will be tested in a similar manner to that described 
above for cohort 1, with the exception that only a single test will be performed: 
𝐻01: 𝑝𝑠𝑒𝑙𝑒𝑐𝑡𝑒𝑑= 𝑝𝑃     𝑣𝑠.     𝐻𝐴1: 𝑝𝑠𝑒𝑙𝑒𝑐𝑡𝑒𝑑< 𝑝𝑃 , 
where pselected represents the true (unknown) percentage of participants treated with the nilotinib 
dose selected in cohort 1 who will tolerate the assigned medication. The hypothesis will be 
assessed via a logistic regression model, adjusted for center (stratification variable).  Due to 
randomization, it is unlikely that important covariates will be imbalanced in this study.  However, 
given the small sample size, this cannot be dismissed.  We will assess for important baseline 


Protocol 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 (PD) 
 
 
Page 138 of 198 
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Date: 21 Feb 2018 
imbalances, and if any imbalances exist, the logistic regression model will also adjust for the 
relevant covariates with important imbalances present.    
Primary Safety Hypothesis:  To assess whether there are clinically important increases in 
adverse experiences for the nilotinib-treated vs. placebo participants. 
The primary safety hypothesis will involve a comparison of the safety profiles for the group of 
participants treated with the chosen dose of nilotinib vs. placebo.  This will be assessed in the 
same manner described above for cohort 1. 
 
14.4.2 SECONDARY OBJECTIVES 
The second cohort will also assess secondary objectives comparing the change in MDS-UPDRS 
scores over time between groups in order to establish both the potential degree of symptomatic 
effect of nilotinib and the impact of nilotinib on the progression of PD disability.  These analyses 
will be examined using a model similar to that described in section 15.3.3, with additional terms 
added to represent the treatment group, additional visits due to extended follow-up time in the 
second cohort, post-treatment visits, and potential interaction terms.  As with the first cohort, the 
interaction terms will be assessed initially.  If significant, then the specific terms will be extracted 
for each comparison: 
 To assess the impact of nilotinib on the progression of PD disability, we will examine 
the change in MDS-UPDRS from baseline to 12 months (evaluated for both the “OFF” 
and “ON” states 
 To assess the degree of symptomatic effect, we will compare both: 
o Change in MDS-UPDRS from baseline to 1 month (MDS-UPDRS ON state) 
 Change in MDS-UPDRS from 12 months (end of treatment) to 13 months (1 month 
post treatment) (MDS-UPDRS ON state ) 
If no significant interaction is observed, then it will be assumed that the effect of nilotinib is 
consistent over time and a single result will be provided. 
Unlike the first cohort, the second cohort involves an early/de novo cohort of PD participants.  It 
is expected that no participants will be on ST initially (as per inclusion/ exclusion criteria).  
However, it is expected that many will need to begin ST over the course of the 12 month follow-
up period.  Hence, we will perform this analysis three separate ways: 
 Using ON scores for those on ST, combined with scores for those not yet having 
started ST, over the entire 12 month period 
 Using OFF scores for those on ST, combined with scores for those not yet having 
started ST, over the entire 12 month period 
 Using only MDS-UPDRS part III scores prior to initiation of ST for each participant.  
Note that this analysis will ignore all information collected post initiation of ST for 
each participant, and will thus involve much less data than the other two comparisons 


Protocol 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 (PD) 
 
 
Page 139 of 198 
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Date: 21 Feb 2018 
 
14.4.3 EXPLORATORY OBJECTIVES 
A number of additional exploratory objectives will be assessed in order to further examine the 
impact of nilotinib on disability, quality of life, and functional status.  These will include, but are 
not limited to: 
 Motor Disability 
o Change in MDS-UPDRS Total Score (Performed for ON and OFF scores) 
o Change in Ambulatory Capacity (sum of 5 MDS-UPDRS questions – falling, 
freezing, walking, gait, postural stability) 
o Analysis of ST utilization as measured by levodopa equivalence dose 
o Severity of motor complications as measured by MDS-UPDRS part IV 
subscale (complications of therapy) 
 Cognitive Disability – Change in cognitive function as measured by the change in 
Mattis dementia rating scale (DRS-2) 
 Sleep Function – Change in sleep quality as measured by the Parkinson’s disease sleep 
scale (PDSS) 
 Measures of Global Disability – Clinician and patient global impression of change 
score (CGI) 
 Measures of Functional Status and Quality of Life 
o Change in the MDS-UPDRS Motor and Non-Motor Experiences of Daily 
Living subscores 
o Change in the modified Schwab and England scale 
o Change in Parkinson Disease Quality of Life Questionnaire 39 (PDQ-39) 
o Change in European Quality of Life Scale (EQ-5D) 
o Explore impact of nilotinib on: 
 Dopaminergic system as measured by an increase in dopamine and its 
metabolites in CSF (e.g., HVA level) 
 Other biomarkers linked to potential mechanism of neuroprotection 
(e.g., CSF alpha-synuclein, total tau, phospho-tau, cytokines, 
neurofilament, Neuron Specific Enolase/NSE, etc.) 
 
14.5  SAMPLE SIZE JUSTIFICATION 
 
14.5.1 SAMPLE SIZE – COHORT 1 
For the purposes of computing the required sample size, we assumed that at least 90% of 
participants on placebo will meet the study definition of “tolerability” (completing the study 
on the assigned dose).  Furthermore, it was determined that an absolute decrease of 30% or 
greater would provide sufficient tolerability concerns that would not warrant further study of 


Protocol 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 (PD) 
 
 
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that dose.  Hence, the sample size was chosen to provide sufficient power to compare an 
expected 90% tolerability rate in the placebo group versus a 60% or lower tolerability rate in 
each of the treatment groups.  Under these assumptions, and considering a one-sided test with 
an alpha of 0.05, a total of 25 participants per group provides 80% power for the 
moderate/advanced cohort. 
For the major secondary objective, we utilized preliminary estimates based on results from 
Table 2 in the Pagan et al (2016) study. Using these estimates, we computed the power of the 
study proposed for cohort 1 to detect “futility” based on comparisons of the change within the 
dosage groups themselves. Converting from the UPDRS used in the Pagan et al (2016) study 
to the MDS-UPDRS proposed for this study, the test is set up in the manner described in 
section 15.3.3. Furthermore, we believe that since the conversion factor maintains the 
relationships between the mean and standard deviation, although the expected values might 
differ the power calculations provided below give a valid estimate of the power for the 
proposed study. Specifically, we assume an alpha level of 0.10 for the one-sided futility 
hypothesis, and assume a standard deviation of 12.9.  The table below shows the power, 
computed across a range of assumed values for the true change from baseline in the nilotinib 
treated participants.  The table below demonstrates the benefits of using the futility hypothesis 
(with differences shown in both UPDRS and converted to MDS-UPDRS units).  When the 
true change in MDS-UPDRS part III over the 6 month treatment period involves an increase 
in scores (implying progression of disease), the test will declare “futility” with high 
probability.  Likewise, when the true change in MDS-UPDRS part III is equal to or greater 
than the observed change in the Pagan et al (2016) study, the study has a very low change of 
incorrectly declaring futility.   If the observed change in the MDS-UPDRS part III is half that 
observed in the prior study (a reduction of 3.5), then the study has marginal power (52%) to 
declare futility. If there is no observed reduction associated with treatment, the study has 92% 
power to declare futility. Given the sample size limitations of this study, we feel that this 
provides a reasonable change of addressing the main futility question of interest regarding 
whether the large observed effect in the prior study can be refuted.  The test of futility will 
have adequate power mainly if the direction of effect is in the opposite direction from that 
observed in the previous study (i.e., if there is no reduction, only a potentially smaller increase 
in MDS-UPDRS over time).  These sample size calculations were based on the observed 
change for the 150mg group in the Pagan et al study9.  Since bigger effects were observed 
over 6 months for the 300mg group, the study has adequate power for addressing futility in 
the 300mg group in a similar manner. 
True Change in 
UPDRS 
 
-7.0 
 
-3.5 
 
0 
 
+3.5 
True Change in 
MDS-UPDRS 
 
-9.8 
 
-4.9 
 
0 
 
+4.9 
Pr(Futility) 
10% 
52% 
92% 
99% 


Protocol 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 (PD) 
 
 
Page 141 of 198 
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Date: 21 Feb 2018 
14.5.2 SAMPLE SIZE – COHORT 2 
For the purposes of computing the required sample size for cohort 2, we make similar 
assumptions to those stated above for cohort 1.  Using these assumptions, a sample size of 40 
participants on the selected dose from cohort 1 and 20 participants on placebo for the early/de 
novo cohort provides 80% power. 
 
14.6 IMPACT OF MISSING DATA 
The primary analysis will follow the intent-to-treat (ITT) paradigm.  All enrolled participants 
must be included in the primary ITT analysis, and will be analyzed in the treatment group to 
which they were initially randomized.  As such, it will be critically important to minimize the 
occurrence of missing data.  Obviously, the optimal strategy for dealing with missing data is 
to make every effort to obtain complete data during the conduct of the study.  Our team of 
data managers and protocol coordinators will work diligently and use a variety of methods in 
order to minimize the percentage of missing data in this trial.  Nevertheless, there is likely to 
be a small percentage of missing data.  For the primary analysis, we will take a conservative 
approach and assume that any participant not completing the study for any reason did not 
tolerate study therapy.  In order to further assess the potential dependence of the results of the 
primary analysis to these missing values, a series of sensitivity analyses will be conducted.  
We will attempt to collect as much detailed information as possible for participants who are 
lost to follow-up or terminate the study early due to any reason.  Any participants who 
terminate treatment or the study early due to tolerability concerns (AEs) will always be 
counted as not tolerating the dose.  For participants that do not provide complete data, and for 
which there is no clear tolerability concern, we will analyze the data using the following 
strategies: 
 Using Only Observed Data (No Imputation) 
 Worst-case scenario: Assume all missing participants in the treatment group did not 
tolerate the dose and all missing participants in the placebo group did tolerate the dose 
 Best-case scenario: Assume all missing participants in the  rituximab group did 
tolerate the dose and all missing participants in the placebo group did not tolerate the 
dose. 
The results of these analyses will provide important information regarding the sensitivity of 
the findings to the missing data, and will be critical to the Steering Committee in assessing 
the full value of the study results. 
 
 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
15. PHARMACOLOGY  
 
15.1 PHARMACOLOGY PLAN 
 Pharmacology Objectives 
 Primary Pharmacology Objective 
 To determine the serum PK of nilotinib in patients with Parkinson’s disease. 
 Secondary Pharmacology Objectives 
 To investigate the ability of nilotinib to cross the blood brain barrier in 
Parkinson’s disease patients at a dose(s) that is tolerable and safe as 
measured by dose-dependent increases in unbound nilotinib levels in the 
CSF. 
 Exploratory Pharmacology Objectives 
 To investigate the relationship between nilotinib exposures in serum and CSF 
with its ability to engage known molecular target(s) (measured by biomarkers 
of pathway inhibition in the blood and CSF (e.g., reduction in phosphor-cAbl).  
 To investigate factors that could affect the PK of nilotinib such as age, sex, PD 
severity, race/ethnicity. 
 
15.2 PHARMACOKINETIC ANALYSIS 
 
 Nilotinib serum and CSF concentrations will be assayed at a laboratory specified in 
the Laboratory Operational Manual  
 For nilotinib serum PK, a nonlinear mixed-effects population PK model will be 
developed from the serum concentration-time data collected from study participants.  
The analysis will focus on characterizing the mean population-level PK parameters 
and variability of nilotinib in PD patients (e.g. apparent oral clearance, volume of 
distribution, etc.).  Participant-level covariates will be incorporated into the 
population PK model to determine their effects on the PK parameters.  Individual 
Bayesian estimates of nilotinib exposure (e.g. apparent oral clearance, Area Under 
the Concentration-Time curve, etc.) will be generated from the final population PK 
model to evaluate their association with pharmacodynamics markers.     
 Nilotinib CSF concentrations will be summarized by geometric means (with 
coefficient of variations) and median values (with interquartile ranges) in aggregate, 
and compared by dose level.   
 
 
 
 


Protocol 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 (PD) 
 
 
Page 143 of 198 
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Date: 21 Feb 2018 
16. REGULATORY/ETHICS 
 
 
 
 
 
16.1 COMPLIANCE STATEMENT 
 
 
 
 
This study will be conducted in accordance with the Good Clinical Practice (GCP) guidelines 
promulgated by the International Conference on Harmonization (ICH) and FDA, and any 
applicable national and local regulations including FDA regulations under 21 CFR Parts 11, 50, 
54, 56, 312 and 314. 
 
All procedures not described in this protocol will be performed according to the study Operations 
Manual unless otherwise stated.  Laboratory tests/evaluations described in this protocol will be 
conducted in accordance with quality laboratory standards as described in the central laboratory 
manual, unless otherwise stated. 
 
 
 
16.2 INFORMED CONSENT  
 
 
 
This study will be conducted in accordance with the provisions of 21 Code of Federal Regulations 
(CFR) Part 50.  Study Sponsor and CTCC must be given an opportunity to review the consent 
form prior to site IRB submission and before it is used in the study. 
 
In accordance with relevant regulations, an informed consent agreement explaining the 
procedures and requirements of the study, together with any potential hazards/risks must be read 
and/or explained to each participant.  Each participant (or participant’s legally authorized 
representative, if applicable) will sign such an informed consent form or give verbal consent.   
 
In this consent, the study must be adequately described as well as all procedures participants will 
need to do, how their confidentiality will be maintained, and explicitly ask for their consent to 
participate. 
 
The participant must be assured of the freedom to withdraw from participation in the study at any 
time. 
 
The consent process for each participant who signs informed consent will be documented in the 
participant’s source documents (e.g., research file, research progress note) and should include the 
title of the study, that the consent was discussed with an opportunity for questions and answers, 
how the participant demonstrated comprehension, that the consent was signed prior to the first 
study procedure, and that the participant received a signed copy of the consent.   
 
 16.3 INSTITUTIONAL REVIEW BOARD 
 
 
 
 
The Study Sponsor and CTCC will supply all necessary information to the  Site Investigator for 
submission of the protocol and consent form to the IRB for review and approval.  The Site 
Investigator agrees to provide the IRB all appropriate material.  The trial will not begin until the 


Protocol 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 (PD) 
 
 
Page 144 of 198 
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Date: 21 Feb 2018 
Site Investigator has obtained appropriate IRB approval.  A copy of the approval letter listing all 
documents and versions approved, including the approved consent form, must be provided to the 
CTCC. 
 
The Site Investigator will request a composition of IRB members reviewing the protocol and 
informed consent from the IRB.  Appropriate reports on the progress of this study by the Site 
Investigator will be made to the IRB and the CTCC in accordance with institutional and 
government regulations.   The Site Investigator is also responsible for annual renewal requests.  
The CTCC will notify the site when the IRB may be notified of study completion. It is the Site 
Investigator’s responsibility to notify the IRB when the study ends.  This includes study 
discontinuation, whether it is permanent or temporary. A copy of the site IRB acknowledgement 
of study completion must be provided to the CTCC. 
 
The Site Investigator will discuss any proposed protocol changes with the CTCC Project Manager 
and no modifications will be made without prior written approval by CTCC and Study Sponsor 
(if applicable), except where clinical judgment requires an immediate change for reasons of 
participant welfare.  The IRB will be informed of any amendments to the protocol or consent 
form, and approval, where and when appropriate, will be obtained before implementation. 
 
 
 
 
 
16.4  PROTOCOL AMENDMENTS  
 
 
 
 
Changes to the protocol should only be made via an approved protocol amendment.  Protocol 
amendments must be approved by the Sponsor, the NILO-PD Steering Committee and each 
respective site’s IRB prior to implementation, except when necessary to eliminate hazards and/or 
to protect the safety, rights or welfare of participants.  (See Investigator’s Agreement.) 
 
 
 
 
 
16.5 PARTICIPANT CONFIDENTIALITY 
 
 
 
 
The Site Investigator must assure that the privacy of participants, including their personal identity 
and personal medical information, will be maintained at all times.  U.S. sites have additional 
privacy obligations to study participants under the Health Insurance Portability and 
Accountability Act (HIPAA).  Participants will be identified by subject ID  numbers on case 
report forms and other documents submitted to the Sponsor, SC and the CTCC. 
 
After a participant signs an informed consent, it is required that the Site Investigator permit the 
study monitor, independent auditor or regulatory agency personnel to review the signed informed 
consent(s) and that portion of the participant’s medical record that is directly related to the study.  
This shall include all study relevant documentation including participant medical history to verify 
eligibility, laboratory test result reports, admission/discharge summaries for hospital admissions 
occurring while the participant is in the study, and autopsy reports for deaths occurring during 
the study (when available).   
 


Protocol 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 (PD) 
 
 
Page 145 of 198 
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Date: 21 Feb 2018 
The Participant’s Authorization allows the Sponsor and CTCC to receive and review the 
Participants’ protected health information that may be re-disclosed to any authorized 
representative of the Sponsor, CTCC or central laboratory facility for review of participant 
medical records in the context of the study. 
 
 
 
 
 
 
17. DOCUMENTATION 
 
 
 
 
 
17.1INVESTIGATOR SITE FILE  
 
 
 
As part of the Trial Master File, the Site Investigator should have the following study documents 
accessible to the Monitor during the study: 
 
1. Signed Form FDA 1572 
2. Curriculum vitae for Site Investigator and staff listed on Form FDA 1572 signed and dated 
within 2 years of initiation of involvement in study 
3. The signed IRB form/letter stating IRB approval of protocol, consent forms (including 
version), and advertisement notices, documentation of the IRB composition, and all IRB 
correspondence including notification/approval of protocol amendments, notification of 
serious adverse events to the IRB per local reporting requirements, and IRB notification 
of study termination 
4. IRB approved consent form (sample) and advertisement materials 
5. Signed protocol investigator agreement (and amendments, where applicable) 
6. Signed and dated participant consent forms 
7. Copies of the completed source document worksheets  
8. Delegation Log with names, signatures, initials, and functional role of all persons 
completing protocol assessments, providing back-up to the Site Investigator and 
Coordinator, if applicable, as well as staff entering data to the EDC system.  Training 
documents for delegated roles should be on file as well. 
9. Copies of laboratory reports/printouts (if applicable) 
10. Any source data/records not kept with the participant’s hospital/medical records 
11. Drug Accountability Log  
12. Laboratory accreditation and relevant laboratory reference ranges (if applicable) 
13. Signed and dated receipt of supplies 
14. Record of all monitoring visits made to study sites by assigned study personnel  
15. Copies of study correspondence to and from site personnel, Study Sponsor, CTCC, 
Clinical Trials Statistical Management Center at the University of Iowa and study vendors. 
16. Record of any Corrective and Preventive Action Plans (CAPA) as required  
17. Package Insert  
18. Certificate for Human Subject Protection Program (HSPP) & Good Clinical Practive 
(GCP) training for each individual named on the Delegation Log and Form FDA 1572 
who have direct participant contact 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
19. Copy of professional licensure/registration, as applicable, for each individual named on 
the Delegation Log, who has direct participant contact ensuring licensure is in the state in 
which the study will be conducted 
20. A Note to File indicating the assessments that will be considered source documents, if 
applicable 
21. Any other documentation as required by the Regulatory Authorities (e.g., Conflict-of-
Interest/Financial Disclosure)  
 
The Site Investigator must also retain all printouts/reports of tests/procedures, as specified in the 
protocol, for each participant.  This documentation, together with the participant’s 
hospital/medical records, is the participant’s source data for the study. 
 
 
 
 
 
17.2  MAINTENANCE AND RETENTION OF RECORDS 
 
 
 
 
It is the responsibility of the Site Investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation.  At the end of the study, Site Investigators will be instructed 
to retain all study records required by the federal regulations in a secure and safe facility with 
limited access. 
 
 
Regulations require retention for: 
 
 A period of at least two years after notification from the Sponsor that a U.S. New Drug 
Application (NDA) has been approved for the indication that was investigated.  
 
 Or if no NDA is filed or approved for such indication, a period of at least two years 
after the investigation is completed or discontinued and the FDA has been notified by 
the Sponsor. 
 
The Site Investigator will be instructed to consult with CTCC before disposal of any study records 
and to notify CTCC of any change in the location, disposition, or custody of the study files. 
 
 
 
 
 
 
17.3  QUALITY ASSURANCE (QA) AUDITS/SITE VISITS   
 
 
 
During the course of the study, and after it has been completed, it is likely that one or more study 
site visits will be undertaken by authorized representatives of the CTCC. 
 
The purpose of the audit is to determine whether or not the study is being, or has been, conducted 
and monitored in compliance with the protocol as well as recognized GCP guidelines and 
regulations.  These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent regulatory authority inspection. 
 


Protocol 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 (PD) 
 
 
Page 147 of 198 
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Date: 21 Feb 2018 
If such audits are to occur, they will be arranged for a reasonable and agreed upon time.   
 
 
 
 
 
 
17.4  REGULATORY INSPECTIONS 
 
 
 
 
This study may be inspected by regulatory agencies, such as FDA.  These inspections may take 
place at any time during or after the study and are based on the local regulations as well as ICH 
guidelines. 
 
 
 
 
 
17.5  DATA MANAGEMENT  
 
 
 
 
Utilizing Electronic Data Capture (EDC).  An Internet accessible EDC system for data 
management will be utilized for this study.  This system is protected by 128-bit server certificates 
and utilizes authenticated, password-protected accounts for each site.  The EDC system is 
designed to ensure timeliness and accuracy of data as well as the prompt reporting of data from 
the study on an ongoing basis to the study principal and co-investigators.  The system is compliant 
with relevant FDA regulatory requirements per 21 CFR Part 11. 
 
The BCC will be responsible for design of the randomization scheme, creation of analytical 
databases, and the statistical analysis plan.  Data management staff at the CTCC will be 
responsible for all data collection procedures. 
 
Utilizing Electronic Data Capture (EDC):  Data review, coding and query processing will be 
done through interaction with the CTCC, site personnel and the Study Monitor.  Queries will be 
generated in real-time as the data is entered.  Once data are submitted to the EDC system, it is 
immediately stored in the central study database located at the CTCC and are accessible for 
review by data management staff.  Changes to the data will be fully captured in an electronic 
audit trail.  As data recorded by sites in eCRFs are received, narrative text of adverse events and 
concomitant medications will be periodically coded using established coding mechanisms.   
 
Utilizing Electronic Data Capture (EDC): The cycle of electronic data entry, review, query 
identification/resolution, and correction occurs over the course of the study period until all 
participants have completed the study and corresponding data has been entered into the EDC. 
   
Data will be securely transferred to the BCC .  Once the BCC and CTCC, in conjunction with the 
Sponsor and the Principal Investigator, agree that all queries have been adequately resolved and 
the database has been deemed “clean”, the database will be officially signed off and deemed 
locked.    All permissions to make changes (append, delete, modify or update) the database are 
removed at this time.   
 
Site personnel, Sponsor, SC and CTCC staff will remain blinded as to treatment assignments 
until after database lock and treatment unblinding at the conclusion of each cohort (cohort 1 and 


Protocol 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 (PD) 
 
 
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Date: 21 Feb 2018 
cohort 2). A designated statistician at the CTCC will be unblinded to treatment assignment for 
the purpose of confirming the balancing the randomization across sites.   
 
 
 
 
 
18. SITE INVESTIGATOR/SITE 
 
 
 
 
This study will be conducted under the supervision and direction of the Investigator(s) listed in 
Section 1 of the Form FDA 1572.  Sub-investigators (if required and/or permitted by the Sponsor) 
are listed in Section 6 of the Form FDA 1572.  The study will be conducted at the address (es) 
listed in Section 3 of the Form FDA 1572. 
 
The Site Investigator must not conduct the study at any sites other than the one(s) stated on the 
Form FDA 1572. 
 
The protocol, informed consent form, and advertisement notices will be approved by the IRB 
listed in Section 5 of the Form FDA 1572. 
 
Each Site Investigator is responsible for providing copies of the protocol and all other information 
relating to the preclinical and prior clinical experience, which were furnished to him/her, to all 
physicians and other study personnel responsible to them who participate in this study.  The Site 
Investigator will discuss this information with them to assure that they are adequately informed 
regarding the study drug and conduct of the study.  The Site Investigator must assure that all study 
staff members are qualified by education, experience and training to perform their specific 
responsibilities. 
 
 
 
 
 
 
19. CLINICAL SAFETY MONITORING 
Refer to the Safety Management Plan for a detailed description of safety management  
 
 
 
19.1 CLINICAL MONITOR 
 
 
 
The Clinical Monitor (CM) is responsible for frequent review of blinded safety data  including 
adverse events, serious adverse events, laboratory and EKG data.  Additionally, the CM is 
responsible for assisting sites in responding appropriately to safety concerns.  If the CM 
encounters significant safety concerns, they will discuss the severity, importance and relevance 
of the safety concern with the PI, the Site Investigator and the PM and work with all parties to 
determine appropriate action.  Refer to the safety management plan for additional details on the 
Clinical Monitor responsibilities. All aspects of the study will be monitored by Authorized 
individuals in compliance with Good Clinical Practice (GCP) and applicable regulations.   
 
19.2 INDEPENDENT MEDICAL MONITOR 
The Independent Medical Monitor (IMM) will review all serious adverse events on occurrence 
and reporting by site personnel and classify the events according to the probability that the 
events are related to treatment, severity, and expectedness. The IMM may determine that the 


Protocol 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 (PD) 
 
 
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Serious Adverse Event is serious, related and unexpected and requires expedited reporting to the 
FDA.  The IMM may communicate with the CM and/or the Principal Investigator for 
clarification but should code events independent from CM and or Site Investigator. Consensus 
between the Site Investigator and the IMM is not required. In case of disagreement between Site 
Investigator and IMM, IMM adjudication prevails for the reporting purposes. The IMM will 
alert the CTCC PM and Principal Investigator of any concerns related to SAEs that should be 
forwarded to the entire DSMB for review via email. The DSMB may suggest changes to the 
protocol or consent form to the Principal Investigator as a consequence of adverse events.  
 
IMM will also review the aggregate reports of all adverse events (serious/not serious, 
expected/unexpected and relationship to study drug) prepared by the DCC/BCC on an agreed 
upon basis or as requested. The events will be presented in tabular form and given to the IMM 
and the DSMB on a periodic basis as agreed upon or as requested. IMM will receive the reports 
by pseudo-blinded group allocation (e.g., A, B, C) unless full unbinding is necessary. IMM may 
participate in the closed DSMB sessions if requested by the DSMB Chair. Refer to the safety 
management plan for additional details on the IMM responsibilities. 
 
 
19.3 STUDY COMMITTEES  
19.3.1 STEERING COMMITTEE 
 
 
 
 
The Steering Committee (SC) is composed of the Principal Investigator, Chief Biostatistician, 
Director of the Coordinating Centers or designees, Clinical Monitor(s), participant representative 
and independent investigator members of the Nilotinib Study Group with expertise in Parkinson’s 
disease.  The SC is responsible, along with the Sponsor, for the design of the study protocol and 
analysis plan, and oversees the clinical trial from conception to analysis and publication. 
 
 
 
 
 
19.3.2   DATA AND SAFETY MONITORING BOARD (DSMB) 
 
 
 
An independent DSMB will be appointed and will be responsible for periodic review of the trial 
conduct and progress and safety data (e.g., surveillance laboratory results, adverse events) 
throughout the trial.  The frequency and format of the DSMB meetings, reports, and guidelines 
for interim analysis will be established and documented prior to study participant enrollment. 
 
 
 
 
 
19.4 CASE REPORT FORMS 
 
 
 
Utilizing Electronic Data Capture (EDC).  Sites will enter participant information and data into 
an electronic case report form (eCRF) in the EDC application.  The eCRFs are used to record 
study data and are an integral part of the study and subsequent reports.  Therefore, the eCRFs 
must be completed for each participant screened or enrolled according to the participant’s source 
data on a per-visit basis. Authorized study personnel will each be granted access to the electronic 
data capture tool via provision of a unique password-protected user-ID that will limit access to 
enter and view data specifically for participants enrolled at their site.   


Protocol 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 (PD) 
 
 
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Data should be entered into the EDC system within 5 business days of a participant’s visit. 
 
Electronic Signatures: 
An electronic signature from the Site Investigator is required on the following eCRFs: 
 
 Signature Form 
 Adverse Event Form 
 Adverse Event Follow-up Log 
 
It is the Site Investigator’s responsibility to ensure that entries are proper and complete.  During 
entry of data, error checks will be performed by the EDC that will immediately flag problematic 
data (i.e., missing, out of range, inconsistent) allowing for sites to correct the data at that time.  
Error checks will be implemented in the EDC based upon specifications defined in the data 
management plan.   
 
The data entered from the eCRFs will be securely transmitted to a central database stored on a 
secure server located at the CTCC.  Upon completion of a participant’s visit or the study, sites 
have the option to print the completed eCRFs depicting the data that were entered. 
 
At the conclusion of the study, the Data Management Team will provided by a PDF (portable 
document format) file on electronic media depicting eCRFs to each site. The PDF file should be 
printed for each participant participating in the study and filed in the participant’s binder. 
 
 
 
 
 
19.5 SITE MONITORING  
 
 
 
To ensure compliance with GCPs and other applicable regulatory requirements, the Study 
Monitor or representative is responsible for monitoring that sites conduct the study according to 
the protocol, standard operating procedures, and other written instructions and regulatory 
guidelines.  Please refer to the Site Monitoring Plan for detailed outline of the procedures. 
 
 
Monitoring visits by a Study Monitor will be arranged in advance, at a mutually-acceptable time, 
with site personnel.  The site personnel must allow sufficient time for the Study Monitor to review 
CRFs and relevant source documents and queries. The Site Coordinator and/or Site 
Investigator(s) should be available to answer questions or resolve data clarifications. 
 
Remote monitoring will  conducted at various intervals throughout the study and/or at study 
closeout, in which the site may be asked to supply source documentation to the Study Monitor or 
Project Manager. 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
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19.6 PRIMARY SOURCE DOCUMENTS 
The Site Investigator must maintain primary source documents supporting significant data for 
each participant in the participant’s medical notes.  These documents, which are considered 
‘source data’, should include the following documentation: 
 
 Demographic information 
 Evidence supporting the diagnosis/condition for which the participant is being 
studied 
 General information supporting the participant’s consent to participate in the 
study 
 General history and physical findings 
 Hospitalization or Emergency Room records (if applicable) 
 Each study visit by date, including any relevant findings/notes by the Site 
Investigator(s), occurrence (or lack) of adverse events, and changes in 
medication usage including the date the study drug commenced and completed 
 Any additional visits during the study 
 Any relevant telephone conversations with the participant regarding the study or 
possible adverse events, and attempts to reach participants by telephone or mail 
 Original, signed informed consent forms for study participation 
 
The Site Investigator must also retain all participant-specific printouts/reports of tests/procedures 
performed as a requirement of the study (e.g., laboratory and ECG reports).  Laboratory reports 
from the central laboratory will be signed and dated by the Site Investigator following review and 
documentation of clinical significance (or not) of any abnormal findings.  The reports will be 
filed with the participant’s source documents. This documentation, together with the participant’s 
hospital/site medical records, is the participant’s ‘source data’ for the study.  During monitoring 
visits, the Study Monitor will need to validate data in the eCRFs against these source data. 
 
 
The CTCC will assist the sites in developing supplemental source document forms. 
 
 
 
 
 
 
19.7 CLOSEOUT PLAN  
 
 
 
Once all participants have completed all study visits and prior to database lock, study monitor(s) 
may conduct an on-site or remote monitoring closeout visit to ensure: 
• all relevant study data has been retrieved 
• all data queries have been resolved 
• any protocol deviations are documented appropriately 
• all major and significant protocol deviations have reported to the site’s IRB 
• study drug and clinical supplies have been/will be properly destroyed per instructions 
provided by the CMSU. 


Protocol 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 (PD) 
 
 
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• unblinding documents/envelope have been retrieved and sent to the appropriate 
designated individual 
• Site Investigator has copies of all study-related data/information on file. 
 
 
 
  
Upon completion of the study protocol requirements, any remaining biospecimens shall be 
owned by the Michael J. Fox Foundation (MJFF) (the study funder) and transferred to a 
biorepository of its choosing. All study participants will be informed that their samples 
collected may be made available for sharing to the scientific community. MJFF shall be entitled 
to release biospecimens for any scientific research purpose related to advancing scientific 
understanding, cures, and therapies for Parkinson’s disease and its complications, subject to 
applicable law, and as allowed by the signed informed consent forms. Any biospecimens will be 
released in compliance with all applicable laws, including those pertaining to patient privacy 
and IRB approval 
 
 
20. PUBLICATION OF RESEARCH FINDINGS 
 
 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the NILO-PD Steering Committee and in accordance with the International Committee of 
Medical Journal Editors (ICJME) Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals (http://www.icmje.org/urm_main.html).  Any presentation, abstract, or 
manuscript will be made available for review by the Michael J. Fox Foundation, Novartis and the 
NILO-PD Steering Committee Members prior to submission. Study publication and authorship 
will be governed by the NILO-PD Steering Committee and Parkinson’s Study Group (PSG) 
authorship policy. 
 
 
21. DATA SHARING 
 
MJFF is a public charity and research conducted with funds from MJFF must be conducted in 
the public interest. MJFF-funded studies require data sharing to advance scientific discovery.  
MJFF may make study data, such data not protected by patient privacy or other law, accessible 
to the scientific community through a secure medium for research purposes after the completion 
of the study. The data will contain no personal identifying information about study participants 
and all study participants will be informed that their collected de-identified data will be made 
available for sharing. The study data collected will be coded and may be used for future 
unspecified research purposes, for example to develop future studies of PD and related 
disorders. The research information collected will be labeled with a unique identification code. 
By using this code, the participant’s identity will not be disclosed to any researchers using this 
data in the future.  Data collected during the NILO-PD study (de identified) may also be shared 
with Novartis and its authorized agents. 
 
 


Protocol 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 (PD) 
 
 
Page 153 of 198 
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Date: 21 Feb 2018 
 
 
 
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cognitive performance. EMBO Mol Med. 2013;5(8):1247-1262. 
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Lonskaya I, Hebron ML, Desforges NM, Schachter JB, Moussa CE. Nilotinib-induced 
autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid 
clearance. J Mol Med (Berl). 2014;92(4):373-386. 
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Mahul-Mellier AL, Fauvet B, Gysbers A, et al. c-Abl phosphorylates alpha-synuclein and 
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pathogenesis of Parkinson's disease. Hum Mol Genet. 2014;23(11):2858-2879. 
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Wenqiang C, Lonskaya I, Hebron ML, et al. Parkin-mediated reduction of nuclear and 
soluble TDP-43 reverses behavioral decline in symptomatic mice. Hum Mol Genet. 
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9. 
Pagan F, Hebron M, Valadez EH, et al. Nilotinib Effects in Parkinson's disease and 
Dementia with Lewy bodies. J Parkinsons Dis. 2016. 
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Wyse RK, Brundin P, Sherer TB. Nilotinib - Differentiating the Hope from the Hype. J 
Parkinsons Dis. 2016. 
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de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet neurology. 
2006;5(6):525-535. 
12. 
Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with 
Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 
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Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson's 
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Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of 
Parkinson's disease-related pathology. Cell and tissue research. 2004;318(1):121-134. 
15. 
Huse DM, Schulman K, Orsini L, Castelli-Haley J, Kennedy S, Lenhart G. Burden of illness 
in Parkinson's disease. Mov Disord. 2005;20(11):1449-1454. 


Protocol 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 (PD) 
 
 
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An estimation based on a 3-month prospective analysis. PharmacoEconomics. 
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Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of 
Parkinson's disease (2001): treatment guidelines. Neurology. 2001;56(11 Suppl 5):S1-S88. 
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Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Practice 
Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an 
evidence-based review): report of the Quality Standards Subcommittee of the American 
Academy of Neurology. Neurology. 2006;66(7):976-982. 
19. 
Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's 
disease. The Parkinson Study Group. N Engl J Med. 1993;328(3):176-183. 
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Jankovic J, Hunter C. A double-blind, placebo-controlled and longitudinal study of riluzole 
in early Parkinson's disease. Parkinsonism & related disorders. 2002;8(4):271-276. 
21. 
Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on 
Parkinson disease progression. Jama. 2002;287(13):1653-1661. 
22. 
A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch 
Neurol. 2004;61(4):561-566. 
23. 
Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N 
Engl J Med. 2004;351(24):2498-2508. 
24. 
Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson's disease with 
ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 2003;54(1):93-101. 
25. 
Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson 
disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541-
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26. 
A randomized, double-blind, futility clinical trial of creatine and minocycline in early 
Parkinson disease. Neurology. 2006;66(5):664-671. 
27. 
A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. 
Neurology. 2007;68(1):20-28. 
28. 
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in 
filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy 
bodies. Proc Natl Acad Sci U S A. 1998;95(11):6469-6473. 
29. 
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-
synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. 
30. 
Mullin S, Schapira A. The genetics of Parkinson's disease. Br Med Bull. 2015;114(1):39-52. 
31. 
Brundin P, Atkin G, Lamberts JT. Basic science breaks through: New therapeutic advances 
in Parkinson's disease. Mov Disord. 2015;30(11):1521-1527. 
32. 
Xilouri M, Brekk OR, Stefanis L. Autophagy and Alpha-Synuclein: Relevance to 
Parkinson's Disease and Related Synucleopathies. Mov Disord. 2016;31(2):178-192. 
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Roskoski R, Jr. A historical overview of protein kinases and their targeted small molecule 
inhibitors. Pharmacol Res. 2015;100:1-23. 
34. 
Turcotte S, Giaccia AJ. Targeting cancer cells through autophagy for anticancer therapy. 
Curr Opin Cell Biol. 2010;22(2):246-251. 


Protocol 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 (PD) 
 
 
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35. 
Imam SZ, Trickler W, Kimura S, et al. Neuroprotective efficacy of a new brain-penetrating 
C-Abl inhibitor in a murine Parkinson's disease model. PLoS One. 2013;8(5):e65129. 
36. 
Ko HS, Lee Y, Shin JH, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits 
parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A. 
2010;107(38):16691-16696. 
37. 
Tanabe A, Yamamura Y, Kasahara J, Morigaki R, Kaji R, Goto S. A novel tyrosine kinase 
inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of 
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38. 
Shin JH, Ko HS, Kang H, et al. PARIS (ZNF746) repression of PGC-1alpha contributes to 
neurodegeneration in Parkinson's disease. Cell. 2011;144(5):689-702. 
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Brahmachari S, Ge P, Lee SH, et al. Activation of tyrosine kinase c-Abl contributes to 
alpha-synuclein-induced neurodegeneration. J Clin Invest. 2016;126(8):2970-2988. 
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Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of 
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Protocol 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 (PD) 
 
 
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APPENDIX 1: TASIGNA PACKAGE INSERT 
 
 
 


HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
TASIGNA safely and effectively. See full prescribing information for 
TASIGNA. 
TASIGNA® (nilotinib) capsules, for oral use 
Initial U.S. Approval: 2007 
WARNING: QT PROLONGATION AND SUDDEN DEATHS 
See full prescribing information for complete boxed warning. 
• Tasigna prolongs the QT interval. Prior to Tasigna administration and 
periodically, monitor for hypokalemia or hypomagnesemia and correct 
deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven 
days after initiation, and periodically thereafter, and following any 
dose adjustments (5.2, 5.3, 5.7, 5.15). 
• Sudden deaths have been reported in patients receiving nilotinib (5.3). 
Do not administer Tasigna to patients with hypokalemia, 
hypomagnesemia, or long QT syndrome (4, 5.2).  
• Avoid use of concomitant drugs known to prolong the QT interval and 
strong CYP3A4 inhibitors (5.8).  
• Avoid food 2 hours before and 1 hour after taking the dose (5.9). 
--------------------------RECENT MAJOR CHANGES---------------------------- 
Dosage and Administration, Discontinuation of treatment after a sustained 
molecular response (MR 4.5) on Tasigna (2.2)                  
    12/2017 
Dosage and Administration, Re-initiation of treatment in  
patients who lose molecular response after discontinuation of  
therapy with Tasigna (2.3) 
 
 
 
    12/2017     
Warnings and Precautions, Embryo-fetal toxicity (5.17)  
    12/2017 
Warnings and Precautions, Monitoring of BCR-ABL transcript levels  
(5.18)  
   
 
 
 
 
    12/2017 
----------------------------INDICATIONS AND USAGE-------------------------- 
Tasigna is a kinase inhibitor indicated for:  
The treatment of newly diagnosed adult patients with Philadelphia 
chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 
(1.1)  
The treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in 
adult patients resistant to or intolerant to prior therapy that included imatinib. 
(1.2) 
--------------------------DOSAGE AND ADMINISTRATION-------------------- 
• Recommended Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice 
daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally 
twice daily. (2.1) 
• Take each Tasigna dose approximately 12 hours apart. Tasigna must be 
taken on an empty stomach. Avoid food for at least 2 hours before the dose 
is taken and avoid food for at least 1 hour after the dose is taken. (2.1) 
• Swallow the capsules whole with water. (2.1) 
• Eligible newly diagnosed patients with Ph+ CML-CP who have received 
Tasigna for a minimum of 3years and have achieved a sustained molecular 
response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to 
imatinib who have received Tasigna for at least 3 years and have achieved 
a sustained molecular response (MR4.5) may be considered for treatment 
discontinuation. (2.2, 2.3) 
• Dose adjustment may be required for hematologic and non-hematologic 
toxicities, and drug interactions. (2.4) 
• A lower starting dose is recommended in patients with hepatic impairment 
(at baseline). (2.4) 
---------------------------DOSAGE FORMS AND STRENGTHS---------------- 
150 mg and 200 mg hard capsules (3) 
---------------------------------CONTRAINDICATIONS---------------------------- 
Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or 
long QT syndrome. (4) 
--------------------------WARNINGS AND PRECAUTIONS--------------------- 
• Myelosuppression: Associated with neutropenia, thrombocytopenia and 
anemia. Obtain CBC every 2 weeks for the first 2 months, then monthly. 
Manage by treatment interruption or dose-reduction. (5.1) 
• Cardiac and Arterial Vascular Occlusive Events: Cardiovascular events 
including ischemic heart disease, peripheral arterial occlusive disease and 
ischemic cerebrovascular events have been reported in patients with newly 
diagnosed Ph+ CML receiving Tasigna. Evaluate cardiovascular status, 
monitor and manage cardiovascular risk factors during Tasigna therapy. 
(5.4) 
• Pancreatitis and elevated serum lipase: Monitor serum lipase monthly or as 
clinically indicated. In case lipase elevations are accompanied by 
abdominal symptoms, interrupt doses and consider appropriate diagnostics 
to exclude pancreatitis. (5.5)  
• Hepatotoxicity: Tasigna may result in elevations in bilirubin, AST/ALT, 
and alkaline phosphatase. Monitor hepatic function tests monthly or as 
clinically indicated. (5.6)  
• Electrolyte abnormalities: Tasigna can cause hypophosphatemia, 
hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct 
electrolyte abnormalities prior to initiating Tasigna and monitor 
periodically during therapy. (5.7, 5.15) 
• Tumor lysis syndrome: Tumor lysis syndrome cases have been reported in 
Tasigna treated patients with resistant or intolerant CML. Maintain 
adequate hydration and correct uric acid levels prior to initiating therapy 
with Tasigna. (5.11) 
• Hemorrhage: Hemorrhage from any site may occur. Advise patients to 
report signs and symptoms of bleeding and medically manage as needed. 
(5.12) 
• Total gastrectomy: May reduce exposure. Consider dose-increase and 
monitor for effectiveness more frequently. (5.13)  
• Fluid retention: Pericardial effusion, pleural effusion, and severe fluid 
retention have occurred in patients receiving Tasigna. Monitor patients for 
signs and symptoms such as unexpected rapid weight gain, swelling, and 
shortness of breath. (5.16)  
• Embryo-Fetal toxicity: Tasigna can cause fetal harm. Advise patients of 
potential risk to a fetus and to use effective contraception. (5.17, 8.1, 8.3) 
• Treatment Discontinuation: Patients must have typical BCR-ABL 
transcripts. An FDA-authorized test with a detection limit below MR4.5 
must be used to determine eligibility for discontinuation. Patients must be 
frequently monitored by the FDA authorized test to detect possible loss of 
remission. (5.18) 
-----------------------------------ADVERSE REACTIONS-------------------------- 
The most commonly reported non-hematologic adverse reactions (greater than 
or equal to 20%) in patients with newly diagnosed Ph+ CML-CP, resistant or 
intolerant Ph+ CML-CP, or resistant or intolerant Ph+ CML-AP) were nausea, 
rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, 
arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse 
drug reactions include myelosuppression: thrombocytopenia, neutropenia and 
anemia. (6.1) 
To report SUSPECTED ADVERSE REACTIONS, contact Novartis 
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
1088 or www.fda.gov/medwatch. 
-----------------------------------DRUG INTERACTIONS-------------------------- 
• Tasigna is an inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2D6. It 
may also induce CYP2B6, CYP2C8 and CYP2C9. Therefore, Tasigna may 
alter serum concentration of other drugs (7.1) 
------------------------------USE IN SPECIFIC POPULATIONS----------------- 
• Lactation: Advise women not to breastfeed. (8.2) 
See 17 for PATIENT COUNSELING INFORMATION and Medication 
Guide 
Revised: 12/2017 
 


FULL PRESCRIBING INFORMATION: CONTENTS* 
WARNING: QT PROLONGATION AND SUDDEN DEATHS 
1 
INDICATIONS AND USAGE 
1.1 
Newly Diagnosed Ph+ CML-CP 
1.2 
Resistant or Intolerant Ph+ CML-CP and CML-AP 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Recommended Dosing 
2.2 
Discontinuation of treatment after a sustained molecular response 
(MR 4.5) on Tasigna 
2.3 
Re-initiation of treatment in patients who lose molecular response 
after discontinuation of therapy with Tasigna. 
2.4 
Dose Adjustments or Modifications 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Myelosuppression 
5.2 
QT Prolongation 
5.3 
Sudden Deaths 
5.4 
Cardiac and Arterial Vascular Occlusive Events 
5.5 
Pancreatitis and Elevated Serum Lipase 
5.6 
Hepatotoxicity 
5.7 
Electrolyte Abnormalities 
5.8 
Drug Interactions 
5.9 
Food Effects 
5.10 Hepatic Impairment 
5.11 Tumor Lysis Syndrome 
5.12 Hemorrhage 
5.13 Total Gastrectomy 
5.14 Lactose 
5.15 Monitoring Laboratory Tests 
5.16  Fluid Retention 
5.17 Embryo-Fetal Toxicity 
5.18 Monitoring of BCR-ABL Transcript Levels 
6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience 
7 
DRUG INTERACTIONS 
7.1 
Effects of Nilotinib on Drug Metabolizing Enzymes and Drug 
Transport Systems 
7.2 
Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes 
7.3 
Drugs that Affect Gastric pH 
7.4 
Drugs that Inhibit Drug Transport Systems 
7.5 
Drugs that May Prolong the QT Interval 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.2 
Lactation 
8.3 
Females and Males of Reproductive Potential 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
8.6 
Cardiac Disorders 
8.7 
Hepatic Impairment 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.3 Pharmacokinetics 
12.5 Pharmacogenomics 
12.6 QT/QTc Prolongation 
13 
NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 
CLINICAL STUDIES 
14.1 Newly Diagnosed Ph+ CML-CP 
14.2 Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP 
14.3 Treatment discontinuation in newly diagnosed Ph+ CML-CP 
patients who have achieved a sustained molecular response 
(MR4.5) 
14.4 Treatment discontinuation in Ph+ CML-CP patients who have 
achieved a sustained molecular response (MR4.5) on Tasigna 
following prior imatinib therapy 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
 
* Sections or subsections omitted from the full prescribing information are not 
listed
 


 
FULL PRESCRIBING INFORMATION  
WARNING: QT PROLONGATION AND SUDDEN DEATHS  
• Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for 
hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at 
baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments 
(5.2, 5.3, 5.7, 5.15). 
• Sudden deaths have been reported in patients receiving Tasigna (5.3). Do not administer Tasigna to 
patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). 
• Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors 
(5.8). 
• Avoid food 2 hours before and 1 hour after taking the dose (5.9). 
1 
INDICATIONS AND USAGE 
1.1 
Newly Diagnosed Ph+ CML-CP 
Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia 
chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is 
based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1)].  
1.2 
Resistant or Intolerant Ph+ CML-CP and CML-AP 
Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive 
chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included 
imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical 
Studies (14.2)].  
2 
DOSAGE AND ADMINISTRATION 
2.1 
Recommended Dosing 
Tasigna should be taken twice daily at approximately 12-hour intervals and must be taken on an empty stomach. 
No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is 
taken. Advise patients to swallow the capsules whole with water [see Boxed Warning, Warnings and 
Precautions (5.9), Clinical Pharmacology (12.3)]. 
For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of 
applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be 
stored for future use [see Clinical Pharmacology (12.3)]. 
Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if 
clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated. 
Dosage in Newly Diagnosed Ph+ CML-CP 
The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3)].  
Dosage in Resistant or Intolerant Ph+ CML-CP and CML-AP 
The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3)]. 


 
2.2 
Discontinuation of treatment after a sustained molecular response (MR 4.5) on Tasigna 
Patient Selection 
Eligibility for Discontinuation of Treatment 
Ph+ CML-CP patients with typical BCR-ABL transcripts who have been taking Tasigna for a minimum of 3 
years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 
0.0032% IS) may be eligible for treatment discontinuation [see Clinical Studies (14.3, 14.4)]. Information on 
FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for 
treatment discontinuation is available at http://www.fda.gov/Companion Diagnostics.  
Patients with typical BCR-ABL transcripts (i.e., 13a2/b2a2 or e14a2/b3a2) who achieve the sustained MR4.5 
criteria are eligible for discontinuation of Tasigna treatment. Patients must continue to be monitored for possible 
loss of molecular remission after treatment discontinuation. Use the same FDA authorized test to consistently 
monitor molecular response levels while on and off treatment.  
Consider discontinuation of treatment in patients with newly diagnosed Ph+ CML-CP who have:  
• been treated with Tasigna for at least 3 years 
• maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for 
one year prior to discontinuation of therapy  
• achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy  
• been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) 
• no history of accelerated phase or blast crisis 
• no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. 
Consider discontinuation of treatment in patients with Ph+ CML-CP that are resistant or intolerant to treatment 
with imatinib who have achieved a sustained molecular response (MR4.5) on Tasigna who have:  
• been treated with Tasigna for a minimum of 3 years  
• been treated with imatinib only prior to treatment with Tasigna 
• achieved a molecular response of MR.4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS) 
• sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy  
• been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) 
• no history of accelerated phase or blast crisis 
• no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. 
Monitor BCR-ABL transcript levels and complete blood count with differential in patients who have 
discontinued Tasigna therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks 
thereafter [see Warnings and Precautions (5.18)]. 
Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01%IS) during the treatment-free phase, 
monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular 
response (MMR, corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1%IS) for 4 consecutive measurements. 
The patient can then proceed to the original monitoring schedule. 


 
2.3 
Re-initiation of treatment in patients who lose molecular response after discontinuation of therapy 
with Tasigna. 
• Newly diagnosed patients who lose MMR must re-initiate treatment within 4 weeks at the dose level 
prior to discontinuation of therapy [see Warnings and Precautions (5.18)]. Patients who re-initiate 
Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until major molecular 
response is re-established and every 12 weeks thereafter.  
• Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 
consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must re-
initiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [see Warnings and 
Precautions (5.18)]. Patients who re-initiate Tasigna therapy should have their BCR-ABL transcript 
levels monitored monthly until previous major molecular response or MR 4.0 is re-established and every 
12 weeks thereafter. 
2.4 
Dose Adjustments or Modifications 
QT Interval Prolongation:  
Table 1: Dose Adjustments for QT Prolongation 
 
 
ECGs with a QTc 
greater than 480 msec 
 
 
 
 
 
 
 
 
 
 
1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, 
and if below lower limit of normal, correct with supplements to within normal 
limits. Concomitant medication usage must be reviewed. 
2. Resume within 2 weeks at prior dose if QTcF returns to less than 450 msec and 
to within 20 msec of baseline. 
3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 
400 mg once daily. 
4. Discontinue Tasigna if, following dose-reduction to 400 mg once daily, QTcF 
returns to greater than 480 msec. 
5. An ECG should be repeated approximately 7 days after any dose adjustment. 
Myelosuppression  
Withhold or dose-reduce Tasigna for hematological toxicities (neutropenia, thrombocytopenia) that are not 
related to underlying leukemia (Table 2). 
Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia 
 
 
 
Newly diagnosed Ph+ 
CML in chronic phase 
at 300 mg twice daily 
 
 
Resistant or intolerant 
Ph+ CML in chronic 
phase or accelerated 
phase at 400 mg twice 
daily 
ANC* less than 1.0 x 109/L 
and/or platelet counts less 
than 50 x 109/L 
 
 
 
 
 
 
 
 
1. Stop Tasigna, and monitor blood counts 
2. Resume within 2 weeks at prior dose if ANC  
greater than 1.0 x 109/L and platelets greater than 
50 x 109/L 
3. If blood counts remain low for greater than 2 
weeks, reduce the dose to 400 mg once daily 
 
 
 
 
 
*ANC=absolute neutrophil count 
See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see 
Adverse Reactions (6.1)]. 


 
Table 3: Dose Adjustments for Selected Non-Hematologic Laboratory Abnormalities 
 
 
Elevated serum 
lipase or amylase  
greater than or 
equal to Grade 3 
1. Withhold Tasigna, and monitor serum lipase or amylase 
2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to less than 
or equal to Grade 1 
Elevated bilirubin  
greater than or 
equal to Grade 3 
1. Withhold Tasigna, and monitor bilirubin 
2. Resume treatment at 400 mg once daily if bilirubin returns to less than or equal to 
Grade 1 
Elevated hepatic 
transaminases 
greater than or 
equal to Grade 3 
1. Withhold Tasigna, and monitor hepatic transaminases 
2. Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or 
equal to Grade 1 
Other Non-Hematologic Toxicities 
If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and 
resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose 
back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-
AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may 
be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 
bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once 
daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and 
Precautions (5.5, 5.6), Use in Specific Populations (8.7)]. 
Hepatic Impairment  
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, 
consider the following dose reduction: 
Table 4: Dose Adjustments for Hepatic Impairment (At Baseline) 
Newly diagnosed Ph+ CML in 
chronic phase at 300 mg twice 
daily 
Mild, Moderate, or Severe* 
An initial dosing regimen of 200 mg 
twice daily followed by dose escalation 
to 300 mg twice daily based on 
tolerability 
 
 
 
Resistant or intolerant Ph+ 
CML in chronic phase or 
accelerated phase at 400 mg 
twice daily 
Mild or Moderate* 
An initial dosing regimen of 300 mg 
twice daily followed by dose escalation 
to 400 mg twice daily based on 
tolerability 
Severe* 
A starting dose of 200 mg twice daily 
followed by a sequential dose escalation 
to 300 mg twice daily and then to 400 
mg twice daily based on tolerability 
*Mild=mild hepatic impairment (Child-Pugh Class A); Moderate=moderate hepatic impairment (Child-Pugh 
Class B); Severe=severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.10), Use 
in Specific Populations (8.7)]. 
Concomitant Strong CYP3A4 Inhibitors  
Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Avoid 
grapefruit products since they may also increase serum concentrations of nilotinib. Should treatment with any of 
these agents be required, therapy with Tasigna should be interrupted. If patients must be coadministered a 


 
strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in 
patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ 
CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 
inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is 
adjusted upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor 
closely for prolongation of the QT interval [see Boxed Warning, Warnings and Precautions (5.2, 5.8), Drug 
Interactions (7.2)]. 
Concomitant Strong CYP3A4 Inducers  
Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital). Also inform patients not to take St. John’s Wort since these 
agents may reduce the concentration of Tasigna. Based on the nonlinear pharmacokinetic profile of nilotinib, 
increasing the dose of Tasigna when coadministered with such agents is unlikely to compensate for the loss of 
exposure [see Drug Interactions (7.2)]. 
3 
DOSAGE FORMS AND STRENGTHS 
150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR.” 
200 mg light-yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” 
4 
CONTRAINDICATIONS 
Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed 
Warning]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Myelosuppression 
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete 
blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. 
Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose 
reduction [see Dosage and Administration (2.4)]. 
5.2 
QT Prolongation 
Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the 
surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology 
(12.6)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, 
which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, 7 days after 
initiation of Tasigna, and periodically as clinically indicated and following dose adjustments [see Warnings and 
Precautions (5.15)]. 
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Before 
initiating Tasigna and periodically, test electrolyte, calcium and magnesium blood levels. Hypokalemia or 
hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored 
periodically during therapy [see Warnings and Precautions (5.15)]. 
Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or 
strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, 
coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or 
medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions 
(5.8, 5.9)]. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval [see 
Warnings and Precautions (5.7, 5.15)]. 
5.3 
Sudden Deaths 
Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 
5,661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib 
suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.  


 
5.4 
Cardiac and Arterial Vascular Occlusive Events 
Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial 
in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving nilotinib 
therapy. With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including 
arterial vascular occlusive events, occurred in 9.3% and 15.2% of patients in the Tasigna 300 and 400 mg twice 
daily arms, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events 
including ischemic heart disease-related cardiac events (5.0% and 9.4% in the Tasigna 300 mg and 400 mg 
twice daily arms respectively, and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 
2.9% in the Tasigna 300 mg and 400 mg twice daily arms respectively, and 0% in the imatinib arm), and 
ischemic cerebrovascular events (1.4% and 3.2% in the Tasigna 300 mg and 400 mg twice daily arms 
respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise 
patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and 
cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to 
standard guidelines [see Dosage and Administration (2.4)]. 
5.5 
Pancreatitis and Elevated Serum Lipase 
Tasigna can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater 
risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing 
and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically 
indicated. 
5.6 
Hepatotoxicity 
Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline 
phosphatase. Monitor hepatic function tests monthly or as clinically indicated [see Warnings and Precautions 
(5.15)]. 
5.7 
Electrolyte Abnormalities 
The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and 
hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and during therapy. Monitor these 
electrolytes periodically during therapy [see Warnings and Precautions (5.15)]. 
5.8 
Drug Interactions  
Avoid administration of Tasigna with agents that may increase nilotinib exposure (e.g., strong CYP3A4 
inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, 
quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, 
clarithromycin, haloperidol, methadone, moxifloxacin and pimozide). Should treatment with any of these agents 
be required, interrupt therapy with Tasigna. If interruption of treatment with Tasigna is not possible, patients 
who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored 
for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.4), Drug Interactions 
(7.2)]. 
5.9 
Food Effects 
The bioavailability of nilotinib is increased with food, thus Tasigna must not be taken with food. No food 
should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. Also avoid 
grapefruit products and other foods that are known to inhibit CYP3A4 [see Boxed Warning, Drug Interactions 
(7.2) and Clinical Pharmacology (12.3)]. 
5.10 
Hepatic Impairment 
Nilotinib exposure is increased in patients with impaired hepatic function. Use a lower starting dose for patients 
with mild to severe hepatic impairment (at baseline) and monitor the QT interval frequently [see Dosage and 
Administration (2.4) and Use in Specific Populations (8.7)]. 


 
5.11 
Tumor Lysis Syndrome 
Tumor lysis syndrome cases have been reported in Tasigna treated patients with resistant or intolerant CML. 
Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these 
cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior 
to initiating therapy with Tasigna. 
5.12 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with Tasigna. In 
a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Tasigna and 
imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the Tasigna 300 mg twice daily arm, in 1.8% 
patients in the Tasigna 400 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage 
occurred in 2.9% and 5.1% of patients in the Tasigna 300 mg twice daily and 400 mg twice daily arms and in 
1.4% of patients in the imatinib arm, respectively. Grade 3 or 4 events occurred in 0.7% and 1.4% of patients in 
the Tasigna 300 mg twice daily and 400 mg twice daily arms, respectively, and in no patients in the imatinib 
arm.  Monitor for signs and symptoms of bleeding and medically manage as needed.  
5.13 
Total Gastrectomy 
Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring 
of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy [see Clinical 
Pharmacology (12.3)]. 
5.14 
Lactose 
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of 
galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing 
products, or of glucose-galactose malabsorption. 
5.15 
Monitoring Laboratory Tests 
Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. 
Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose 
prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation and periodically 
thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Monitor lipid profiles 
and glucose periodically during the first year of Tasigna therapy and at least yearly during chronic therapy. 
Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid 
elevations, evaluate the potential for a drug-drug interaction before initiating therapy as certain HMG-CoA 
reductase inhibitors are metabolized by the CYP3A4 pathway [see Drug Interactions (7.1)]. Assess glucose 
levels before initiating treatment with Tasigna and monitor during treatment as clinically indicated. If test 
results warrant therapy, physician should follow their local standards of practice and treatment guidelines. 
5.16  Fluid Retention 
In the randomized trial in patients with newly diagnosed Ph+ CML in chronic phase, severe (Grade 3 or 4) fluid 
retention occurred in 3.9% and 2.9% of patients receiving Tasigna 300 mg twice daily and 400 mg twice daily, 
respectively, and in 2.5% of patients receiving imatinib. Effusions (including pleural effusion, pericardial 
effusion, ascites) or pulmonary edema, were observed in 2.2% and 1.1% of patients receiving Tasigna 300 mg 
twice daily and 400 mg twice daily, respectively, and in 2.1% of patients receiving imatinib. Effusions were 
severe (Grade 3 or 4) in 0.7% and 0.4% of patients receiving Tasigna 300 mg twice daily and 400 mg twice 
daily, respectively, and in no patients receiving imatinib. Similar events were also observed in postmarketing 
reports. Monitor patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) and 
for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during Tasigna treatment; 
evaluate etiology and treat patients accordingly. 


 
5.17 
Embryo-Fetal Toxicity 
Based on findings from animal studies and its mechanism of action, Tasigna can cause fetal harm when 
administered to a pregnant woman. In animal reproduction studies, administration of nilotinib to pregnant rats 
and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal lethality/fetal 
effects (small renal papilla, fetal edema, and skeletal variations) in rats and increased resorptions of fetuses and 
fetal skeletal variations in rabbits at maternal AUCs approximately 2 and 0.5 times, respectively, the AUC in 
patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise 
females of reproductive potential to use effective contraception during treatment and for at least 14 days after 
the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 
5.18 
Monitoring of BCR-ABL Transcript Levels  
Monitoring of BCR-ABL Transcript Levels in Patients Who Discontinued Tasigna 
Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA authorized 
test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 
0.0032% IS). In patients who discontinue Tasigna therapy, assess BCR-ABL transcript levels monthly for one 
year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation 
[see Clinical Studies (14.3,14.4) and Dosage and Administration (2.2)].  
Newly diagnosed patients must reinitiate Tasigna therapy within 4 weeks of a loss of Major Molecular 
Response (MMR, corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1%IS).  
Patients resistant or intolerant to prior treatment which included imatinib must reinitiate Tasigna therapy within 
4 weeks of a loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks 
showing loss of MR4.0, corresponding to = BCR-ABL/ABL ≤ 0.01%IS).  
For patients who fail to achieve MMR after three months of treatment re initiation, BCR-ABL kinase domain 
mutation testing should be performed. 
Monitoring of BCR-ABL Transcript Levels in Patients who have Reinitiated Therapy after Loss of Molecular 
Response 
Monitor CBC and BCR-ABL transcripts in patients who re-initiate treatment with Tasigna due to loss of 
molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 
weeks.  
6 
ADVERSE REACTIONS 
The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other 
sections of labeling: 
• Myelosuppression [see Warnings and Precautions (5.1)] 
• QT Prolongation [see Boxed Warning, Warnings and Precautions (5.2)] 
• Sudden Deaths [see Boxed Warning, Warnings and Precautions (5.3)] 
• Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions (5.4)] 
• Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions (5.5)] 
• Hepatotoxicity [see Warnings and Precautions (5.6)] 
• Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions (5.7)] 
• Hemorrhage [see Warnings and Precautions (5.12)] 
• Fluid Retention [see Warnings and Precautions (5.16)] 
6.1 
Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. 


 
In Patients with Newly Diagnosed Ph+ CML-CP 
The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML 
in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on 
treatment in the nilotinib 300 mg twice daily group was 61 months (range 0.1 to 71 months). The median actual 
dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group. 
The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, 
nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, 
arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or 
equal to 10% and greater than 5%) and have been of mild-to-moderate severity, manageable and generally did 
not require dose reduction.  
Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice 
daily treatment group. No patient had an absolute QTcF of greater than 500 msec while on study drug. 
The most common hematologic adverse drug reactions (all grades) were myelosuppression including: 
thrombocytopenia (18%), neutropenia (15%) and anemia (8%). See Table 7 for Grade 3/4 laboratory 
abnormalities. 
Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of 
patients. 
In Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP 
In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP 
resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-
AP=137) at the recommended dose of 400 mg twice daily. 
The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 
(range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 
mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 
400 mg twice daily dosing. 
The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), 
and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234). 
In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or 
equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The 
common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were 
thrombocytopenia, neutropenia and anemia. 
In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (greater than or 
equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or 
equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, 
leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. 
Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-
state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients 
and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [see Boxed Warning, Warnings 
and Precautions (5.2, 5.3), Clinical Pharmacology (12.6)]. 
Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.  
Most Frequently Reported Adverse Reactions 
Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding 
laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 
10% of patients who received at least 1 dose of Tasigna are listed.  


 
Table 5: Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP 
(Greater than or equal to 10% in Tasigna 300 mg Twice Daily or Imatinib 400 mg Once Daily Groups) 60-Month Analysisa 
 
Patients with Newly Diagnosed Ph+ CML-CP 
TASIGNA 
300 mg 
twice daily 
Imatinib 
400 mg 
once daily 
TASIGNA 
300 mg 
twice daily 
Imatinib 
400 mg 
once daily 
N=279 
N=280 
N=279 
N=280 
Body System and Adverse Reaction 
All Grades (%) 
CTC Gradesb 3/4 (%) 
Skin and subcutaneous tissue disorders 
Rash 
38 
19 
<1 
2 
 
Pruritus 
21 
7 
<1 
0 
 
Alopecia 
13 
7 
0 
0 
 
Dry skin 
12 
6 
0 
0 
Gastrointestinal disorders 
Nausea 
22 
41 
2 
2 
 
Constipation 
20 
8 
<1 
0 
 
Diarrhea 
19 
46 
1 
4 
 
Vomiting 
15 
27 
<1 
<1 
 
Abdominal pain upper 
18 
14 
1 
<1 
 
Abdominal pain  
15 
12 
2 
0 
 
Dyspepsia 
10 
12 
0 
0 
Nervous system disorders 
Headache 
32 
23 
3 
<1 
 
Dizziness 
12 
11 
<1 
<1 
General disorders and administration site conditions 
Fatigue 
23 
20 
1 
1 
 
Pyrexia 
14 
13 
<1 
0 
 
Asthenia 
14 
12 
<1 
0 
 
Peripheral edema 
9 
20 
<1 
0 
 
Face edema 
<1 
14 
0 
<1 
Musculoskeletal and connective tissue disorders 
Myalgia 
19 
19 
<1 
<1 
 
Arthralgia 
22 
17 
<1 
<1 
 
Muscle spasms 
12 
34 
0 
1 
 
Pain in extremity 
15 
16 
<1 
<1 
 
Back pain 
19 
17 
1 
1 
Respiratory, thoracic and mediastinal disorders 
Cough 
17 
13 
0 
0 
 
Oropharyngeal pain 
12 
6 
0 
0 
 
Dyspnea 
11 
6 
2 
<1 
Infections and infestations 
Nasopharyngitis 
 
  27 
21 
0 
0 
 
Upper respiratory tract infection 
17 
14 
<1 
0 
 
Influenza 
13 
9 
0 
0 
 
Gastroenteritis 
7 
10 
0 
<1 
Eye disorders 
Eyelid edema 
1 
19 
0 
<1 
 
Periorbital edema 
<1 
15 
0 
0 
Psychiatric disorders 
Insomnia 
11 
9 
0 
0 
Vascular disorder 
Hypertension 
10 
4 
1 
<1 


 
aExcluding laboratory abnormalities 
bNCI Common Terminology Criteria for Adverse Events, Version 3.0 
Table 6: Most Frequently Reported Non-Hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving TASIGNA 400 mg Twice Daily 
(Regardless of Relationship to Study Drug) (Greater than or equal to 10% in any Group) 24-Month Analysisa 
 
 
Body System and Adverse Reaction 
CML-CP 
CML-AP 
N=321 
N=137 
All Grades (%) 
CTC Gradesb 3/4 (%) 
All Grades (%) 
CTC Gradesb 3/4 (%) 
Skin and subcutaneous tissue disorders 
Rash 
36 
2 
29 
0 
 
Pruritus 
32 
<1 
20 
0 
 
Night sweat 
12 
<1 
27 
0 
 
Alopecia 
11 
0 
12 
0 
Gastrointestinal disorders 
Nausea 
37 
1 
22 
<1 
 
Constipation 
26 
<1 
19 
0 
 
Diarrhea 
28 
3 
24 
2 
 
Vomiting 
29 
<1  
13 
0 
 
Abdominal pain  
15 
2 
16 
3 
 
Abdominal pain upper 
14 
<1 
12 
<1 
 
Dyspepsia 
10 
<1 
4 
0 
Nervous system disorders 
Headache 
35 
2 
20 
1 
General disorders and administration site conditions 
Fatigue 
32 
3 
23 
<1 
 
Pyrexia 
22 
<1 
28 
2 
 
Asthenia 
16 
0 
14 
1 
 
Peripheral edema 
15 
<1 
12 
0 
Musculoskeletal and connective tissue disorders 
Myalgia 
19 
2 
16 
<1 
 
Arthralgia  
26 
2 
16 
0 
 
Muscle spasms 
13 
<1 
15 
0 
 
Bone pain 
14 
<1 
15 
2 
 
Pain in extremity 
20 
2 
18 
1 
 
Back pain 
17 
2 
15 
<1 
 
Musculoskeletal pain 
11 
<1 
12 
1 
Respiratory, thoracic and mediastinal disorders 
Cough 
27 
<1 
18 
0 
 
Dyspnea 
15 
2 
9 
2 
 
Oropharyngeal pain 
11 
0 
7 
0 
Infections and infestations 
Nasopharyngitis 
24 
<1 
15 
0 
 
Upper respiratory tract 
infection 
12 
0 
10 
0 
Metabolism and nutrition disorders 
Decreased appetitec 
15 
<1 
17 
<1 
Psychiatric disorders 
Insomnia 
12 
1 
7 
0 
Vascular disorders 
Hypertension 
10 
2 
11 
<1 
aExcluding laboratory abnormalities   bNCI Common Terminology Criteria for Adverse Events, Version 3.0   cAlso includes preferred term anorexia 


 
Laboratory Abnormalities 
Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities 
in patients who received at least one dose of Tasigna. 
Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities 
 
Patient Population 
 
 
Newly Diagnosed Ph+ CML-CP 
Resistant or Intolerant Ph+ 
CML-CP 
CML-AP 
TASIGNA 300 mg 
twice daily 
N=279 
(%) 
Imatinib 400 mg 
once daily 
N=280 
(%) 
TASIGNA 400 mg  
twice daily 
N=321 
(%) 
TASIGNA 400 mg 
twice daily 
N=137 
(%) 
Hematologic Parameters 
 
 
 
 
Thrombocytopenia 
10 
9 
301 
423 
Neutropenia 
12 
22 
312 
424 
Anemia 
4 
6 
11 
27 
Biochemistry Parameters 
 
 
 
 
Elevated lipase 
9 
4 
18 
18 
Hyperglycemia  
7 
<1 
12 
6 
Hypophosphatemia 
8 
10 
17 
15 
Elevated bilirubin (total) 
4 
<1 
7 
9 
Elevated SGPT (ALT) 
4 
3 
4 
4 
Hyperkalemia 
2 
1 
6 
4 
Hyponatremia 
1 
<1 
7 
7 
Hypokalemia 
<1 
2 
2 
9 
Elevated SGOT (AST) 
1 
1 
3 
2 
Decreased albumin 
0 
<1 
4 
3 
Hypocalcemia 
<1 
<1 
2 
5 
Elevated alkaline phosphatase 
0 
<1 
<1 
1 
Elevated creatinine  
0 
<1 
<1 
<1 
*NCI Common Terminology Criteria for Adverse Events, version 3.0 
1CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4 
2CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4 
3CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4 
4CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4 
Elevated total cholesterol (all grades) occurred in 28% (Tasigna 300 mg twice daily) and 4% (imatinib). Elevated triglycerides (all 
grades) occurred in 12% and 8% of patients in the Tasigna and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 
50% and 31% of patients in the Tasigna and imatinib arms, respectively. 
Most common biochemistry laboratory abnormalities (all grades) were alanine aminotransferase increased (72%), blood bilirubin 
increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood 
cholesterol increased (28%), and blood triglyceride increased (12%). 
Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained molecular response (MR 
4.5) 
In eligible patients who discontinued Tasigna therapy after attaining a sustained molecular response (MR4.5), 
musculoskeletal symptoms (e.g. myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or 
musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as 
noted in Table 8. The rate of new musculoskeletal symptoms generally decreased in the second year after 
treatment discontinuation.  


 
In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR 
phase, 23/53 (43.4%) had not resolved by the TFR end date or data cut-off date. In the population previously 
treated with imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 
(56.1%) had not resolved by the data cut-off date.  
The rate of musculoskeletal symptoms decreased in patients who entered the nilotinib treatment re-initiation 
(NTRI) phase, at 11/88 (12.5%) in the newly diagnosed population and 14/56 (25%) in the population 
previously treated with imatinib. Other adverse reactions observed in the Tasigna re-treatment phase were 
similar to those observed Tasigna use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant 
Ph+ CML-CP and CML-AP. 
Table 8: Musculoskeletal symptoms occurring upon treatment discontinuation in the context of 
treatment-free remission (TFR) 
 
Entire TFR period in all TFR 
patients 
By time interval, in subset of patients in TFR greater than 48 weeks 
Ph+ CML-
CP patients 
 
N 
Median 
follow-
up in 
TFR 
Patients with 
musculoskeletal 
symptoms 
 
N 
Year prior to 
TASIGNA 
discontinuation 
1st year after  
TASIGNA 
discontinuation 
2nd year after 
TASIGNA 
discontinuation 
All 
Grades 
Grade 
3/4 
All 
Grades 
Grade 
3/4 
All 
Grades 
Grade 
3/4 
All 
Grades 
Grade 3/4 
Newly 
Diagnosed 
 
190 
76 
weeks 
 
27.9% 
 
1.1% 
 
100 
 
17.0% 
 
0% 
 
34.0% 
 
2.0% 
 
9.0% 
 
0% 
Previously 
treated with 
imatinib 
 
126 
 
99 
weeks 
 
45.2% 
 
2.4% 
 
73 
 
13.7% 
 
0% 
 
47.9% 
 
2.7% 
 
15.1% 
 
1.4% 
Additional Data from Clinical Trials 
The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the 
recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent 
first using the following convention: common (greater than or equal to1% and less than 10%), uncommon 
(greater than or equal to 0.1% and less than 1%), and unknown frequency (single events). For laboratory 
abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 5 and 6, 
are also reported. These adverse reactions are included based on clinical relevance and ranked in order of 
decreasing seriousness within each category, obtained from 2 clinical studies: 
1. Newly diagnosed Ph+ CML-CP 60 month analysis and, 
2. Resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis. 
Infections and Infestations: Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, 
candidiasis (including oral candidiasis). Unknown frequency: hepatitis B reactivation, sepsis, subcutaneous 
abscess, anal abscess, furuncle, tinea pedis. 
Neoplasms Benign, Malignant, and Unspecified: Common: skin papilloma. Unknown frequency: oral 
papilloma, paraproteinemia. 
Blood and Lymphatic System Disorders: Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, 
lymphopenia. Unknown frequency: thrombocythemia, leukocytosis. 
Immune System Disorders: Unknown frequency: hypersensitivity. 
Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: 
hyperparathyroidism secondary, thyroiditis. 
Metabolism and Nutrition Disorders: Very Common: hypophosphatemia. Common: electrolyte imbalance 
(including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, 
hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, 


 
hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, 
hypoglycemia.  
Psychiatric Disorders: Common: depression, anxiety. Unknown frequency: disorientation, confusional state, 
amnesia, dysphoria. 
Nervous System Disorders: Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: 
intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of 
consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: basilar 
artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. 
Eye Disorders: Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). 
Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, 
conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilledema, diplopia, 
photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface 
disease. 
Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. 
Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, 
extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. 
Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery 
stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, 
pericarditis, ejection fraction decrease.  
Vascular Disorders: Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, 
intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock 
hemorrhagic, hypotension, thrombosis, peripheral artery stenosis. 
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea exertional, epistaxis, dysphonia. 
Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, 
pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing. 
Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, 
flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, 
stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer 
perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, 
enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. 
Hepatobiliary Disorders: Very Common: hyperbilirubinemia. Common: hepatic function abnormal. 
Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. 
Skin and Subcutaneous Tissue Disorders: Common: eczema, urticaria, erythema, hyperhidrosis, contusion, 
acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, 
pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, 
palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous 
hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, 
hyperkeratosis.  
Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, 
musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal 
stiffness, joint swelling. Unknown frequency: arthritis. 
Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. 
Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. 
Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. 
Unknown frequency: breast induration, menorrhagia, nipple swelling. 


 
General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac 
chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, 
feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema. 
Investigations: Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase 
increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol 
increased, blood triglycerides increased. Common: hemoglobin decreased, blood amylase increased, gamma-
glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, 
weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, 
blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin 
C-peptide decreased, blood parathyroid hormone increased. 
7 
DRUG INTERACTIONS  
7.1 
Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems 
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially 
increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib 
may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by 
these enzymes. 
In patients with CML, multiple doses of Tasigna increased the systemic exposure of oral midazolam (a substrate 
of CYP3A4) 2.6-fold. Tasigna is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of drugs 
metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when coadministered 
with Tasigna. Dose adjustment may be necessary for drugs that are CYP3A4 substrates, especially those that 
have narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
sirolimus and tacrolimus) when coadministered with Tasigna. 
Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and 
pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of multiple doses of Tasigna to induce 
metabolism of drugs other than midazolam has not been determined in vivo. Monitor patients closely when 
coadministering Tasigna with drugs that have a narrow therapeutic index and are substrates for CYP2B6, 
CYP2C8, or CYP2C9 enzymes. 
Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna is administered with drugs that are substrates of P-
gp, increased concentrations of the substrate drug are likely, and caution should be exercised. 
7.2 
Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes 
Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of 
CYP3A4 can increase or decrease nilotinib concentrations significantly. Avoid the administration of Tasigna 
with agents that are strong CYP3A4 inhibitors [see Boxed Warning, Dosage and Administration (2.4), 
Warnings and Precautions (5.2, 5.8)]. Concomitant use of Tasigna with medicinal products and herbal 
preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant 
extent. Therefore, in patients receiving Tasigna, select alternative therapeutic agents with less potential for 
CYP3A4 induction for concomitant use.  
Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, 
systemic exposure (AUC) to nilotinib was increased approximately 3-fold. 
Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, 
systemic exposure (AUC) to nilotinib was decreased approximately 80%. 
7.3 
Drugs that Affect Gastric pH 
The concomitant use of proton pump inhibitors with Tasigna is not recommended. Nilotinib has pH-dependent 
solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid 
secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In 


 
healthy subjects, coadministration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a 
proton-pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna 
when coadministered with such agents is not likely to compensate for the loss of exposure. Since proton pump 
inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the 
interaction.  
In healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg 
dose of Tasigna was administered 10 hours after and 2 hours before famotidine (an H2 blocker). Therefore, 
when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before 
and approximately 2 hours after the dose of Tasigna.  
Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to healthy subjects, 2 
hours before or 2 hours after a single 400 mg dose of Tasigna did not alter nilotinib pharmacokinetics. 
Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours 
after the dose of Tasigna. 
7.4 
Drugs that Inhibit Drug Transport Systems 
Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with 
drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised. 
7.5 
Drugs that May Prolong the QT Interval 
The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines 
should be avoided [see Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2, 
5.8)]. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Risk Summary 
Based on findings from animal studies and the mechanism of action, Tasigna can cause fetal harm when 
administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 
There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction 
studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse 
developmental outcomes including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at 
maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the 
recommended dose (see Data). Advise pregnant women of the potential risk to a fetus. 
The background risk of major birth defects and miscarriage for the indicated population is unknown. All 
pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general 
population, the estimated background risk of major birth defects and miscarriage in clinically recognized 
pregnancies are 2-4% and 15-20%, respectively. 
Data 
Animal Data 
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 
100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. 
In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day. At ≥ 30 
mg/kg/day skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and 
there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was 
associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food 
consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the 
fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 


 
mg/kg/day. Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite 
sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. 
In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and 
increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, 
bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, 
frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity. 
Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at 
this dose. 
At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72700 
ng*hr/mL and 17100 ng*hr/mL respectively, representing approximately 2 and 0.5 times the exposure in 
humans at the highest recommended dose 400 mg twice daily. 
When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects 
included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the 
pups when they reached maturity, all at a maternal dose of 60 mg/kg (i.e., 360 mg/m2, approximately 0.7 times 
the clinical dose of 400 mg twice daily based on body surface area). At doses up to 20 mg/kg (i.e., 120 mg/m2, 
approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects 
were seen in the maternal animals or the pups. 
8.2 
Lactation 
Risk Summary 
No data are available regarding the presence of nilotinib or its metabolites in human milk or its effects on a 
breastfed child or on milk production. However, nilotinib is present in the milk of lactating rats. Because of the 
potential for serious adverse reactions in a nursing child, advise lactating women not to breastfeed during 
treatment with Tasigna and for at least 14 days after the last dose. 
Animal Data 
After a single 20 mg/kg of [14C] nilotinib dose to lactating rats, the transfer of parent drug and its metabolites 
into milk was observed. The overall milk-to-plasma exposure ratio of total radioactivity was approximately 2, 
based on the AUC0-24h or AUC0-∞ values. No rat metabolites of nilotinib were detected that were unique to milk. 
8.3 
Females and Males of Reproductive Potential 
Pregnancy 
Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in 
Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting 
treatment with Tasigna. 
Contraception 
Females 
Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in 
Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during 
treatment with Tasigna and for at least 14 days after the last dose. 
Infertility 
The risk of infertility in females or males of reproductive potential has not been studied in humans. In studies in 
rats and rabbits, the fertility in males and females was not affected [see Nonclincal Toxicology (13.1)]. 
8.4 
Pediatric Use 
The safety and effectiveness of Tasigna in pediatric patients have not been established. 


 
8.5 
Geriatric Use 
In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ 
CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively. 
• Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between 
patients aged less than 65 years and those greater than or equal to 65 years. 
• Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate 
between patients aged less than 65 years and those greater than or equal to 65 years. 
• Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients less than 
65 years of age and 29% in patients greater than or equal to 65 years. 
No major differences for safety were observed in patients greater than or equal to 65 years of age as compared 
to patients less than 65 years. 
8.6 
Cardiac Disorders 
In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including 
recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, were 
excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, 
Warnings and Precautions (5.2)]. 
8.7 
Hepatic Impairment 
Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to 
severe hepatic impairment following a single dose administration of 200 mg of Tasigna, the mean AUC values 
were increased on average of 35%, 35%, and 56% in subjects with mild (Child-Pugh class A, score 5 to 6), 
moderate (Child-Pugh class B, score 7 to 9) and severe hepatic impairment (Child-Pugh class C, score 10 to 
15), respectively, compared to a control group of subjects with normal hepatic function. Table 9 summarizes the 
Child-Pugh Liver Function Classification applied in this study. A lower starting dose is recommended in 
patients with hepatic impairment and the QT interval should be monitored closely in these patients [see Dosage 
and Administration (2.4), and Warnings and Precautions (5.10)]. 
Table 9: Child-Pugh Liver Function Classification 
Assessment  
Degree of Abnormality 
Score 
Encephalopathy Grade 
None 
1 
  
1 or 2 
2 
  
3 or 4 
3 
Ascites 
Absent 
1 
  
Slight 
2 
  
Moderate 
3 
Total Bilirubin (mg/dL) 
<2 
1 
  
2–3 
2 
  
>3 
3 
Serum Albumin (g/dL) 
>3.5 
1 
  
2.8–3.5 
2 
  
<2.8 
3 
Prothrombin Time (seconds prolonged) 
<4 
1 
  
4–6 
2 
  
>6 
3 
10 
OVERDOSAGE 
Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in 
combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event 
of overdose, the patient should be observed and appropriate supportive treatment given. 


 
11 
DESCRIPTION 
Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors. 
Nilotinib drug substance, a monohydrate monohydrochloride, is a white to slightly yellowish to slightly 
greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • 
H2O and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not 
optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4. 
The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-
[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown 
below: 
 
Tasigna (nilotinib) capsules, for oral use, contain 150 mg or 200 mg nilotinib base, anhydrous (as 
hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, 
lactose monohydrate, magnesium stearate and poloxamer 188. The capsules contain gelatin, iron oxide (red), 
iron oxide (yellow), iron oxide (black), and titanium dioxide. 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of 
the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine 
leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the 
assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out 
of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model. 
Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 
to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM). 
12.3 
Pharmacokinetics 
Absorption and Distribution  
The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 
1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. Peak concentrations of nilotinib 
are reached 3 hours after oral administration. 
Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic 
exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib 
following 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. 
Steady state exposure (AUC) of nilotinib with 400 mg twice daily dosing was 13% higher than with 300 mg 
twice daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 
months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg 
twice daily to 600 mg twice daily. 


 
The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the 
systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal. 
Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and 
administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg 
intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on 
the basis of in vitro experiments. 
Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy 
compared to patients who had not undergone surgeries [see Warnings and Precautions (5.13)]. 
Pharmacokinetics, Metabolism and Excretion 
The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing 
was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions 
were achieved by Day 8. An increase in serum exposure to nilotinib between the first dose and steady state was 
approximately 2-fold for daily dosing and 3.8-fold for twice daily dosing. 
Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main 
circulating component in the serum. None of the metabolites contribute significantly to the pharmacological 
activity of nilotinib. 
After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was 
eliminated within 7 days: mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose. 
Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib. 
Renal Impairment 
Clinical studies have not been performed in patients with impaired renal function. Clinical studies have 
excluded patients with serum creatinine concentration greater than 1.5 times the upper limit of the normal range. 
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated 
in patients with renal impairment. 
Drug-Drug Interactions 
In a Phase 1 trial of nilotinib 400 mg twice daily in combination with imatinib 400 mg daily or 400 mg twice 
daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib. 
12.5 
Pharmacogenomics 
Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms 
of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the 
(TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia 
relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were 
observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients [see Warnings and Precautions (5.6)]. 
12.6 
QT/QTc Prolongation 
In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, 
administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean 
placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive 
control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study 
were 26% lower than those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings 
and Precautions (5.2), and Adverse Reactions (6.1)]. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15, and 40 mg/kg/day. 
Exposures in animals at the highest dose tested were approximately 2- to 3-fold the human exposure (based on 


 
AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings. A 26-week 
carcinogenicity study was conducted orally in Tg.rasH2 mice, a model genetically modified to enhance 
susceptibility to neoplastic transformation, at nilotinib doses of 30, 100, and 300 mg/kg/day. Nilotinib induced 
in the skin and subcutis statistically significant increases in the incidence of papillomas in females and of 
papillomas and combined papillomas and carcinomas in males at 300 mg/kg/day. The no-observed-adverse-
effect-level (NOAEL) for skin neoplastic lesions was 100 mg/kg/day.  
Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome 
aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse 
lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral 
treatments at doses up to 2000 mg/kg/dose. 
There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in 
rats (approximately 4- to 7-fold for males and females, respectively, the AUC in patients at the dose of 400 mg 
twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice 
daily). The effect of Tasigna on human fertility is unknown. In a study where male and female rats were treated 
with nilotinib at oral doses of 20 to 180 mg/kg/day (approximately 1- to 6.6-fold the AUC in patients at the dose 
of 400 mg twice daily) during the pre-mating and mating periods and then mated, and dosing of pregnant rats 
continued through gestation Day 6, nilotinib increased post-implantation loss and early resorption, and 
decreased the number of viable fetuses and litter size at all doses tested. 
14 
CLINICAL STUDIES 
14.1 
Newly Diagnosed Ph+ CML-CP 
The ENESTnd (Evaluating Nilotinib Efficacy and Safety in clinical Trials-Newly Diagnosed patients) study 
(NCT00471497) was an open-label, multicenter, randomized trial conducted to determine the efficacy of 
Tasigna versus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. 
Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea 
and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily 
group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily 
group. 
Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% 
of patients greater than or equal to 65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily 
and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female 
patients in all groups (56%, 56%, and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and 
nilotinib 400 mg twice daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 
25% were Asian. 
The primary data analysis was performed when all 846 patients completed 12 months of treatment (or 
discontinued earlier). Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of 
treatment (or discontinued earlier). The median time on treatment was approximately 61 months in all three 
treatment groups. 
The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study 
medication. MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured 
by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from 
standardized baseline. Efficacy endpoints are summarized in Table 10. 
Two patients in the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 
months of treatment) while 12 patients on the imatinib arm progressed to either accelerated phase or blast crisis 
(7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 
patient within 18 to 24 months). 


 
Table 10: Efficacy (MMR and CCyR) of TASIGNA Compared to Imatinib in Newly Diagnosed Ph+ 
CML-CP (ENESTnd) 
 
TASIGNA 
300 mg 
twice daily 
Imatinib 
400 mg 
once daily 
 
N=282 
N=283 
MMR at 12 months (95% CI) 
44% (38.4, 50.3) 
22% (17.6, 27.6) 
     P-Valuea  
<0.0001 
CCyRb by 12 months (95% CI) 
80% (75.0, 84.6) 
65% (59.2, 70.6) 
MMR at 24 months (95% CI) 
62% (55.8, 67.4) 
38% (31.8, 43.4) 
CCyRb by 24 months (95% CI) 
87% (82.4, 90.6) 
77% (71.7, 81.8) 
aCMH test stratified by Sokal risk group 
bCCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the percentage of Ph+ metaphases among greater than or equal to 
20 metaphase cells in each bone marrow sample. 
By the 60 months, MMR was achieved by 77% of patients on Tasigna and 60% of patients on imatinib; MR4.5 
was achieved by 53.5% of patients on Tasigna and 31.4% on imatinib. Median overall survival was not reached 
in either arm. At the time of the 60-month final analysis, the estimated survival rate was 93.7% for patients on 
Tasigna and 91.7% for patients on imatinib.  
14.2 
Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP 
Study CAMN107A2101 (referred to as Study A2101) (NCT00109707) was a single-arm, open-label, 
multicenter study conducted to evaluate the efficacy and safety of Tasigna (400 mg twice daily) in patients with 
imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The 
definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), 
cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease 
after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of 
treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-
off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were 
enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 
80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older. 
Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior 
imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included 
hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median 
highest prior imatinib dose was 600 mg per day for patients with CML-CP and CML-AP, and the highest prior 
imatinib dose was greater than or equal to 600 mg/day in 74% of all patients with 40% of patients receiving 
imatinib doses greater than or equal to 800 mg/day. 
Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients 
with CML-AP. 
The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included 
complete and partial cytogenetic responses. 
The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete 
hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-
AP patients are reported in Table 11. 
Median durations of response had not been reached at the time of data analysis. 


 
Table 11: Efficacy of TASIGNA in Resistant or Intolerant Ph+ CML-CP and CML-AP (Study A2101) 
Cytogenetic Response Rate (Unconfirmed) (%)a 
 
 
Chronic Phase 
(n=321) 
Major (95% CI) 
51% (46%–57%) 
Complete (95% CI) 
37% (32%–42%) 
Partial (95% CI) 
15% (11%–19%) 
 
Accelerated Phase 
(n=137) 
Hematologic Response Rate (Confirmed) (95% CI)b 
39% (31%–48%) 
Complete Hematologic Response Rate (95% CI) 
30% (22%–38%) 
No Evidence of Leukemia (95% CI) 
9% (5%–16%) 
aCytogenetic response criteria: Complete (0% Ph + metaphases) or partial (1% to 35%). Cytogenetic responses were based on the 
percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample. 
bHematologic response=CHR + NEL (all responses confirmed after 4 weeks). 
CHR (CML-CP): WBC less than 10 x 109/L, platelets less than 450,000/mm3, no blasts or promyelocytes in peripheral blood, less than 
5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. 
CHR (CML-AP): neutrophils greater than or equal to 1.5 x 109/L, platelets greater than or equal to 100 x 109/L, no myeloblasts in 
peripheral blood, myeloblasts less than 5% in bone marrow, and no extramedullary involvement. 
NEL: same criteria as for CHR but neutrophils greater than or equal to 1.0 x 109/L and platelets greater than or equal to 20 x 109/L 
without transfusions or bleeding. 
Patients with Chronic Phase 
The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 
months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of 
exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of 
them had MCyR lasting more than 18 months. The CCyR rate was 37%.  
Patients with Accelerated Phase 
The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to 
first hematologic response among responders was 1 month (range 1 to 14 months). Among the CML-AP 
patients who achieved HR, 44% of them had a response lasting for more than 18 months. 
After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of 
accelerated phase CML patients who were evaluated for mutations. 
14.3 
Treatment discontinuation in newly diagnosed Ph+ CML-CP patients who have achieved a 
sustained molecular response (MR4.5) 
The ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in clinical Trials-freedom) study 
(NCT01784068) is an open-label, multicenter, single-arm study, where 215 adult patients with Ph+ CML-CP 
treated with Tasigna in first-line for ≥ 2 years who achieved MR4.5 as measured with the MolecularMD 
MRDx™ BCR-ABL Test were enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna 
consolidation phase).  
Of the 215 patients, 190 patients (88.4%) entered the “Treatment-free Remission” (TFR) phase after achieving a 
sustained molecular response (MR4.5) during the consolidation phase, defined by the following criteria:  
• 
The 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR-ABL/ABL  
≤ 0.01% IS), and maintained for 1 year 
• 
The last assessment being MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS)  
• 
No more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR-ABL/ABL 
≤ 0.01% IS). 


 
The median age of patients who entered the TFR phase was 55 years, 49.5% were females, and 21.1% of the 
patients were ≥ 65 years of age. BCR-ABL levels were monitored every 4 weeks during the first 48 weeks of 
the TFR phase. Monitoring frequency was intensified to every 2 weeks upon the loss of MR4.0. Biweekly 
monitoring ended at one of the following time points: 
• 
Loss of MMR requiring patient to re-initiate Tasigna treatment 
• 
When the BCR-ABL levels returned to a range between MR4.0 and MR4.5 
• 
When the BCR-ABL levels remained lower than MMR for 4 consecutive measurements (8 
weeks from initial loss of MR4.0).  
Any patient with loss of MMR during the TFR phase re-initiated Tasigna treatment at 300 mg twice daily or at a 
reduced dose level of 400 mg once daily if required from the perspective of tolerance, within 5 weeks after the 
collection date of the blood sample demonstrating loss of MMR. Patients who required re-initiation of Tasigna 
treatment were monitored for BCR-ABL levels every 4 weeks for the first 24 weeks and then every 12 weeks 
thereafter in patients who regained MMR. 
Efficacy was based on the 96-week analysis data cut-off date, by which time, 91 patients (47.9%) discontinued 
from the TFR phase due to loss of MMR, and 1 (0.5%), 1 (0.5%), 1 (0.5%) and 3 patients (1.6%) due to death 
from unknown cause, physician decision, lost to follow-up and subject decision, respectively. Among the 91 
patients who discontinued the TFR phase due to loss of MMR, 88 patients restarted Tasigna treatment and 3 
patients permanently discontinued from the study. 
By the 96-week data cut-off, of the 88 patients who restarted treatment due to loss of MMR in the TFR phase, 
87 patients (98.9%) patients regained MMR (one patient discontinued study permanently due to subject 
decision after 7.1 weeks of retreatment without regaining MMR) and 81 patients (92.0%) regained MR4.5 by 
the time of the cut-off date. The cumulative rate of MMR and MR4.5 regained at 24 weeks since treatment re 
initiation was 97.7% (86/88 patients) and 86.4% (76/88 patients), respectively. 
Table 12: Efficacy Results for ENESTfreedom 
Patients Who Entered the Treatment Free Remission (TFR) Phase (Full Analysis Set, N=190) 
 
Patients in TFR phase1 
at the specified time point 
 
Loss of MMR2 by the specified time point  
 
 
% 
95% CI 
% 
24 weeks 
62.1 
(54.8, 69.0) 
35.8 
48 weeks 
51.6 
(44.2, 58.9) 
45.8 
96 weeks 
48.9 
(41.6, 56.3) 
47.9 
1Patients in MMR at the specified time point in the TFR phase 
2Based on the time to event (loss of MMR) data during the TFR phase  
Among the 190 patients in the TFR phase, 98 patients had a treatment-free survival (TFS) event (defined as 
discontinuation from TFR phase due to any reason, loss of MMR, death due to any cause, progression to AP/BC 
up to the end of TFR phase, or re-initiation of treatment due to any cause in the study) by the 96-week cut-off 
date.  


 
Figure 14-1 
Kaplan-Meier estimate of treatment-free survival after start of TFR (Full Analysis Set 
ENESTfreedom) 
 
1. For a given time point, the points on the dashed curves represent the 95% confidence limits for the associated KM estimate on the 
solid curve. 
2. By the time of the 96-week data cut-off date, one single patient lost MMR at week 120, at the time when only 8 patients were 
considered at risk. This explains the artificial drop at the end of the curve. 
14.4 
Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained molecular 
response (MR4.5) on Tasigna following prior imatinib therapy 
The ENESTop (Evaluating Nilotinib Efficacy and Safety in clinical Trials-STop) study (NCT01698905) is an 
open-label, multicenter, single-arm study, where 163 adult patients with Ph+ CML-CP taking tyrosine kinase 
inhibitors (TKIs) for ≥ 3 years (imatinib as initial TKI therapy for more than 4 weeks without documented 
MR4.5 on imatinib at the time of switch to Tasigna, then switched to Tasigna for at least 2 years), and who 
achieved MR4.5 on Tasigna treatment as measured with the MolecularMD MRDx™ BCR-ABL Test were 
enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna consolidation phase). Of the 163 
patients, 126 patients (77.3%) entered the TFR phase after achieving a sustained molecular response (MR4.5) 
during the consolidation phase, defined by the following criterion: 
• 
The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 
(BCR-ABL/ABL ≤ 0.0032% IS) during 1 year. 
The median age of patients who entered the TFR phase was 56 years, 55.6% were females, and 27.8% of the 
patients were ≥ 65 years of age. The median actual dose intensity during the 52-week Tasigna consolidation 
phase was 771.8 mg/day with 52.4%, 29.4%, 0.8%, 16.7% and 0.8% of patients receiving a daily Tasigna dose 
of 800 mg, 600 mg, 450mg, 400mg and 300mg just before entry into the TFR phase, respectively. 
Patients who entered the TFR phase but experienced two consecutive measurements of BCR-ABL/ABL > 
0.01% IS were considered having a confirmed loss of MR4.0, triggering re-initiation of Tasigna treatment. 
Patients with loss of MMR in the TFR phase immediately restarted Tasigna treatment without confirmation. All 
patients who restarted Tasigna therapy had BCR-ABL transcript levels monitored every 4 weeks for the first 24 
weeks, then once every 12 weeks.  
Efficacy was based on the 96-week analysis data cut-off date, by which time, 61 patients (48.4%) had 
discontinued from the TFR phase: 58 patients (46.0%) due to loss of MMR or confirm loss of MR4.0, 2 patients 
(1.6%) due to subject/guardian decision and one patient (0.8%) due to pregnancy. Among the 58 patients who 


 
discontinued from the TFR phase due to confirmed loss of MR4.0 or loss of MMR, 56 patients restarted 
Tasigna therapy and 2 patients permanently discontinued from the study.  
By the 96-week data cut-off, of the 56 patients who restarted Tasigna treatment due to confirmed loss of MR4.0 
or loss of MMR in the TFR phase, 52 patients (92.9%) regained MR4.0 and MR4.5; 4 patients (7.1%) did not 
regain MR4.0 by the time of the cut-off date. The cumulative rate of MR4 and MR4.5 regained by 48-weeks 
since treatment re-initiation, was 92.9% (52/56 patients) and 91.1% (51/56 patients), respectively. 
Table 13: Efficacy Results for ENESTop 
Patients Who Entered the Treatment Free Remission (TFR) Phase (Full Analysis Set, N=126) 
 
Patients in TFR phase1 
at the specified time point 
 
Loss of MMR or confirmed loss of MR42 by 
the specified time point  
 
 
% 
95% CI 
% 
24 weeks 
60.3 
(51.2, 68.9) 
38.9 
48 weeks 
57.9 
(48.8, 66.7) 
41.3   
96 weeks 
53.2 
(44.1, 62.1) 
 43.7 
1Patients without loss of MMR or confirmed loss of MR4 by specified time point of TFR phase 
2Based on the time to event (loss of MMR or confirmed loss of MR4) data during the TFR phase 
Among the 126 patients in the TFR phase, 61 patients (48.4%) had a treatment-free survival (TFS) event 
(defined as discontinuation from TFR phase due to any reason, loss of MMR, confirmed loss of MR4, death due 
to any cause, progression to AP/BC up to the end of TFR phase, or re-initiation of treatment due to any cause in 
the study) on or before the 96-month cut-off date.  
Figure 14-2 
Kaplan-Meier estimate of treatment-free survival after start of TFR (Full Analysis Set 
ENESTop) 
 
1. For a given time point, the points on the dashed curves represent the 95% confidence limits for the associated KM 
estimate on the solid curve. 


 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint 
“NVR/BCR.” Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the 
red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs. 
150 mg 
Carton of 4 blister packs of (4x28) ...............................................................................NDC 0078-0592-87 
Blisters of 28 capsules ..................................................................................................NDC 0078-0592-51 
200 mg 
Carton of 4 blister packs of (4x28) ...............................................................................NDC 0078-0526-87 
Blisters of 28 capsules ..................................................................................................NDC 0078-0526-51 
Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F 
to 86°F) [see USP Controlled Room Temperature]. 
17 
PATIENT COUNSELING INFORMATION 
Advise the patient to read the FDA-approved patient labeling (Medication Guide).  
A Medication Guide is required for distribution with Tasigna. The complete text of the Medication Guide is 
reprinted at the end of this document. 
Myelosuppression 
Advise patients that treatment with Tasigna can cause serious thrombocytopenia, neutropenia, and anemia. 
Advise patients to seek immediate medical attention if symptoms suggestive of low blood counts occur, such as 
fever, chills or other signs of infection, unexplained bleeding or bruising, or unexplained weakness or shortness 
of breath [see Warnings and Precautions (5.1)]. 
QT Prolongation 
Advise patients that Tasigna can cause possibly life-threatening, abnormal heart beat. Advise patients to seek 
immediate medical attention if symptoms of abnormal heart beat occur, such as feeling light-headed, faint or 
experiencing an irregular heartbeat [see Warnings and Precautions (5.2)]. 
Cardiac and Arterial Vascular Occlusive Events 
Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive 
disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical 
attention if any symptoms suggestive of a cardiovascular event occur, such as chest or leg pain, numbness or 
weakness, or problems walking or speaking occur suddenly [see Warnings and Precautions (5.4)]. 
Pancreatitis and Elevated Serum Lipase 
Advise patients that Tasigna can increase the risk of pancreatitis and that patients with a previous history of 
pancreatitis may be at greater risk.  Advise patients to seek immediate medical attention if symptoms suggestive 
of pancreatitis occur, such as sudden stomach area pain with accompanying nausea and vomiting [see Warnings 
and Precautions (5.5)]. 
Taking Tasigna 
Advise patients to take Tasigna doses twice daily approximately 12 hours apart. The capsules should be 
swallowed whole with water. 
Advise patients to take Tasigna on an empty stomach. No food should be consumed for at least 2 hours before 
the dose is taken and for at least 1 hour after the dose is taken. Patients should not consume grapefruit products 
and other foods that are known to inhibit CYP3A4 at any time during Tasigna treatment [see Dosage and 
Administration (2.4), Warnings and Precautions (5.8, 5.9) and Medication Guide]. 
If the patient missed a dose of Tasigna, the patient should take the next scheduled dose at its regular time. The 
patient should not take two doses at the same time.  


 
Should patients be unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon 
of applesauce and the mixture swallowed immediately (within 15 minutes). 
Tumor Lysis Syndrome 
Advise patients that Tasigna can cause tumor lysis syndrome and to seek immediate medical attention if any 
symptoms suggestive of tumor lysis syndrome occur such as an abnormal heartbeat or less urine production [see 
Warnings and Precautions (5.11)]. 
Hemorrhage 
Advise patients that serious hemorrhagic events, including fatal events, have occurred in patients with CML 
treated with Tasigna.  Advise patients to seek immediate medical attention if symptoms suggestive of 
hemorrhage occur, such as uncontrolled bleeding, changes in eyesight, unconsciousness, or sudden headache or 
sudden confusion in surroundings [see Warnings and Precautions (5.12)]. 
Fluid Retention 
Advise patients that Tasigna can cause fluid retention and to seek immediate medical attention if any symptoms 
suggestive of fluid retention such as shortness of breath, rapid weight gain, or swelling occur [see Warnings and 
Precautions (5.16)]. 
Treatment Free Remission (TFR) 
Advise patients that frequent monitoring is required to detect possible loss of remission if TFR is attempted. 
Advise patients that musculoskeletal symptoms such as muscle pain, pain in extremity, joint pain, bone pain, or 
spinal pain, may occur more frequently than before treatment discontinuation [see Warnings and Precautions 
(5.18) and Medication Guide]. 
Drug Interactions 
Advise patients that Tasigna and certain other medicines, including over the counter medications or herbal 
supplements (such as St. John’s Wort), can interact with each other [see Warnings and Precautions (5.8) and 
Drug Interactions (7)].  
Embryo-Fetal Toxicity 
Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female 
patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. 
Advise females of reproductive potential to use effective contraception during treatment and for at least 14 days 
after receiving the last dose of Tasigna [see Warnings and Precautions (5.17) and Use in Specific Populations 
(8.1, 8.3)]. 
Lactation 
Advise lactating women not to breastfeed during treatment with Tasigna and for at least 14 days after the last 
dose [see Use in Specific Populations (8.2)]. 
Compliance 
Advise patients of the following: 
 Continue taking Tasigna every day for as long as their doctor tells them. 
 This is a long-term treatment. 
 Do not change dose or stop taking Tasigna without first consulting their doctor. 
 If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed 
capsules. 
 
T2017-125 
 


 
 
Medication Guide 
TASIGNA® (ta-sig-na) 
(nilotinib) 
capsules 
What is the most important information I should know about Tasigna? 
Tasigna can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an 
irregular heartbeat, which may lead to sudden death. 
Your healthcare provider should check the electrical activity of your heart with a test called an electrocardiogram 
(ECG): 
• 
before starting Tasigna 
• 7 days after starting Tasigna 
• 
with any dose changes 
• regularly during Tasigna treatment 
You may lower your chances for having QTc prolongation with Tasigna if you: 
• Take Tasigna on an empty stomach:  
○ 
Avoid eating food for at least 2 hours before the dose is taken, and  
o 
Avoid eating food for at least 1 hour after the dose is taken.  
• Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Tasigna. Food and 
grapefruit products increase the amount of Tasigna in your body.  
• Avoid taking other medicines or supplements with Tasigna that can also cause QTc prolongation. 
• Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening 
side effects. 
• Do not take any other medicine while taking Tasigna unless your healthcare provider tells you it is okay to do so. 
• If you cannot swallow Tasigna capsules whole, you may open the Tasigna capsule and sprinkle the contents of each 
capsule in 1 teaspoon of applesauce (puréed apple). Swallow the mixture right away (within 15 minutes). For more 
information, see “How should I take Tasigna?” 
Call your healthcare provider right away if you feel lightheaded, faint, or have an irregular heartbeat while taking 
Tasigna. These can be symptoms of QTc prolongation. 
What is Tasigna? 
Tasigna is a prescription medicine used to treat a type of leukemia called Philadelphia chromosome positive chronic 
myeloid leukemia (Ph+ CML) in adults who: 
• are newly diagnosed, or 
• are no longer benefiting from previous other treatments, including treatment with imatinib (Gleevec), or 
• have taken other treatments, including imatinib (Gleevec), and cannot tolerate them 
It is not known if Tasigna is safe and effective in children. 
Who should not take Tasigna? 
Do not take if you have: 
• low levels of potassium or magnesium in your blood 
• long QTc syndrome 
Before taking Tasigna, tell your healthcare provider about all of your medical conditions, including if you : 
• have heart problems 
• have had a stroke or other problems due to decreased blood flow to the brain 
• have problems with decreased blood flow to your legs 
• have irregular heartbeat 
• have QTc prolongation or a family history of it 
• have liver problems 
• have had pancreatitis 
• have low blood levels of potassium or magnesium in your blood 
• have a severe problem with lactose (milk sugar) or other sugars. Tasigna capsules contain lactose. Most people who 
have mild or moderate lactose intolerance can take Tasigna. 
• have bleeding problems 
• had a surgical procedure involving the removal of the entire stomach (total gastrectomy) 
•   are pregnant or plan to become pregnant. Tasigna can harm your unborn baby. Tell your healthcare provider right 
away if you are pregnant, or if you become pregnant during treatment with Tasigna.  


 
In females who are able to become pregnant: 
o 
Your healthcare provider should do a pregnancy test before you start treatment with Tasigna.  
o 
Use effective birth control (contraception) during treatment with Tasigna and for at least 14 days after the last 
dose. 
• 
are breastfeeding or plan to breastfeed. It is not known if Tasigna passes into your breast milk. Do not breastfeed 
during treatment and for at least 14 days after your last dose of Tasigna.  
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, 
vitamins and herbal supplements.  
If you need to take antacids (medicines to treat heartburn) do not take them at the same time that you take Tasigna. If you 
take: 
• a medicine to block the amount of acid produced in the stomach (H2 blocker): Take these medicines about 10 
hours before you take Tasigna, or about 2 hours after you take Tasigna. 
• an antacid that contains aluminum hydroxide, magnesium hydroxide, and simethicone to reduce the amount 
of acid in the stomach: Take these medicines about 2 hours before or about 2 hours after you take Tasigna. 
Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening 
side effects. See “What is the most important information I should know about Tasigna?” 
How should I take Tasigna? 
• Take Tasigna exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking Tasigna 
unless your healthcare provider tells you. 
• Tasigna is a long-term treatment. 
• Your healthcare provider will tell you how many Tasigna capsules to take and when to take them. 
• Tasigna must be taken on an empty stomach. 
o 
Avoid eating food for at least 2 hours before the dose is taken, and 
o 
Avoid eating food for at least 1 hour after the dose is taken. 
• Swallow Tasigna capsules whole with water. If you cannot swallow Tasigna capsules whole, tell your healthcare 
provider. 
• If you cannot swallow Tasigna capsules whole: 
o 
Open the Tasigna capsules and sprinkle the contents in 1 teaspoon of applesauce (puréed apple). 
 Do not use more than 1 teaspoon of applesauce. 
 Only use applesauce. Do not sprinkle Tasigna onto other foods. 
o 
Swallow the mixture right away (within 15 minutes). 
• Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during 
treatment. See “What is the most important information I should know about Tasigna?” 
• If you miss a dose, just take your next dose at your regular time. Do not take 2 doses at the same time to make up for 
a missed dose. 
• If you take too much Tasigna, call your healthcare provider or poison control center right away. Symptoms may include 
vomiting and drowsiness.  
• During treatment with Tasigna your healthcare provider will do tests to check for side effects and to see how well 
Tasigna is working for you. The tests will check your: 
o 
heart 
o 
blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every 2 weeks 
for the first 2 months and then monthly. 
o 
electrolytes (potassium, magnesium) 
o 
pancreas and liver function 
o 
bone marrow samples 
Your healthcare provider may change your dose. Your healthcare provider may have you stop Tasigna for some time or 
lower your dose if you have side effects with it. 
• 
Your healthcare provider will monitor your CML during treatment with Tasigna to see if you are in a remission. After at 
least 3 years of treatment with Tasigna, your healthcare provider may do certain tests to determine if you continue to 
be in remission. Based on your test results, your healthcare provider may decide if you may be eligible to try stopping 
treatment with Tasigna. This is called Treatment Free Remission (TFR).  
• 
Your healthcare provider will carefully monitor your CML during and after you stop taking Tasigna. Based you your 
test results, your healthcare provider may need to re-start your Tasigna if your CML is no longer in remission.  
• 
It is important that you are followed by your healthcare provider and undergo frequent monitoring to find out if you 


 
need to re-start your Tasigna treatment because you are no longer in TFR. Follow your healthcare provider’s 
instructions about re-starting Tasigna if you are no longer in TFR.  
What are the possible side effects of Tasigna? 
Tasigna may cause serious side effects, including:  
• See “What is the most important information I should know about Tasigna?” 
o Low blood cell counts. Low blood cell counts (red blood cells, white blood cells, and platelets) are common with 
Tasigna, but can also be severe. Your healthcare provider will check your blood counts regularly during treatment with 
Tasigna. Call your healthcare provide or get medical help right away if you develop any signs or symptoms of low 
blood counts including: 
o 
fever 
o 
chills or other signs of infection 
o 
unexplained bleeding or bruising 
o 
unexplained weakness 
o 
shortness of breath 
• Decreased blood flow to the leg, heart, or brain. People who have recently been diagnosed with Ph+ CML and take 
Tasigna may develop decreased blood flow to the leg, the heart, or brain.  
Get medical help right away if you suddenly develop any of the following symptoms:  
o 
chest pain or discomfort 
o 
numbness or weakness 
o 
problems walking or speaking 
o 
leg pain 
o 
your leg feels cold 
o 
change in the skin color of your leg 
• Pancreas inflammation (pancreatitis). Tell your healthcare provider right away if you develop any symptoms of 
pancreatitis including sudden stomach area pain with nausea and vomiting.  
• Liver problems. Symptoms include yellow skin and eyes. 
• Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have: 
○  
kidney failure and the need for dialysis treatment 
○ 
an abnormal heart beat 
Your healthcare provider may do blood tests to check you for TLS. 
• Bleeding problems. Serious bleeding problems and death have happened during treatment with Tasigna. Tell your 
healthcare provider right away if you develop any signs and symptoms of bleeding during treatment with Tasigna. 
• Fluid retention. Your body may hold too much fluid (fluid retention). Symptoms of fluid retention include shortness of 
breath, rapid weight gain, and swelling. 
The most common side effects of Tasigna include: 
• 
nausea 
• 
rash 
• 
headache 
• 
tiredness 
• 
itching 
• 
vomiting 
• 
diarrhea  
• 
cough 
• 
constipation 
• 
muscle and joint pain 
• 
runny or stuffy nose, sneezing, sore throat 
• 
fever 
• 
night sweats 
If you and your healthcare provider decide that you can stop taking Tasigna and try treatment free remission (TFR), you 
may have more muscle and bone (musculoskeletal) symptoms than before you stopped treatment. Symptoms may 
include: 
• 
muscle pain 
• 
arm and leg pain 
• 
joint pain 
• 
bone pain  
• 
spine pain 
These are not all of the possible side effects of Tasigna.  
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 
How should I store Tasigna? 
• 
Store Tasigna at room temperature between 68°F to 77°F (20°C to 25°C). 
• 
Safely throw away medicine that is out of date or no longer needed. 
Keep Tasigna and all medicines out of the reach of children. 


 
General information about the safe and effective use of Tasigna. 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tasigna for a 
condition for which it was not prescribed. Do not give Tasigna to other people, even if they have the same symptoms that 
you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Tasigna that is 
written for health professionals. 
What are the ingredients in Tasigna? 
Active ingredient: nilotinib 
 
Inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 
188.  
The capsule shell contains gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide. 
Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936  
 
© Novartis 
 
For more information, go to www.Tasigna.com or call 1-866-411-8274. 
This Medication Guide has been approved by the U.S. Food and Drug Administration. 
                                                                                        Revised: December 2017 
 
T2017-126 


Protocol 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 (PD) 
 
 
Page 191 of 198 
Version  4 
Date: 21 Feb 2018 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 2: EXCLUSIONARY AND PRECAUTIONARY MEDICATIONS 
 
NOTE: This list is not exhaustive but is designed to give examples of more commonly 
used drug classes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 192 of 198 
Version  4 
Date: 21 Feb 2018 
 
Table 1.  Exclusionary Medications: Known risk to prolong the QT interval 
Antimicrobials 
Antipsychotics (all have some risk) 
Erythromycin 
Fluphenazine 
Azithromycin (systemic) 
Haloperidol 
Levofloxacin (systemic) 
Pimozide 
Sparfloxacin 
Chlorpromazine 
Ciprofloxacin (systemic) 
Droperidol 
Clarithromycin 
Aripiprazole 
Telithromycin 
Thioridazine 
Moxifloxacin 
Sulpiride 
Fluconazole (systemic) 
Sertindole 
Antiprotozoal, Antimalarials, Antituberculosis 
 
            Pentamidine 
Antidepressant 
            Mefloquine 
 Citalopram/escitalopram* 
            Chloroquine 
              Trimipramine 
            Quinine 
               Clomipramine 
 Delamanid 
               Dosulepin 
 Bedaquiline 
Mirtazapine 
 Mesoridazine 
Trazodone 
Antiarrhythmics 
Venlafaxine 
Dronedarone 
               Lofepramine 
Sotalol 
Antineoplastics 
  Dofetilide 
Arsenic trioxide 
Ibutilide 
Ceritinib 
Quinidine 
Dabrafenib 
Amiodarone 
Dasatinib 
Disopyramide 
Pazopanib 
Antiplatelet 
Bosutinib 
  Cilostazol 
Panobinostat 
Antiemetics 
Lapatinib 
Domperidone 
Crizotinib 
Cisapride 
Bortezomib 
Granisetron 
Oxaliplatin 
Droperidol 
Ribociclib 
Ondansetron//Granisetron 
Vandetanib 
Propafenone 
             Osimertinib 
Procainamide 
             Pazopanib 
Flecainide 
             Romidepsin 
Others 
Sunitinib 
Methadone 
             Tamoxifen 


Protocol 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 (PD) 
 
 
Page 193 of 198 
Version  4 
Date: 21 Feb 2018 
Sevoflurane 
             Toremifene 
Anagrelide 
             Vemurafenib 
Levomethadyl 
Vilanterol 
Propofol 
Hepatitis C Antivirals 
Probucol 
Telaprevir 
Halofantrine 
Boceprevir 
Tacrolimus 
Anticholinergic 
Nicardipine 
Solifenacin 
*stable regimen of Citalopram (<20mg) or escitalopram (<10mg) will be allowed     provided 
that the baseline EKG did not demonstrate QT prolongation  
 
 
 
Table 2. Exclusionary Medications: Strong CYP3A4 Inhibitors 
Generic 
Brand 
Ketoconazole (systemic use) 
-- 
Itraconazole 
Onmel; Sporanox; Sporanox Pulsepak 
Posaconazole 
Noxafil 
Clarithromycin 
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; 
Omeclamox-Pak 
Aprepitant 
Emend 
Domperidone 
-- 
Atazanavir 
Reyataz; Evotaz 
Indinavir 
Crixivan 
Nefazodone 
-- 
Nelfinavir 
Viracept 
Ritonavir 
Norvir; Kaletra; Technivie; Viekira Pak; Viekira XR 
Saquinavir 
Invirase 
Telithromycin 
Ketek 
Voriconazole 
Vfend 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 194 of 198 
Version  4 
Date: 21 Feb 2018 
 
 
Table 4. Exclusionary Medications: Strong CYP3A4 Inducers 
Generic 
Brand 
Carbamazepine 
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR 
Dexamethasone (systemic 
use) 
Dexamethasone Intensol; DexPak; DoubleDex 
Phenytoin 
Dilantin; Dilantin Infatabs; Phenytek; Phenytoin Infatabs 
Phenobarbital 
Phenobarb; Donnatal; Donnatal Extentabs; Phenohytro 
Rifampin 
Rifadin; Rifamate; Rifater 
Rifabutin 
Mycobutin 
St. John’s Wort 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3. Exclusionary Medications: Proton Pump Inhibitors 
Generic 
Brand 
Dexlansoprazole 
Dexilant 
Esomeprazole 
Nexium; Vimovo 
Lansoprazole 
First-Lansoprazole; GoodSense Lansoprazole [OTC]; 
Heartburn Relief 24 Hour [OTC]; Heartburn Treatment 24 
Hour [OTC]; Prevacid 24HR [OTC]; Prevacid SoluTab; 
Prevpac 
Omeprazole 
First-Omeprazole; Omeclamox-Pak; 
Omeprazole+Syrspend SF Alka; Prilosec [OTC]; 
Yosprala; Zegrid 
Pantoprazole 
Protonix 
Rabeprazole 
Aciphex; AcipHex Sprinkle 


Protocol 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 (PD) 
 
 
Page 195 of 198 
Version  4 
Date: 21 Feb 2018 
Table 5. Exclusionary Medications: P-glycoprotein Inhibitors 
Generic 
Brand 
Amiodarone 
Cordarone; Nexterone; Pacerone 
Clarithromycin 
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; 
Omeclamox-Pak 
Erythromycin (systemic use) 
EES; Ery-Tab; EryPed; Erythrocin; PCE 
Ketoconazole (systemic use) 
-- 
Quinidine 
BioQuin Durules; Quinate; Nudexta 
Saquinavir 
Invirase 
Verapamil 
Calan; Calan SR; Isoptin SR; Verelan; Tarka 
 
 
Table 6. Exclusionary Medications: P-glycoprotein Inducers 
Generic 
Brand 
Carbamazepine 
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR 
Rifampin 
Rifadin; Rifamate; Rifater 
St. John’s wort 
-- 
Tipranavir 
Aptivus 
 
 
Table 7. Exclusionary Medications: Anticoagulants 
 
Generic Name 
Brand Name 
Warfarin 
Coumadin 
Dabigatran 
Pradaxa 
Edoxaban 
Savaysa 
Rivaroxaban 
Xarelto 
Apixaban 
Eliquis 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 196 of 198 
Version  4 
Date: 21 Feb 2018 
Table 8. Precautionary Medications: Drugs with possible or conditional risk of Torsades de 
Pointes 
Anticholinergic 
Antibiotics 
CNS Stimulants 
Tolterodine 
Garenoxacin 
Amphetamine 
Anticonvulsants 
Gemifloxacin 
Dexmethylphenidate 
Ezogabine 
Norfloxacin 
Dextroamphetamine 
Felbamate 
Ofloxacin 
Lisdexamfetamine 
Fosphenytoin 
Metronidazole 
Methamphetamine 
Antidepressants 
Sulfamethoxazole and 
Trimethoprim 
Methylphenidate 
Amitriptyline 
Telavancin 
Phentermine 
Desipramine 
Antineoplastics 
Contrast Media 
Doxepin 
Capecitabine 
Gadobenate 
Fluoxetine 
Degarelix 
Iodinated ionic 
contrast media 
Fluvoxamine 
Eribulin 
Perflutren lipid 
microspheres 
Imipramine 
Lenvatinib 
Diuretics 
Maprotiline 
Leuprolide 
Bendroflumethiazide 
Nortriptyline 
Sorafenib 
Furosemide 
Paroxetine 
Vorinostat 
Hydrochlorothiazide 
Sertraline 
Antipsychotics 
Indapamide 
Antiemetics 
Amisulpiride 
Torsemide 
Dolasetron 
Asenapine 
GI Agents 
Promethazine 
Clozapine 
Famotidine 
Tropisetron 
Cyamemazine 
Metoclpramide 
Antihistamines 
Flupentixol 
Opioids 
Diphenhydramine 
Iloperidone 
Buprenorphine 
Hydroxyzine 
Olanzapine 
Hydrocodone 
Antifungals 
Paliperidone 
Miscellaneous 
Amphotericin B 
Perphenazine 
Alfuzosin 
 
Pimavanserin** 
 
Itraconazole 
Pipamperone 
Apomorphine 
 
Quetiapine** 
 
Ketoconazole 
Risperidone 
Atomoxetine 
Posaconazole 
Ziprasidone 
Chloral hydrate 
Voriconazole 
Zotepine 
Fingolimod 
Antimalarials 
Beta-agonists 
Galantamine 
Artenimol + 
piperaquine 
Albuterol 
Ivabradine 
Hydroxychloroquine 
Arformoterol 
Lithium 


Protocol 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 (PD) 
 
 
Page 197 of 198 
Version  4 
Date: 21 Feb 2018 
Antiretrovirals 
Formoterol 
Loperamide 
Atazanavir 
Isoproterenol 
Mifeprisfepristone 
Efavirenz 
Levalbuterol 
Mirabegron 
Nelfinavir 
Metaproterenol 
Moxepril 
Rilpivirine 
Olodaterol 
Octreotide 
Ritonavir 
Salmetrol 
Oxytocin 
Saquinavir 
Terbutaline 
Pasireotide 
 
 
Ranolazine 
Antiviral  
Calcium Channel Blockers 
Tetrabenazine 
Foscarnet 
Isradipine 
Tiapride 
 
 
Vardenafil 
 
 
Tizanidine 
**Pimavanserin and Quetiapine are also metabolized by CYP3A4.  Therefore, low doses of 
quetiapine should be used when given with nilotinib (moderate inhibitor of CYP3A4).  For 
pimavanserin, a dose of 17 mg once daily is recommended when given with a strong CYP3A4 
inhibitor. For quetiapine, it is recommended to decrease the dose by one-sixth when given with a 
strong CYP3A4 inhibitor.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 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 (PD) 
 
 
Page 198 of 198 
Version  4 
Date: 21 Feb 2018 
APPENDIX 3: STEERING COMMITTEE 
 
Brian Fiske, PhD 
Senior Vice President, Research Programs, MJFF, New York, NY  
 
Kalpana Merchant, PhD 
President and CSO TransThera Consulting Co, Portland, OR (MJFF Consultant, Therapeutic Development) 
 
Professor Christopher S. Coffey, PhD 
Chief Biostatistics, University of Iowa, Iowa City IA,  
 
Helen Matthews 
Chief Operating Officer, The Cure Parkinson’s Trust, UK 
 
Richard Wyse, MD 
Director Research and Development, The Cure Parkinson’s Trust, UK  
 
Professor Patrik Brundin 
Van Andel Research Institute, Grand Rapids, MI 
 
Professor David Simon 
Harvard Medical School Beth Israel Deaconess Medical Center, Boston, MA 
 
 
Professor Michael Schwarzschild 
Massachusetts General Hospital, Boston, MA 
 
David Weiner, MD,  
Chief Medical Officer Lumos Pharma, Austin, TX (MJFF Consultant, Therapeutic Development)  
 
Charles Venuto, Pharm D 
CHET CTCC, University of Rochester, Rochester, NY  
 
Gary Rafaloff, MS 
Parkinson’s Disease Patient Advocate 
 
 

SAP_001.pdf: 
 
 
NILO-PD 
 
Statistical Analysis Plan 
(Cohort 1) 
 
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 (PD) 
 
 
Tanya Simuni, MD  
Professor of Neurology 
Director, Parkinson’s Disease and Movement Disorders Center 
Northwestern University Feinberg School of Medicine  
Principal Investigator 
 
Christopher S. Coffey, PhD 
Professor of Biostatistics 
University of Iowa 
Principal Investigator of Biostatistics Coordinating Center 
 
 
 
VERSION 1.0 
September 24, 2019 
 
 
 




PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analyses for cohort 1 of the NILO-PD study, funded 
by the Michael J. Fox Foundation for Parkinson’s Research (MJFF). The planned analyses identified in this 
SAP are intended to support the completion of a final report for cohort 1 that will be prepared and presented to 
the study sponsor. Should the study continue to enroll cohort 2, a separate SAP will be prepared for that 
cohort. All final, planned analyses identified in this SAP will be performed only after the last randomized study 
participant in cohort 1 has completed the study, and all data have been cleaned and verified in accord with 
applicable standard operating procedures at the NILO-PD Data Coordinating Center (DCC). Once all cohort 1 
data have been cleaned and verified, a "locked" version of the data will be used for reporting the final study 
results. Key statistics and study results will be presented verbally to the PI, Clinical Coordinating Center (CCC), 
DCC, Data and Safety Monitoring Board (DSMB), and Steering Committee (SC) for review and discussion 
following database lock and prior to completion of the final report for cohort 1. 
Due to the exploratory nature of this study, we will not attempt to make any type of adjustment for multiple 
comparisons. Correspondingly, unless specified differently, all hypotheses will be assessed at the 0.05 
significance level. 
1. STUDY DESIGN 
Nilotinib is approved by the U.S. Food and Drug Administration (FDA) for certain types of leukemia, but not for 
Parkinson’s disease (PD). A small number of cell and animal models suggest that nilotinib may positively affect 
the alpha (α)-synuclein pathology observed in PD (Hebron et al, 2013; Hebron et al, 2014; Karuppagounder et 
al, 2014; Lonskaya et al, 2013; Lonskaya et al, 2014a; Lonskaya et al, 2014b; Mahul-Mellier et al, 2014; 
Wenqiang et al, 2014). A small open-label clinical study that lacked a placebo control group tested the safety 
and tolerability of nilotinib in PD patients for the first time, and explored its efficacy (Pagan et al, 2016). 
Although preliminary data appear promising, the study design precludes firm conclusions about safety, 
tolerability, optimal dose, or efficacy (Wyse et al, 2016). Hence, an opportunity exists to rigorously establish the 
safety, tolerability, and optimal dose of nilotinib to enable and inform the conduct of future definitive efficacy 
studies in PD patients. All participants will be treated for 6 months, and followed for two months post drug 
evaluation. Hence, the duration for each participant in cohort 1 is expected to be approximately 8.5 months 
from screening to post drug evaluation. 
The primary objective of cohort 1 is to determine whether either of the doses are sufficiently safe and tolerated 
to justify consideration of moving forward with cohort 2 (early/de novo PD patients). This objective will be 
accomplished by comparing the percentage of participants who complete the study on their assigned dose 
across the three arms. Although the decision will be primarily based on tolerability, we will also compare the 
safety profiles and CSF PK analysis across the three groups and utilize all this information in making a final 
decision. At the end of cohort 1, we will make one of three decisions: 
• 
If the 300 mg dose is tolerable, and has an acceptable safety profile, this dose will be chosen for 
consideration in the second cohort. 
• 
If the 300 mg dose is not tolerable, or if the 300 mg dose is tolerable but has an unacceptable safety 
profile, then we will consider the 150 mg dose. If the 150 mg dose is tolerable, and has an acceptable 
safety profile, this dose will be chosen for consideration in the second cohort. 
• 
If neither dose is tolerable, or if all tolerable doses have unacceptable safety profiles, we will conclude 
that no dose appears suitably safe and tolerable for inclusion in the second cohort. Under this scenario, 
the trial will not proceed to a second cohort. 
A key secondary objective of cohort 1 is to conduct a single group futility hypothesis in each PD group 
comparing the observed change in MDS-UPDRS Part III between baseline and month 6 to determine whether 
the study can rule out the large change previously reported in the prior clinical study (Pagan et al, 2016). Other 
secondary objectives will involve examining the degree of symptomatic effect of nilotinib as measured by the 
change in MDS-UPDRS Part III shortly after initiation of study drug (between baseline and 1 month), and after 
discontinuation of study drug [between month 6 (end of treatment) and month 7 (1 month after treatment)]. For 
all participants, assessment of the potential symptomatic effect will be done using the MDS-UPDRS Part III 
collected in the ON (at least one-hour post dose) state. An additional secondary objective will assess the 
impact of nilotinib on the progression of PD disability over the course of the 6-month treatment period. Sparse 


PK sampling will be conducted to assess serum and CSF concentrations of nilotinib throughout the duration of 
the study. 
Dosage reductions for tolerability or safety can occur at any time during the study. If study drug is temporarily 
suspended for occurrences other than study drug related safety or tolerability issues, study drug may be 
resumed by the site investigator. Drug suspensions lasting more than 7 days require re-titration. If drug 
suspension is less than 7 days, the participant can restart study drug at prior dosing level. Participants will not 
be allowed to remain in the study if study drug is permanently discontinued. Once the decision to permanently 
discontinue study drug is made, a premature withdrawal visit should be conducted. The participant will be 
required to return to the study site for the 30 and 60-day safety follow-up visits (V05 & V06). 
The site investigator may also withdraw study drug from a participant in the event of intercurrent illness, 
adverse events, other reasons concerning the health or well-being of the participant, non-compliance, protocol 
violation, or other administrative reasons. Premature withdrawal will also be implemented in the case of 
emergency disclosure of study drug treatment. Reasons for withdrawal of the participant prior to completion of 
the study must be stated in the eCRF and in the site source documentation for all study participants who were 
enrolled in the study. The participant will be encouraged to remain in the study, and return for the 1 month and 
2-month post-drug evaluations (V05 & V06) as a safety follow-up. 
Since the data on the safety profile of the drug, and prior clinical experience with nilotinib, were limited to an 
advanced PD population with cognitive deficits, PDD, and/or DLB, it was felt prudent to validate and expand 
the data on nilotinib safety and tolerability in the moderate/advanced PD population. It is expected that 
tolerability of nilotinib in this moderate/advanced cohort will be lower than that observed in an early/de novo PD 
population. Such data are important to establish, provided that nilotinib, if shown to have disease modifying 
benefit, will be administered long-term to PD patients across all disease stages. Another important objective of 
the study is to establish the magnitude of potential symptomatic effect of nilotinib and dopaminergic therapy 
interaction. These data will be essential for the design of the future disease modifying trials. 
If shown to be safe and well tolerable, future development of nilotinib will target disease modification 
objectives. Disease modification has historically been tested in cohorts of de novo PD population. To pursue 
future disease modification trials, safety and tolerability of nilotinib must be established in the de novo 
population as well. While we do not expect that the de novo population will have a lower tolerability and safety 
threshold, this hypothesis must be tested in a subsequent study. If at least one dose is shown to be safe and 
tolerable in cohort 1, and nilotinib CSF PK samples demonstrate expected CNS penetration, the study steering 
committee will consider the possibility of selecting a dose for consideration in cohort 2. If the study proceeds, 
participants in cohort 2 will be treated with the selected dose determined in cohort 1 or matching placebo. 
1.1 Primary Objective 
The primary objective is to assess the safety and tolerability of the daily oral administration of nilotinib (150 
mg or 300 mg once daily) in moderate/advanced PD participants. 
1.2 Key Secondary Objective 
To conduct a futility analysis within each treated group in Cohort 1 by comparing the observed change in 
MDS-UPDRS Part III “ON” score between baseline (BL) and Month 6 (V04). 
1.3 Additional Secondary Objectives 
(1) To establish the degree of symptomatic effect of nilotinib as measured by the change in MDS-UPDRS 
Part III score in the defined medications ON state between: 
(a) Baseline (BL) & 1 Month (V02) 
(b) Final Visit on Study Drug (V04 or PW) & 30 Days Off Study Drug (V05) 
(2) To explore the impact of nilotinib on progression of PD disability as measured by the change in the 
MDS-UPDRS Part III score in the defined medications OFF state between baseline and 6 months. 


2. PRIMARY ENDPOINTS 
2.1. Tolerability 
The primary endpoint for tolerability is defined as the proportion (percentage) of study participants who 
completed the 6-month study treatment period while active on their originally assigned dose. Study completion 
can occur despite temporary drug interruptions, protocol deviations, etc. Conversely, any participant who must 
be removed from study drug (either participant-initiated or researcher initiated), completes the study on a dose 
below their assigned dose, or fails to complete the study (for any reason) will be deemed not to have tolerated 
their assigned medication. Tolerability will be assessed by comparing the percentage of participants enrolled in 
each dosage group who are able to complete the study on their originally assigned dosage group across all 
groups. 
Dosage reductions can occur at any time during the study. In case of intolerability at two capsules, daily 
dosage reduction to one capsule daily should be attempted prior to discontinuing study drug. Participants will 
reduce their dosage in a blinded fashion by 1 capsule (equivalent to 150 mg of nilotinib or placebo). 
Participants unable to tolerate one capsule will be taken off the study drug and will not be allowed to continue 
in the study. Following dosage reductions for tolerability reasons, participants may be re-challenged once 
during the study titration phase at the discretion of the site investigator. Participants may resume titration to two 
capsules daily dosage at the discretion of the site investigator, provided the intolerability issues have resolved. 
Participants that are unable to tolerate the dose increase will be reduced to one capsule daily and enter the 
maintenance phase of the study. Participants unable to tolerate one capsule daily will be taken off the study 
drug and will follow procedures outlined for premature withdrawal. No rechallenges will be allowed after safety 
visit 02 (SV02 – Day 60). Visit 03 (Day 90) will be the formal beginning of the maintenance phase of the study. 
Dose adjustments may also be needed for safety reasons, including dose adjustment for QT prolongation 
(ECG with QTc > 480 msec), for myelosuppression, for selected non-hematologic laboratory abnormalities, or 
for new cardiac and vascular occlusive events. If a participant discontinues study drug for safety reasons, the 
participant should complete a premature withdrawal visit either while the participant is still taking the study drug 
or as soon as possible after the drug discontinuation. Adverse events will be followed for 30 days after a 
participant’s last dose of study drug. Participants will be encouraged to return for the 30 and 60 days post drug 
evaluation (V05 & V06). Dosage suspension for safety reasons can occur at any time during the study. Re-
challenge will be allowed when abnormalities have resolved fully. 
2.2 Safety 
The primary endpoint for safety is defined as the proportion of study participants who experience any 
treatment-related serious adverse events (SAEs). Safety will be primarily assessed by examining the 
frequency of treatment-related SAEs across all treatment groups. Additional safety assessments will involve 
further comparisons of adverse events (AEs) and overall SAEs across the three groups. 
For the purposes of this study, an AE is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. FDA and Office of Human Research Protection 
(OHR) requirements for reporting AEs will be followed. AEs are generally detected in two ways: 
• 
Clinical → Symptoms reported by the study participant or signs detected on examination 
• 
Ancillary Tests → Abnormalities of vital signs, laboratory tests, and other diagnostic procedures 
An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, and does not imply any judgment about causality. An AE 
can arise with any use of the drug (e.g., off-label use, use in combination with another drug), and with any 
route of administration, formulation, or dose (including an overdose). Some examples of potential AEs are: 
• 
A change, excluding minor fluctuations, in the nature, severity, frequency, or duration of a pre-existing 
condition 
• 
A deterioration in the participant’s condition due to the participant’s primary disease or a pre-existing 
condition 
• 
Development of an intercurrent illness during the study 
• 
Development of symptoms which may or may not be related to the use of a concomitant medication or 
study drug 


• 
Appearance of abnormal laboratory results or significant shifts from baseline, but still within the 
reference ranges, which the investigator considers clinically important. 
At each visit, the site study staff will assess AEs by recording all voluntary complaints of the participant, and by 
assessment of clinical and laboratory features. At each study visit, the occurrence of AEs should be sought by 
non-leading questioning of the participant and caregiver during the study. AEs may also be identified when the 
participant and/or caregiver spontaneously volunteered them. Collection of AEs will begin immediately 
following signing of the ICF through the final study visit. When possible, AEs should be reported by diagnosis 
(if known) rather than individual signs and symptoms. The site investigator is responsible for monitoring each 
participant closely, and recording all observed or volunteered AEs. All AEs identified should be recorded into 
the AE eCRF in the EDC within 5 business days of the site learning of a new AE. The AE description must 
include: 
• 
Type of Event 
• 
Start and Stop Dates (when available) 
• 
Intensity / Severity 
• 
Seriousness (does the AE meet the definition of an SAE) 
• 
Causality (relation to investigational product and disease) 
• 
Outcome 
• 
Action taken regarding investigational product 
Study participants who sign consent and receive investigational treatment will be monitored for AEs from the 
time they sign consent. All AEs will be followed until resolution, stabilization, or 30 days after a participant’s last 
dose of study drug (whichever occurs first). All AEs will be recoded into MedDRA terms by the DCC. 
The Site Investigator will assess the severity (intensity) for each AE reported during the study. The assessment 
will be based on the Site Investigator’s clinical judgment as follows: 
• 
Mild: An event that causes no limitations of usual activities 
• 
Moderate: An event that causes some limitations of usual activities 
• 
Severe: An event that prevents carrying out usual activities 
The Site Investigator is initially responsible for classifying AEs as serious or non-serious. A serious adverse 
event (SAE) is an AE or suspected adverse reaction occurring at any dose of the investigational product 
(including placebo) that is considered serious if it meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (i.e., a study participant is at substantial risk of death at the time the AE occurs, on 
continued use of the medical product might have resulted in death; not an AE where occurrence in a 
more serious form might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o Emergency room visits that do not result in admission to the hospital should be evaluated for 
one of the other serious outcomes (e.g., life-threatening; required intervention to prevent 
permanent impairment or damage; other serious medically important event) 
o Does not include hospitalization for: 
 
Elective or pre-planned treatment for a pre-existing condition which has not worsened 
since signing the informed consent 
 
Social reasons (study participant admitted for reasons other than medical, e.g., lives far 
from the hospital or has no place to sleep) and/or respite care in the absence of any 
deterioration of the participant’s general condition 
o Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization of fulfills any other serious criteria, the event is an SAE 
• 
Results in persistent or significant disability or permanent damage 
o This serious criterion applies if the “disability” caused by the reported AE results in a substantial 
disruption of the study participant’s ability to carry out normal life function (i.e., if the AE resulted 


in a significant, persistent, or permanent change, impairment, damage, or disruption in the 
patient’s body function/structure, physical activities, and/or quality of life) 
• 
Results in a congenital anomaly / birth defect 
o Applicable if there is suspicion that exposure to the medical product prior to conception or 
during pregnancy may have resulted in an adverse outcome in the child 
• 
Other Serious (Important Medical Events) 
o Applicable when the AE does not fit the other outcomes, but the event may jeopardize the 
participant and may require medical or surgical intervention (treatment) to prevent one of the 
other outcomes. 
o Category also includes any event the site investigator or Independent Medical Monitor (IMM) 
judges to be serious or which would suggest a significant hazard, contraindication, side effect, 
or precaution. Examples include allergic bronchospasm (a serious problem with breathing) 
requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or 
seizures/convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse. 
o Can also involve the withdrawal of a participant from a study due to abnormal lab values 
(excluding screening labs) 
For the purposes of this study, a treatment-related AE (also referred to as an Adverse Drug Reaction) is 
defined as any noxious or unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product and an AE is 
at least a reasonable possibility, i.e., the relationship cannot be ruled out. Therefore, a subset of AEs can be 
classified as treatment related if there is thought to be a causal relationship to study drug. For each reported 
AE, the causality (i.e., relationship to study treatment) must be assessed by the site investigator and recorded 
on the AE Log according to the classifications below. Ambiguous cases should be considered as having a 
reasonable possibility of a causal relationship unless further evidence becomes available to refute this. 
• 
Definite (Causal relationship is certain): The temporal relationship between drug exposure and AE 
onset/course is reasonable, there is a clinically compatible response to dechallenge, other causes have 
been eliminated, and the event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary 
• 
Probable (High degree of certainty for causal relationship): The temporal relationship between drug 
exposure and AE onset/course is reasonable. There is a clinically compatible response to dechallenge 
(rechallenge is not required), and other causes have been eliminated or are unlikely 
• 
Possible (Causal relationship is uncertain): The temporal relationship between drug exposure and AE 
onset/course is reasonable or unknown, dechallenge or rechallenge information is either unknown or 
unequivocal, and while other potential causes may not exist, a causal relationship to the study drug 
does not appear probable 
• 
Unlikely (Not reasonable related, although a causal relationship cannot be rule out): While the temporal 
relationship between drug exposure and AE onset/course does not preclude causality, there is a clear 
alternate cause that is more likely to have caused the AE than the study drug 
• 
Unrelated (No possible relationship): The temporal relationship between drug exposure and AE 
onset/course is unreasonable or incompatible, or a causal relationship to study drug is implausible 
As this is a double-blind study, the causality assessment should be made under the assumption that the study 
participant is receiving active study medication. If considering unblinding, this assessment should be made 
prior to unblinding to avoid bias. For the purposes of this study, an SAE is considered to be treatment-related if 
the attribution is possible, probable, or definite. The site investigator determines causality of the AE for the 
purposes of initial SAE reporting. The IMM will make the final adjudication on causality. 
Expectedness will also be determined for each SAE reported during the study. The assessment of “Expected” 
vs. “Unexpected” will be based on the IMM clinical judgement. The judgement will be based on the known 
spectrum of AEs reported with the investigational drug nilotinib, as reported in the package insert (Tasigna, 
revised 2018), and limited data from a previous study in a small PD population (Pagan et al, 2016). 


3. SECONDARY ENDPOINTS 
A key secondary efficacy outcome will involve a comparison of the Movement Disorder Society Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) over time. The other secondary objectives will also utilize 
the MDS-UPDRS, which has four parts: 
• 
Part I (Non-motor experiences of daily living), compromising: 
o Part IA concerning behaviors that are assessed by the site investigator with all pertinent 
information from patients and caregivers 
o Part IB that is completed by the patient with or without the aid of the caregiver, but 
independently of the site investigator 
• 
Part II (Motor experiences of daily living), designed to be a self-administered questionnaire like Part 1B, 
but similarly can be reviewed by the site investigator to ensure completeness and clarity 
• 
Part III (Motor examination) has instructions for the rater to give or demonstrate to the patient; it is 
completed by the clinician rater 
• 
Part IV (Motor complications) to be completed by the clinician rater 
All participants will have an assessment of the motor exam (Part III) in both the practically defined medications 
OFF (12 hours post dose) and ON (based on the participant / site investigator defined best ON and/or 
approximately 1-hour post dose) states for designated visits per the schedule of activities. Participants will self-
administer Parts IB and II, but will review responses for accuracy and clarity with the site investigator or 
coordinator. Parts IA, III, and IV must be conducted by the site investigator. All parts of the MDS-UPDRS will 
be conducted at study visits, as indicated on the schedule of activities. The use of the MDS-UPDRS is 
responsive to core instrument recommendations for the Quality of Life subdomain of the National Institute of 
Neurological Disorders and Stroke (NINDS) Common Data Elements (CDEs) for PD, and to FDA guidance 
encouraging the use of patient-reported outcomes (PROs) as a substantial portion of the responses are 
patient-reported. Ideally, the same site investigator should assess all participants in parts IA and III of the 
MDS-UPDRS at all study visits. 
While the study is not powered to test efficacy of nilotinib as a putative disease modifying intervention, the data 
on the magnitude of the effect of nilotinib versus placebo on the rate of progression in PD disability will be 
collected. These data will guide the decision to pursue further clinical evaluation for that indication as well as 
provide essential data for the power calculations and sample size estimation for future disease modifying trials. 
4. ENROLLMENT & RANDOMIZATION 
A total of approximately 75 study participants will be randomized into the study. Participants will be assigned a 
Participant ID number at the time they sign/date the informed consent form. An Enrollment ID number will be 
assigned at the randomization visit to confirm enrollment and proper receipt of the randomized study drug 
assignment. Following the screening phase, study participants who continue to meet entry criteria will be 
enrolled and randomly assigned in a 1:1:1 manner to one of three treatment groups: nilotinib 150 mg, nilotinib 
300 mg, or matching placebo. The BCC will generate the randomization codes that identify the Enrollment 
ID/randomization numbers that will be included on the labels of the bottles/kits that will be supplied to sites. 
The treatment assignment for each participant will be assigned by a randomized code using randomizations 
tables generated by the NILO-PD DCC. The process will proceed as follows: 
• 
Once the participant qualifies for the randomized phase of the study, the Site Investigator or Study 
Coordinator will enter data into the eClinical system that will assign a unique, 4-digit Enrollment ID 
(randomization kit) number that will match a study drug kit. These numbers are assigned in a 
randomized order, rather than sequentially. 
• 
The randomization algorithm and participant enrollment process will be implemented through the 
Internet accessible Electronic Data Capture (EDC) system using authenticated, password-protected 
accounts for each study site. The EDC system will verify participant eligibility based on 
inclusion/exclusion criteria. 
• 
Once the online enrollment process is completed, the site will print an Enrollment Verification Report 
that verifies the participant has been randomized. The report will note the Enrollment ID number that 
was assigned that corresponds to the drug kit number and the upcoming study visit windows. 


• 
Once a participant has been allocated an Enrollment ID number, this number cannot be assigned to 
another participant. 
5. TABULATIONS 
All study participants who provide informed consent will be accounted for in this study. The number of 
randomized participants and their study disposition will be reported overall, and by treatment group. A 
CONSORT diagram summarizing the final status of all study participants will be provided. The proportion of 
randomized study participants completing each visit will be summarized as in Table 1 below. 
Table 5.1: Completeness of Study Data by Visit 
Visit 
Placebo 
(N = XX) 
150 mg 
(N = XX) 
300 mg 
(N = XX) 
BL 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V01 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V02 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V03 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V04 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V05 
XX (XX%) 
XX (XX%) 
XX (XX%) 
V06 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Additional summary reports will describe: 
• 
Number of study participants consented, eligible, and randomized by site 
• 
Reasons for exclusion 
• 
Completeness of study visits, case report forms, and collection of LPs 
• 
Protocol deviations 
• 
Study Drug Dose Reductions 
• 
Study Drug Suspensions 
• 
Early Study Terminations 
• 
Reportable Events 
• 
Study Drug Compliance: The number of expected doses of nilotinib or placebo received will be 
summarized as a continuous variable. Study participants will be deemed as “compliant” if the 
percentage of pills taken falls between 80% and 125% (inclusive) of expected pills. 
Baseline participant data will also be summarized by treatment group (nilotinib 150 mg / nilotinib 300 mg / 
placebo) with respect to important demographic characteristics. Distribution of numeric and categorical 
variables will be tabulated by treatment group and overall. Numeric variables will be summarized by the mean, 
standard deviation, minimum, and maximum. Categorical variables will be tabulated by proportions of 
percentages. Variables that will be summarized include: 
• 
Demographic Characteristics: 
o Age 
o Gender 
o Race 
o Ethnicity 
o PD Duration (Years) 
o Age at Diagnosis 
o Initial Symptoms 
 
Resting Tremor 
 
Rigidity 
 
Bradykinesia 


 
Postural Instability 
 
Other 
• 
Baseline Motor Disability PD Characteristics 
o MDS-UPDRS Total “OFF” Score 
o MDS-UPDRS Total “ON” Score 
o Hoehn & Yahr “ON” Score 
o Levodopa Equivalent Dose 
o Class of Dopaminergic Therapy 
 
Dopamine Replacement 
 
COMT Inhibitors 
 
Dopamine Agonists 
 
MAOB Inhibitors 
 
Other 
• 
Other Baseline PD Characteristics 
o Education-Adjusted MOCA Score 
o Beck Depression Inventory (BDI) II Score 
o Mattis Dementia Rating Scale 
o Parkinson’s Disease Sleep Scale (PDSS) 
o Modified Schwab & England (S&E) 
o Parkinson’s Disease Quality of Life Questionnaire 39 (PDQ-39) 
o European Quality of Life Scale (EQ-5D) 
6. ANALYSIS POPULATIONS 
6.1. Primary and Secondary Efficacy Analyses (6 Month Treatment Period) 
6.1.1. Intent-to-Treat (ITT) Population 
For the primary safety and tolerability outcomes, as well as all secondary outcomes during the 6 month 
treatment period, all analyses will be performed consistent with the intention-to-treat (ITT) principle – per the 
recent JAMA Guide to Statistics and Medicine (Detry, 2014). All participants will be analyzed as-randomized, 
which means they will be analyzed based on the treatment to which they were randomized, whether or not they 
remained compliant with respect to taking study medication. 
6.1.2. Per Protocol (PP) Population 
To assess the sensitivity of key results, and to obtain knowledge regarding the potential effects when the 
protocol was strictly adhered to, we will also replicate all primary and key secondary efficacy objectives using a 
per protocol population. The per-protocol population includes the subset of all ITT participants who satisfy both 
of the following conditions: 
• 
Completed full 6-month treatment period with no dosing interruptions, and with 80% to 125% 
compliance (both limit values inclusive) with assigned study medication as randomized in the double-
blind phase 
• 
No major protocol deviations (defined as any alteration/modification to the protocol that has the 
potential to negatively impact participant safety, integrity of the study, or ability to draw conclusions 
from study data) 
6.2. Post Treatment Analyses 
Assessment of the post-treatment secondary objective will include the subset of all randomized participants 
who satisfy both of the following conditions: 
• 
Had a final visit on treatment at 3 months or later past randomization 
• 
Had a 30-day safety assessment after stopping treatment 


7. PRIMARY ANALYSES 
Primary Tolerability Hypothesis: To assess whether either 150 mg or 300 mg once daily dosing of 
nilotinib is sufficiently tolerable, compared to placebo 
The first primary objective of this study is to evaluate the tolerability of nilotinib versus placebo. This primary 
objective will be met by conducting a comparison of the proportion of study participants who complete the 
study while active on their assigned dose among the placebo group and each of the treatment groups. 
Separate tests will be conducted for each of the treatment arms (i.e., a separate test for placebo vs. nilotinib 
150 mg & placebo vs. nilotinib 300 mg) with a significance level of 0.05 for each test. 
Below, we introduce some key notation that we will use to describe the analysis plan for the proposed trial: 
• 
Let p150 represent the true (unknown) percentage of participants treated with nilotinib 150 mg who will 
tolerate the assigned medication and dosage 
• 
Let p300 represent the true (unknown) percentage of participants treated with nilotinib 300 mg who will 
tolerate the assigned medication and dosage 
• 
Let pp represent the true (unknown) percentage of participants treated with placebo who will tolerate the 
assigned medication 
The primary tolerability null hypotheses being tested in this trial are that participants treated with either dose of 
nilotinib will have similar tolerability to participants treated with placebo. The primary hypotheses will compare 
the overall tolerability rates for each nilotinib arm vs. placebo participants. Using the notation above, the two 
one-sided hypothesis tests below will be assessed: 
H01: p150 = pp     vs.     HA1: p150 < pp 
AND 
H02: p300 = pp     vs. HA2: p300 < pp 
Therefore, rejecting the null hypothesis suggests that the particular dose group of nilotinib shows significantly 
less tolerability relevant to the placebo group. If we do not reject the null hypothesis, this would imply that there 
are not significant enough concerns with tolerability to preclude moving forward with further study of one or 
both doses of nilotinib. Specifically, this would provide justification for proceeding with further study of the drug 
(pending the results of the safety assessment). Each hypothesis will be assessed via a Pearson chi-square 
test. Due to randomization, it is unlikely that important covariates will be imbalanced in this study. However, 
given the small sample size, this cannot be dismissed. We will assess for important baseline imbalances, and if 
any imbalances exist, we will fit a logistic regression model that will allow adjustment for the relevant covariates 
with important imbalances present. 
The results of the tolerability analysis will be summarized graphically, with a bar plot showing the proportion 
difference and one-sided CI for each group comparison. The results will also be depicted as in Table 2 below. 
Table 7.1. Proportion of Participants Meeting Study Definition for Tolerability 
Group 
Placebo 
(N = XX) 
150 mg 
(N = XX) 
300 mg 
(N = XX) 
Number (%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
P-Value for comparison versus 
placebo 
N/A 
p = X.XX 
p = X.XX  
Decision 
N/A 
Tolerable (Yes/No?) 
Tolerable (Yes/No?) 
The primary tolerability analysis will follow the intent-to-treat (ITT) paradigm. All randomized participants must 
be included in the primary ITT analysis, and will be analyzed in the treatment group to which they were initially 
randomized. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the 
optimal strategy for dealing with missing data is to make every effort to obtain complete data during the 
conduct of the study. The DCC data managers and CCC protocol coordinators will work diligently and use a 
variety of methods to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a 
small percentage of missing data. For the primary analysis, we will take a conservative approach and assume 
that any participant not completing the study for any reason did not tolerate study therapy. To further assess 
the potential dependence of the results of the primary analysis to these missing values, a series of sensitivity 


analyses will be conducted. We will attempt to collect as much detailed information as possible for participants 
who are lost to follow-up or prematurely withdraw from the study due to any reason. Any participants who 
terminate treatment or the study early due to tolerability concerns (AEs) will always be counted as not 
tolerating their assigned treatment dose. For participants that do not provide complete data, and for which 
there is no clear tolerability concern, we will analyze the data using the following strategies: 
• 
Using Only Observed Data (No Imputation) 
• 
Worst-Case Scenario: Assume all missing participants in the treatment group did not tolerate the dose, 
and all missing participants in the placebo group did tolerate the dose 
• 
Best-Case Scenario: Assume all missing participants in the treatment group did tolerate the dose, and 
all missing participants in the placebo group did not tolerate the dose 
The results of these analyses will provide important information regarding the sensitivity of the findings to the 
missing data, and will be critical to the steering committee in assessing the full value of the study results. 
Primary Objective #2: The second primary objective is to assess the safety of the daily oral administration of 
nilotinib (150 mg or 300 mg once daily) 
The safety objective will be assessed by comparing the proportion of study participants with any SAE among 
the placebo group and each of the treatment groups (separate tests for placebo vs. nilotinib 150 mg & placebo 
vs. nilotinib 300 mg). The safety analysis will be conducted in a similar manner as the tolerability analysis. 
Each study participant will be classified according to whether they experienced a treatment-emergent SAE 
(“yes” or “no”). The specific safety primary hypotheses will be assessed in two ways. First, the percentage of 
participants who experience any treatment-related SAE, overall and by body system, will be compared across 
each of the treatment groups versus placebo using standard chi-square tests. Then, the rates of treatment-
related SAEs across the treatment groups will be compared using a Poisson regression model. If there are 
specific differences within any specific SOC, then additional assessments will compare differences across 
groups for specific MedDRA terms within that SOC to further explore the cause of the observed differences. To 
provide an overall summary of the safety of each nilotinib dose, additional safety assessments will involve 
further comparisons of AEs and SAEs across the three groups. In addition to detailed safety tables that will be 
provided as part of a final version of standard DSMB tables, high level safety results will be summarized as 
shown in Table 7.2 below. 
Table 7.2. Summary of Safety Analyses 
 
Placebo 
(N = XX) 
150 mg 
(N = XX) 
300 mg 
(N = XX) 
p-value 
(150 vs. pbo) 
p-value 
(300 vs. pbo 
Any AE 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Any Treatment-Related AE 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Any Serious AE 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Early Drug Reductions (Any) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Early Drug Reductions (Due to AE) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Early Drug Discontinuations (Any) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Early Drug Discontinuations (Due to AE) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Premature Withdrawals (Any) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Premature Withdrawals (Due to AE) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Deaths (Any) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Deaths (Due to AE) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
X.XX 
X.XX 
Decision Algorithm Based on Primary Tolerability & Safety Hypotheses 
All this information will be synthesized and reviewed by the Sponsor and steering committee at the end of 
cohort 1. This summary information will be critical for making the dosing decision for consideration in cohort 2 
(or deciding not to proceed with cohort 2). At the end of cohort 1, a decision rule will be invoked to decide 
regarding the “best” dose for consideration of moving forward with in a potential second cohort of early/de novo 
PD participants. This decision will be based on a combination of the results from the tolerability and safety 
hypotheses. In general, the decision algorithm will proceed as follows: 


• 
Did the 300 mg nilotinib group show suitable tolerability? 
o If ‘Yes’, then did the 300 mg nilotinib group show suitable safety? 
 
If ‘Yes’, then recommend the 300 mg nilotinib dose for consideration in a second 
cohort 
 
If ‘No’, then did the 150 mg nilotinib group show suitable tolerability? 
• 
If ‘Yes’, then recommend the 150 mg nilotinib dose for consideration in a 
second cohort 
• 
If ‘No; then conclude that neither dose is sufficiently safe and tolerable to 
justify further exploration 
o If ‘No’, then did the 150 mg nilotinib group show suitable tolerability? 
 
If ‘Yes’, then did the 150 mg nilotinib group show suitable safety? 
• 
If ‘Yes’, then recommend the 150 mg nilotinib dose for consideration in a 
second cohort 
• 
If ‘No’, then conclude that neither dose is sufficiently safe and tolerable to 
justify further exploration 
 
If ‘No’, then conclude that neither dose is sufficiently safe and tolerable to justify 
further exploration 
If either of the doses are considered sufficiently safe and tolerable, the study steering committee will also 
review the results of the CSF PK analysis. If at least one dose is shown to be safe and tolerable, and nilotinib 
CSF PK samples demonstrate expected CNS penetration, the steering committee will consider moving that 
dose forward into a second cohort of early/de novo PD participants. 
8. KEY SECONDARY ANALYSES 
Key Secondary Objective: To conduct a futility analysis within each treated group. 
A key secondary objective of this study is to conduct a single group hypothesis within each PD group to assess 
“futility” for replicating the large difference observed in a previously published study (Pagano et al, 2016). This 
key secondary objective will be assessed by conducting a futility analysis to examine the change of the MDS-
UPDRS Part III between baseline and 6 months. Within each of the two dose groups, this futility analysis will 
compare the observed change in MDS-UPDRS Part III to the observed change from the Pagan et al (2016) 
study to determine whether we can rule out the large change previously reported – i.e., declare “futility”. This 
will be based on a single group hypothesis test within each dose group comparing the observed change in the 
MDS-UPDRS Part III scores collected ON (at least one-hour post dose) between baseline and 6 months to the 
observed change reported from the Pagan et al (2016) study to determine whether we can rule out the large 
change previously reported. Based on the results from Table 2 in the Pagan et al (2016) publication, which 
used the UPDRS: 
• 
Mean change over 6 months in the 150 mg nilotinib group = 7.0 reduction (std dev = 12.9) 
• 
Mean change over 6 months in the 300 mg nilotinib group = 10.8 reduction (std dev = 7.8)  
For consistency, we will test a similar hypothesis within each group using the smallest observed reduction. 
However, since we will be using the MDS-UPDRS, we include a correction factor of 1.4 as specified in Goetz 
et al (2012) and use the smallest reduction for both futility tests. In other words, the futility test within each 
nilotinib dose group will be based on the following set of hypotheses: 
H0: δ ≤ -9.8 (7 x 1.4)     vs.     HA: δ > -9.8 
Where δ represents the change from baseline to 6 months in the corresponding group being tested. Since this 
is an early phase exploratory study, and we want to ensure adequate power for ruling out the large effects 
previously observed, we assume an alpha level of 0.10 for each one-sided hypothesis of interest. 
The raw data for all three treatment groups will be summarized graphically, as in the following table: 
 


Table 8.1: Descriptive Statistics of MDS-UPDRS Part III “ON” Scores Over Time 
Visit 
Nilotinib 150 mg 
(N = XX) 
Nilotinib 300 mg 
(N = XX) 
Placebo 
(N = XX) 
Baseline 
Mean (SD) 
(Min, Max) 
Missing 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
Day 14 (Month = 0.5) 
Mean (SD) 
(Min, Max) 
Missing 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
Day 30 (Month = 1) 
Mean (SD) 
(Min, Max) 
Missing 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
Month 3 
Mean (SD) 
(Min, Max) 
Missing 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
Month 6  
Mean (SD) 
(Min, Max) 
Missing 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
 
XX.X (XX) 
(XX.X , XX.X) 
XX 
The null hypotheses of interest can be evaluated based on an assessment of parameter estimates from a 
linear mixed effects model (LMM: Laird & Waire, 1982). LMMs are advantageous for longitudinal clinical trials 
because they can account for dependency due to repeated measures with relatively few parameters, which 
potentially enhances statistical efficiency. Furthermore, LMMs can accommodate incomplete cases (i.e., 
missing data), which is expected in this study due to dropout. LMMs are typically estimated using maximum 
likelihood methods (Verbeke & Molenberghs, 2000) that yield valid inferences with incomplete cases under the 
widely applicable assumption that the missing data are ignorable (Little & Rubin, 2002). 
For this analysis, assuming linear change over time, the LMM can be written in the following manner: 
Yij = α + β1jX1ij + β2tijX2i + β3tijX3i + β4tijX4i + ai + bi + εij 
where: 
• 
Yij is the MDS-UPDRS Part III “ON” score for the ith participant at the jth time point (day 14, day 30, 
month 3, month 6, or time of PW visit) 
• 
α is the common intercept parameter 
• 
tij denotes time (in months) 
• 
X1i = LEDD for the ith participant at the jth time point 
• 
X2i = 1 if ith participant is in the nilotinib 150 mg group; = 0 otherwise 
• 
X3i = 1 if ith participant is in the nilotinib 300 mg group; = 0 otherwise 
• 
X4i = 1 if ith participant is in the placebo group; = 0 otherwise 
• 
ai and bi are random effects (random intercepts and slopes) 
• 
εij is a random error term 
Assuming a common intercept constrains the baseline means to be equal, which controls for any initial 
imbalance that might occur due to empirical randomization (Senn, 2013). We make the typical assumptions: 
ቂ𝑎𝑎𝑖𝑖
𝑏𝑏𝑖𝑖ቃ ~ N(0,G),     εij ~ N(0,σ2Ii),     and   ቂ𝑎𝑎𝑖𝑖
𝑏𝑏𝑖𝑖ቃ ┴ εij 
The main parameters of interest are β1, β2, and β3, which correspond to the estimated slopes in the two 
treatment and placebo groups, respectively. The two desired tests of interest for this key secondary objective 
can be obtained by testing the null hypothesis of the following contrasts: 
• 
For the nilotinib 150 mg group comparison: 
H0: 6β2 ≤ -9.8     vs.     HA: 6β2 > -9.8 
• 
For the nilotinib 300 mg group comparison: 
H0: 6β3 ≤ -9.8     vs.     HA: 6β3 > -9.8 


Each null hypothesis can be evaluated with the corresponding likelihood ratio test. Rejecting the null 
hypothesis implies that a future study is unlikely to observe the large effects reported in the Pagan et al (2016) 
study. However, that would not rule out potentially meaningful effects on a smaller scale. Furthermore, note 
that failure to reject the null hypothesis does not imply that a significant difference has been observed. If the 
null hypothesis is not rejected, or if the hypothesis is rejected but the observed differences seem potentially 
meaningful (just on a smaller scale of magnitude than previously reported), further study should be warranted. 
Since the longitudinal measurements will span up to five time points per participant (baseline, 14 days, 30 
days, 3 months, and 6 months), there is a possibility that the MDS-UPDRS Part III “ON” trajectories will not be 
linear. To assess the sensitivity of the results to the assumption of linearity, non-linear trends will be modeled 
by inserting time as a categorical variable, modeling change from baseline, and including baseline values as a 
covariate. For this modeling approach, visits that were performed outside of an expected scheduled visit will be 
categorized into the next expected scheduled visit. We will compare model fit between the non-linear and 
linear models using the Akaike Information Criterion (AIC), and will report results from the non-linear model if 
the AIC suggests that the nonlinear model provides a better fit. In this case, the primary comparisons will 
involve a comparison of the estimated change from baseline means within each of the two groups at the 6-
month visit. 
The residuals of the fitted statistical models will be examined for evidence of departure from assumptions, such 
as normality. If assumptions appear to be grossly violated, then transformations of response variables might be 
considered. Finally, the proposed study involves multiple sites, which is a potential source of additional 
variation. Patients within a site tend to be correlated due to similarity of environment, e.g. because of testing by 
the same set of clinicians (Localio et al, 2001). Sensitivity analyses may also be conducted to account for site 
variation by augmenting the models described above with additional random effects and associated variance 
components.  
9. ADDITIONAL SECONDARY ANALYSES 
The study will also assess additional secondary objectives comparing the change in MDS-UPDRS scores over 
time between groups to establish both the potential degree of symptomatic effect of nilotinib and to assess the 
impact of nilotinib on the progression of PD disability. 
Additional Secondary Objective #1: To establish the degree of symptomatic effect of nilotinib as measured 
by the change in MDS-UPDRS Part III ON score between baseline and visit 2 (1 month). 
To assess the degree of symptomatic effect of nilotinib, we will compare the change in MDS-UPDRS Part III 
ON score from baseline to 1 month. To assess this hypothesis, the same LMM described in section 8 will be 
used. Assuming the linear model provides the best fit, an initial two degree of freedom test will be utilized to 
test for any differences among the slopes for the three groups:  
𝐻𝐻0: ൤𝛽𝛽2 −𝛽𝛽4
𝛽𝛽3 −𝛽𝛽4൨= ቂ0
0ቃ     𝑣𝑣𝑣𝑣.     𝐻𝐻𝐴𝐴: ൤𝛽𝛽2 −𝛽𝛽4
𝛽𝛽3 −𝛽𝛽4൨≠ቂ0
0ቃ 
If this hypothesis is not rejected, then we will conclude that there is not sufficient evidence to conclude that 
either nilotinib treatment group shows a symptomatic effect on MDS-UPDRS Part III “ON” scores during the 
first month of the treatment period. If the null hypothesis is rejected, pairwise comparisons will be utilized to 
assess which pairs of treatment groups show significant differences over time with respect to the MDS-UPDRS 
Part III “ON” scores. 
If a non-linear model is chosen to provide a better fit in the analysis described in section 8 above, the primary 
comparisons for this additional secondary objective will involve a two degree of freedom test for differences in 
the change from baseline means between each treatment group versus placebo at the month 1 visit. 
Additional Secondary Objective #2: To establish the degree of symptomatic effect of nilotinib as measured 
by the change in MDS-UPDRS Part III ON score between the final visit on study drug & 30 days off study drug. 
To further assess the degree of symptomatic effect, we will also examine the change in MDS-UPDRS Part III 
ON after the end of treatment or final study visit. For this analysis, the following LMM will be used: 
Yij = α + β1X1i + β2X2i + β3tijX3i + β4tijX4i + β5tijX5i + ai + bi + εij 


where: 
• 
Yij is the change from final visit on study drug to the jth time point (day 30 post, day 60 post) for the ith 
participant 
• 
α is the common intercept parameter 
• 
tij denotes time (in months; day 30 = 1 & day 60 = 2) 
• 
X1i represents the MDS-UPDRS Part III “ON” score at the final visit on study drug 
• 
X2i = LEDD for the ith participant at the jth time point 
• 
X3i = 1 if ith participant is in the nilotinib 150 mg group; = 0 otherwise 
• 
X4i = 1 if ith participant is in the nilotinib 300 mg group; = 0 otherwise 
• 
X5i = 1 if ith participant is in the placebo group; = 0 otherwise 
• 
ai and bi are random effects (random intercepts and slopes) 
• 
εij is a random error term 
Assuming the linear model provides the best fit, and initial two degree of freedom test will be utilized to test for 
any differences among the slopes for the three groups: 
𝐻𝐻0: ൤𝛽𝛽3 −𝛽𝛽5
𝛽𝛽4 −𝛽𝛽5൨= ቂ0
0ቃ     𝑣𝑣𝑣𝑣.     𝐻𝐻𝐴𝐴: ൤𝛽𝛽3 −𝛽𝛽5
𝛽𝛽4 −𝛽𝛽5൨≠ቂ0
0ቃ 
If this hypothesis is not rejected, then we will conclude that there is not sufficient evidence to conclude that 
either nilotinib treatment group shows a symptomatic effect on MDS-UPDRS Part III “ON” scores during the 
first month after the end of treatment. If the null hypothesis is rejected, pairwise comparisons will be utilized to 
assess which pairs of treatment groups show significant differences over time with respect to the MDS-UPDRS 
Part III “ON” scores. 
As above, to assess the sensitivity of the results to the assumption of linearity, non-linear trends will be 
modeled by inserting time as a categorical variable. We will compare model fit between the non-linear and 
linear models using the AIC, and will report results from the non-linear model if the AIC suggests that the non-
linear model provides a better fit. If the assumption of linearity is supported, any significant findings would 
suggest symptomatic effects at both 30 and 60 days. If a non-linear model is chosen to provide a better fit, the 
primary comparisons for this additional secondary objective will involve a two degree of freedom test for 
differences in the change from baseline means between each treatment group versus placebo at 30 days 
following the end of treatment. If a significant symptomatic effect is observed for either treatment arm versus 
placebo at 30 days post dose in the non-linear model, we will also examine the effect at 60 days post dose to 
explore the longevity of the effect.  
Additional Secondary Objective #3: To explore the impact of nilotinib in progression of PD disability as 
measured by the change in the MDS-UPDRS Part III in the defined medications OFF state between baseline 
and 6 months. 
To assess the impact of nilotinib on the progression of PD disability, we will examine the change in MDS-
UPDRS from baseline to 6 months (evaluated for both the “OFF” and “ON” states). 
To assess this hypothesis for the MDS-UPDRS Part III “ON” scores, the same LMM described in section 8 will 
be used. Assuming the linear model provides the best fit, an initial two degree of freedom test will be utilized to 
test for any differences among the slopes for the three groups: 
𝐻𝐻0: ൤𝛽𝛽2 −𝛽𝛽4
𝛽𝛽3 −𝛽𝛽4൨= ቂ0
0ቃ     𝑣𝑣𝑣𝑣.     𝐻𝐻𝐴𝐴: ൤𝛽𝛽2 −𝛽𝛽4
𝛽𝛽3 −𝛽𝛽4൨≠ቂ0
0ቃ 
If this hypothesis is not rejected, then we will conclude that there is not sufficient evidence to conclude that 
either nilotinib treatment group shows differences in the progression of MDS-UPDRS Part III “ON” scores over 
the 6-month treatment period. If the null hypothesis is rejected, pairwise comparisons will be utilized to assess 
which pairs of treatment groups show significant differences over time with respect to the MDS-UPDRS Part III 
“ON” scores. 
If a non-linear model is chosen to provide a better fit in the analysis described in section 8 above, the primary 
comparisons for this additional secondary objective will involve a two degree of freedom test for differences in 
the change from baseline means between each treatment group versus placebo at the month 6 visit. 


A similar approach will be utilized to assess the MDS-UPDRS Part III “OFF” scores over time, except the 
model specified in section 8 will be simplified to include only baseline, month 3, and month 6 values (since an 
“OFF” assessment was not performed at days 14 and 30 per the SOA). 
10. OTHER EXPLORATORY ANALYSES 
Several additional exploratory analyses are also planned, but will not be included as part of the final report. 
These exploratory analyses will be assessed to further examine the impact of nilotinib on disability, quality of 
life, and functional status. These additional analyses will include, but are not limited to: 
• 
Change in Motor Disability 
o The change in MDS-UPDRS Total score (ON and OFF scores) 
o The change in the ambulatory capacity (Sum of 5 MDS-UPDRS questions: Falling, Freezing, 
Walking, Gait, Postural Stability) 
o Analysis of ST utilization as measured by levodopa equivalent dose 
o Severity of motor complications as measured by MDS-UPDRS Part IV subscale (complications 
of therapy) 
• 
Change in Cognitive Disability – Changes in cognitive function, as measured by the change in Mattis 
Dementia Rating Scale (DRS-2) 
• 
Changes in Sleep Function – Changes in sleep quality, as measured by the Parkinson’s Disease Sleep 
Scale (PDSS) 
• 
Measures of Global Disability – Clinician and Participant Global Impression of Change Score (CGI) 
• 
Measures of Functional Status and Quality of Life 
o The change in the MDS-UPDRS Motor and Non-Motor Experiences and Daily Living subscores 
o The change in the Modified Schwab and England scale (S&E) 
o The change in Parkinson Disease Quality of Life Questionnaire 39 (PDQ-39) 
o The change in European Quality of Life Scale (EQ-5D) 
• 
Blindedness and treatment expectations assessments, as measured by questionnaires completed by 
the site investigator and participant 
• 
Pharmacokinetics and Pharmacodynamics 
o To determine serum PK of nilotinib in patients with PD 
o To investigate ability of nilotinib to cross the blood brain barrier in patients at a dose(s) that is 
tolerable and safe, as measured by dose-dependent increases in unbound nilotinib 
concentrations in the cerebrospinal fluid (CSF) 
o To investigate factors that could affect the PK of nilotinib, such as age, sex, PD severity, 
race/ethnicity 
o To investigate the ability of nilotinib to engage its known molecular target(s) at a dose that is 
tolerable and safe, as measured by biomarkers of pathway inhibition in the serum and CSF 
o To investigate the relationship between nilotinib exposures in serum and CSF with its ability to 
engage known molecular target(s), as measured by biomarkers of pathway inhibition in the 
serum and CSF 
• 
To explore impact of nilotinib on: 
o Dopaminergic system as measured by an increase in dopamine and its metabolites in CSF 
[e.g., homovanillic acid (HVA) level] 
o Other biomarkers linked to potential mechanism of neuroprotection (including, but not limited to, 
CSF α-synuclein, total tau, phosphorylated tau, etc.) 
Additional blood/serum/plasma/DNA/CSF samples will be collected and stored for future research. 


11. SAMPLE SIZE JUSTIFICATION 
11.1. Primary Objective 
For the purposes of computing the required sample size, we assumed that at least 90% of participants on 
placebo will meet the study definition of “tolerability” (completing the study on the assigned dose). Furthermore, 
it was determined that an absolute decrease of 30% or greater with respect to tolerability for active treatment 
arms versus placebo would provide sufficient tolerability concerns that would not warrant further study of that 
dose. Hence, the sample size was chosen to provide sufficient power to compare an expected 90% tolerability 
rate in the placebo group versus a 60% or lower tolerability rate in each of the treatment groups. Under these 
assumptions, and considering a one-sided test with an alpha = 0.05, a total of 25 participants per group 
provides 80% power for the moderate/advanced cohort. With three groups, this leads to a total of 
approximately 75 required participants for cohort 1. 
11.2 Major Secondary Objective 
For the major secondary objective, we utilized preliminary estimates from the Pagan et al (2016) publication, 
as described in section 8. Converting from the UPDRS used in the Pagan et al (2016) study to the MDS-
UPDRS utilized in this study, the test is set up in the manner described in section 15.3.3. Furthermore, we 
believe that since the conversion factor maintains the relationships between the mean and standard deviation, 
although the expected values might differ the power calculations shown below give a valid estimate of the 
power for the proposed study. Using these estimates, we computed the power of the study to detect “futility” 
based on comparisons of the change within the two nilotinib dosage groups. Specifically, we assume an alpha 
level of 0.10 for the one-sided futility hypothesis, and assume a standard deviation of 12.9. The table below 
shows the power for rejecting the null hypothesis of interest (i.e., declaring “futility”), computed across a range 
of assumed values for the true change from baseline in the nilotinib treated patients. This table demonstrates 
the benefits of using the futility hypothesis (with differences shown in both UPDRS and converted MDS-
UPDRS units). 
Table 11.1. Power for Futility Analysis for Key Secondary Objective 
True Change in UPDRS 
-7.0 
-3.5 
0 
+3.5 
True Change in MDS-UPDRS 
-9.8 
-4.9 
0 
+4.9 
Pr(Futility) 
10% 
52% 
92% 
99% 
When the true change in MDS-UPDRS part III ON score over the 6-month treatment period involves an 
increase in scores (implying progression of the disease), the test will declare “futility” with high probability. 
Likewise, when the true change in MDS-UPDRS part III ON score is equal to or greater than the observed 
change in the Pagan et al (2016) study, the trial has a very low chance of incorrectly declaring futility. If the 
observed change in the MDS-UPDRS Part III ON score is half that observed in the prior study (a reduction of 
3.5), then the study has marginal power (52%) to declare futility. If there is no observed reduction associated 
with treatment, the study has 92% power to declare futility. Given the sample size limitations of the study, this 
provides a reasonable chance of addressing the main futility question of interest regarding whether the 
observed large observed effect in the prior study can be refuted. The test of futility will have adequate power 
mainly if the direction of effect is in the opposite direction from that observed in the previous study (i.e., if there 
is no reduction, only a potentially smaller increase in the MDS-UPDRS over time). These sample size 
calculations were based on the observed change for the nilotinib 150 mg group in the Pagan et al (2016) study. 
Since bigger effects were observed over 6 months for the nilotinib 300 mg group, the trial has adequate power 
for addressing futility in the nilotinib 300 mg group in a similar manner. 
12. SAFETY MONITORING 
All aspects of the study will be monitored by authorized individuals in compliance with Good Clinical Practice 
(GCP) and applicable regulations. Refer to the Safety Management Plan for additional details. 
12.1 
Clinical Monitor 
The Clinical Monitor (CM) is responsible for frequent review of blinded safety data, including AEs, SAEs, 
laboratory and EKG data. Additionally, the CM is responsible for assisting sites in responding appropriately to 
safety concerns. If the CM encounters significant safety concerns, they will discuss the severity, importance, 


and relevance of the safety concern with the PI, the Site Investigator, and the Project Manager, and will work 
with all parties to determine appropriate action. 
12.2 
Independent Medical Monitor 
The study sponsor will appoint an Independent Medical Monitor (IMM). The IMM will review (in real-time) all 
events that meet the definition of an SAE. The IMM will review SAE reports, and classify each with respect to 
causality, severity, and expectedness as outlined in the Safety Management Plan. The IMM may determine 
that the SAE is serious, related, and unexpected and requires expedited reporting to the FDA. When this 
occurs, the IMM may communicate with the CM and/or PI for clarification and to provide further information on 
the event – especially if the event has not resolved or stabilized by the time of completing of the initial report. 
This may involve contacting other clinicians responsible for the participant’s care, with participant’s 
authorization for release of information, to obtain information on diagnoses, investigations performed, and 
treatment given. However, the IMM should code all events independent from the CM and/or Site Investigator. 
Consensus between the Site Investigator and IMM is not required. In case of disagreement between the Site 
Investigator and IMM, the IMM adjudication prevails for reporting purposes. The IMM will also alert the CTCC 
PM and PI of any concerns related to SAEs that should be forwarded to the entire Data and Safety Monitoring 
Board (DSMB) for review via email.  
12.2 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be appointed by MJFF, and will be responsible for periodic 
review of trial conduct, progress, and safety data throughout the trial. The DSMB will meet at approximately 
three-month intervals (or as determined by MJFF) to review partially unblinded study data provided by the 
study statistician. The DSMB will periodically review and evaluate the accumulated data for participant safety, 
adverse events, study conduct, and study progress. The DSMB may suggest changes to the protocol or 
consent form to the PI because of AEs. The DSMB may also make recommendations to MJFF concerning 
continuation, modification, or termination of the study. The frequency and format of DSMB meetings and 
reports will be established and documented prior to study participant enrollment. 
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