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Study Protocol & Schedule of Activities CLINICAL 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) 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 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. 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 of Nilotinib in Participants with Parkinson’s Disease (PD) STUDY ACRONYM: N1LO-PD -tf’-2ë Tanya Simuni, MD Date Principal Investigator 3/14/18 Christopher S. Coffey, PhD Date B iostatistician \) - \ Cynthiçasaceli, MB Date ClinicaJria1s Coordinat on Center Administrative Principal Investigator Page 2 of 198 Version 4 Date: 21 feb2018 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) 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 Page 3 of 198 Version 4 Date: 21 Feb 2018 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) DOCUMENT HISTORY Document Date of Summary of Changes Version Issue 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). Page 4 of 198 Version 4 Date: 21 Feb 2018 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) 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) Page 5 of 198 Version 4 Date: 21 Feb 2018 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) 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 Page 6 of 198 Version 4 Date: 21 Feb 2018 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) PROTOCOL SYNOPSIS A Randomized, Double-Blind, Placebo-Controlled, Phase IIa, Parallel Group, Two-Cohort Study to Define the Safety, Tolerability, Clinical and Protocol Title 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 Planned enrollment duration: approximately six (6) months for each cohort. Duration of post randomization follow up: Study Period Cohort 1 (moderate to advanced PD): Six (6) months Cohort 2 (early/de novo PD): Twelve (12) months 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 N Participants (the selected dose from cohort 1: placebo). Randomization in this cohort will not commence unless a safe & tolerable dose is determined from Cohort 1. 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
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