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Study Protocol with Amendment 01 Clinical Study Protocol with Amendment 01 A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients with I nadequate Response to Prior Preventive Treatments Study Number TV48125-CNS-30068 NCT03308968 Protocol with A mendment 01 Approval Date: 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 Clinical Study Protocol Amendment 01 Study Number TV48125-CNS-30068 A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior Preventive Treatments A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label Period on Efficacy and Safety of Fremanezumab in Adults with Migraine A Study to Test if Fremanezumab is Effective in Preventing Migraine in Patients Who Did Not Respond to Prior Preventive Migraine Treatments Efficacy and Safety Study (Phase 3) IND number: 106,533; NDA number: Not applicable; BLA number: Not applicable; EudraCT number: 2017-002441-30 EMA Decision number of Pediatric Investigation Plan: Not applicable Article 45 or 46 of 1901/2006 does not apply Protocol Approval Date: 27 July 2017 Protocol with Amendment 1 Approval Date: 23 October 2017 Sponsor Teva Branded Pharmaceutical Products R&D, Inc. 41 Moores Road Frazer, Pennsylvania 19355 United States of America Information regarding clinical laboratories and other departments and institutions is found in Appendix A 1 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the region of the study); national country legislation; and the sponsor’s Standard Operating Procedures (SOPs). Confidentiality Statement This document contains confidential and proprietary information (including confidential commercial information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no information contained herein may be published or disclosed without written approval from the sponsor. © 2017 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 2 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 AMENDMENT HISTORY The protocol for study TV48125-CNS-30068 (original protocol dated 27 July 2017) has been amended and reissued as follows: Amendment 01 23 October 2017 0 patients randomized/enrolled to date The Summary of Changes to the Protocol includes the corresponding reason/justification for each change and is provided in Section 16. 3 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 INVESTIGATOR AGREEMENT Original Protocol Dated 27 July 2017 Clinical Study Protocol with Amendment 01 IND number: 106,533; NDA number: Not applicable; BLA number: Not applicable; EudraCT number: 2017-002441-30 EMA Decision number of Pediatric Investigation Plan: not applicable Article 45 or 46 of 1901/2006 does not apply A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior Preventive Treatments Principal Investigator: Title: Address of Investigational Center: Tel: I have read the protocol with Amendment 01 and agree that it contains all necessary details for carrying out this study. I am qualified by education, experience, and training to conduct this clinical research study. The signature below constitutes agreement with this protocol and attachments, and provides assurance that this study will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to national or local legal and regulatory requirements and applicable regulations and guidelines. I will make available the protocol and all information on the investigational medicinal product (IMP) that were furnished to me by the sponsor to all physicians and other study personnel reporting to me who participate in this study and will discuss this material with them to ensure that they are fully informed regarding the IMP and the conduct of the study. I agree to keep records on all patient information, investigational medicinal products (IMP) shipment and return forms, and all other information collected during the study, in accordance with national and local Good Clinical Practice (GCP) regulations as well as all other national and international laws and regulations. Principal Investigator Signature Date 4 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo - C o ntr oll e d St u d y – Mi gr ai n e Cli ni c al St u d y Pr ot o c ol wit h A m e n d m e nt 0 1 Study T V48125 -C N S -30068 SPONSOR PROTOCOL APP R OVAL 5 Pr ot o c ol V ersi o n 2 wit h A m e n d m e nt 0 1, 2 3 O ct o b er 2 0 1 7 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 COORDINATING INVESTIGATOR AGREEMENT 6 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 CLINICAL STUDY PROTOCOL SYNOPSIS with Amendment 01 Study TV48125-CNS-30068 Title of Study: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior Preventive Treatments Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. Investigational New Drug (IND) Number: 106,533 New Drug Application (NDA) Number: Not Applicable Biological License Application (BLA) Number: Not Applicable EudraCT Number: 2017-002441-30 EMA Decision number of Pediatric Investigation Plan: Not applicable Article 45 or 46 of 1901/2006 does not apply Name of Test Investigational Medicinal Product (IMP): Fremanezumab (TEV-48125) EudraVigilance (EV) code for the IMP, if applicable: SUB181665 Type of the Study: Efficacy and Safety Study (Phase 3) Indication: Fremanezumab is intended for migraine prophylaxis Is this study conducted to investigate the New Use of an approved, marketed product? No Number of Investigational Centers Planned: The study is planned to be conducted in approximately 120 investigational centers. Countries Planned: The study is planned to be conducted in approximately 15 countries. Planned Study Period: 4Q 2017 to 4Q 2019 Number of Patients Planned (total): Approximately 804 patients (268 patients per treatment group) Study Population: The study population will be composed of male and female patients, aged 18 to 70 years, inclusive, with a history of migraine (as defined by International Classification of Headache Disorders, 3rd revision [ICHD-3] criteria [IHS 2013]) for at least 12 months prior to screening and diagnosis of episodic migraine (EM) or chronic migraine (CM) prospectively documented via a review of headache data recorded daily in an electronic headache diary device during a 28-day run-in period. At the time of screening, patients must have documented inadequate response to 2 to 4 classes of prior preventive migraine medications (as defined in Appendix H) within the past 10 years (in medical chart or by treating physician’s confirmation, see Appendix I for acceptable documentation of previous treatment failure). A subset of these patients (at least 120 patients) must have documented inadequate response to 2 to 3 classes of prior preventive medications (as defined in Appendix H) and in addition inadequate response to valproic acid. All inadequate responses must be within the past 10 years 7 Protocol Version 2 with Amendment 01, 23 October 2017 Placebo-Controlled Study–Migraine Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30068 (in medical chart or by treating physician’s confirmation; see Appendix I for acceptable documentation of previous treatment failure). Inadequate response to prior preventive migraine medications (including valproic acid) is defined as (see also Appendix H): no clinically meaningful improvement per treating physician’s judgment, after at least 3 months of therapy at a stable dose considered appropriate for migraine prevention according to accepted country guidelines, or when treatment has to be interrupted because of adverse events that made it intolerable by the patient, or the medication is contraindicated or not suitable for the prophylactic treatment of migraine for the patient. The 3-month period does not apply if the drug is intolerable or contraindicated or not suitable. If onabotulinumtoxinA is the previously failed preventive medication, at least 2 sets of injections and 3 months must have passed since the last set of injections prior to
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