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Study Protocol with Amendment 04 Clinical Study Protocol with Amendment 04 A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood Eosinophils Study Number C38072-AS-30025 NCT02452190 Protocol with Amendment 04 Approval Date: 24 October 2016 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 Clinical Study Protocol with Amendment 04 Study Number C38072-AS-30025 A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood Eosinophils Phase 3 IND number: 101,399 EudraCT number: 2015-000865-29 Protocol Approval Date: 24 October 2016 Sponsor Monitor Teva Branded Pharmaceutical Products R&D, Inc. 41 Moores Road Frazer, Pennsylvania 19355 United States Authorized Representative Teva Branded Pharmaceutical Products R&D, Inc. Sponsor’s Medical Expert Sponsor’s Safety Representative Teva Global R&D Teva Branded Pharmaceutical Products R&D, Inc Confidentiality Statement This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the provisions of the International Conference on Harmonisation (ICH); United States Code of Federal Regulations (CFR) and European Union Directives (as applicable in the region of the study); local country regulations; and the sponsor’s Standard Operating Procedures (SOPs). This document contains confidential and proprietary information (including confidential commercial information pursuant to 21CFR§20.61) and is a confidential communication of Teva Pharmaceuticals. The recipient agrees that no information contained herein may be published or disclosed without written approval from the sponsor. © 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 1 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 AMENDMENT HISTORY The protocol for Study C38072-AS-30025 (original protocol dated 26 March 2015) has been amended and reissued as follows: Amendment 04 24 October 2016 468 patients enrolled to date Amendment 03 25 July 2016 368 patients enrolled to date Administrative Letter: 21 March 2016 Reiteration of eosinophil count 85 patients enrolled to date Administrative Letter: 08 March 2016 Change in Medical Monitor 67 patients enrolled to date Administrative Letter: 26 February 2016 Change in Sponsor’s Medical Expert 57 patients enrolled to date Amendment 02 25 January 2016 24 patients enrolled to date Administrative Letter: 22 July 2015 Contraception Use 0 patients enrolled to date Amendment 01 04 May 2015 0 patients enrolled to date Addendum Letter: 22 April 2015 Change in estimated total blood volume taken 0 patients enrolled to date Administrative Letter : 14 April 2015 Change in Central Spirometry and ECG Vendor 0 patients enrolled to date 2 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 INVESTIGATOR AGREEMENT 3 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 COORDINATING INVESTIGATOR AGREEMENT 4 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS Central Institutional Review Board Central Clinical Laboratory Electronic Data Capture Web and Phone Integrated Interactive Response Technology Bioanalytical Pharmacokinetics Evaluation Teva Pharmaceuticals Global Bioassay and Technology West Chester, PA 19380 5 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 Bioanalytical Immunogenicity Evaluation Teva Pharmaceuticals Global Bioassay and Technology West Chester, PA 19380 Exploratory Asthma Biomarker Evaluation Teva Pharmaceuticals Global Bioassay and Technology West Chester, PA 19380 Central Spirometry, e-diary and ECG Spirometry and e-diary: ECG: 6 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 CLINICAL STUDY PERSONNEL CONTACT INFORMATION For medical issues, contact the physician listed below: Oversight Lead Medical Monitor: For centers in North America For Centers in Latin America For centers in Europe and countries outside the Americas EMEA: APAC: For operational issues, contact the operational lead listed below: For serious adverse events: Send by e-mail to the local safety officer/contract research organization (LSO/CRO). The email address will be provided in the serious adverse event report form. In the event of difficulty transmitting the form, contact the sponsor’s study personnel identified above for further instruction. 7 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 CLINICAL STUDY PROTOCOL SYNOPSIS Study C38072-AS-30025 Title of Study: A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood Eosinophils Sponsor: Teva Branded Pharmaceutical Products R&D, Inc IND Number: 101,399 EudraCT Number: 2015-000865-29 Name of Active Ingredient: Reslizumab Name of Investigational Product: Reslizumab for subcutaneous injection, 110 mg/mL Phase of Clinical Development: 3 Number of Investigational Centers Planned: ~275 Countries Planned: ~30 Planned Study Period: Q3 2015 to Q3 2017 Number of Patients Planned: Approximately 225 patients per treatment group for a total of 450 patients. Study Population: Asthma patients 12 years of age and older (Patients 12 to <18 years of age are excluded from participating in South Korea and Argentina, and patients 66 years of age and older are excluded from participating in South Korea.) Primary Objective: The primary objective of this study is to determine the effect of reslizumab (110 mg) administered subcutaneously every 4 weeks on clinical asthma exacerbations (CAEs) in adults and adolescents with asthma and elevated blood eosinophils who are inadequately controlled on standard-of-care asthma therapy. Secondary Objectives: Secondary efficacy objectives are to evaluate the effects of reslizumab compared with placebo on a range of clinical markers of asthma control including pulmonary function (forced expiratory volume in 1 second [FEV1]). Other Objectives: Other objectives of this study are to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of reslizumab. Study Endpoints: Primary Efficacy Endpoint: The primary efficacy endpoint is the frequency of CAEs per patient during the 52-week treatment period. For this study, a CAE is defined as a clinically judged deterioration in asthma control as determined by the investigator and as evidenced by new or worsening asthma signs or symptoms based on the patient history, asthma control diary, physical examination, and/or ambulatory or clinic visit assessment of lung function and that results in a medical intervention, including at least 1 of the following: • use of systemic corticosteroids (oral or injection) or at least a doubling from a stable maintenance oral corticosteroid dose for at least 3 days • asthma-specific hospital admission • asthma-specific emergency department visit Additional medication and/or medical intervention that would satisfy the CAE definition occurring within 7 days of the last day of a prior CAE event will be considered as part of the same event for analysis purposes. Secondary Efficacy Endpoints: The secondary efficacy endpoints are as follows: • change in pre-bronchodilator FEV1 from baseline/the day of randomization (DoR) at week 52 8 Placebo-Controlled Study–Asthma Clinical Study Protocol with Amendment 04 C38072-AS-30025 • change in Asthma Quality of Life Questionnaire for patients 12 years and older (AQLQ +12) score from baseline/DoR at week 52 • change in 6-item Asthma Control Questionnaire (ACQ-6) score from baseline/DoR at week 52 • change in total asthma symptom scores (day and night) from baseline at week 52 • percentage of asthma control days from baseline/DoR to week 52 • change in St. George’s Respiratory Questionnaire (SGRQ) score from baseline/DoR at week 32 • time to first CAE during the 52-week treatment period • frequency of exacerbations requiring hospitalization or emergency department visits per patient during the 52-week treatment period • frequency of moderate exacerbations defined as exacerbations requiring additional asthma controller medication that was not a systemic corticosteroid and that did not result in an asthma-specific hospitalization or emergency department visit during the 52-week treatment period Target Biomarker Endpoints: The target biomarker endpoints are the blood eosinophil counts at baseline/DoR; weeks 2, 4, 8, 12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). Immunogenicity Endpoints: Samples for immunogenicity assessment for development of anti-drug antibodies will be obtained before the administration of study drug at DoR; weeks 4, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). An additional sample will be obtained at the late follow-up visit (approximately week 76). Pharmacokinetic Endpoints: The PK endpoints are the serum reslizumab concentrations at baseline/DoR; weeks 1 (patients in US study centers only), 2, and prior to study drug administration at weeks 4, 8, 12, 16, 20, 32, 48, 52 or early withdrawal; and the follow-up visit (approximately week 64). An
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