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Study Protocol: Amendment 1 CLINICAL STUDY PROTOCOL Study Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 25mg QD in Subjects with Chronic Hepatitis B who are Virologically Suppressed Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 IND Number: 115561 EudraCT Number: 2016-003632-20 Indication: Chronic Hepatitis B Protocol ID: GS-US-320-4018 Gilead Sciences Name: PPD Study Director: Telephone: PPD Fax: PPD Mobile: PPD Email: PPD Gilead Sciences Name: PPD Medical Monitor: Telephone: PPD Fax: PPD Mobile: PPD Email: PPD Protocol Version/Date: Original: 30 September 2016 Amendment 1: 21 December 2016 CONFIDENTIALITY STATEMENT The information contained in this document, particularly unpublished data, is the property or under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent Ethics Committee. The information is only to be used by you in connection with authorized clinical studies of the investigational drug described in the protocol. You will not disclose any of the information to others without written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. Vemlidy®, Tenofovir Alafenamide (TAF) Protocol GS-US-320-4018 Final Gilead Sciences, Inc. Amendment 1 TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................5 PROTOCOL SYNOPSIS ..............................................................................................................................................6 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18 1. INTRODUCTION ..............................................................................................................................................22 1.1. Background ............................................................................................................................................22 1.2. Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................24 1.2.1. General Information .............................................................................................................24 1.2.2. Preclinical Pharmacology and Toxicology...........................................................................25 1.2.3. Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................27 1.3. Information about Tenofovir Disoproxil Fumarate (TDF).....................................................................44 1.4. Rationale for This Study ........................................................................................................................44 1.5. Risk/Benefit Assessment for the Study..................................................................................................44 1.6. Compliance ............................................................................................................................................45 2. OBJECTIVES.....................................................................................................................................................46 3. STUDY DESIGN................................................................................................................................................48 3.1. Study Treatment Plan and Regimen.......................................................................................................48 3.2. Biomarker Testing..................................................................................................................................49 3.2.1. Biomarker Samples to Address the Study Objectives ..........................................................49 3.2.2. Biomarker Samples for Optional Future Research...............................................................50 3.2.3. PPD ............................................50 3.3. End of Study...........................................................................................................................................50 3.4. Post Study Care......................................................................................................................................50 4. SUBJECT POPULATION..................................................................................................................................51 4.1. Number of Subjects and Subject Selection ............................................................................................51 4.2. Inclusion Criteria....................................................................................................................................51 4.3. Exclusion Criteria...................................................................................................................................51 5. INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................53 5.1. Randomization, Blinding and Treatment Codes ....................................................................................53 5.1.1. Procedures for Breaking Treatment Codes...........................................................................53 5.2. Description and Handling of Tenofovir Alafenamide (TAF) and TDF..................................................53 5.2.1. Formulation ..........................................................................................................................53 5.2.2. Packaging and Labeling .......................................................................................................54 5.2.3. Storage and Handling ...........................................................................................................54 5.3. Dosage and Administration of Tenofovir Alafenamide (TAF) and TDF...............................................55 5.4. Prior and Concomitant Medications.......................................................................................................55 5.5. Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos...................................................................................................................................56 5.5.1. Investigational Medicinal Product Return or Disposal.........................................................57 6. STUDY PROCEDURES ....................................................................................................................................58 6.1. Subject Enrollment and Treatment Assignment.....................................................................................58 6.2. Pretreatment Assessments......................................................................................................................58 6.2.1. Screening Visit .....................................................................................................................58 6.2.2. Baseline Assessments...........................................................................................................59 CONFIDENTIAL Page 2 21 December 2016 Vemlidy®, Tenofovir Alafenamide (TAF) Protocol GS-US-320-4018 Final Gilead Sciences, Inc. Amendment 1 6.3. Treatment Assessments..........................................................................................................................60 6.3.1. Double Blind Visits (Visit Window ± 3 days) .....................................................................60 6.3.2. Open Label Visits (Visit Window ± 7 days) ........................................................................65 6.4. Post-Treatment Assessments..................................................................................................................67 6.4.1. HBsAg Loss and Seroconversion Subjects ..........................................................................67 6.4.2. All Other Subjects Who Discontinue Study Drug................................................................67 6.4.3. Treatment-Free Follow Up Visit Assessments (All Subjects)..............................................67 6.5. Assessments for Premature Discontinuation from Study.......................................................................68 6.6. Criteria for Discontinuation of Study Treatment....................................................................................69 6.7. Other Evaluations...................................................................................................................................69 6.7.1. Bone and Renal Markers ......................................................................................................69 6.8. Resistance Surveillance and Virologic Rebound Management..............................................................70 7. ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................71 7.1. Definitions
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