(!') GILEAU CLINICAL STUDY PROTOCOL Study Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy ofTenofovir Alafenamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment of HBeAg-Negative, Chronic Hepatitis B Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 IND Number: 11 5, 561 EudraCT Number 2013-000626-63 ClinicalTrial s.gov NCT01940341 Identifier Indication: HBeAg-negative Chronic Hepatitis B Protocol ID: GS-US-320-0108 Gilead Sciences Study Name: John Flaherty, Phatm D Director: Telephone: PD Fax: PPD Mobile: PPD Email: PPD Gilead Sciences Medical Name: Benedetta Massetto, MD, PhD Monitor Telephone: PPD Fax (paper): PPD Mobile: PPD Email: PPD I Protocol Version/Date: Amendment 2.1 20 Febmmy 2015 CONFIDENTIALITY STATEMENT The inf01mation contained in this document, patticularly lmpublished data, is the propetty 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, yom staff, and an applicable Institutional Review Bom·d or Independent Ethics Committee. The inf01mation is only to be used by you in connection with authorized clinical studies of the investigational dmg described in the protocol. You will not disclose any of the inf01m ation to others without written authorization from Gilead Sciences, Inc., except to the extent necessaty to obtain inf01m ed consent from those persons to whom the dmg may be administered. Tenofovir Alafenamide (TAF), GS-7340 Protocol GS-US-320-0108 Final Gilead Sciences, Inc. Amendment 2.1 TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................5 LIST OF IN-TEXT FIGURES ......................................................................................................................................5 PROTOCOL SYNOPSIS ..............................................................................................................................................6 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19 1. INTRODUCTION ..............................................................................................................................................23 1.1. Background ............................................................................................................................................23 1.2. Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................25 1.2.1. General Information .............................................................................................................25 1.2.2. Preclinical Pharmacology and Toxicology...........................................................................26 1.2.3. Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................29 1.2.4. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF).........................................................................................................................40 1.3. Rationale for This Study ........................................................................................................................49 1.3.1. Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B .................................49 1.3.2. Rationale for the Current Study............................................................................................50 1.3.3. Rationale for Dose Selection................................................................................................52 1.4. Compliance ............................................................................................................................................53 2. OBJECTIVES.....................................................................................................................................................54 3. STUDY DESIGN................................................................................................................................................56 3.1. Treatment Plan and Regimen .................................................................................................................56 3.2. Biomarker Testing..................................................................................................................................57 3.2.1. Biomarker Samples to Address the Study Objectives:.........................................................57 3.2.2. Biomarker Samples for Optional Pharmacogenomic Research............................................58 3.3. Intensive PK Substudy (Optional)..........................................................................................................58 3.4. Opthalmologic Substudy (Optional) ......................................................................................................58 4. SUBJECT POPULATION..................................................................................................................................59 4.1. Number of Subjects and Subject Selection ............................................................................................59 4.2. Inclusion Criteria....................................................................................................................................59 4.3. Exclusion Criteria...................................................................................................................................60 5. INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................62 5.1. Randomization and Blinding..................................................................................................................62 5.1.1. Procedures for Breaking Treatment Codes...........................................................................62 5.2. Description and Handling of Tenofovir Alafenamide (TAF), GS-7340, Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos.................................................................................................63 5.2.1. Formulation ..........................................................................................................................63 5.2.2. Packaging and Labeling .......................................................................................................64 5.2.3. Storage and Handling ...........................................................................................................64 5.3. Dosage and Administration of TAF and TDF and Matched Placebos ...................................................64 5.4. Prior and Concomitant Medications.......................................................................................................65 5.5. Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos...................................................................................................................................66 5.5.1. Investigational Medicinal Product Return or Disposal.........................................................67 6. STUDY PROCEDURES ....................................................................................................................................68 CONFIDENTIAL Page 2 20 February 2015 Tenofovir Alafenamide (TAF), GS-7340 Protocol GS-US-320-0108 Final Gilead Sciences, Inc. Amendment 2.1 6.1. Subject Enrollment and Treatment Assignment.....................................................................................68 6.2. Pretreatment Assessments......................................................................................................................68 6.2.1. Screening Visit .....................................................................................................................68 6.2.2. Baseline Assessments...........................................................................................................69 6.3. Treatment Assessments..........................................................................................................................70 6.3.1. Double Blind Visits..............................................................................................................70 6.3.2. Open Label Visits.................................................................................................................79 6.4. Post-treatment Assessments ...................................................................................................................81 6.4.1. HBsAg Loss and Seroconversion Subjects .........................................................................81 6.4.2. All other subjects who discontinue study drug.....................................................................81 6.4.3. Follow up visit assessments (all subjects) ............................................................................81 6.5. Early Discontinuation (ED) from Study.................................................................................................82 6.6. Criteria for Discontinuation of Study Treatment....................................................................................82