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Amendment 4: 23 April 2015 (rJ GILEAU CLINICAL STUDY PROTOCOL Study Title: A Phase 2b, Open-Label Study of200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected Subjects with Renal Insufficiency Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404, USA IND No.: 106739 EudraCT No: 2013-002897-30 Indication: Hepatitis C Vims Infection Protocol ID: GS-US-3 34-0154 Gilead Sciences Name: PPD Study Director Telephone: PPD Fax: PPD E-mail: t-'t-'U I ~--------------~ Gilead Sciences Name: Theo Sarif, MD Medical Monitor Telephone: PD Fax: PPD E-mail: t-'t-'U Protocol Version/Date: Original: 11 July 2013 Amendment 1: 05 September 2013 Amendment 2: 20 Febmmy 2014 Amendment 3: 23 Febmmy 2015 Amendment 4: 23 April 2015 CONFIDENTIALITY STATEMENT The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or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 infonnation 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 infonnation to others without written authorization from Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those persons to whom the dmg may be administered. Sovaldi® (Sofosbuvir) Protocol GS-US-334-0154 Final Gilead Sciences, Inc. Amendment 4 TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................5 PROTOCOL SYNOPSIS ..............................................................................................................................................6 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11 1. INTRODUCTION ..............................................................................................................................................14 1.1. Background ............................................................................................................................................14 1.2. Sofosbuvir (formerly GS-7977) .............................................................................................................14 1.3. Ribavirin (RBV).....................................................................................................................................14 1.4. Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................15 1.5. Preliminary Results of Study GS-US-334-0154, Cohort 1.....................................................................15 1.5.1. Pharmacokinetics .................................................................................................................15 1.5.2. Safety....................................................................................................................................16 1.5.3. Efficacy ................................................................................................................................16 1.6. Rationale for the Current Study .............................................................................................................16 1.6.1. Cohorts 1 and 2 ....................................................................................................................17 1.6.2. Cohort 3................................................................................................................................17 1.7. Rationale for SOF Dose Selection .........................................................................................................19 1.8. Rationale for RBV Dose Selection.........................................................................................................19 1.9. Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose Selection .........................20 2. OBJECTIVES.....................................................................................................................................................22 3. STUDY DESIGN................................................................................................................................................23 3.1. Treatment Plan and Regimen .................................................................................................................23 3.2. Visit Schedule ........................................................................................................................................23 3.3. Virologic Response-Based Stopping Criteria.........................................................................................24 3.4. Treatment Discontinuation Criteria........................................................................................................24 4. SUBJECT POPULATION..................................................................................................................................25 4.1. Number of Subjects and Subject Selection ............................................................................................25 4.2. Inclusion Criteria....................................................................................................................................25 4.3. Exclusion Criteria...................................................................................................................................27 5. INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................29 5.1. Sofosbuvir (SOF) ...................................................................................................................................29 5.1.1. Formulation ..........................................................................................................................29 5.1.2. Packaging and Labeling .......................................................................................................29 5.1.3. Storage and Handling ...........................................................................................................29 5.1.4. Sofosbuvir (SOF) Dosage and Administration.....................................................................30 5.2. Ribavirin (RBV).....................................................................................................................................30 5.2.1. Formulation ..........................................................................................................................30 5.2.2. Packaging and Labeling .......................................................................................................30 5.2.3. Storage and Handling ...........................................................................................................30 5.2.4. RBV Dosage and Administration.........................................................................................30 5.3. Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) ..............................................................31 5.4. Ledipasvir/ Sofosbuvir (LDV/SOF).......................................................................................................31 5.4.1. Formulation ..........................................................................................................................31 5.4.2. Packaging and Labeling .......................................................................................................31 5.4.3. Storage and Handling ...........................................................................................................31 5.4.4. LDV/SOF Dosage and Administration ................................................................................32 CONFIDENTIAL Page 2 23 April 2015 Sovaldi® (Sofosbuvir) Protocol GS-US-334-0154 Final Gilead Sciences, Inc. Amendment 4 5.5. Study Drug Compliance.........................................................................................................................32 5.6. Dispensing and Accountability of Study Drugs .....................................................................................32 5.7. Study Drug Return or Disposal ..............................................................................................................33 5.8. Concomitant Medications ......................................................................................................................33 5.8.1. Cohorts 1 and 2 ....................................................................................................................33 5.8.2. Cohort 3................................................................................................................................34 5.8.3. All Cohorts ...........................................................................................................................35 6. STUDY PROCEDURES ....................................................................................................................................39
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