Clinical trial NCT02745535
Conditions: Chronic Hepatitis C
Keywords: Hepatitis C relapse
Sponsor: University of Maryland, Baltimore
Start date: 2016-05-01; Completion date: 2018-10-24
Enrollment: 77 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety, tolerability, and efficacy of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in adults with chronic hepatitis C infection who have failed to eradicate hepatitis C despite previous combination directly acting antiviral therapy.

Detailed description:
The treatment of chronic Hepatitis C with combination directly acting antiviral agents (DAAs) represents a dramatic improvement over previous therapies in safety, tolerability and efficacy, but these therapies are not universally effective. Some patients fail to achieve sustained virologic response (SVR) following therapy with combination DAAs, yet the ideal retreatment strategy for these patients has not yet been determined. As DAA medications become more widely available outside clinical trial settings, it is important to evaluate retreatment strategies in patients who fail combination DAA therapy, regardless of whether they had virologic failure, post-treatment relapse, or discontinued treatment prematurely.

The RESOLVE study will evaluate the safety, tolerability, and efficacy of treatment with a fixed dose combination of sofosbuvir (an approved NS5B inhibitor), velpatasvir (formerly GS-5816, a second generation NS5A inhibitor) and voxilaprevir (formerly GS-9857, an approved NS3/4A protease inhibitor) in HCV infected patients with early and advanced liver disease, including those with HIV or hepatitis B, who have failed previous combination DAA therapy. Patients with early stage and compensated cirrhosis will receive 12 weeks of therapy, and be followed for adverse events and SVR following completion of therapy.

RESOLVE will aid our understanding of the determinants of response to re-treatment with combination DAA therapy

* With and without cirrhosis
* In patients with HCV GT1 subtypes a and b
* In patients who previously failed DAA therapy
* With and without HIV or hepatitis B

RESOLVE will also examine factors associated with treatment response, including

* the viral and pharmacokinetics of patients receiving the combination of SOF/VEL/VOX, in patients with and without cirrhosis
* differential interferon sensitive gene responses
* host genetic and proteomic factors
* evolution of HCV quasispecies and resistance associated variants at baseline and in response to therapy
* changes in host HCV-specific immunity in patients with and without advanced liver disease

Arms: arm 1: Fixed dose combination of SOF/VEL/VOX (Sofosbuvir 400mg/Velpatasvir 100mg/ Voxilaprevir 100mg) dosed once daily for 12 weeks.
Interventions: intervention 1: Sofosbuvir/Velpatasvir/Voxilaprevir
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Version 6.0 
September 11, 2017 
 
RESOLVE Protocol 
 
Safety, Tolerability and Efficacy of Sofosbuvir, Velpatasvir, and Voxilaprevir 
in Subjects with previous DAA experience 
 
Sponsored by 
Institute of Human Virology, University of Maryland School of Medicine 
Baltimore, MD 
And  
Gilead Sciences, Inc.  
Foster City, California 
 
IND Number 
128754 
 
IND sponsored by 
Institute of Human Virology, University of Maryland School of Medicine 
Baltimore, MD 
 
Medical Monitor 
Theo Heller, MD 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
Eleanor Wilson, MD, MHS 
Assistant Professor of Medicine 
Institute of Human Virology 
University of Maryland School of Medicine 
725 W Lombard Street, Room S218 
Baltimore MD 21201  
Phone: (410) 706-1710 
 
IRB Initial Approval:   February 22, 2016 


RESOLVE PROTOCOL 
 
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Page 2 of 55 
 
STUDY ROSTER AND CONTACT INFORMATION 
 
Principal Investigator: 
Eleanor Wilson, MD, MHS 
Assistant Professor of Medicine 
Institute of Human Virology 
University of Maryland School of Medicine 
725 W Lombard Street, Room S218 
Baltimore MD 21201  
Phone: (410) 706-1710 
EWilson@ihv.umaryland.edu  
 
Research contact/Study Coordinator: 
Jennifer Hoffmann, MSN, MPH 
 
Associate Investigators: 
Elizabeth Akoth, RN 
Benjamin Emmanuel, MPH 
Emily Comstock, MSN, CRNP 
Emily Covert, BS 
Janet Gripshover, MSN, CRNP 
Chloe Gross, RN 
Jennifer Hoffmann, MSN, MPH 
Sarah Kattakuzhy, MD 
Mariam Khambaty, MD 
Shyam Kottilil, MD PhD 
Poonam Mathur, MD 
Lydiah Mutumbi, RN 
Amy Nelson, RN 
Angie Price, MSN, CRNP 
Elana Rosenthal, MD 
Rachel Silk, RN, MPH 
Lydia Tang, MD 
Haley Ward, BS 
 
Study Sites: 
Institute for Human Virology, University of 
Maryland School of Medicine, Baltimore, MD 
Unity Health Care Parkside and Walker-Jones,  
Washington, DC 
 
Pharmacy: 
Lisa Langer, RPh 
Christina Dickson, RPh 
 
 
Protocol Statistician: 
Søren Bentzen, Ph.D., 
Biostatistics Research Branch 
University of Maryland 
 
 
Collaborating Investigators: 
Gebeyehu Teferi, MD, Unity Health Care 
 
Collaborating Institutions: 
 
Unity Health Care, Inc./Walker Jones 
Site AI: Gebeyehu Teferi, MD  
FWA: 00009653, expiration date 6/19/2018 
40 Patterson Street, NE 
Washington, DC 20002 
Phone: (202) 354-1150 
FAX: (202) 548 6534 
E-mail:  GTeferi@UnityHealthCare.org 
 
Unity Health Care, Inc./Parkside 
Site AI: Gebeyehu Teferi, MD  
FWA: 00009653, expiration date 6/19/2018 
765 Kenniworth Terrace, NE 
Washington, DC 20002 
Phone: (202) 388-8160 
FAX: (202) 388-8746 
E-mail:  GTeferi@UnityHealthCare.org 
 
 
IND Sponsor: Institute of Human Virology 
 
Medical Monitor: 
Theo Heller, MD 
 
IRB of Record: 
University of Maryland, Human Research 
Protections Office, Institutional Review Board 
620 West Lexington Street, Second Floor 
Baltimore, Maryland 21201 


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Page 3 of 55 
 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
STUDY ROSTER AND CONTACT INFORMATION ............................................................ 2 
ABBREVIATIONS ....................................................................................................................... 6 
ABBREVIATIONS FOR HCV STUDY AGENTS & FDA APPROVED AGENTS ............. 9 
PRÉCIS ........................................................................................................................................ 10 
STUDY SUMMARY ................................................................................................................... 11 
STUDY SCHEMA ...................................................................................................................... 13 
1 
INTRODUCTION AND RATIONALE ........................................................................ 14 
1.1 Chronic Hepatitis C Infection: Background ..................................................................... 14 
1.2 Rationale for New Combination DAA Therapies ............................................................. 14 
1.3 RATIONALE FOR SELECTION OF ALLOWED CONCOMITANT ARV REGIMENS
 15 
1.4 SOFOSBUVIR .................................................................................................................. 15 
1.5 SOF/VEL .......................................................................................................................... 15 
1.6 SOF/VEL/VOX................................................................................................................. 16 
1.6.1 
Voxilaprevir .......................................................................................................... 16 
1.6.2 
Summary of Clinical Experience with SOF/VEL/VOX ......................................... 16 
1.6.3 
FDA-approval ....................................................................................................... 16 
1.6.4  Phase 3 Studies with Vosevi ........................................................................................ 16 
1.7 Pharmacokinetics of SOF/VEL/VOX ............................................................................... 17 
1.8 Safety of SOF/VEL/VOX ................................................................................................. 17 
1.9 Rationale for Dose Selection of SOF/VEL/VOX ............................................................. 17 
1.10 Overall Risk/Benefit Assessment ..................................................................................... 18 
2 
STUDY DESIGN AND METHODS.............................................................................. 18 
2.1 Primary Objective ............................................................................................................. 19 
2.2 Secondary Objectives........................................................................................................ 19 
2.3 Exploratory Objectives ..................................................................................................... 19 
2.3.1 
Rationale for Immunologic studies ....................................................................... 19 
2.4 Study Population ............................................................................................................... 21 
2.4.1 
Inclusion Criteria .................................................................................................. 21 
2.4.2 
Exclusion Criteria ................................................................................................. 24 
2.5 Pharmacokinetic and Viral Kinetic Substudy ................................................................... 25 
2.6 Recruitment Plan ............................................................................................................... 25 
2.7 Human Subjects Protections ............................................................................................. 25 
2.7.1 
Gender, Ethnicity, and Race Considerations ........................................................ 26 
2.7.2 
Rationale for the Exclusion of Children and Pregnant Women ........................... 26 
2.7.3 
Contraception ....................................................................................................... 26 
2.8 Clinical Procedures and Schedule of Evaluations ............................................................ 26 


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2.8.1 
Screening............................................................................................................... 27 
2.9 Randomization and Blinding ............................................................................................ 28 
2.10 History and Physical ......................................................................................................... 28 
2.11 Starting SOF/VEL/VOX (Day 0)...................................................................................... 29 
2.12 Optional PK/VK Substudy ................................................................................................ 29 
2.13 Week 1 Visit ..................................................................................................................... 29 
2.14 Week 2 Visit ..................................................................................................................... 29 
2.15 Week 4 Visit ..................................................................................................................... 29 
2.16 Week 8 Visit ..................................................................................................................... 29 
2.17 Week 12 / End of Treatment Visit .................................................................................... 29 
2.18 Follow-up Visits after Study Drug Discontinuation ......................................................... 29 
2.19 Failures, Early Termination and Early Treatment Discontinuation .................................. 30 
2.20 Evaluation of Safety .......................................................................................................... 30 
2.20.1 
Follow-up of Abnormal Laboratory Test Values .................................................. 30 
2.20.2 
Criteria for Premature Withdrawal and Stopping Rules ...................................... 31 
3 
STUDY AGENTS............................................................................................................ 31 
3.1 Disposition and Dispensation ........................................................................................... 31 
3.2 Packaging and Labeling of Study Drugs .......................................................................... 31 
3.2.1 
Formulation .......................................................................................................... 32 
3.2.2 
Packaging and Labeling ....................................................................................... 32 
3.2.3 
Storage and Handling ........................................................................................... 32 
3.3 Treatment of Subjects ....................................................................................................... 32 
3.4 Dose Modifications / Toxicities ........................................................................................ 32 
3.4.1 
Dose Modification for SOF/VEL/VOX.................................................................. 33 
3.4.2 
Treatment Failure / Drug Discontinuation ........................................................... 33 
3.4.3 
Treatment Failure Criteria After Stopping SOF/VEL/VOX ................................. 33 
3.4.4 
Viral Co-infection Rebound Schema ..................................................................... 34 
3.5 Concomitant Medications ................................................................................................. 34 
4 
STATISTICAL CONSIDERATIONS .......................................................................... 36 
4.1 Sample Size ....................................................................................................................... 36 
4.1.1 
Primary Endpoint.................................................................................................. 37 
4.1.2 
Secondary Endpoints ............................................................................................ 38 
4.1.3 
Safety Endpoints.................................................................................................... 38 
4.1.4 
Analysis Sets.......................................................................................................... 38 
4.2 Data Handling Conventions .............................................................................................. 39 
4.3 Demographic Data and Baseline Characteristics .............................................................. 39 
4.4 Adverse Events ................................................................................................................. 39 
5 
STUDY TESTS................................................................................................................ 40 
5.1 Schedule of Tests .............................................................................................................. 40 
6 
HAZARDS/DISCOMFORTS/RISKS ........................................................................... 44 
6.1 Drugs ................................................................................................................................. 44 
6.1.1 
Sofosbuvir ............................................................................................................. 44 


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6.1.2 
Velpatasvir ............................................................................................................ 44 
6.1.3 
Voxilaprevir .......................................................................................................... 45 
6.1.4 
Resistance ............................................................................................................. 45 
6.2 Procedures ......................................................................................................................... 45 
6.2.1 
Phlebotomy ........................................................................................................... 45 
6.2.2 
Electrocardiogram ................................................................................................ 45 
6.2.3 
Liver Biopsy .......................................................................................................... 45 
7 
BENEFITS/COMPENSATION/ALTERNATIVES .................................................... 46 
7.1 Benefits ............................................................................................................................. 46 
7.2 Alternatives ....................................................................................................................... 46 
7.3 Compensation ................................................................................................................... 46 
8 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ........................................ 47 
8.1 Definitions......................................................................................................................... 47 
8.2 Investigator Assessment of Adverse Events ..................................................................... 48 
8.2.1 
Severity Grading ................................................................................................... 48 
8.2.2 
Causality ............................................................................................................... 49 
8.3 Safety Oversight................................................................................................................ 49 
8.3.1 
Medical Monitor ................................................................................................... 49 
8.4 Safety Monitoring Plan ..................................................................................................... 50 
8.5 Specific Study  Halting Criteria ........................................................................................ 50 
8.5.1 
Criteria to Pause Enrollment ................................................................................ 50 
8.6 Investigator Reporting Responsibilities ............................................................................ 50 
8.6.1 
Adverse Events ...................................................................................................... 50 
8.6.2 
Serious Adverse Events ......................................................................................... 51 
8.6.3 
Gilead Safety Data Reporting ............................................................................... 51 
8.7 Documenting and Recording Adverse Events .................................................................. 51 
8.8 Follow-up of Adverse Events and Serious Adverse Events ............................................. 51 
8.9 Reporting Procedures to the IRB ...................................................................................... 52 
8.9.1 
Expedited Reporting to the UMD IRB .................................................................. 52 
8.9.2 
Waiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and 
Deaths to the UMD IRB ........................................................................................ 52 
8.9.3 
Annual Reporting to the IRB ................................................................................. 52 
9 
DATA HANDLING AND RECORD KEEPING ......................................................... 53 
9.1 Data Handling ................................................................................................................... 53 
9.2 Study record retention ....................................................................................................... 53 
10 
REFERENCES ................................................................................................................ 54 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Term 
3TC 
Lamivudine 
ABC 
Abacavir 
AE 
Adverse event 
AI 
Associate investigator 
ALT 
Alanine aminotransferase 
APRI 
AST to platelet ratio index 
AR 
Adverse Reaction 
ARV 
Antiretroviral therapy 
AST 
Aspartate transaminase 
BMI 
Body mass index 
c 
Cobicistat 
CBC 
Complete blood count 
CFR 
Code of federal regulations 
CSO 
Clinical safety office 
CyTOF 
Cytometry by time-of-flight 
DAA 
Direct acting antiretroviral 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
DRV 
Darunavir 
EBR 
Elbasvir 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
ESAs 
Erythropoiesis stimulating agents 
ETR 
End of Treatment Response 
EVG 
Elvitegravir 
FDA 
Food and Drug Administration 
FDC 
Fixed dose combination 
GCP 
Good Clinical Practices 
GCSF 
Granulocyte colony stimulating factor 
GS 
Gilead Sciences, Inc. 
GT-1, -2, and -3 
Genotype 1,2, and 3 
GZR 
Grazoprevir 
HbA1c 
Hemaglobin A1C 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IB 
Investigator’s Brochure 


RESOLVE PROTOCOL 
 
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IL28B 
Interleukin 28B 
IND 
Investigational new drug application 
IFN 
Interferon 
IRB 
Institutional Review Board 
ISR 
Interferon sensitive gene 
LDV 
Ledipasvir  
LIL 
Liver infiltrating lymphocytes 
MM 
Medical Monitor 
NS3/4 
Non-structural proteins 3 and 4, protease 
NS5A 
Non-structural protein 5A 
NS5B 
Non-structural protein 5B, polymerase 
NSAID 
Nonsteroidal anti-inflammatory drug 
PBMC 
peripheral blood mononuclear cells 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PPI 
Proton pump inhibitor 
PrOD 
Paritaprevir (co-dosed with ritonavir [paritaprevir/r]), ombitasvir, 
dasabuvir 
RAL 
Raltegravir 
RAV 
Resistance Associated Variants 
RBV 
Ribavirin 
r  
Ritonivir 
RPV 
Rilpivirine 
RNA 
Ribonucleic acid 
SAE 
serious adverse event 
SAR 
Suspected adverse reaction 
SC 
Study Coordinator 
SERF 
Safety expedited report form 
SIM 
Simeprevir 
SOF 
Sofosbuvir 
SUSAR 
Serious and unexpected suspected adverse reaction 
SVR 
Sustained virologic response 
SVR4 
HCV RNA < LLOQ 4 weeks after completion of treatment 
SVR8 
HCV RNA < LLOQ 8 weeks after completion of treatment 
SVR12 
HCV RNA < LLOQ 12 weeks after completion of treatment 
SVR24 
Sustained virologic response <LLOQ HCV RNA 24 weeks (or 6 
months) after the end of treatment 
TPO 
Thrombopoeitin 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
UPnonAE 
Unanticipated problem that is not an adverse event 
VEL 
Velpatasvir 
VK 
Viral kinetics 


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VOX 
Voxilaprevir 
WBC 
White blood cell 
 
 
 


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ABBREVIATIONS FOR HCV STUDY AGENTS & FDA APPROVED AGENTS 
 
GS-7977, SOF 
Sofosbuvir, nucleotide NS5B inhibitor, an FDA approved treatment for 
HCV  
GS-5816, VEL 
Velpatasvir, second generation NS5A inhibitor, an HCV study agent 
GS-9857, VOX 
Voxilaprevir, second generation NS3/4A protease inhibitor, an HCV study agent 
SOF/VEL/VOX 
FDC, Vosevi 
Fixed dose combination of sofosbuvir, an FDA-approved NS-5B nucleotide 
inhibitor, 400mg; velpatasvir, an FDA-approved NS5A inhibitor, 100mg; and 
GS-9857, a second generation FDA-approved NS3/4A protease inhibitor, 300 mg 
IFN, PegIFN, 
PEG 
Interferon (known as pegylated IFN or pegIFN) 
RBV 
Ribavirin, an FDA approved standard of care treatment for HCV when 
used with Interferon and/or an additional agent  
Viekira Pak, 
PrOD 
Ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), 
dasabuvir  
 
 
 


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PRÉCIS 
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated 
180 million people infected worldwide. In the United States, an estimated 4.1 million people 
are infected, and HCV is the principal cause of death from liver disease and leading indication 
for liver transplantation. While treatment with combination directly acting antiviral agents 
(DAAs) represents a dramatic improvement over previous therapies in safety, tolerability and 
efficacy, these therapies are not universally effective and some patients fail to achieve sustained 
virologic response (SVR).  As DAA medications become more widely available outside clinical 
trial settings, it is important to evaluate retreatment strategies in patients who fail combination 
DAA therapy.  As of yet, the ideal retreatment strategy and predictors of response in these 
patients have not yet been determined.  In this trial, we will test the safety, tolerability, and 
efficacy of treatment with sofosbuvir (an approved NS5B inhibitor), velpatasvir (formerly GS-
5816, a second generation NS5A inhibitor) and voxilaprevir (formerly GS-9857, an NS3/4A 
protease inhibitor) (trade name Vosevi) in HCV infected patients with early and advanced liver 
disease, including those coinfected with HIV and or hepatitis B, who have failed previous 
combination DAA therapies. The findings from this study will aid in our understanding of 
determinants of response to combination DAA regimens in HCV infected patients for 
subgroups of patients with early as compared to advanced liver disease, in patients with HCV 
GT 1 subtypes a and b, in patients coinfected with HIVand or hepatitis B, and in patients 
previously failing different combination DAA therapies. 
 
 
 


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STUDY SUMMARY 
 
Title: 
Safety, Tolerability and Efficacy of Sofosbuvir, Velpatasvir and Voxilaprevir in 
Subjects who failed previous DAA Therapy 
Short Title:  
RESOLVE Protocol 
Clinical Phase:  
Phase IIb 
 
IND Sponsor:  
IHV/University of Maryland SOM 
 
Principal  
Investigator:  
Eleanor Wilson, MD, MHS 
 
Sample Size: 
N=120 
 
N=20 participants in a pharmacokinetic/viral kinetic sub study 
 
     10 with and 10 without cirrhosis 
 
Accrual Ceiling: 
N=150 
 
Study Population: 
HCV, genotype 1, infected subjects, with or without HIV, who have previously 
been treated with unsuccessful combination DAA-based therapy 
 
Accrual Period:  
1 year 
 
Study Design: 
Open-label phase IIb study to examine safety, tolerability, and efficacy of 
SOF/VEL/VOX in subjects with chronic HCV infection who have failed to 
eradicate HCV despite previous combination DAA therapy. Subjects with cirrhosis 
and those without cirrhosis will receive 12 weeks of therapy and will be stratified 
by initial combination DAA therapy. 
Study  
Agents: 
SOF/VEL/VOX is a fixed dose combination of sofosbuvir, an FDA-approved NS-
5B nucleotide inhibitor, 400mg; velpatasvir, an FDA-approved NS5A inhibitor, 
100mg; and voxilapravir, an FDA approved NS3/4A protease inhibitor, 100 mg, 
dosed once daily.  
Treatment 
Duration: 
Subjects with and without cirrhosis will receive 12 weeks of therapy  
 
Primary 
Objectives: 
To assess the safety, tolerability, and efficacy of 12 weeks of SOF/VEL/VOX in 
subjects with chronic HCV infection who have previously failed FDA approved 
DAA-based therapy, with compensated cirrhosis and without cirrhosis, with and 
without HIV coinfection. 
 
Secondary 
Objectives: 
1. To evaluate the immunologic, virologic, and host genetic/proteomic predictors of 
response to therapy with SOF/VEL/VOX in HCV infected subjects who have failed 
previous combination DAA-based therapy. 
 
 
2. To compare HCV quasispecies and resistance associated variants (RAVs) at 
baseline and throughout treatment, especially in the case of relapse or 


RESOLVE PROTOCOL 
 
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breakthrough, and assess the influence of past DAA experience on evolution of 
RAVs and virologic response to treatment  
 
3. To determine the kinetics of plasma HCV RNA during treatment and after 
treatment discontinuation  
 
4. To evaluate the effect of SOF/VEL/VOX on peripheral markers of T cell 
activation 
 
5. To evaluate the proportion of subjects whose alanine aminotransferase (ALT) 
levels normalize between baseline and SVR4,12,24.  
6. To delineate the precise effects of specific HCV lifecycle inhibitors on host immune 
recovery in patients receiving single (SPARE), or combination DAA-based therapy 
(RESOLVE). 
 
Primary 
Endpoints: 
The incidence of grade 3 and 4 adverse events (AEs) following 12 weeks of 
treatment with SOF/VEL/VOX in HCV infected subjects who have previously 
failed FDA approved DAA-based therapy.  
 
The proportion of subjects who achieve sustained virologic response 12 weeks after 
completion of treatment, SVR12. 
  
Secondary 
Endpoints: 
1. Correlation and comparison of the slope of HCV viral load decline (early viral 
kinetics) with end of treatment response (ETR) and sustained virologic response 4, 
12, and 24 weeks post treatment in patients with early and advanced stage liver 
disease, in patients with HCV GT 1 subtypes a and b, and in patients who 
previously failed different combination DAA therapies. 
 
 
2. Comparison of HCV viral kinetics (VK) and pharmacodynamic (PD) parameters 
in subjects who achieve SVR and those who do not. 
 
 
3. Percentage and comparison of subjects who achieve ETR, SVR4 and SVR24 in 
patients with early and advanced stage liver disease, in patients with HCV GT-1 
subtypes a and b, and in patients failing different combination DAA therapies. 
 
 
4. Comparison of pharmacokinetics (PK) of SOF/VEL/VOX in subjects who 
achieve SVR and those who do not. 
 
 
5. Comparison of differential interferon sensitive gene (ISR) response to therapy in 
patients who do and do not attain SVR, as well as in subgroups of patients with 
early as compared to advanced liver disease, in patients with HCV GT-1 subtypes a 
and b, and in patients failing different combination DAA therapies. 
 
 
6. Detection of host genetic/proteomic factors associated with differential response 
to SOF/VEL/VOX overall and in subgroups of patients with early and advanced 
stage liver disease, in patients with HCV GT-1 subtypes a and b, and in patients 
failing different combination DAA therapies. 
 
 
7. Evaluation of HCV quasispecies fitness at baseline, during therapy, and at the 
time of viral relapse to determine the emergence of resistant HCV and 
immunologic (adaptive and innate) correlates of SVR. 
 
 
 
8. Changes in HCV specific CD8 responses in patients with cirrhosis and not with 
cirrhosis. 


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9. Changes in HCV specific immune responses in patients treated with single 
(NS5B) DAA versus dual (NS5B + NS5A) versus triple combination DAA (NS5B 
+ NS5A + NS30) using samples from SPARE, SYNERGY, and this study 
 
 
Study  
Duration:       
Subjects will be evaluated by 10 clinic visits over approximately 38 weeks.   
 
STUDY SCHEMA  
 
  


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1 
INTRODUCTION AND RATIONALE 
1.1 
CHRONIC HEPATITIS C INFECTION: BACKGROUND  
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated 
180 million people infected worldwide1. In the United States, an estimated 2.7 million people are 
infected2. HCV is the principal cause of death from liver disease and leading indication for liver 
transplantation in the Western world3,4. According to the CDC, in 2013, over 19,000 deaths were 
attributed to HCV infection and its complications, although this is likely an underestimate, by as 
much as five fold by some reports5. HCV now surpasses human immunodeficiency virus as a 
cause of death within the United States6. Of those patients with chronic HCV infection, as many 
as 20% are estimated to go on to develop complications including cirrhosis, end-stage liver 
disease, and hepatocellular carcinoma (HCC)7. Until recently, standard of care treatment with 
pegylated interferon (pegIFN) and ribavirin (RBV) was associated with low response rates8,9, 
from 27-39%, depending on the patient population, but was associated with complicated drug 
interactions and high rates of toxicity, including psychiatric illness, constitutional side effects, 
and cytopenias. 
Recent advances in therapy have dramatically improved the prognosis of those with chronic 
HCV infection.  The development of directly-acting antivirals (DAAs) represents a major 
advance in HCV treatment. Modern combination DAA-based regimens are shorter in duration, 
better tolerated, and result in higher sustained virologic response (SVR) rates than prior 
therapies. The safety and efficacy of combination DAA-based regimens has been demonstrated 
in patients with a broad range of disease stages from patients naïve to HCV therapy with minimal 
fibrosis to patients with advanced fibrosis and cirrhosis who have failed previous interferon-
based therapies10-15. Even patients failing early single DAA therapies have shown high response 
rates to combined therapy with a fixed-dose combination (FDC) of ledipasvir (LDV) and 
sofosbuvir (SOF)16, with excellent safety and tolerability profiles 17,18.   
 
1.2 
RATIONALE FOR NEW COMBINATION DAA THERAPIES 
Despite the high efficacy of currently approved combination DAA therapies, some patients do 
not successfully clear HCV, either due to non-adherence, viral resistance, virologic 
breakthrough, or virologic relapse.  The ideal strategy for pursing HCV clearance in these 
patients remains uncertain, and careful clinical trials assessing the safety and efficacy of 
retreatment strategies in these patients need to be conducted. While some groups have 
demonstrated high response rates (>90%) after previous failure of a short course regimen19, 
despite the presence of resistance associated HCV variants (RAVs), others have reported low 
treatment response rates, in some cases less than 50%, related to treatment emergent NS5A 
RAVs20. In these small studies, it is unclear whether viral, treatment or host factors drive the low 
response rates.  This study seeks to address this question and determine whether a universal 
“salvage” regimen would be safe, tolerable, and effective in patients failing a diverse array of 
combination DAA-based therapies.   
Sofosbuvir, a nucleotide analogue chain terminating inhibitor of the NS5B HCV viral 
polymerase, was approved by the FDA in December 2013, and of note, treatment emergent 
resistance to NS5B inhibitors has not been observed in patients failing SOF-based regimens21. 
The investigational agents Velpatasvir (VEL, formerly GS-5816) which inhibits the NS5A 
protein, and Voxilapravir, the NS3/4 viral protease, have shown promise in early clinical 
studies22-24, including efficacy of approximately 90% in patients who had previously failed 


RESOLVE PROTOCOL 
 
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combination DAA-based therapy25, 30,31. In patients who have previously failed combination 
DAA therapy, including LDV/SOF, paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD), and 
elbasvir/grazoprevir (EBR/GZR)-based combination DAA regimens, we hypothesize that 
retreatment with at least two novel drugs will be safe and effective, overcoming baseline or 
treatment emergent viral resistance and inhibiting viral replication. 
 
1.3 
RATIONALE FOR SELECTION OF ALLOWED CONCOMITANT ARV 
REGIMENS 
HIV ARV regiments allowed in this study include emtricitabine (FTC)/tenofovir alafenamide 
(TAF), FTC/tenofovir disoproxil fumarate (TDF) , or abacavir (ABC)/lamivudine (3TC) plus:  
 Ritonavir (r) and darunavir (DRV), or  
 Raltegravir (RAL), or  
 Elvitegravir (EVG)/Cobicistat (c), or  
 Rilpivirine (RPV) 
Fixed dose combinations of approved regimens (ie, FTC/TAF [Descovy], EVG/c/FTC/TAF 
[Genvoya], RPV/FTC/TAF [Odefsey], FTC/TDF [Truvada] EVG/c/FTC/TDF [Stribild], 
RPV/FTC/TDF [Complera]) will be allowed as part or all of an approved ARV regimen. 
Alternative ARV regimens will be considered on an individual basis, based on available drug-
drug interaction (DDI) data at the discretion of the principal investigator. 
 
Protocol-approved ARV regimens were selected based on the results from the DDI studies that 
demonstrated co-administration of these ARVs with SOF/VEL/VOX would not require dose 
adjustment to any of these agents (Study GS-US-367-1657 [Section Error! Reference source 
not found.]; Study GS-US-380-1999 [Section Error! Reference source not found.]. The 
protocol-approved ARV regimens must be administered as indicated in the prescribing 
information of the package insert for the treatment of HIV infection. 
 
1.4 
SOFOSBUVIR 
Sofosbuvir (SOF) is an FDA-approved nucleotide analog that is a potent and selective inhibitor 
of the NS5B HCV polymerase and was approved for the treatment of HCV infection by the FDA 
in December of 2013 as a component of an antiviral treatment regimen. Please refer to the 
product insert for additional information. 
 
 
1.5 
SOF/VEL  
Epclusa (SOF/VEL) in an FDA-approved fixed dose combination (FDC) of SOF and the NS5A 
inhibitor Velpatasvir (VEL). This combination was approved by the FDA in June 2016 for the 
treatment of HCV infection both with and without cirrhosis. Please refer to the product insert for 
additional information.  
 


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1.6 
SOF/VEL/VOX   
1.6.1  Voxilaprevir 
Voxilaprevir (Gilead product no. GS-9857) is a novel macrocyclic HCV NS3 protease inhibitor 
with potent in vitro antiviral activity against genotypes 1 to 6 HCV, broad coverage of NS3 
protease polymorphs, and an improved resistance profile compared with PIs approved by the 
Food and Drug Administration (FDA) or currently in clinical development. Please refer to the IB 
for SOF/VEL/VOX for additional information on Voxilaprevir including: 
 In Vitro Anti-Hepatitis C Virus Activity 
 Nonclinical PK and In Vitro Metabolism 
 Nonclinical Pharmacology and Toxicology 
 Clinical Experience 
 
1.6.2 Summary of Clinical Experience with SOF/VEL/VOX 
Data from three Phase 2 studies, GS-US-337-1468 (LEPTON), GS-US-367-1168, and 
GS-US-367-1169, support the efficacy of 12 week therapy with SOF/VEL/VOX in subjects with 
DAA experience. In the LEPTON study, 67% (20/30) subjects who had previously failed 
2 DAAs and then received 6 weeks of SOF/VEL+VOX achieved SVR12. In Study GS-US-367-
1168, 100% (63/63) genotype 1 subjects that had previously failed DAAs and received 12 weeks 
of SOF/VEL+VOX achieved SVR12. In study GS-US-367-1169, 98.5% (64/65) subjects 
infected with genotypes 2-6 HCV who were treatment experienced, including 38 subjects who 
had failed a DAA, and received 12 weeks of SOF/VEL+VOX achieved SVR12. Treatment was 
safe and generally well tolerated. No safety signal associated with the administration of these 
agents was identified.  
1.6.3 FDA-approval 
The fixed dose combination with SOF/VEL/VOX was approved in the U.S. by the FDA on 17 
July 2017 and is indicated for the treatment of adult patients with chronic HCV infection without 
cirrhosis or with compensated cirrhosis (Child-Pugh A) who have:  
• genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen 
containing an NS5A inhibitor.  
• genotype 1a or 3 infection and have previously been treated with an HCV regimen containing 
sofosbuvir without an NS5A inhibitor.  
 
1.6.4  Phase 3 Studies with Vosevi 
The efficacy of VOSEVI was evaluated in two Phase 3 trials (GS-US-367-1171 [POLARIS-1], 
GS-US-367-1170 [POLARIS-4] in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 
HCV infection without cirrhosis or with compensated cirrhosis. In these studies, 445 subjects 
received SOF/VEL/VOX (400/100/100 mg). The results from these studies are described within 
the Package Insert, but across all POLARIS studies, the efficacy of SOF/VEL/VOX ranged from 
95-97%. The most common (at least 10%) adverse reactions were headache, fatigue, diarrhea, 
and nausea.  
 


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1.7 
PHARMACOKINETICS OF SOF/VEL/VOX 
Please refer to the Vosevi (SOF/VEL/VOX) package insert for information on the 
pharmacokinetics of these agents.  
 
1.8 
SAFETY OF SOF/VEL/VOX 
To date, over 2600 subjects have received SOF/VEL+VOX clinical studies and there have been 
no clinical safety issues identified. There is no expectation of significant overlapping or new, 
unexpected toxicities upon coformulation of SOF/VEL with VOX as an FDC; data from study 
GS-US-367-1176 comparing SOF/VEL+VOX with SOF/VEL/VOX- were consistent with this. 
However, a potential risk of the study includes the identification of previously undetected 
adverse effects.  
There is a potential risk for subjects to develop multiclass resistance if treatment in this study is 
unsuccessful. However, VOX has the highest reported barrier to resistance among NS3/4A PIs 
and so the anticipated clinical risk of developing drug-resistant mutants with VOX is anticipated 
to be lower than that associated with first and second generation NS3/4A PIs 26. Accordingly, 
there was a lack of any viral breakthrough during therapy with VOX in the 3-day monotherapy 
study. Mutants generated in vitro to be resistant to VOX remain sensitive to SOF and VEL, 
supporting the clinical use of VOX in combination with other classes of HCV inhibitors. Lastly, 
this risk is balanced by the high efficacy shown in evaluations of SOF/VEL+VOX in Phase 2 
studies and a very low rate of emergent resistance among subjects who relapsed. 
 
Please see the Investigators Brochure for SOF/VEL/VOX for further information about 
SOF/VEL/VOX. 
 
1.9 
RATIONALE FOR DOSE SELECTION OF SOF/VEL/VOX 
Sofosbuvir 400 mg, once daily is the approved marketed dose of SOF for the treatment of HCV 
infection.  
Velpatasvir 100 mg has been administered in combination with SOF for 12 weeks to more than 
1500 subjects infected with HCV genotypes 1-6 in Phase 2 and 3 studies. The favorable safety 
and efficacy profile of this combination support selection of SOF 400 mg and VEL 100 mg for 
co-formulation into an FDC with VOX.  
Voxilaprevir 100 mg dose was selected for co-formulation with SOF 400 mg and VEL 100 mg 
based on the anti-HCV activity of VOX established in the phase 1 study GS-US-338-1121 (50 – 
300 mg VOX dose evaluated).  
Results from the relative bioavailability study GS-US-367-1176 show that the SOF/VEL/VOX 
FDC formulation achieves similar exposures of the relevant analytes to those observed with 
SOF/VEL+VOX. Additionally, the favorable safety and efficacy profile of SOF/VEL+VOX 
from Phase 2 studies support further evaluation of the combination of SOF/VEL/VOX 
400/100/100 mg. 
 


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1.10 OVERALL RISK/BENEFIT ASSESSMENT 
The potential benefits of SOF/VEL/VOX for the treatment of chronic HCV for patients included 
in the current study population are: 
 Addressing the unmet medical need of the growing population of patients who have failed 
prior therapies, particularly those including DAAs such as SOF; 
 Provision of a once-daily, single tablet, pangenotypic therapy for patients who have failed 
prior therapies and have no current treatment options. 
Based on the well-characterized nonclinical toxicology profile of SOF, VEL, and VOX, and the 
clinical experience with SOF, VEL, and VOX, there is no expectation of significant overlapping 
or new, unexpected toxicities upon administration of SOF/VEL/VOX. 
There is a potential risk for subjects to develop previously undetected adverse events or 
multiclass resistance. However, the development of resistance is anticipated to be low due to the 
high efficacy rate of the SOF/VEL + VOX combination therapy, as seen in Phase 2 studies, and 
the high resistance barrier of VOX. 
In summary, this treatment is approved for HCV-infected patients who have failed therapy with 
DAAs other than first-generation PIs in combination with Peg-IFN+RBV. If high rates of SVR 
can be obtained with a 12-week pangenotypic regimen, the anticipated value of achieving an 
SVR for patients with no current therapeutic options, with a safe and tolerable regimen, offers a 
favorable risk-benefit determination. 
 
2 
STUDY DESIGN AND METHODS 
This is a Phase IIb, open-label, study to evaluate the safety, tolerability, and efficacy of 
SOF/VEL/VOX in subjects with chronic HCV infection who have failed to eradicate HCV in 
response to combination DAA-based therapy, including subjects coinfected with HIV.  We will 
also evaluate the viral mutants, HCV quasispecies, as well as immunologic, virologic, and host 
genetic/proteomic predictors of response to SOF/VEL/VOX in study subjects.  
We hypothesize that the combination SOF/VEL/VOX will result in high SVR rates in patients 
with chronic HCV infection who are treatment-experienced after previous combination DAA-
based therapy with an FDA-approved regimen, including LDV/SOF and Viekira Pak 3D regimen 
consisting of paritaprevir (co-dosed with ritonavir [paritaprevir/r]), ombitasvir, dasabuvir 
(PrOD), dosed with or without ribavirin (RBV).  
All participants will receive 12 weeks of SOF/VEL/VOX. Patients will be followed for 
approximately 44 weeks from the screening period through the end of follow up visits: 
 8-week screening period 
 12-week treatment period  
 12-week post-treatment follow-up visit (SVR12) 
 24-weeks post-treatment visit to assess late viral relapse. 
Subjects that experience virologic failure or relapse and identified to have mutations leading to 


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SOF, VEL, and/or VOX resistance, following sequencing and phenotypic, analysis will be 
requested to return at 12-week intervals for this or a natural history protocol for up to 44 weeks 
to determine the time required for the resistant virus to return to background levels. 
2.1 
PRIMARY OBJECTIVE 
 To assess the safety, tolerability, and efficacy of 12 weeks of SOF/VEL/VOX in subjects 
with chronic HCV infection who have previously failed FDA approved DAA-based 
therapy, with compensated cirrhosis and without cirrhosis, with and without HIV 
coinfection.   
2.2 
SECONDARY OBJECTIVES 
 To evaluate the immunologic, virologic, and host genetic/proteomic predictors of 
response to therapy with SOF/VEL/VOX in HCV infected subjects who have failed 
previous combination DAA-based therapy 
 To compare HCV quasispecies and resistance associated variants (RAVs) from baseline 
and throughout treatment, especially in the case of relapse or breakthrough, and assess 
the influence of past DAA experience on evolution of RAVs and on virologic response to 
treatment. 
 To determine the kinetics of plasma HCV RNA during treatment and after treatment 
discontinuation.  
 To evaluate the effect of SOF/VEL/VOX on peripheral markers of T cell activation. 
 To evaluate the proportion of subjects whose alanine aminotransferase (ALT) levels 
normalize between baseline and SVR4,12,24. 
 To delineate the precise effects of specific HCV lifecycle inhibitors on host immune recovery in 
patients receiving single (SPARE), or combination DA therapy (RESOLVE). 
  
2.3 
EXPLORATORY OBJECTIVES 
 Characterize immunologic, virologic, and host genetic/proteomic predictors of response 
 Viral kinetic investigations, including early viral kinetics, resistance associated variants, 
HCV quasispecies 
 To determine the impact of liver cirrhosis in SVR when treated with potent combination 
DAA therapy 
 To delineate the precise effects of specific HCV lifecycle inhibitors on host immune 
recovery in patients receiving combination DAA therapy 
 To compare the immunophenotypic responses of patients receiving SOF/VEL/VOX who 
have previously failed double and triple DAA therapy. 
2.3.1 Rationale for Immunologic studies 
We propose to study the B and T cell immune responses most associated with chronic HCV 
eradication after DAA therapy, in order to more fully understand the utility of new ultra short 
duration therapies for those chronically infected with HCV. We will define T cell 
immune responses associated with protective immunity in chronic HCV infection and 
further advance our understanding about host immunity that is associated with SVR. Studies on 


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B and T cell responses in HCV or HCV/HIV dual infection and the relationships to 
treatment outcomes require large numbers of patients and extensive clinical trials of DAA 
therapy. Our research team is making a major impact on the clinical understanding of DAA. 
We have collected and maintain a large specimen repository that is sufficient for our initial 
characterization of B and T cells and how they are related to protective immunity. 
Chronic HCV infection is characterized by dysfunction of the adaptive immune system. DAA 
therapy is successful in resolving HCV infection and provides cure in up to 99% cases, except 
for late stage disease. Whether cure is associated with reconstituted immune regulation and 
what role the adaptive immune system plays in viral clearance is not known. Faster 
resolution of secondary infection after spontaneous clearance of HCV in humans and in 
chimpanzees points to a role for immunological memory in HCV control. Defining the immune 
correlates of DAA mediated sustained virologic response will help understand the immune 
defects that may be associated with treatment failure. 
 
Hypothesis 
Hypothesis #1: Augmentation of HCV specific cellular immune responses with DAA therapy is 
associated with SVR.  
Hypothesis #2: Healthy (non cirrhotic) liver is critical in mounting HCV specific cellular 
immunity in DAA treated patients 
Hypothesis #3: Specific inhibition of stages of HCV lifecycle leads to precise immune recovery 
in chronic HCV infected patients treated with combination DAA therapy. 
 
Study Design and Analysis 
 
To achieve these objectives, we will analyze peripheral and intrahepatic cellular immunity in 
patients who are cirrhotic and those who are not, as described in detail below. The 
responses/changes observed over time with DAA therapy will be compared between the two 
groups to evaluate first objective.  
 
 
 
 
 
To address the second objective, we will utilize samples collected from previous studies that 
used either single DAA (SPARE), dual or multiple DAA therapy (present study) to determine the 


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differential effect of specific HCV lifecycle inhibitors (NS5B alone, NS5B with NS5A and 
NS5B with NS5A and NS3 inhibitors). The assays that will characterize peripheral and 
intrahepatic cellular immunity are described in detail below. The changes from baseline to the 
end of therapy (or full viral suppression) will be compared in all patients receiving various 
regimens to determine the differential effect of added suppression of NS5A and or NS3.  
 
 
 
 
2.4 
STUDY POPULATION 
It is anticipated that approximately 150 HCV infected subjects, including screening failures and 
drop-outs, will be screened for this study.  The target population is chronic HCV patients who 
are treatment-experienced with combination DAA therapy and failed to achieve SVR12 in the 
United States. This study is designed to target an understudied demographic of the HCV 
epidemic in the United States in which current therapy has had poor results. There will be no 
racial, ethnic, religious, or gender discrimination. Persons in jail or prison are not eligible for this 
study. We will be enrolling participants from ongoing clinical trials with collaborators, as well as 
recruiting referrals.  Healthy adults will be recruited through Institutional Review Board (IRB)-
approved advertising to HCV providers and screened to confirm eligibility requirements for 
participation.  
The following eligibility criteria will be used: 
2.4.1 Inclusion Criteria 
A subject must meet all of the following criteria: 
1. At least 18 years of age or older at screening. 
2. Available for clinical follow-up through Week 44 after enrollment. 


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3. Recurrent HCV GT-1 infection as documented by ≥ 1 measurement of serum HCV 
RNA ≥ 1,000 IUM/mL during screening and documented history of receiving prior 
HCV treatment.   
4. Exposure to combination DAA therapy, including, but not limited to, the following 
regimens: 
a. LDV/SOF ± RBV  
b. Viekira Pak ± RBV 
c. EBR/GZR± RBV 
 
5. Ability to communicate effectively with the study investigator and other key personnel. 
 
6. Opioid-dependent individuals must be participating in a supervised treatment program 
or considered stable at the discretion of the investigator. 
 
7. Subjects must have a primary care doctor for their medical management. 
8. Able and willing to complete the informed consent process. 
9. Willing to donate blood for sample storage to be used for future research. 
10. Female study participants with childbearing potential (as defined below) and all 
male study participants must be willing to practice either: 
 
 Complete abstinence from sexual intercourse with a member of the opposite sex  
OR 
 At least one form of effective contraception from the list below, in addition to correct 
use of either a male or female condom with spermicide, throughout dosing and for a 
defined period following the last dose (30 days for women, 14 days for men) of 
study medication.: 
i. Intrauterine device with a failure rate of <1% per year 
ii. Tubal sterilization 
iii. Bilateral tubal occlusion 
iv. Vasectomy in a male partner  
v. Female barrier method (diaphragm or cervical cap) with spermicide 
vi. Hormonal methods 
1. Oral contraceptives 
2. Injectable progesterone 
3. Implants of levonorgestrel or etonorgestrel 
4. Transdermal contraceptive patch 
5. Contraceptive vaginal ring 
11. Hepatitis B coinfected participants, must have evidence of chronic infection and 
controlled on treatment.   
12. HIV coinfected participants only must have HIV status of one of the following: 
a. HIV untreated for ≥8 weeks prior to Screening 


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i. CD4 T-cell count >500 cells/mm3 at Screening 
ii. No intention of initiating ARV therapy for the duration of trial 
  
 
OR 
b. HIV suppressed on a stable, protocol-approved, ARV regimen for ≥ 4 weeks 
prior to Screening 
i. Completed at least 3 months of any prior HIV ARV therapy and 
maintained HIV RNA < 50 copies/mL (or < LLOQ if the local 
laboratory assay’s LLOQ is ≥50 copies/mL) prior to Screening. Subjects 
with an isolated or unconfirmed HIV RNA > 50 copies/mL (or > LLOQ 
if the local laboratory assay’s LLOQ is ≥50 copies/mL) are not 
excluded.  
ii. CD4 count >100 cells/mm3 at Screening 
iii. HIV antiretroviral (ARV) agents allowed in this study include  
 FTC/TAF [Descovy®], FTC/TDF [Truvada®], or ABC/3TC 
[Epzicom®] 
 
plus 
 
 Ritonavir (r) and darunavir (DRV), OR 
 Raltegravir (RAL), OR 
 Elvitegravir (EVG) ± Cobicistat (c), or  
 Rilpivirine (RPV) 
 
Or 
 
Fixed dose combinations as below  
 FTC/RPV/TAF [Odefsey®] 
 FTC/RPV/TDF [Complera®] 
 EVG/c/TAF/FTC [Genvoya®] 
 EVG/c/TDF/FTC [Stribild®] 
 
Alternative ARV regimens will be considered on an individual basis, 
based on available DDI data at the discretion of the principal 
investigator 
iv. The subject is expected to continue the current ARV regimen for the 
duration of the trial 
Cirrhosis Criteria: 
13. Liver fibrosis staging as determined by an AASLD/IDSA guideline-approved 


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measurement, within three years of Screening, including any one of the following: 
a. Imaging 
b. Liver biopsy 
c. Transient elastography  
d. Noninvasive markers 
Liver imaging within 6 months of Day 0 to exclude hepatocellular carcinoma (HCC) is required 
in patients with cirrhosis. 
2.4.2 Exclusion Criteria 
A subject will be excluded if one or more of the following conditions apply: 
1. Combination DAA therapy was completed or discontinued less than 8 weeks prior to 
enrollment.  
2. Current or prior history of any of the following:   
a. Clinically significant illness (other than HCV) or any other major medical 
disorder that may, in the opinion of the investigator, interfere with the subject 
treatment, assessment of compliance with the protocol; subjects currently under 
evaluation for a clinically-significant illness (other than HCV) are also excluded  
b. Gastrointestinal disorder with post-operative condition that could interfere with 
the absorption of the study drugs  
c. Poor venous access interfering with required study blood collection  
d. Hepatic impairment or decompensation (e.g., Child-Pugh class B [moderate] or 
Child-Pugh class C [severe])  
e. Solid organ transplantation 
f. Significant pulmonary disease, significant cardiac disease, or porphyria.  
g. Unstable psychiatric disease, including hospitalization, suicide attempt, and/or a 
period of disability as a result of their psychiatric illness within 2 years prior to 
Screening (subjects with psychiatric illness that is well-controlled on a stable 
treatment regimen or currently not requiring medication may be included)  
h. Any malignancy or its treatment that in the opinion of the PI may cause ongoing 
interference with host immunity; subjects under evaluation for malignancy are 
not eligible  
i. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s 
disease, alfa-1 antitrypsin deficiency, cholangitis) 
3. Abnormal hematological and biochemical parameters at screening, unless the test has 
been repeated and at least one subsequent result is within the acceptable range prior to 
study drug administration, including: 
a. Neutrophil count <750 cells/mm3  
b. Hemoglobin level <10 g/dL  
c. Platelet count ≤50,000 cells/mm3 
d. Estimated glomerular filtration rate, calculated by the chronic kidney disease 
epidemiology collaboration formula: <30 mL/min/1.73 m2 
e. ALT or AST level ≥10 times upper limit of normal (ULN) 
f. Serum lipase level ≥1.5 times ULN at screening or during the screening period 
in a patient with symptoms of pancreatitis 


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g. Total bilirubin level ≥2.0 times ULN, except in subjects with Gilbert’s 
syndrome or other clinical explanation at the discretion of the PI.  
h. Albumin level <3 g/dL 
 
4. Poorly controlled diabetes as indicated by a screening glycosylated hemoglobin 
(HbA1c) >10 
5. Known hypersensitivity to any of the study medications  
6. Screening ECG with clinically significant findings 
7. Need for the use of the following medications from 21 days prior to the start of study 
drugs through the end of treatment:  
a. Hematologic stimulating agents, erythropoiesis stimulating agents (ESAs), 
granulocyte colony stimulating factor (GCSF), thrombopoeitin (TPO) mimetics 
b. Chronic systemic antineoplastic or immunomodulatory treatment including 
supraphysiologic doses of immunosuppressants such as corticosteroids (e.g., 
prednisone equivalent >10 mg/day for >2 weeks), azathioprine or monoclonal 
antibodies (e.g., infliximab) 
c. Investigational agents or devices for any indication 
d. Use of certain medications and herbal/natural supplements per PI discretion, 
expected to result in increases or decreases in exposure to study or non-study 
medications as listed in section 3.5 (Table 3-1). 
 
8. Any medical, psychiatric, social condition, occupational reason or other responsibility 
that, in the judgment of the investigator, is a contraindication to protocol participation 
or impairs a volunteer’s ability to give informed consent. 
Female-specific criteria: 
9. Woman who is breast-feeding or planning to become pregnant during the first 24 weeks 
after study drug administration. 
2.5 
PHARMACOKINETIC AND VIRAL KINETIC SUBSTUDY 
Participants, N=20 (10 participants with cirrhosis and 10 without cirrhosis) that meet the above 
criteria and who are willing to participate will be eligible for a voluntary 24 hour and 72 hour 
pharmacokinetic (PK) and viral kinetic (VK) substudy.  
 
2.6 
RECRUITMENT PLAN 
The study will be advertised and posted using flyers. All advertisements will be IRB approved 
before use.  
 
2.7 
HUMAN SUBJECTS PROTECTIONS 
Subjects will be fully counseled prior to entry into the study as to the potential risks of the study 
and consenting using good clinical practice. Subjects who, in the opinion of the study team, do 


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not fully comprehend these potential risks will not be offered participation in the study. Subjects 
will be monitored closely during their participation in the study. 
 
2.7.1 Gender, Ethnicity, and Race Considerations 
Subjects will not be excluded based on gender.  This study is designed to target an 
underrepresented demographic of the HCV epidemic in the United States with poor 
representation in clinical trials, and in which current therapy has had poor results.  
 
2.7.2 Rationale for the Exclusion of Children and Pregnant Women 
This study will be limited to adults aged 18 years or older. Insufficient data are available to 
evaluate the safety and efficacy of SOF, VEL and VOX in the pediatric population. The risks of 
SOF or VEL or VOX during pregnancy have not been evaluated; therefore, pregnant or nursing 
women will be excluded from this study. Any woman of child-bearing potential must have a 
negative pregnancy test on Day 0 prior to receiving the first dose of SOF/VEL/VOX and use 
effective contraception throughout the study.  
 
2.7.3 Contraception  
Male subjects, as well as female subjects who are potentially capable of becoming pregnant, will 
be required to use at least 2 forms of contraception, one method must be correct use of a condom 
with spermicide, from 2 weeks prior to Day 0 until after completing study drug (30 days post 
completion for women, 14 days for men following the last dose of study drug.  Female partners 
of male study subjects may rely upon hormonal contraceptives as one of the 2 forms, however 
female study subjects may not.  As study drugs are investigational agents, prevention of 
pregnancy, in a subject or partner, during and after treatment is important as the risks are as yet 
unknown.  
 
Definitions:  
a. Definition of Childbearing Potential: For the purposes of this study, a female born subject is 
considered of childbearing potential from menarche until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.   
 
Women are considered to be in a post-menopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.  
 
b. Definition of Male Fertility: For the purposes of this study, a male born subject is considered 
of fertile after the initiation of puberty unless permanently sterile by bilateral orchiectomy or 
medical documentation. 
 
 
2.8 
CLINICAL PROCEDURES AND SCHEDULE OF EVALUATIONS 
This section describes the clinical procedures for evaluating study participants and follow-up 
after administration of study drug.   


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Study visits, including screening, will occur at the UMB Institute of Human Virology clinic or 
one of the clinics mentioned in the study roster based upon scheduling availability to 
accommodate each treatment group. Participants in the pharmacokinetic or viral kinetic substudy 
will be seen at the University of Maryland Medical Center. 
 
UMB Study Team Roles at Washington, DC community clinics:  Members of the study team 
have been actively involved in patient care at the community clinics (Unity’s Parkside and 
Walker-Jones). Unity will sign a UMB Reliance Agreement prior to initiating any study 
activities. The site AI and collaborating investigator may see subjects at non-study visits and will 
communicate findings to UMB study team. The UMB research coordinators will also oversee 
research operations in the clinics and at the UMB IHV clinic. The UMB study staff will see 
participants for all scheduled and unscheduled visits and study withdrawal. 
 
If subjects are seen in the Community: All phlebotomy will be done by a phlebotomist 
working in the clinic or clinic staff. A specimen bag and specimen tubes will be prepared by 
UMB staff and will be labeled with the participant’s first three initials of last and first name and 
study number.  All laboratory studies will be performed by UMB and will be reviewed by 
UMB staff on a weekly basis. Copies of results will be sent to the primary care provider and 
scanned into the electronic medical record at the participating clinic. 
Clinic staff will not participate in study-related visits unsupervised by UMB study staff. 
Participants will be given a calendar of scheduled study visits and will be informed that any 
clinic visits outside of scheduled study visits may be either unscheduled visits or non-study 
visits. All visits related to the treatment of HCV will be considered study related. Any other 
medical problems will be addressed by the participant’s primary provider. Participants will 
receive this information when given the visit calendar. 
The primary responsibility of the site AI and the community clinics is to provide timely and 
effective communication regarding any potential adverse events if a subject/patient is seen for 
care outside of the normal study visit.   
 
2.8.1 Screening 
Each patient will provide informed consent of his/her free will prior to commencement of any 
study procedures according to ICH and Code of Federal Regulations (CFR).  Each patient will be 
provided a copy of the signed informed consent form. 
 
After a patient has provided informed consent, the Investigator and other study personnel will 
determine if the patient is eligible for participation in the study.  Screening may begin up to 8 
weeks prior to dosing to allow for a possible liver biopsy if one has not been performed within 
36 months prior to the first dose of study drug (Day 0) and is indicated for disease staging as 
specified in the inclusion criteria. An optional research liver biopsy will be offered to subjects 
during screening (and at end of treatment) with the aim of having paired research samples on up 
to 20 subjects on the study.   
 


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Screening will include a review of the inclusion/exclusion criteria and completion of all 
screening procedures as outlined in the Schedule of Tests, Section 5.1. Screening tests within the 
last 8 weeks prior to screening visit that have been done as part of routine medical care or at an 
outside facility (with the exception of chemistries, hCG, HIV, CBC with differential, coagulation 
studies) can be used if within the acceptable time frame. Known HIV infected participants will 
not have an HIV test, but will have HIV RNA and CD4 T-Cell count testing. 
  
The standard consent includes permission for HIV testing (in those not previously known to be 
infected), optional liver biopsy, and storage of blood and tissue samples. HLA testing may be 
tested for this study if not on file, because this information will be useful for the evaluation of 
HCV-specific immune responses.   
 
Screening procedures do not need to be repeated within the 8 week screening window unless 
clinically indicated. Once the screening window has elapsed, patients may be rescreened at the 
discretion of the PI. 
 
2.9 
RANDOMIZATION AND BLINDING 
This is an open-label, phase IIB clinical trial, and will be without blinding. Randomization will 
not be employed, as all participants will be allocated to 12 weeks of the same therapy.  
 
 
2.10 HISTORY AND PHYSICAL 
All subjects will have a History and Physical during the screening process as part of final 
determination of protocol eligibility.  Physical exams will be performed with study point visits at 
Day 0, Week 4, Week 12 and Post-treatment Weeks 12 and 24. Directed physical exam will be 
done as needed at other study points. On arrival at the clinic for study visits, subjects will have 
their vital signs obtained and females of childbearing potential will undergo a pregnancy test (if 
appropriate per visit day, see Schedule of Tests, Section 5.1), clinical laboratories drawn, and a 
review of the study restrictions. Subjects will be asked about their state of health and use of any 
concomitant medication since the previous study visit.  They will also be questioned about AEs, 
their adherence with study restrictions, and their adherence to study drug administration. A 
complete list of study procedures and lab tests to be performed is in the Schedule of Tests, 
Section 5.1.  
 
In addition, subjects may be seen at unscheduled visits for a grade 3 or 4 AE or any unexpected 
AE (adverse event) or potential toxicity.  
 
Some of the visits have flexibility regarding when they need to occur. The window period for 
visit schedules is as follows: 
 Days 0, 3(PK/VK participants only), no window 
 Optional Week 1 (+/- 3 days) 
 Weeks 2, 4 (+/- 3 days) 
 Weeks 8 and 12 (+/- 7 days) 
o Optional End of therapy Liver Biopsy (+/-14 days) 
 Post Therapy Weeks 4, 12, 24 (+/- 10 days) 
 


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2.11 STARTING SOF/VEL/VOX (DAY 0) 
The participant will be started on SOF/VEL/VOX on Day 0. Blood will be drawn for HCV viral 
loads, immunologic studies, and for storage prior to dosing. A pregnancy test will be done for 
females with childbearing potential and the pregnancy test must be negative prior to dosing with 
study drugs.  The subject will undergo a history and physical exam on Day 0, prior to starting 
study medications.  
 
2.12 OPTIONAL PK/VK SUBSTUDY 
Participants who are eligible and interested in participating in the optional PK/VK substudy will 
undergo timed blood draws at baseline, 1, 2, 4, 8, 24, and 72 hours after initiating study 
medication.  
 
2.13 WEEK 1 VISIT 
Participants will either have a telephone phone follow up visit to assess for adverse events and 
adherence or they will come to the clinic for an in person study visit that will include clinical and 
research blood draw. 
 
2.14 WEEK 2 VISIT 
In addition to scheduled study events, the second bottle of study medication will be dispensed. 
 
2.15 WEEK 4 VISIT 
 
During this visit, HCV RNA will be obtained to determine if virologic-response based treatment 
stopping criteria have been met. Subjects who fail to achieve >2 log10 HCV RNA drop at this 
time (unless >2 log drop would be below LLOQ) will be discontinued from therapy unless a 
review by the PI/LAI/Medical Monitor (MM) determines otherwise, and the last bottle of study 
medication will be dispensed.  
 
2.16 WEEK 8 VISIT 
During this visit, HCV RNA will be obtained to determine if virologic-response based treatment 
stopping criteria have been met.  
 
2.17 WEEK 12 / END OF TREATMENT VISIT  
Week 12 will mark the last dose of SOF/VEL/VOX FDC to be administered. In addition, if a 
patient’s participation terminates prior to Week 12, the Week 12 assessments may be performed 
at any end-of-treatment visit.  
 
2.18 FOLLOW-UP VISITS AFTER STUDY DRUG DISCONTINUATION 
After discontinuation of the study drug, subjects will be followed at Weeks 4, 12, and 24 after 
completion of therapy. All subjects will be assessed for sustained virologic response (SVR12) at 
the post-treatment week 12 visit, to occur at study week 24. A serum pregnancy test will be done 


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with each visit up to 30 days after stopping study drug, in women of childbearing potential, as 
appropriate.  
 
2.19 FAILURES, EARLY TERMINATION AND EARLY TREATMENT DISCONTINUATION 
Participants who prematurely discontinue study agents due to toxicity will be followed closely 
for resolution of symptoms, until final outcome is known or until the end of the study follow-up 
period.  
 
Participants requiring discontinuation, as well as those who elect to discontinue study drugs prior 
to treatment completion for medical or personal reasons, will continue to follow the general 
study schedule of assessments unless unwilling to do so, in which case they may be seen at least 
every 12 weeks for safety and research labs until the end of the study.  The participant should 
have an end of treatment visit scheduled as soon as possible after all therapy is discontinued if 
willing. Any subject continuing in the study will be followed closely for resolution of active 
laboratory abnormalities or adverse events that are considered related to the study agents. 
Participants with undetectable HCV RNA at the end of treatment should continue to follow the 
scheduled SVR4, SVR12, and SVR24 visits following the date of their last dose of therapy while 
remaining undetectable.  
 
 
Participants who have detectable HCV RNA at the end of treatment or who relapse post-
treatment will be asked to return for additional visits at least every 12 weeks after the end of 
treatment for up to a total of 24 weeks or on a separate natural history protocol to determine the 
persistence of any HCV populations with treatment-emergent substitutions conferring resistance 
to SOF or GS-5885 or VOX. Any subject continuing in the study will be followed closely for 
resolution of active laboratory abnormalities or adverse events that are considered related to the 
study agents.  
 
Samples collected will be used to determine the durability of response or the dynamics of any 
changes in resistance conferring mutations. The reason for any early termination should be 
documented.   
 
2.20 EVALUATION OF SAFETY 
All enrolled subjects who have received SOF/VEL/VOX FDC will be evaluated for safety. 
Safety will be assessed by physical examination, vital signs, hematology, and chemistries. The 
severity of signs, symptoms, and AEs will be determined by using the 2004 DAIDS Toxicity 
Severity Scale. 
 
2.20.1 Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found.  If a clear explanation is established it should be 
recorded. 
 


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2.20.2 Criteria for Premature Withdrawal and Stopping Rules  
Subjects have the right to withdraw from the study at any time for any reason.  Subjects who 
withdraw early or who are terminated from study by the Investigator will not be replaced unless 
they have received no study drugs.  In addition to the criteria for stopping subject treatment 
described in Dose Modification and Treatment Failure Sections, the Investigator or designee also 
has the right to withdraw subjects from the study for any of the following: 
1. Development of life-threatening infection (requiring withdrawal of study drugs for more 
than 6 weeks) or malignancy. 
2. Participant’s desire to leave study. 
3. Pregnancy or breastfeeding.  
4. Participant’s non-compliance. If a subject misses 5 or more total study visits or > 3 weeks 
of study drug, the subject will be removed from the protocol at the discretion of the 
Investigator or designee.  
5. Termination of study. 
6. Development of liver decompensation with elevated Child-Turcotte-Pugh score of 8 or 
more. 
7. If SOF/VEL/VOX FDC is permanently discontinued by the pharmaceutical company. 
8. Development of a medical condition, such as hepatocellular carcinoma, that in the 
opinion of the Investigator, it is in the subject’s best interest to discontinue study drug 
even if criteria requiring drug discontinuation have not been met. 
9. Request of the primary care provider or Investigator if s/he thinks the study is no longer 
in the best interest of the subject.  
10. Clinical reasons believed life threatening by the physician.  
11. If the subject is judged by the Investigator to be at significant risk. 
12. Subjects may decide at any point not to have their samples stored. This will be treated as 
a withdrawal of the consent and in this case, the Principal Investigator will assure the 
destruction of all known remaining samples and report what was done to both the subject 
and to the IRB. This decision will affect the subject’s participation in this protocol but 
may not affect participations in any other protocols at UMD. 
 
 
3 
STUDY AGENTS 
3.1 
DISPOSITION AND DISPENSATION  
Study agents will be distributed via the IHV Pharmacy according to standard pharmacy 
procedures. 
All drug products will be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration will be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions will be followed to avoid 
direct eye contact or exposure through inhalation when handling study drugs. 
 
3.2 
PACKAGING AND LABELING OF STUDY DRUGS 
Each bottle will be individually labeled with the patient ID number, dosing instructions, 
recommended storage conditions, the name and address of the manufacturer, Investigational Use 


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Statement (“Caution: New Drug – Limited by Federal [USA] Law to Investigational Use”) and 
that the agent should be kept out of reach of children. 
3.2.1 Formulation 
SOF/VEL/VOX fixed dose combination (FDC) tablets are beige, capsule-shaped, film-coated 
tablets containing 400 mg of sofosbuvir, 100 mg of VEL, and 100 mg of VOX. The tablets are 
debossed with “GSI” on one side and “3” on the other side. In addition to the active ingredients, 
the tablets contain the following inactive ingredients: copovidone, microcrystalline cellulose, 
lactose monohydrate, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.  
The tablet film-coating material also contains polyvinyl alcohol, titanium dioxide, macrogol/PEG 
3350, talc, iron oxide yellow, iron oxide red, ferrosoferric oxide.   
3.2.2 Packaging and Labeling 
SOF/VEL/VOX FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. 
Each bottle contains 28 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with 
an induction-sealed, aluminum-faced liner. 
Sufficient quantities of SOF/VEL/VOX FDC tablets to complete the entire study will be shipped 
from Gilead Sciences Materials & Logistics (or its designee). 
3.2.3 Storage and Handling 
SOF/VEL/VOX FDC bottles should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77F); excursions are permitted 
between 15C and 30C (59F to 86F). 
All drug products will be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product will not be stored prior to dispensing in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and disposal 
through measures that minimize drug contact with the body. Appropriate precautions should be 
followed to avoid direct eye contact or exposure through inhalation when handling 
SOF/VEL/VOX FDC. 
3.3 
TREATMENT OF SUBJECTS  
All subjects will receive 12 weeks of treatment with SOF/VEL/VOX. 
SOF/VEL/VOX FDC will be administered orally once a day. The 1st dose will be taken on Day 
0.  
3.4 
DOSE MODIFICATIONS / TOXICITIES 
Maximal suppression of HCV replication is most likely accomplished by sustained delivery of 
antiviral agents at their current recommended doses. Dose reduction would compromise this goal 
and predispose to the emergence of drug-resistant viral variants.  Hence, no dose reduction will 
be allowed for SOF/VEL/VOX.  
 


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3.4.1 Dose Modification for SOF/VEL/VOX 
Dose modifications will not be permitted. If a subject forgets to take the medication at the correct 
time, it may be taken later in the day; however, no more than a single dose should be taken on 
any calendar day. The subject should resume the standing dosing schedule on the next day.  Any 
treatment interruption or discontinuation will be recorded including the reason for the 
interruption or discontinuation.  
 
3.4.2 Treatment Failure / Drug Discontinuation 
See also Criteria for premature withdrawal of subjects (2.20.2). Subjects will be considered 
treatment failures and will discontinue SOF/VEL/VOX FDC if they meet any of the following 
criteria while taking study drugs: 
 HCV RNA greater than LLOQ after 2 prior consecutive HCV RNA values 
less than the LLOQ 
 Greater than a 1 log10 increase in HCV RNA from nadir 
 Less than a 2 log10 decline in HCV RNA after 4 weeks of treatment (unless 
>2 log drop would be below LLOQ) 
 HCV RNA ≥ LLOQ after 8 weeks of treatment 
 
If any of these should occur in a patient who is currently on study drugs, the subject should 
return within one week for a confirmatory test. If the confirmatory test also meets the same 
criteria, the subject will be considered a treatment failure and should be discontinued from 
therapy. The anticipated clinical impact of discontinuation should be discussed in advance with 
the Medical Monitor (MM) if possible, particularly if discontinuation is thought to pose a risk to 
the overall clinical wellbeing of the subject. Those who are discontinued will continue to follow 
the general study schedule of assessments unless unwilling to do so, in which case they may be 
seen at least every 12 weeks for safety and research labs until the end of the study.  Subjects will 
be followed closely for resolution of active laboratory abnormalities or adverse events which are 
considered related to the study agents prior to starting the revised schedule. 
 
Subjects who meet any of the following laboratory criteria must stop all study medication(s): 
 
 Elevation of ALT >5x OR AST >5x Day 0, confirmed by immediate repeat testing 
 Abnormal elevation of ALT >3 x Day 0 and total bilirubin >2 x ULN, confirmed 
by immediate repeat testing 
 Elevation of ALT >15 x ULN confirmed by immediate repeat testing 
 Any Grade 3 or greater rash associated with constitutional symptoms 
 Any Grade 4 event assessed as related to treatment with SOF/VEL/VOX FDC   
 Pregnancy  
3.4.3 Treatment Failure Criteria After Stopping SOF/VEL/VOX 
 Have detectable HCV RNA during the post-treatment period (after having achieved 
HCV RNA <LLOQ at end of treatment).  If virus is detected after subject achieves 
SVR12, will confirm with repeat viral testing, and then evaluate for reinfection 
versus relapse with viral subtyping and sequencing.  


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3.4.4 Viral Co-infection Rebound Schema 
For HIV suppressed subjects taking ARVs, at least two consecutive and uptrending post-
baseline visit plasma HIV RNA levels ≥ 400 copies/mL (at least two weeks apart) will be 
considered HIV virologic rebound. 
 
Following an initial HIV RNA result of ≥ 400 copies/mL, subjects will continue to take 
their current ARV regimen and be asked to return to the clinic after 2 weeks for a 
scheduled or unscheduled blood draw for confirmation of HIV virologic rebound. If HIV 
virologic rebound is confirmed at the scheduled or unscheduled visit, the blood samples 
from this visit will be used for HIV genotype/phenotype testing. If no resistance to the 
subject’s current ARV regimen is detected, the subject may continue on current ARV 
regimen. 
 
HCV study drug should be continued unless safety events or HCV response based 
stopping criteria warrant the discontinuation of the study drug, as outlined in Section 3.4 
of the protocol. 
 
For those with chronic HBV infection taking chronic suppressive therapy, if HBV flare 
does occur, monitoring and treatment plan will be discussed with medical monitor on an 
individual basis.  
 
3.5 
CONCOMITANT MEDICATIONS 
Concomitant medications taken within 30 days of screening through 30 days following 
discontinuation of study treatment need to be recorded in the source documents. 
The following medications are prohibited from 28 days prior to the Day 0 visit through the end 
of treatment: 
 Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics) 
 Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of >10 mg/day for >2 weeks), azathioprine, or monoclonal antibodies 
(e.g., infliximab)  
 Investigational agents or devices for any indication 
 Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers 
of drug transporters i.e., P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in increases or decreases in exposure of study drug(s).  Examples of representative 
medications which are prohibited from 21 days prior to Day 0 through the end of treatment 
are listed below.  
 Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed 
in the study. 


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 Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the medical monitor must be consulted prior to initiation of the new medication 
 
 


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Table 3-1:  Disallowed and Concomitant Medications to be Used with Caution 
Drug Class 
Agents Disallowed 
Use with Caution 
Acid Reducing Agentsa 
 
Proton-Pump Inhibitors, H2-Receptor 
Antagonists, Antacids 
Anticoagulants 
 
Dabigatran Etexilated 
Anticonvulsants b 
Phenobarbital, Phenytoin, Carbamazepine,  
Oxcarbazepine 
 
Antimycobacterials b 
Rifabutin, Rifapentine, Rifampicin 
 
Cardiac Medications 
Amiodarone c 
Digoxind 
Herbal/Natural 
Supplementsb 
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang) 
 
HMG-CoA Reductase  
Inhibitorse 
Rosuvastatin 
Pravastatin 
a 
Proton-pump inhibitors (PPIs) comparable to omeprazole 20 mg once-daily may be taken. H2 receptor antagonists 
must not exceed the equivalent of 40 mg of famotidine twice daily. Antacids that directly neutralize stomach pH (i.e. 
Tums, Maalox) may not be taken within 4 hours (before or after) of SOF/VEL/VOX FDC administration. 
b 
May result in a decrease in the concentrations of study drugs. 
c 
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Day-1 through the end of treatment. 
d 
May result in an increase in the concentration of study drugs and/or concomitant medications 
e 
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis. Pravastatin may be administered with 
SOF/VEL/VOX FDC at a dose that does not exceed pravastatin 40 mg. 
4 
STATISTICAL CONSIDERATIONS 
This study is a single-center trial to assess the safety and tolerability of SOF/VEL/VOX. 
4.1 
SAMPLE SIZE 
 
We anticipate enrolling approximately 60 patients with cirrhosis and 60 patients without 
cirrhosis, for a total of 120 HCV, genotype 1, infected subjects who have previously been treated 
with unsuccessful combination DAA-based therapy.  
 
An anticipated sample size of approximately 120 patients will provide a 97% power to detect at 
least an absolute 15% improvement in SVR12 from the conservative estimate of 70%20 by using a 
2-sided, exact, 1-sample binomial test at a significant level of 0.05 (See Table 4-1). 
Table 4-1 Power calculations for observed SVR12 rate compared to Historical rate of 70% 
Ho SVR12 
Ha SVR12 
Sample Size 
Power 
70% 
80% 
120 
0.641 
70% 
85% 
120 
0.968 
70% 
90% 
120 
>0.999 
70% 
95% 
120 
>0.999 
 


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In terms of safety, a sample size of 120 is sufficient to have high probability of observing at least 
1 adverse event of probability 5% or more.  If the true event probability is 5% or more, there is 
about a 99.8% chance of observing at least 1 such adverse event. Consequently, if no one has a 
given type of AE, we can be confident that its true probability is under 5%. This trial will 
provide preliminary evidence on the safety and efficacy of SOF/VEL/VOX.  A previous study of 
SOF/VEL FDC in subjects with genotype 1 led to a sustained virologic response at Week 12 
(SVR12) in all participants.  We therefore expect SVR to 80% or higher.  If the true suppression 
rate is 80%, we will be able to estimate the probability of suppression to within approximately 
±1.96[(.8)(1-.8)/120]1/2=.07  (Table 4-2). For sample sizes shown in row 1, row 2 gives the 
accuracies of the estimates of the proportion of patients suppressed to below the limit of 
detection (based on a 95% confidence interval). 
Table 4-2:  Sample Size 
 
 
n=50 
n=75 
n=100 
n=120 
±.11 
±.09 
±.08 
±.07 
 
AE probabilities are shown in Table 4-3, wherein for a given N, the probability of observing at 
least 1 participant with the AE among study participants. We selected at least 100 participants 
based on the ability to detect adverse event rates of a frequency of 1% and 5% with 63% and 
99% probability, respectively.  
 
Table 4-3:  Adverse Event Probability Table 
 
 
Probability of Adverse Event 
 
0.01 
0.05 
0.10 
0.15 
N=75 
52% 
98% 
>99.9% 
>99.9% 
N=100 
63% 
99% 
>99.9% 
>99.9% 
N=120 
70% 
99.8 
>99.9% 
>99.9% 
 
4.1.1 Primary Endpoint 
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of 
therapy).  
The primary statistical hypothesis for efficacy is that SVR12 rate is higher than the conservative 
estimate of 70%20.  
 
 Ho: SVR12 = 70% 
 Ha: SVR12 ≠ 70% 
 
The primary analysis will be intention-to-treat, including all enrolled subjects into the study and 
received at least one dose of study drug, performed after all enrolled subjects have been followed 
through 12 weeks post-treatment or discontinued from study. 


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4.1.2 Secondary Endpoints 
Secondary efficacy endpoints include: HCV RNA < LLOQ at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24); viral breakthrough; and relapse. 
Descriptive summaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure and other endpoints of interest including 
ALT normalization, serum HCV RNA actual values, and change from baseline.  
Exploratory analyses may be performed to assess the relationship between demographic, baseline 
characteristics, (including baseline viral load, genotype, age, sex, race, ethnicity, 
presence/absence of cirrhosis, baseline ALT level, prior treatment experience, response to 
previous treatment [if applicable], and BMI) and antiviral activity (HCV RNA reduction, 
proportion of subjects with HCV RNA <LLOQ at various time points during and following 
discontinuation of all therapy). Predictive factors of antiviral activities may be examined using 
regression type of analysis. Changes in HCV specific CD8 responses in patients with cirrhosis 
and not with cirrhosis.  Changes in HCV specific immune responses in patients treated with 
single (NS5B) DAA versus dual (NS5B + NS5A) versus triple combination DAA (NS5B + 
NS5A + NS3) using samples from SPARE and this study 
4.1.3 Safety Endpoints 
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s).  
4.1.3.1 Other Endpoints of Interest 
Additional efficacy evaluations may include HCV RNA change from Day 0; ALT normalization; 
and viral kinetic parameters. 
4.1.4 Analysis Sets 
4.1.4.1 Efficacy 
The analysis set for antiviral activity analyses will include subjects who were enrolled into the 
study and received at least one dose of study drug.  
4.1.4.2 Safety 
The primary analysis set for safety analyses will include subjects who received at least one dose 
of study drug. 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, and 
vital signs measurements at various time points during the study, as well as the documentation of 
AEs. 
On treatment data will be analyzed and defined as data collected from the first dose of study drug 
through the date of last dose of study drug plus 30 days.  
4.1.4.3 Pharmacokinetics 
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study medication.  The PK analysis set will be used for analyses of general PK. The intensive 
PK analysis will include the 20 participants who were enrolled in the sub study.  


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4.2 
DATA HANDLING CONVENTIONS 
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed.  
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
preceded and followed in time by values that are deemed successes, then the missing data point 
will be termed a success; otherwise the data point will be termed a failure. 
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points on, or following, the date of discontinuation. If no HCV 
RNA values are obtained after the last dose of study medication, the subject will be considered a 
treatment failure for the SVR endpoints.  
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, 
 If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary. 
 If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values. 
Values for missing vital signs data will not be imputed; however, a missing Day 0 result will be 
replaced with a screening result, if available. 
4.3 
DEMOGRAPHIC DATA AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment arm and overall. 
Demographic data will include sex, self-identified race/ethnicity, and age. 
Baseline characteristic data will include body mass index (BMI), presence or absence of 
cirrhosis, HCV RNA level (log10 IU/mL), HCV genotype, and additional endpoints as necessary. 
4.4 
ADVERSE EVENTS 
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the 
date of first dose of study drug up to the date of last dose of study drug plus 30 days.  
Summaries (number and percentage of subjects) of treatment-emergent adverse events will be 
provided.  
 


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5 
STUDY TESTS 
5.1 
SCHEDULE OF TESTS 
Laboratory Studies 
Screening tests that have been done as part of other studies or standard of care within the last 8 
weeks or at an outside facility (with the exception of safety labs chemistries, hCG, CBC with 
differential, coagulation studies) can be used if within the 8 weeks prior to Day 0. HIV test does 
not need to be done in participants known to be HIV infected. Similarly, HBV serologic testing 
does not need to be done in participants known to be chronically HBV infected who are on 
suppressive therapy.  
 
Serum Chemistry and Hematologic Profiles  
Acute Care Panel, Hepatic Panel, Mineral Panel, and CBCs (with differential) will be performed 
to monitor clinical status, document drug-related benefits and detect potential drug-related 
toxicities. These may be done on screening, days 0, 7, 14, and every scheduled visit thereafter 
through post-treatment Week 24.  Highly sensitive C-reactive protein may also be done at Days 
0, weeks 1 (optional), 2, 4, 12 (end of therapy), as well as post-treatment weeks 12 and 24, again 
dependent upon blood volume availability by patient. 
 
Prothrombin Time and Partial Thromboplastin Time 
Measured by standard assay on screening, end of therapy (Week 12), prior to liver biopsy and 
post-treatment Week 24. 
 
Creatine Kinase, Lactate Dehydrogenase, Lipase, Amylase. 
Measured by standard assay on screening and Weeks 4, end of therapy (Week 12) and post-
treatment Week 12. 
 
Alpha Fetoprotein, HCV genotype, Hemoglobin A1C, HIV testing. 
Measured by standard assays as part of screening.   Hemoglobin A1C will be repeated at Day 0, 
End of therapy: (Weeks 12), and post-treatment Weeks 12 and 24. 
 
Serum/Urine Pregnancy Test 
Measured by standard assay on screening, on Day 0, and then every 4 weeks while on treatment 
and at every visit post treatment completion for women of childbearing potential. 
 
SOF/VEL/VOX level  
Measured at scheduled study visit continuing through the End of Treatment visit.  Actual date 
and time of PK sample collection and study drug administration will be recorded. 
 
HCV RNA Levels (HCV Viral Loads) 
This will be performed at the following study points: screening; day 0; weeks 1 (optional visit), 
2, 4, 8; end of therapy (week 12); post treatment weeks 4, 12, and 24.  
 
HCV Genotype Assay 
This will be performed at screening if not on file. A result from an outside lab can be used if it 
was completed after documented treatment failure.  
 


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HIV RNA Test  
This will be performed in HIV coinfected individuals at the following study points: screening, 
day 0, weeks 4, 8, 12 and post-treatment week 12. 
 
CD4 Test  
This will be performed in HIV coinfected individuals at the following study points: screening, 
week 12 and post-treatment week 12. 
 
HBV DNA Test 
This will be performed in chronically HBV-infected individuals at the following study points: 
day 0, on-treatment weeks 4, 8, and 12 and post-treatment weeks 4 and 12.  
 
VK/PK Sub Study 
Subjects will have blood drawn at time points 0, 1, 2, 4, 8, 24 and 72 hours after administration 
of drug to assess drug levels and HCV viral load levels.  
 
Research tests 
HCV Virologic Studies 
Full length HCV genome pyro sequencing may be performed using the protocol as described and 
compared for variability of sequences27. 
 
DNA Methylation Studies  
Promoter methylation status for candidate genes or at a whole genome level using methylation–
specific PCR may be performed on tissue samples28. 
 
rs12979860 (IL28B) Genetic Variant 
IL28B genetic variants have been shown to predict HCV treatment induced clearance29. The 
IL28B assay is a real-time PCR assay that utilizes 5-prime nuclease activity of a thermostable 
polymerase and unique primers and SNP-specific probes to determine the genotype. Test results 
will not be used as inclusion or exclusion criteria. 
 
Immune Responses to HCV 
Both humoral and cellular immunity against HCV will be estimated before and during treatment 
to assess the effect of HCV treatment on host immune response against HCV. We may also 
perform multiplex PCR assays to detect ISGs before and during treatment. 
 
HCV Genotypic and Phenotypic Resistance Monitoring 
Serum samples for genotypic and phenotypic monitoring will be collected. Resistance 
monitoring will be completed in all subjects who received study drug and where virologic 
failures as defined.  
 
Subjects who are determined by sequencing and phenotypic analysis to have had mutations 
leading to SOF resistance will be requested to return at 12 week intervals for up to 48 weeks 
after the last dose of study drug to determine the time for the resistant virus to return to 
background levels.  
 
Immunophenotyping for T cells  


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We will study the effectiveness of DAA therapy for normalizing effector T and B cell 
populations. Peripheral or hepatic lymphocytes will be evaluated using flow cytometry for 
different activation and exhaustion markers. Lymphocytes will be stained with conjugated-
antibodies against CD3, CD4, CD8, CD56, CD45RA, CCR7, CD69, CD25, HLA-DR, CD38, 
Ki67, FoxP3, CTLA4, Tim-3, PD-1 and CD57.  The percentage of cells expressing each and 
multiple markers will be determined by flow cytometry (BD FACSAria). Data will be analyzed 
using FlowJo (TreeStar) software. 
 
Determination of HCV specific polyfunctional CD4 and CD8 T cells 
For characterization of HCV specific T cell phenotype and function, peripheral T cells will be 
isolated from PBMCs by Ficoll-paque density gradient separation to be stimulated with pooled 
HCV genotype specific peptides.  For this experiment, we will use HCV 15-18-mer peptides 
with 11 or 12 amino acid overlaps spanning the entire HCV polyprotein (Mimotopes, Peptide 
Array, HCV), reconstituted in 5% sterile dimethylsulphoxide (DMSO), pooled consecutively 
into twenty-one groups and aliquotted until use. The number of HCV-responsive IFN-γ-
producing PBMC will be quantified by standard ELISPOT assay (BD Biosciences), in which 96 
well ELISPOT plates are coated with anti-IFN-γ biotinylated capture antibody and incubated 
overnight at 4°C. Plates will be blocked using lymphocyte medium, and PBMC allowed to rest 
for 6 hours at 37°C.  PBMC will be plated between 250,000- 400,000 cells per well with either 
phytohaemagglutinin (PHA) as a positive control (5 mg/ml), DMSO as a negative control 
(0.05%), or pooled HCV peptides (3 mg/ml/peptide). All cultures will be performed in duplicate. 
After incubating for 12 hours at 37°C, cells will be removed, and plated with streptavidin 
detection antibody, enzyme conjugate, and substrate. The plates will then be air dried in the dark 
overnight, and developed spots will be enumerated using an ELISPOT plate reader.  
 
Further testing of HCV responsive T cells will be conducted by flow cytometric analysis. To 
identify HCV responsive cell populations, carboxyfluoresceinsuccinimidyl ester (CFSE) dilution 
will be utilized. PBMC will be washed and incubated with 2.5mM CFSE (Invitrogen) at 37°C for 
6 minutes, quenched with PBS + 5% fetal calf serum (FCS), and washed three times with 
lymphocyte medium. PBMC will be incubated at 5x106 in 1.2 mL with either pools of 
overlapping HCV peptides spanning the entire proteome (3mg/mL/peptide) or DMSO (1%) and 
NH4OH (0.7mM) as a vehicle control for a total of 48 hours. Brefeldin A and monensin will be 
added at 36 hours to block the Golgi apparatus and allow intracellular cytokine accumulation. 
Following incubation, PBMC will be harvested and stained with LIVE/DEAD Near-IR 
(Invitrogen) for 30 minutes on ice. The percentage of live, CFSE+ cells will be assessed by flow 
cytometry data (FACSAria) and analyzed using FlowJo software (TreeStar) for phenotype and 
function using the antibodies described previously. To assess secreted cytokine production, 100 
μl of supernatant will be collected at 36 hours and frozen at -80°C until used.  Samples will be 
thawed and analyzed for cytokine production using Mesoscale Discovery Human TH1/TH2 10-
plex ultra-sensitive kit (catalog #K15010C-1) according to manufacturer’s protocol. All samples 
will be tested in duplicate. 
 
Determination of T cell defects in liver with mass cytometry using CYTOF 
Liver infiltrating lymphocytes (LIL) will be isolated from liver biopsy specimen and evaluated 
for markers of immune exhaustion and activation on effector and memory T cell subsets.  
Because we are able to obtain limiting number of lymphocytes from liver biopsies (up to 1 
million cells per biopsy) it will be critical to use a technology that maximize the spectrum of T 
cell phenotypes visualized. Although flow cytomtery-based immunophenotyping has been 


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extensively used to connect polyfunctionality and memory phenotypes of T cells, it is limited by 
its inability to discern all distinct cellular phenotypes and relate them to one another without the 
ability to evaluate simultaneously at many phenotypic markers, functional capacity, and antigen 
specificity in individual cells. Flow cytometry is limited by its ability to evaluate 12–18 
parameters because of overlapping excitation and emission spectra between different 
fluorophores. We plan to use a recently developed single-cell mass spectrometric (cytometry by 
time-of-flight or CyTOF) approach in which heavy metal isotopes are used to label antibodies 
and then labeled cells are analyzed by high throughput mass spectrometry to quantify 34 
parameters at the single-cell level, with very little crosstalk between channels. This approach will 
allow us to evaluate more than 30 functional phenotypes represented by distinct CD8+ T cell 
subsets, a nearly combinatorial diversity in the critical liver infiltrating lymphocyte population. 
Phenotypic and functional characterization of liver cells will be done on 10 subjects with no liver 
fibrosis and compared with 10 advanced stage liver fibrosis subjects using mass cytometry 
analysis. We will test the samples for levels and exhaustion status of their HCV specific 
polyfunctional T cells. The University of Maryland School of Medicine Cellular Flow Cytometry 
Core Lab will provide technical assistance in design, data acquisition and analysis of all CyTOF 
experiments on fee-for-service basis. 
 
Flow cytometry for B cell phenotyping 
B cell subpopulations will be phenotyped by flow cytometry at baseline (pre-treatment) and at 
the end of treatment and compared with samples from healthy volunteers as controls, matched 
for age and gender. Multicolor flow cytometry analyses will be performed on cryopreserved 
PBMC. Lymphocyte counts will be determined by a core facility following standard procedures. 
The frequency of each B cell subpopulation will be determined by flow cytometry. The 
following fluorochrome-conjugated monoclonal antibodies will be used in the B cell staining 
strategy: V450 anti-CD3 (BD Biosciences, Carlsabad, CA); PerCP-Cy5.5anti-CD19, PE-Cy7 
anti-CD27 (eBioscience, San Diego, CA); FITC anti-CD21 (Beckman Coulter, Brea, 
CA);allophycocyanin (APC) anti-CD10, APC-H7 anti-CD20 (BD Biosciences, San Jose, CA); 
PE anti-CD95 (BD Biosciences, Carlsabad, CA). Analyses will be performed on a FACSAria 
flow cytometer (BD Biosciences,San Jose, CA) with FlowJo software (TreeStar, Ashland, OR). 
The following B cell subpopulations will be defined: immature/transitional, naïve, resting 
memory, tissue-like memory, plasmablast, and activated memory. 
 
Determination of antigen specificity of B cells 
In previous work, we performed immunophenotyping of B cells, which demonstrated persistence 
of abnormal phenotype of peripheral B cells in chronic HCV infected subjects undergoing 
treatment with 3DAAs. In this regard, there was a higher percentage of TLM B cells present in 
the peripheral blood of patients at the end of antiviral therapy. Using samples stored from 
patients from previous protocols, we will determine the antibody responses to HCV antigens 
during and after treatment in this study. Ruc-antigen fusions, including HCV core, have been 
previously described. We modified the LIPS technology for simultaneously screening protein 
panels arranged in a 96-well microtiter plate format. For these studies, extracts of Ruc fusions 
with proteins from HCV, and Influenza were first produced and stored frozen at−80°C to be used 
to generate an “antigen cell” for each protein. After incubation with serum samples, the serum-
Ruc-antigen mixtures from each well of the microtiter plate were transferred to microtiter filter 
plates containing protein A/G beads. Each 96-well filter plate was then processed in the standard 
LIPS format for washing and measuring light units (LU) using a plate luminometer. Luciferase 
immunoprecipitation assays for profiling and quantification of these Ruc-antigens will be 


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performed in duplicate as previously described at baseline, weeks 4, 12 and 24 using 50 uL of 
cryopreserved serum per assay. Antibody titers, reported in LU, will be reported as the average 
of two independent experiments, after correction for background LU values. Changes in antibody 
titer from baseline and absolute antibody titers will be measured in patients undergoing treatment 
and compared.  
 
RNA Seq Analysis.   
We will perform transcriptional analysis of whole blood (Paxgene) and LILs. Illumina RNAseq 
libraries will be prepared with the TruSeq RNA Sample Prep kit (Illumina). Between first and 
second strand cDNA synthesis, the primers and nucleotides will be removed from the samples 
with NucAway spin columns (Ambion). The second strand will be synthesized with a dNTP mix. 
Adapters containing 6 nucleotide indexes will be ligated to the double-stranded cDNA. After 
adapter ligation, the second strand cDNA will be digested with 2 units of Uracil-N-Glycosylase 
(Applied Biosystems). The DNA will be purified between enzymatic reactions and the size 
selection of the library will be performed with AMPure XT beads (Beckman Coulter Genomics). 
The quantity and size of the libraries were assessed on the LabChip GX (Perkin Elmer) and with 
the Library Quantification Kit for Illumina (Kapa Biosciences)30. Analysis of data, including 
alignment and statistical analysis  
 
6 
HAZARDS/DISCOMFORTS/RISKS 
6.1 
DRUGS 
6.1.1 Sofosbuvir 
SOF is an FDA-approved medication for the treatment of HCV.  As per the package insert, 
common side-effects of SOF therapy include, but are not limited to fatigue, headache, dizziness, 
and nausea. There may be additional side effects of SOF that are not yet known. SOF has been 
administered to over 10,000 subjects in combination with a DAA, Peg-IFN, and/or RBV in 
Gilead’s clinical development programs as of July 2015. No clinical safety issues related to SOF 
have been identified to date.  
 
6.1.2 Velpatasvir 
In early studies done on those with HCV using VEL, participants experienced mild to moderate 
headache (20%), frequent daytime urination (20%), and upper respiratory infection. Other side 
effects seen less frequently were drowsiness, nausea and dizziness, which were seen in the same 
frequency as the group taking a placebo.  In healthy volunteers, the following mild side effects 
were seen in more than two participants:  headache, chest pain, feeling hot, constipation, rash 
with itching, and upper respiratory infection.  One participant had more serious abdominal pain, 
but also had a history of abdominal pain prior to the study.  No significant laboratory changes 
occurred in either group requiring any type of intervention. There may be additional side effects 
of VEL that are not yet known. 


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The safety profile of the regimen of SOF 400 mg and VEL 100 mg administered for 12 weeks 
has been established in approximately 230 subjects enrolled in Phase 2 studies. No clinical safety 
issues specifically related to VEL or SOF+VEL have been identified to date.  
 
6.1.3 Voxilaprevir 
To date, over 2600 subjects have received SOF/VEL+VOX in the Phase 1, 2, and 3 studies and 
there have been no clinical safety issues identified. There is no expectation of significant 
overlapping or new, unexpected toxicities upon coformulation of SOF/VEL with VOX as an 
FDC; data from study GS-US-367-1176 comparing SOF/VEL+VOX with SOF/VEL/VOX were 
consistent with this. However, a potential risk of the study includes the identification of 
previously undetected adverse effects.  
6.1.4 Resistance 
There is a potential risk for subjects to develop multiclass resistance if treatment in this study is 
unsuccessful. However, VOX has the highest reported barrier to resistance among NS3/4A PIs 
and so the anticipated clinical risk of developing drug-resistant mutants with VOX is anticipated 
to be lower than that associated with first and second generation NS3/4A PIs Accordingly, there 
was a lack of any viral breakthrough during therapy with VOX in the 3-day monotherapy study. 
Mutants generated in vitro to be resistant to VOX remain sensitive to SOF and GS-5816, 
supporting the clinical use of VOX in combination with other classes of HCV inhibitors. Lastly, 
this risk is balanced by the high efficacy shown in evaluations of SOF/VEL/VOX in Phase 2 
studies and a very low rate of emergent resistance among subjects who relapsed. 
 Development of such resistance could affect future therapeutic options. However all efforts will 
be made to manage the development of class specific mutations that could lead to cross 
resistance to other NS5B, NS5A, and NS3 inhibitors. 
  
6.2 
PROCEDURES 
6.2.1 Phlebotomy 
The primary risks of phlebotomy include occasional bleeding or bruising of the skin at the site of 
needle puncture, and the sensation of transient lightheadedness or rarely, fainting and infection. 
The amount of blood drawn will be within the limits allowed for adult subjects (450 ml over 6 
weeks).  
6.2.2 Electrocardiogram 
This will be performed at screening for all participants and if medically indicated while on study. 
Subjects may experience itching, redness or irritation at the site of the electrodes. 
6.2.3 Liver Biopsy 
Liver biopsies performed within 36 months prior to Day 0, either the University of Maryland or 
outside institutions, will be acceptable as inclusion criteria based upon the written pathology 
report. 
 


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If a liver biopsy is required for inclusion, it can be performed as part of the screening process. A 
separate procedure consent will be obtained prior to each liver biopsy.  An ultrasound of the liver 
or other imaging will only be performed if medically indicated prior to biopsies. Subjects will be 
admitted and released after the procedure according to the site policies for subjects receiving 
conscious sedation. The adverse effects of liver biopsy include both early and late 
manifestations. All side effects will be recorded and classified as minor and major complications. 
The minor complications include pain and vasovagal reaction. The major complications include 
clinically significant hemorrhage, bowel perforation, infection, pneumothorax, and rarely death. 
All subjects will be followed as outpatients after discharge from the site so as to detect any major 
late manifestations of complications associated with liver biopsy. 
 
 
7 
BENEFITS/COMPENSATION/ALTERNATIVES 
7.1 
BENEFITS 
Subjects may have the benefit of suppression and in some cases eradication of hepatitis C virus. 
Study drugs and study-related routine clinical monitoring tests will be provided free of charge to 
all subjects. The results of any specialized tests performed as part of the study will be made 
available to interested study subjects and their physicians. 
 
In the event of injury occurring as a result of participation in this research study, subjects will be 
advised to seek immediate necessary medical care from their home physician and to contact the 
PI. Short-term medical care will be provided, as needed, for such injury. There is no provision 
for long-term free medical care or for monetary compensation from any injury from the 
physicians conducting this study, from the Institute of Human Virology, University of Maryland 
or Gilead Sciences 
 
7.2 
ALTERNATIVES 
Subjects can receive hepatitis C treatment through their private physician or decide not to be 
treated at this time.   
 
7.3 
COMPENSATION 
Subjects will receive remuneration for the immediate costs associated with their study-related 
expenses like travel expenses, lodging, etc. Subjects will also receive financial compensation for 
the additional time associated with study related procedures such as research blood draws for the 
PK/VK sub study and liver biopsy. Subjects will be financially compensated for the 
inconvenience of the procedures necessary to obtain the samples. The compensation will be as 
follows: 
 Liver Biopsy with research specimens:  $250 cash per biopsy (maximum of 2) 
 VK sub study:  $200 cash after completion of all time points. 
 Scheduled Study Visits: $25 cash or grocery gift card for lab visits and $50 cash or grocery 
gift card for study visits. 
 


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8 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
8.1 
DEFINITIONS 
Adverse Event (AE): An adverse event is any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the research. 
 
Serious Adverse Event (SAE):  
A Serious Adverse Event is an AE that results in one or more of the following outcomes: 
 
 death 
 a life-threatening (i.e., an immediate threat to life) event 
 an inpatient hospitalization or prolongation of an existing hospitalization; 
 a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
 a congenital anomaly/birth defect 
 a medically important event* 
 
* Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed above. 
 
Unexpected Adverse Event:  An AE is unexpected if it is not listed in the Investigator’s 
Brochure or Package Insert (for marketed products) or is not listed at the specificity or severity 
that has been observed.  It is the responsibility of the IND Sponsor to make this determination. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR):  A SUSAR is a Suspected 
Adverse Reaction that is both Serious and Unexpected.   
 
Unanticipated Problem That Is Not An Adverse Event (UPnonAE): An unanticipated 
problem that does not fit the definition of an adverse event, but which may, in the opinion of the 
investigator, involve risk to the subject, affect others in the research study or significantly impact 
the integrity of the research data.  Such events would be considered a non-serious UP.  For 
example, we will report occurrences of breaches of confidentiality, accidental destruction of 
study records, or unaccounted-for study drug. 
 
Protocol Deviation: Any change, divergence, or departure from the IRB approved study 
procedures in a research protocol.  Protocol deviations are designated as serious or non-serious 
and further characterized as: 
 
1. Those that occur because a member of the research team deviates from the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
Non-compliance: The failure to comply with applicable IRB requirements, or regulatory 
requirements for the protection of human subjects. Non-compliance is further characterized as 


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1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the UMD IRB 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 
 
8.2 
INVESTIGATOR ASSESSMENT OF ADVERSE EVENTS 
If a diagnosis is clinically evident, the diagnosis rather than the individual signs and symptoms or 
lab abnormalities will be recorded as the AE. 
 
Laboratory abnormalities that are gradable per the toxicity table will be recorded as AEs or 
SAEs. All other laboratory abnormalities without clinical significance are not recorded as AEs or 
SAEs. Laboratory abnormalities that require medical or surgical intervention or lead to study 
drug interruption, modification or discontinuation must be recorded as an AE or SAE if 
applicable.  
 
Laboratory assessments that are associated with signs and/or symptoms must be recorded as an 
AE or SAE if they meet the definition.  
 
All AEs occurring from the time of ingesting one dose of the medications through the end of 
study will be documented, recorded, and reported.  The Investigator will evaluate all AEs with 
respect to Seriousness (criteria listed above), Severity (intensity or grade), and Causality 
(relationship to study agent and relationship to research) according to the following guidelines.  
8.2.1 Severity Grading 
The investigator will grade the severity of each AE according to the “Division Of AIDS Table 
For Grading The Severity Of Adult And Pediatric Adverse Events” (Version 1.0, December, 
2004; Clarification August 2009), which can be found at: http://rsc.tech-
res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_a
dverse_events.pdf  
  
Please note that changes in hemoglobin will be graded only by the absolute value for this study 
and not by change from baseline. 
Adverse Events not found in the Toxicity Table will be assessed for severity and classified into 
one of the categories below: 
 Grade 1 (Mild): Event requires minimal or no treatment and do not interfere with the 
participant’s daily activities. 
 Grade 2 (Moderate): Event results in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with functioning. 
 Grade 3 (Severe): Event interrupts a subject’s usual daily activity or functioning and may 
require systemic drug therapy or other treatment.  Severe events are usually incapacitating. 
 Grade 4 (Potentially Life threatening):  Events causing inability to perform basic self-
care functions OR Medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death. 


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 Grade 5 (Death) 
8.2.2 Causality  
Causality (likelihood that the event is related to the study agent) will be assessed from 
the time study dosing begins until 30 days following the last dose considering the 
factors listed under the following categories:  
 
Definitely Related 
   
 reasonable temporal relationship 
 follows a known response pattern 
 clear evidence to suggest a causal relationship 
 there is no alternative etiology 
 
Probably Related 
 
 reasonable temporal relationship 
 follows a suspected response pattern (based on similar agents) 
 no evidence of a more likely alternative etiology 
 
Possibly Related 
 
 reasonable temporal relationship 
 little evidence for a more likely alternative etiology 
 
Unlikely Related 
 
 does not have a reasonable temporal relationship  
OR 
 good evidence for a more likely alternative etiology 
 
Not Related 
 
 does not have a temporal relationship 
         
OR 
 definitely due to an alternative etiology 
 
Note:  Other factors (e.g., dechallenge, rechallenge) should also be considered for each 
causality category when appropriate. Causality assessment is based on available 
information at the time of the assessment of the AE. The Investigator may revise the 
causality assessment as additional information becomes available. 
 
8.3 
SAFETY OVERSIGHT 
Safety oversight will be conducted according to the Safety Monitoring Plan (see below) in a 
collaboration between the Principal Investigator (PI), lead Study Coordinator (SC) and the 
independent Medical Monitor.  
 
8.3.1 Medical Monitor 
An independent Medical Monitor (MM) has been appointed for oversight of safety in this 
clinical study. If at any point in the trial halting rules are met, the study team (PI and SC) will 
arrange a teleconference so that the event can be reviewed and the discussion documented. At the 


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end of each MM review meeting, the MM will be asked to provide a formal recommendation as 
to whether or not the protocol should be halted. A written summary of each MM review meeting 
will be provided to the MM and appropriate individuals.  Participants on the MM teleconferences 
will include the MM, the PI and appropriate study team members. 
 
8.4 
SAFETY MONITORING PLAN  
Ongoing Safety Monitoring by the Study Team: Cumulative safety data will be monitored by the 
study team (PI and SC).  Upon recognition of any safety concerns, a teleconference may be held 
with the MM to discuss the concern.  The PI will notify the MM and Gilead Clinical Safety 
Office (CSO) when enrollment begins and will provide verification of safety assessments to the 
MM and CSO. The ISM will review the viral kinetic, pharmacokinetic and resistance data to 
advise regarding continued study enrollment. The study team in collaboration with the study 
sponsor will then make a determination about whether the study enrollment needs to shut down.  
 
Patient safety will be monitored by the PI and study team. Patient clinical data, safety data and 
virologic response will be monitored at weekly (or less frequently, as indicated by protocol 
activity) meetings by the study team and a summary report of these reviews will be retained as 
part of the study records. A complete evaluation of safety and efficacy data will be obtained 
when the first 20 patients complete 12 weeks of therapy. Thereafter, safety and data analysis will 
be performed every 12 weeks through completion of the study. 
Additionally, the PI will be responsible for submitting the IRB Continuing Review package and 
will provide the necessary safety data for the FDA IND Annual Report. 
 
8.5 
SPECIFIC STUDY  HALTING CRITERIA  
8.5.1 Criteria to Pause Enrollment 
 Study will be paused and the MM will be asked to review the data if 1: 3 participants 
experience virologic or therapeutic treatment failure while receiving treatment (see Dose 
Modification 3.4.1 and Treatment Failure Sections3.4.2) 
 
Dosing will be discontinued if 3 or more participants develop a similar related Grade 4 
toxicity (excluding neutropenia, anemia, anorexia, weight loss and ALT and AST 
elevations). Further dosing will require review and approval after discussion with the 
MM.  Grade 4 toxicities that result from patient non-compliance with medications for 
unrelated events will not be considered toward discontinuation.   
 Enrollment will also be halted if the PI decides to stop or cancel the study or if the IRB or 
the FDA requests that the study be stopped.  
 
8.6 
INVESTIGATOR REPORTING RESPONSIBILITIES  
8.6.1 Adverse Events 
Line listings, frequency tables, and other summary AE data will be submitted to the IND 
Sponsor when needed for periodic safety assessments, review of IND annual reports, review of 
IND safety reports, and preparation of final study reports. 


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8.6.2 Serious Adverse Events 
Any SAE will be reported to the IRB per institutional guidelines. SAEs (regardless of 
relationship) must be reported to Gilead Drug Safety & Public Health (DSPH) Office within 15 
calendar days of first becoming aware of the event. Reporting any unexpected fatal or life-
threatening suspected adverse reactions to the Division of Antiviral Agents at the FDA no later 
than 7 calendar days after initial receipt of the information. Safety reporting to the FDA will be 
done within the reporting requirement under 21 CFR 312.32 
8.6.3 Gilead Safety Data Reporting 
The Gilead DSPH will be notified via email (Safety_FC@gilead.com) of any potential safety 
issues or any protocol amendments or changes to the informed con sent form arising from a 
safety concern associated with any Gilead product within fifteen calendar days of first becoming 
aware of such event. Except for periodic safety reports, copies of all reports submitted to 
government agencies that are related to the study, as well as any correspondence with such 
authorities will be provided to Gilead.  
 
Upon completion of the study, a listing of all safety information that has been sent to Gilead 
during the study will be sent to Gilead at standards.&collaborations@DSPH.com. At a minimum 
the listing must contain protocol number, patient ID number, case reference number, Gilead 
product and event term   
 
8.7 
DOCUMENTING AND RECORDING ADVERSE EVENTS  
Adverse events will be collected from the time the subject signs the informed consent document 
through the end of the study follow-up period.  
At each contact with the subject as outlined above, information regarding AEs will be elicited by 
appropriate questioning and examinations and will be: 
 immediately documented in the subject’s medical record/source document. Source 
documents will include: case report forms (CRFs), progress notes, laboratory reports, 
consult notes, phone call summaries, survey tools and data collection tools. Source 
documents will be reviewed in a timely manner by the research team. The onset date, the 
end date, the severity of each reportable event, and the Investigator’s judgment of the 
AEs relationship to SOF, VEL and VOX will also be recorded. 
8.8 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Adverse events that occur following initiation of investigational agent on day 0 will be followed 
at a minimum until a final outcome is known (resolution of the AE or a return to baseline 
laboratory value) or until the end of the study follow-up period (Week 60).  
SAEs that occur after the study follow-up period that are reported to and are assessed by the 
Investigator to be possibly, probably, or definitely related must be reported to the CSO and MM, 
as described above. 
 


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8.9 
REPORTING PROCEDURES TO THE IRB  
8.9.1 Expedited Reporting to the UMD IRB 
 
Any serious and non-serious events, deaths, serious deviations, and serious or continuing non-
compliance experienced by a subject or other individual which in the opinion of the primary 
investigator is unexpected and at least probably related to the Human Research procedures and 
suggests that the research places subjects or others at a greater risk of harm than was previously 
known or recognized will be reported within 7 calendar days of investigator awareness.  .  
 
8.9.2 Waiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and Deaths 
to the UMD IRB 
Anticipated deviations in the conduct of the protocol will not be reported to the IRB unless they 
occur at a rate greater than anticipated by the study team. Expected adverse events will not be 
reported to the IRB unless they occur at a rate greater than that known to occur in Hepatitis C. If 
the rate of these events exceeds the rate expected by the study team, the events will be classified 
and reported as though they are unanticipated problems. Deaths related to the natural history of 
hepatitis C will be reported at the time of continuing review.  
8.9.3 Annual Reporting to the IRB 
The following items will be reported to the IRB in summary at the time of continuing Review: 
 Serious and non-serious unanticipated problems  
 Expected serious adverse events that are possibly, probably, or definitely related to the 
research 
 Serious adverse events that are not related to the research 
 All adverse events except expected AEs and deaths granted a waiver of reporting.  
 Serious, continuing, and minor non-compliance 
 Serious and Non-serious protocol deviations which in the opinion of the Investigator 
should be reported 
 Any trends or events which in the opinion of the Investigator should be reported 
 
 
8.6.4  Reporting a Pregnancy 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be 
SAEs.  Pertinent obstetrical information of all pregnancies will be reported to the CSO via fax or 
email within 3 business days from site awareness of the pregnancy.  Study drug must be stopped 
immediately.  The participant will be advised to notify her obstetrician of study agent exposure.   
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the 
pregnancy, presence of absence of birth defects, congenital abnormalities, or other 
complications) will be reported to the MM and CSO within 3 business days of the site’s 
awareness on a protocol-specified form.   
 


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9 
DATA HANDLING AND RECORD KEEPING 
9.1 
DATA HANDLING 
All research data and results will be recorded using data collection forms. Source documents will 
support the data collected and will include, but not limited to; clinical findings and observations, 
laboratory and test data, hospital medical records, physician or office charts, physician or nursing 
notes, recorded data from automated instruments, x-rays, etc. Research data will be entered into a 
secure electronic database  
 
9.2 
STUDY RECORD RETENTION 
The investigator is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline.  All essential documentation for all study subjects is to be 
maintained by the investigators in a secure storage facility for a minimum of 5 years.  The FDA 
requires study records to be retained for up to 2 years after marketing approval or disapproval 
(21 CFR 312.62), or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational agent for a specific indication. These records are 
also to be maintained in compliance with IRB/EC, state, and federal medical records retention 
requirements, whichever is longest. All stored records are to be kept confidential to the extent 
required by federal, state, and local law. 
 
 
 


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