Conditions: Chronic Hepatitis C
Keywords: Oral Therapy Liver Biopsy Chronic Hepatitis C
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 72
Healthy volunteers: no

Brief summary:
Background:

\- Chronic hepatitis C is a serious liver disease. Current treatments have side effects. New drugs have been developed, but they work better in some people than others. Researchers want to learn why.

Objective:

\- To learn why new hepatitis C drugs sometimes do not work. Also, to learn if these drugs are safe and how well they work in people with different virus strains.

Eligibility:

\- Adults age 18 and older who are infected with hepatitis C virus genotypes 1-4 and who have either never been treated or treated previously with an interferon regimen (with or without ribavirin) that failed to clear the virus.

Design:

* Participants will be screened with medical history and physical exam. They will have blood and urine tests and complete questionnaires.
* Participants will have a Fibroscan, an ultrasound that measures liver stiffness and other liver scans. They will have an electrocardiogram.
* Eligible participants will have a liver biopsy.
* Participants will be admitted to the Clinical Center. They will have a physical exam and blood tests, and complete questionnaires.
* They will take the first study drug dose as a tablet taken once daily.
* Participants will take the drug at home for 12 weeks.
* Participants will have 6 study visits. They will have blood and vital signs taken, and complete questionnaires.
* At week 4, participants will have another liver biopsy.
* After their last drug dose, participants will have 5 follow-up visits. They will have blood and vital signs taken, and complete questionnaires. They will discuss their medications and side effects. They may have another Fibroscan.

Detailed description:
Up to 140 patients with chronic hepatitis C, genotypes 1-4, who were never treated or previously treated but failed a course of therapy with any interferon and ribavirin combination regimen will be eligible to be enrolled into this pilot study to evaluate the combination of sofosbuvir and GS-5816 as a fixed dose tablet to improve response to antiviral therapy. To enrich the study population with subjects with a greater likelihood of virological relapse after stopping therapy, we plan to enroll a minimum of 60% treatment-experienced subjects and 50% with cirrhosis. These two drugs inhibit key enzymes that are necessary for viral replication. Sofosbuvir, an NS5B polymerase inhibitor is already approved for use in combination with interferon and ribavirin for the treatment of HCV genotype 1 infection. GS-5816 is an NS5A replication complex inhibitor with potent activity against most strains of hepatitis C virus. Combining these two agents into a single pill should improve patient compliance and improve tolerability because interferon and ribavirin will not be part of the regimen. After medical evaluation and liver biopsy, patients will receive combination therapy with sofosbuvir and GS-5816 one pill a day for 12 weeks. The baseline liver biopsy is necessary to assess the amount of liver damage caused by the HCV and to measure expression of genes associated with clearance of HCV. Blood samples will be collected to monitor safety and response to therapy and for research purposes. HCV RNA levels will be monitored frequently for the initial 4 weeks and then at monthly intervals for the remaining 8 weeks of antiviral therapy. All subjects will undergo a second liver biopsy, 4 weeks after starting therapy. The second biopsy is being performed for research purposes so investigators can determine specifically which liver genes are associated with failure of therapy (and response to therapy). Subjects who refuse the second liver biopsy will continue to receive SOF/GS-5816 treatment for the planned 12 week duration Patients in whom serum HCV RNA is greater than or equal to lower limit of quantification (LLOQ) after 2 consecutive HCV RNA \< LLOQ or who have a confirmed \> 1 log10 increase from nadir will discontinue therapy (because continuing therapy is considered futile i.e. it is unlikely to work). The major endpoints will be changes in interferon stimulated gene and protein expression in the liver and changes in HCV RNA levels in liver and serum between baseline and 4 weeks and rates of sustained virologic response at post-treatment week 12. Secondary endpoints will be safety and sustained virologic response at post-treatment week 24 weeks.

Arms:
arm 1: Combination of sofosbuvir and GS-5816 agent into a single pill will be used.

Interventions: intervention 1: Sofosbuvir intervention 2: GS-5816
Intervention descriptions: intervention 1: An NS5B polymerase inhibitor that is already approved for use in combination with interferon and ribavirin for the treatment of HCV genotype 1 infection intervention 2: An NS5A replication complex inhibitor with potent activity against most strains of hepatitis C virus.

Protocol document:
Prot_SAP_001.pdf: 
6/9/15 Marked version 
CLINICAL RESEARCH PROTOCOL 
 
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES 
 
DATE: November 25, 2019   
CLINICAL PROTOCOL NO.15-DK-0143  
IND NO:126497 
 
 
  
IND Name: Sofosbuvir/GS-5816 
IND HOLDER: NIDDK 
TITLE:  Investigation Of Viral Kinetics, Interferon Stimulated Genes (ISGs) and 
mirRNA Among Subjects Infected With Different Hepatitis C Virus Genotypes During 
Therapy With Sofosbuvir and GS-5816 
SHORT TITLE: Once daily all oral therapy for chronic hepatitis C  
IDENTIFYING WORDS: Sofosbuvir, GS-5816, Direct Acting Antivirals, Chronic 
Hepatitis C, Treatment naive, Relapsers, Cirrhosis, Liver Biopsy.  
PRINCIPAL INVESTIGATOR: Marc Ghany, M.D., MHSc, Liver Diseases Branch 
(LDB), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)* 
LEAD ASSOCIATE INVESTIGATOR: T. Jake Liang, M.D., Chief, Liver Diseases 
Branch (LDB), National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK)* 
ASSOCIATE SENIOR INVESTIGATORS:   
Barbara Rehermann, M.D., Senior Investigator, LDB, NIDDK 
Elizabeth Wright, Ph.D. OD, NIDDK 
David Kleiner, M.D., PhD., Laboratory of Clinical Pathology, NCI 
Robert Shamburek, M.D., Lipid Section, Translational Medicine Branch, NHLBI  
ASSOCIATE STAFF INVESTIGATORS: 
Elenita Rivera, R.N., Research Nurse, LDB, NIDDK 
*Investigators with this designation are authorized to obtain informed consent for this protocol 
ESTIMATED DURATION OF STUDY: 3 Years 
NUMBER AND TYPE OF PATIENTS: 140 patients with chronic hepatitis C, ages 
above 18 years, both male and female 
SUBJECTS OF STUDY:     


 
2
Number of patients: 140     
Sex:  Male & Female       
 
 Age Range: Above 
18 years 
Volunteers: None 
PROJECT USES IONIZING RADIATION:  Yes, for medical indications only. 
PROJECT USES "DURABLE POWER OF ATTORNEY":  No 
OFF-SITE PROJECT: No       MULTI-INSTITUTIONAL PROJECT:   No 
 
 


 
3
Table of Contents 
Précis ............................................................................................................................................. 6 
A. Background: Chronic Hepatitis C and Current Therapy: ........................................ 7 
B. Hypothesis and Aims: .......................................................................................................... 9 
B.1 Hypothesis: ......................................................................................................................................9 
B.2 Aims: ..................................................................................................................................................9 
C. Trial design ............................................................................................................................. 9 
D. Summary Of Investigational Agents ........................................................................... 11 
D.1.Sofosbuvir (SOF) (formerly GS-7977) ................................................................................ 11 
D.2. GS-5816 ........................................................................................................................................ 11 
D.3. SOF/GS-5816 Fixed Dose Combination (FDC) ................................................................ 11 
E. Protocol ................................................................................................................................. 11 
F. Study Population ................................................................................................................ 12 
F.1. Inclusion Criteria ....................................................................................................................... 12 
F.2. Exclusion Criteria ...................................................................................................................... 14 
G. Treatments........................................................................................................................... 16 
G.1 Description and Handling of SOF/GS-5816 FDC ............................................................. 16 
G.1.1 Formulation .......................................................................................................................................... 16 
G.1.2 Packaging and Labeling ................................................................................................................... 16 
Sofosbuvir/GS-5816 FDC and placebo-to-match tablets are packaged in white, high-
density polyethylene bottles. Each bottle contains 28 tablets and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. .................................................................... 16 
G.1.3 Storage and Handling ....................................................................................................................... 16 
G.1.4 Stability ................................................................................................................................................... 16 
G.1.5 Dosage and Administration of SOF/GS-5816 FDC ............................................................... 17 
G.2.Study Drug Adherence and Drug Accountability ........................................................... 17 
G.3.Concomitant Medications ....................................................................................................... 17 
H. Study Procedures .............................................................................................................. 18 
H.1 Consent Process ......................................................................................................................... 18 
H.1.2 Short Form Consent .......................................................................................................................... 19 
H.2 Investigator Responsibilities ................................................................................................ 19 
H.3. Pre-treatment Phase: (Screening)...................................................................................... 20 
H.3.1 Outpatient Screening Visit: ............................................................................................................ 20 
H.3.2 Ancillary Study procedure ............................................................................................................. 20 
H.4 Completion of Screening / Admission for Pre-Treatment Liver Biopsy / Start of 
Treatment: ........................................................................................................................................... 21 
H.5 Monitoring .................................................................................................................................... 22 
H.5.1 Weeks 1, 2 & 3,  ( 3 days): ............................................................................................................ 22 


 
4
H.5.2. Week 4: ( 5 days) ............................................................................................................................ 22 
H.5.3 Week 8 ( 3 days): ............................................................................................................................. 23 
H.5.4 End of Treatment (Week 12  3 days)) .................................................................................... 23 
H.5.5 Ancillary Study Procedure ............................................................................................................. 24 
H.6  Post-treatment weeks 2, 4, 8 and 12 ( 5 days) ............................................................ 24 
H.7 Final study visit week 24 post-treatment ( 5 days) .................................................... 24 
I. Discontinuation of Subjects from Treatment ........................................................... 25 
I.1 Virologic Response-Based Treatment Stopping Criteria: ............................................ 25 
I.2 Other Stopping Criteria:............................................................................................................ 25 
I.3 Early Termination (ET) Visit ................................................................................................... 26 
J. Unscheduled Visits ............................................................................................................. 26 
K. Procedures ........................................................................................................................... 27 
K.1 Assays for Monitoring HCV RNA levels and Genotype/Subtype determination: 27 
K.2 Management of non-response ............................................................................................... 27 
K.3 Management of virological breakthrough ........................................................................ 27 
K.4 Medical History ........................................................................................................................... 27 
K.5 Complete Physical Examination ........................................................................................... 27 
K.6 Vital Signs ..................................................................................................................................... 27 
K.7 Creatinine Clearance ................................................................................................................ 28 
K.8 Body Mass Index (BMI) ............................................................................................................ 28 
K.9 12-Lead ECGs ............................................................................................................................... 28 
K.10 Viral RNA Sequencing / Phenotyping Sample .............................................................. 28 
K.11 IL28B Testing ............................................................................................................................ 28 
K.12 Pregnancy Testing .................................................................................................................. 28 
K.13 Health Related Quality of Life Surveys ............................................................................ 29 
K.14 Nuclear Medicine Resonance Lipoprotein Profile ...................................................... 29 
L.   Hazards and Discomforts .............................................................................................. 29 
L.1 The risks and discomforts of frequent phlebotomy:..................................................... 29 
L.2 The risks and discomforts of HIV testing. ......................................................................... 29 
L.3 The risks and discomfort of percutaneous and transjugular liver biopsy. .......... 30 
L.4 The risks and hazards of sofosbuvir therapy. ................................................................. 30 
L.5 The risks and hazards of GS-5816 therapy ....................................................................... 32 
L.5.1 Adverse Events  ............................................................................................................................... 32 
L.5.2 Death ........................................................................................................................................................ 33 
L.5.3 Serious Adverse Events .................................................................................................................... 33 
L.5.4 The risks and hazards of sofosbuvir and GS-5816 combination therapy safety 
conclusions ....................................................................................................................................................... 34 
L.6 The risks and hazards of lymphaphoresis ........................................................................ 35 
M. Safety Assessments .......................................................................................................... 35 
N. Toxicity Management ....................................................................................................... 36 


 
5
O. Adverse Event Reporting ................................................................................................ 36 
O.1 Reporting to the IRB ................................................................................................................. 36 
O.2. Reporting to the FDA ............................................................................................................... 37 
O.3  Reporting to Gilead .................................................................................................................. 37 
P. Protocol Monitoring Plan................................................................................................ 38 
Q. Viral Resistance.................................................................................................................. 38 
R. Efficacy Assessments ........................................................................................................ 39 
R.1 Primary Efficacy Assessment................................................................................................. 39 
R.2 Secondary Efficacy Assessment ............................................................................................ 39 
R.3 Other Assessments (Endpoint Definitions): .................................................................... 39 
S. Statistical analysis ............................................................................................................. 40 
S.1 Planned Interim Analysis for Futility: ................................................................................ 40 
S.2 Demographics and Baseline Characteristics .................................................................... 40 
S.3 Analysis plan ................................................................................................................................ 40 
S.4 Analysis methodology ............................................................................................................... 41 
T. Enrollment of Children, Women and Minority Individuals ................................ 41 
U. Additional Potentially Vulnerable Subject Populations ...................................... 42 
V. Research Use, Storage and Disposition of Human Samples and Data: ........... 42 
W. Protocol Modifications ................................................................................................... 43 
References: ............................................................................................................................... 44 
Appendix I ................................................................................................................................. 47 
Ancillary Study I ................................................................................................................................. 47 
Ancillary Study II ............................................................................................................................... 50 
Appendix II ........................................................................................................................................... 52 
Appendix III ......................................................................................................................................... 52 
Appendix IV ......................................................................................................................................... 52 
 
 
 


 
6
Précis 
• Up to 140 patients with chronic hepatitis C, genotypes 1-4, who were never treated or 
previously treated but failed a course of therapy with any interferon and ribavirin 
combination regimen will be eligible to be enrolled into this pilot study to evaluate 
the combination of sofosbuvir and GS-5816 as a fixed dose tablet to improve 
response to antiviral therapy. To enrich the study population with subjects with a 
greater likelihood of virological relapse after stopping therapy, we plan to enroll a 
minimum of 60% treatment-experienced subjects and 50% with cirrhosis. These two 
drugs inhibit key enzymes that are necessary for viral replication. Sofosbuvir, an 
NS5B polymerase inhibitor is already approved for use in combination with 
interferon and ribavirin for the treatment of HCV genotype 1 infection. GS-5816 is an 
NS5A replication complex inhibitor with potent activity against most strains of 
hepatitis C virus. Combining these two agents into a single pill should improve 
patient compliance and improve tolerability because interferon and ribavirin will not 
be part of the regimen. After medical evaluation and liver biopsy, patients will 
receive combination therapy with sofosbuvir and GS-5816 one pill a day for 12 
weeks. The baseline liver biopsy is necessary to assess the amount of liver damage 
caused by the HCV and to measure expression of genes associated with clearance of 
HCV. Blood samples will be collected to monitor safety and response to therapy and 
for research purposes. HCV RNA levels will be monitored frequently for the initial 4 
weeks and then at monthly intervals for the remaining 8 weeks of antiviral therapy. 
All subjects will undergo a second liver biopsy, 4 weeks after starting therapy. The 
second biopsy is being performed for research purposes so investigators can 
determine specifically which liver genes are associated with failure of therapy (and 
response to therapy). Subjects who refuse the second liver biopsy will continue to 
receive SOF/GS-5816 treatment for the planned 12 week duration Patients in whom 
serum HCV RNA is ≥ lower limit of quantification (LLOQ) after 2 consecutive HCV 
RNA < LLOQ or who have a confirmed > 1 log10 increase from nadir will 
discontinue therapy (because continuing therapy is considered futile i.e. it is unlikely 
to work). The major endpoints will be changes in interferon stimulated gene and 
protein expression in the liver and changes in HCV RNA levels in liver and serum 
between baseline and 4 weeks and rates of sustained virologic response at post-
treatment week 12. Secondary endpoints will be safety and sustained virologic 
response at post-treatment week 24 weeks. (Word count =370) 
 
 
 


 
7
A. Background: Chronic Hepatitis C and Current Therapy: 
Chronic hepatitis C (CHC) is a global health problem. The World Health Organization 
(WHO) estimates that up to 3% of the world’s population is infected with HCV 
amounting to an estimated 170 million to 200 million chronic HCV infections 
worldwide.1, 2 The prevalence varies with geographic region, with the highest regions 
being Southeast Asia and Africa.3-5 The Centers for Disease Control estimates that there 
are approximately 3.2 million people chronically infected with hepatitis C virus (HCV) in 
the United States.6 CHC is a major cause of chronic liver disease, cirrhosis and 
hepatocellular carcinoma. A recent analysis suggested that the number of cases of 
cirrhosis in persons who were infected in the 70s and 80s will not peak until 2020;7 
without therapy, a significant proportion of these persons will develop complications of 
their disease. In 2007 alone, it is estimated that over 15,000 people in the United States 
died from HCV-related complications. HCV now surpasses human immunodeficiency 
virus (HIV) as a cause of death in the United States.8 
The recommended therapy for chronic hepatitis C genotype 1 infection used to be a 48- 
week course of the combination of peginterferon (1.5 µg/kg [PegIntron] or 180 µg 
[Pegasys] once weekly) and ribavirin (600 to 1200 mg daily based upon body weight).9 
Recommendations changed in 2011 when two new agents, boceprevir and telaprevir, 
were approved for use in CHC genotype 1infection.10, 11 Both agents are NS3/NS4A 
protease inhibitors specific for HCV genotype 1 and must be used in combination with 
peginterferon and ribavirin. Both agents were shown to significantly increase the SVR 
rate compared to standard peginterferon and ribavirin therapy.  Thus, in HCV genotype 1 
patients, the SVR rates were increased from 40-45% with standard combination therapy 
to 69-75% with triple therapy.11, 12 Boceprevir and telaprevir were associated with 
additional morbidity and mortality, above and beyond that which results from 
peginterferon and ribavirin. Skin rash, anemia and ano-rectal discomfort were dose-
limiting side effects of telaprevir,11 whereas anemia and dysgeusia were the major 
additional adverse events associated with boceprevir.12 Response rates varied greatly by 
virologic, host and disease characteristics, such as viral level (higher rates with lower 
baseline HCV RNA concentrations), race (lower in African Americans, higher in Asians), 
and disease severity (lower in patients with cirrhosis or advanced fibrosis).11, 12 Treatment 
recommendations for HCV genotype 1 were updated again in 2013, with the approval of 
another once daily HCV protease inhibitor simiprevir and a NS5B polymerase inhibitor, 
sofosbuvir, both used on combination with peginterferon and ribavirin for 24 and 12 
weeks, respectively.13-15 These new regimens represented substantial improvement over 
existing regimens in that they were of shorter duration, much simpler to administer, 
associated with less side effects and more efficacious.13-15 
For patients with genotype 2 and 3, the recommended therapy is a 12 to 24 week course 
of the combination of sofosbuvir and weight-based ribavirin.16 The optimal regimen for 
patients with genotypes 4, 5 and 6 is yet to be defined.16  
The development of an IFN-free regimen for the treatment of chronic HCV infection has 
the potential to have a major impact on the global incidence, prevalence and burden of 
disease due to HCV infections. New treatment options are especially crucial in patient 
populations for whom treatment with peginterferon is not possible, undesired, or without 


 
8
sufficient efficacy. These interferon free treatments hold the promise for simpler 
regimens with short duration of therapy, minimal side effects and high efficacy. One such 
regimen is the combination of sofosbuvir and GS-5816. A 12 week course of this 
regimen is associated with sustained viral eradication in ≥90% of subjects with genotypes 
1-6 infection.17 Other interferon free regimens are being developed and evaluated but 
none have such a broad activity against all the major HCV genotypes. 
Results of the phase 3 trial evaluating the efficacy of sofosbuvir and ribavirin for 
genotypes 2 and 3 chronic HCV infection noted a marked difference in response rates 
between genotypes 2 and 3-genotype 2 subjects had an SVR rate of 97% compared to 
56% for genotype 3 subjects.13 The primary reason for treatment failure among HCV 
genotype 3 subjects was virological relapse. The cause for this high relapse rate is 
unknown. In addition, the usual cause for failure of interferon-free regimens in other viral 
genotypes, although much lower, is predominantly virological relapse. We hypothesize 
that a strong innate immune response in addition to the potency of the antiviral agents are 
necessary to achieve an SVR during therapy with direct acting antiviral agents and that 
the innate immune response is reduced among genotype 3 subjects compared to genotype 
2 subjects and among relapsers of other genotypes in general. 
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate diverse 
biological processes primarily through control of expression of cellular messenger RNAs 
(mRNAs).18  MiRNAs target and regulate essentially all biological processes and cell 
types, including those in the liver. miRNAs have been detected in serum and plasma, 
called circulating miRNAs and distinct patterns have been described among the healthy 
and diseased state.19, 20 Thus, they may have value as potential biomarkers. For example, 
circulating mir-122 and mir-155 were identified as inflammatory markers in different 
forms of liver injury.21-23 Furthermore, mir-122 has been shown to be important for HCV 
replication.24, 25 Indeed, an inhibitor of mir-122 is in clinical trials as a therapeutic 
approach to treating chronic HCV infection.26 However, little is known whether 
mirRNAs may play a role in eradication of HCV or could be used as an early predictor of 
response to therapy.  
The primary focus of this proposal will be to evaluate the clinical safety and efficacy of 
sofosbuvir and GS-5816 among HCV genotypes 1-4 (since both sofosbuvir and GS-
5816) have pangenotypic activity) and to understand the mechanisms of virological 
relapse; specifically the role of the antiviral innate immune system (induction of antiviral 
interferon-stimulated genes and natural killer cells) and miRNA in clearance of HCV, 
particularly between HCV genotypes 2 and 3. We propose to study both the role of 
endogenous ISG gene expression and miRNA and to correlate it with HCV clearance. 
Untreated and previously treated subjects, with HCV genotypes 1-4 who have failed to 
achieve SVR will be assessed for IL28b genotype, ISG gene expression before and 
during therapy, viral kinetic response to treatment and circulating and intrahepatic 
mirRNA levels during treatment with an interferon-free regimen consisting of sofosbuvir 
and GS-5816. The study population will be enriched with treatment-experienced subjects 
with cirrhosis for two reasons: first this is a patient population of highest urgency to be 
treated because of an increased risk of progressive liver disease and complications from 
HCV and second to increase the chance of failure with sofosbuvir and GS-5816 to allow 
for accrual of relapse patients. 


 
9
B. Hypothesis and Aims:   
B.1 Hypothesis: 
• Phase 1 viral kinetics will vary among different HCV genotypes and will be 
predictive of relapse following 12 weeks of therapy. 
• Relapse is related to: 
i) 
differences in early viral kinetics 
ii) 
differences in innate immune response 
iii) 
different intrahepatic and circulating miRNA profiles 
iv) 
presence of hepatic steatosis and insulin resistance 
 
B.2 Aims: 
1) Assess safety and efficacy of sofosbuvir and GS-5816 among subjects with HCV 
genotypes 1-4 
2) Assess innate immune response, mirRNA and early viral kinetics in patients with 
chronic hepatitis C infected with HCV genotypes 1-4. 
3) Correlate early viral kinetics, SVR and relapse with degree of hepatic steatosis 
and presence of insulin resistance. 
 
C. Trial design  
 


 
10
 
SafetyAndEfficacyOFSofosbuvirAndGS-5816
FixedDoseCombina onInHCVGenotypes1-4
GTs1-4never
andpreviously
treated
Sofosbuvir400mg/GS-5816100mg
12weeks
0
Gt1n=40
Gt2n=40
Gt3n=40
Gt4n=20
4
LiverBiopsy
EndofTreatment
Post-treatment
24weeks
SVR12
-12
LiverBiopsy


 
11
 
D. Summary Of Investigational Agents  
 
D.1.Sofosbuvir (SOF) (formerly GS-7977) 
D.2. GS-5816  
D.3. SOF/GS-5816 Fixed Dose Combination (FDC) 
Please refer to the Investigator’s Brochures (IB) for information on SOF and GS-5816 
including: 
• In Vitro Anti-HCV Activity 
• Nonclinical Pharmacokinetics and In Vitro Metabolism 
• Nonclinical Pharmacology and Toxicology 
 
Please refer to Appendix II for Clinical Experience with SOF and GS-5816. 
E. Protocol 
Up to 140 patients with chronic hepatitis C, genotypes 1-4, who were never treated or 
previously treated but failed a course of therapy with any interferon and ribavirin 
combination regimen will be eligible to be enrolled into this pilot study to evaluate the 
combination of sofosbuvir and GS-5816 as a fixed dose tablet to improve response to 
antiviral therapy. This regimen was approved by the Food and Drug Administration in 
May 2016 for the treatment of adults with genotype 1-6 chronic hepatitis C virus 
infection. So it is possible to obtain the same treatment outside of this protocol and 
participation in this study is now an alternative to standard clinical care. To enrich the 
study population with subjects with a greater likelihood of virological relapse after 
stopping therapy, we plan to enroll a minimum of 60% treatment-experienced subjects 
and 50% with cirrhosis. These two drugs inhibit key enzymes that are necessary for viral 
replication. Sofosbuvir, an NS5B polymerase inhibitor is already approved for use in 
combination with interferon and ribavirin for the treatment of HCV genotype 1 infection. 
GS-5816 is an NS5A replication complex inhibitor with potent activity against most 
strains of hepatitis C virus. Combining these two agents into a single pill should improve 
patient compliance and improve tolerability because interferon and ribavirin will not be 
part of the regimen. After medical evaluation and liver biopsy, patients will receive 
combination therapy with sofosbuvir and GS-5816 one pill a day for 12 weeks. The 
baseline liver biopsy is necessary to assess the amount of liver damage caused by the 
HCV and to measure expression of genes associated with clearance of HCV. Blood 
samples will be collected to monitor safety and response to therapy and for research 


 
12
purposes. HCV RNA levels will be monitored frequently for the initial 4 weeks and then 
at monthly intervals for the remaining 8 weeks of antiviral therapy. All subjects will 
undergo a second liver biopsy, 4 weeks after starting therapy. The second biopsy is being 
performed for research purposes so investigators can determine specifically which liver 
genes are associated with failure of therapy (and response to therapy). Subjects who 
refuse the second liver biopsy will continue to receive SOF/GS-5816 treatment for the 
planned 12 week duration. Patients in whom serum HCV RNA is ≥ lower limit of 
quantification (LLOQ) after 2 consecutive HCV RNA < LLOQ or who have a confirmed 
> 1 log10 increase from nadir will discontinue therapy (because continuing therapy is 
considered futile i.e. it is unlikely to work).  
The major endpoints will be changes in interferon stimulated gene and protein expression 
in the liver and changes in HCV RNA levels in liver and serum between baseline and 4 
weeks and rates of sustained virologic response at post-treatment week 12. Secondary 
endpoints will be safety and sustained virologic response at post-treatment week 24 
weeks. 
F. Study Population 
140 subjects will be enrolled in this study. (40 genotype 1, 40 genotype 2, 40 genotype 3 
and 20 genotype 4-treatment naïve or experienced). 
F.1. Inclusion Criteria  
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. 
1) Willing and able to provide written informed consent. 
2) Male or female, age  18 years. 
3) Body mass index (BMI)  18 kg/m2. 
4) HCV RNA  104 IU/mL at Screening 
5) HCV genotypes 1a, 1b, 2, 3 or 4 at screening  
6) Confirmation of chronic HCV infection documented by either: 
a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV 
genotyping test at least 6 months prior to the Baseline/Day 1 visit, or 
b) A liver biopsy performed within 12 weeks prior to the Baseline/Day 1 visit with 
evidence of chronic HCV infection. A prior biopsy would be acceptable if 
performed with 12 weeks AND liver tissue stored in RNALater was available. 
7) Screening ECG without clinically significant abnormalities. 


 
13
8) Subjects must have the following laboratory parameters at screening:  
a) ALT  10  the upper limit of normal  (ULN) 
b) AST  10  ULN 
c) Direct bilirubin  1.5 ULN 
d) Platelets  > 70,000 
e) HbA1c  8.5%  
f) eGFR  60 mL /min, as calculated by the CKD-EPI equation.  
g) Hemoglobin    10g/dL. 
h) Albumin  3g/dL  
i) INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an 
anticoagulant regimen affecting INR. 
9) A female subject is eligible to enter the study if it is confirmed that she is: 
a) Not pregnant or nursing 
b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have 
both ovaries removed or medically documented ovarian failure, or are 
postmenopausal - women > 50 years of age with cessation (for 12 months) of 
previously occurring menses),  
OR 
c) Of childbearing potential (i.e., women who have not had a hysterectomy, have not 
had both ovaries removed, and have not had medically documented ovarian 
failure). Women ≤ 50 years of age with amenorrhea will be considered to be of 
childbearing potential. These women must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior 
to randomization. They must also agree to one of the following from 3 weeks 
prior to Baseline/Day 1 until 90 days after last dose of study drug:  
i) Complete abstinence from intercourse. Periodic abstinence from intercourse 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not 
permitted. 
ii) Consistent and correct use of 1 of the following methods of birth control listed 
below in addition to a male partner who correctly uses a condom from the date 
of Screening until 90 days after last dose of study drug:   
(1) intrauterine device (IUD) with a failure rate of < 1% per year 
(2) female barrier method: cervical cap or diaphragm with spermicidal agent 


 
14
(3) tubal sterilization 
(4) vasectomy in male partner 
(5) hormone-containing contraceptive: 
1. implants of levonorgestrel 
2. injectable progesterone 
3. oral contraceptives (either combined or progesterone only) 
4. contraceptive vaginal ring  
5. transdermal contraceptive patch 
10) All male study participants must agree to consistently and correctly use a condom, 
while their female partner agrees to use 1 of the methods of birth control listed above, 
from the date of Screening until 90 days after last dose of study drug. 
 
11) Male subjects must agree to refrain from sperm donation from 90 days after their last 
dose of study drug. 
12) Subject must be of generally good health, with the exception of chronic HCV 
infection, as determined by the Investigator.  
13) Subject must be able to comply with the dosing instructions for study drug 
administration and able to complete the study schedule of assessments, including all 
required post-treatment visits. 
 
F.2. Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not to be enrolled in this 
study. 
1) Current or prior history of any of the following: 
a) Clinically-significant illness (other than HCV) or any other major medical 
disorder that may interfere with subject treatment, assessment or compliance with 
the protocol; subjects currently under evaluation for a potentially clinically-
significant illness (other than HCV) are also excluded.   
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug.  
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy. 


 
15
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal 
hemorrhage). 
e) Solid organ transplantation. 
f) Significant pulmonary disease, significant cardiac disease or porphyria. 
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a 
result of their psychiatric illness within the last 5 years. Subjects with psychiatric 
illness (without the prior mentioned conditions) that is well-controlled on a stable 
treatment regimen for at least 12 months prior to randomization or has not 
required medication in the last 12 months may be included.  
h) Malignancy within 5 years prior to screening, with the exception of specific 
cancers that are entirely cured by surgical resection (basal cell skin cancer, etc). 
Subjects under evaluation for possible malignancy are not eligible.  
i) Significant drug allergy (such as anaphylaxis or hepatotoxicity).  
2) Any prior treatment with a direct acting antiviral agent (protease inhibitors, NS5A 
inhibitors and NS5B polymerase inhibitors/non-nucleoside polymerase inhibitors.) 
3) Pregnant or nursing female or male with pregnant female partner.  
4) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s 
disease, alfa-1 antitrypsin deficiency, cholangitis). 
5) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV). 
6) Clinically-relevant drug abuse within 12 months of screening. A positive drug screen 
will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator. 
7) Use of any prohibited concomitant medications as described in Section G.3 and Table 
1 within 21 days of the Baseline/Day 1 visit; this washout period does not apply to 
PPIs, which can be taken up to 7 days before baseline Day 1. 
8) Use of antiviral medications within the last 30 days. 
9) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day). 
10) Known hypersensitivity to GS-5816, SOF, or formulation excipients.  
 


 
16
G. Treatments 
G.1 Description and Handling of SOF/GS-5816 FDC 
G.1.1 Formulation 
Sofosbuvir/GS-5816 FDC tablets, 400 mg/100 mg, are available as pink, diamond-
shaped, film-coated tablets debossed with “GSI” on one side and “7916” on the other 
side. In addition to the active ingredients, SOF/GS-5816 FDC tablets also contain 
copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, macrogol, talc, and iron oxide red. 
 
G.1.2 Packaging and Labeling 
Sofosbuvir/GS-5816 FDC and placebo-to-match tablets are packaged in white, high-
density polyethylene bottles. Each bottle contains 28 tablets and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. 
G.1.3 Storage and Handling 
Sofosbuvir/GS-5816 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). 
Sofosbuvir/GS-5816 FDC products should 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 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. 
G.1.4 Stability 
It is the policy of Gilead Sciences to monitor the stability of each formulation of clinical 
drug product until the time when the shelf life or a reevaluation period is established for 
the drug product. Stability studies evaluate the labeled storage conditions and accelerated 
conditions, if appropriate. The frequency of stability testing is every 3 months for the first 
year, every 6 months for the second year, and annually thereafter for a minimum of the 
clinical study duration. Studies conducted under accelerated conditions serve to identify 
any stability trend before its occurrence under the labeled storage conditions. 
Through the combined approach of accelerated-condition studies and long-term stability 
monitoring with frequent testing, the purported identity, strength, and quality will be 
assured for all lots of drug product used in clinical studies. 


 
17
G.1.5 Dosage and Administration of SOF/GS-5816 FDC  
Sofosbuvir/GS-5816 FDC tablet is to be administered once daily with or without food. 
Each subject must be given instructions to maintain approximately the same daily dosing 
interval between study drug doses. 
For missed dose(s) of study drug, subjects should be instructed to take the missed dose(s) 
of study drug as soon as possible during the same day.  Subjects should be cautioned 
never to double the next dose with a missed dose of study drug under any circumstances. 
G.2.Study Drug Adherence and Drug Accountability 
Compliance will be documented through the use of pill counts and patient diaries. 
Subjects will be instructed to bring unused study medication containers to each 4-week 
visit as well as any empty bottles. The dates and number of tablets dispensed and returned 
will be recorded by the research nurse. Open bottles of SOF/GS-5816 are collected every 
four weeks and new bottles will be dispensed by the Clinical Center Pharmacy. Subjects 
will be instructed to record dosing in a dosing diary, which will be reviewed at each visit, 
in combination with drug accountability to confirm treatment compliance. 
 
G.3.Concomitant Medications 
The following medications are prohibited during the screening period and for a minimum 
of 21 days prior to the Baseline/Day 1 visit through the end of treatment: 
• Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); 
granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics) 
• Chronic use of systemic immunosuppressants including, but not limited to, 
corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, 
or monoclonal antibodies (eg, infliximab) 
• Investigational agents or devices for any indication 
Concomitant use of amiodarone is prohibited during the screening period and for a 
minimum of 60 days prior to the Baseline/Day 1 visit through the end of treatment. 
Concomitant use of certain medications or herbal/natural supplements (inhibitors or 
inducers of drug transporters ie, P-gp) with study drug(s) may result in PK interactions 
resulting in increases or decreases in exposure of study drug(s) and are prohibited from 
21 days prior to Baseline/Day 1 through the end of treatment. Examples of 
representative medications are listed below:  


 
18
 
 
Medications for disease conditions excluded from the protocol (eg, HIV-1 infection, 
active cancer, transplantation) are not listed under this Concomitant Medication section 
and are disallowed in the study.  
H. Study Procedures 
There will be a total of 13 study visits comprising of a screening visit (which may be 
completed with the admission for liver biopsy/initiation of therapy visit), on-treatment 
weeks 1, 2, and 3, admission for repeat biopsy/week 4 visit, outpatient week 8 and 12 
visits and post-treatment visits weeks 2, 4, 8, 12, and 24. 
Information on the specific clinical assessments and laboratory parameters to be 
monitored are provided below. 
H.1 Consent Process  
Potential study subjects will be informed of study rationale, design, participation burden, 
risks, benefits and side effects of therapy during routine LDB clinic visits and will have 
an opportunity to ask questions about the proposed study. They will be provided a copy 
of the study consent form to take home and review in more detail. If a subject indicates a 
desire to participate in the research study they will be asked to sign consent after which, 
he/she will have all screening laboratories, radiologic imaging and if necessary, liver 


 
19
biopsy, performed through the current protocol. The initial liver biopsy for participation 
in this study will be medically indicated and for research purposes. However, the second 
liver biopsy will be only for research purposes. Patients will be made aware of this.. 
Subjects who refuse the second liver biopsy will continue to receive SOF/GS-5816 
treatment for the planned 12 week duration. The final study sample size accounts for a 
drop out rate of up to 20%. Patients will only be replaced if the dropout rate exceeds this 
proportion. Subjects who are eligible to participate in the ancillary study and agree to 
undergo lymphapheresis will be consented via a separate consent under this protocol.” 
H.1.2 Short Form Consent  
We do not plan to enroll non-English speaking subjects; however they are not excluded 
from participation either.  Should a non-English speaking subject be enrolled, IRB 
approval will be obtained to use the short form process in the absence of a fully translated 
consent document.  Requests for IRB approval will be obtained prior to implementing the 
short form consent process.  The short form consent process will be incompliance with 
SOP 12.9.1 of 45 CFR 46.117(b)(2). 
H.2 Investigator Responsibilities 
The PI or physician associate investigator following the patient is responsible for 
obtaining written informed consent from each individual participating in this study after 
adequate explanation of the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures. The PI and AIs are also responsible 
for ensuring that signed consents and documentation of the consent process are both placed 
in the subject’s permanent CC and/or electronic medical record (CRIS). The Investigators 
responsible for obtaining informed consent are as follows: 
• Dr. Marc Ghany 
• Dr. Jake Liang 
• Dr. Edward Doo 
• Dr. Theo Heller 
• Dr. Yaron Rotman 
• Dr. Christopher Koh 
• Dr. Devika Kapuria 
• Dr. Ahmad Alawad 
• Dr. Gil Ben Yakov  
• Dr. Walter Lai 
 
These Investigators will also be responsible for assessment of AEs, side effects, and 
patient response to treatment. The RN associate investigators will be responsible for 
scheduling patients, completing study drug logs, assisting patients with completing 
questionnaires, and medication reconciliation. 
 


 
20
H.3. Pre-treatment Phase: (Screening) 
Patients will be seen by the Liver Diseases Branch of NIDDK, in the outpatient clinic of 
the Clinical Center, NIH, under protocol 91-DK-0214, where they will be assessed for 
enrollment based upon history of never receiving therapy, or failure of a prior adequate 
course of interferon-based and ribavirin and HCV genotype.  An adequate course of 
therapy is defined as a minimum of 24 weeks of interferon and ribavirin for relapsers and 
partial responders and 12 weeks for null responders. Patients who qualify will be 
approached regarding enrollment and the risks and benefits discussed in detail. Patients 
who qualify and agree will be asked to sign the consent form. Patients will undergo 
screening labs as outpatients, and then be scheduled for inpatient admission within 12 
weeks to complete the screening assessment, undergo liver biopsy and start therapy. 
Patients may have the option to defer initiation of therapy if they so wish but they should 
begin therapy within 12 weeks of the screening assessment. If additional testing is 
required, then patients will have up to 20 weeks from the Screening visit to start study 
treatment. A prior biopsy would be acceptable in lieu of the baseline biopsy ONLY if 
performed with 12 weeks of starting therapy AND liver tissue stored in RNALater was 
available.  
H.3.1 Outpatient Screening Visit: 
(1) Obtain signed informed consent 
(2) History and physical examination 
(3) Symptom questionnaire 
(4) Fatigue questionnaire (Promise 7) 
(5) Visual analogue scale 
(6) Routine blood panel: Chemistry 20 (sodium, chloride, potassium, 
bicarbonate, calcium, phosphate, magnesium, glucose, blood urine nitrogen, 
creatinine, uric acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and 
direct bilirubin, albumin, total protein), CBC (hematocrit, hemoglobin, white 
blood cell count and differential, platelet count), HgbA1C, and HCV RNA 
levels. Testing will also be done for anti-HAV, HBsAg, anti-HBs, anti-HBc, 
anti-HCV, HCV genotype, anti-HIV-1. 
(7) Extended blood panel: alpha fetoprotein, gGT, immunoglobulins, rheumatoid 
factor, ANA, SMA, lipid panel, thyroid panel, INR, reticulocyte count, ESR. 
(8) Serum pregnancy test for females of childbearing potential 
(9) Research blood for storage (5 mL of blood separated into serum and stored 
frozen in 0.5-1.0 mL aliquots). The stored serum will be used to measure 
selected cytokines, interferon-stimulated gene products [including IP10] and 
HCV RNA repeat testing or sequencing as needed and for future research. 
(10) Research blood for ancillary study (40mL of blood in heparin) 
(11) Urine tests: routine urinalysis  
H.3.2 Ancillary Study procedure 
Genotype 1 HLA-2A+ patients who agree will undergo double-pass lymphopheresis 
(preferred) or undergo blood draw of 100 ml of blood for ancilary study I.  


 
21
 
H.4 Completion of Screening / Admission for Pre-Treatment Liver Biopsy / Start of 
Treatment:  
Patients who are not excluded based on outpatient screening will be admitted to the 
Clinical Center as inpatients to complete screening tests (ultrasound, EKG), undergo the 
pre-treatment liver biopsy, to start treatment, and for timed blood draws. Patients will 
have the option to divide this visit into two visits, completing the screening assessments 
and liver biopsy over three days and then being re-admitted at a later date for four days to 
begin treatment. Patients who elect to divide this visit into two should initiate therapy 
within 12 weeks after the screening assessment. 
1) 12-lead EKG 
2) Transient elastography (Fibroscan) 
3) Abdominal ultrasound  
4) Brief clinical evaluation 
5) Review patient’s eligibility for study  
6) Chemistry 20 (sodium, chloride, potassium, bicarbonate, calcium, phosphate, 
magnesium, glucose, blood urine nitrogen, creatinine, uric acid, ALT, AST, LDH, 
CPK, Alkaline Phosphatase, total and direct bilirubin, albumin, total protein), 
lipase, plasma lipids and lipoproteins, serum insulin, CBC (hematocrit, 
hemoglobin, white blood cell count and differential, platelet count).  
7) Liver biopsy cut into four sections, one (at least 1.5 cm) placed in formalin for 
routine light microscopy and the other 3 (at least 0.3 cm) placed in RNAlater and 
flash frozen in liquid nitrogen for RNA and protein analyses and flow cytometry. 
Patients with a transient elastography score ≥13 will undergo a transjugular liver 
biopsy with concomitant measurement of wedged and free hepatic vein pressure 
to estimate the hepatic portal venous gradient 
8) Symptom questionnaire 
9) Visual analogue scale 
10) Fatigue questionnaire (Promise 7) 
11) Review concomitant medications for possible drug interactions 
12) Females of child bearing potential: Urine pregnancy test  
13) Research Blood for Ancillary Study I (40mL blood in heparin) 
14) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
15) Start Sofosbuvir/GS-5816  
16) HCV RNA levels prior to starting therapy, then at 6, 12 and 18 hours 
 
Days 1, 2 and 3, completed during inpatient admission: 
1) Assessment for side effects/adverse events 
2) HCV RNA levels at 24, 48 and 72 hours. 
3) Blood sample for storage (5 mL of blood separated into serum and stored 
frozen in 0.5-1.0 mL aliquots) 
4) Blood sample for plasma lipids and lipoproteins 
5) Discharge from hospital after blood draw on day 3 


 
22
 
If a patient chooses to separate the biopsy and start of treatment admission by more than 
one week, an additional 40ml blood for Ancillary Study I will be collected at biopsy as 
well as start of treatment. 
  
H.5 Monitoring 
Patients will be monitored closely for the first four weeks of treatment, and then monthly 
after that until completing treatment at week 12. 
H.5.1 Weeks 1, 2 & 3,  ( 3 days):  
Outpatient visit 
1) Symptom questionnaire 
2) Visual analogue scale 
3) Fatigue questionnaire (Promise 7) (week 2 only) 
4) Chemistry 20 (sodium, chloride, potassium, bicarbonate, calcium, phosphate, 
magnesium, glucose, blood urine nitrogen, creatinine, uric acid, ALT, AST, LDH, 
CPK, Alkaline Phosphatase, total and direct bilirubin, albumin, total protein), 
lipase, CBC (hematocrit, hemoglobin, white blood cell count and differential, 
platelet count).  
5) HCV RNA levels weeks 1, 2, 3, and 4 
6) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
7) Week 1 only: plasma lipids and lipoproteins, Serum Insulin 
8) Week 2 only: Research blood for ancillary study I (40mL blood in heparin) 
 
H.5.2. Week 4: ( 5 days) 
Admission to the clinical center will occur within the fourth week after starting treatment. 
1) Admission to hospital 
2) Symptom questionnaire 
3) Fatigue questionnaire (Promise 7) 
4) Visual analogue scale 
5) Chemistry 20 (sodium, chloride, potassium, bicarbonate, calcium, phosphate, 
magnesium, glucose, blood urine nitrogen, creatinine, uric acid, ALT, AST, LDH, 
CPK, Alkaline Phosphatase, total and direct bilirubin, albumin, total protein), 
lipase, plasma lipids and lipoproteins, serum insulin, Hemoglobin A1c, CBC 
(hematocrit, hemoglobin, white blood cell count and differential, platelet count).  
6) HCV RNA level 
7) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
8) Research blood for ancillary study I (40mL of blood in heparin) 
9) Females of child bearing potential: Pregnancy test 


 
23
10) Liver biopsy cut into four sections, one (at least 1.0 cm) placed in formalin for 
routine light microscopy and three sections (at least 0.3 cm) placed in RNAlater 
and flash frozen in liquid nitrogen for RNA and protein analyses. 
 
H.5.3 Week 8 ( 3 days): 
After 4 weeks patients will continue to receive sofosbuvir and GS-5816 for a total of 12 
weeks. For participants having side effects related to treatment or adherence issues, more 
frequent visits can be undertaken at the discretion of the study physician. Patients in 
whom HCV RNA is ≥ LLOQ after 2 consecutive HCV RNA < LLOQ or who have a 
confirmed > 1 log10 increase from nadir will discontinue therapy (stopping rule for 
futility). 
Each outpatient visit will include assessment of compliance, adverse events reporting, 
vital signs, weight, symptoms evaluation, record of concomitant medications, drug 
dispensing 
1) Symptom questionnaire 
2) Visual analogue scale 
3) Fatigue questionnaire (Promise 7) 
4) Blood will be drawn for Chemistry 20 (sodium, chloride, potassium, bicarbonate, 
calcium, phosphate, magnesium, glucose, blood urine nitrogen, creatinine, uric 
acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and direct bilirubin, 
albumin, total protein), lipase, CBC (hematocrit, hemoglobin, white blood cell 
count and differential, platelet count). 
5) HCV RNA level 
6) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
7) Females of child bearing potential: Pregnancy test 
H.5.4 End of Treatment (Week 12  3 days)) 
At week 12, all subjects will discontinue therapy and undergo the following evaluation: 
1) Physical examination 
2) Symptom questionnaire 
3) Fatigue questionnaire (Promise 7) 
4) Visual analogue scale 
5) Assessment of adverse events, concomitant medications and adherence 
6) Blood will be drawn for Chemistry 20 (sodium, chloride, potassium, bicarbonate, 
calcium, phosphate, magnesium, glucose, blood urine nitrogen, creatinine, uric 
acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and direct bilirubin, 
albumin, total protein), lipase, plasma lipids and lipoproteins, serum insulin, CBC 
(hematocrit, hemoglobin, white blood cell count and differential, platelet count). 
7) Research blood for ancillary study I (40mL blood in heparin for genotype 2, 3, 4 
and 1 patients who are not HLA-A2+) 
Urine tests: routine urinalysis and creatinine, phosphate and beta-2-microglobulin 


 
24
8) HCV RNA level. 
9) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
10) Females of child bearing potential: Pregnancy test 
 
H.5.5 Ancillary Study Procedure 
For genotype 1 patients who are HLA-A2+, lymphapheresis or 100mL blood in heparin 
will be performed within 24 weeks of stopping treatment. 
H.6  Post-treatment weeks 2, 4, 8 and 12 ( 5 days) 
Patients who complete 12 weeks of therapy will be seen at weeks 2, 4, 8, 12 and 24 after 
therapy is stopped. Two criteria for a sustained virologic response will be used (HCV 
RNA negative at 12 [SVR 12] and 24 weeks [SVR 24] after stopping therapy).  
1) Limited clinical evaluation 
2) Symptom questionnaire 
3) Visual analogue scale 
4) Routine blood panel: Chemistry 20 (sodium, chloride, potassium, bicarbonate, 
calcium, phosphate, magnesium, glucose, blood urine nitrogen, creatinine, uric 
acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and direct bilirubin, 
albumin, total protein), lipase, CBC (hematocrit, hemoglobin, white blood cell 
count and differential, platelet count). 
5) HCV RNA level  
6) Research blood for ancillary study I (40mL blood in heparin for genotype 2, 3 and 
4 patients) 
7) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
8) Females of child bearing potential: Urine pregnancy test (week 4, 8 and 12) 
9) Weeks 4 and 12 only: plasma lipids and lipoproteins, Serum Insulin 
10) Week 12 only: Hemoglobin A1c 
 
H.7 Final study visit week 24 post-treatment ( 5 days) 
1) Limited clinical evaluation 
2) Symptom questionnaire 
3) Fatigue questionnaire (Promise 7) 
4) Visual analogue scale 
5) Routine blood panel: Chemistry 20 (sodium, chloride, potassium, bicarbonate, 
calcium, phosphate, magnesium, glucose, blood urine nitrogen, creatinine, uric 
acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and direct bilirubin, 
albumin, total protein), lipase, plasma lipids and lipoproteins, serum insulin, 
Hemoglobin A1c, CBC (hematocrit, hemoglobin, white blood cell count and 
differential, platelet count). 


 
25
6) Extended blood panel: alpha fetoprotein, gGT, immunoglobulins, rheumatoid 
factor, ANA, SMA, lipid panel, INR, reticulocyte count, ESR. 
7) Research blood for ancillary study I (40mL blood in heparin) 
8) HCV RNA level  
9) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
10) Transient elastography 
 
For patients who fail treatment, resistance testing will be carried out to post-
treatment week 48 
 
 
I. Discontinuation of Subjects from Treatment 
 
I.1 Virologic Response-Based Treatment Stopping Criteria:  
The following on-treatment virologic response-based treatment stopping criteria will be 
utilized: 
• Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ 
• Confirmed > 1 log10 increase from nadir 
• Confirmation should be performed as soon as possible and must occur no later 
than 2 weeks after an initial observation indicating virologic failure during the on-
treatment phase.  
 
I.2 Other Stopping Criteria: 
• Unacceptable toxicity, as defined in the protocol, or toxicity that, in the judgment 
of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest 
• Pregnancy of female subject 
• Significant protocol violation that adversely affects the health care of the 
subject(s) or compromises the interpretation or integrity of the research 
• Subject request to discontinue for any reason; it is important to determine whether 
the withdrawal of consent is primarily due to an AE, lack of efficacy or other 
reason 
• Discontinuation of the study at the request of Gilead, regulatory agency or an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
 
Subjects who meet any of the following laboratory criteria must stop all study drug(s): 
 
• Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by 
immediate repeat testing 


 
26
• Abnormal elevation of ALT > 3 x Baseline/Day 1 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 adverse event or laboratory abnormality assessed as related to 
SOF/GS-5816 FDC 
 
Gilead Sciences will be notified as soon as possible, when a subject comes off 
treatment due to an AE. 
 
I.3 Early Termination (ET) Visit  
If a subject discontinues treatment early for any reason then the following assessments 
for the ET Visit will be performed:  
1) Physical examination 
2) Symptom questionnaire 
3) Fatigue questionnaire (Promise 7) 
4) Visual analogue scale 
5) Assessment of adverse events, concomitant medications and adherence 
6) Blood will be drawn for Chemistry 20 (sodium, chloride, potassium, bicarbonate, 
calcium, phosphate, magnesium, glucose, blood urine nitrogen, creatinine, uric 
acid, ALT, AST, LDH, CPK, Alkaline Phosphatase, total and direct bilirubin, 
albumin, total protein), CBC (hematocrit, hemoglobin, white blood cell count and 
differential, platelet count). 
7) Research blood for ancillary study I 
8) HCV RNA level. 
9) 12 lead EKG 
10) Blood sample for storage (5 mL of blood separated into serum and stored frozen 
in 0.5-1.0 mL aliquots) 
11) Females of child bearing potential: Pregnancy test 
12) Assess compliance with study drug dosing regimen including pill count and 
review of dosing diary data with subject 
All subjects who terminate treatment early will complete the ET visit, and the 4, 8, 12 
and 24-Week Post Treatment visits, based on their last dose date.  
J. Unscheduled Visits 
A subject should attend an unscheduled visit if requested by the investigator. The 
assessments are at the investigator’s discretion, and will at a minimum collect AE and 
concomitant medication information.  
At all unscheduled visits initiated for the purpose of confirming virologic failure a 
research sample will be obtained for Viral RNA Sequencing / Phenotyping. 


 
27
K. Procedures 
 
K.1 Assays for Monitoring HCV RNA levels and Genotype/Subtype determination: 
The Roche COBAS AmpliPrep/:  COBAS TaqMan  HCV Test will be used for HCV 
RNA quantification and the VERSANT HCV Genotype 2.0 Assay (LiPA) will be used 
for HCV genotype/subtype determination. The VERSANT HCV Genotype 2.0 Assay 
(LiPA) targets sequence motifs from the core and 5’UTR regions of HCV.  
 
 
K.2 Management of non-response 
Patients in whom HCV RNA is ≥ LLOQ after 2 consecutive HCV RNA < LLOQ or who 
have a confirmed > 1 log10 increase from nadir will discontinue therapy (stopping rule for 
futility). These patients will continue to be monitored as per the post-treatment 
monitoring schedule. The management of non-responders to DAA regimens is unknown. 
These patients may be eligible for future investigational regimens at the Clinical Center 
or other research centers when such options become available.  
K.3 Management of virological breakthrough 
Patients who develop confirmed virological breakthrough (confirmed within 2 weeks of 
initial observation) will discontinue therapy. These patients will continue to be monitored 
as per the post-treatment monitoring schedule. An additional research sample will be 
drawn for investigation of resistance-associated variants as outlined in section Q. The 
management of virological resistance to sofosbuvir and GS-5816 is unknown. These 
patients may be eligible for future investigational regimens at the Clinical Center or other 
research centers when such options become available.  
K.4 Medical History 
Medical history including details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is currently ongoing, and medication history will be collected on all 
subjects during screening.   
 
K.5 Complete Physical Examination 
A complete physical examination must include source documentation of general 
appearance, and the following body systems: Head, neck and thyroid; eyes, ears, nose, 
throat, mouth and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph 
nodes, abdomen; skin, hair, nails; musculoskeletal; neurological.  
 
K.6 Vital Signs 
Vital sign collection will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature. 
 


 
28
K.7 Creatinine Clearance 
Renal function will be assessed by estimated glomerular filtration rate (eGFR) using the 
CKD-EPI equation. 
The CKD-EPI equation is: GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 
1.018 [if female] X 1.159 [if black] where SCr is serum creatinine (mg/dL), k is 0.7 for 
females and 0.9 for males, a is -0.329 for females and -0.411 for males, min indicates the 
minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1. 
 
 
K.8 Body Mass Index (BMI) 
BMI is calculated by the following equation. 
 
 
BMI = weight (pounds)  703           or            weight in kilograms 
 
 
 
   (height in inches)2                                (height in meters)2 
 
K.9 12-Lead ECGs 
The investigator (or qualified designee) should review the ECG traces recorded in real 
time for clinically significant abnormalities.  On treatment ECGs, obtained for medically 
indicated reasons, should be compared to the subject’s Baseline as part of routine safety 
monitoring.  
 
K.10 Viral RNA Sequencing / Phenotyping Sample  
Serum/plasma samples will be collected at each visit for viral sequence analysis. 
Additionally, at any unscheduled visit initiated for the purpose of confirming virologic 
breakthrough, a viral sequence analysis plasma sample must be collected. Unused 
samples may be archived. 
 
K.11 IL28B Testing 
A blood sample will be obtained at Screening for specific genetic analysis of the 
rs12979860 (IL28B) genetic variant. Results of the test will be made available to subjects 
if they wish to receive these results. Results of this test will not be used for eligibility or 
stratification. Samples will be analyzed retrospectively for IL-28B under our natural 
history protocol 91-DK-0214 which, all patients who agree to genetic testing would have 
signed. 
 
K.12 Pregnancy Testing 
Women of child bearing potential must have a negative serum -HCG at screening and a 
negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 24 hours prior to the start of investigational product. All females of childbearing 
potential will have urine pregnancy testing every 4 weeks during the dosing period and 
for a minimum of 3 months following the last dose of sofosbuvir and GS-5816. 


 
29
Specifically, urine pregnancy will be performed at treatment week 4, 8 and 12, and at 
post-treatment weeks 4, 8 and 12. If a positive urine pregnancy test is reported, the 
subject will be asked to return to the clinic for a confirmatory serum pregnancy test.    
 
K.13 Health Related Quality of Life Surveys 
Quality of life surveys included in this study are Symptom questionnaire, Visual analog 
scale, and Fatigue questionnaire (Promise 7) which will be completed by subjects at Day 
1 (Baseline), On-treatment Weeks 2, 4, 8 and 12, Post-treatment Weeks 4, 8, 12 and 24 
and Early Termination (if applicable).  The subject should read the questionnaire by 
himself/herself and write/mark answers directly onto the questionnaire. 
K.14 Nuclear Medicine Resonance Lipoprotein Profile 
Plasma lipid analysis, including VLDL, LDL and HDL particle size and number will 
measured by nuclear magnetic resonance (NMR) spectroscopy using the Vantera 
Clnincal Analyzer (LipoScience Inc., Raleigh, North Carolina).  VLDL-P, LDL-P, and 
HDL-P will be quantified based on lipoprotein particle size using the amplitudes of their 
distinct lipid methyl group NMR signals to calculate the different lipoproteins.  
Lipoprotein particles will be further subdivided into large, medium, and small particles 
based on the mean particle sizes as the weighted average of related subclasses. 
L.   Hazards and Discomforts 
 
L.1 The risks and discomforts of frequent phlebotomy:  
To document virological and biochemical response to therapy and to monitor the effects 
and toxicities of the combination of sofosbuvir and GS-5816, frequent blood sampling 
will be required. Patients will have between 15 and 18 venipunctures during the 36 weeks 
of the study. Each venipuncture will be for approximately 20 to 75 cc of blood. However, 
the total amount of blood drawn during an 8 week period will not exceed 10.5 ml/Kg 
(550 mls). 
 
L.2 The risks and discomforts of HIV testing.  
 
Patients will have blood tested for anti-HIV at entry.  Mention of anti-HIV is made in the 
consent form which includes the exact language used in the standard consent form used 
for anti-HIV testing at the Clinical Center. It is important to test for HIV infection as HIV 
infection may affect response to therapy. 
 


 
30
L.3 The risks and discomfort of percutaneous and transjugular liver biopsy.  
Patients will undergo two liver biopsies in this protocol namely: one before therapy and a 
second 4 weeks later. Patients with inadequate platelet counts (<70,000/mm3) or 
coagulation parameters (prothrombin time > 15 seconds, INR>1.7) will not undergo liver 
biopsy as a part of this protocol and will be excluded from participation in this trial. 
Patients already enrolled whose platelet counts fall below 70,000/mm3 or whose 
coagulation parameters exceed (prothrombin time > 15 seconds, INR>1.7) will not 
undergo the second liver biopsy but will remain on study drugs. Patients requiring liver 
biopsy will be admitted to the Clinical Center for two days for this procedure and other 
blood testing. The major side effects of liver biopsy are pain, bacteremia, puncture of 
another organ and bleeding. Local pain and discomfort at the liver biopsy site occurs in 
about 20% of persons undergoing percutaneous liver biopsy. This is transient (lasting one 
to twelve hours) and is usually mild, rarely requiring analgesics.  Bacteremia occurs in 
1-2% of persons undergoing liver biopsy.  In the absence of bile duct obstruction, this is 
almost always self-limited and is rarely symptomatic.  Significant bleeding after liver 
biopsy is the most serious side effect of this procedure.  In the absence of a blood 
coagulation defect or hepatic malignancy, significant bleeding is rare, occurring in less 
than one in a thousand cases of liver biopsy.  Death due to bleeding after liver biopsy has 
been reported in less than 1/10,000 cases.  At the NIH Clinical Center, the Liver Diseases 
Branch has performed approximately 150 liver biopsies each year for the last 20 years. 
During this time, only three patients died as a complication of biopsy.  One of these 
patients had cirrhosis and advanced hepatocellular carcinoma, the second had severe 
coagulation disorders and the third had underlying malignancy (acute lymphocytic 
leukemia) and a biopsy was performed for investigation of abnormal liver function tests 
after a bone marrow transplant. All patients bled from the liver biopsy site and died after 
surgical and interventional radiological attempts to stop the bleeding were unsuccessful. 
There is no evidence that performance of a second liver biopsy within a two week period 
is associated with a substantial increase in risk of complications. 
 
L.4 The risks and hazards of sofosbuvir therapy.  
The risks of sofosbuvir are discussed in detail in the drug package insert (Appendix 
II). The most common adverse events (incidence greater than or equal to  
20%, all grades) observed with sofosbuvir in combination with ribavirin  
were fatigue and headache. Treatment-emergent adverse events observed in ≥15% of 
subjects in clinical trials are provided in Table below. 
 
The proportion of subjects who permanently discontinued treatment due to adverse  
events was 4% for subjects receiving placebo, 1% for subjects receiving  
sofosbuvir and ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir and 
ribavirin for 24 weeks.  
  
 
 
Placebo x 12 
weeks 
Sofosbuvir + 
Ribavirina x 12 
weeks 
Sofosbuvir + 
Ribavirina x 24 
weeks 


 
31
 
N=70 
N=650 
N=250 
Fatigue 
24% 
38% 
30% 
Headache 
20% 
24% 
30% 
Nausea 
18% 
22% 
13% 
Insomnia 
4% 
15% 
16% 
Pruritus 
8% 
11% 
27% 
Anemia 
0% 
10% 
6% 
Asthenia 
3% 
6% 
21% 
Rash 
8% 
8% 
9% 
Decreased 
appetite 
10% 
6% 
6% 
Chills 
1% 
2% 
2% 
Influenza like 
illness 
3% 
3% 
6% 
Pyrexia 
0% 
4% 
4% 
Diarrhea 
6% 
9% 
12% 
Neutropenia 
0% 
<1% 
<1% 
Myalgia 
0% 
6% 
9% 
Irritability 
1% 
10% 
10% 
a. Subjects received weight-based ribavirin (1000 mg per day if weighing 
<75Kg or 1200 mg per day if weighing ≥75Kg) 
 
With the exception of anemia and neutropenia, the majority of events presented in the 
Table occurred at severity of grade 1 in sofosbuvir-containing regimens.  
Less Common Adverse Reactions Reported in Clinical Trials (<1%):  
The following Adverse Reactions occurred in <1% of subjects receiving sofosbuvir in a 
combination regimen in any one trial. These events have been included because of their 
seriousness or assessment of potential causal relationship.  
Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant 
pegylated interferon).  
Psychiatric Disorders: severe depression (particularly in subjects with pre-existing 
history of psychiatric illness), including suicidal ideation and suicide.  
Laboratory Abnormalities:  
Changes in selected hematological parameters are described in Table 4. A side-by-side 
tabulation is to simplify presentation; direct comparison across trials should not be made 
due to differing trial designs.  
Bilirubin Elevations  


 
32
Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in 
the sofosbuvir + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of 
subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + ribavirin 12 weeks 
and sofosbuvir + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during 
the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline 
levels by post-treatment Week 4. These bilirubin elevations were not associated with 
transaminase elevations.  
Creatine Kinase Elevations  
Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, 
asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed 
in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir 
+ peginterferon alfa + ribavirin 12 weeks and sofosbuvir + ribavirin 12 weeks groups, 
respectively.  
Lipase Elevations  
Isolated, asymptomatic lipase elevation of greater than 3xULN was observed in <1%, 
2%, 2%, and 2% of subjects in the sofosbuvir + peginterferon alfa + ribavirin 12 weeks, 
sofosbuvir + ribavirin 12 weeks, sofosbuvir + ribavirin 24 weeks and peginterferon alfa + 
ribavirin 24 weeks groups, respectively.  
 
 
 
L.5 The risks and hazards of GS-5816 therapy 
The risks of GS-5816 are discussed in detail in the Investigator’s Brochure. 
 
L.5.1 Adverse Events  
In phase 1b and 2b clinical trials involving 377 patients with chronic hepatitis C, the AEs 
occurring with > 10% incidence across all treatment groups included fatigue and 
headache. The treatment groups administered RBV had higher incidence of AEs that 
have been previously observed with RBV treatment such as fatigue, headache, insomnia, 
and rash. Rates of AEs were similar in subjects receiving GS-5816 25 mg versus 100 mg 
with no discernible dose-related toxicity. 
 
Treatment-emergent AEs occurring in at least 10% of subjects in any treatment group by 
preferred term are shown in Table 4-24. Additional AEs occurring in at least 10% of 


 
33
subjects in any treatment group in other phase 2 studies included pruritus, upper 
respiratory tract infection, lethargy, back pain and vomiting. 
 
The proportion of subjects who permanently discontinued treatment due to adverse  
events was 3/802 (<1%) for palpatations and dizziness (n=1), elevated ALT and gGT 
(n=1) and eczema infected and eye inflammation (n=1). 
 
 
 
L.5.2 Death 
 
As of 07 April 2014, 1 death was reported in the ongoing Phase 2 studies. The death 
is described below. 
A 36-year-old white male had an extensive psychiatric history that included bipolar 
disorder, depressive disorder, anxiety, and drug and alcohol abuse. The subject was 
administered SOF 400 mg + GS-5816 25 mg and committed suicide after completing 
12 weeks of treatment. The investigator assessed the event as not related to study 
drug, but precipitated by acute external events (impending re-incarceration) in the 
setting of underlying severe psychiatric disease. 
 
L.5.3 Serious Adverse Events 
 
As of 07 April 2014, a total of 19 SAEs were reported in the ongoing Phase 2 studies. 
Only one was assessed by investigators as being related to study drug. Notable SAEs 
occurring in one patient each were post-infectious hypersensitivity vasculitis that did 


 
34
not result in treatment interruption and a seizure in a subject with known seizure 
disorder felt to be due to non-compliance with anti-seizure medication. 
 
In phase 2 studies including 377 patients, treatment-emergent Grade 3 and 4 
laboratory abnormalities were infrequent and are presented in Table 4-27. 
There was a higher incidence of Grade 3 hemoglobin decrease and Grade 3 bilirubin 
increase in ribavirin-treated subjects consistent with ribavirin-induced hemolysis. A 
total of 4 subjects reported Grade 3 lipase and 1 subject reported Grade 4 lipase; in all 
cases the lipase elevations were transient and asymptomatic. One subject had a Grade 
3 creatinine increase that normalized on treatment and was assessed as being due to 
dehydration and volume depletion by the investigator. An additional laboratory 
abnormality that led to treatment interruption was grade 4 elevation in serum ALT. 
  
 
 
L.5.4 The risks and hazards of sofosbuvir and GS-5816 combination therapy safety 
conclusions 
As of 07 April 2014, a total of 1167 subjects have been administered GS-5816, of which 
872 were subjects with chronic HCV infection. 
GS-5816 was well tolerated in Phase 1 studies at doses up to 450 mg for 7 days. There 
were no deaths or SAEs reported in any Phase 1 studies to date. 
Phase 2 safety data from over 800 subjects in Phase 2 studies indicates that SOF 400 mg 
+ GS-5816 25 mg ± RBV or SOF 400 mg + GS-5816 100 mg ± RBV for 8 or 12 weeks 
was well tolerated. The most frequently reported AEs were fatigue, headache, nausea, 


 
35
insomnia, and upper respiratory tract infection. One subject death (suicide) was reported 
in a subject with extensive psychiatric medical history. There was a low rate of treatment 
discontinuation for AEs. There was a low incidence of SAEs, and severe or life-
threatening AEs, and Grade 3 and 4 laboratory abnormalities. 
L.6 The risks and hazards of lymphaphoresis 
This section applies only for subjects who qualify and agree to undergo a lymphaphoresis 
procedure. Lymphapheresis refers to the separation and removal of large numbers of 
white blood cells (lymphocytes) from the rest of the circulating blood, using an 
automated cell separator or apheresis device. Your pulse, blood pressure and temperature 
will be taken, and then you will be asked to lie on a recliner or bed. Your blood will be 
withdrawn using a needle placed in one arm and directed into a cell separator machine, 
which separate the blood cells by spinning.  
 
The white blood cells will be retained in a plastic bag inside the machine, while your red 
cells and plasma are returned to you through the same needle. A short-acting blood 
thinner named citrate is given to you through one of the needles to prevent your blood 
from clotting while it is in the machine. Depending on how many white cells are 
collected, the procedure may last from one to two hours. The number of white cells 
collected is a tiny fraction of the total number of these cells in your body. They are 
quickly replaced by your body. The procedure will be performed in the Apheresis Clinic 
of the NIH Department of Transfusion Medicine (Blood Bank).  
The major risks and hazard of undergoing a lymphapohoresis procedure include pain and 
bruising at the needle placement site. As with other kinds of blood drawing, temporary 
lowering of the blood pressure may occur, and lightheadedness, dizziness and even 
fainting may result from this. Use of the anticoagulant may cause tingling sensations 
around the mouth, fingers, and toes, chills, nausea, heartburn, and mild muscle cramps.  
These symptoms are easily treated by temporarily interrupting the procedure. Very rarely, 
there may be loss of as much as one pint of blood due to machine malfunction.  Because 
lymphapheresis may affect how certain medications work, the procedure will not be 
performed in subjects receiving interferon.  
 
M. Safety Assessments 
 
Adverse events will be evaluated using the National Cancer Institute Common 
Terminology Criteria for Adverse Events. 
 


 
36
N. Toxicity Management 
 
Due to a clinical or laboratory event, administration of all study drugs(s) may be 
discontinued. There is no option for SOF/GS-5816 FDC dose reduction. If SOF/GS-5816 
FDC is stopped due to toxicity, it will not be restarted; if SOF/GS-5816 FDC is 
discontinued, the subject must complete an ET visit. Post Treatment 4, 8, 12 and 24-
Week visits will be scheduled from the last dose of study drug.  
O. Adverse Event Reporting  
 
O.1 Reporting to the IRB 
 
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated 
Adverse Device Effects (UADEs), serious adverse events, sponsor and serious, are 
defined as described in NIH HRPP SOP 16 (“Reporting Requirements for Unanticipated 
Problems, Adverse Events and Protocol Deviations.”).  All adverse events at least 
possibly related to the patient’s participation in the research protocol, including those 
observed by or reported to the research team, will be recorded.  Serious unanticipated 
problems and serious protocol deviations will be reported to the IRB and CD as soon as 
possible but not more than 7 days after the PI first learns of the event.  Not serious 
unanticipated problems will be reported to the IRB and CD as soon as possible but not 
more than 14 days after the PI first learns of the event. 
 
Non-serious protocol deviations will only be reported to the IRB (within 14 days after the 
PI first learns of the event) if they represent a departure from NIH policies for the 
conduct of human subjects research, adversely affect the health care of the subject(s) or 
compromise the interpretation or integrity of the research.  Non-serious protocol 
deviations that result from normal subject scheduling variations or technical issues such 
as those associated with sampling that do not impact the health of the subject or the 
interpretation of the study data will not be reported. 
 
Adverse events that are expected as a part of treatment or procedures outlined in the 
protocol will not be reported to the IRB unless they occur at a rate or severity greater than 
known to occur in patients undergoing the treatment or procedures. If AEs associated 
with the treatment and procedures in the study occur at a rate or severity greater than 
known to occur, they will be reclassified as a UP and reported as such. AEs with known 
relation to the natural history of chronic hepatitis C or to other pre-existing conditions 
will not be reported unless they occur at a rate or severity greater than known to occur in 
patients with hepatitis C or the subject’s other pre-existing conditions. AEs that are 
unrelated to the research will not be reported. The PI is responsible for summarizing all 
reportable serious adverse events and adverse events at least possibly related at the time 
of Continuing Review. Deaths will be reported to the Clinical Director and IRB within 7 
days after the PI first learns of the event.  
 


 
37
O.2. Reporting to the FDA 
The sponsor will notify the FDA by telephone and/or facsimile of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible but no later than 7 
calendar days after the sponsor's initial receipt of the information.   This should be 
followed with a written report as specified by the FDA but no later than 15 days after the 
sponsor’s initial receipt of the information using the MedWatch Form 3500a. 
Other Serious and Unexpected Suspected Adverse Reactions (SUSARs) will be reported 
to the FDA in writing using the MedWatch Form 3500a no later than 15 calendar days 
after the sponsor's initial receipt of the information.     
The following safety information will be summarized by the PI in annual reports to the 
FDA: 
• All adverse events thought to be possibly, probably, or definitely related to study 
drug will be summarized, tracked, and reported to the FDA at the time of the 
annual report.  Any adverse events with known relation to the natural history of 
the disease or to other pre-existing conditions will not be reported.  Any accident, 
which results in an AE and is unrelated to the protocol, will not be reported.  
• All SAEs will be reported in a summary format to the FDA at the time of the 
annual report.  SAEs that arise after the Informed Consent is signed until 30 days 
after the last dose of study drug will be reported.   
• All SUSARs submitted to the FDA during the past year will be summarized. 
• A list of subjects who died during study participation with the cause of death for 
each subject. 
• A list of subjects who withdrew or were withdrawn from the study during the past 
year with the reason for their withdrawal. 
• Any new information available to the study investigator/sponsor that pertains to 
the risk benefit profile of the study drug. 
 
O.3  Reporting to Gilead 
Gilead Sciences is required to expedite to worldwide regulatory authorities reports of 
SAEs, Serious Adverse Drug Reactions (SADRs) or Suspected Unexpected Serious 
Adverse Reactions (SUSARs) in line with relevant legislation, including the applicable 
US FDA Code of Federal Regulation, the European Commission Clinical Trials Directive 
(2001/20/EC); therefore, Gilead Sciences will be notified immediately regarding the 
occurrence of any SAE or SADR that occurs after the subject consents to participate in 
the study, including SAEs/SADRs resulting from protocol‑associated procedures as 
defined in relevant legislation including 2001/20/EC.   For fatal or life-threatening events, 
the investigator will also e-mail or fax copies of hospital case reports, autopsy reports, 
and other documents when requested and applicable. Transmission of such documents 
should occur with Personal Subject Details de‑identified, without losing the traceability 
of a document to the Subject Identifiers.  Gilead Sciences may request additional 
information from the investigator to ensure the timely completion of accurate safety 
reports. 


 
38
All SAEs and deaths will be reported to Gilead within 24 hours (but in no case later than 
seven (7) calendar days (for a death or life-threatening event) or fifteen (15) days (for all 
other SAEs) of the investigator’s knowledge of the event. SAEs will be reported to: 
 
Gilead Sciences DSPH:   
fax 1-650-522-5477 
email Safety_FC@gilead.com 
 
P. Protocol Monitoring Plan 
 
Study procedures will be subject to audits and/or monitoring visits to ensure compliance 
with the protocol and applicable regulatory requirements consistent with the NIDDK 
quality assurance program plan.  Audit and/or monitoring visits results will be reported to 
the Principal Investigator for further reporting as appropriate.  Study documents and 
pertinent hospital or clinical records will be reviewed to verify that the conduct of the 
study is consistent with the protocol plan. 
 
Q. Viral Resistance 
 
Resistance selection of HCV subgenomic replicon cells with sofosbuvir has identified the 
S282T mutation within the HCV NS5B to be associated with reduced susceptibility to 
sofosbuvir in genotypes 1-5 with EC50 values ranging from 117-346 nm (~2.4-16.2 fold 
higher compared to wild type EC50 values. S282T mutants remained fully susceptible to 
GS-5816, GS-9669, GS-9451 and tegobuvir. 
 
To define the resistance profile of GS-5816, HCV genotype 1a and 1b replicon cells were 
treated with various concentrations of GS-5816 for 3 weeks (8, 40, 200, and 1000 × EC50 
for genotype 1a, and 2, 4, 6.6, 13, and 33 × EC50 for genotype 1b), which resulted in 
selection of resistant colonies at each drug concentration (Study PC-281-2013). 
Individual colonies and pooled colonies were isolated and analyzed for RAVs in the 
NS5A gene. 
 
In genotype 1a, most resistant clones encoded the single RAVs L31V or Y93H. Other 
single RAVs included Q30K, L31M and Y93N, although they occurred at much lower 
frequencies. Double mutations Q30R/Y93H, Q30H/Y93H or L31V/Y93H were observed 
in a small number of clones resistant to GS-5816. 
 
In genotype 1b, all GS-5816-resistant clones and pools encoded at least 2 amino acid 
substitutions within the NS5A region. Interestingly, unlike what has been observed with 
LDV and DCV, Y93H was never present as a single mutation and instead always 


 
39
emerged in combination with other RAVs in NS5A, including L31F, L31M, and L31V, 
suggesting that GS-5816 has a high barrier to resistance against genotype 1b HCV when 
compared with LDV and DCV. 
Monitoring for mutations in the non-structural 5b polymerase (NS5b) and non-structural 
5a gene regions of HCV will be performed on serum samples obtained at baseline, and on 
all serum samples that have HCV RNA ≥15 IU/ml from patients receiving sofosbuvir and 
GS-5816 therapy. Monitoring for resistance mutations will be performed by Gilead 
Sciences. Novel mutations will be correlated with the clinical response. 
 
R. Efficacy Assessments 
R.1 Primary Efficacy Assessment 
The primary analysis will focus on changes in ISG expression in the liver and its 
association with decline in circulating and hepatic HCV RNA concentrations by week 4. 
The degree of hepatic ISG induction after 4 weeks of therapy relative to that present in 
the baseline liver biopsy will be evaluated.  
R.2 Secondary Efficacy Assessment 
Secondary analyses will be comparisons of very early viral kinetics, (rates of rapid 
virological response [RVR], end-of-treatment response [ETR]), rates of SVR12 and 
SVR24 and virological relapse in comparison with expected rates in treatment naïve and 
experienced patients to peginterferon and ribavirin therapy, measurement of cytokine 
levels, serum aminotransferase levels, improvement in transient elastography scores, rates 
of sofosbuvir and GS-5816 resistance, and safety of sofosbuvir and GS-5816 focusing 
largely on the first 4 weeks and end of therapy compared to baseline.  
R.3 Other Assessments (Endpoint Definitions): 
R.3.1 RVR: rapid virological response (HCV RNA <LLOQ Target not Detected) at week 
4) 
R.3.2 ETR: end of treatment response (HCV RNA <LLOQ Target not Detected at 
week24) 
R.3.3 SVR 12: sustained virological response at follow-up week 12. 
R.3.4 SVR 24: sustained virological response at follow-up week 24. 
R.3.5 Virological breakthrough: a ≥1 log10 IU/L increase in HCV RNA level from 
nadir in two consecutive samples at least one week apart in a patient with an initial 
virological response while on study medications (in the absence of non-compliance) 
R.3.6 Virological relapse: HCV RNA LLOQ level after therapy is stopped in a patient 
who previously achieved an end-of-treatment virological response. 


 
40
R.3.7 Definition of on-treatment hepatitis flares: an on-treatment hepatitis flare will be 
defined as an increase in ALT to ≥400 U/L AND >3 times baseline (week 0) value. A 
severe on-treatment hepatitis flare will be defined as an ALT ≥800 U/L.  
R.3.8 Failure of therapy: may be due to inadequate virological response, breakthrough, 
relapse, or a serious adverse event requiring discontinuation of treatment. 
S. Statistical analysis 
Variables to be analyzed in association with a virological response will include: baseline 
ALT and HCV RNA level, liver histology, HCV subtype, IL28B genotype and previous 
response to therapy, whether a partial or null responder and ISG levels. Patients with 
missing data or who drop out of the study will be considered as treatment failures on an 
intention to treat basis. For comparison of means, Student’s t-test will be used. All 
reported p-values will be 2-sided.  
 
S.1 Planned Interim Analysis for Futility: 
An analysis of the SVR rate will be performed after the first 70 subjects have been 
followed for 4 weeks. If the SVR rate is >90% (<7 failures) then protocol modifications 
will be considered.  This cut-off was chosen based on a 95% CI for 6/70 of 3.2%-17.7%.  
If the failures occur primarily in a few risk groups then those groups will be continued, 
otherwise the trial will be modified or stopped early. 
 
S.2 Demographics and Baseline Characteristics 
The following will be summarized for treated subjects: 
• Demographics: age, race, gender, geographic region, ethnicity; 
• Disease characteristics at baseline: HCV RNA level, HCV genotype and subtype, 
IL28B SNP genotype and cirrhosis status, prior response to pegIFNα/ribavirin; 
• Physical measurements at baseline; height, weight, body mass index, hip and waist 
circumference; 
• Laboratory tests at baseline; 
• Prior medications. 
S.3 Analysis plan 
To address the primary hypothesis that ISG levels are related to virological relapse, the 
ISG analysis of the on treatment liver biopsy at week 4 will be correlated with off-
therapy virological outcome. To address the hypothesis that ISG levels are related to viral 
level, the ISG analysis of the on treatment liver biopsy at week 4 will be compared to that 
of the pre-treatment biopsy. We expect that the majority of ISGs will be down-regulated 
due to the dramatic reduction in viral load expected with this potent combination of 
antiviral agents. The analyses will be stratified by HCV RNA level comparing subjects 


 
41
with HCV RNA levels <LLOQ Target not Detected) to those with HCV RNA levels 
<LLOQ but target detected. 
We will also explore whether there is a difference in ISG levels amongst the 4 genotypes 
at baseline and after 4 weeks of therapy.  
S.4 Analysis methodology 
The analysis will be based on standard approaches to analysis of microarray data. Since 
the software and approaches change frequently in this field, we will provide a broad 
outline of the approach rather than detailed, specific steps.  
a) We will perform quality control and background normalization of the gene array 
data.  
b) Expression value estimates will be obtained and quantile normalization and 
median scaling of the genes will be performed.  
c) A list of genes up- or down-regulated >2-fold with p>0.05 will be prepared using 
the following procedure: 
1. For each patient, genes up- or down-regulated >2-fold in the second 
biopsy compared to the first will be identified. 
2. Lists will be prepared of genes that are up- or down-regulated >2-fold for 
any of the subjects. 
3. A paired t-test will be used to identify genes from this list that have a p 
value <0.05 (Difference is not equal to zero). 
4. The subset of the genes in (3) that are up- or down-regulated in >50% of 
patients in groups defined relapse and/or presence of cirrhosis will be 
identified. 
5. This procedure will be repeated with p < 0.01, but the primary analysis 
will be based on the genes selected using p < 0.05. 
d) The false discovery rate (FDR) of the t test will be estimated. 
A more detailed statistical analysis plan will be developed prior to the start of data 
analysis. 
 
T. Enrollment of Children, Women and Minority Individuals 
The current protocol excludes children (age limit > 18 years) as sofosbuvir and GS-5816 
have not been used in children for the treatment of chronic hepatitis C. Currently 
peginterferon and ribavirin are approved for use in children.  Moreover, chronic hepatitis 
C is uncommon in children in the U.S., and the requirement for two liver biopsies may be 
prohibitive. 
Chronic hepatitis C is about twice as common among men than women.  We expect to 
include women in the proportions that occur in this disease.  Thus, we expect 30% to 
40% of patients to be women.  The exclusion of women interested in getting pregnant or 


 
42
who are not able to practice adequate birth control would be the only possible bias 
introduced in attaining adequate representation of women in this study.    
The distribution of minority individuals in our study, Viral Kinetics and Liver Gene 
Expression in Response to Ribavirin and Peginterferon Therapy of Chronic Hepatitis C, 
(08-DK-0182), at the NIH Clinical Center has been previously reported to the NIDDK, 
IRB. In this study 40% of subjects were considered minorities, 8% of whom were 
Hispanic or Latino, based on self-reported race and ethnicity and NIH, HHS guidelines 
for defining minority race. Thus, we believe minority individuals will be adequately 
represented in this study. 
 
U. Additional Potentially Vulnerable Subject Populations 
This study does not plan to accrue adult subjects who are pregnant or who may be unable 
to provide consent as this is a more than minimal risk study.  NIH employees are not 
categorically recruited, but in the event that an eligible subject presents who happens to 
be an NIH employee, we will follow the guidelines outlined in the inclusion of 
employees in NIH intramural research studies. 
V. Research Use, Storage and Disposition of Human Samples and Data:   
Patients will have serum stored from selected time points during this study.  These 
specimens will be used for repeat virological testing and special tests as needed (such as 
for viral levels, HCV RNA sequencing, HCV resistance testing or measurement of serum 
levels of cytokines, IL28b testing or interferon induced genes) and for future research.  
Samples may be used to assess factors associated with response or non-response to 
antiviral therapy.  Liver biopsy tissue may be stored if a biopsy is done and residual 
tissue is available after samples are taken for routine histological staining and evaluation 
and ISG determination.  ISG determination will be evaluated in the Liver Diseases 
Branch and the routine histological evaluation by the surgical pathology services of the 
Clinical Center. Stored serum will be used to perform in vitro antiviral susceptibility and 
cross resistance testing in selected patients who develop virological breakthrough and 
antiviral resistance. Gilead Sciences will conduct these assays and serum samples will not 
contain any patient identifiers. Samples will be sent as soon as virologic breakthrough is 
identified and Gilead Sciences will have 6 months after receipt of the sample in which to 
provide LDB, NIDDK with the results. Research records and data as well as liver biopsy 
slides, biopsy reports, liver tissue and sera with the patient’s name and a unique identifier 
will be stored indefinitely in our locked offices and freezers, the medical record 
department and the pathology department.  These materials will be protected and tracked 
by standard operating procedures in the medical record and pathology departments as 
well as a compulsive filing system in our locked offices and freezers.  There will be 
redundant storage of clinical information in the medical record department and our 
offices. Likewise, there will be redundant storage of biopsy information and materials in 
the pathology department and our offices.  This should minimize the risk of loss or 
destruction of information and specimens. If that were to occur we would report it to the 


 
43
IRB.  We do not plan to destroy this personal medical information or the liver biopsy 
specimens or research subject sera or cryopreserved PBMC after completion of the study 
because it may be critically important for physicians (here or elsewhere) to have access 
them when caring for these patients in the future.  
W. Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be approved by Gilead Sciences before implementation. All protocol modifications 
must be submitted to the IRB in accordance with local requirements. Approval must be 
obtained before changes can be implemented. 
 
 
 


 
44
References:  
 
1. 
Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus 
infection. Lancet Infect Dis 2005;5:558-67. 
2. 
Lavanchy D. The global burden of hepatitis C. Liver Int 2009;29 Suppl 1:74-81. 
3. 
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48:148-62. 
4. 
Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and 
temporal trends. Semin Liver Dis 2000;20:1-16. 
5. 
Kamal SM, Nasser IA. Hepatitis C genotype 4: What we know and what we don't 
yet know. Hepatology 2008;47:1371-83. 
6. 
Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus 
infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705-
14. 
7. 
Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected 
persons in the United States: a multiple cohort model of HCV prevalence and 
disease progression. Gastroenterology 2010;138:513-21, 521 e1-6. 
8. 
Ly KN, Xing J, Klevens RM, et al. The increasing burden of mortality from viral 
hepatitis in the United States between 1999 and 2007. Ann Intern Med 
2012;156:271-8. 
9. 
Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and 
treatment of hepatitis C: an update. Hepatology 2009;49:1335-74. 
10. 
Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 
chronic hepatitis C virus infection: 2011 practice guideline by the American 
Association for the Study of Liver Diseases. Hepatology 2011;54:1433-44. 
11. 
Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously 
untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16. 
12. 
Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV 
genotype 1 infection. N Engl J Med 2011;364:1195-206. 
13. 
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic 
hepatitis C infection. N Engl J Med 2013;368:1878-87. 
14. 
Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 
2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus 
genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled 
phase 3 trial. Lancet 2014;384:414-26. 
15. 
Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 
2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus 
genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-
controlled trial. Lancet 2014;384:403-13. 
16. 
http://www.hcvguidelines.org/. Recommendations for Testing, Managing, and 
Treating Hepatitis C. 
17. 
Everson GT, TT, Towner, WJ,  Davis, WN, Wyles, D, Nahass, R, McNally, J,  
Brainard, DM et al.  . Safety and Efficacy of Treatment with the Interferon-Free, 
Ribavirin-Free Combination of Sofosbuvir + GS-5816 for 12 Weeks in 
Treatment-Naïve Patients with Genotype 1‒6 HCV Infection. Abstract #O-111. 


 
45
Presented at: The International Liver Congress 2014; April 9-13, 2014; London. 
2014. 
18. 
Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 
2013;10:542-52. 
19. 
Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel 
biomarkers. PLoS One 2008;3:e3148. 
20. 
Brase JC, Wuttig D, Kuner R, et al. Serum microRNAs as non-invasive 
biomarkers for cancer. Mol Cancer 2010;9:306. 
21. 
Wang K, Zhang S, Marzolf B, et al. Circulating microRNAs, potential biomarkers 
for drug-induced liver injury. Proc Natl Acad Sci U S A 2009;106:4402-7. 
22. 
Starkey Lewis PJ, Dear J, Platt V, et al. Circulating microRNAs as potential 
markers of human drug-induced liver injury. Hepatology 2011;54:1767-76. 
23. 
Bala S, Petrasek J, Mundkur S, et al. Circulating microRNAs in exosomes 
indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and 
inflammatory liver diseases. Hepatology 2012;56:1946-57. 
24. 
Jopling CL, Schutz S, Sarnow P. Position-dependent function for a tandem 
microRNA miR-122-binding site located in the hepatitis C virus RNA genome. 
Cell Host Microbe 2008;4:77-85. 
25. 
Jopling CL, Yi M, Lancaster AM, et al. Modulation of hepatitis C virus RNA 
abundance by a liver-specific MicroRNA. Science 2005;309:1577-81. 
26. 
Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by 
targeting microRNA. N Engl J Med 2013;368:1685-94. 
27. 
Mancone C, Steindler C, Santangelo L, et al. Hepatitis C virus production requires 
apolipoprotein A-I and affects its association with nascent low-density 
lipoproteins. Gut 2011;60:378-86. 
28. 
Sorrentino V, Nelson JK, Maspero E, et al. The LXR-IDOL axis defines a 
clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR 
internalization and lysosomal degradation. J Lipid Res 2013;54:2174-84. 
29. 
Syed GH, Tang H, Khan M, et al. Hepatitis C virus stimulates low-density 
lipoprotein receptor expression to facilitate viral propagation. J Virol 
2014;88:2519-29. 
30. 
Butt AA, Yan P, Simon TG, et al. Changes in circulating lipids level over time 
after acquiring HCV infection: results from ERCHIVES. BMC Infect Dis 
2015;15:510. 
31. 
Cromwell WC, Otvos JD, Keyes MJ, et al. LDL Particle Number and Risk of 
Future Cardiovascular Disease in the Framingham Offspring Study - Implications 
for LDL Management. J Clin Lipidol 2007;1:583-92. 
32. 
Jung HJ, Kim YS, Kim SG, et al. The impact of pegylated interferon and ribavirin 
combination treatment on lipid metabolism and insulin resistance in chronic 
hepatitis C patients. Clin Mol Hepatol 2014;20:38-46. 
33. 
National Cholesterol Education Program Expert Panel on Detection E, Treatment 
of High Blood Cholesterol in A. Third Report of the National Cholesterol 
Education Program (NCEP) Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final 
report. Circulation 2002;106:3143-421. 
 


 
46
 
 


 
47
Appendix I 
Ancillary Study I 
Natural killer (NK) and HCV-specific T cells are an important component of the innate 
and adaptive immune response and play a role in the outcome of HCV infection.  Both 
NK cells and HCV-specific T cells have been shown to be impaired in their function (in 
particular in the production of IFN-gamma) in chronic HCV infection.  
For T cells this impairment has been attributed to chronic T cell receptor stimulation 
resulting in upregulation of inhibitory molecules such as PD-1, Tim-3 and CTLA-4 – the 
molecular signature of a functionally “exhausted” T cell phenotype (reviewed in 
Rehermann, B, Nat Med. 2013 Jul;19(7):859-68).   For NK cells this impairment has 
been attributed to direct exposure to HCV proteins (J Exp Med. 2002 Jan 7;195(1):35-41, 
to HCV-infected hepatocytes (J Virol. 2011 Dec;85(23):12557-69) and to chronic 
exposure to HCV-induced endogenous interferon-alpha which thwarts their function from 
IFN-gamma production to predominantly cytotoxicity (Rehermann et al., 
Gastroenterology. 2010 Jan;138(1):325-35).  
It is also known that a sustained virological response to interferon-based therapy does not 
restore HCV-specific T cell function and NK cell IFN-gamma production (Rehermann et 
al., Hepatology. 2004 Jul;40(1):87-97; Rehermann et al., Gastroenterology. 2011 
Oct;141(4):1231-9) and this may impact immunosurveillance of viral relapse  and 
longterm immunity against reinfection.  Interestingly, it has recently been shown that 
HCV-specific T cell responses recover during an interferon-free regimen of direct acting 
antivirals (Robert Thimme, U of Freiburg, Germany, personal communication, Nov 
2013). 
This ancillary immunological study will answer the following two questions: 
1.  AIM 1: What is the mechanism underlying the recovery of HCV-specific T cell 
responses?  We will differentiate between the possibility that HCV-specific T cells with 
an exhausted functional and molecular phenotype re-gain their function and convert into 
memory T cells and the alternative possibility that a small subset of not-exhausted and 
not functionally impaired HCV-specific T cells, that is below the detection limit of 
immunological assays in chronic infection, has a growth advantage becomes the 
dominant population when the inhibitory effects of HCV are removed by successful 
interferon-free antiviral therapy.  The distinction between both possibilities is important 
because to date it is believed that an exhausted T cell phenotype is irreversible.  This is 
relevant not just for HCV, but also for HIV and cancer immunology, where exhausted T 
cell responses are observed.  If reversion of an exhausted phenotype can be observed at 
the single cell level, we will analyze the molecular mechanisms that govern the change in 
T cell differentiation and expression of inhibitory molecules. 


 
48
These studies require prospectively collected lymphocytes to follow changes in T cell 
markers and function throughout the study using a panel of ex vivo and in vitro 
immunological assays (see below as described under aim 2). This study will be limited to 
the genotype 1 infected patients (n=40) because the most comprehensive set of 
immunological reagents (peptides, T cell epitopes, MHC class I tetramers) is available for 
the HCV genotype 1 sequence.  About 50% of these genotype 1-infected patients 
(selected based on expression of HLA-A2) will be asked to donate  a larger number of 
lymphocytes (isolated from either lymphopheresis or 100 ml of full blood) from a time 
point before and a time point after HCV clearance, so that HCV-specific CD4 and CD8 T 
cells can be sorted by flow cytometry using HLA-A2/HCV peptide tetramers and 
analyzed on a single cell basis for the underlying molecular mechanisms.  The large 
number of lymphocytes is required because CD8 T cells that are specific for any given 
HCV epitope constitute about 0.02% to 0.5% of the CD8 T cells in the blood and CD4 T 
cells that are specific for any given HCV epitope are about 100-fold less frequent. 
The following biospeciments are required (genotype 1 patients only): 
Blood:  
Screening visit: 40ml of heparin-blood from all genotype 1 patients 
Prior to treatment: HLA class I and II typing of genotype 1 patients 
 After HLA classification, prior to treatment:  double-pass lymphopheresis (preferred) or 
100 ml of blood only from HLA-A2+ genotype 1 patients.   
If pre-treatment biopsy is more than one week before start of treatment, at biopsy: 40 ml 
of heparin-blood from all genotype 1 patients.  
Day 0 before initiation of treatment, week 2, week 4, week 12 on treatment: 40 ml of 
heparin-blood from all genotye 1 patients irrespective of HLA-type 
Week 12 (end of therapy):  double-pass lymphopheresis (preferred) or 100 ml of blood 
from HLA-A2+ genotype 1 patients. 
Week 24 post end of therapy: 40 ml of heparin-blood from all genotype 1 patients. 
Liver biopsy:  
A small (5 mm) fragment in RPMI/10% FCS for analysis of intrahepatic NK and T cell 
responses pre-treatment and at week 4 of therapy. 
 


 
49
2.  AIM 2: Does restoration of T and NK cell function that follows the DAA-induced 
decrease in HCV titer improve immune surveillance of small traces of persisting virus 
thereby decreasing the risk of a virological breakthrough?  Can T cell and NK function be 
used as a predictor of virological relapse at time points at which HCV RNA is 
undetectable in the blood by standard molecular assays. 
This immunological study will be conducted with blood and liver biopsy specimens from 
genotype 3 infected patients, because a high (33%) chance of virological relapse is 
expected in this group, and in genotype 2 and 4-infected patients, because the chance of 
virological relapse is still unknown for these groups.  Immunological testing will include 
cytotoxicity and cytokine production of NK cells and proliferation and cytokine 
production of CD4 and CD8 T cells in response to HCV proteins and overlapping 
peptides covering the entire HCV genome. As for aim 1 all tests will be performed in the 
section of Dr. Barbara Rehermann, Liver Diseases Branch, on the following samples: 
 
The following biospeciments are required (genotype 2, 3 and 4 patients only).  
Blood: 
Screening visit: 40ml of heparin-blood 
If pre-treatment biopsy is more than one week before start of treatment, at biopsy: 40 ml 
of heparin-blood. 
Day 0 before initiation of treatment, week 2, week, 4, week 12 on therapy, and post-
therapy visits week 2, 4, 8, 12, 24: 40 ml of heparin-blood . 
Liver biopsy:  
A small (5 mm) fragment in RPMI/10% FCS for analysis of intrahepatic NK and T cell 
responses pre-treatment and at week 4 of therapy. 
 
 
 
 
 
 


 
50
Ancillary Study II 
Chronic HCV infection is intimately involved with lipid metabolism of the cell.  HCV 
exploits the host lipoprotein machinery to complete many phases of its life cycle from 
viral entry to virion production.27-29  As a result of this interaction, chronic HCV infection 
may lead to a relative hypolipidemia with reduced low-density lipoprotein (LDL-C), 
high-density lipoprotein (HDL-C), serum triglycerides and total serum cholesterol.30  
This observation suggests that sustained eradication of HCV might lead to dyslipidemia 
(defined as an elevated serum cholesterol with low HDL-C and elevated LDL-C,) and 
increased risk for cardiovascular disease.  
Indeed, follow-up studies after successful clearance of HCV with pegylated interferon-
based therapy have reported increases in LDL-C.32 However, these results may have been 
influenced by changes in weight, thyroid dysfunction and hypertriglyceridemia related to 
therapy with pegylated interferon. Thus, the true impact of successful eradication of HCV 
on lipid and lipoprotein levels has not been clearly defined. The availability of very 
potent and safe direct acting antivirals are not associated with changes in weight or 
endocrine function and would permit a more unbiased assessment of changes in lipid and 
lipoprotein levels during and after successful HCV treatment.   
Dyslipidemia, characterized by elevated serum cholesterol with low HDL-C and elevated 
LDL-C, is a major contributor to development of atherosclerotic diseases including 
stroke, coronary artery disease (CAD) and peripheral vascular disease.33  More recently it 
has been shown that higher LDL particle number is strongly associated with 
cardiovascular risk. Therefore this study will aim to characterize the changes in serum 
lipids and lipoproteins during and after therapy with direct acting antiviral agents and 
assess cardiovascular risk following eradication of HCV based on serum/plasma LDL 
particle number.  
Specific hypotheses to be tested: 
1) Suppression of HCV viremia will lead to rapid changes (with 24-72 hours) in 
serum/plasma cholesterol, LDL and LDL particle number 
2) Sustained eradication of HCV will result in increased cardiovascular risk as 
determined by an increase in LDL particle number  
 
Specific Aims: 
Aim 1: To characterize changes in serum/plasma lipids and lipoproteins and its relation to 
HCV viral kinetics in among subjects with CHC genotype 1-4 during therapy with 
sofosbuvir and GS5816.  
 


 
51
Aim 2: To characterize changes in serum/plasma lipids and lipoproteins after successful 
eradication of HCV among subjects with genotype 1-4 following therapy with sofosbuvir 
and GS5816 (post-treatment weeks 12 and 24). 
Aim 3:  An exploratory aim will be to assess whether subjects with pre-existing 
dyslipidemia on lipid lowering therapy will require an increase in therapy following 
eradication of HCV.   
The analysis will control for weight and insulin sensitivity. Insulin resistance will be 
calculated using fasting Homeostatic Model Assessment of Insulin Resistance (HOMA-
IR) and Hemoglobin A1c.   
The schedule for additional tests is shown on the table below: 
 
Pre-
Rx 
On Treatment 
Post-
Treatment 
 
Pre-
Rx 
liver 
biops
y 
Star
t of 
Rx 
24 
hour
s 
48 
hour
s 
72 
hour
s 
W
k 1 
W
k 4 
W
k 
12 
W
k 4 
W
k 
12 
W
k 
24 
Serum/Plasm
a lipid panel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum/plasm
a lipoprotein 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum insulin 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
Hgb A1C 
x 
 
 
 
 
 
x 
x 
 
x 
x 
 
Additional blood draws will be limited to lipoprotein levels since serum/plasma lipid and 
insulin levels can be evaluated from existing blood obtained for hepatic and mineral 
panels and Hgb A1C can be assessed from blood drawn for CBC. The increase in blood 
volume is estimated  to be 33 ml over 9 month. The total amount of blood drawn during 
an 8-week period will not exceed 10.5 ml/Kg (550 mls). 
 


 
52
Appendix III 
Package insert for sofosbuvir 
Appendix IV 
IB for GS-5816 
Appendix V 
IB for Sofosbuvir and GS-5816  

ICF_000.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Institute of Diabetes and Digestive and Kidney Diseases 
 
 
STUDY NUMBER: 
15-DK-0143 
PRINCIPAL INVESTIGATOR:  Marc Ghany, M.D.   
 
 
STUDY TITLE: 
Investigation Of Viral Kinetics, Interferon Stimulated Genes (ISGs) and mirRNA Among Subjects 
Infected With Different Hepatitis C Virus Genotypes During Therapy With Sofosbuvir and GS-
5816 
 
 
Continuing Review Approved by the IRB on 07/25/17 
Amendment Approved by the IRB on 02/05/18 (I) 
 
 
 
Date Posted to Web:  02/10/18 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
PURPOSE OF THE STUDY 
 
Why is this research being done? 
 
Chronic hepatitis C is a disease caused by a virus (known as the hepatitis C virus) that infects the liver. Over time, 
inflammation caused by the viral infection may cause scarring (fibrosis) of the liver and cirrhosis, which affects the way 
your liver functions. In time, if the virus is not treated, some infected people may develop liver cancer and/or need a liver 
transplant. Current treatments for chronic hepatitis C require the use of drugs that specifically block the production of 
new virus inside the liver. However, these drugs must be combined with interferon or ribavirin. Interferon has numerous 
side effects that make it difficult to tolerate and must be given by injection. Ribavirin also has side effects such as 
lowering your blood count or causing a rash. Interferon works by boosting your immune system and helping the liver cell 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  2  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
to make proteins that can eliminate the hepatitis C virus. It does not directly kill the virus. We do not know exactly how 
ribavirin works. In contrast, the new class of drugs developed to treat hepatitis C act by directly blocking important 
enzymes that the virus needs for its lifecycle –so called direct acting antiviral drugs. Different combinations of these drugs 
are very effective at suppressing the virus without the need for interferon and ribavirin, a so-called interferon free 
regimen. The advantages of these new drugs are higher efficacy, shorter courses of treatment and fewer side effects. 
These new drugs work better in some persons than others. As someone with chronic hepatitis C who has either never 
been treated or previously treated and failed to clear the hepatitis C virus, you are being invited to participate in this 
research study. The primary aim of this study is to learn more about why these new drugs being developed for treatment 
of hepatitis C sometimes fail to work. Sometimes the drugs don’t work because people take them incorrectly or because 
the virus becomes resistant to the action of the drugs. Alternatively, the body’s immune system may be important for 
helping the drugs to clear the virus from the liver. We believe the immune response to the virus in persons who fail 
treatment is different from those who clear the virus successfully. In order to understand this better we plan to compare 
immune responses of your liver cells to treatment in patients who fail and those who respond to treatment. Two liver 
biopsies are needed so we can compare the difference between how your liver cells are working before the treatment and 
then with the treatment. This will help us to understand what role the immune system plays with clearance of the 
hepatitis C virus and if so, which part of the immune system plays this role. Please be aware that the medicines being 
used in this study were approved by the Food and Drug Administration (FDA) in May 2016 so participation in this study is 
now an alternative to standard clinical care. Please also consider that the second liver biopsy is purely for research 
purposes and is not medically necessary. The second biopsy will provide research information that we will need to achieve 
the scientific goals of this study. Please consider carefully whether you will be willing to undergo the second biopsy before 
deciding to participate in the study. Another aim is to determine if these new drugs are safe and how well they work in 
persons with different strains of the virus. 
 
As part of this study, we plan to monitor changes to your cholesterol levels before, during and after treatment to 
understand how cholesterol levels change as your body recovers from hepatitis C infection. Typically, persons with 
chronic hepatitis C have lower cholesterol levels compared to a person without hepatitis C infection because the hepatitis 
C virus uses some of the cholesterol produced by the liver to make new copies of itself. Therefore, it is possible that after 
you clear the hepatitis C virus from your blood, your cholesterol levels will increase. In this study we are planning to 
measure this change in greater detail by also studying the particles that carry cholesterol in your blood to and from the 
liver. These particles are called lipoproteins. High cholesterol and high lipoprotein levels in blood may increase your risk 
for heart disease and stroke. Therefore, understanding what happens to cholesterol and lipoprotein levels after clearance 
of hepatitis C virus could have important implications for your health. We will inform you of the results of this study and 
advise you if you need to follow up with your primary healthcare provider. 
 
Who is being asked to take part in this research study? 
 
Subjects with chronic hepatitis C genotypes 1, 2, 3 and 4 infection who were either never treated or treated previously 
with any interferon regimen with or without ribavirin and failed to eliminate the hepatitis C virus will be eligible to 
participate.  
 
Who is conducting the research study? 
 
The research will be conducted by The Liver Diseases Branch of the National Institute of Diabetes and Digestive and 
Kidney Diseases (NIDDK) of the National Institutes of Health (NIH). The NIH is providing the funding for this study.  
Gilead Sciences, the manufacturer of sofosbuvir and GS-5816, will provide the study medications and perform resistance 
testing on coded samples from subjects whose viral level increases while on the study drugs or in whom the virus returns 
after the treatment is stopped. 
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  3  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
How many people will take part in the research study? 
 
Approximately 140 adult men and women will participate in this research study.  
 
Study Population 
 
This study includes patients who are at least 18 years of age and who are known to be infected with hepatitis C virus 
genotypes 1-4 and who have either never been treated or treated previously with an interferon regimen with or without 
ribavirin and failed to clear the virus. 
 
There are several reasons you may be not be able to participate in this study and may include one or more of the 
following: 
 
• 
If you are infected with HBV or HIV, you will not be able to participate in this study. You will be tested to see if you 
are infected with hepatitis B virus (HBV) or with human immunodeficiency virus (HIV), the virus that causes AIDS. 
We will tell you what the results mean, how to find care, how to avoid infecting others, how we report HBV and 
HIV infection, and the importance of informing your partners at possible risk because of your HBV or HIV infection. 
 
• 
If you have history of severe psychiatric disorders like schizophrenia, bi-polar, mania, or others, you are not 
eligible to participate in this study. 
 
• 
If you are currently taking certain drugs which are sometimes abused, you may not be able to participate in this 
study.  
 
• 
If you are currently pregnant or become pregnant during the study, you are not eligible to participate in this 
study.    
 
• 
If you are a sexually active man and your partner is pregnant at the time of your pre-treatment assessment, you 
are not eligible to participate in this study.  
 
• 
You will not be eligible to participate in this study if you are a sexually active woman of childbearing potential and 
you are unwilling or unable to use two acceptable methods to avoid pregnancy (e.g. a male condom and an 
intrauterine device) beginning at screening, for the duration of the treatment phase and after the treatment 
phase for 3 months. 
 
• 
You will not be eligible to participate in this study if you are sexually active man whose female partner is a 
woman of childbearing potential and you are unwilling or unable to use a condom while your partner uses a 
second birth control method to avoid pregnancy.  Two effective methods of contraception must be used (e.g. a 
male condom and an intrauterine device) beginning at screening, for the duration of the treatment phase and 
after the treatment phase for 3 months. 
 
• 
If you are a sexually active man whose female partner is a woman of childbearing potential then you must agree 
to inform your partner of the contraception requirements and pregnancy testing recommendations for this study or 
you are not eligible to participate.  
 
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  4  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Study Treatment 
 
If you qualify for the study, you will receive the following treatment: 
• 
Sofosbuvir at the dose of 400 mg  
• 
GS-5816 at the dose of 100 mg  
In a fixed dose combination tablet once per day taken orally 
 
The total length of treatment:  
You will receive the study drugs for 12 weeks. 
 
Duration of the Study 
 
Your participation in this study will last up to 48 weeks.  
Study visit 
Purpose 
Screening phase 
To determine if you qualify to take part in the study 
Admission for baseline liver biopsy  
To assess how damaged your liver is and to obtain liver tissue 
for research and to start treatment  
Admission to start treatment (within 12 weeks of 
screening). If additional evaluation is required, you 
may delay therapy up to 20 weeks from screening) 
Only required if you declined to start therapy during the 
admission for first liver biopsy 
Day 0 (First day of treatment), 6, 12 and 18 hours 
Take first dose of study medications and monitor how quickly 
the virus is cleared from your blood 
Days 1, 2 and 3. Discharge on day 3 
Monitoring how quickly the virus is cleared from your blood 
Week 1 
Monitor how well the medications are working and assess side 
effects 
Week 2 
Monitor how well the medications are working and assess side 
effects 
Week 3 
Monitor how well the medications are working and assess side 
effects 
Week 4 Admission for second liver biopsy 
This is to obtain liver tissue for research purposes only  
Week 8 
Monitor how well the medications are working and assess side 
effects 
Week 12 End of treatment 
Stop treatment 
Post-treatment week 2 
To check if the treatment worked and to monitor for side 
effects 
Post-treatment week 4 
To check if the treatment worked and to monitor for side 
effects 
Post-treatment week 8 
To check if the treatment worked and to monitor for side 
effects 
Post-treatment week 12  
To check if the treatment worked and to monitor for side 
effects 
Post-treatment week 24 
To check if the treatment worked and to monitor for side 
effects 
Note: Additional visits may be required if you develop a side effect or the medications stop working.  
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  5  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
The study is made up of the following parts:  
 
• 
Screening Phase:  Includes at least one visit to your study doctor lasting approximately 2 to 3 hours.  Your study 
doctor will draw some blood and do some tests or procedures to see if you meet the requirements for being in the 
study.  You will also be asked to complete some questionnaires and discuss the study schedule. If you meet the 
requirements, you will have up to 12 weeks from the Screening visit to start the study treatment, unless additional 
testing is required. If additional testing is required, then you will have up to 20 weeks from the Screening visit to start 
study treatment. 
 
• 
Admission for Liver Biopsy:  Admission to the Clinical Center for ~1 1/2 days and includes an overnight stay. The 
purpose of the liver biopsy is to assess how much damage the virus has done to your liver and to obtain a small sample 
of liver tissue for research purposes. If you have undergone a liver biopsy within 12 weeks of your planned treatment 
start date AND liver tissue was saved in a special preservative (RNAlater) then you will not need to undergo the first 
biopsy. Please understand that if you recently had a liver biopsy, then the need to repeat a biopsy would be only to 
obtain liver tissue for research. 
 
• 
Admission for Start of Treatment: Days 0-3 (1st four days of taking study drug) may be combined with the admission 
for liver biopsy or will require a separate admission to the Clinical Center. 
o 
Day 0 is the first day of the study treatment phase. If you meet all the requirements, blood will be drawn to 
measure your viral level and you will be asked to take the first dose of study drug in the Clinical Center. 
Additional blood draws will be performed at 6,12 and 18 hours to monitor your viral level. 
o 
You will have your blood drawn in the morning on days 1, 2 and 3 to monitor your viral level. If you desire, 
you may leave the Clinical Center on pass after your blood draw, returning in the evening. You will be discharged 
from the clinical center after the blood draw on day 3.  Your doctor will provide you with the study drugs to 
take home before you are discharged. The study staff will provide you with a schedule for each clinic visit per 
the study plan. You will be given instructions on how to take the study drugs at home. 
 
• 
Study Treatment Phase: 12 weeks of study drug treatment, including 6 visits lasting 1 to 2 hours each. The details of 
these visits are provided below. 
 
• 
Admission for Liver Biopsy at Week 4:  You will be admitted to the Clinical Center at treatment week 4 for a second 
liver biopsy. This visit will last ~1 ½ days and include an overnight stay. This second biopsy is purely for research 
purposes. (See page 6 under What procedures will be performed for research purposes? for a more detailed 
explanation of the planned research using the liver tissue.) If after starting the therapy you decide against undergoing 
the second biopsy, you will continue to receive sofosbuvir and GS-5816 treatment for the planned 12 week duration. 
 
• 
Follow-Up Phase:  You will be asked to return to the clinical center for outpatient visits for five visits over 24 weeks 
after your last dose of study drug. Each visit will last 1-2 hours and will occur at 2 weeks, 4 weeks, 8 weeks, 12 weeks 
and 24 weeks after you take your last dose of study drug.  
 
All study visits will be conducted at the Liver Diseases Branch of the Clinical Center, NIH. The research staff will give you 
instructions where to report for the study visit appointments. 
 
DESCRIPTION OF STUDY PROCEDURES 
 
Before any study procedures are done, the study doctor and research staff will explain the study to you and ask you to 
read this consent form. They will answer any questions you may have about the study and what you are being asked to 
do.  If you decide to participate you will be asked to sign this consent form and a copy will be given to you. You will then 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  6  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
be ready to begin the first part of the study called the screening visit. If you qualify for the study, you will be asked to come 
for additional visits as described below.  
 
What procedures are considered experimental? 
The experimental procedure in this study is combining two oral drugs sofosbuvir and GS-5816 in a fixed dose combination 
tablet for treatment of chronic hepatitis C. The approved treatment for hepatitis C genotypes 1 and 4 infection is the 
combination of peginterferon with ribavirin plus sofosbuvir or simeprevir for 12 or 24 weeks. The approved treatment for 
treatment of genotype 2 is the combination of sofosbuvir and ribavirin for 12 weeks. The approved treatment for treatment 
of genotype 3 is the combination of sofosbuvir and ribavirin for 24 weeks.  
 
What procedures will be performed for research purposes? 
A liver biopsy will be performed at week 4 of treatment. The study is trying to understand why some people fail to respond 
to the virus. It is not known if your immune system is important for helping the antiviral drugs to clear the virus from the 
liver. We believe that the immune system is important and the immune response to the virus in persons who fail treatment 
is different from those who clear the virus successfully. In order to understand this better we plan to compare the activity 
of genes associated with the immune response to the virus in the liver before and during treatment in persons who fail and 
patients who respond to treatment. This will help us to understand what role the immune system plays with clearance of 
the hepatitis C virus and if so, which part of the immune system plays this role. You may be asked to undergo a procedure 
called a lymphapheresis. This will be explained in a separate consent form. 
 
A description of all procedures performed at each visit appears below: 
 
Screening 
 
At this visit, you will discuss and have time to review this consent form in detail and you will have time to have all of your 
questions answered. You will be asked to give informed consent by signing and dating this form. In addition, you will be 
asked questions about your current and past health and any medications you are taking.  
 
The following procedures will be done at the screening visit(s): 
 
• 
A doctor will do a complete physical exam.   
• 
Height and weight will be measured. 
• 
Blood pressure, heart rate, respiratory rate, and temperature will be taken 
• 
Fatigue questionnaire (Promise 7) 
• 
Visual analogue scale to assess your symptoms- a measurement tool used to assess your symptoms during 
treatment. For a particular symptom for example fatigue, you will be asked to make a mark along a continuous line 
ranging from worse to best, indicating how you feel about that particular symptom. 
• 
Fibroscan - ultrasound (a procedure that uses high frequency sound waves to create an image of part of the inside 
of the body) to measure the stiffness of your liver and determine if cirrhosis is present 
• 
Ultrasound, CT (Computed Tomography) or MRI (Magnetic Resonance Imaging) scan on your liver to rule out liver 
cancer if you have not had one in the last 6 months 
• 
ECG (or “electrocardiogram,” which is a recording of the electrical activity of your heart).  You will be asked about 
what other medications you are taking and if you are experiencing any side effects 
• 
Blood and urine samples for safety tests (to check how your liver, muscles, kidney, blood cells and other body 
systems are working)   
 
In addition, your blood will be tested for: 
o 
HIV, the virus that causes AIDS.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  7  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
o 
Hepatitis B virus, another virus that causes hepatitis 
o 
Hepatitis C virus (the type and amount of virus in your blood) 
o 
Blood glucose levels to assess how well the sugar in your blood is controlled 
o 
Thyroid (a gland in your neck that makes hormones) function test 
o 
Coagulation tests to measures the time your blood takes to clot 
o 
Alfa feto protein a test to help determine if you have liver cancer 
o 
Lipid profile to assess overall cholesterol along with “good” and “bad cholesterol levels  
o 
Lipoprotein profile, to assess amount and size of particles of “good” and “bad” cholesterol  
o 
Serum Insulin, the level of a hormone that controls that amount of sugar in your bloodstream 
o 
Hemoglobin A1c, a test to estimate the average sugar level in your bloodstream for last 3 months. 
o 
Serum pregnancy test, if you are a woman who could become pregnant  
o 
IL28B genotype test to obtain information on the potential ability to respond to treatment 
o 
Research serum sample 
 
If you cannot perform or do not want to do any of these procedures, you should not agree to be in this study. 
 
Your study doctor will look at the results of your Screening tests to see if you qualify for the study. If you qualify and would 
like to take part, you will be asked to return to begin the study treatment phase. 
 
Admission for Liver Biopsy 
 
Before you begin treatment, a liver biopsy will be performed to assess the severity of damage to your liver and to obtain a 
sample of liver tissue to measure activity of liver genes. You may begin therapy the day after the biopsy or schedule another 
date to begin treatment. 
 
Study Treatment Phase 
 
Treatment will last for 12 weeks. At scheduled times during the study treatment phase you will need to come to the hospital. 
You will have the following hospital visits during the study treatment phase: 
 
Your scheduled On-treatment visits are Day 0, 6 hours, 12 hours, 18 hours, 24 hours, 48 hours and 72 hours and then end 
of Weeks 1, 2, 4, 8 and 12. 
 
At each visit, you will be asked about how you are feeling. You will also be asked if you have taken any medicine including 
any non-prescription (over-the-counter) medications other than the study drug(s).  
 
Day 0, 1, 2 and 3 (Day 0 is 1st day of taking study drug) 
Day 0 is the first day of the study treatment phase. Your study doctor or the study staff will do the procedures listed above. 
In addition, the following procedures will be done: 
 
• 
Review of the study entrance criteria to see if you are still able to participate 
• 
A doctor will do a brief physical exam  
• 
Symptom questionnaire 
• 
Visual analogue scale 
• 
Review concomitant medications for possible drug interactions 
• 
Blood tests to see that you are still able to participate 
• 
Virus level prior to starting therapy 
• 
Blood for immunological studies 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  8  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
• 
Lipid profile 
• 
Lipoprotein profile 
• 
Serum Insulin 
• 
Blood sample for storage  
• 
Pregnancy test (day 0 only) 
• 
Pregnancy prevention counselling 
If you meet all the requirements, you will take the first dose of study drug(s) in the hospital. You will be discharged from 
hospital on Day 3. You will be given instructions on how to take the study drug(s) at home.   
 
Weeks 1, 2, 3, 8 and 12 and early termination visits 
 
You will come back to the Outpatient Clinic for each of your visits. The following procedures will occur at these study 
treatment phase visits: 
 
• 
Blood pressure, heart rate, respiratory rate, and temperature will be taken 
• 
Blood samples will be taken by a needle stick into a vein in your arm. During the entire study, approximately 875 mL 
or 60 tablespoons or just less than 2 pints of blood will be taken. This volume is consistent with NIH guidelines which 
specify that no more than approximately one pint may be drawn for research purposes in any 8 week period. The 
following tests will be performed: 
 
o 
The blood will be tested to see if there are changes in safety tests (which check how your liver, muscles, 
kidney, blood cells and other body systems are working) while you are in the study and any changes in the 
extent of cirrhosis of your liver 
o 
Blood samples to measure the amount of virus in your body  
o 
Various measurements of your immune system: 
 
 
Your doctor may ask you to return to the hospital for additional blood sample(s) to confirm any results and you 
may be withdrawn from the study if the amount of hepatitis C virus in your blood increases past a certain level, 
or you do not clear the hepatitis C virus from your blood. You may have to stop treatment if you develop a 
complication of the study medications such as elevated liver enzymes or if you develop a rash. You will still be 
asked to return for the end of study treatment visit and/or a post treatment follow-up visit. 
 
 
Test your blood sample to look for hepatitis C viral resistance (if the virus has become resistant to the study 
drug). This testing will show how the virus is structured and is also known as “viral sequencing.” You will 
continue to have this sample taken at every visit. This testing is required for the study. Because there is limited 
information on the development of resistance by the hepatitis C virus to the study drugs, the blood samples 
will be stored indefinitely in order to allow the researchers to perform additional resistance testing on the virus 
once resistance to the drugs used in this study is better understood. 
 
• 
Three Health Related Quality of Life questionnaires. These forms ask questions about your health, activities and 
emotional well-being. You will be shown how to complete these forms. You will read the questions yourself and 
write/mark answers directly onto the questionnaire. 
• 
Urine pregnancy test, if you are a woman who could get pregnant (weeks 8 and 12 only) 
 
Week 4 
A second liver biopsy will be performed for research purposes to measure activity of liver genes since starting treatment. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  9  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
The same procedures outlined for weeks 1, 2, 3, 8 and 12 will also be obtained at week 4, including a urine pregnancy test 
if you are a women who could get pregnant. 
 
At every visit you must bring all study drug(s) (including empty bottles) and all study material with you. The study staff will 
count how many pills you have taken. You will also be asked to complete a diary card to keep track of how much medication 
you have taken and when. 
 
Your physician will give you a new bottle of study drug(s) to take home every 4 weeks.  The study staff will instruct you 
when to return for your next visit per the study plan. 
 
Early Termination Visit 
• 
If you stop treatment early, you will need to have a special visit to return your study drug(s) and be checked by your 
doctor.  All of your study drug bottles must be returned to your study doctor/staff at this time.   
 
Follow-Up Phase 
 
You will return to the outpatient clinic for follow-up visits starting 2 weeks after your last dose of study drug(s). These visits 
will check to see if any HCV can be found in your blood. The follow-up visits will be scheduled at 2 weeks, 4 weeks, 8 weeks 
and 12 weeks, after your last dose of study drug(s).  Each visit will last about 1 to 2 hours.   
 
The following procedures will occur at all of the follow-up visits: 
 
• 
Blood pressure, heart rate, respiratory rate, and temperature will be taken.   
• 
Weight  
• 
Three Health Related Quality of Life surveys will be completed. You will read the questionnaire yourself and 
write/mark answers directly onto the questionnaire. 
• 
Obtain blood samples to measure the amount of virus in your blood (your HCV RNA level)  
• 
Asked about what other medications you are taking and ask if you are experiencing any side effects 
• 
Obtain blood samples to see if there are changes in safety tests (which check how your liver, muscles, kidney, blood 
cells and other body systems are working) while you are in the study. 
• 
Research blood 
 
Week 24, Final study visit 
 
The following procedures will occur at all of the follow-up visits: 
 
• 
Blood pressure, heart rate, respiratory rate, and temperature will be taken.   
• 
Weight  
• 
Three Health Related Quality of Life surveys will be completed. You will read the questionnaire yourself and write/mark 
answers directly onto the questionnaire. 
• 
Obtain blood samples to measure the amount of virus in your blood (your HCV RNA level)  
• 
Asked about what other medications you are taking and ask if you are experiencing any side effects 
• 
Obtain blood samples to see if there are changes in safety tests (which check how your liver, muscles, kidney, blood 
cells and other body systems are working) while you are in the study. 
• 
Obtain blood samples to see the cholesterol changes in your body. 
• 
Additional blood testing to measure levels of antibodies and autoantibodies in your blood, alfa feto protein (a test for 
liver cancer)  
• 
Research blood 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  10  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
• 
A Fibroscan test to measure stiffness of your liver 
 
After all the follow-up visits and procedures are completed, you will have completed this study. 
 
If you do not clear the hepatitis C virus from your blood, researchers would be interested in following your HCV viral 
sequence (how the virus is structured) for up to 3 years.  
 
If you clear the hepatitis C virus from your blood by the end of the study (24 week follow-up visit), we would be interested 
in following your HCV status for a minimum of 5 years after you stop taking study drug. You will be asked to sign a separate 
consent form for a different study to take part in long-term follow-up visits if this applies to you. 
 
All the blood test results done at Liver Diseases Branch, Clinical Center, NIH will be shared with you.  
 
Alternative Treatments 
 
Your doctor can provide detailed information about HCV and the benefits of other treatments that are available to you. A 
decision regarding when to begin treatment for your HCV disease should be made after discussion between you and your 
health care provider.  It is not always necessary to begin treatment immediately, depending on the status of your 
disease.  You are encouraged to discuss treatment options with your doctor.   
 
Sofosbuvir and simeprevir, sofosbuvir and ledipasvir, ombitasvir/paritaprevir/ritonavir with dasabuvir with or without 
ribavirin are new treatments that were recently approved by the United States Food and Drug Administration for the 
treatment of chronic hepatitis C genotype 1 infection.  Patients who use these new treatments are more likely to achieve a 
sustained reduction of their HCV RNA level than patients who use pegylated interferon-α and ribavirin alone.  In some 
cases, patients on these new treatments may be eligible for a shorter course of therapy than if treated with only 
peginterferon alfa and ribavirin. Sofosbuvir and ribavirin were recently approved by the United States Food and Drug 
Administration for the treatment of chronic hepatitis C genotypes 2 and 3 infection. The standard of care for chronic hepatitis 
C genotype 4 infection is peginterferon and ribavirin given for 24 or 48 weeks.  
 
Your doctor can provide you with more information about the side effects associated with these new treatments, as well as 
the potential benefits.  At this time, it is unknown whether the experimental therapy in this study is more or less effective 
or more or less safe than sofosbuvir plus peginterferon and ribavirin, simeprevir plus peginterferon and ribavirin. 
 
Other studies evaluating other interferon-free regimens are being conducted by other investigators and pharmaceutical 
companies. It is possible that you might qualify for one of these studies. At this time, it is unknown whether other 
experimental therapies will be more or less effective or more or less safe than the experimental therapy used in this study. 
 
Risks, Inconveniences and Discomforts 
 
Your condition may or may not improve and could even get worse if you take part in this study.  The study doctor and 
study staff will monitor you for any signs of new or unexpected side effects. Please tell your study doctor if you have a side 
effect or feel unwell while in this study.  Contact your study doctor immediately if you experience a side effect that concerns 
you, or are unable to perform your daily functions. You should contact your study doctor if you start any 
prescription drug or other medication (including over-the-counter drugs and herbal supplements) not 
prescribed by the study doctor. 
 
The possible risks of participating in this research study include the blood draws, receiving the study drugs, and/or the liver 
biopsy and loss of confidentiality. Drugs that affect hepatitis C virus may not completely remove the virus from your body. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  11  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
If that happens, your hepatitis C virus may develop drug resistance.  Drug resistance may affect your ability to respond to 
future drugs if they are similar to sofosbuvir and GS-5816. As with any research study, there may be adverse events or 
side-effects that are currently unknown. It is possible that some of these unknown risks could be permanent, serious or life 
threatening. 
 
A. Blood draw: The risks of blood drawing may rarely, in less than 1% of people (or less than 1 out of 100 people) lead 
to infection, fainting, or bleeding or may infrequently, in 1% to 10% of people (or 1 to 10 out of 100 people), lead to 
bruising, soreness, discomfort at the site of the blood draw, or lightheadedness. This may be reduced by applying pressure 
to the blood draw site or lying down. 
 
B. Risks of the study drugs:  
 
Sofosbuvir Common Adverse Events 
The safety profile of sofosbuvir in patients is based on the combined safety data from 4 studies where it was given for 12-
16 weeks. In these studies, sofosbuvir was given at 400 mg once a day, in combination with ribavirin to 664 patients and 
in combination with ribavirin and pegylated interferon alfa 2a to 327 patients.  
 
In patients taking sofosbuvir with ribavirin for 12-16 weeks, the most commonly reported adverse drug reactions (≥10%) 
were fatigue (41%), trouble sleeping (18%), and irritability (10%). 
 
In patients taking sofosbuvir with ribavirin for 12-24 weeks, the most commonly reported adverse drug reactions (≥10%) 
were:   
 
        fatigue (24-38%) 
        headache (20-30%) 
        nausea (18-22%) 
        trouble sleeping (4-16%) 
        low red blood cell count (0-10%) 
        decreased appetite (6-10%) 
        fever (0-4%) 
        rash (8-9%) 
        chills (1-2%) 
        decreases in the blood cells that fight  
infection (<1%) 
        itchiness (8-27%) 
        flu-like illness (3-6%) 
        muscle pain (0-9%) 
        irritability (1-10%) 
        diarrhea (6-12%) 
 
         
        
         
         
         
         
Most of these side effects were considered to be mild. These side effects overall were similar to those seen in subjects who 
took pegylated interferon and ribavirin without sofosbuvir. About one in sixty-five subjects taking sofosbuvir with ribavirin 
had to stop their study medications early because of side effects. Most of these side effects were believed to have been 
caused by ribavirin. 
 
GS-5816 Common Adverse Events 
GS-5816 has been given alone or with other investigational drugs to over 1000 HCV-infected patients. 
The most common side effect reported (>10%) in about 800 subjects taking GS-5816 with other investigational drugs 
and ribavirin for at least 12 weeks were: 
• 
Fatigue (Tiredness) (22%) 
• 
Headache (20%) 
• 
Nausea (12%) 


 
  
CONTINUATION SHEET for either: 
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NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
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CONTINUATION:  page  12  of  21  pages 
 
 
 
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P.A.: 09-25-0099 
 
 
• 
Diarrhoea (7%) 
• 
Constipation (6%) 
• 
Insomnia (Trouble sleeping) (6%) 
• 
Nasopharyngitis (sore throat and stuffy nose) (5%) 
• 
Rash (5%) 
 
Most of these side effects were considered to be mild.  
 
Rare, but serious: 
 
• 
One subject who had a prior history of seizure disorder, received sofosbuvir and GS-5816 25 mg, for 8 weeks and 
experienced a seizure on post-treatment Day 1 and was hospitalized. The subject was discharged 7 days later. The 
investigator assessed the event as not related to study drug. The investigator suspected that the subject may have 
been noncompliant with seizure medication. 
 
• 
One subject stopped sofosbuvir and GS-5816 25 mg after experiencing abdominal pain, palpitations, and dizziness 
on treatment Day 6. The subject discontinued study drugs on treatment Day 7. A physical exam and ECG were 
performed on treatment Day 7 and were both normal. The palpitations and dizziness resolved on post-treatment 
Day 2. The abdominal pain has not yet resolved. The investigator assessed the events as related to study drug. 
 
• 
One subject administered sofosbuvir and GS-5816 25 mg + ribavirin, stopped the study drug due to elevated liver 
tests. On Day 71, the subject’s ALT was found to have increased from the previous visit 2 weeks earlier from 95 
U/L to 146 U/L (normal range 6 to 34 U/L) and aspartate aminotransferase (AST) from 73 U/L to 114 U/L (normal 
range 9 to 34 U/L). Local laboratory results performed several days later confirmed the ALT and AST elevations 
and the investigator stopped the study medications. The ALT and AST liver enzymes returned to normal within 30 
days of stopping the study medications. This event was assessed as related to study drugs. If your ALT rises greater 
than 5 times your baseline value and is confirmed on repeat testing or if your ALT rises more than 3 times the 
upper limit your baseline value and your bilirubin increases above 2 mg/dL, your study medications will be stopped. 
 
• 
One subject discontinued study drugs due to eczema and eye inflammation. This subject had an undisclosed recent 
history of allergic eyelid inflammation and eczema on the cheeks and right eyelid. The patient had only received 
study drug for 8 days. The investigator assessed the events as related to study drug. 
 
• 
One death, due to suicide was reported after completing 12 weeks of treatment with sofosbuvir and GS-5816. The 
patient a 36-year-old male had an extensive psychiatric history that included bipolar disorder, depressive disorder, 
anxiety, and drug and alcohol abuse. The investigator assessed the event as not related to study drug, but 
precipitated by acute external events (impending re-incarceration) in the setting of underlying severe psychiatric 
disease. 
 
• 
Asymptomatic elevations in creatine kinase (a muscle enzyme) and lipase (a pancreatic enzyme) have been 
observed in 1-2 percent (1-2 per 100) of subjects treated with sofosbuvir and ribavirin or sofosbuvir and GS-5816. 
In all cases, these elevations were transient and not associated with symptoms. If you develop elevations in your 
creatine kinase or lipase enzymes, you may be asked to return for additional visits until the lab tests improve. Your 
study doctor will determine whether it is safe for you to continue taking the study medications or whether you will 
have to stop. 
 
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  13  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Sofosbuvir/GS-5816 
 
The safety profile for Sofosbuvir/GS-5816 combination is primarily based on extensive clinical experience with administration 
of Sofosbuvir and GS-5816, as single agents. There is limited safety data in healthy volunteers. The most common adverse 
event experienced was constipation. The most common adverse events related to Sofosbuvir/GS-5816 were headache (2 
subjects) and diarrhea (1 subject). 
 
C. Unknown risks: The possibility exists that complications and side effects which are unknown at this time could occur. You 
will be informed of any significant new findings that may develop with sofosbuvir and GS-5816 which may affect your 
willingness to continue participation in the study.  
 
D. Allergic reactions: Occasionally, people have allergic reactions to medications.  A severe allergic reaction can be life-
threatening or fatal.  Examples of an allergic reaction include:  rash, shortness of breath, wheezing, sudden drop in blood 
pressure, swelling (around the mouth, throat, or eyes), fast pulse, and sweating. You should inform the study staff and 
seek medical assistance promptly if you develop symptoms of an allergic reaction. 
 
E. Liver biopsy: A liver biopsy is a standard procedure used by liver specialists to assess the health of your liver. The 
procedure involves numbing the skin over the liver with a local anesthetic, followed by passing a needle through the skin 
into the liver and removing a small core of liver tissue.  A specialist will examine the tissue carefully under the microscope.  
There may be some discomfort associated with the procedure. A more detailed explanation of the procedure will now be 
provided:  
 
You will first undergo an ultrasound examination of your liver. This test will identify exactly where your liver is, its size, and 
where the needle should be placed to do the biopsy. The liver biopsy will be performed in your bed in the hospital room.  
We often will inject a sedative medication into an arm vein to make you drowsy and relaxed for the biopsy.  This needle 
will be left in place for the biopsy and for an hour or two thereafter.  
 
For the biopsy, you will lie on your back at the edge of the bed.  The physician will clean the skin over the liver on the right 
side of your lower chest wall and place sterile drapes over the area.  The doctor will then inject Xylocaine to numb the skin 
area where the biopsy is done.  Xylocaine is the numbing medication that is most often used for minor surgical or dental 
procedures.  The needlestick needed to inject the Xylocaine may be slightly uncomfortable. With the skin numbed, the 
doctor will place the liver biopsy needle into the skin in preparation for the biopsy.  The doctor will then ask you to take a 
breath in and then blow it out completely and hold it out.  You will be asked to practice this once or twice.  Then when you 
have been prepared, and have exhaled completely, and are holding your breath, the doctor will do the biopsy by passing 
the biopsy needle rapidly into and out of the liver.  The biopsy itself takes about one second.  You may or may not feel it 
happen at all, but some people feel a slight sharp pain when the needle enters the liver.  
 
More than 90 percent of the time, an adequate piece of liver is obtained with one attempt.  However, sometimes the liver 
moves away when the biopsy is attempted, and at other times the piece of liver is too small.  In these situations, additional 
attempts will be made to ensure that an adequate piece of tissue is obtained. For the second research biopsy no more than 
three passes will be tried.  Furthermore, you can at any time refuse to have another attempt made.  
 
After the biopsy, you will be asked to roll on your right side and lie on that side for two hours.  This puts pressure on the 
site of the biopsy.  During this time, you will have your blood pressure and pulse taken frequently, and the nurse will check 
on you regularly.   
 
You will be asked to remain in bed for the rest of the day, but may be allowed to get up to go to the bathroom if you find 
it impossible to use a bed pan.  Between 4 and 6 hours after the biopsy you will have a blood sample drawn to check your 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  14  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
red blood cell count; this is to make sure that there is no evidence of internal bleeding. The following morning you will be 
checked by the doctor, and if all is well you will be allowed to go home.  You will be asked not to engage in heavy exercise 
or lifting for the next three days. 
 
The following are the known complications of liver biopsy: 
 
(a) 
Pain.  About 20% of persons who undergo a liver biopsy experience pain in the side of body over the liver after the 
biopsy.  This pain usually lasts from a few minutes to several hours and may require pain medication.  In rare cases, the 
pain lasts a day or two. 
 
(b) 
Fainting.  Just as some people faint after giving blood, about 2% of persons pass out after a liver biopsy.  Since 
you will be lying in bed, you are not going to fall down if you faint and this reaction is unlikely to cause you harm.  
Furthermore, we will give you a medication (atropine) to reverse the cause of fainting if it occurs.  If you are the type of 
person who faints a lot, we can give you this medication before the biopsy to prevent you from fainting. 
 
The other complications of liver biopsy are very rare. 
 
(c) 
Infection.  A rare complication of liver biopsy is infection that spreads to the rest of the body because the needle 
goes through skin that is not completely clean or sterile or goes through infected bile (as occurs in patients with gallstones 
sometimes).  Antibiotics can treat such infections. 
 
(d) 
Biopsy of another organ.  In rare instances, the biopsy needle misses the liver and hits another internal organ, such 
as the lung, gallbladder, kidney, or intestine.  This complication can be avoided by carefully selecting the site for the liver 
biopsy and using ultrasound to identify exactly where the liver is and the best position for the biopsy.  Usually, the other 
organ is not damaged by the needle puncture; however, it is possible that surgery might be needed to repair the hole. 
 
(e) 
The most important complication of liver biopsy is bleeding.  A small amount of bleeding probably occurs in many 
patients after liver biopsy, but the amount of bleeding is usually too small to be detected or felt.  Severe bleeding occurs in 
about one of every 1000 liver biopsies.  Severe bleeding is most likely to occur in someone with cancer of the liver or with 
abnormal clotting studies, but bleeding can also occur in patients with mild forms of liver disease.  Most cases of severe 
bleeding stop on their own with bed rest and observation for several days in the hospital.  In rare instances, a blood 
transfusion or even surgery is needed to sew up the tiny hole in the liver made by the biopsy.  Very rarely, in less than one 
in 10,000 cases, death has occurred from bleeding after a liver biopsy. Over 40 year period, liver specialists at the NIH have 
performed over 4,000 liver biopsies. Three deaths have occurred due to severe bleeding that could not be controlled- two 
patients had clotting problems and one had cancer that may have contributed to the inability to stop the bleeding. It is 
because of these possible side effects that you will be kept overnight in the Clinical Center after the liver biopsy with careful 
monitoring for any evidence of bleeding. 
 
(f) 
The risks and discomforts of receiving the medications used during liver biopsy:  Three medications are often used 
during a liver biopsy:  Xylocaine to numb the skin, a sedative such as Versed (midazolam) to make you drowsy during the 
biopsy and atropine if you have a tendency to faint.  All three medications are safe when given in the usual doses.  In rare 
instances, they can induce allergic reactions which can be a skin rash, itching, wheezing, an asthma attack, or even 
anaphylaxis - or allergic shock.  [If you have any allergies to medications, you should remind the doctors of these.]  All of 
the allergic complications can and will be treated if they arise.  Xylocaine, when given in high doses can also cause heart 
blockage, seizures, coma, or even death; but, in the doses given in this study it has no obvious effect on the heartbeat.  
Atropine can cause dryness of the eyes and mouth, difficulty focusing the eyesight, constipation and difficulty passing urine.  
All these side effects will disappear within a few hours.  Versed or Midazolam which is used for sedation causes sleepiness 
and forgetfulness.  In high doses, it can cause over-sedation with coma and depression of breathing and even death.  This 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  15  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
medication is given in small amounts with careful monitoring of how deeply you are sedated.  Medications and equipment 
are at hand during the liver biopsy to deal with the situation if you become too sedated and stop breathing normally.  At 
the Liver Diseases Section, we have never had an emergency or serious reaction to these three medications during the 
years that they have been used in performing liver biopsies. 
 
F. Viral Resistance 
 
Treatment with drugs that directly inhibit the hepatitis C virus has been shown to lead to development of hepatitis C virus 
that is resistant to that drug and other drugs with the same type of action.  These resistance mutations have been observed 
in the body as late as 4 to 5 years after treatment has ended. It is unknown whether having these resistance mutations 
might reduce the chance of treatment success with future drugs with the same type of action or with different types of 
action (such as protease inhibitors). It is possible that if you are treated with the drugs in this study and treatment doesn’t 
work, you might have resistance mutations that would make future treatment less successful. 
 
G. Risks to Reproduction, Unborn Babies and Nursing Infants 
 
General Statement 
 
You must not be pregnant or breastfeeding, and you should not become pregnant or breastfeed while you are taking the 
study treatments, and for 12 weeks after stopping treatment. You must use two methods of birth control to avoid pregnancy 
for the duration of this study and for 3 months after taking the study medication. You should immediately contact your 
study doctor if there is a change in your method to avoid pregnancy or if you start any prescription drug or other medication 
(including over-the-counter drugs and herbal supplements) not prescribed by the study doctor.  
 
It is unclear how long the investigational drugs, sofosbuvir and GS-5816 may last in the body’s tissues, and the safety of 
this drug in women who are pregnant or nursing has not yet been established. If you are a woman who is pregnant or a 
female with the intent of becoming pregnant or a female who is currently nursing (breastfeeding) a child, you cannot be in 
this study.  If you are a man whose partner is currently pregnant or wishing to become pregnant, you cannot be in this 
study. 
 
You must protect yourself or your partner from becoming pregnant before, during, and after the study.  Women, and men 
with female partners capable of becoming pregnant, must use two effective methods of birth control as described below.  
Your study doctor will need to document what type(s) of birth control you are using. 
 
Women only: 
 
Women who can get pregnant should not take study drug(s) unless they and their partner do not have intercourse ever or 
are using 2 methods of birth control for the duration of the study (starting 3 weeks prior to the Day 0 visit) and for a 
minimum of 3 months after last dose of study medications or longer as directed by your study doctor.  
 
At least one method of birth control must be a condom used correctly by your male partner.  Acceptable birth control 
methods (in addition to a male partner who correctly uses a condom) include:  
• 
an intrauterine device (IUD) with a failure rate of <1% per year 
• 
female barrier method: cervical cap or diaphragm with spermicidal agent 
• 
tubal sterilization (having your tubes tied) 
• 
hormone containing contraceptives 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  16  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Women who can get pregnant must have a negative serum pregnancy test at screening and urine pregnancy test at the 
Day 0 visit, prior to taking the first dose of study medication.  Pregnancy tests will be repeated every 4 weeks during the 
study treatment and post treatment phases.   
 
You must tell your study doctor immediately if you become pregnant while in this study and for 12 weeks after stopping 
study drugs, or for as long as you have been directed by your study doctor to use contraception.  The study doctor will tell 
you about the possible risks to your unborn child and options available to you.   
 
In the event of a positive urine pregnancy result, you will be instructed to stop study drugs immediately and return to the 
study clinic as soon as possible for a serum (blood) pregnancy test.  The pregnancy will be followed to its completion and 
the outcome, including any premature termination, must be reported to your doctor. 
 
You should be counseled and monitored by your own doctor.  As the risk to the unborn baby is unknown, it is recommended 
you seek medical supervision from your own doctor during the pregnancy and for the baby after it is born.  Neither the 
study doctor nor the provider of the study medications (Gilead Sciences) will be responsible for providing routine medical 
care relating to the pregnancy.   
 
Men only: 
 
If you have a female partner who cannot become pregnant, you must still consistently and correctly use a condom. 
 
If you have a female partner who can become pregnant, you and your partner must use two forms of birth control for the 
entire study and for a minimum of 12 weeks after the last dose of study medications or longer as directed by your study 
doctor.  You must use a condom while your female partner uses 1 other method of birth control.  Your study doctor will 
discuss with you other methods of birth control that can be used in combination with a condom.  
 
If your female sex partner becomes pregnant while you are in the study or within 12 weeks after your last dose of study 
drug, the study drug may harm an unborn baby.  If you have a female partner who becomes pregnant or suspects that she 
has become pregnant while you are in the study or within 12 weeks after your last dose of study drug, you will be required 
to notify your study doctor immediately.  As the risk to your partner and unborn baby are not known, it is recommended 
for your partner to receive appropriate prenatal care.  If you agree, your partner will be asked to release her medical 
information related to pregnancy.  Your study doctor may need to disclose to your partner details of this study and your 
taking part in it.  Neither the study doctor nor the manufacturer of the study medications (Gilead Sciences) will be 
responsible for the costs related to the pregnancy, delivery, or care of your child.   
 
Male subjects must also agree not to donate sperm from the time you first take your first dose of study medication until 12 
weeks after the last dose of study medications. 
 
Please note: Hormonal birth control may be more effective when taken for at least 3 months.  Even if you and your female 
partner use a medically proven birth control method, you could still cause your partner to become pregnant.  
 
Please share this information with your partner.  
 
Unforeseeable Risks 
 
There may be unknown risks to you, your unborn baby or nursing infant if you are or become pregnant during this study 
or are breastfeeding during this study.  
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  17  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Risk of Embryo-Fetal Abnormalities Based on Laboratory & Animal Findings 
 
While laboratory and animal studies have been conducted to determine possible risks, the results do not necessarily show 
what will happen when the drug is used in humans. Fertility and embryo-fetal development studies in rats indicate that 
doses of sofosbuvir and GS-5816 which were not harmful to the pregnant animal did not cause abnormalities to the fetus 
or embryo.  
 
Human Pregnancy Outcomes 
 
There is currently no available data on pregnancy outcomes with sofosbuvir and GS-5816. 
 
Requirements for Pregnancy Testing  
 
During this study you will have up to 7 pregnancy tests. Pregnancy will be determined on basis of a urine and / or blood 
sample. The pregnancy tests will be at the screening assessment, Day 0, treatment weeks 4, 8 and 12, and for post-
treatment Weeks 4, 8, and 12. Women of child bearing potential must have a negative serum -HCG at screening and a 
negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start 
of investigational product.   
 
Occurrence of Pregnancy or Suspected Pregnancy 
 
If you become pregnant, suspect pregnancy or if you missed your period or it is late, or if you have a change in your usual 
menstrual cycle (e.g., heavier bleeding during your period or bleeding between periods), you should immediately contact 
your study doctor.  
 
Discontinuation from the Study 
 
Should you become pregnant during this study, you will have the investigational products discontinued and be referred for 
obstetric care. The NIH has not set aside any funds to pay for any aspects of obstetric, child or related care and does not 
plan to pay for them. 
 
Pregnancy Reporting 
 
In case of a pregnancy, your pregnancy and its outcome will be reported to Gilead Sciences, the manufacturer of the study 
medications. 
 
H. Potential risks of a breach of confidentiality 
 
Participation does involve the potential risks of a breach of confidentiality of the information and associated privacy of the 
participants.  A breach of confidentiality could impact future insurability and employability. The risks will be minimized by 
1) removing identifiers (names, social security numbers, medical record numbers) from stored samples; 2) limiting access 
to information linking codes assigned to samples by storing identifying information in a separate location; and 3) limiting 
access to information to study investigators at the Liver Diseases Branch, Clinical Center, NIH.  
 
Benefits 
 
Preliminary results of treatment with sofosbuvir and GS-5816 are promising and suggest that 90% or more of subjects 
receiving this regimen are cured of hepatitis C. Follow-up studies of patients with hepatitis C cured with other regimens 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  18  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
show that the rate of complications from hepatitis C such as variceal bleeding (bleeding from large veins in the food pipe), 
ascites (fluid in the abdomen) and liver cancer are substantially decreased compared to patients who are not cured. 
 
There is no guarantee that you will receive personal benefit from taking part in this study.  Sofosbuvir and GS-5816 may 
not improve your chronic hepatitis C. There is the possibility that your chronic hepatitis C may worsen.  However, clinical 
research studies such as this are a way for doctors to determine if a drug is useful in fighting a disease.  By taking part in 
this study, you may benefit if sofosbuvir and GS-5816 is effective in curing HCV.  By you taking part in this study, it may 
benefit the community, scientists, and doctors who work with HCV by providing increased knowledge and information about 
the treatment of your disease. By taking part in this study, you will have close medical monitoring of your health condition 
by blood tests and other tests during clinic visits.  
 
Knowing your cholesterol levels would help assess your risk for heart disease and stroke and may require additional medical 
intervention to lower this risk.  Additionally, if you are already have high cholesterol and you are already on a cholesterol 
lowering medication, we would be able to tell you if you might need an increase in the medication. Your primary healthcare 
provider will be responsible for managing your cholesterol medication. 
 
Compensation 
 
You will not receive any compensation for participating in this study. Participation in this study will be free of charge. Neither 
you nor your insurance will be charged for research testing of your stored blood or liver samples. Sometimes, research 
results in findings or inventions that have value if they are made or sold. These findings or inventions may be patented or 
licensed, which could give a company the sole right to make and sell products or offer testing based on the discovery. There 
are no plans to offer you compensation for any present or future products, processes, and /or therapies developed as a 
result of this research. 
 
Right of Withdrawal and Conditions for Early Withdrawal 
 
You may tell us at any time that you no longer wish to participate in this study. You have the right to change your mind 
about allowing us to have access to your personal health information. If you choose to take away this permission you must 
inform the Principal Investigator in writing. Your withdrawal of this consent to participate will be effective immediately. Any 
information collected up to the time you choose to take away your permission will still be used. Deciding to no longer 
participate or withdrawing permission to access your personal health information will not result in any penalty or loss of 
benefits to you. 
 
Discussion of New Findings with You 
 
You will be promptly notified if any new significant information (either good or bad) develops during the conduct of this 
research study which may cause you to change your mind about continuing to participate. If new information is provided 
to you, your consent to continue participation in this study will be re-obtained. This does not apply to findings from the use 
of de-identified blood and liver samples in the future. 
 
Study Termination 
 
The study investigators and/or sponsor may terminate your participation in the study for various reasons. Some examples 
are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in the study. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  19  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
• 
You do not follow instructions from the researchers. 
• 
The study is suspended or canceled. 
 
The study investigator and/or manufacturer of the study medications may also terminate this study for safety, scientific, or 
administrative reasons at any time.  
 
Confidentiality 
 
Your participation in this study will be kept confidential. No one other than the study personnel at the clinical center will 
be given your name, address, and other personal identifying information.  
 
Representatives of the National Institutes of Health and Gilead may review your records at visits to the clinic. This is part 
of the ongoing monitoring of the study. In addition, representatives from the United States Food and Drug Administration 
(FDA) or the Institutional Review Board at this institution may review your study records, including your medical records.  
 
Who will have access to identifiable information related to my participation in this research study?  
 
In addition to all members of the research team at the Clinical Center, NIH the following individuals will, or may, have 
access to identifiable information (which may include your identifiable medical information) related to your participation in 
this research study:  
 
Authorized representatives of the Clinical Center, NIDDK, NIH Institutional Review Board/Research Ethics Board 
(IRB/REB) may review your information to monitor the appropriate conduct of this research study. In unusual cases, the 
investigators may be required to release your information in response to an order from a court of law. 
 
Authorized representatives of Gilead Sciences may view your study information. The purpose of providing this information 
is to monitor the accuracy and completeness of the research data.   
 
Authorized representatives of Clinical Center, NIH or other affiliated health care providers may have access to your study 
information. This may be used for internal hospital operations and quality assurance. 
 
You will receive a copy of this consent form. A copy will be placed in your hospital medical record so that any doctors who 
are treating you will know that you are participating in the study. 
 
For how long will the investigators be permitted to use and disclose identifiable information related to my 
participation in this research study?  
 
The investigators may continue to use and disclose, for purposes described above, identifiable information (which may 
include your identifiable medical information) related to your participation in this research study for a minimum of 7 years 
and for as long (indefinite) as it may take to complete this research study. 
 
Research Use of Stored Samples and Data 
 
Research blood samples will be initially stored at the Clinical Center, NIH. Some of the research blood samples may be sent 
to Gilead Sciences under code for resistance testing. These results will be shared with you.  
 
The remaining research blood samples will be kept and maintained in locked freezers by the National Institute of Diabetes 
and Digestive and Kidney Diseases (NIDDK) to be stored for future testing.  Some clinical information about you will also 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  20  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
be stored in password-protected computers to help investigators interpret the results of tests done on the blood. Your blood 
samples and clinical information will be identified only by a code.  
 
Liver biopsy samples obtained in this study will be read and stored at the Clinical Center, NIH. Results of the reading will 
be shared with you. A small piece of liver tissue will be saved to assess the gene response in the liver following receipt of 
treatment. If any liver tissue is remaining after this analysis is complete, it will be stored for future research.  This material 
may help scientists develop new medical tests, treatments, and ways to prevent diseases.  
 
Will my information for this study be used for any other studies?  
 
Yes. If you choose to be in this study, other researchers may use your unidentifiable study information for studies of liver 
and non-liver diseases in the future.   
 
May I have access to my medical information that results from my participation in this research study? 
 
You are allowed to access medical information contained in your medical records, including information resulting from your 
participation in this research study. Any information from research laboratory tests obtained from use of banked blood and 
liver samples will not be placed in your medical records. By agreeing to participate in this study, you do not waive any right 
that you may have regarding access to and disclosure of your records.  For further information on those rights, please 
contact Dr. Ghany (PI) at 301-496-1721. 
 
Conflict of Interest 
 
The National Institutes of Health reviews NIH employees at least yearly for conflicts of interest.  The following link contains 
details on this process http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf. You may ask your research 
team for additional information or a copy of the Protocol Review Guide. 
 
This protocol has investigator(s) who are not NIH employees.  They are expected to comply with their Institution’s conflict 
of interest policies. 
 
Research Study Registry 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This Website 
will not include information that can identify you.  At most, the Website will include a summary of the results.  You can 
search this Website at anytime. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
15-DK-0143 
CONTINUATION:  page  21  of  21  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, the 
people who take part are not named and identified.  In most cases, the NIH will not release any information about your 
research involvement without your written permission.  However, if you sign a release of information form, for example, 
for an insurance company, the NIH will give the insurance company information from your medical record.  This information 
might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Marc Ghany M.D.; Building 10, Room 
9B-16, Telephone: 301-496-1721.  Other researchers you may call are: Elenita Rivera, RN at 301-435-6125, or the NIH 
operator 301-496-1211. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JULY 25, 2017 THROUGH AUGUST 29, 2018. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
Print Name 
Signature of Witness 
Date 
 
 
Print Name