Clinical trial NCT02858180
Conditions: Hepatitis C, Chronic Heart Failure Pulmonary Disease, Chronic Obstructive Lung Diseases, Interstitial
Sponsor: Duke University
Start date: 2016-12-01; Completion date: 2019-07-04
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter study in Hepatitis C Virus (HCV) infected adult patients who also have advanced cardiac disease or advanced lung disease.

Detailed description:
This is a multicenter study in HCV infected adult patients who also have either advanced cardiac disease, or advanced lung disease. Advanced cardiac disease is defined as a marked limitation of physical activity, or discomfort upon physical activity. The patients in the advanced cardiac disease group must also have been hospitalized for heart failure within the last 12 months.

Advanced lung disease is defined as patients who have been diagnosed with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). Patients in the COPD group must have abnormalities in their forced expiratory volume (FEV) test, which measures the amount of air exhaled. They may or may not need supplemental oxygen. Patients in the ILD group must have been diagnosed with ILD and require supplement oxygen at all times.

Arms: arm 1: Harvoni (sofosbuvir/ledipasvir fixed dose combination)

1 pill once daily Includes 400 mg sofosbuvir (SOF) and 90 mg ledipasvir (LDV) arm 2: Harvoni (sofosbuvir/ledipasvir fixed dose combination)

1 pill once daily Includes 400 mg sofosbuvir and 90 mg ledipasvir
Interventions: intervention 1: Sofosbuvir/ledipasvir fixed dose combination(SOF/LDV FDC)
Intervention descriptions: intervention 1: 1 pill once daily of SOF/LDV FDC

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 
 
 
 
 
STUDY PROTOCOL 
 
 
Study Title: 
A multicenter, open-label study of Harvoni ® (sofosbuvir 
ledipasvir fixed dose combination) in subjects infected with 
chronic hepatitis C and advanced heart failure or lung disease 
 
 
Sponsor: 
Andrew Muir, MD 
Duke Clinical Research Institute 
Durham, NC 
2400 Pratt Street 
Durham, NC 27715 
 
 
 
 
 
 
Principal investigator: 
Name: 
Andrew Muir, M.D. 
Office telephone: 
(919) 668-7193 
Mobile telephone:       (919) 812-6696 
Email: 
andrew.muir@duke.edu 
 
 
 
 
 
 
Protocol Version Date: 
12 April 2016 
 
 
 
 
 
Protocol Number: 
DCRI69602 
 
 
  NCT02858180 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 2 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................. 2 
PROTOCOL SYNOPSIS ........................................................................................................................................... 4 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................... 8 
1. 
INTRODUCTION ................................................................................................................................................ 9 
1.1. Background ................................................................................................................................................. 9 
1.2. Rationale for the current study ................................................................................................................. 9 
2. 
OBJECTIVES .................................................................................................................................................... 10 
3. 
SUBJECT POPULATION ................................................................................................................................ 11 
3.1. Treatment plan and regimen ................................................................................................................... 11 
3.2. Visit schedule ............................................................................................................................................ 11 
3.3. Number of subjects and subject selection ............................................................................................ 11 
3.4. Inclusion criteria ........................................................................................................................................ 11 
3.5. Exclusion Criteria ...................................................................................................................................... 13 
4. 
PACKAGING AND LABELING ....................................................................................................................... 14 
5. 
STUDY PROCEDURES .................................................................................................................................. 15 
5.1. Subject Enrollment ................................................................................................................................... 15 
5.2. Study Visit Procedures............................................................................................................................. 15 
5.2.1. 
Screening Visit (Day -28 to -1)......................................................................................... 15 
5.2.2. 
Baseline/Day 1 Assessments .......................................................................................... 16 
5.2.3. 
Weeks 2 and 8 for 12-week duration and weeks 16 and 20 for 24-
week duration (± 5 days) .................................................................................................. 16 
5.2.4. 
Week 4 (± 5 days) for all durations ................................................................................. 16 
5.2.5. 
Week 12 for 12-week duration and Week 24 for 24-week duration 
(± 5 days) ............................................................................................................................ 17 
5.2.6. 
Early Termination (ET) or Unscheduled Visit ................................................................ 17 
5.2.7. 
Post-Treatment Weeks 4 and 12 (± 5 days) .................................................................. 17 
5.3. Visit Specifications .................................................................................................................................... 18 
5.3.1. 
Clinical Laboratory Analytes ............................................................................................ 18 
5.3.2. 
Medical History................................................................................................................... 18 
5.3.3. 
Complete Physical Examination ...................................................................................... 18 
5.3.4. 
Creatinine Clearance ........................................................................................................ 18 
5.3.5. 
Body Mass Index (BMI) .................................................................................................... 19 
5.3.6. 
Vital Signs ........................................................................................................................... 19 
5.3.7. 
12-Lead ECGs ................................................................................................................... 19 
5.3.8. 
HCV Genotyping ................................................................................................................ 19 
6. 
STOPPING CRITERIA .................................................................................................................................... 20 
6.1. Virologic Response-Based Stopping Criteria ....................................................................................... 20 
6.2. Stopping Rules for Individual Subjects .................................................................................................. 20 
6.3. Criteria for Discontinuation of Study Treatment ................................................................................... 20 
6.4. Discontinuations........................................................................................................................................ 20 
6.5. Assessments for Premature Discontinuation from Study ................................................................... 21 
7. 
ADVERSE EVENTS ........................................................................................................................................ 22 
7.1. Adverse Events ......................................................................................................................................... 22 
7.2. Assessment of Adverse Events .............................................................................................................. 22 
7.3. Serious Adverse Events .......................................................................................................................... 22 
7.3.1. 
Serious Adverse Event Reporting Requirements ......................................................... 23 


 
Page 3 
 
 
7.3.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events .................................... 24 
8. 
STATISTICAL CONSIDERATIONS .............................................................................................................. 25 
8.1. Analysis Objectives and Endpoints ........................................................................................................ 25 
8.1.1. 
Analysis Objectives ........................................................................................................... 25 
8.1.2. 
Primary Endpoint ............................................................................................................... 25 
8.1.3. 
Secondary Endpoints ........................................................................................................ 25 
8.1.4. 
Safety Endpoints ................................................................................................................ 25 
8.1.5. 
Analysis Conventions ........................................................................................................ 25 
8.2. Analysis Sets ............................................................................................................................................. 25 
8.2.1. 
Efficacy ................................................................................................................................ 25 
8.2.2. 
Safety .................................................................................................................................. 26 
8.3. Demographic Data and Baseline Characteristics ................................................................................ 26 
8.4. Primary Analysis ....................................................................................................................................... 26 
8.5. Secondary Analyses ................................................................................................................................ 26 
8.6. Safety Analysis.......................................................................................................................................... 26 
8.6.1. 
Adverse Events .................................................................................................................. 26 
8.6.2. 
Laboratory Evaluations ..................................................................................................... 26 
9. 
INVESTIGATOR & SPONSOR RESPONSIBILITIES ................................................................................. 27 
9.1. Investigator Responsibilities ................................................................................................................... 27 
9.1.1. 
Good Clinical Practice ....................................................................................................... 27 
9.1.2. 
Institutional Review Board (IRB) ..................................................................................... 27 
9.1.3. 
Informed Consent .............................................................................................................. 27 
9.1.4. 
Confidentiality ..................................................................................................................... 27 
9.1.5. 
Drug Accountability ........................................................................................................... 27 
9.1.6. 
Study Files and Retention of Records ............................................................................ 28 
9.1.7. 
Case Report Forms ........................................................................................................... 28 
9.1.8. 
Inspections .......................................................................................................................... 28 
9.1.9. 
Protocol Compliance ......................................................................................................... 28 
9.1.10. 
Access to Information for Monitoring .............................................................................. 29 
9.2. Sponsor Responsibilities ......................................................................................................................... 29 
9.2.1. 
Protocol Modifications ....................................................................................................... 29 
9.2.2. 
Study Drug: ......................................................................................................................... 29 
9.3. Study Discontinuation .............................................................................................................................. 29 
10. REFERENCES ................................................................................................................................................. 30 
APPENDIX 1. 
STUDY PROCEDURES TABLE ..................................................................................... 31 
 
 


 
Page 4 
 
 
PROTOCOL SYNOPSIS 
 
Study Title: 
A multicenter, open-label study of sofosbuvir ledipasvir fixed dose 
combination in subjects infected with chronic hepatitis C and 
advanced heart failure or lung disease 
 
Study sites: 
5  
 
Objectives: 
The primary objective is: 
• 
To evaluate the safety and tolerability of sofosbuvir (SOF) + 
ledipasvir (LDV) fixed dose combination (FDC) for 12-24 weeks 
in subjects with chronic HCV and advanced heart failure or lung 
disease. 
 
The secondary objective is:  
• 
To determine the antiviral efficacy of SOF/LDV FDC for 12-24 
weeks in subjects with chronic HCV and  advanced  heart 
failure or  lung disease  as measured by sustained virologic 
response 12 weeks after discontinuation of therapy (SVR12 
defined as HCV RNA < lower limit of quantitation 12 weeks 
post-treatment).  
 
 
Study Design: 
Approximately 25 subjects with chronic HCV and advanced heart 
failure and 25 subjects with chronic HCV and lung disease will be 
enrolled.  Subjects must have genotype 1, 4, 5 or 6 HCV.  All 
subjects will receive 12 weeks of the SOF/LDV FDC except for 
treatment experienced genotype 1 subjects with cirrhosis, who will 
receive 24 weeks of treatment. 
 
 
Number of Subjects: 
Approximately 50 subjects 
 
Eligibility Criteria: 
All subjects must meet all of the follow HCV criteria: 
 
• 
Genotype 1, 4, 5, or 6    
• 
HCV RNA > 103 IU/mL at screening 
• 
Age ≥ 18 years  
• 
Diagnosis of chronic HCV infection, defined as positive HCV 
antibody or HCV RNA more than 6 months prior to 
screening OR an assessment of fibrosis F2 or greater prior 
to screening. 
 
Subjects in the advanced heart failure cohort must meet ALL HCV 
criteria, and all of the following criteria: 
 
• 
New York Heart Association (NYHA) Class III or IV 
functional classification 
o NYHA Class III: Subjects with cardiac disease 
resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary 


 
Page 5 
 
 
physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
o NYHA Class IV: Patient with cardiac disease 
resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be 
present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
• 
ejection fraction ≤ 30% 
• 
hospitalized for heart failure in last 12 months 
 
 
Subjects in the advanced lung disease cohort must have been 
diagnosed with chronic obstructive pulmonary disease (COPD) 
or interstitial lung disease (ILD) must meet ALL HCV criteria, 
and meet the following criteria for COPD or ILD: 
 
• 
ILD criteria: diagnosis of interstitial lung disease with chronic 
supplemental oxygen requirement at rest and/or with 
exertion. 
• 
COPD criteria (one of the following): 
o Forced expiratory volume (FEV1)< 30% predicted 
o OR any FEV1 with chronic supplemental oxygen 
requirement at rest and/or with exertion 
o OR any FEV1 with chronic hypercapnea (baseline 
partial pressure of arterial carbon dioxide [PaCO2] > 
45) 
 
Subjects may not present with any of the criteria: 
• 
Genotype 2 or 3 infection 
• 
Treatment with any of the following agents 
o Amiodarone.  Subjects previously treated with 
amiodarone must have stopped the amiodarone at 
least 60 days prior to day 1 of SOF/LDV FDC 
o Carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine 
o Rifabutin, rifampin or rifapentine 
o HIV regimens containing tenofovir or 
tipranavir/ritonavir 
o St. John’s wort 
o Rosuvastatin 
• 
Have any serious or active medical or psychiatric illness 
which, in the opinion of the investigator, would interfere with 
subject treatment, assessment, or compliance 
• 
History of hepatic encephalopathy or variceal hemorrhage 
• 
Hepatitis B surface antigen positive 
• 
Abnormal hematological and biochemical parameters, 
including: 
o Hemoglobin (Hb) < 8 g/dL 


 
Page 6 
 
 
o Platelets ≤ 50,000/mm3 
o ALT (alanine aminotransferase),  AST (aspartase 
aminotransferase), or alkaline phosphatase ≥ 10 
times ULN 
o Total bilirubin > 3 mg/dl 
o Severe renal impairment creatinine clearance (CrCl), 
i.e. < 30 mL/min. 
• 
History of major organ transplantation with an existing 
functional graft. 
• 
History of clinically-significant drug allergy to 
nucleoside/nucleotide analogs. 
• 
Pregnant women or women planning to become pregnant 
• 
Women who are breastfeeding 
• 
Active or recent history (≤ 1 year) of drug or alcohol abuse 
 
 
 
Study 
Procedures/ 
Frequency: 
Study visits will occur at screening, baseline/day 1, weeks 2, 4, 8, 
12 for the 12-week treatment group and also weeks 16, 20 and 24 
for the 24-week treatment group.  Post-treatment follow-up visits 
will be performed at 4 and 12 weeks following the last dose of study 
drug for both groups. 
 
Screening assessments include physical examination with height 
and weight measurements, vital signs, medical history review for 
eligibility determination, safety laboratory tests, HCV RNA and HCV 
genotyping, HIV and HBV testing, serum β-hCG (females of 
childbearing potential only), ECG, and Fibroscan (if needed) 
 
On-treatment assessments include adverse events (AEs) 
assessments, concomitant medications, physical examination, vital 
signs, safety laboratory tests, HCV RNA, ECG 
 
Post-treatment assessments include adverse events (AEs) 
assessments, concomitant medications, physical examination, vital 
signs, safety laboratory tests, HCV RNA, ECG 
   
Test Product, 
Dose, and Mode 
of Administration: 
All study subjects will receive the sofosbuvir 400 mg and ledipasvir 
90 mg fixed dose combination.  Subjects will take one tablet in the 
morning. 
 
Evaluation criteria 
Safety 
 
 
 
 
 
Efficacy 
 
 
 
AEs that lead to discontinuation, SAEs and safety laboratory tests 
will be collected until 4 weeks after the last dose of study drug.  
Safety endpoints will include   
• 
Completion of full course of therapy 
• 
Discontinuation for adverse events 
• 
Serious adverse events 
 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA by PCR.  All endpoints will be summarized with descriptive 


 
Page 7 
 
 
statistics by cohort.  Number and percent of subjects in each cohort 
will be presented for categorical variables. For continuous 
variables, N, mean, SD, Median, Q1, Q3, minimum and maximum 
will be presented. 
The primary efficacy endpoint will be the SVR12 defined as HCV 
RNA < LLoQ for 12 weeks post-treatment.    
 


 
Page 8 
 
 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BW 
Body weight 
CLcr 
creatinine clearance 
COPD 
Chronic obstructive pulmonary disease 
CRF 
case report form(s) 
dL 
deciliter 
ECG 
electrocardiogram 
e.g. 
For example 
ET 
Early termination 
FDA 
(United States) Food and Drug Administration 
FDC 
Fix Dosed Combination 
FEV1 
Forced expiratory volume 
GCP 
Good Clinical Practice (Guidelines) 
Hb 
hemoglobin 
hCG 
human chorionic gonadotropin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
i.e. 
for explanation 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IRB 
institutional review board 
LDV 
ledipasvir 
LLoQ 
lower limit of Quantification 
MCV 
Mean corpuscular volume 
mg 
milligram 
mL 
milliliter 
Min 
minutes 
NYHA 
New York Heart Association 
PaCO2 
Partial pressure of arterial carbon dioxide 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PT 
Prothrombin time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
serious adverse event 
Scr 
Serum creatinine 
SD 
Standard deviation 
SOF 
sofosbuvir 
SVR 
Sustained Virologic Response, generally at 4 and 12 weeks after last 
dose of medication 
ULN 
upper limit of the normal range 
WBC 
White blood cell 
WHO 
World Health Organization 


 
Page 9 
 
 
1. 
INTRODUCTION 
 
1.1. Background 
Approximately 180 million people worldwide and more than 3 million Americans are infected 
with Hepatitis C virus (HCV).1,2  Chronic HCV infection is a leading cause of cirrhosis and 
hepatocellular carcinoma and remains the most common indication for transplantation in the 
United States.  For more than 20 years, HCV regimens included interferon-α, which led to a 
number of adverse events including constitutional symptoms, neuropsychiatric symptoms, and 
cytopenias.  These adverse events meant that many patients were ineligible or could not 
tolerate treatment.3 Due to the challenging side effect profile and moderate efficacy, a number of 
direct acting antiviral medications have been developed.  Interferon-free regimens are now 
available and are well tolerated and offer sustained virologic response (SVR) rates over 90% for 
many patient groups.4,5  
 
The development of these well tolerated, interferon-free regimens has led to the consideration 
of HCV treatment of patient groups felt to previously be ineligible.  In the past with interferon 
regimens, patients with advanced heart and lung disease were not offered HCV treatment 
generally due to the risk of exacerbation of the underlying disease.  At most transplant centers, 
the diagnosis of HCV infection is a contraindication to heart or lung transplantation.  Case series 
among HCV-seropositive heart transplant recipients have demonstrated increased mortality 
related to cardiovascular disease and progressive liver disease.6,7  Although a smaller number 
of patients, cases of progressive liver failure after lung transplantation have been reported in 
patients with HCV infection.8,  Successful treatment of HCV infection for patients with advanced 
heart and lung disease would potentially bring back the possibility of transplantation for these 
patients.   
 
1.2. Rationale for the current study  
The fixed dose combination of sofosbuvir/ledipasvir is a Food and Drug Administration (FDA) 
approved regimen for the treatment of chronic HCV infection.  Sofosbuvir/ledipasvir is 
recommended by the American Association for the Study of Liver Diseases and the Infectious 
Disease Society of America as a first line option for the treatment of genotype 1 and 4 patients.  
SVR rates over 90% were initially reported in the registration trials of sofosbuvir/ledipasvir for 
genotype 1 treatment naïve and experienced patients.4,9  Sofosbuvir/ledipasvir has subsequently 
been evaluated in other genotypes, and recent studies have demonstrated SVR rates greater 
than 90% for sofosbuvir/ledipasvir in genotypes 2, 3, 4 and 6.10,11  For genotype 3 infection, 
these high SVR rates require the addition of ribavirin to sofosbuvir/ledipasvir.  The main adverse 
event of ribavirin is hemolytic anemia, which may not be tolerated by patients with underlying 
heart and lung disease.  The protocol has therefore been restricted to genotypes 1, 4, 5 and 6 
given the ability to treat with the ribavirin-free regimen of the sofosbuvir/ledipasvir fixed dose 
combination. 
 


 
Page 10 
 
 
2. 
OBJECTIVES 
 
The primary objective is:  
 
• 
To evaluate the safety and tolerability of sofosbuvir (SOF) + ledipasvir (LDV) fixed dose 
combination (FDC) for 12-24 weeks in subjects with chronic HCV and advanced heart failure 
or lung disease 
 
The secondary objective is: 
 
• 
To determine the antiviral efficacy of SOF/LDV FDC for 12-24 weeks in subjects with chronic 
HCV and  advanced  heart failure or  lung disease  as measured by sustained virologic 
response 12 weeks after discontinuation of therapy (SVR12 defined as HCV RNA < lower 
limit of quantitation 12 weeks post-treatment).  


 
Page 11 
 
 
3. 
SUBJECT POPULATION 
3.1. Treatment plan and regimen 
 
Approximately 25 subjects with chronic HCV and advanced heart failure; and 25 subjects with 
chronic HCV and advanced lung disease will be enrolled.  Subjects must have genotype 1, 4, 5 
or 6 HCV.  All subjects will receive SOF/LDV FDC.  The duration of treatment will be 12 weeks 
for treatment naïve subjects with or without cirrhosis.  All subjects will receive 12 weeks of the 
SOF/LDV FDC except for treatment experienced genotype 1 subjects with cirrhosis, who will 
receive 24 weeks of treatment. All subjects will continue in the study follow-up period for 12 
weeks after treatment has been completed.   
 
3.2. Visit schedule 
All subjects will complete screening, on-treatment, and post-treatment follow up assessments. 
Screening assessments will be completed within 28 days of the baseline/day 1 visit. Study visits 
will occur at screening, baseline/day 1, weeks 2, 4, 8, 12 for the 12-week duration subjects and 
then also weeks 16, 20 and 24 for the 24-week duration group.  Post-treatment follow-up visits 
will be performed at 4 and 12 weeks following the last dose. 
 
3.3. Number of subjects and subject selection 
 
A total of approximately 50 subjects will be enrolled.  Approximately 25 subjects with advanced 
heart failure and 25 subjects with advanced lung disease will be enrolled.   
 
3.4. Inclusion criteria 
 
All subjects must meet all of the follow HCV criteria: 
 
• 
Genotype 1, 4, 5, or 6    
• 
HCV RNA > 103 IU/mL at screening 
• 
Age ≥ 18 years  
• 
Diagnosis of chronic HCV infection, defined as positive HCV antibody or HCV RNA more 
than 6 months prior to screening OR an assessment of fibrosis F2 or greater prior to 
screening. 
 
Subjects in the advanced heart failure cohort must meet ALL HCV criteria, and all of the 
following criteria: 
 
• 
New York Heart Association (NYHA) Class III or IV functional classification 
o NYHA Class III: Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary physical 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 


 
Page 12 
 
 
o NYHA Class IV: Patient with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
• 
ejection fraction ≤ 30% 
• 
hospitalized for heart failure in last 12 months 
 
 
Subjects in the advanced lung disease cohort must have been diagnosed with chronic 
obstructive pulmonary disease (COPD) or interstitial lung disease (ILD) must meet ALL 
HCV criteria, and meet the following criteria for COPD or ILD: 
 
• 
ILD criteria: diagnosis of interstitial lung disease with chronic supplemental oxygen 
requirement at rest and/or with exertion. 
• 
COPD criteria (one of the following): 
o Forced expiratory volume (FEV1)< 30% predicted 
o OR any FEV1 with chronic supplemental oxygen requirement at rest and/or with 
exertion 
o OR any FEV1 with chronic hypercapnea (baseline partial pressure of arterial 
carbon dioxide [PaCO2] > 45) 
 
 


 
Page 13 
 
 
3.5. Exclusion Criteria 
 
• 
Genotype 2 or 3 infection 
• 
Treatment with any of the following agents 
o Amiodarone.  Subjects previously treated with amiodarone must have stopped 
the amiodarone at least 60 days prior to day 1 of SOF/LDV FDC 
o Carbamazepine, phenytoin, phenobarbital, oxcarbazepine 
o Rifabutin, rifampin or rifapentine 
o HIV regimens containing tenofovir or tipranavir/ritonavir 
o St. John’s wort 
o Rosuvastatin 
• 
Have any serious or active medical or psychiatric illness which, in the opinion of the 
investigator, would interfere with subject treatment, assessment, or compliance 
• 
History of hepatic encephalopathy or variceal hemorrhage 
• 
Hepatitis B surface antigen positive 
• 
Abnormal hematological and biochemical parameters, including: 
o Hemoglobin (Hb) < 8 g/dL 
o Platelets ≤ 50,000/mm3 
o ALT (alanine aminotransferase),  AST (aspartase aminotransferase), or alkaline 
phosphatase ≥ 10 times ULN 
o Total bilirubin > 3 mg/dl 
o Severe renal impairment creatinine clearance (CrCl), i.e. < 30 mL/min. 
• 
History of major organ transplantation with an existing functional graft. 
• 
History of clinically-significant drug allergy to nucleoside/nucleotide analogs. 
• 
Pregnant women or women planning to become pregnant 
• 
Women who are breastfeeding 
• 
Active or recent history (≤ 1 year) of drug or alcohol abuse 
 


 
Page 14 
 
 
4. 
PACKAGING AND LABELING 
Sufficient quantities of SOF/LDV FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Almac.  Almac will receive marketed product, and label it 
specifically for this study. 


 
Page 15 
 
 
5. 
STUDY PROCEDURES 
 
 
5.1. Subject Enrollment  
All subjects will complete screening, on-treatment, and post-treatment follow up assessments. 
Screening assessments will be completed within 28 days of the Baseline/Day 1 Visit.  All 
subjects will receive 12 weeks of the SOF/LDV FDC except for treatment experienced genotype 
1 subjects with cirrhosis, who will receive 24 weeks of treatment.  Study visits will occur at 
screening, baseline/day 1, weeks 2, 4, 8, 12 for subjects receiving 12 weeks of treatment and 
then weeks 16, 20 and 24 for subjects receiving 24 weeks of treatment.  Post-treatment 
follow-up visits will be performed at 4 and 12 weeks following the last dose of study drug. 
 
5.2. Study Visit Procedures 
 
5.2.1. 
Screening Visit (Day -28 to -1) 
Subjects will be screened within 28 days before baseline/Day 1 visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening: 
• 
Obtain written informed consent.  
• 
Review of inclusion and exclusion criteria including: 
 Adequate documentation of the following for treatment-experienced subjects: 
■ Documentation of chronic HCV infection 
■ Start and stop dates for prior HCV treatment history 
■ Prior viral response data, if prior treatment taken  
 Review of excluded medications/concomitant medications 
• 
Obtain medical history 
• 
Complete physical examination including, vital signs, body weight, and height 
• 
ECG 
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 PT-INR 
 HCV RNA and HCV genotype and subtype 
 Serology for HBV and HIV 
 Serum β-hCG (females of child bearing potential only) 
• 
Adequate documentation of chronic HCV infection, defined as positive HCV antibody; or 
HCV RNA more than 6 months prior to screening; or an assessment of fibrosis F2 or greater  
• 
Fibroscan (unless performed within 6 months of screening) 
 
Subjects who consent to the study and meet all of the inclusion criteria and none of the 
exclusion criteria may return to the clinic within 28 days after screening for enrollment 
into the study and baseline assessments. 
 


 
Page 16 
 
 
5.2.2. 
Baseline/Day 1 Assessments 
The following baseline tests and procedures must be completed prior to dosing/dispensing and 
administration of study drug: 
• 
Review of inclusion and exclusion criteria and expectations for subject participation and 
protocol adherence, including list of excluded medications 
• 
Perform complete physical examination 
• 
Obtain vital signs and body weight 
• 
Assessment of AEs  and concomitant medications 
• 
Pregnancy prevention counseling 
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 HCV RNA  
• 
Urine β-hCG pregnancy test (females of child bearing potential only). If positive, a serum 
β-hCG must be performed and confirmed to be negative prior to initiation of study drug. 
• 
Dispense drug 
• 
Instruct the subject on the packaging, storage and administration of drug 
 
5.2.3. 
Weeks 2 and 8 for 12-week duration and weeks 16 and 20 for 
24-week duration (± 5 days)  
The following tests and procedures are to be completed: 
• 
Obtain vital signs 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 HCV RNA levels 
• 
Urine β-hCG pregnancy test (females of child bearing potential only). If positive, a serum 
β-hCG must be performed and confirmed to be negative prior to initiation of study drug. 
• 
Review medication compliance   
 
5.2.4. 
Week 4 (± 5 days) for all durations 
The following tests and procedures are to be completed: 
• 
Obtain vital signs 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 HCV RNA  
• 
Urine β-hCG pregnancy test (females of child bearing potential only). If positive, a serum 
β-hCG must be performed and confirmed to be negative prior to initiation of study drug. 
• 
ECG 
• 
Review medication compliance   
 
 


 
Page 17 
 
 
5.2.5. 
Week 12 for 12-week duration and Week 24 for 24-week 
duration (± 5 days) 
The following tests and procedures are to be completed: 
• 
Obtain vital signs 
• 
Obtain weight 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 PT-INR 
 HCV RNA  
• 
Urine β-hCG pregnancy test (females of child bearing potential only). If positive, a serum 
β-hCG must be performed and confirmed to be negative prior to initiation of study drug. 
• 
ECG 
• 
Review medication compliance   
 
 
 
5.2.6. 
Early Termination (ET) or Unscheduled Visit 
Subjects should complete an Early Termination (ET) Visit as soon as possible after study drug 
is discontinued. The subject should follow the scheduled Post-Treatment follow-up visits 
(refer to Section 6.4) based on the date of their last dose of study drug. 
The following tests and procedures are to be completed at the Early Termination visit: 
• 
Perform complete Physical examination 
• 
Obtain vital signs 
• 
Obtain weight  
• 
Assessment of AEs and concomitant medications 
• 
Review medication compliance with subject  
• 
Obtain blood samples for: 
 Hematology 
 Chemistry 
 PT-INR 
 HCV RNA  
• 
Urine β-hCG pregnancy test (females of child bearing potential only).  
• 
ECG 
 
5.2.7. 
Post-Treatment Weeks 4 and 12 (± 5 days) 
• 
Obtain vital signs (includes resting blood pressure, pulse, respiratory rate and temperature) 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for:   
 Hematology 
 Chemistry  
 HCV RNA 
• 
Urine β-hCG pregnancy test (females of child bearing potential only).  
• 
ECG 


 
Page 18 
 
 
 
5.3. Visit Specifications 
 
5.3.1. 
Clinical Laboratory Analytes 
 
Laboratory evaluations will be performed at the sites’ local laboratory. Laboratory data will be 
entered into the REDCap database by the site.  
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, Reticulocyte count and MCV. 
Coagulation: INR, Prothrombin time (PT) 
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Serum Creatinine, Total Bilirubin (Direct Bilirubin as reflex if 
total is elevated), Glucose, Lipase, Potassium, and Sodium. 
Virologic Tests: Serology studies for HBV and HIV. HCV RNA by Polymerase Chain Reaction 
(PCR), HCV genotype and subtype,   
Pregnancy Tests: Serum β-hCG at screening, Urine β-hCG at other visits (if positive, requires 
immediate confirmation with Serum β-hCG) 
 
5.3.2. 
Medical History 
Medical history including previous treatment, 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. In addition, previous HCV treatment and response to that 
treatment (null responder, partial responders or relapser) will be captured in the source 
documents and database. 
 
5.3.3. 
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.  
 
5.3.4. 
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation12 using actual body weight 
(BW).  
Male:  
CLcr (mL/min) = [140 − age (years)] × BW(kg) 
 
 
 
 
 
 
72 × Scr
 
 
Female: 
CLcr (mL/min) = [140 − age (years)] × BW(kg) × 0.85 
 
 
 
 
 
 
72 × Scr 
Scr = serum creatinine (mg/dL) 
Creatinine clearance will be calculated by the site, and entered into the database.  


 
Page 19 
 
 
 
5.3.5. 
Body Mass Index (BMI) 
Height and weight will be measured without shoes. Height will be measured at screening only; 
weight should be obtained at each study visit. BMI will be calculated at Screening for inclusion 
criteria using the following formula: 
BMI = 
weight (pounds) × 
703 
(height in inches)2 
or 
weight in kilograms 
(height in meters)2 
 
BMI will be calculated by the site, and entered into the database. 
 
 
5.3.6. 
Vital Signs 
Subjects will have a resting blood pressure, pulse, respiratory rate and temperature recorded. 
5.3.7. 
12-Lead ECGs 
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
gross abnormalities. 
 
5.3.8. 
HCV Genotyping 
HCV genotype (subtype) will be performed during Screening by the local laboratory using 
whatever standard testing is approved at the laboratory. This data will be entered into the 
database. 
 


 
Page 20 
 
 
6. 
STOPPING CRITERIA 
 
6.1. Virologic Response-Based Stopping Criteria 
HCV RNA ≥LLoQ through 8 weeks of treatment 
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation. The investigator is responsible for reviewing HCV RNA data to determine if 
confirmation or retesting is required,  
 
6.2. Stopping Rules for Individual Subjects 
Subjects who meet any of the following criteria should be discontinued from the study and 
complete an Early Termination Visit and return for Post-treatment Follow-up visits: 
• 
Elevation of ALT and/or AST >5x baseline or 5x nadir (unrelated to any interventional 
procedure) 
• 
Confirmed total bilirubin >3x baseline or 3x nadir with the total bilirubin > 5 mg/dL  
 If total bilirubin > 5mg/dL, bilirubin should be monitored on a weekly basis.  
 If direct bilirubin > 3mg/dL, study drugs should be discontinued. 
• 
Any non-laboratory Grade 4 event assessed as related to treatment with SOF/LDV  
• 
Worsening of disease state as evidenced by progressing hepatic decompensation  
 
The investigator is responsible for reviewing local laboratory results to determine if a stopping 
rule has been met. 
 
 
6.3. Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or create a safety risk for the subject.   
• 
Unacceptable toxicity, as defined in the toxicity management section of 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 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy or partner pregnancy during the study 
• 
Discontinuation of the study at the request of study sponsor,  regulatory agency or an IRB 
  
6.4. Discontinuations 
If the subject meets the Virologic Response-Based Criteria (Section 6.6), the Stopping Rules for 
Individual Subjects (Section 6.7) or other criteria for discontinuation of study treatment 
(Section 6.8), the subject should complete an Early Termination Visit as soon as possible after 
all therapy is discontinued. The subject should continue to follow the applicable Post-Treatment 
visit schedule. Evaluation of stopping rules for each subject will be determined by the Principal 
Investigator (PI) at the site.   
 


 
Page 21 
 
 
Subjects discontinuing treatment prior to completion of the assigned dosing period for reasons 
other than those described in Section 6 should complete the assessments for early termination 
as described in Section 5.2.6.  
 
Subjects with HCV RNA < LLoQ who permanently discontinue all study drugs for any reason 
including safety and/or tolerability concerns prior to completion of the assigned dosing period 
should complete the early termination visit and will be followed according to the post-treatment 
study assessments to determine whether the subject achieves SVR. 
 
6.5. Assessments for Premature Discontinuation from Study 
If a subject discontinues medication dosing (for example, as a result of an adverse event [AE]), 
every attempt should be made to keep the subject in the study and continue to perform the 
required study-related follow-up and procedures. If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study. 
 
 
 


 
Page 22 
 
 
7. 
ADVERSE EVENTS  
7.1. Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
AEs also include the following: 
• 
Pre- or post-treatment complications that occur as a result of protocol mandated procedure 
(e.g. such as venipuncture, biopsy) during or after screening (before the administration of 
study medicinal product). 
• 
Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study medicinal product phase of a human clinical trial, will also be 
considered an AE. 
• 
Complications and termination of pregnancy  
 
An AE does not include the following: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure is an adverse event 
• 
Pre-existing diseases or conditions or laboratory abnormalities present or detected before 
the screening visit that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions) 
• 
Overdose without clinical sequelae  
• 
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered pre-existing and should be documented on the medical history CRF. 
• 
Uncomplicated pregnancy. 
• 
An induced elective abortion to terminate a pregnancy without medical reason. 
 
Only adverse events that lead to drug discontinuation or withdrawal will be entered 
into the database. 
7.2. Assessment of Adverse Events 
All AEs will be assessed by the investigator or qualified designee and only AEs that lead to 
discontinuation will be recorded on the AE CRF page. The AE entry should indicate whether or 
not the AE was serious, the start date (AE onset), the stop date (date of AE resolution), whether 
or not the AE was related to medicinal product, the action taken with medicinal product due to 
the AE, and the severity of the AE..   
 
7.3. Serious Adverse Events 
A serious adverse event (SAE) is defined as follows: 
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes: 


 
Page 23 
 
 
• 
Death 
• 
Life-threatening situation (subject is at immediate risk of death) 
• 
In-patient hospitalization or prolongation of existing hospitalization (excluding those for study 
therapy or placement of an indwelling catheter, unless associated with other SAEs) 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect in the offspring of a subject who received medicinal product 
• 
Other: medically significant events that may not be immediately life-threatening or result in 
death or hospitalization, but based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above 
Examples of such events are as follows: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 
Clarification of Serious Adverse Events 
• 
Death is an outcome of an AE, and not an adverse event in itself. In reports of death due to 
“Disease Progression,” where no other information is provided, the death will be assumed to 
have resulted from progression of the disease being treated with the medicinal product(s). 
• 
The subject may not have been on medicinal product at the occurrence of the event. Dosing 
may have been given as treatment cycles or interrupted temporarily before the onset of the 
SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department. 
• 
The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
 
A distinction should be drawn between seriousness and severity of AEs. An AE that is assessed 
as Grade 4 (potentially life-threatening) should not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed 
as Grade 4. An event is defined as “serious” when it meets one of the predefined outcomes 
described above in Section 7.3. 
 
7.3.1. 
Serious Adverse Event Reporting Requirements 
Investigators are to submit a MedWatch 3500 form to FDA on any event that, in the 
investigator’s opinion, is related to the study drug and is unexpected. Send a copy of the 
MedWatch form to the DCRI. 
 


 
Page 24 
 
 
7.3.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that lead to discontinuation must be recorded as an AE, as 
well as an SAE, if applicable.  
 
 
 


 
Page 25 
 
 
8. 
STATISTICAL CONSIDERATIONS 
8.1. Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objective of this study is: 
• 
To evaluate the safety and tolerability of SOF/ FDC for 12-24 weeks in subjects with 
advanced  heart failure or  lung disease 
The secondary objective of this study is:  
• 
To determine the antiviral efficacy of SOF/LDV FDC for 12-24 weeks in subjects with chronic 
HCV and  advanced  heart failure or  lung disease  as measured by sustained virologic 
response 12 weeks after discontinuation of therapy (SVR12 defined as HCV RNA < lower 
limit of quantitation 12 weeks post-treatment).  
8.1.2. 
Primary Endpoint 
The primary safety endpoint is the proportion of subjects who complete a full course of therapy.  
The primary efficacy endpoint is SVR12 (HCV RNA < lower limit of Quantification [LLoQ] 
12 weeks after last dose of study drug).  
 
8.1.3. 
Secondary Endpoints 
The main efficacy endpoint will be the measurement of SVR12, 12  weeks after discontinuation 
of therapy. Secondary efficacy endpoints include SVR4, 4 weeks after discontinuation of 
therapy. 
8.1.4. 
Safety Endpoints 
In addition to the primary endpoint of completion of full course of therapy, safety endpoints will 
include rates of discontinuation for adverse events and serious adverse events.  Safety will also 
be assessed with adverse events and laboratory tests. 
8.1.5. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS software version 9.2 or higher (SAS Institute, Cary, North Carolina, 
USA).In general, all endpoints will be summarized with descriptive statistics by treatment group 
and analysis time point. For categorical variables, number and percentage of subjects in each 
category will be presented. Continuous variables will be descriptively summarized with n, mean, 
standard deviation (SD), median, Q1, Q3, minimum and maximum by treatment group. For SVR 
endpoints 95% confidence intervals will also be constructed. 
 
8.2. Analysis Sets 
8.2.1. 
Efficacy 
The primary analysis set for efficacy analyses will include all subjects with HCV infection who 
received at least one dose of study drug. 


 
Page 26 
 
 
 
8.2.2. 
Safety 
The primary analysis set for safety analyses will include all subjects with HCV infection who 
received at least one dose of study drug. 
 
8.3. Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment arm and overall.  Demographic summaries will include sex, race/ethnicity, 
stratification group, age.  Baseline data will include a summary of body weight, height, body 
mass index, HCV genotype, and HCV RNA level (log10 IU/mL).  
 
8.4. Primary Analysis 
The primary efficacy analysis will report the number and percent of subjects achieving SVR12 
response will be calculated for each arm along with exact 95% confidence intervals.   
 
8.5. Secondary Analyses 
The proportion of subjects with HCV RNA below the LLoQ over time (including SVR endpoints) 
will be presented by treatment arm in tabular and graphical form.  
 
8.6. Safety Analysis 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, at various time points during the study, and by the documentation of AEs. 
All safety data collected while “on treatment” (i.e., on or after the first dose of study drug 
administration up to 30 days after the last dose of study drug) will be summarized by treatment 
arm according to the study drug received.   
 
8.6.1. 
Adverse Events 
Clinical and laboratory adverse events will be summarized on the basis of the date of onset for 
the event. A treatment-emergent adverse event will be defined as any adverse event that begins 
on or after the date of first dose of medicinal product up to the date of last dose of medicinal 
product plus 30 days.  
 
8.6.2. 
Laboratory Evaluations 
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) and study visit along with corresponding change from Baseline/Day 1.  These 
laboratory data to be analyzed are: 
Hematology: Hemoglobin (Hb), Platelet count, White blood cell count (WBC)  
Coagulation: INR, Prothrombin time (PT) 
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Serum Creatinine, Total Bilirubin (Direct Bilirubin as reflex if 
total is elevated) 
Virologic Tests: HCV RNA; HCV genotype and subtype; HIV  
 


 
Page 27 
 
 
9. 
INVESTIGATOR & SPONSOR RESPONSIBILITIES 
9.1. Investigator Responsibilities 
9.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” as expressed in the International Conference on Harmonisation (ICH) 
guidelines (ICH E6), or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study subject.   
 
9.1.2. 
Institutional Review Board (IRB) 
This protocol will be submitted by the investigator to an IRB (for studies conducted in the 
United States. Approval from the IRB must be obtained before starting the study and should be 
documented in a letter to the investigator specifying the protocol number, protocol version, 
protocol date, documents reviewed, and date on which the committee met and granted the 
approval. A copy of the IRB-approved Informed Consent Form (ICF) should be included with the 
approval documents. Any modifications made to the protocol after receipt of IRB approval must 
also be submitted to the IRB, for approval before implementation. 
 
9.1.3. 
Informed Consent 
The investigator 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 
investigator must utilize an IRB- approved consent form for documenting written informed 
consent. Each informed consent will be appropriately signed and dated by the subject or the 
subject’s legally authorized representative and the person obtaining consent. 
 
9.1.4. 
Confidentiality 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are not disclosed to unauthorized parties. Only an identification code (i.e. not names, 
initials, or date of birth) should be recorded on any form or biological sample submitted to the 
Sponsor, IRB, or laboratory. The investigator agrees that all information received from the 
sponsor, including but not limited to the protocol, CRFs, and any other study information, remain 
the sole and exclusive property of the sponsor during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
 
9.1.5. 
Drug Accountability 
The investigator is responsible for ensuring accountability of all used and unused study drug. 
This includes acknowledgment of receipt of each shipment of study product (quantity and 
condition), subject dispensing records, and returned or destroyed study product.  Dispensing 


 
Page 28 
 
 
records will document quantities received and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication. Documentation will be maintained by the site; no data will be entered 
into the database.  
 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study.  
 
The investigator’s study file will contain the protocol/amendments, IRB approval, approved ICF, 
and drug records, at a minimum, source records to be documented in the medical record by the 
investigator are listed below: 
• 
subject identification by study code; 
• 
documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria); 
• 
participation in trial (including trial number); 
• 
date of informed consent; 
• 
dates of all visits; 
• 
documentation that protocol specific procedures were performed; 
• 
results of efficacy parameters, as required by the protocol; 
• 
start and end date (including dose regimen) of medication record of all adverse events and 
other safety parameters (start and end date, and preferably including causality and 
intensity); 
• 
concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated); 
• 
date of trial completion and reason for early discontinuation, if applicable. 
 
9.1.7. 
Case Report Forms 
For each subject enrolled, REDCAP database screens must be completed by the investigator or 
designee within a reasonable time period after patient visit. This also applies to records for 
those subjects who fail to complete the study. Information on subjects who choose to not enroll 
or screen fail, will not be collected. If a subject withdraws from the study, the reason must be 
noted in the database. If a subject is withdrawn from the study because of a treatment-limiting 
adverse event, thorough efforts should be made to clearly document the outcome. 
 
9.1.8. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from DCRI or its representatives, to IRBs, and to 
regulatory authorities as needed.  
 
 
9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
 


 
Page 29 
 
 
9.1.10. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice guidelines (ICH E6), the study monitor or other 
study personnel must have direct access to the investigator’s source documentation in the event 
source data verification is required. The investigator agrees to cooperate with the monitor to 
ensure that any discrepancies detected in the course of data monitoring are resolved. 
 
 
9.2. Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may 
be made only by the sponsor. All protocol modifications must be submitted to the IRB in 
accordance with local requirements. Approval must be obtained before changes can be 
implemented. 
 
9.2.2. 
Study Drug: 
 
All study subjects will receive the sofosbuvir 400 mg and ledipasvir 90 mg fixed dose 
combination.  Subjects will take one tablet in the morning. 
 
Study medication will be provided by Gilead. Gilead will ship drug to Almac, for distribution to 
the sites. Sites will be responsible for tracking drug, and reordering if needed. For questions 
related to study drug, contact the sponsor Project Leader who will work with Almac to resolve 
any questions.  
 
 
9.3. Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authority and IRBs. In terminating the study, the sponsor and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests. 


 
Page 30 
 
 
10. 
REFERENCES 
1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of 
hepatitis C virus infection: new estimates of age-specific antibody to HCV 
seroprevalence. Hepatology. 2013; 57(4):1333-42. 
2. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The 
prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann 
Intern Med. 2006;144(10):705-14. 
3. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment 
of hepatitis C: an update. Hepatology. 2009;49(4):1335-74. 
4. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
Sofosbuvir for Untreated HCV Genotype 1 Infection. N Engl J Med. 2014. 
5. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. Treatment of 
HCV with ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin. N Engl J Med. 2014.  
6. (1)Lee I, Localio R, Brensinger CM, Blumberg EA, Lautenbach E, Gasink L, et al. 
Decreased post-transplant survival among heart transplant recipients with pre-transplant 
hepatitis C virus positivity. J Heart Lung Transplant. 2011;30(11):1266-74. 
7. Fagiuoli S, Minniti F, Pevere S, Farinati F, Burra P, Livi U, et al. HBV and HCV infections 
in heart transplant recipients. J Heart Lung Transplant. 2001;20(7):718-24. 
8. Sahi H, Zein NN, Mehta AC, Blazey HC, Meyer KH, Budev M. Outcomes after lung 
transplantation in patients with chronic hepatitis C virus infection. J Heart Lung 
Transplant. 2007;26(5):466-71.(2) 
9. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 
2014;370(16):1483-93. 
10. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia ES, Pang PS, et al. Once Daily 
Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the 
ELECTRON trial. Hepatology. 2013;58(Suppl 1):243A. 
11. Kapoor R, Kohli A, Sidharthan S, Sims Z, T.L. P, Osinusi A, et al. All Oral Treatment for 
Genotype 4 Chronic Hepatitis C Infection with Sofosbuvir and Ledipasvir: Interim Results 
from the NIAID SYNERGY Trial. Hepatology. 2014;60(Suppl 4):321A. 
12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
 
 


 
 
Page 31 
 
 
APPENDIX 1. 
STUDY PROCEDURES TABLE 
Procedure 
Screening: 
Day -28 to 
-1 
Baseline   
Day 11 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Early Term 
or 
Unscheduled 
Post-
treatment 
Week 4 
Post-
treatment 
Week 12 
Informed Consent 
X 
Eligibility review2 
X 
X 
AE and con meds 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy prevention 
counseling 
X 
Dispense and instruct 
on use of drug 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
Physical exam3 
X 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight5 
X 
X 
X 
X 
X 
                                                 
1 All physical procedures and review procedures to be performed prior to dispensing or dosing with drug 
2 Includes adequate documentation of start/stop dates for prior HCV therapy; prior viral response data; and chronic HCV infection. Includes review of excluded 
concomitant medications. 
3 General appearance; body system review: head, neck, thyroid, eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory, cardiovascular; 
lymph nodes, abdomen; skin, hair nails;  musculoskeletal; neurological 
4 Resting blood pressure, pulse, respiratory rate, and temperature 
5 Weight to be obtained at last treatment visit, either week 12 or week 24 


 
 
Page 32 
 
 
Procedure 
Screening: 
Day -28 to 
-1 
Baseline   
Day 11 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Early Term 
or 
Unscheduled 
Post-
treatment 
Week 4 
Post-
treatment 
Week 12 
Height 
X 
ECG6 
X 
X 
X 
X 
X 
X 
X 
Fibroscan7 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments 
Hematology8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation10 
X 
X 
X 
X 
HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV 
Genotype 
X 
 
HIV serology 
X 
HBV serology 
X 
Serum β-hCG   
X 
Urine β-hCG11   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
6 After resting in supine position for ≥ 5 minutes 
7 If not done within 6 months of screening 
8 Includes hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white blood cell count (WBC) with differential (absolute and percentage) 
including lymphocytes, monocytes, neutrophils, eosinophils, basophils, reticulocyte count and MCV 
9 Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SCOT), albumin, alkaline phosphatase, serum creatinine, total bilirubin (direct 
bilirubin as reflex if total is elevated), glucose, lipase, potassium, and sodium 
10 Includes INR, and Prothrombin time (PT) 
11 If positive, requires immediate confirmation with serum β-hCG   


 
 
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