Clinical trial NCT02304159
Conditions: Hepatitis C Cirrhosis
Keywords: HCV Genotype 3 Treatment naive Treatment experienced
Sponsor: Tarek I. Hassanein, M.D., FACP, FAG, AGAF
Start date: 2015-01-01; Completion date: 2017-08-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open label, single center safety and efficacy study. At least 40 cirrhotic subjects with HCV genotype 3 will receive standard of care treatment of sofosbuvir and ribavirin (SOF/RBV) as well as 60 mg daily of Daclatasvir (investigational product). Subjects will be randomized in a 1:1 to receive either:

* Group A: 16 weeks of DCV/SOF/RBV
* Group B: 24 weeks of DCV/SOF/RBV

Subjects will return to the study center at various time points throughout the 16 or 24 weeks of treatment in addition to 12 weeks post taking last dose of study drug to monitor safety and efficacy. These visits will be according to standard of care.

Detailed description:

Arms: arm 1: Combination of sofosbuvir 400 mg daily, ribavirin 1000-1200 mg daily (weight based) and daclatasvir 60 mg daily for 16 weeks arm 2: Combination of sofosbuvir 400 mg daily, ribavirin 1000-1200 mg daily (weight based) and daclatasvir 60 mg daily for 24 weeks
Interventions: intervention 1: daclatasvir intervention 2: Sofosbuvir, Sovaldi intervention 3: Ribavirin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Protocol for Investigator Initiated Study: 
 
A Randomized Study to Evaluate the Safety and Efficacy of Adding Daclatasvir to 
the Combination of Sofosbuvir (SOF) and Ribavirin (RBV) for 16 Weeks Versus 
24 Weeks in Cirrhotic Subjects with Chronic Hepatitis C Infection Genotype 3 
(AI444284) 
 
 
 
 
 
 
 
 
 
 
 
Phase: IV 
Investigational Product: Daclatasvir  
Central Study Site: Southern California Research Center (SCRC) 
 
Version 0 Release Date: September 29, 2014 
Version 1 Release Date: October 29, 2014 
Version 2 Release Date: October 31, 2014 
Version 3 Release Date: November 17, 2014 
Version 4 Release Date: December 16, 2014 
Version 5 Release Date: January 7, 2015 
Version 6 Release Date: February 3, 2015 
Version 7 Release Date: September 5, 2015 
 
Confidentiality Statement 
 
The information contained in this document is confidential and proprietary property of Southern 
California Research Center, Inc.  Any distribution, copying, or disclosure is strictly prohibited 
unless federal regulations or state law requires such disclosure.  Prior written authorization of 
Southern California Research Center, Inc., is required for any disclosure or use of the 
information contained herein.  Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 


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Protocol Table of Contents 
1. 
ABBREVIATIONS ........................................................................................................................... 4 
2. 
BACKGROUND ............................................................................................................................... 8 
2.1 Chronic Hepatitis C ...................................................................................................................... 8 
2.2 Sofosbuvir .................................................................................................................................... 9 
2.3 Daclatasvir ................................................................................................................................... 9 
2.4 Daclatasvir / Sofosbuvir Combination ....................................................................................... 10 
2.5 Rationale for Dose Selection ..................................................................................................... 12 
2.6 Rationale for treatment duration ................................................................................................ 13 
2.7 Rationale for study ..................................................................................................................... 13 
3. 
STUDY OBJECTIVES .................................................................................................................... 14 
3.1 Primary Objective ...................................................................................................................... 14 
3.2 Secondary Objectives ................................................................................................................. 14 
4. 
INVESTIGATIONAL PLAN .......................................................................................................... 15 
4.1 Study Design Overview ............................................................................................................. 15 
4.2 Study Population ........................................................................................................................ 15 
4.3 Study Drug ................................................................................................................................. 19 
4.4 Randomization ........................................................................................................................... 20 
4.5 Concomitant and Excluded Therapy .......................................................................................... 20 
4.6 Lost to follow-up ........................................................................................................................ 21 
4.7 Study Termination ..................................................................................................................... 21 
5. 
SAFETY AND EFFICACY ASSESSMENTS ................................................................................ 22 
5.1 Safety Variables and Assessments ............................................................................................. 22 
5.2 Efficacy Variables and Assessments ......................................................................................... 22 
5.3 Study Assessments ..................................................................................................................... 22 
6. 
ADVERSE EVENTS ....................................................................................................................... 24 
6.1 Adverse Event (AE) ................................................................................................................... 24 
6.2 Serious Adverse Event (SAE) .................................................................................................... 25 
6.3 Severity ...................................................................................................................................... 26 
6.4 Relationship ............................................................................................................................... 26 
6.5 Recording Adverse Events or Serious Adverse Events ............................................................. 27 
6.6 Follow-up of Adverse Event or Serious Adverse Event and Outcome ...................................... 27 
6.7 Pregnancy ................................................................................................................................... 27 
6.8 Overdose .................................................................................................................................... 28 
7. 
EXPECTED ADVERSE EVENTS AND MANAGEMENT .......................................................... 28 
7.1 DCV 28 
7.2 Standard of care treatment and DCV ......................................................................................... 31 
7.3 Other expected adverse events ................................................................................................... 32 
7.4 Pregnancy ................................................................................................................................... 33 
8. 
STATISTICAL ANALYSIS ........................................................................................................... 33 


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8.1 Sample Size ................................................................................................................................ 33 
8.2 Statistical Methods and Analysis Populations ........................................................................... 34 
8.3 Interim Analysis ......................................................................................................................... 34 
9. 
STUDY ADMINISTRATION: ETHICAL AND LEGAL ASPECTS ........................................... 34 
9.1 Human Subjects and Informed Consent .................................................................................... 34 
9.2 Institutional Review Board/Independent Ethics Committee ...................................................... 34 
9.3 Obligations of the Investigator ................................................................................................... 35 
9.4 Quality Assurance ...................................................................................................................... 35 
9.5 Study Documentation and Records Retention ........................................................................... 35 
10. REFERENCES ................................................................................................................................ 36 
11. APPENDICES ................................................................................................................................. 36 
A. Schedule of Assessments ........................................................................................................... 37 
B. History of Protocol Changes ...................................................................................................... 39 


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1. ABBREVIATIONS  
 
Abbreviation  
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APRI 
aspartate aminotransferase platelet ratio index 
AST 
aspartate aminotransferase 
ASV 
Asunaprevir 
HCG 
human chorionic gonadotrophin 
BID 
bis in die, twice daily 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb 
BOC 
boceprevir  
BUN 
blood urea nitrogen 
C 
Celsius 
CFR 
Code of Federal Regulations  
CHC 
chronic hepatitis C 
CI 
confidence interval 
Cm 
Centimeter 
Cmax, CMAX 
maximum observed concentration 
Cmin, CMIN 
trough observed concentration 
CrCl 
creatinine clearance 
CRF 
Case Report Form, paper 
CVR 
combined virologic response 
CYP 
cytochrome p-450 
D/C 
discontinue 
DAA 
direct acting antiviral 
DCV 
daclatasvir 
DCV/ASV 
daclatasvir and asunaprevir combination therapy 
DCV/SOF 
daclatasvir and sofosbuvir combination therapy 
DILI 
drug-induced liver injury 


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dL 
Deciliter 
DMC 
Data Monitoring Committee 
DSM IV 
Diagnostic and Statistical Manual of Mental Disorders (4th 
Edition) 
DUAL 
daclatasvir/asunaprevir therapy 
EAP 
Expanded Access Program 
ED50 
50% effective concentration 
ECG 
electrocardiogram 
E.g. 
exempli gratia (for example) 
EOT 
End of Treatment 
ERCP 
endoscopic retrograde cholangiopancreatography 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
G 
gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GT 
genotype 
H 
hour 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
heptaocellular carcinoma 
HCV 
hepatitis C virus 
HE 
hepatic encephalopathy 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal products 
IND 
Investigational New Drug Exemption 
IRB 
Institutional Review Board 
IU 
International Unit 
IUD 
intrauterine device 
Kg 
kilogram 


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L 
liter 
LDV 
ledipasvir 
LLOQ 
lower limit of quantification 
LT 
liver transplant 
Mg 
milligram 
Min 
minute 
mITT 
modified intent-to-treat 
mL 
milliliter 
mg 
microgram 
N 
number of subjects or observations 
N/A 
not applicable 
NIMP 
non-investigational medicinal products  
NVCB 
Next Value Carried Backwards 
pegIFN 
pegylated interferon 
PI 
protease-inhibitor 
PK 
pharmacokinetics 
QD, qd 
quaque die, once daily 
QUAD 
daclatasvir/asunaprevir/pegylated interferon/ribavirin therapy 
RBV 
ribavirin 
RCI 
replication complex inhibitor 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SOC 
standard of care 
SOF 
sofosbuvir 
SOP 
Standard Operating Procedures 
SVR 
sustained virologic response 
TD 
target detected 
TND 
target not detected 
TVR 
telaprevir  
USPI 
United States Package Insert 
VBT 
virologic breakthrough 
WBC 
white blood cell 


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WOCBP 
women of childbearing potential 
 
 
 


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2. BACKGROUND 
 
2.1 Chronic Hepatitis C 
Approximately 170 million people worldwide are chronically infected with hepatitis C virus 
(HCV), including approximately 4 million in the United States. The majority of individuals 
infected progress to chronic hepatitis, which can lead to cirrhosis, liver failure and 
hepatocellular carcinoma (HCC). HCV is the leading indication for liver transplantation in 
most countries and a major cause of HCC. 
 
There are 6 major HCV genotypes with many subtypes based on sequence heterogeneity of the 
genome [1]. Genotypes (GT) 1 - 3 have a worldwide distribution (with genotype 1 being the 
major genotype in the United States, Europe, Japan, and South America, genotypes 4 and 5 are 
found principally in Africa, and genotype 6 is distributed primarily in Asia. Although genotype 
does not predict the outcome of infection, different genotypes are associated with differential 
responses to treatment, and allow dosage of current pegylated interferon (pegIFN)-based 
treatment to be tailored to the genotype being treated [2-4]. 
 
 
Over 20-30 years of chronic HCV infection, 20% of the patients develop end stage liver 
disease and cirrhosis. Hepatocellular carcinoma occurs in patients with cirrhosis at a rate of 1% 
to 4% per year.  Progression to cirrhosis is often silent, until patients present with 
complications of End Stage Liver Disease (ESLD) or HCC. HCV imposes burdens on both 
society and individuals. A major economic burden on the society is the hospital outpatient 
costs, which have reached $11 billion in the US in direct medical costs alone.  
 
Two first generation direct acting antivirals (DAAs), the HCV protease inhibitors, telaprevir 
(TVR) and boceprevir (BOC), were approved in the US and EU in 2011 for the treatment of 
GT-1 chronic hepatitis C (CHC). These regimens are now considered the standard of care 
(SOC) for treating GT-1 CHC in countries where they are available.  
 
The ability of daclatasvir (DCV) and sofosbuvir (SOF) combination is uniquely related to the 
limited and/or manageable drug-drug interaction potential with the concurrent medications in 
addition to its potent antiviral activity and safety in patients with hepatic impairment. The 
ability of DCV and SOF to be used in HIV/HCV coinfected population is uniquely related to 
the limited and/or manageable drug-drug interaction potential of these drugs in addition to this 
combination’s potent antiviral activity and safety in patients with hepatic impairment.  
 
Finally, the ability of DCV and SOF to treat GT-3 has the potential to improve on the currently 
limited all-oral options for this particular group of patients. This study will evaluate the safety 
and efficacy of DCV and SOF in subjects infected with HCV Genotype 3. 
 
Epidemiological surveys have shown a geographical variation in the prevalence and 
distribution of hepatitis C genotypes throughout the world. HCV genotypes 1–3 (GT1–3) have 
a worldwide distribution. Although GT1a and GT1b account for 60% of global HCV 
infections, GT3 is endemic in Southeast Asia and is variably distributed in different countries. 
 


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2.2 Sofosbuvir 
SOF is a potent and selective inhibitor of the HCV nonstructural protein 5B (NS5B) 
polymerase, an RNA-dependent RNA polymerase that is responsible for viral RNA synthesis 
and is essential for viral replication. In vitro, SOF demonstrates nanomolar potency against 
HCV GT-1 through-6. 
 
In the SOF Phase 3 clinical program, the SOF + RBV treatment regimen for 12 or 16 weeks 
was evaluated in subjects with GT-2 or -3 HCV infection and the SOF + pegIFN/RBV 
treatment regimen for 12 weeks was evaluated in subjects with GT-1, -4,-5, or 6 HCV 
infection. Across all relevant HCV genotypes and multiple patient populations, SOF, in 
combination with RBV with or without pegIFN demonstrated similar or superior efficacy to 
currently available treatment. A 90% rate of SVR was reported in the single-arm NEUTRINO 
study that treated 327 GT-1, -4, -5 or-6 HCV-infected subjects (98% were either GT-1 or GT-
4) following 12 weeks of SOF plus pegIFN/RBV [7] SOF and RBV combination regimen was 
investigated in GT-2 or GT-3 HCV infected patients in three phase 3 studies, FISSION, 
POSITRON and FUSION. The efficacy data from these studies are summarized below. 
 
Efficacy Results for Phase 3 studies of SOF/RBV in patients with HCV GT-2, -3 
Infection 
Study 
Population 
Treatment Groups 
Overall 
SVR12 
SVR12 in 
Genotype 
2 
SVR12 in 
Genotype 
3 
FISSION 
GT-2, 
-3 
treatment-
naive 
SOF + RBV for 12 weeks 
or 
PegIFNα+ RBV for 24 
weeks 
67% 
67% 
97% 
78% 
56% 
63% 
POSITRON 
GT-2, -3, IFN 
intolerant, 
ineligible 
or 
unwilling 
SOF + RBV for 12 weeks 
or 
Placebo for 12 weeks 
78% 
0% 
92% 
0% 
61% 
0% 
FUSION 
GT-2, 
-3 
treatment 
-
experienced 
SOF + RBV for 12 weeks 
or 
SOF + RBV for 16 weeks 
50% 
73% 
86% 
94% 
30% 
62% 
 
Interim data from the Phase 3 VALENCE study demonstrate that extending the length of 
SOF+RBV combination therapy to 24 weeks vs. 12 weeks for GT3 subjects can provide much 
improved SVR rates (overall SVR12- 85%) with no additional safety signal  [6, 9]. SVR for 
GT2 subjects in this study was 93% after 12 weeks of combination therapy. Collectively, the 
Phase 3 SOF program has demonstrated that high rates of efficacy are attainable with an all-
oral regimen across HCV genotypes (1-6) without compromising the enhanced safety profile 
that has become the expectation of interferon-free alternatives. These data also provide great 
promise for the potential benefit associated with regimens that combine potent but well 
tolerated DAA agents, such as DCV+SOF. 
 
2.3 Daclatasvir 
DCV is a first-in-class, highly selective NS5A replication complex inhibitor (RCI) with 
picomolar potency and broad genotypic coverage in vitro. As a RCI, DCV inhibits HCV 


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replication with 50% effective concentration (EC50) values of 9 and 50 pM against genotypes 
GT-1b and GT-1a, respectively, in replicon assays and EC50 values ranging from pM to low 
nM for replicons with NS5A coding sequences derived from GT-2a, -3a, -4a, -5a and -6a.  
 
Data from the DCV non-clinical studies can be found in the Investigator Brochure (IB) as 
included in IND 79,599. 
 
A thorough review of clinical efficacy studies including DCV is available in the IB. Briefly, 
DCV has been studied as part of several IFN containing and IFN-free treatment combinations 
in treatment-naive and treatment experience patients infected with different HCV GTs. 
Selected results are presented below. 
 
• DCV 60 mg once daily (QD) combined with pegIFNα/RBV has demonstrated high 
virologic response rates across all GTs tested (GT-1, -2/-3, and -4) in treatment-naive 
subjects. Sustained virologic response rates at follow-up Weeks 12 and 24 (SVR12/24) 
were 64% - 100%. Fifty GT-3 treatment naive subjects received DCV and pegIFNα/RBV 
combination therapy in BMS study AI444031. 83% (44/53) of them met the criteria of 
protocol defined response (PDR+, defined as HCV RNA at Week 4 < LLOQ, target 
detected or target not detected) and were eligible for shortening treatment duration to 12 
weeks or 16 weeks. Among these PDR+ subjects, 80% (35/44) achieved SVR12 with 
shortened treatment duration. The SVRs for non-PDR subjects and subjects receiving 
placebo and pegIFNα/RBV combination are not available yet. 
• Quad therapies including DCV (DCV + ASV + pegIFNα/RBV) have demonstrated 
efficacy in several hard-to-treat GT-1/-4 populations, including null responders to prior 
pegIFNα/RBV treatment. In the expansion of study AI447011, QUAD therapy including 
60mg of DCV and ASV achieved SVR12 rates of 95%. 
• DCV has been extensively studied as part of the IFN-free “DUAL” therapy in combination 
with ASV in patients infected with HCV GT-1b. In the expansion of BMS Study 
AI447011, GT-1b infected prior null responders were treated with DCV (60 mg QD) plus 
twice-daily ASV (200 mg) (N=18) and 89% (16/18) achieved SVR24 (based upon HCV 
RNA < LLOQ TD or TND). A larger group of GT-1b infected patients who were prior 
non-responders to IFN-based therapy were treated with DCV (60mg QD) plus twice daily 
ASV (200mg) in BMS Study AI447026. The SVR24 was 80.5% (70/87) and it was 
similarly effective among subgroups regardless of baseline characteristic including gender, 
age, HCV RNA and cirrhosis. 
• In an ongoing study of the IFN-free regimen of DCV/ASV/BMS-791325 (75 mg twice 
daily [BID]) triple therapy in treatment-naive subjects infected with HCV GT-1a, -1b 
produced SVR12 rates of 94% after 12 weeks of treatment. 
• As was seen in Study AI444040, 12 or 24 weeks of combination treatment of DCV and 
SOF with or without RBV led to an SVR12 of 98.4% in treatment-naïve HCV genotype 1 
infected patients; an SVR12 of 97.6% (40/41) in GT-1 infected patients who had previously 
failed protease inhibitor; and an SVR12 of 90.9% (40/44, 2 missing patients and 2 with 
virologic failure) in treatment-naive patients infected with HCV GT-2 and -3.  
 
2.4 Daclatasvir / Sofosbuvir Combination 
Daclatasvir (DCV, BMS-790052) is an NS5A inhibitor, and sofosbuvir (SOF) is a nucleotide 
NS5B (polymerase) inhibitor. Together, this IFN and RBV free combination is an important 


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potential addition to the future anti-HCV armamentarium whose initial clinical data (study 
AI444040) demonstrates a well tolerated combination with potent in vivo anti-viral activity 
delivering > 90% sustained viral responses in HCV genotypes 1, 2, and 3. 
 
DCV is an inhibitor of NS5A, a multifunctional protein necessary for HCV replication that is 
an essential component of the HCV replication complex. NS5A has three structural domains (I, 
II, and III). Domain I (N-terminus of the protein) contains a zinc binding motif and potential 
RNA binding pocket, and is required for NS5A dimer formation. Inhibitor-binding, resistance 
mapping and computer modeling indicate that DCV inhibits NS5A function(s) by interacting 
with the N terminus of the protein (domain I). In vitro 50% effective concentration (EC50) 
values of DCV ranged from pM to low nM in replicons with NS5A coding sequences derived 
from GT-1b, GT-1a, GT-2a, -3a, -4a, -5a and 6a. Among all tested genotypes, DCV 
demonstrates potent inhibitory activity towards GT-3 HCV with EC50 of 146pM [5]. 
 
Genotype Coverage by DCV 
HCV Replicon Genotype 
DCV (nM) 
1a (H77, wildtype)a 
0.020 ± 0.009 
1b (Con1, wildtype) a 
0.004 ± 0.002 
2a (JFH1) virus 
0.020 ± 0.004 
2a (JFH1) a replicon 
0.034 ± 0.019 
2a hybrid replicon (HC-J6 and 2 clinical 
isolates*) 
8.8 - 19 
3a hybrid replicon (4 clinical isolates) 
0.14 -1.25 
4a hybrid replicon (3 clinical isolates) a 
0.007 - 0.013 
5a hybrid replicon (3 clinical isolates) a 
0.003 - 0.019 
6a hybrid replicon 
0.054 ± 0.008 
a 
Cell lines used routinely in the lab; these are EC50 (SD values as of 6-Nov-2012, (n) > 20. 
*Values for two GT-2a clinical isolates were derived from transient replication assay; others were derived from 
stable cell lines. 
 
SOF is a potent inhibitor of NS5B (polymerase) and therefore inhibits RNA replication. It is a 
nucleotide analogue that is phosphorylated within the host hepatocyte to the active triphosphate 
and competes with natural nucleotides leading to chain termination of RNA replication of the 
viral genome. The active triphosphate of SOF has been shown to have activity in vitro against 
HCV genotypes 1-6. Potent activities were observed across all genotypes with EC50 values 
ranging from 14 nM to 181 nM. EC50 of SOF against GT-3 HCV replicon is only 81 nM. .In 
vitro and in vivo studies showed that the CYP450 system was not involved in the metabolism 
of SOF, that there was no significant inhibition or induction of CYP450 enzymes by these 
compounds, and that clinically significant drug interactions mediated by CYP450 were 
unlikely [6]. 
 
Daclatasvir and sofosbuvir demonstrates activity as treating genotype 1-3 HCV infection 
(Study AI444040): 
 
The combination of DCV and SOF was first shown to be safe and highly effective in the Phase 
2 Study AI444040. This is an open-label study that treated 211 GT-1, GT-2 and GT-3-infected 
subjects with this once-daily combination with or without RBV for either 12 or 24 weeks. The 


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overall SVR12 in GT-2/3 infected subjects (n = 44) following 24 weeks of treatment was 
90.9% (40/44). The combination of DCV and SOF was well tolerated. Most adverse events 
were mild or moderate and did not lead to treatment discontinuation. 
 
Therefore, this once-daily combination of DCV plus SOF was well tolerated and achieved high 
rates of SVR12 in both treatment-naïve HCV genotypes 1-3-infected subjects, as well as in 
subjects who failed PI-based therapy with no other treatment options [7-8]. 
 
Summary of Efficacy Results for Study AI444040 
Treatment 
group 
Patient 
population 
Treatment regimen 
Treatment 
duration 
Efficacy results 
% (N achieving 
endpoint/N 
treated) 
B 
GT-2,-3 
naive 
SOF 400 mg QD Lead in for 
7 days then add DCV 60mg 
QD 
24 weeks 
SVR 12 88% 
(14/16) 
D 
GT-2, 
-3 
naive 
SOF 400 mg QD + DCV 60 
mg QD 
24 weeks 
SVR 12 100% 
(14/14) 
F 
GT-2,-3 
naive 
SOF 400 mg QD + DCV 60 
mg QD + RBV 
24 weeks 
SVR 24 86%  
(12/14) 
 
In summary, treatment with the DCV and SOF combination regimen shows promise as a 
therapeutic option as demonstrated by very high SVR and favorable AE profile. 
 
2.5 Rationale for Dose Selection  
The choice of 60 mg DCV as the dose to be used in this study was based on the following data: 
• AI444014 is a Phase 2a study that evaluated DCV (3 mg, 10 mg, and 60 mg once daily vs. 
placebo) plus pegIFNα/RBV for 48 weeks of triple therapy for subjects infected with HCV 
GT-1. The analysis on the clinical results demonstrated similar efficacy at the Week 12 
analysis and remained similar through SVR12. However, exposures in the 10 mg group 
overlapped with those of the sub-therapeutic 3 mg group. This suggests that the 10 mg dose 
may provide subtherapeutic exposures in some subjects, an observation that could prove 
deleterious in the context of a direct-acting antiviral only regimen. No meaningful 
relationships between exposure and safety events were identified in AI444014, for any 
DCV dose, based on safety data from 48 weeks of triple therapy. The safety and tolerability 
of DCV plus pegIFNα/RBV was undistinguishable from control for any DCV treatment 
group. Specifically, there was no evidence of hepatic or hematologic safety signals 
observed. 
• In study AI447011, DCV 60 mg QD was delivered for 24 weeks in combination with a 
protease inhibitor, ASV, and demonstrated a favorable safety profile. Although a clinically 
relevant trend in elevated hepatic transaminases was identified in this study it was 
attributed to the 600 mg BID ASV dose of the protease inhibitor administered in the study 
as indicated by similar findings in the ASV program without DCV in regimen. There were 
no serious adverse events, discontinuations due to adverse events, and no other clinically 
significant safety signals.  


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• As discussed previously, DCV 60 mg QD has been examined in combination with SOF in 
study AI444040 in subjects infected with HCV GT-1, -2, and -3 (N = 211) and has 
demonstrated high efficacy and favorable tolerability.  
 
Therefore, based on the safety and efficacy of the 60 mg DCV observed in these studies, this 
dose will be used for this study. 
 
2.6 Rationale for treatment duration  
Available data suggests that 12 weeks of therapy with a potent treatment regimen is adequate 
to achieve SVR in many HCV patient types. This data includes the following observations. 
 
Data from 3 Phase 3 studies, FISSION, POSITRON and FUSION also demonstrated GT-2 and 
GT-3 treatment naive subjects can be cured with 12 weeks of SOF and RBV combination 
therapy, achieving 86% - 97% SVR in GT-2 patients and 30%-56% SVR in GT-3 patients. 
Relatively lower SVR observed in GT-3 subjects treated with SOF is mainly due to the higher 
relapse rate compared to that of GT-2, which may be due to slower viral clearance. Thus, the 
higher rate of relapse in HCV GT3 infected subjects treated with SOF may reflect a reduced 
rate of virologic clearance possibly due to the underlying fibrosis or steatosis characteristic of 
HCV GT3. The addition of RBV with the potent antiviral DCV would be predicted to provide 
more rapid and intensive viral suppression and enhanced viral clearance. 
 
In summary, we conclude that the combination of DCV and SOF/RBV is likely to have a high 
rate of SVR following 12 weeks of treatment in non-cirrhotic patients infected with GT-3 
HCV. However, emerging data from clinical trials indicates that 24 weeks of treatment in 
cirrhotics is needed. Accordingly, a conservative approach will be taken and cirrhotic GT-3 
subjects will be randomized to either 16 weeks or 24 weeks of DCV and SOF/RBV. 
 
2.7 Rationale for study  
Given the higher risk of disease progression compared to other genotypes, patients with 
chronic GT-3 HCV infection and cirrhosis represent a population with high unmet medical 
need. However, the efficacy and safety profile with the current standard of care (SOF/RBV), 
are still suboptimal with disappointing SVR rates at best comparable to pegIFNα/RBV. 
Therefore, new treatment options with better efficacy, safety, treatment duration and minimal 
drug-drug interaction potential are needed for treating HCV GT-3 infection in patients with 
cirrhosis. 
 
The regimen of SOF plus RBV has been investigated in GT-2 or GT-3 HCV infected patients 
in three Phase 3 studies, FISSION, POSITRON and FUSION. The data demonstrated the 
patients with chronic GT-2 or GT-3 HCV infections can be cured with 12 weeks of SOF in 
combination with the weak antiviral RBV. Consistently high SVRs were observed in GT-2 
subjects, including HCV treatment naive (SVR12 86% - 97%). Relatively lower SVRs were 
observed in GT-3 patients (SVR12 30% - 56%). The reason for the lower rates of sustained 
virologic response among patients with HCV GT-3 infection, as compared with those who had 
HCV GT-2 infection, a difference that has also been observed among patients treated with 
pegIFN/RBV, remains unclear. Although virologic declines during treatment are similar with 
the two genotypes, the higher rates of relapse among patients with HCV GT-3 infection 
indicate that virologic clearance is likely to be slower in some patients with HCV GT-3 


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infection, which may due to the underlying fibrosis and steatosis, adding a potent DAA is 
anticipated to eliminate the impact of these negative factors. 
 
Treatment-experienced GT-3 infected patients also represent a population of high unmet 
medical need, especially patients with cirrhosis. These patients face further disease progression 
and limited treatment options. Results from the VALENCE study demonstrated an SVR12 rate 
of 85% in non-cirrhotic treatment-experienced GT-3 subjects following 24 weeks of 
SOF+RBV. Unfortunately, the response was considerably lower in cirrhotic treatment-
experienced GT3 subjects (60%) despite the 24-week treatment duration [6, 9]. These results 
suggest that the optimal treatment duration with a SOF/RBV regimen is 24 weeks for GT-3 
infected patients, similar to the currently approved pegIFNα-based regimen. Thus, there 
remains a need to improve treatment response in GT-3 cirrhotic patients who have advanced 
disease. 
 
DCV demonstrates consistent SVR in non-cirrhotic and compensated cirrhotic subjects 
Responses of cirrhotic subjects treated with DCV are similar to subjects without cirrhosis. 
DCV has been investigated within different combination regimens as an add-on antiviral to 
PegIFNα/RBV and as part of dual combination of DCV and asunaprevir (ASV). 
 
Therefore, available efficacy data across DCV programs, including data from IFN-free 
combinations suggests consistent SVR in non-cirrhotic subjects and compensated cirrhotic 
subjects treated with DCV based regimens. 
 
DCV has been approved by the U.S. FDA on July 24, 2015. 
 
  
3. STUDY OBJECTIVES 
 
3.1 Primary Objective 
The primary objectives of this study are: 
1. 
To demonstrate the safety and tolerability of 16 weeks versus 24 weeks of DCV plus 
standard therapy SOF/RBV, in cirrhotic HCV genotype 3 subjects. 
2. 
To explore the efficacy of 16 weeks versus 24 weeks of DCV plus standard therapy 
SOF/RBV in improving SVR12, defined as HCV RNA < LLOQ target detected at follow 
up Week 12, in cirrhotic HCV genotype 3 subjects. 
 
3.2 Secondary Objectives 
The secondary objectives of this study are:  
• To evaluate SVR24 of 16 weeks versus 24 weeks of DCV/SOF/RBV in HCV genotype 3 
subjects with cirrhosis. 
• To evaluate the proportion of cirrhotic subjects who receive DCV/SOF/RBV for 16 weeks 
and achieve HCV RNA < LOQ TND at various time points (actual time points will depend 
on the availability of data) during and post treatment compared to a historical population 
that took 24 weeks of SOF/RBV. 
• To evaluate the proportion of cirrhotic subjects who receive DCV/SOF/RBV for 24 weeks 
and achieve HCV RNA < LOQ TND at various time points (actual time points will depend 


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on the availability of data) during and post treatment compared to a historical population 
that took 24 weeks of SOF/RBV. 
 
4. INVESTIGATIONAL PLAN 
 
4.1 Study Design Overview 
This is a randomized, open label, single center safety and efficacy study. At least 40 cirrhotic 
subjects with HCV genotype 3 will receive standard of care treatment of SOF/RBV as well as 
60 mg daily of Daclatasvir (investigational product).  Subjects will be randomized in a 1:1 to 
receive either: 
• Group A: 16 weeks of DCV/SOF/RBV 
• Group B: 24 weeks of DCV/SOF/RBV 
 
Subjects will return to the study center at various time points throughout the 16 or 24 weeks of 
treatment in addition to 12 weeks post taking last dose of study drug to monitor safety and 
efficacy. These visits will be according to standard of care.  
 
The total planned duration of subject participation in Group A is up to 36 weeks (a maximum 
of 8 weeks of screening, 16 weeks of treatment and 12 weeks of post last dose of study drugs 
follow-up). The total planned duration of subject participation in Group B is up to 44 weeks (a 
maximum of 8 weeks of screening, 24 weeks of treatment and 12 weeks of post last dose of 
study drugs follow-up). 
 
 
4.2 Study Population 
Approximately 40 subjects aged 18-75 years (all sexes, races and ethnic backgrounds) with 
chronic hepatitis C infection based on history of positive anti-HCV antibody and/or HCV RNA 
in serum will complete the study. Only genotype 3 subjects with cirrhosis will be considered 
for enrollment. Of note, treatment-naïve subjects with no previous exposure to an interferon 
formulation (i.e., IFNa, pegIFNa), RBV, or HCV DAA (protease, polymerase inhibitor, etc.) as 
well as treatment-experienced subjects who failed previous treatment with interferon 
formulation (i.e., IFNa, pegIFNa), RBV, or HCV DAA (excluding NS5A inhibitors) will be 
considered.  
 
All subjects must meet the following eligibility criteria: 
 
4.2.1 Inclusion Criteria 
1. Signed, written, informed consent must be available from the subject before any study-
specific procedures are performed; 
2. Male or female 18-75 years of age; 
3. All of the following at least 6 months prior to screening visit: 
• Documented HCV infection based on history of a positive serum anti-HCV 
antibody test and/or detectable levels of HCV RNA >= 10,000 IU/mL, and 
• Documented HCV genotype 3. 
4. Subjects with evidence of cirrhosis defined by either a liver biopsy <= 3 years from 
screening demonstrating a Metavir Fibrosis Score of F4 (or equivalent); OR 


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Fibroscan® <= 1 year from screening > 12.5 kPa. If a subject is evaluated by more than 
one testing method, then the liver biopsy results take precedence; 
5. Women of childbearing potential (WOCBP) must: 
• have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 24 hours prior to the start of study drug. 
• WOCBP must agree to follow instructions for method(s) of contraception for 7 
months post-treatment completion.   
• Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the following duration for 7 months post-treatment 
completion.   
• Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy Investigators shall advise WOCBP and male subjects who 
are sexually active with WOCBP on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of < 1% 
per year when used consistently and correctly. 
6. At minimum the subject agrees to the use of two methods of contraception, with at least 
one method being highly effective as listed below: 
Highly Effective Methods of Contraception 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® 
by male subject’s WOCBP partner. Female partners of male subjects 
participating in the study may use hormone-based contraceptives as one of the 
acceptable methods of contraception since they will not be receiving study drug. 
WOCBP cannot use hormonal contraception as one of the two methods of 
contraception because there are no data on the effectiveness of systemic hormonal 
contraceptives in women taking SOF. However, WOCBP can continue to use 
hormonal contraceptives, if necessary, in addition to 2 other non-hormonal methods 
of contraception 
•  Nonhormonal IUDs, such as ParaGard® 
• Tubal Ligation 
• Vasectomy 
• Complete Abstinence – defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable alternate 
methods of highly effective contraception must be discussed in the event that the 
subject chooses to forego complete abstinence. 
 
Less Effective Methods of Contraception 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge 
• Male condom without spermicide 
• Progestin only pills 


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• Female condom; A male and female condom must not be used together 
 
Azoospermic males, women who are not of childbearing potential and WOCBP who 
abstain from heterosexual activity on a continuous basis, are exempt from 
contraceptive requirements. However, WOCBP who abstain from heterosexual activity 
on a continuous basis must still undergo pregnancy testing. 
 
4.2.2 Exclusion Criteria 
1. Subjects who lack capacity to consent for themselves; 
2. HCV Genotypes other than GT-3 infection; mixed genotype infections are not 
permitted; 
3. Liver histology consistent with any other co-existing cause of chronic liver disease 
(apart from fatty liver and/or Chronic Hepatitis B Virus); 
4. Body Mass Index > 40 at the Screening visit; 
5. Any of the following within one month of screening: 
• Uncontrolled diabetes; 
• Unstable or uncontrolled thyroid disease (subjects requiring medication to control 
their thyroid disease are eligible if all other inclusion/exclusion criteria are met). 
6. Any of the following within 6 months of screening visit, any of the following:  
• Decompensated liver disease, esophageal variceal bleeding, or a hepatic mass lesion 
suspicious for hepatocellular carcinoma (HCC); 
• Subjects who have been treated for HCV infection; 
• History of unstable or deteriorating cardiovascular or cerebrovascular disease; 
• Alcohol and/or drug. 
7. QTcF ≥ 500 ms at the baseline visit. 
8. Any of the following laboratory abnormalities within 8 weeks of the baseline visit: 
• Hemoglobin <8 g/dL; 
• Absolute neutrophil count <0.50 x 103 cells/µL; 
• Platelet count <25 x 103 cells/µL; 
• Total bilirubin >=3 mg/dL or >=34 mol/L (with the exception of subjects with 
Gilbert’s syndrome); 
• Albumin <2.5g/dL; 
• Creatinine Clearance (CrCl) <=50 mL/min (as estimated by Cockcroft and Gault). 
• Serum ALT >=10 × ULN; 
• Alpha-fetoprotein >200ng/mL. 
9. Prior exposure to NS5A inhibitors is prohibited but other classes and pegIFN/RBV are 
acceptable for treatment-experienced subjects; 
10. Use of any prohibited or restricted treatment at least is five half-lives or 14 days 
(whichever is longer) of the first dose of study drug (refer to section 4.5); 
11. History of cancer within 1 year of the screening visit with the exception of localized 
basal or squamous cell carcinoma; 
12. Any gastrointestinal disease or surgical procedure that may impact the absorption of 
study drug. (Subjects who have had cholecystectomy are permitted to enter the study); 
13. Known HIV infection; 
14. Confirmed, uncontrolled hypertension (any screening systolic blood pressure 
≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg should be excluded); 


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15. Presence or history of non-HCV chronic liver disease, including autoimmune hepatitis, 
alpha-1-antitrypsin deficiency, hemochromatosis, Wilson's disease, drug- or toxin-
induced liver disease, alcohol-related liver disease, primary biliary cirrhosis and 
sclerosing cholangitis. Subjects with fatty liver and/or chronic hepatitis B virus in 
addition to HCV may be considered in the study; 
16. Uncontrolled seizures disorder; 
17. History of hemoglobinopathies, (e.g., thalassemia, sickle cell anemia, spherocytosis) or 
other cause of hemolytic anemia, including autoimmune causes; 
18. Active disease at screening visit known to cause significant alteration in immunologic 
function including hematologic malignancy, sarcoidosis or autoimmune disorder (e.g., 
rheumatoid arthritis, systemic lupus erythematosis, leukemia, lymphoma, autoimmune 
thyroid disease, scleroderma, unstable psoriasis, and multiple sclerosis); 
19. Pregnant or lactating women or women who plan to become pregnant during the study; 
20. History of hypersensitivity to drugs with a similar biochemical structure to DCV or 
SOF or RBV; 
21. Any other criteria or known contraindication that would exclude the subject from 
receiving SOF or RBV (per the local label) or DCV; 
22. Inability to tolerate oral medication; 
23. Subjects, who in the opinion of the Investigator, are not suitable candidates for 
enrollment or who would not comply with the requirements of the study. 
 
4.2.3 Discontinuation of IMP 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
• Subject’s request to stop study treatment 
• Virologic breakthrough defined as any confirmed >1 log10 increase in HCV RNA over 
nadir OR confirmed increase in HCV RNA ≥ LLOQ if HCV RNA previously declined 
to <LLOQ TD/TND 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, 
in the opinion of the investigator, indicates that continued participation in the study is 
not in the best interest of the subject 
• Pregnancy 
• Termination of the study by Bristol-Myers Squibb (BMS) 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness 
• Laboratory or Clinical Criteria: If any of the following laboratory or clinical criteria is 
obtained for any patient, the result must be repeated /confirmed within 72 hours. If the 
results are confirmed, the patient must discontinue treatment. Clinical criteria must 
have Principal Investigator or Sub-Investigator assessment prior to proceeding to 
permanent discontinuation: 
− Evidence of confirmed hepatic decompensation (Child-Pugh Class B or C, Score > 
6); 
− ALT > 2 ´ baseline and 5 ´ ULN, and either total bilirubin > 4 ´ ULN or INR > 2.5; 
− Any Grade 4 AE or clinically significant laboratory abnormality considered study 
drug-related.  


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• Virologic Breakthrough:  
 
If discontinuation of therapy is required, this must occur no later than the next study visit. 
 
It is expected that all subjects who are on study will complete the protocol-defined 
durations for treatment and follow-up. Subjects who discontinue all study drugs prior to 
completing the assigned dosing regimen should complete 12 weeks of follow-up. However, 
if alternative HCV therapy is initiated in the post-treatment period for any reason, subject 
must withdraw from the study once the post-treatment Week 4 visit has occurred. 
 
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures. The only exception to this requirement is when a subject withdraws 
consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness). 
 
4.2.4 Subject Withdrawal 
In accordance with the regulations governing human subject protection, a subject has the 
right to withdraw from the study at any time for any reason without jeopardy to his/her 
future of their medical care at the institution. Furthermore, reasons for terminating subjects 
from the study include but are not limited to the following: 
• Any of the stopping rules included under “Expected Adverse Events and 
Management”. 
• Subject non-compliance. 
• Pregnancy occurring on study. 
• Intolerable adverse event (decision to be removed from study made by either the 
investigator or subject). 
• Unrelated medical illness or complication. 
• Evidence of hepatic decompensation. 
• Decision by the investigator that it is in the subject’s best medical interest. 
• Lost to follow-up. 
• Death 
• Termination of the study by Bristol-Myers Squibb (BMS) 
 
If the subject is going to be withdrawn from the study, all efforts will be made to complete 
the early termination/discontinuation visit. 
 
4.2.5 Subject Replacement 
Subjects who receive at least 1 dose of the study drug and discontinue prematurely will not 
be replaced. 
 
4.3 Study Drug  
4.3.1 Standard of care treatment – non investigational medicinal product (NIMP) 
The recommended daily sofosbuvir dose (single pill) for patients with HCV genotype 3 
(U.S. prescribing information) is 400 mg with or without food. The recommended daily 
ribavirin dose (divided into two doses) for patients with HCV genotype 3 (U.S. prescribing 


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information) is 1000 mg (<75 mg) or 1200 mg (>= 75 mg) with food. Standard of care 
treatment of Sofosbuvir (SOF) and Ribavirin will be prescribed and supplied directly to 
participant per standard of care protocol. This combination is not considered 
investigational. 
 
4.3.2 Daclatasvir – investigational medicinal product (IMP) 
In addition to the standard of care treatment mentioned above, subjects will take one tablet 
in the morning daily of Daclatasvir (BMS-790052-05), which will be supplied by Bristol-
Myers Squibb. Each film coated tabled is 60 mg (as the free base) in potency. Each tablet is 
plain, green, biconvex, pentagonal and film-coated. There will be 33 tablets/bottle as open 
label. The dose can be taken with or without food. 
 
Only subjects enrolled in the study may receive investigational product in accordance with 
all applicable regulatory requirements. Study drugs will be dispensed to subjects at 
scheduled study visits (refer to appendix Error! Reference source not found. for schedule of 
assessment). Subjects will be instructed on administration and storage. Study staff assigned 
by the site’s investigator will dispense study drugs, perform and maintain accountability 
logs. 
 
Study drug will be stored in a secure area with access limited to the investigator and 
authorized site staff and under physical conditions that are consistent with specific 
requirements. Storage will be at 15°C-25°C (59°F-77°F). Store in a tightly closed 
container. 
 
4.4 Randomization 
A randomized schedule will be generated prior to the initiation of the study. Following 
acquisition of the signed informed consent, successful completion of screening evaluations, 
and satisfaction of all eligibility criteria, subjects will be randomized in a 1:1 ratio in blocks of 
2 to either Group A or Group B. Randomization will be centralized. 
 
4.5 Concomitant and Excluded Therapy 
All concomitant medications, including over the counter medications, vitamins, nutritional 
supplements and other herbal preparations, taken during the study as well as the reason for use 
will be recorded. The use of concomitant medication will be recorded at each visit. 
 
The following treatments are prohibited during dosing with DCV and SOF and should be 
discontinued at least is five half-lives or 14 days (whichever is longer) of the first dose of study 
drug. 
• Strong inhibitors of CYP3A4 are prohibited, including, but not limited to: 
ketoconazole, troleandomycin, itraconazole, voriconazole, mibefradil, clarithromycin, 
telithromycin, grapefruit juice and grapefruit-containing products, Seville oranges, 
juices and products that contain Seville oranges, conivaptan, nefazodone, etc.; 
• Strong CYP3A4 inducers are prohibited, including but not limited to: rifampin, 
rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, phenobarbital, St 
John's wort, etc.; 


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• Strong P-gp inhibitors are prohibited (e.g., ketoconazole, indinavir, lapatinib, quinidine, 
amiodarone, ranolazine, erythromycin, clarithromycin, and azithromycin (azithromycin 
will be allowed for a duration of 7 days or less or once weekly); 
• CYP3A substrates with narrow therapeutic index are prohibited, including but not 
limited to alfentanil, cisapride, dihydroergotamine, ergotamine, fentanyl, pimozide, and 
quinidine; 
• P-gp inducers are prohibited, including but not limited to, avasimibe, carbamazepine, 
oxcarbazepine, phenytoin, rifampin, rifabutin, rifapentine, St John’s wort, and boosted 
tipranavir; 
• Amiodarone or any of its trade/brand names/formulas. 
 
The following treatments should be used with caution during dosing with DCV and SOF.  
• Substrates of OATP1B1 and OATP1B3 should be used with caution (e.g., glyburide, 
bosentan, rosuvastatin, pravastatin, and pitavastatin); 
• Substrates of BCRP should be used with caution (e.g., rosuvastatin); 
• P-gp substrates with a narrow therapeutic index (e.g., digoxin) should be used with 
caution and at the lowest efficacious dose with appropriate monitoring (e.g., therapeutic 
drug monitoring). 
 
In addition, the following will apply: 
• Medications with known or potential anti-HCV activity other than the assigned study 
treatment are prohibited during the on treatment period. If alternative HCV therapy is 
initiated in the post-treatment period for any reason, subject must withdraw from the 
study once the post-treatment Week 4 visit has occurred. If the subject receives HCV 
therapy after post treatment Week 4, the subject should be discontinued from the study 
and a post Week 24 visit should be completed; 
• Any prescription or herbal product which is not prescribed by the investigator or 
licensed physician for treatment of a specific clinical condition is prohibited; 
• Methadone and buprenorphine should be used with caution. These drug levels may 
change with concomitant use of DCV and SOF; 
 
4.6 Lost to follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of 
death. 
 
4.7 Study Termination 
Reasons for terminating the study may include but are not limited to the following: 
• Subject enrollment is unsatisfactory. 
• Good clinical practice is not being maintained and/or followed adequately.  
• Administrative reasons. 
 


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5. SAFETY AND EFFICACY ASSESSMENTS 
 
5.1 Safety Variables and Assessments 
Safety will be assessed through vital signs, physical examinations, adverse events, concomitant 
medication assessments as well as laboratory test. Subjects will return to clinic visits per the 
standard of care schedule at weeks 2, 4, 6, 8, 10, 12, and16 for all subjects as well as weeks 20 
and 24 for subjects in Group B. All subjects will return for treatment-free follow-up 4, 12 and 
24 weeks post discontinuation of study drug or early termination visit (if applicable). Also, an 
ECG will be conducted at screening, end of treatment (week 16 or week 24) and follow-up 
weeks 12 and 24 for safety. For women of child-bearing potential, serum or urine pregnancy 
tests will be performed at every visit. Refer to appendix Error! Reference source not found. for 
schedule of assessments.  
 
The safety data will be tabulated and, the proportion of subjects with the following will be 
summarized for each arm of the study and cumulatively: 
• Adverse events using the grading system outlined in section 6. 
• Abnormal laboratory safety tests (liver injury tests as measured by AST, ALT, GGT, 
Total Bilirubin and Albumin as well as blood picture tests as measured by WBC, RBC, 
Hgb, Hct, Plts) and those requiring dose reduction, interruptions or discontinuations. 
 
All blood sample collection will be part of the standard of care schedule, with the exception of 
any additional blood collection, outside standard of care, that are required to monitor the 
subject’s safety. 
 
5.2 Efficacy Variables and Assessments 
Efficacy will be assessed through HCV RNA assessments that will be conducted at various 
time points during study drug period and follow-up. Refer to appendix Error! Reference source 
not found. for a detailed schedule of assessments.  
 
Primary Efficacy Assessment: The HCV RNA collected at post-treatment follow-up Week 12, 
for subjects treated with DCV/ SOF/RBV for 16 or 24 weeks (depending on the group) will be 
used for the primary antiviral assessment in this study.  
 
Secondary Efficacy Assessments: HCV RNA collected at each of the following Weeks: 2, 4, 6, 
8, 10, 12, 16 as well as weeks 20 and 24 for subjects in Group B; post-treatment Weeks 4, 12 
and 24 will be used for the secondary antiviral assessment in this study. 
 
5.3 Study Assessments 
The results of all procedures listed below will be documented in the subject’s source 
documents. Refer to appendix Error! Reference source not found. for an overview of the 
schedule of assessments. 
 
5.3.1 Informed Consent 
Written informed consent will be obtained using the site’s Institutional Review Board 
(IRB) or the Independent Ethics Committee (IEC) approved informed consent form prior to 
the initiation of screening procedures. Site staff will obtain informed consent by following 
the institution’s procedures and regulations for the informed consent process. 


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5.3.2 Screening Visit 
The results of the following procedures and evaluations will be used to determine subject 
eligibility for enrollment into this study. The assessments must be completed and results 
obtained within 8 weeks prior to the Baseline (Day 1) visit: 
• Informed consent. 
• Obtain medical history, list of concomitant medications used and ensure it meets 
inclusion/exclusion criteria. 
• Vitals: height, weight, blood pressure, pulse, temperature, respiration rate and BMI. 
• Physical examination. 
• Obtain 
documentation 
of 
the 
laboratory 
and 
procedures 
results 
per 
the 
inclusion/exclusion criteria. 
• Serum or urine HCG, if female of childbearing potential.  
• ECG. 
 
Any subject who signs an informed consent but does not meet inclusion/exclusion criteria 
will be considered a screen failure. The reason for screen fail will be included in the study 
chart. 
 
5.3.3 Baseline (Day 1) Visit 
All assessments will be performed before administration of first dose. The following 
assessments will be performed: 
• Confirm that all the results of the screening procedures have been obtained, 
documented and that the subject meets eligibility criteria. 
• Vitals: weight, blood pressure, pulse, temperature and respiration rate. 
• Adverse events collection and symptoms directed physical exam. 
• Concomitant medications review. 
• Laboratory testing as per standard of care and appendix A. 
• Serum or urine HCG, if female of childbearing potential. 
• Administration of first dose of study drug in clinic. 
 
5.3.4 Study Drug Period  
All subjects will return for visits at weeks 2, 4, 6, 8, 10, 12, and 16. Subjects in Group B 
will additionally return at weeks 20 and 24. The following assessments will be performed: 
• Vitals: weight, blood pressure, pulse, temperature and respiration rate. 
• Laboratory testing as per standard of care and appendix A.  
• Serum or urine HCG, if female of childbearing potential. 
• Adverse events collection and symptoms directed physical exam. 
• Concomitant medications review. 
• Compliance assessment at every visit. The necessity for study drug compliance will be 
reinforced with the study participant at each study visit.  
• IMP study drug dispensing will occur at weeks 4, 8, and 12 for Groups A and B 
subjects as well as weeks 16 and 20 for Group B subjects. 
• IMP study drug return and accountability at each visit.  
• ECG at end of treatment (week 16 or 24, depending on group subject randomized to). 
 


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5.3.5 Post-Study Drug Follow-up Period 
Subjects will return for follow-up at 4, 12 and 24 weeks post last dose of study drug. The 
following assessments will be performed: 
• Vitals: weight, blood pressure, pulse, temperature and respiration rate. 
• Laboratory testing as per standard of care. 
• Serum or urine HCG, if female of childbearing potential. 
• Adverse events collection and symptom directed physical exam. 
• Concomitant medications review. 
• Any remaining study drug return and accountability. 
• ECG at week 24. 
 
5.3.6 Study Visits Window 
Treatment weeks 2, 4, 6, 8, 10, 12, 16, 20, 24: ± 3 days. 
Post treatment follow-up weeks 4, 12 and 24: ± 1 week. 
 
5.3.7 Unscheduled Visit 
Unscheduled visits will be conducted if necessary for the purposes of evaluating or 
following adverse events or to improve subject compliance and retention. Results from any 
evaluations including physical examination, or additional testing that are performed will be 
recorded.  
 
5.3.8 Early Termination Visit 
The following assessments will be conducted in case of an early withdrawal of a subject. 
Every effort should be made to collect the following information within 2-4 weeks of the 
last dose of study drug, if possible. The following will be performed: 
• Physical examination. 
• Vitals: weight, blood pressure, pulse, temperature and respiration rate. 
• Laboratory testing as per standard of care and appendix A. 
• Serum or urine HCG, if female of childbearing potential. 
• Adverse events collection. 
• Concomitant medications review. 
• Compliance assessment, if applicable. 
• Any remaining study drug return and accountability. 
• ECG. 
 
6. ADVERSE EVENTS 
The investigator is responsible for monitoring subject’s safety, as well as detection and 
documentation of events meeting the criteria and definition of an AE or SAE, according to the 
following guidelines. In addition, the investigator is responsible for providing appropriate medical 
care. Frequency of follow-up of any particular adverse event is left to the discretion of the 
investigator.  
 
6.1 Adverse Event (AE) 
6.1.1 Definition 
An AE is any unfavorable, harmful or pathologic change or unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) that occurs in a 


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subject throughout the duration of the study regardless of relationship to study drug. This 
definition includes surgery for a condition that was present prior to informed consent 
signature and unexpectedly worsens during the study. Lack of drug effect is not considered 
an AE. 
 
6.1.2 Reporting Requirement 
AEs will be collected and reported after the subject signs the informed consent until the 
subject’s last visit for the study. 
 
Study staff will instruct subjects to report any physical changes or new symptoms they may 
notice during the course of the study. In addition, AEs should be elicited with minimal 
connotations. Whenever possible, a diagnosis should be given for AE signs and symptoms 
of a common pathology. 
 
As for laboratory assessments, all Grade 3 and 4 laboratory toxicities will be reported as 
adverse events. If a subject’s dose is reduced or discontinued as a result of an AE, study 
site will clearly document this into the reason leading to any such dose reduction or 
discontinuation of study drug. AEs and SAEs will be reported according the guidelines 
outlined in this document regardless of less stringent regulatory requirements that might 
apply. 
 
6.2 Serious Adverse Event (SAE) 
6.2.1 Definition 
An expected or unexpected adverse event is considered a serious adverse event (SAE) if it 
meets any of the following: 
• Results in death. 
• Is life-threatening: at the occurrence of the event, the subject was at immediate risk of 
death. It does not refer to an event that hypothetically might have caused death had the 
event been more severe nor is likely to cause death in the distant future if left untreated. 
• Requires hospitalization or prolongs existing hospitalization: when in doubt as to 
whether “hospitalization”  occurred or was necessary, the AE should be considered 
serious. Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent or significant disability or incapacity that does not allow the 
subject to perform activities of daily living. 
• Requires medical intervention to prevent one of the outcomes listed above. 
• Is a congenital anomaly or birth defect. 
• Is medically significant. 
• A grade 4 laboratory toxicity requiring medical or surgical intervention, hospitalization, 
dose reduction or interruption, as well as toxicities that are symptomatic and considered 
clinically significant by the investigator. 
 
6.2.2 Reporting Requirement 
AEs will be collected and reported after the subject signs the informed consent until the 
subject’s last visit for the study.  
 


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Regardless of the SAEs relationship to the study drug, the event must be described in the 
source documentation. 
 
All SAE’s will be reported to the U.S. Food and Drug Administration (FDA) and the 
respective governing regulatory agencies as required by local regulations and guidelines. In 
addition, SAEs will be reported to the site’s IRB/IEC as required by local regulations and 
guidelines. 
 
In addition, SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS (or designee) within 24 hours. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form. When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to: 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804. 
 
The paper forms should be used and submitted immediately. When paper forms are used, 
the original paper forms are to remain on site. 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
the BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.  
 
6.3 Severity 
Severity of adverse events will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE). If the AEs are not covered by 
these criteria, then severity of AEs are to be graded as follows: 
 
• Grade 1: Mild; Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
• Grade 2: Moderate; Mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/ therapy required. 
• Grade 3: Severe; Marked limitation in activity; some assistance usually required; medical 
intervention/ therapy required, hospitalization possible.  
• Grade 4: Life threatening or disabling; Extreme limitation in activity; significant assistance 
required; significant medical intervention/ therapy required, hospitalization or hospice care 
probable. 
• Grade 5: Death. 
 
6.4 Relationship 
The relationship of study drug to the AE will be determined by the investigator based on the 
following definitions: 
 


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• Not Related: Another cause of the event is most plausible; or clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study drug administration; or a 
causal relationship is considered biologically implausible. 
• Possibly Related: An event that follows a reasonable temporal sequence from 
administration of the study drug or a known or expected response pattern to the suspected 
drug, but that could readily have been produced by a number of other factors. 
• Probably Related: An event that follows a reasonable temporal sequence from 
administration of the study drug, and there is a biologically plausible mechanism for study 
drug causing or contributing to the AE and the event could not be reasonably explained by 
the known characteristics of the subject’s clinical state. In addition, the relationship may be 
confirmed by improvement on stopping and reappearance of the event on repeated 
exposure. 
 
6.5 Recording Adverse Events or Serious Adverse Events 
If possible, AEs and SAEs medical terminology will be recorded according to the CTCAE. 
Moreover, if known, the diagnosis rather than individual signs and symptoms will be recorded. 
AEs/SAEs occurring as secondary to other events (sequelae) should be identified by primary 
cause. The action taken, relationship to study drug and outcome of AE/SAE will also be 
recorded. 
 
6.6 Follow-up of Adverse Event or Serious Adverse Event and Outcome 
Non-serious adverse events will be followed until the event resolves or stabilizes or until the 
last study visit, whichever comes first, and must be recorded. If the adverse event is serious and 
is assessed as possibly or probably related to study drug, it must be followed until either the 
event is considered stable or resolved. Any SAE assessed as not related to study drug will be 
followed as clinically indicated until its resolution or, if non-resolving, until considered stable 
or until the final study visit, whichever comes first. 
 
By the last study visit, each reported AE/SAE must have one of the following outcomes: 
• Resolved without sequelae. 
• Resolved with sequelae. 
• Unresolved. 
• Death. 
 
6.7 Pregnancy 
Pregnancies should be reported from the time of informed consent until 24 weeks after the last 
dose of study drug, depending on which occurs first. Pregnancies must be followed until 
termination of the pregnancy or for a minimum of six months following the birth of the child. 
If a female subject becomes pregnant while participating in this study, study drug will be 
immediately discontinued. Any pregnancy complication or elective termination of a pregnancy 
for medical reasons will be recorded as an AE or SAE. 
 
Serum or urine pregnancy tests will be performed throughout the study. Refer to appendix 
Error! Reference source not found. for the schedule of assessments. 
 
In addition, if, following initiation of the investigational product, it is subsequently discovered 
that a study subject is pregnant or may have been pregnant at the time of study drug exposure, 


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including during at least 5 half lives after product administration, the investigator must 
immediately notify the BMS of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting 
procedures. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (e.g., dose tapering if necessary for subject safety). 
 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject. Any pregnancy that occurs in a female partner 
of a male study participant should be reported to BMS. Information on this pregnancy will be 
collected on the Pregnancy Surveillance Form. 
 
6.8 Overdose 
An overdose is defined as the consumption of a single dose that is greater than the scheduled 
dose of study drug. For the purposes of this study, an overdose is considered a total daily dose 
of >200 mg of DCV. 
 
7. EXPECTED ADVERSE EVENTS AND MANAGEMENT 
All complications, which occur or are exacerbated during the course of the subject’s involvement 
in the study, will be recorded. All subjects will be given a 24-hour number where the principal 
investigator or a qualified member of the research team can be reached. Management of adverse 
events will be in accordance with standard of care guidelines as well as the following; however in 
the case of life-threatening adverse events, the drug may be discontinued permanently. 
 
7.1 DCV 
Thus far, more than 6000 subjects have exposed to DCV in clinical trial setting. In general, 
DCV has a favorable safety profile. No DCV specific safety signal has been identified. 
 
The safety profile of DCV (60 mg QD)/pegIFNα/RBV therapy in the Phase 2 studies was 
consistent with the established safety profile of pegIFNα/RBV when these drugs were part of 
the 
background 
therapy. 
Few 
subjects 
treated 
with 
DCV/ASV 
DUAL, 
DCV/ASV/pegIFNα/RBV QUAD or DCV/ASV/BMS-791325 Triple therapy reported serious 
adverse events (SAEs) or adverse events (AEs) leading to discontinuation of study drugs. As 
expected, Grade 3/4 hematologic abnormalities (decreased neutrophils and lymphocytes) were 
more common with DCV/ASV/pegIFNα/RBV QUAD therapy (up to 16%) compared with 
DCV/ASV DUAL therapy (up to 4%) and DCV/ASV/BMS-791325 Triple therapy (up to 3%). 
No cases of potential drug induced liver injury (DILI) were reported with DCV/pegIFNαRBV, 
DCV/ASV Dual, DCV/ASV/pegIFNαRBV Quad, or DCV/ASV/BMS-791325 Triple therapy 
(with ASV 200 mg BID, tablet). 
 
In Study AI444040, 167 GT-1 HCV infected subjects and 44 GT-2, -3 HCV infected 
non-cirrhotic subjects received either 12 weeks or 24 weeks combination treatment of DCV 
and SOF. An interim analysis was performed when all subjects had reached at least SVR12. 
The data showed the combination of DCV plus SOF was well tolerated. Overdose was the only 
SAE “related” to treatment. No other SAEs or discontinuations of study treatment were 
reported by investigators to be related to therapy. Most AEs were mild or moderate and did not 


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lead to treatment discontinuation. No Grade 3/4 events of elevated ALT, AST or total or direct 
bilirubin were observed. 
 
Overall, 4 subjects have died while participating in DCV studies. This includes 3 subjects 
treated with DCV 20 mg QD/pegIFNαRBV [sudden death due to unknown causes, death due 
to an intraventricular hemorrhage (in the post-treatment period), death due to cardiopulmonary 
failure exacerbated by asthma [in the post-treatment period]; all 3 deaths were considered not 
to be related to study drugs by the investigator]. One subject treated with 60 mg QD + BMS-
986094 200 mg QD died due to cardiogenic shock with multisystem organ failure, including 
biventricular heart failure and renal failure; the investigator considered the death to be possibly 
related to BMS-986094, a nucleotide polymerase (NS5B) inhibitor no longer in clinical 
development. 
 
In Japanese subjects treated with the DUAL combination of DCV and ASV, a constellation of 
clinical symptoms (pyrexia, eosinophilia, and liver test abnormalities) was identified in 
1 Japanese subject (sentinel case) treated with DCV/ASV Dual therapy in the Phase 3 
AI447026 study. A total of 6 serious adverse reactions (SAR) of pyrexia were identified 
including the sentinel case; 4 of the 6 subjects experienced eosinophilia (> 0.6 x 103 cells/µL) 
and 2/6 subjects had elevated ALT/AST > 5 x upper limit of normal (ULN). All cases were 
reported from studies conducted in the Japanese population with DCV/ASV Dual therapy. No 
SAR of pyrexia was identified in the non-Japanese population. At this time, it is not known 
conclusively if these findings are directly related to study medication or other factors but the 
constellation appears limited to Japanese subjects treated with ASV. 
 
The lack of similar liver toxicity or concurrent pyrexia/eosinophilia in DCV studies not 
including ASV indicates that these events are less likely to be related to DCV. Otherwise, DCV 
was well tolerated at durations up to 12, 24, or 48 weeks, depending on the study. 
 
Bristol-Myers Squibb has received 5 adverse event (AE) reports describing clinical significant 
arrhythmias, most involving severe bradycardia, when patients receiving amiodarone were 
administered daclatasvir (DCV) in combination with sofosbuvir (SOF) for treatment of 
hepatitis C virus (HCV) infection. These reports were received from the DCV Expanded 
Access Program (EAP) or from spontaneous post-marketing reports initiated by a local 
provider, in subjects with pre-existing cardiovascular comorbidity. None of these events 
occurred in the context of BMS sponsored clinical trials, where amiodarone was seldom, if 
ever, used by subjects in the trials. At this time, BMS is unable to determine if this potential 
drug-drug interaction with amiodarone results from interaction of amiodarone with DCV, SOF 
or both. However, to remain conservative regarding patient safety while this potential 
interaction is further investigated, BMS has decided to exclude amiodarone from use in clinical 
studies at this time. 
 
Overall exposure to DCV includes approximately 7900 patients in clinical trials, 5500 patients 
in the EAP, and reportedly >10,000 patients in Japan; exposure to DCV/SOF has been 
approximately 707 patients in BMS clinical trials and 4111 patients in EAP programs. 
 
Amiodarone was excluded from use in most DCV clinical trials (amiodarone was permitted to 
be “used with caution” in UNITY trials of DCV/ASV/beclabuvir [BCV]). Approximately 30 of 


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4111 patients enrolled in the French cohort Autorisation Temporaire d'Utilisation (ATU; 
compassionate use program) were receiving amiodarone upon initiation of hepatitis antiviral 
therapy. To date, no reports of potential amiodarone Drug-Drug Interactions (DDIs) have been 
received for the Dual regimen (DCV/ASV) in either clinical trials or the post-marketing 
setting; all reports have involved DCV/SOF. 
 
In DCV-TRIO protocols with active dosing, including AI443123 and AI443131, amiodarone 
was categorized as “use with caution” due to its strong inhibition of P-glycoprotein. These 
protocols will be amended to prohibit amiodarone use during treatment with DCV-TRIO, with 
or without SOF. 
 
Potential Drug Induced Liver Injury (DILI): 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is 
defined as:  
• ALT ≥ 5 times baseline or nadir value, whichever is lower, AND ≥ 10 x ULN (upper limit 
of normal, AND 
• Total bilirubin ≥ 2.5 x ULN, AND 
• No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia, 
including, but not limited to, acute viral hepatitis, cholestasis, pre-existing hepatic disease 
excluding HCV or the administration of other drug(s), herbal medications or substances 
known to be hepatotoxic. 
 
Most common AEs with DCV: 
No AEs or clinical laboratory abnormalities directly attributable to DCV are identified. The 
most common AEs reported with DCV treatment include headache, dizziness, nausea, diarrhea, 
fatigue, back pain, insomnia, abdominal pain and flatulence. The AE profiles of combined 
therapy are consistent with placebo or backbone of therapy when DCV was administrated in 
combination with other DAAs or pegIFNαRBV. 
 
Dose reductions: 
Dose modifications of DCV are not permitted. 
 
Dose interruptions: 
If an AE including a laboratory abnormality leads to dose interruption then close monitoring of 
the laboratory abnormality or AE that led to interruption of study drug(s) should occur at least 
until the interrupted drug can be restarted or until AE is resolved. When AEs occur that are 
considered by investigators to be unsafe, the necessity of dose interruption of DCV should be 
discussed with the principal investigator. If interruption is required for more than 7 days, 
treatment with DCV must be permanently discontinued. 
 
Missed doses 
• If the missed dose is remembered within 12 hours of the scheduled dose time, the dose 
should be taken as soon as possible.  
• If the missed dose is remembered later than 12 hours after the scheduled dose time, the 
dose should be skipped and the next dose taken at the appropriate time. 


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7.2 Standard of care treatment and DCV 
 
Dose adjustments and interruptions of SOF/RBV (NIMP – standard of care treatment) will be 
according to standard of care.  
 
Data demonstrates no clinically meaningful PK interaction between DCV and SOF. 
  
In Study AI444040, Population PK sampling occurred in all subjects while serial PK sampling 
occurred on Days 7 and 14 in a subgroup of subjects (N = 31). Plasma concentrations of DCV, 
SOF, and the SOF predominant circulating metabolite GS-331007 were determined by 
validated LC/MS/MS methods. Noncompartmental PK parameters were derived. Pooled data 
of DCV exposures across all arms (N = 87) were compared to historical data from study 
AI447011 (DCV 60 mg once-daily in combination with the NS3 protease inhibitor 
asunaprevir). The results showed the PK of GS-331007 was unchanged by the presence of 
DCV. No apparent effect of SOF on DCV PK was observed. 
SOF is a substrate of Pgp. As such, SOF may be susceptible to Pgp transporter-based drug 
interactions. Potent intestinal inducers (rifampin and St John’s wort) of Pgp may decrease SOF 
plasma concentration and reduce the therapeutic effect of SOF; as such, rifampin or St John’s 
wort should not be used with SOF. Coadministration of SOF with drugs that inhibit Pgp may 
increase SOF plasma concentration. Based on these results, SOF may be administered with 
inhibitors of Pgp. SOF is not an inhibitor of Pgp and thus is not expected to increase exposures 
of drugs that are substrates of these transporters. 
 
Development of Resistance: 
Development of drug resistance has been observed with HCV replication inhibitors. Early 
emergence of resistant variants occurred in HCV-infected subjects dosed with DCV 
monotherapy (Study AI444004). However, such DCV resistant variants can be partially or 
fully suppressed when DCV is administrated as part of a potent DAA combination, in 
particular SOF. Viral breakthrough (VBT), in particular, is rare in subjects taking SOF and not 
expected in this study. In the SOF Phase 2 and 3 program results reported to date, only a single 
case of viral breakthrough occurred in a subject taking SOF. This particular subject was found 
to have undetectable SOF levels in PK analysis and clearly non-adherent to therapy.  
 
In study AI444040, only one GT-3 subject receiving the combination DCV and SOF met a 
protocol definition of VBT. This subject demonstrated undetectable levels prior to 
administration of rescue therapy (addition of pegIFNαRBV) and thus does not appear to 
represent a true virologic failure. One additional GT-3 subject experienced virologic relapse at 
post treatment week 4. This subject demonstrated an A30K polymorphism at baseline and 
relapse. No emergent resistance variants were identified in the relapse virus. 
 
Relapse has occurred in many patients who have been treated with SOF; however, the precise 
reason for relapse remains unclear. SOF resistant variants have been rare. There was a single 
case of the signature S282T mutation conferring resistance to SOF, which was reported in a 
GT-2 patient who relapsed post-treatment. The detection was transient and viral sequences 
reverted to wild-type during follow-up. An additional GT1 infected patient experienced viral 
relapse following 12 weeks of treatment with SOF and the NS5A inhibitor ledipasvir. The 


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S282T variant was detectable at low levels using next generation sequencing methods in the 
relapse virus in addition to NS5A resistance substitutions. Both of these patients were 
successfully retreated with longer durations of SOF containing therapy. 
   
In summary, the risk of viral resistance is low and mitigated by the following: 
• The high clinical efficacy rates cited previously suggest that the risk of developing two 
drug resistance as result of study participation is low during or after treatment.  
• Subjects participating in this study will be closely monitored for viral breakthrough or 
relapse. 
• In addition, as there is no cross resistance between DCV/SOF and other classes of DAAs, 
in particular telaprevir or boceprevir.  
• Finally, since the SOF S282T mutation appears rare with rapid reversion to wild-type when 
detected, successful retreatment with a SOF-based regimen may be possible. 
 
Resistance analysis is planned to take place after all subjects have completed the study drug 
period. The following will be analyzed (refer to appendix A): 
• Nucleotide sequencing of the NS5A gene at baseline for all subjects and at the end of 
treatment for all subjects with evaluable viral loads; 
• NS5B gene in the resistance analysis for subjects with previous sofosbuvir experience at 
baseline and at the end of treatment. 
 
Potential Benefits of Treatment with DCV in Combination with SOF: 
Based on data from the AI444040 study, the key potential benefits of a treatment regimen 
consisting of DCV/SOF in HCV GT-3 infected patients include: 
• Improved rates of SVR compared to currently available therapies  
• Better tolerability without interferon/RBV associated AEs  
• The potential for shortened duration of treatment compared to pegIFNαRBV 
• Convenient once daily dosing schedule and low pill burden 
 
In summary, the overall Risk/Benefit for patients who may participate in this study is highly 
favorable. The currently available treatments for GT-3 patients are unsatisfactory due to 
suboptimal efficacy and tolerability issues related to pegIFNαRBV side effects. Thus, this 
pegIFNαRBV sparing combination regimen, shown to be well tolerated and highly potent in a 
study of > 200 patients is expected to provide significant benefit to participating subjects. 
 
7.3 Other expected adverse events 
• Drawing Blood: This is will be according to standard of care. Taking blood samples for 
tests can create certain discomfort and occasionally cause a small hemorrhage (bleeding), 
swelling, or bruising at the point of insertion of the needle, and in rare occasions, fainting 
or infection. The risk of blood draws will be managed according to standard of care and 
local regulations. 
• Giving urine samples can cause discomfort. 
• There are generally no risks associated with ECG. Because this procedure merely monitors 
the electrical impulses and does not give or send out electricity, there is no risk of shock. 
ECG will be performed according to the center’s standard operating procedures. 


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• Another possible risk is loss of confidentiality. Every effort will be made to keep the study 
participant’s identity confidential. The risk of loss of confidentiality will be minimized by 
keeping records in a secure location and on password-protected computers. Data collection 
forms and blood samples will be marked only with the initials of the subject and a code 
number.  
 
7.4 Pregnancy  
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea 
in a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.  
 
*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal. 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months.  
 
It is unknown if the study drug may cause harm to an unborn child. A serum or urine 
pregnancy test will be performed for women of childbearing potential before study drug is 
initiated and throughout the study. Refer to appendix Error! Reference source not found. for the 
schedule of assessments. It is essential for both fertile women and men to use two reliable 
forms of effective birth control to prevent pregnancy while participating in this study.  
 
If a pregnancy occurs at any time during the study, demonstrated by a positive serum or urine 
pregnancy test, study drug will be discontinued immediately.. 
 
8. STATISTICAL ANALYSIS 
The purpose of this study is to evaluate the safety, tolerability and efficacy of DCV and 
standard of care therapy of SOF/RBV for 16 weeks versus 24 weeks in HCV-infected genotype 
3 subjects. 
 
8.1 Sample Size  
This is a randomized, open label, single center safety and efficacy study. This is a small study 
of at least 40 cirrhotic subjects with HCV genotype 3 will receive standard of care treatment of 
SOF/RBV as well as 60 mg daily of Daclatasvir (investigational product).  Subjects will be 
randomized in a 1:1 to one of the following groups: 
• Group A: 20 subjects will receive 16 weeks of DCV/SOF/RBV 
• Group B: 20 subjects will receive 24 weeks of DCV/SOF/RBV 


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8.2 Statistical Methods and Analysis Populations 
Analyses of safety and efficacy data will use the intent-to-treat (ITT) subject population. The 
ITT subject population will include all subjects who are randomized. 
 
In all hypotheses tests for treatment effects, the null hypothesis is that there is no difference 
between triple therapy with DCV/SOF/RBV versus standard of care therapy of SOF/RBV 
(based on historical). The alternative hypothesis is that there is a difference between the two 
groups, regardless of direction (two-sided alternative). 
 
Missing values will not be imputed for any variables, meaning all missing values will be 
treated as missing data. Descriptive statistics will be used to describe the sample. Correlational 
analyses will be used to explore relationships. The distribution of the variables will be 
conducted first to determine whether parametric or non-parametric measures should be used. In 
case parametric measures are used, paired t-tests will be employed for interval variables and 
chi-square for ordinal/nominal variables. In case the data is non-parametric, Wilcoxon Mann-
Whitney tests will be used. Univariate and multivariate logistic regression may be used to 
evaluate factors associated with improvement.  
 
8.3 Interim Analysis 
Interim analysis will not be conducted. 
 
9. STUDY ADMINISTRATION: ETHICAL AND LEGAL ASPECTS 
This study will be conducted in compliance with GCP as described in FDA regulations and ICH. 
These practices are consistent with the principles stated in the Declaration of Helsinki. The study 
will be conducted in accordance with all applicable regulatory requirements for a US IND 
application and in keeping with local legal and regulatory requirements. 
 
9.1 Human Subjects and Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
individual participating in this study after adequate explanation. The investigator must utilize 
an IRB or IEC 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, the person obtaining consent and the investigator. 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  In 
the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. 
 
9.2 Institutional Review Board/Independent Ethics Committee  
This protocol, any amendments and any accompanying material to be provided to the subject 
(such as a consent form, diary, advertisements) will be submitted to a properly constituted IRB 
or IEC, in agreement with local legal prescriptions, for formal approval of the study conduct. 
The decision of the IRB/IEC concerning the conduct of the study will be made in writing to the 


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investigator and a copy of this decision must be on file before starting the study or use of the 
material. 
 
9.3 Obligations of the Investigator 
The investigator will also ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998, are adhered to. 
 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. The investigator should ensure that all 
persons involved in the conduct of the study are qualified by education and training, informed 
about the protocol, protocol amendments, study procedures, and any study-related duties. 
 
The investigator is also responsible for obtaining informed consent from each subject 
participating in the study in accordance with the regulations. Informed consent must be 
obtained from the subject before any screening procedure is undertaken that is not part of 
routine care. The investigator will also ensure that all subjects enrolled meet the eligibility as 
defined in the protocol. The investigator must assure that subjects’ anonymity will be strictly 
maintained and that their identities are protected from unauthorized parties. The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and 
for all subjects enrolled in the trial.  
 
All appendices attached hereto and referred to herein are made part of this study protocol. Any 
amendment to the study protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation, except where necessary to eliminate an immediate hazard(s) to 
study subject. In some instances, an amendment may require a change to the consent form. The 
investigator must receive an IRB/IEC approval/favorable opinion concerning the revised 
consent form prior to implementation of the change. Any necessary amendments to the study 
protocol and/or consent form will be prepared by the sponsor and provided to the investigator 
for submission to the IRB. Refer to appendix B for a history of all the changes made to the 
study protocol. 
 
9.4 Quality Assurance 
The principal investigator(s) will ensure that the study will be appropriately monitored by 
ensuring that all the rights of the subjects are adequately protected, that the trial data are 
accurate, complete and verifiable from source documents and that the conduct of the trial is in 
compliance with the protocol and its subsequent amendments, with GCP and with applicable 
regulatory requirements. Accurate, consistent, and reliable data will be ensured through the use 
of standard GCP.  
 
9.5 Study Documentation and Records Retention 
Source data is all information, original records of clinical findings, observations, or other 
activities conducted as part of the study and are necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents such as hospital records, clinical 
and office charts, laboratory notes, subjects’ diaries, pharmacy dispensing records. The 
minimum retention time will meet the strictest standard applicable to that site for the study, as 


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dictated by any institutional requirements or local laws or regulations, otherwise, the retention 
period will default to 15 years.  
 
10. REFERENCES 
 
1. Simmonds P. Viral heterogeneity of the hepatitis C virus. J Hepatol 1999; 31 (Suppl 1): 54-
60. 
2. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin 
compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a 
randomized trial. Lancet 2001; 358(9286): 958-965.   
3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic 
hepatitis C virus infection. N Engl J Med 2002; 347(13): 975-982.  
4. Hadziyannis SJ, Sette H, Jr, Morgan TR, et al. Peginterferon alpha-2a and ribavirin 
combination therapy in chronic hepatitis C: a randomized study of treatment duration and 
ribavirin dose. Ann Intern Med 2004; 140(5):346-355. 
5. M. Gao, N.A. Meanwell et al., Nature, 2010, 465, 96-100. 
6. Sovaldi (sofosbuvir) US product information label.  Gilead Sciences. December 2013. 
7. Daclatasvir (BMS-790052) Investigator Brochure (Version 7). Bristol-Myers Squibb 
Pharmaceutical Research Institute; November 2012. Refer to IND 79,599. 
8. IDSA 2013 Abstract Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± 
Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients Who Previously 
Failed Telaprevir (TVR) or Boceprevir (BOC). 
9. Zeuzem S, Dusheiko GM, Salupere R et al.  Sofosbuvir + ribavirin for 12 or 24 weeks for 
patients with HCV genotype 2 or 3: the VALENCE trial.  AASLD 2013 (abstract 1085). 
 
11. APPENDICES 
 
 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 37 of 42 
A. Schedule of Assessments 
Procedure 
Scree
ning 
BL 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
1Wk 
20 
1Wk 
24 
Post 
Wk 
4 
Post 
Wk 
12 
Post 
Wk 
24 
Early 
Term 
Consent and HIPPA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver fibrosis assessment 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals3 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Symptom Directed Physical 
Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE Collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP Study Drug Dispensing 
 
X 
 
X 
 
X 
 
X 
X5 
X 
 
 
 
 
 
IMP Study Drug Return and 
Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
X6 
 
X 
 
 
X 
X 
Laboratory 
Assessments7 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV Genotype, 
and HIV Testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NS5A and NS5B 
X 
 
 
 
 
 
 
 
X6 
 
X5 
 
 
 
X 
                                                      
 
1 Weeks 20 and 24 visits are for Group B subjects only. 
2 This entails obtaining documentation of results. See inclusion criteria. 
3 Vitals include weight, blood pressure, pulse, temperature and respiration rate. 
4 Height and BMI must also be performed. 
5 For Group B subjects only. 
6 For Group A subjects only. 
7 Screening laboratory results will be based on previously documented results as per inclusion/exclusion criteria. All subsequent labs will be done per standard of care. 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 38 of 42 
Procedure 
Scree
ning 
BL 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
1Wk 
20 
1Wk 
24 
Post 
Wk 
4 
Post 
Wk 
12 
Post 
Wk 
24 
Early 
Term 
gene resistance 
analysis8 
Serum or Urine HCG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
                                                      
 
8 Refer to section 7.2 on which analyses will be performed and on which subjects. 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 39 of 42 
B. History of Protocol Changes 
 
The following is a list of changes made to the study protocol from version 0 dated September 
29, 2014 to version 1 dated October 29, 2014: 
 
Protocol Section 
Rationale for Change 
Page 1 
Updated the project title to reflect the revision in the study 
design (variation in the treatment duration). Subjects without 
cirrhosis will receive 12 weeks of DCV/SOF/RBV, while 
subjects 
with 
cirrhosis 
will 
receive 
24 
weeks 
of 
DCV/SOF/RBV. 
Page 1 
Updated the Central Study Site name for accuracy. 
Page 1 and footer 
Updated the version number. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 2.6 
Added the rationale for varying the duration of treatment 
depending on the presence of cirrhosis. Subjects without 
cirrhosis will receive 12 weeks of DCV/SOF/RBV, while 
subjects 
with 
cirrhosis 
will 
receive 
24 
weeks 
of 
DCV/SOF/RBV. 
Sections 3.1 and 3.2 
Updated the study’s primary and secondary objectives in light 
of the variation of treatment duration, which will be dependent 
on the subject’s cirrhosis status. 
Section 4.1 
Updated the study design overview to clarify that the subjects 
will be classified according to one of two groups: group A will 
include those without cirrhosis (“Non-cirrhotics”) and group B 
will include those with cirrhosis (“Cirrhotics”). Since subjects 
with F3 will be classified under group A, the number of 
subjects anticipated in each group has been revised. 
Section 4.2.1 
Revised inclusion criterion 4 to indicate the amended cut-point 
for a subject to be classified as cirrhotic on Fibroscan. 
Section 4.2.2 
Added exclusion criterion 8. Subjects with prior exposure to 
NS5A will be excluded. The subsequent exclusion criteria 
numbering has been revised accordingly. 
Section 4.2.3 
Added the virologic breakthrough and its definition as a reason 
for discontinuing IMP. 
Sections 5.1 and 5.2, 5.3.4 
and 5.3.6  
Updated and added the visit weeks/assessments/window for 
Group B subjects. 
Section 8.1 
Updated the groups to reflect the update in study design. 
Appendix A 
Revised to include the additions of study visits/assessment for 
subjects in Group who will be receiving treatment for 24 
weeks instead of 12 weeks. 
Appendix B 
Added the list of changes made to the study protocol from 
version 0 dated September 29, 2014 to version 1 dated October 
29, 2014 
 
 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 40 of 42 
The following is a list of changes made to the study protocol from version 1 dated October 29, 
2014 to version 2 dated October 31, 2014: 
 
Protocol Section 
Rationale for Change 
Page 1 
Updated the project title to reflect the revision in the study 
design. Only subjects with HCV genotype 3 and cirrhosis will 
be considered for the study. They will be randomized to two 
groups: Group A will receive 16 weeks of DCV/SOF/RBV, 
while subjects in Group B will receive 24 weeks of 
DCV/SOF/RBV. 
Page 1 and footer 
Updated the version number. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 2.1, 2.6 and 2.7 
Minor revisions to clarify that only cirrhotic subjects will be 
considered and that subjects will be randomized to receive 
either 16 weeks or 24 weeks of DCV/SOF/RBV. 
Sections 3.1 and 3.2 
Updated the study’s primary and secondary objectives in light 
of the amended study design. 
Section 4.1 
Updated the study design overview to state that this is a 
randomized study. Only subjects with HCV genotype 3 who 
have cirrhosis will be considered. Randomization will be in a 
1:1 ratio to either group A or group B. Group A subjects will 
receive 16 weeks of DCV/SOF/RBV, while Group B subjects 
will receive 24 weeks of DCV/SOF/RBV. 
Section 4.2 
Updated study population overview in light of the amended 
study design. 
Section 4.2.1 
Revised inclusion criterion 4 to indicate that only subjects with 
evidence of cirrhosis will be included. 
Section 4.4 
Added this section on randomization in light of the amended 
study design. All subsequent numbering has been updated 
accordingly. 
Sections 5.1 and 5.2, 5.3.4 
and 5.3.6  
Updated the timing of various assessments in light of the 
treatment duration for groups A and B. Also, corrected a 
discrepancy between section 5.1 and the Appendix A on the 
schedule of pregnancy assessments. 
Section 8 and 8.1 
Revised to reflect the update in study design. 
Appendix A 
Updated assessment for subjects to correspond to section 5 of 
the protocol in light of the amended study design. 
Appendix B 
Added the list of changes made to the study protocol from 
version 1 dated October 29, 2014 to version 2 dated October 
31, 2014 
 
The following is a list of changes made to the study protocol from version 2 dated October 31, 
2014 to version 3 dated November 17, 2014: 
 
Protocol Section 
Rationale for Change 
Page 1 and footer 
Updated the version number. 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 41 of 42 
Page 1 
Updated the Central Study Site name for accuracy. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 4.2.2 
Revised criterion 9 to indicate last use of a prohibited or 
restricted treatment. 
Section 4.3.1 
Added dosing information for standard of care Sofosbuvir and 
Ribavirin. 
Section 4.3.2 
Specified that IMP can be taken with or without food. 
Section 4.5  
Added information on the last use of a prohibited or restricted 
treatment and corrected a typographical error. 
Sections 5.3.3, 5.3.4 and 
5.3.8 
Updated to accurately specify that laboratory testing will be 
done according to standard of care and appendix A. 
Section 7.2 
Added a sentence that dose adjustments and interruptions for 
NIMP (SOF/RBV) will be per standard of care. Also, added 
the resistance analysis plan. 
Appendix A 
Amended to include the planned resistance analysis plan. 
Appendix B 
Updated changes made to the protocol from version 0 to 1 and 
version 1 to 2 to specify that the footers were also revised from 
one version to the other. This was inadvertently previously not 
included in the tables. In addition, added the list of changes 
made to the study protocol from version 2 dated October 31, 
2014 to version 3 dated November 17, 2014. 
 
The following is a list of changes made to the study protocol from version 3 dated November 
17, 2014 to version 4 dated December 16, 2014: 
 
Protocol Section 
Rationale for Change 
Page 1 and footer 
Updated the version number. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 4.1 
Updated to clearly state the total duration of subject 
participation for each study group. 
Section 4.2.1 
Amended inclusion criterion 1 to exclude legal representatives. 
Section 4.2.2 
Added exclusion criterion 1 (all others have been re-numbered 
accordingly) to state that subjects who lack capacity to consent 
for themselves will be excluded. 
 
Also, updated timeframe in exclusion 8 from 60 days to 8 
weeks for consistency with screening window. 
Section 5.3.2 
Updated screening window to reflect it in weeks instead of 
days for clarity and consistency. 
Section 8.1 
Revised section title for accuracy and clarified that this is a 
small scale study. 
Appendix B 
Updated the changes made to Appendix B in the table of 
changes made from study protocol version 2 to 3 for accuracy. 
In addition, added the list of changes made to the study 
protocol from version 3 dated November 17, 2014 to version 4 
dated December 16, 2014. 


T. Hassanein – Daclatasvir (AI444284) 
Version 7 – September 5, 2015 
Page 42 of 42 
 
The following is a list of changes made to the study protocol from version 4 dated December 
16, 2014 to version 5 dated January 7, 2015: 
 
Protocol Section 
Rationale for Change 
Page 1 and footer 
Updated the version number. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 4.1 
Corrected a typographical error to refer to the correct group. 
Section 5.1 
Deleted extra space. 
Section 5.3.4 
Clarified IMP study drug dispensing for both groups. 
Section 7.2 
Minor grammatical correction. 
Appendix A 
Corrected the following: 
• Week 16 footnote for ECG by adding footnote 6. All 
subsequent numbering of footnotes have been updated.  
• Weeks 16 and 24 footnotes for NS5A and NS5B gene 
resistance analysis.  
• Footnote 1 description. 
 
The following is a list of changes made to the study protocol from version 5 dated January 7, 
2015 to version 6 dated February 3, 2015: 
 
Protocol Section 
Rationale for Change 
Page 1 and footer 
Updated the version number. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 4.5 
Added amiodarone or any of its trade/brand names/formulas to 
the list of prohibited treatments. 
Section 7.1 
Added summary information on the adverse events reports 
regarding the use of amiodarone and DCV.  
 
 
The following is a list of changes made to the study protocol from version 6 dated February 3, 
2015 to version 7 dated September 5, 2015: 
 
Protocol Section 
Rationale for Change 
Page 1 and footer 
Updated the version number. 
Page 1 
Changed the study phase as the study drug has been approved 
by the U.S. FDA on July 24, 2015. 
Protocol Table of Contents 
Updated to reflect new page numbers. 
Section 2.7 
Added information on the approval of study drug by the U.S. 
FDA. 
Section 4.2.2 
Updated exclusion criterion # 6 for accuracy to exclude only 
subjects with decompensated cirrhosis and not those with 
stable cirrhosis. 
 
 

ICF_001.pdf: 
 
APPROVED 
 
AS MODIFIED 
 
Nov 23, 2015 
 
WIRB® 
 
 
AI444284 Protocol Version 6 – 3Feb15 
Page 1 of 14 
WIBR Study No. 1150498 
RESEARCH AND CONSENT FORM AND HIPAA AUTHORIZATION 
 
 
TITLE: 
A Randomized Study to Evaluate the Safety and Efficacy of 
Adding Daclatasvir to the Combination of Sofosbuvir (SOF) and 
Ribavirin (RBV) for 16 Weeks Versus 24 Weeks in Cirrhotic 
Subjects with Chronic Hepatitis C Infection Genotype 3 
 
PROTOCOL NO.: 
AI444284 
 
SPONSOR: 
Tarek Hassanein, M.D. 
 
INVESTIGATOR: 
Tarek I. Hassanein, MD 
 
Suite 101 
 
131 Orange Avenue 
 
Coronado, California 92118 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Tarek Hassanein, MD 
 
619-522-0330 (24 hours) 
 
 
Purpose of This Consent Form 
 
This consent form is written to help you decide if you want to participate in a research study and 
take an experimental drug for your condition.  An experimental drug is one that is not approved by 
the U.S. Food and Drug Administration (FDA).  For you to receive this experimental drug, you 
must give your informed consent.  Informed consent includes: 
 
• Reading this consent form, 
• Having your doctor or your doctor’s staff explain the study and experimental drug to you, 
and 
• Asking your doctor or your doctor’s staff about anything that is not clear. 
 
In addition: 
 
• You may take home an unsigned copy of this consent form. 
• You can think about it or talk to family or friends before you decide. 
 
You should not sign this consent form until all your questions have been answered and you are 
satisfied with the answers. 
 


 
APPROVED 
 
AS MODIFIED 
 
Nov 23, 2015 
 
WIRB® 
 
 
AI444284 Protocol Version 6 – 3Feb15 
Page 2 of 14 
WIBR Study No. 1150498 
Please read this consent form carefully.  This form may contain words that you do not 
understand.  Please ask the doctor or his staff to explain any words or procedures that you do not 
clearly understand. 
 
Purpose and Description of the Study 
 
You are being asked to participate in this research study because you have been diagnosed with 
hepatitis C infection (HCV) genotype 3 and cirrhosis (very severe scarring of the liver). You 
have either never received treatment for it or did, but your body did not respond to conventional 
therapy.  You are now considering the use of Daclatasvir with sofosbuvir plus ribavirin.  
Sofosbuvir and ribavirin are FDA-approved drugs and the standard of care treatment. The 
standard duration of treatment with sofosbuvir and ribavirin for someone with HCV genotype 3 
is 24 weeks.  But Daclatasvir is experimental for your condition, and not all its risks or side 
effects are known.  
 
You should be aware that:  
• Some of the side effects may be life threatening. 
• There is no promise that your condition will be helped. 
• You do not have to take part in this study.  Your decision about what to do must be made 
voluntarily. About 40 subjects are planned to complete the study.   
 
Your doctor wants to see if Daclatasvir in combination with sofosbuvir and ribavirin is a superior 
treatment for chronic HCV infection than standard therapy of sofosbuvir and ribavirin alone. The 
study will also look at the safety of adding Daclatasvir to sofosbuvir and ribavirin.  
 
Daclatasvir may not improve your chronic HCV.  There is also the possibility that your chronic 
HCV may worsen.  
 
More detailed information about Daclatasvir, sofosbuvir plus ribavirin follows.  Please read it 
carefully. 
 
Procedures for This Study 
 
If you agree to take part in this study, no procedures will be done until you sign and date this 
consent form.  
 
You will be randomized into one of two groups. This means that it will be randomly decided (by 
chance) if you will go into either Group A or Group B. You will have a  50/50 chance of being 
assigned to Group A or Group B: 
 
• Group A: If you are in this group you will take Daclatasvir with sofosbuvir plus ribavirin 
for 16 weeks (4 months).  
 


 
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AI444284 Protocol Version 6 – 3Feb15 
Page 3 of 14 
WIBR Study No. 1150498 
• Group B: If you are in this group you will take Daclatasvir with sofosbuvir plus ribavirin 
for 24 weeks (6 months). 
 
Once you are randomized to a study, the study staff will tell you which group you were 
randomized to.  
 
Once each day, you will take a 60 mg tablet of Daclatasvir (with or without food), a 400 mg 
tablet of sofosbuvir (with or without food), and twice each day you will take a 500-600 mg tablet 
of ribavirin (the exact dose will be determined according to standard of care). Ribavirin has to be 
taken with food (after eating). The duration of taking this combination will depend on which 
group you were randomized to. 
 
Your doctor will see you every two weeks or more frequently until month 4 (if you are in Group 
A) or until month 6 (if you are in Group B). Regardless of which group you were in, the doctor 
will see you at weeks 4, 12 and week 24 after you finish your medications. 
 
At each visit, you will be asked about how you are feeling.  You will also be asked if you have 
taken any medicine other than the study drugs (including non-prescription medications).   
 
The following procedures will be done at these visits: 
 
• Physical exam 
• Review of any side effects or problems 
• Review of any medications, vitamins or herbal treatments you take 
• Weight  
• Blood pressure, heart rate, and temperature  
• Blood samples (by a needle stick into a blood vessel in your arm). The blood will be 
tested to see if there are changes in your liver, muscles, kidney, blood cells and other 
body systems and for measurements of the hepatitis C virus as well as storage for future 
testing, which will include testing to see how your body has reacted to the study drug (no 
genetic testing of your DNA will be done). At the end of the treatment period, any HCV 
still present will be tested to see whether it developed resistance to the study drug 
compared with similar testing performed at the start of your study participation.  
You will be also tested for HIV (AIDS virus).  State law requires that positive results for 
this test be reported to a local health agency.   
• ECG (electrocardiogram) (Screening, week 16 [Group A only], week 24 [Group B only] 
and post study drug week 24).  An ECG records the electrical activity of the heart. 
• Blood or urine pregnancy test (women of childbearing potential only). 
 


 
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AI444284 Protocol Version 6 – 3Feb15 
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WIBR Study No. 1150498 
Your Responsibilities/Restrictions 
 
• Tell your doctor all of the medications that you have been taking for at least 30 days 
before you take part in the study.  This includes vitamins, minerals, and medications that 
do not require a doctor’s prescription.  Some medications are not allowed.  Your doctor 
will discuss these with you in detail. 
• Ask your doctor before you take any new medications. 
• Attend all visits as scheduled. 
• Only you should take the study drugs.  Keep them out of the reach of children and away 
from people who may not be able to read or understand the labels. 
• If you have sexual intercourse with a female who could get pregnant, you must use two 
effective methods of birth control during the study and for 7 months after your last dose 
of ribavirin.  Please see the “Reproductive Risks” section for more information. 
• If you are a woman who can get pregnant, you must use two effective methods of birth 
control during the study and for 7 months after your last dose of ribavirin. Please see the 
“Reproductive Risks” section for more information. 
 
Risks or Discomforts 
 
Your condition may or may not improve and could even get worse if you take part in this study.  
The doctor will monitor you for any signs of a new or unexpected side effect.  Tell your doctor if 
you have a side effect or feel unwell.  Contact your doctor immediately if you: 
 
• have a side effect that concerns you, or 
• are unable to perform your daily functions. 
 
Drugs that affect hepatitis C virus may not completely stop the virus from increasing in your 
body.  If the drugs that you are taking do not completely stop the virus from increasing, your 
hepatitis C virus may develop drug resistance.  Drug resistance may affect the ability of 
Daclatasvir to lower the amount of hepatitis C in your body and may also affect your ability to 
respond to future drugs if they are similar to Daclatasvir.  
 
Experimental Drug Daclatasvir and Sofosbuvir 
 
Thus far, more than 6000 subjects have exposed to Daclatasvir in clinical trials.  In general, 
Daclatasvir has been well tolerated.  No Daclatasvir specific safety concerns have been 
identified.   
 
In a study of Daclatasvir and sofosbuvir, 167 subjects with chronic hepatitis C genotype 1, and 
44 subjects with chronic hepatitis C genotype 2 or 3 were given 12 weeks or 24 weeks 
combination treatment.  An interim analysis was performed. The data showed the combination 
was generally well tolerated.  
 


 
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Nov 23, 2015 
 
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AI444284 Protocol Version 6 – 3Feb15 
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WIBR Study No. 1150498 
No side effects were directly attributable to Daclatasvir. The most common side effects reported 
with Daclatasvir in combination with other treatment such as interferon or others include 
 
• headache,  
• dizziness,  
• nausea,  
• diarrhea,  
• fatigue,  
• back pain,  
• insomnia,  
• abdominal pain, and  
• flatulence.  
 
In rare cases there have been reports that Daclatasvir when taken with sofosbuvir and 
amiodarone can cause arrhythmias (a problem with the rate or rhythm of the heartbeat) in 
particular severe bradycardia (slow heart rate). It is not known whether this resulted from the 
interaction of amiodarone with Daclatasvir, sofosbuvir or both.  Therefore, amiodarone is one of 
the medications that you will not be allowed to use during this research study. The study doctor 
will discuss what options are available for you if you have been taking it or in case you need to 
take it. 
 
Sofosbuvir 
 
The most commonly reported side effects (20% or more of patients) of sofosbuvir in 
combination with ribavirin are fatigue and headache. 
 
Other common side effects include: 
• Nausea,  
• Insomnia,  
• Itching,  
• Rash,  
• Decreased appetite,  
• Diarrhea, 
• Increased bilirubin, 
• Irritability 
 
Ribavirin 
 
The most serious side effect seen with ribavirin is anemia (a decrease in the number of red blood 
cells in the body that carry oxygen).  This may cause tiredness and lack of energy. Anemia 
associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and 
non-fatal heart attacks. 
 


 
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AI444284 Protocol Version 6 – 3Feb15 
Page 6 of 14 
WIBR Study No. 1150498 
Ribavirin is usually taken with pegylated interferon (a once per week shot, which you will not 
receive during this study). 
 
The most common side effects when taking RBV combined with pegylated interferon are flu-like 
symptoms consisting of: 
• Body aches and pains 
• Fever 
• Chills 
• Headache 
• Overall feeling of sickness 
• Rash 
 
Other common side effects are: anxiety, mood changes, depression and irritability. 
 
In general 
 
It is not expected that you will have all of these side effects.  In addition, other side effects may 
occur that are not listed here or were not seen before.  Talk to your doctor for more information.  
Side effects are usually temporary and can often be treated.  However, it is very important that 
you report all side effects to the study staff, as it is possible that these side effects could be 
serious or fatal. 
 
Allergic Reaction 
 
Occasionally, people have allergic reactions (including life-threatening reactions) when taking a 
medication.  Symptoms of a serious allergic reaction can include: rash, hives, itching and/or 
trouble breathing, closing of the throat, swelling of the lips, tongue, or face, and rarely, death.  
Get emergency medical care immediately if you have any of these symptoms.  Stop taking 
your drug drugs and let your doctor know. 
 
In general, allergic reactions to medicines are more likely to occur in people who already have 
allergies.  If you are allergic to other drugs, foods, or things in the environment, such as dust or 
grass, or if you have asthma, let your doctor know.  
 
Blood Draw Risks 
 
Possible side effects from drawing blood include dizziness, redness and swelling of the vein, 
pain, bruising, or bleeding from the site of the needle puncture.  Rarely, a clot or infection could 
occur that would require treatment.  Some people feel faint or sick when blood is taken. 
 
ECG Risks 
 
An ECG is a painless test, but you might have redness, irritation, or a rash on the skin where the 
adhesive patches are placed. 


 
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AI444284 Protocol Version 6 – 3Feb15 
Page 7 of 14 
WIBR Study No. 1150498 
Unknown Risks 
 
Daclatasvir is an experimental drug and might have other side effects, which are not known at 
this time.  Taking Daclatasvir in combination with sofosbuvir and ribavirin could also have 
unknown side effects.  Any unknown side effects could be serious. 
 
Do not drive, operate machinery, or do other activities requiring mental alertness until you know 
how the medication will affect you.  Discuss all side effects with your doctor. 
 
Reproductive Risks/Birth Control 
 
The effects of Daclatasvir on the fetus (unborn child) are not known.  You must protect 
yourself/your female partner(s) from becoming pregnant before, during, and after the study.  If 
you have sexual intercourse, you must use effective methods of birth control as described below.  
Your doctor will need to document what type(s) of birth control you are using. 
 
Ribavirin has been shown to cause significant birth defects in animals and may cause birth 
defects in humans.  Ribavirin can persist in the body for as long as 6 months after it has been 
discontinued. 
 
If you/your female partner can become pregnant, you and your partner must use two forms of 
birth control for the entire study and for a minimum of 7 months after you stop taking the drugs 
or longer as directed by your doctor.  One birth control method must be a barrier method (such as 
a condom with spermicide).  Your doctor will discuss other methods of birth control that may be 
used in combination with a barrier method. 
 
Tell your doctor if your female partner gets pregnant during this study or for up to 7 months after 
you stop taking the drug(s).  Your doctor will want to know about the pregnancy and its 
outcome.  The outcome, including any premature termination, must be reported to Bristol-Myers 
Squibb, Inc. (the company that will provide Daclatasvir for this study).  
 
New Information 
 
You will be told about any new information that might change your decision to be in this study. 
 
Possible Benefits 
 
The study drugs might improve your condition.  However, there is no guarantee of this. The 
information gained during this study may benefit patients with your condition in the future. 
 
Payment for Participation 
 
You will not be paid for being in this study. 
 


 
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Alternatives 
 
Instead of being in this study, you could choose to receive/continue to receive standard care for 
your HCV. The current standard care for your condition is sofosbuvir and ribavirin for 24 weeks 
(as received by Group B) or pegylated interferon alfa-2a with ribavirin.   
 
Ask the study doctor to discuss these alternatives with you. You do not need to be in this study to 
receive treatment for your condition.  
 
Costs to You 
 
Daclatasvir will be provided at no cost to you.  Tests and procedures that are done only for the 
study will not be billed to you or your health insurance company. 
 
You or your health insurance company will be billed for any standard medical care you are given 
during this study.  These are costs that you would normally have if you were being treated for 
your disease with standard care. You or your health insurance will be responsible for providing 
you with sofosbuvir and ribavirin (standard of care treatment) according to the standard of care 
duration. The approximate cost of sofosbuvir and ribavirin for 24 weeks (6 months) for 
individuals with Hepatitis C genotype 3 is around $170,000. 
 
You may wish to consult your health insurance company about its payment policy for standard 
treatment received during a research study. 
 
You might have unexpected expenses from being in this study. Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor. This discussion should include who will 
pay the costs of treating possible side effects. 
 
Confidentiality and Release of Medical Records 
 
We will try to protect the confidentiality of information about you as much as possible.  
However, we cannot guarantee complete confidentiality because the following groups may be 
given access to your original and study medical records: 
 
• U.S. Food and Drug Administration (FDA),  
• the Department of Health and Human Services (DHHS),  
• similar health agencies in other countries 
• Western Institutional Review Board® (WIRB®) 
 
These groups may confirm procedures or data without violating your confidentiality to the extent 
permitted by the applicable laws and regulations.   
 
Results from this study may be published or presented at scientific meetings, but your identity 
will not be revealed. 


 
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By signing this consent form, you are authorizing access to your medical records.  
 
Compensation for Study-Related Injury 
 
If you are injured or become ill from the experimental drug, medical treatment will be provided 
to you.  Contact your study doctor at the number on the first page of this document to find out 
where to go for treatment.  You or your health insurance company will be billed for the cost of 
the treatment.  Neither Bristol-Myers Squibb, Inc. nor the doctor plans to provide other 
compensation in the event of an injury. 
 
This does not restrict your right to pursue a claim through the legal system.  You do not give up 
any legal rights by signing this consent form. 
 
Voluntary Participation/Withdrawal 
 
Your participation in this study is voluntary.  You may decide not to take the experimental drug 
or you may freely withdraw from the study at any time.  Your decision will not result in any 
penalty or loss of benefits to which you are entitled. 
 
In addition, your doctor may stop your participation in this study.  This may happen without your 
consent at any time and for any reason, including any of the following reasons: 
 
• your doctor determines it is in your best interest; 
• you are not responding to the experimental drug; 
• if you do not consent to continue in the study after being told of changes in the research 
that may affect you; 
• you do not follow the study instructions; or 
• Daclatasvir is no longer available to your doctor. 
 
If you stop taking part in this study before the final visit, your doctor may ask you to have some 
final tests. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
If You Have Questions 
 
Contact Tarek Hassanein, MD, at 619-522-0330 (24 hours) for any of the following reasons: 
 
• if you have any questions or concerns about being in this study,  
• if you have a study-related injury or reaction to the drug(s), or  
• if you have a complaint about the study. 
 


 
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If you have questions about your rights as a subject in this study or if you have questions, 
concerns, or complaints about the study, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite, 120 
Puyallup, Washington 98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail:  Help@wirb.com 
 
WIRB is a group of people who independently review research. 
 
WIRB will not be able to answer some study specific questions, such as questions about 
appointment times.  However, you may contact WIRB if research staff cannot be reached or if 
you wish to talk to someone other than the research staff. 
 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
 
If you agree to be in this study, you will receive a signed and dated copy of this consent form for 
your records. 
 


 
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Your Consent 
• I have been told that this is a research study. 
• I have been given enough time and information to decide to be in this study. 
• I have had enough time to ask my doctor questions about this study.  My questions so far 
have been answered to my satisfaction. 
• I do not give up my legal rights by signing this consent form. 
• I authorize access to my medical records the FDA, DHHS agencies, similar health 
agencies in other countries, and WIRB®. 
• I have been told that I will receive a signed and dated copy of this consent form. 
 
I agree to take part in this study. 
 
 
 
 
Signature of Patient 
Date 
 
 
________________________________________________ 
Printed Name of Patient 
 
I certify that the information provided was given in language that was understandable to the patient. 
 
 
 
 
Signature of Person Obtaining Consent 
Date 
 
 
________________________________________________ 
Printed Name of Person Obtaining Consent 


 
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HIPAA AUTHORIZATION 
 
The United States government has issued a privacy rule to protect the privacy 
rights of patients (Privacy Rule).  This rule was issued under a law called the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  The 
Privacy Rule is designed to protect the confidentiality of your personal health 
information.  The document you are reading, called an “Authorization,” describes 
your rights and explains how your health information will be used and disclosed 
(shared). 
 
As the sponsor, Tarek I. Hassanein, MD, will use and share personal health 
information about you.  This is information about your health that also includes 
your name, address, telephone number, or other facts that could identify the health 
information as yours.  This includes information in your medical record and 
information created or collected during the study.  This information may include 
your medical history, physical exam, and laboratory test results including results of 
HIV (AIDS virus) testing.  Some of these tests may have been done as part of your 
regular care.  The doctor will use this information about you to complete this 
study. 
 
In most cases, the doctor will use your initials and assign a code number to your 
information that is shared with the sponsor.  The sponsor and its representatives 
may review or copy your personal health information at the study site.  Regulatory 
authorities and Western Institutional Review Board® (WIRB®) may also review or 
copy your information to make sure that the study is done properly or for other 
purposes required by law. 
 
By signing this Authorization, you allow the doctor to use your personal health 
information to carry out and evaluate this study.  You also allow the study doctor 
to share your personal health information with 
 
• the Western Institutional Review Board (WIRB), 
• the U.S. Food and Drug Administration (FDA), and 
• other regulatory agencies. 
 
Your personal health information may be further shared by the groups above.   


 
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If shared by them, the information will no longer be covered by the Privacy Rule 
and may be disclosed without your permission.  However, these groups are 
committed to keeping your personal health information as confidential as possible. 
 
You have the right to see and get a copy of your records related to the study for as 
long as the doctor has this information.  However, by signing this Authorization, 
you agree that you might not be able to review or receive some of your records 
related to the study until after it has been completed. 
 
You may choose to withdraw this Authorization at any time, but you must notify 
the doctor in writing.  Send your written withdrawal notice to the address below: 
 
Tarek Hassanein, MD 
Southern California Research Center 
131 Orange Avenue, Suite 101 
Coronado, California 92118 
 
If you withdraw from the study and withdraw your Authorization, no new 
information will be collected for study purposes unless the information concerns a 
drug-related side effect.  If a side effect occurs, your entire medical record may be 
reviewed.  All information that has already been collected for study purposes and 
any new information about a side effect related to the study will be sent to the 
sponsor. 
 
If you withdraw from the study but do not withdraw your Authorization, new 
personal health information may be collected until this study ends. 
 
This Authorization will expire December 31, 2074, unless you withdraw it in 
writing before then.  Your doctor will keep this Authorization for at least 6 years. 
 
If you do not sign this Authorization, you cannot participate in this study or receive 
the experimental drug.  Your decision to withdraw your Authorization or not to 
participate in the study will not involve any penalty or loss of access to treatment 
or other benefits to which you are entitled. 
 


 
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AUTHORIZATION 
 
I authorize the release of my medical records and personal health information 
related to this study to the sponsor and its representatives, the Western Institutional 
Review Board (WIRB), the FDA, and other regulatory agencies as described 
above.  
 
I have been told that I will receive a signed and dated copy of this Authorization 
for my records. 
 
 
 
 
 
 
Signature of Patient 
 
Date 
 
 
 
 
Printed Name of Patient 
 
 
 
 
 
 
Signature of Person Obtaining Authorization 
 
Date 
 
 
 
 
Printed Name of Person Obtaining Authorization