Conditions: Hepatitis C, Chronic
Keywords: VIEKIRA PAK
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 200
Healthy volunteers: no

Brief summary:
This is a Phase IV, open-label, multi-center study to evaluate the real world sustained virological response rate, subject adherence, and subject reported outcomes during and after treatment of non-cirrhotic genotype 1 chronic hepatitis C subjects aged 18 years and older, with VIEKIRA PAK (ombitasvir, paritaprevir/r, dasabuvir), with or without RBV (ribavirin).

Detailed description:
This is a Phase IV, open-label, multi-center study to evaluate the real world sustained virological response rate, subject adherence, and subject reported outcomes during and after treatment of non-cirrhotic genotype 1 chronic hepatitis C subjects aged 18 years and older, with the AbbVie 3 direct-acting antiviral (3-DAA) regimen of VIEKIRA PAK (ombitasvir, paritaprevir/r, dasabuvir), with or without RBV (ribavirin).

Subjects may be treatment-naïve or treatment experienced with pegylated-interferon based regimens excluding regimens with direct-acting antiviral agents. The study will be conducted at multiple Kaiser Permanente Southern California Medical Centers.

The primary objective of this open label study is to evaluate the rate of sustained virological response rate 12 weeks after completion of treatment (SVR12) with VIEKIRA PAK, with or without ribavirin in a large real world setting.

Arms:
arm 1: Study participants with chronic Hepatitis C Genotype 1A receiving VIEKIRA PAK (two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir tablets, and two 250 mg dasabuvir tablets) and RBV (ribavirin tablets) for 12 weeks. arm 2: Study participants with chronic Hepatitis C Genotype 1B receiving VIEKIRA PAK (two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir tablets, and two 250 mg dasabuvir tablets) for 12 weeks.

Interventions: intervention 1: ombitasvir, paritaprevir/r, dasabuvir + ribavirin intervention 2: ombitasvir, paritaprevir/r, dasabuvir
Intervention descriptions: intervention 1: VIEKIRA PAK (two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir tablets, and two 250 mg dasabuvir tablets) + RBV (ribavirin tablets) for 12 weeks intervention 2: VIEKIRA PAK (two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir tablets, and two 250 mg dasabuvir tablets)

Protocol document:
Prot_SAP_000.pdf: 
 Southern California Permanente Medical Group 
 
 
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A Phase IV, Multisite Study of the Treatment of Chronic Hepatitis C Virus Infection 
Genotype 1 in a Real World Large Health Maintenance Organization: An Evaluation of 
Real World Sustained Virological Response and Patient Reported Outcomes 
 
 
Sponsor-Investigator 
Principal Investigator: 
Lisa M. Nyberg, MD, MPH 
 
Contact Information: 
 
Lisa.M.Nyberg@kp.org 
Main Study Site: 
Kaiser Permanente Medical Center  
 
San Diego, CA 92154 
Additional Kaiser Permanente Medical 
Center Study Sites: 
Anders H. Nyberg, MD 
Site Lead Investigator 
 
San Marcos, CA 92078 
 
Amandeep Sahota, MD 
Site Lead Investigator 
 
Los Angeles, CA 90027 
 
Henry K. Niho, MD 
Site Lead Investigator 
 
Irvine, CA 92618 
Collaborator: 
AbbVie, Inc. 
Amendments/ Revisions: 
Amendment 05 
Version Number: 
1.0 
Version Date: 
01 Mar 2016 
 
 
 


 Southern California Permanente Medical Group 
Real World Study: Genotype 1 Chronic HCV Treatment and Evaluation of Real World SVR and PROs 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
............................................................................................................. 2 
LIST OF ABBREVIATIONS 
........................................................................................................ 6 
PROTOCOL SUMMARY 
............................................................................................................ 8 
1 BACKGROUND AND HYPOTHESIS 
.................................................................................13 
1.1 Phase 3 Placebo-Controlled Studies: SAPPHIRE-I and SAPPHIRE-II 
........................15 
1.2 Phase 3 Regimen-Controlled Studies .........................................................................15 
1.3 Phase 3 Study in Cirrhotics:  Study TURQUOISE-II 
....................................................16 
1.4 Integrated Safety Results 
............................................................................................17 
1.5 Study Risks versus Benefits 
........................................................................................19 
FDA Approval ....................................................................................................................20 
1.6 Hypothesis 
..................................................................................................................20 
2 OBJECTIVES ....................................................................................................................20 
2.1 Primary Objective........................................................................................................20 
2.2 Secondary Objective 
...................................................................................................20 
3 STUDY DESIGN 
................................................................................................................21 
3.1 Description of the Study 
..............................................................................................21 
3.2 Subject Population 
......................................................................................................21 
3.3 Treatment Arms 
..........................................................................................................22 
3.4 Study Duration 
............................................................................................................22 
Study Discontinuation ........................................................................................................22 
4 STUDY PRODUCT INFORMATION ..................................................................................22 
4.1 Description 
..................................................................................................................22 
4.1.1   VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) 
...........................................22 
4.1.2 Ribavirin 
...............................................................................................................24 
4.2 Acquisition and Accountability 
.....................................................................................25 
4.3 Formulation, Packaging, Labeling, and Storage 
..........................................................25 
4.3.1 VIEKIRA PAK ......................................................................................................25 
4.3.2 Ribavirin 
...............................................................................................................25 
4.4 Dosage and Administration 
.........................................................................................26 
4.5 Dose Modification .......................................................................................................26 
4.6 Toxicity and Safety Information 
...................................................................................26 


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4.6.1 VIEKIRA PAK ......................................................................................................26 
4.6.2 Ribavirin 
...............................................................................................................27 
4.7 Prohibited Medication .................................................................................................27 
5 SELECTION OF SUBJECTS 
.............................................................................................28 
5.1 Inclusion Criteria 
.........................................................................................................28 
5.2 Exclusion Criteria 
........................................................................................................29 
6 STUDY ASSESSMENTS 
...................................................................................................30 
6.1 Study Procedures .......................................................................................................30 
6.1.1 Informed Consent ................................................................................................30 
6.1.2 Eligibility Review 
..................................................................................................30 
6.1.3 Medical History 
....................................................................................................30 
6.1.4 Complete Physical Examination 
...........................................................................30 
6.1.5 Liver Fibrosis Assessment 
...................................................................................30 
6.1.6 Vital Signs, Weight, and Height 
............................................................................31 
6.1.7 Pregnancy Test 
....................................................................................................31 
6.1.8 Clinical Laboratory Samples ................................................................................31 
6.1.9 Concomitant Medication Assessment ..................................................................32 
6.1.10 Adverse Event (AE) Assessment 
.........................................................................32 
6.1.11 Study Drug Dispensing 
........................................................................................32 
6.1.12 Study Drug Accountability/ Compliance Review 
...................................................33 
6.2 STUDY VISITS 
...........................................................................................................33 
6.2.1 Screening Visit Procedures (- 28 days to Baseline/Day 1) (Visit 1) ......................33 
6.2.2 Baseline/Day 1 Procedures (Visit 2) 
.....................................................................33 
6.2.3 Treatment Period 
.................................................................................................34 
6.2.3.1 
Week 2 (Visit 3) 
................................................................................................34 
6.2.3.2 
Week 4 (Visit 4) and Week 8 (Visit 5) 
...............................................................34 
6.2.3.3  Week 12 (Visit 6) - End of Treatment (EOT) Procedures 
..................................35 
6.2.4 Post-Treatment (PT) Period 
.................................................................................35 
6.2.4.1 
Post-Treatment (PT) Week 4 (Visit 7) 
...............................................................35 
6.2.4.2 
Post-Treatment (PT) Week 12 (Visit 8) - End of Study/ Early Termination (ET) 
36 
6.2.4.3 
Unscheduled Visits and Labs ...........................................................................37 
6.2.4.4 
Unscheduled Drug Dispensing 
.........................................................................37 
6.3 Subject Discontinuation ..............................................................................................37 


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6.3.1 Subject Initiated Discontinuation 
..........................................................................37 
6.3.2 Investigator Initiated Discontinuation 
....................................................................37 
6.3.3 Discontinuation of Subjects Meeting Virologic Failure Criteria 
..............................38 
6.3.4 Pregnancy ...........................................................................................................38 
7 DATA COLLECTION AND MONITORING 
.........................................................................38 
7.1 Data Management and Record Keeping 
.....................................................................38 
7.2 Data Monitoring Plan ..................................................................................................38 
7.3 Data Safety Monitoring Board (DSMB) 
........................................................................39 
7.4 Retention of Study Record 
..........................................................................................39 
8 STATISTICAL CONSIDERATIONS ...................................................................................39 
8.1 Demographics 
.............................................................................................................40 
8.2 Safety Outcome Measures 
..........................................................................................40 
8.3  Efficacy Analysis 
.........................................................................................................40 
8.3.1 Primary Efficacy Endpoint 
....................................................................................40 
8.3.2 Secondary Efficacy Endpoint 
...............................................................................41 
9 ASSESSMENT OF SAFETY 
..............................................................................................41 
9.1 Safety Parameter and Definitions 
................................................................................41 
9.1.1 Adverse Event (AE) .............................................................................................41 
9.1.2 Serious Adverse Event (SAE) 
..............................................................................41 
9.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
..................42 
9.2 Methods and Timing for Capturing Safety Parameters 
................................................42 
9.2.1 Timing of Adverse Event (AE) Reporting 
..............................................................42 
9.2.1 Reportable Adverse Event (AE) or Serious Adverse Event (SAE) 
........................43 
9.2.2 Assessment of Serious, Severity, Causality and Unexpectedness 
.......................43 
10 
ADMINISTRATIVE STRUCTURE 
...................................................................................43 
11 
REGISTRATION GUIDELINE ........................................................................................43 
11.1 No randomization 
........................................................................................................43 
11.2  Forms and Records for Registration ...........................................................................43 
12 
BIOHAZARD CONTAINMENT .......................................................................................44 
13 
COMPLIANCE WITH LAWS AND REGULATIONS 
........................................................44 
13.1 Informed Consent .......................................................................................................44 
Non-English Speaking Subject 
...........................................................................................44 
13.2 Institutional Review Board (IRB) .................................................................................44 


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13.3 Confidentiality 
.............................................................................................................45 
13.4 Conflict of Interest 
.......................................................................................................45 
14  PROTOCOL SIGNATURE PAGE 
...................................................................................46 
Appendix A: Study Visit/ Procedures Table 
...............................................................................47 
Appendix B: References ...........................................................................................................49 
Appendix C: Site Lead Investigator Signature Page 
..................................................................51 
Appendix D: Protocol History/ Summary of Protocol Changes ..................................................52 
 
 
 


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LIST OF ABBREVIATIONS 
ABT-450 
NS3/NS4A (non-structural protease inhibitor) 
ABT-450/r 
Ritonavir (pharmacokinetic enhancer) 
ABT-267  
Ombitasvir (NS5A inhibitor) 
ABT-333 
Dasabuvir (NS5B non-nucleoside polymerase inhibitor) 
AE 
Adverse Event 
ALT 
Alanine aminotransferase (also SGPT) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis Of Variance 
Anti-HIV Ab Anti-Human Immunodeficiency Virus Antibody 
APRI 
Aspartate aminotransferase to Platelet Ratio Index 
AUC 
Area Under the Curve 
β-hCG 
βeta-human Chorionic Gonadotropin 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CRO 
Contract Research Organization 
CYP 
Cytochrome P450 
CYP2C8 
Cytochrome P450 2C8 
CYP3A 
Cytochrome P450 3A 
DAA  
Direct-Acting Antiviral 
DMC 
Data Monitoring Committee 
dL 
Deciliter 
DNA 
Deoxyribonucleic Acid 
FDA 
Food and Drug Administration (United States) 
FSH 
Follicle-Stimulating Hormone 
ECG 
Electrocardiogram 
FibroScan 
A non-invasive ultrasound procedure  
eRVR 
Extended Rapid Virologic Response 
GCP 
Good Clinical Practice 
g/dl 
gram/deciliter  
Gr 
Grade 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HCVAb 
Hepatitis C Virus Antibody 
HIV  
Human Immunodeficiency Virus 
HRQoL 
Health Related Quality of Life  
HT 
Height 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio (of prothrombin time) 


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IRB 
Institutional Review Board 
IU 
International Unit 
IWRS 
Interactive Web Response System 
kg 
kilogram 
KPSC 
Kaiser Permanente Southern California 
L 
Liter 
LLOQ 
Lower Limit of Quantification 
mg 
milligram 
min 
minute 
mL 
milliliter 
N 
Number 
NDC 
National Drug Code 
P 
Pulse Rate 
PBO 
Placebo 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PK 
Pharmacokinetic 
pegIFN 
pegylated-interferon 
PRO 
Patient Reported Outcomes 
RBV 
Ribavirin 
RNA 
Ribonucleic Acid 
SCPMG 
Southern California Permanente Medical Group 
SD 
Standard Deviation 
SOC 
Standard Of Care 
SOP 
Standard Operating Procedure 
SVR 
Sustained Virologic Response 
SVR4 
Sustained Virologic Response at 4 Weeks after treatment completion 
SVR12 
Sustained Virologic Response at 12 Weeks after treatment completion 
TSH 
Thyroid Stimulating Hormone 
WT 
Weight (body) 
ULN 
Upper Limit of Normal  
 


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PROTOCOL SUMMARY 
Title 
A Phase IV, Multisite Study of the Treatment of Chronic Hepatitis C Virus 
Infection  Genotype  1  in  a  Real  World  Large  Health  Maintenance 
Organization: An Evaluation of Real World Sustained Virological Response 
and Patient Reported Outcomes 
Short Title 
Real World Study: Genotype 1 Chronic HCV Treatment and Evaluation of 
Real World SVR and PROs 
Protocol Number 
IRB 10568 
Study Phase 
Phase IV 
Study Site(s) 
Multiple Kaiser Permanente Southern California Medical Centers 
Number of Subjects 200 
Study Arms 
Two study arms  
• Genotype 1a: VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) + 
RBV (ribavirin) 
• Genotype 1b: VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) 
Indication 
Treatment  of  patients  with  genotype  1  chronic  hepatitis  C  virus  (HCV) 
infection 
Primary Objective 
The  primary  objective  of  this  open  label  study  is  to  evaluate  the  rate  of 
sustained virological response rate 12 weeks after completion of treatment 
(SVR12) with VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir), with 
or without ribavirin in a large real world setting. 
Overview  of  Study 
Design 
This is a Phase IV, open-label, multi-center study to evaluate the real world 
sustained virological response rate, subject adherence, and subject reported 
outcomes  during  and  after  treatment  of  non-cirrhotic  genotype  1  chronic 
hepatitis C subjects aged 18 years and older, with the AbbVie 3 direct-acting 
antiviral  (3-DAA)  regimen  of  VIEKIRA  PAK  (ombitasvir,  paritaprevir/r, 
dasubuvir),  with  or  without  
ribavirin.  Subjects  may  be  
treatment-naïve  or 
treatment experienced with pegylated-interferon based regimens excluding 
regimens with direct-acting antiviral agents. 
Investigational 
Product 
Administration 
VIEKIRA  PAK (ombitasvir,  paritaprevir/r,  dasubuvir)VIEKIRA  PAK  is 
ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged 
with dasabuvir tablets.  
 
Ombitasvir, paritaprevir, ritonavir fixed dose combination tablet includes a 
hepatitis  C  virus  NS5A  
inhibitor (ombitasvir), a  hepatitis  C  virus  NS3/4A 
protease  inhibitor  (paritaprevir),  and  a  CYP3A  inhibitor  (ritonavir)  that 
inhibits  CYP3A  mediated  metabolism  of  paritaprevir,  thereby  providing 
increased  plasma  concentration  of  paritaprevir.  Dasabuvir  
is  a  hepatitis  C 
virus non-nucleoside NS5B palm polymerase inhibitor, which is supplied as 
separate tablets in the copackage. Both tablets are for oral administration.  
 
VIEKIRA PAK is dispensed in a monthly carton for a total of 28  days  of 
therapy.  Each  monthly  carton  contains  
four  weekly  cartons.  Each  weekly 
carton contains seven daily dose packs. Each child resistant daily dose pack 
contains four tablets: two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir 


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tablets and two 250 mg dasabuvir tablets, and indicates which tablets need to 
be taken in the morning and evening. The NDC number is NDC 0074-3093-
28. 
VIEKIRA PAK: 
• Two  ombitasvir,  paritaprevir,  ritonavir  tablets  once  daily  (in  the 
morning) with a meal without regard to fat or calorie content and 
• One  dasabuvir  
tablet  
twice  daily  (morning  and  evening)  with  a  meal 
without regard to fat or calorie content.  
Ribavirin 
Ribavirin is a synthetic nucleoside analogue (purine analogue). The chemical 
name of ribavirin is 1-β-D-ribofuranosyl-1H -1,2,4-triazole-3-carboxamide. 
Ribavirin  capsules  USP,  200  mg  are  white,  opaque,  hard  gelatin  capsules 
imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body. 
 
RBV  (ribavirin):  Dosage  is  based  on  weight  and  adjusted  for renal 
impairment subjects. 
• If subject weighs less than or equal to 75 kg, 1000 mg daily in two 
divided doses with food. 
• If subject weighs greater than 75 kg, 1200 mg daily in two divided 
doses with food. 
Eligibility Criteria 
Inclusion Criteria 
1. Male or female at least 18 years of age at time of screening. 
2. Subject voluntarily signed the Informed Consent Form for the study. 
3. Subject is able to adhere to study visit/ procedure schedule and protocol 
requirements 
4. Subject,  if  female  must  not  use  estrogen-containing  hormonal 
contraception  including  oral,  injectable,  implantable,  patch  and  ring 
varieties during study drug treatment 
5. Subject, if female must meet at least one of the following: 
• Subject of childbearing potential must agree to either 
o practice  2    effective  contraceptive  methods  for  study 
duration, starting at the Screening 
Visit 
through 30 days after 
stopping study drug if not receiving ribavirin, 7 months/or 
as directed by ribavirin label if receiving ribavirin 
o practice total abstinence from sexual intercourse (minimum 
1 complete menstrual cycle) 
o Sexually active with female partner only 
• Postmenopausal defined as age appropriate amenorrhea for > 2 years 
prior to screening and post-menopausal state confirmed by follicle-
stimulating hormone (FSH) level 
• Surgically  sterile  defined  as  bilateral  tubal  ligation  or  bilateral 
oophorectomy or hysterectomy 
• Has male sexual partner with vasectomy 


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6. Subject, if male, who is not surgically sterile and is sexually active with 
female partner of childbearing 
potential must agree to practice 2 effective 
contraceptive methods for study duration, starting at Screening through 
30 days after stopping study drug if not receiving ribavirin, 7 months/or 
as directed by ribavirin label if receiving ribavirin  
7. Subject  must  have  at  
least  one  of  
the  following  
indicators  of  chronic 
hepatitis C virus infection prior to study enrollment: 
• Positive anti-HCV antibody or HCV RNA > 10,000 IU/mL at least 
6 months before screening, and positive for HCV RNA at the time 
of screening  
• HCV RNA > 10,000 IU/mL at screening and liver biopsy consistent 
with chronic HCV infection 
• Credible evidence of chronic hepatitis C as per the investigator and 
HCV RNA > 10,000 IU/mL at the time of screening. 
8. Subject  has  a  screening  
laboratory  
result  
indicating  HCV  genotype  1-
infection. Historical genotype within 6 months of screening may be used 
at the discretion of the investigator. 
Exclusion Criteria 
1. Subject declined to sign the Informed Consent Form for the study. 
2. Subject, if female is pregnant or is breastfeeding, or if male, with female 
partner who is currently pregnant.  
3. Subject  has  positive test  result  for  hepatitis  B  surface  antigen  or 
confirmed positive anti-HIV antibody test 
4. Subject  received  study  contraindicated  medications  including  but  not 
limited  to  
those  
listed  
in Table 5,  or  medications  contraindicated  for 
ritonavir or ribavirin per FDA label prior to study drug administration 
and unwilling to discontinue prior to starting the study drug. For those 
that receive ribavirin, contraindicated medications must be discontinued 
at  least  2  weeks  or  10  half-lives  prior  to  study  drug  administration, 
whichever is longer. 
5. Use  of  known  strong  inducers  of  cytochrome  P450  3A  (CYP3A)  or 
strong inducers of cytochrome P450 2C8 (CYP2C8) or strong inhibitors 
of  CYP2C8  within  2  weeks  of  the  respective  medication/supplement 
prior to initial dose of study drug (see Table 5). 
6. Clinically significant abnormalities or co-morbidities, other than HCV 
infection that in opinion of the investigator makes subject unsuitable for 
this study or drug regimen 
7. Current  enrollment  
in  another  
interventional  clinical  study  or  prior  or 
current use of any investigational or commercially available anti-HCV 
agents other than interferon or ribavirin including previous exposure to 
ABT450 (paritaprevir) , ABT-267 (ombitasvir) or ABT-333 (dasabuvir) 
or receipt of any investigational product within 6 weeks prior to study 
drug administration 
8. Prior treatment of chronic HCV infection with a direct acting antiviral 
agent(s):  
telaprevir,  boceprevir,  sofosbuvir,  simeprevir,  or  other  direct 
acting antiviral 


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9. History of solid organ transplant 
10. Screening  laboratory  analyses  shows  any  of  the  following  abnormal 
laboratory results: 
• Glomerular  filtration  rate  <  30  mL/min  as  estimated  by  the 
Cockcroft-Gault equation 
• Hemoglobin  < 12 gram per deciliter for male 
• Hemoglobin  < 11 gram per deciliter for female 
11. Evidence of cirrhosis, documented by one of the following:  
• Liver biopsy histologic diagnosis: Metavir Score  > 3 (includes 3 - 4 
or 3/4) or Ishak score  > 4  
• In the absence of liver biopsy: a FibroScan score  > 12.5 kPa 
• In the absence of a FibroScan: an APRI score > 1.5 
• In  
the judgment  of the investigator  clinical findings are  consistent 
with cirrhosis. 
In general, a non-cirrhotic result from a Fibroscan will 
supersede evidence of cirrhosis based on APRI and a liver biopsy not 
showing cirrhosis will supersede both Fibroscan and APRI 
12. History  of  liver  decompensation:  ascites  noted  on  a  physical  exam, 
imaging or other test; variceal bleeding; hepatic encephalopathy 
13. Confirmed presence of hepatocellular carcinoma indicated on computed 
tomography, magnetic resonance, or other imaging techniques within 3 
months prior to screening 
14. HCV genotype performed during screening indicates infection with any 
genotype other than genotype 1 
15. Recent history of drug or alcohol abuse that could, in the opinion of the 
investigator, affect adherence to the study protocol 
Study Endpoint 
The primary efficacy endpoint is to assess SVR12 in two subgroups of HCV 
(genotype 1a or 1b). The simple percentage of subjects achieving SVR12 will 
be calculated and a two-sided 95% confidence interval of the percentage will 
be computed based on Wilson
's score method. We cannot know a priori how 
the  200  patients  will  be  split  
into  
the  
two  subgroups,  but  we  expect  each 
group to have approximately 100 patients (presumably between 80 and 120). 
Assuming  a  subgroup  size  of  100  each,  the  lower  bound  of  the  95% 
confidence interval will be within 7 percentage points of the observed SVR12 
rate. 
Once the groups are fixed, the actual lower bound of the 95% confidence 
interval can be computed. 
 
The observed SVR12 rate and confidence interval will be discussed in the 
context of results from randomized clinical trials, such as the SAPPHIRE-
I/II  
trials  and  PEARL-II/III/IV  
trials described in the  Background  section.  
While formal statistical inference comparing results of this study to those of 
the randomized clinical trials will not be conducted, the point estimates and 
confidence intervals will be compared to assess the degree to which results 
from  the  real  world  setting  are  similar  to  or  different  from  those  in  the 
randomized clinical trial setting. 
 


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Results by prior treatment experience and response may be summarized if 
appropriate, based on the number of subjects enrolled in each subgroup.  No 
subgroup sample size targets have been established. 
Statistical Methods 
This  is  an  open  label,  non-randomized,  study  with  two  study  arms. 
Descriptive  statistics  will  be  used  to  describe  the  observed  sustained 
virological response rate and patient adherence to the treatment regimen. The 
primary  analysis,  to  evaluate  SVR12,  will  occur  after  all  subjects  have 
completed or prematurely discontinued the study. 
 
The  intent-to-treat  population  will  consist  of  all  enrolled  subjects  in  this 
study. The primary efficacy analysis on clinical outcomes will be performed 
on all subjects in the intent-to-treat population. The modified intent-to-treat 
population will include all who receive at least one dose of study drug.  
No  data  will  be  imputed  for  any  efficacy  or  safety  analyses  except  for 
analyses of the HCV RNA endpoints.  
 
HCV  RNA  values  will  be  selected  for  the  SVR12 analysis  based  on  the 
defined visit. The visit window for analysis of SVR4 is post-treatment days 
2-56, and the visit window for analysis of SVR12 is post-treatment days 57-
168.  The latest available value within each window will be used to define 
the SVR 4 or SVR12 result. 
 
 


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1  
BACKGROUND AND HYPOTHESIS    
  
  
 
Hepatitis C viral (HCV) infection is a global health problem. 170 million individuals are chronically 
infected worldwide and at risk of developing liver cirrhosis, hepatocellular carcinoma, or both.[1] 
Cirrhosis develops after prolonged hepatitis C virus infection.
[2] Complications of cirrhosis include 
hepatic decompensation (ascites; encephalopathy; variceal hemorrhage; hepato-renal syndrome or 
hepatic synthetic dysfunction) and hepatocellular carcinoma, which ensues at a rate of about 3% 
per year.
[3-6] Without liver transplantation, decompensated cirrhosis leads to death in 50% to 72% 
of patients after 5 years.
[7] As a result of the high prevalence of hepatitis C virus (HCV) infection 
and resultant complications, HCV is the leading indication for liver transplantation in the United 
States and the world as a whole.
[8]  
 
Treatment of hepatitis C virus-infected patients could reduce the risk of cirrhosis, decompensation, 
cancer,  and liver-related  deaths. Among  patients treated with pegylated interferon  and  
ribavirin 
therapy
, achieving a sustained virologic response (SVR) was associated with significant reduction 
in all-cause death compared to subjects who did not achieve sustained virologic response (5-year 
mortality rate in HCV genoty
pe 1-infected patients: 6.7% versus 14.4%, respectively).
[9]   
 
In  addition,  the  5-year  occurrence  of  
the  composite  clinical  events of  death, liver  failure,  and 
hepatocellular carcinoma were  significantly  lower  in hepatitis C  virus-infected  patients with 
advanced  fibrosis or cirrhosis  who achieved sustained  virologic  
response versus those without 
sustained  virologic  response  (9.2%  versus  28.2%,  respectively).
[10]  Patients with sustained 
virologic response  
following treatment with pegylated  
interferon with or  without ribavirin have 
also  shown improvement  in  liver  histology  and  a  reduction  in liver-related  death  in  several 
studies.
[11-13] 
 
Moreover,  patients with  compensated  cirrhosis who achieve sustained  virologic  response 
essentially eliminate their subsequent risk of decompensation, may achieve histologic regression, 
and decrease their risk of hepatocellular carcinoma by two-thirds.
[14-16] In patients with advanced 
fibrosis and  cirrhosis,  viral  suppression by  more  than  4  logs10 with  pegylated  interferon  and 
ribavirin was associated with marked reduction in death/liver transplantation, and in liver-related 
morbidity and death.[17] 
 
Combinations of direct-acting antiviral (DAA) agents targeting different steps of viral replication 
have the potential to significantly  
improve hepatitis C virus treatment,  compared to the current 
interferon-containing  regimens  for HCV genotype  1  infection.  Combination  DAA  allows  for 
increased/sustained virologic response rates, elimination of interferon as a component of therapy
, 
increased safety, and tolerability of treatment, shortened duration of therapy and simplifying the 
treatment algorithm. 
 
Wider  application  of direct-acting  antiviral  agent  
therapy and  better  
responses with  combination 
direct-acting antiviral agent regimen(s) could significantly reduce the public health burden of this 
disease.  
 
AbbVie
's  interferon-free  regimen  for  the  treatment  of  chronic hepatitis  C  virus  genotype  1 
infection includes three direct-acting antiviral agents targeting different steps in hepatitis C virus 


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replication: ABT-450 is a nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease 
inhibitor co-administered with a pharmacokinetic (PK) enhancer, ritonavir (ABT-450/r); an NS5A 
inhibitor ABT-267 (ombitasvir) and ABT-333 (dasabuvir) an NS5B non-nucleoside polymerase 
inhibitor.  
 
The  three  direct-acting  antiviral  (3-DAA)  agents  regimen  has  been  studied  with  and without 
ribavirin in over 2,300 patients in Phase 3 trials across a variety of patient populations including 
those with compensated cirrhosis. Based on Phase 3 data, the regimen with or without ribavirin 
appears to be safe, well tolerated, and efficacious in treatment-naïve and treatment-experienced 
hepatitis C virus genotype 1-infected subjects including those  with compensated cirrhosis. The 
overall efficacy results (intent-to-treat) from the Phase 3 studies are listed in Table 1. 
 
Table 1  - Combined  SVR  12  Rates  (Intent-to-treat,  missing  =  failure)  from  Phase  3 
Studies by Subpopulation of Subtype, Prior Treatment History, and Presence or Absence 
of Cirrhosis 
Subpopulation 
3-DAA 
12 Weeks 
SVR12 
3-DAA + RBV 
12 Weeks 
SVR12 
3-DAA + RBV 
24 Weeks 
SVR12 
Genotype 1b non-cirrhotics 
     Naïve 
     Null 
     Partial 
     Relapser 
99.0 
100 
100 
100 
98.9 
94.4 
98.1 
98.5 
-- 
-- 
-- 
-- 
Genotype 1a non-cirrhotics 
     Naïve 
     Null 
     Partial 
     Relapser 
90.2 
-- 
-- 
-- 
95.7 
95.4  
100 
94.0 
-- 
-- 
-- 
-- 
Genotype 1b cirrhotics 
     Naïve 
     Null 
     Partial 
     Relapser 
-- 
-- 
-- 
-- 
100 
100 
85.7* 
100 
100 
100 
100 
100 
Genotype 1a cirrhotics 
     Naïve 
     Null 
     Partial 
     Relapser 
-- 
-- 
-- 
-- 
92.4 
80.0 
100 
93.3 
92.9  92.9 
100 
100 
DDA = Direct-Acting Antiviral; * Based on N = 7; 6/7 achieved SVR 
The data outlined in Table 1 (above) and Table 2 (below) are based on the following studies: 


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1.1 Phase 3 Placebo-Controlled Studies: SAPPHIRE-I and SAPPHIRE-II  
Study  SAPPHIRE-I  and SAPPHIRE-II  are  randomized,  placebo-controlled  studies  that 
assessed the safety and efficacy of 12 weeks of therapy with three direct-acting antiviral (3-
DAA)  agents  and  ribavirin  
in  hepatitis  C  virus  (HCV)  genotype  1-infected  
treatment-naïve 
subjects (Study SAPPHIRE-I) and prior pegylated-interferon/ribavirin non-responders (Study 
SAPPHIRE-II) without cirrhosis. Subjects received 3-DAA agents and ribavirin (RBV) for 12 
weeks of treatment. Subjects randomized to the placebo arm received placebo for 12 weeks, 
after  which  they  received  open-label  3-DAA  agents  and  RBV  for  12  weeks.  In  Study 
SAPPHIRE-I 631 subjects were randomized and received at least one dose of study drug, of 
which 67.7% had HCV  genotype 1a  and 32.3%  had  HCV  genotype 1b.  The SVR12 rate  
for 
treatment-naïve  subjects  receiving  3-DAA  agents  and  ribavirin  for  12  weeks  was  96.2%. 
Virologic  failure  was  noted  in  7/322  (2.2%)  genotype  1a  subjects  (on  treatment  virologic 
failure: n = 1; relapse: n = 6) and 1/151 (0.7%) genotype 1b subjects (relapse).  
 
In Study SAPHIRE-II, a total of 394 subjects were randomized and received at least one dose 
of  study  drug,  of  which  58.4%  had  hepatitis  C  virus  
(HCV)  genotype  1a,  41.4%  had  HCV 
genotype  1b,  49.0%  were  prior  pegylated-interferon/ribavirin  null  responders,  21.9/%  were 
prior  pegylated-interferon/ribavirin  partial  responders,  and  29.2%  were  prior  pegylated-
interferon/ribavirin  relapsers.  The  SVR
12 rate  for  treatment-experienced  subjects  receiving 
three direct-acting antiviral (3-DAA) agents and ribavirin for 12 weeks was 96.3%. Virologic 
failure (all relapse) was noted in 5/173 (2.9%) genotype 1a subjects and 2/123 (1.6%) genotype 
1b subjects.  
1.2 
Phase 3 Regimen-Controlled Studies: (3DAA  ± RBV): Studies PEARL-II, 
PEARL-III, PEARL-IV, and M14-002  
Studies PEARL-II, PEARL-III, and PEARL-IV are randomized, regimen-controlled trials that 
assessed  
the  safety  and  efficacy  of  12  weeks  of  
treatment  with  
three  direct-acting  antiviral 
agents  with  or  without  ribavirin.  Studies  PEARL-III  and  PEARL-IV  are  ribavirin  placebo-
controlled studies, while Study PEARL-II is an open-label study. The patient population was 
different in each of the three studies. Study PEARL-II enrolled genotype 1b-infected subjects 
with prior non-response to pegylated-interferon/ribavirin, Study PEARL-III enrolled genotype 
1b-infected subjects who were treatment-naïve, and Study PEARL-IV enrolled genotype 1a-
infected subjects who were treatment-naïve. All three studies excluded subjects with cirrhosis.  
In Study PEARL-II, a total of 186 subjects were randomized and received at least one dose of 
study  drug,  of  which  34.9%  were  prior  pegylated-interferon/ribavirin  (pegIFN/RBV)  null 
responders, 28.5% were prior pegIFN/RBV partial responders, and 36.6% were pegIFN/RBV 
relapsers. The SVR
12 rates were 96.6% in the three direct-acting agents with ribavirin arm and 
100% in the three direct-acting antiviral agents without ribavirin arm. The difference in SVR
12 
rates between the two regimens met the protocol-specified criteria for noninferiority. Hence, 
the  three  direct-acting  antivirals  (3-DAA)  regimen  without  ribavirin  demonstrated 
noninferiority  compared  to  the  (3-DAA)  agents  and  ribavirin.  No  subject  in  either  arm 
experienced on treatment virologic failure or post-treatment relapse. 
 


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In the PEARL-III study, 419 subjects were randomized and received at least one dose of study 
drug.  The  SVR12 rates  for  treatment-naïve  subjects  with  HCV  genotype  1b-infection,  who 
received  either  3-DAA  with,  or  without  ribavirin  for  12  weeks  were  99.5%  and  99.0%, 
respectively. The difference in SVR
12 rates between the two regimens in this study also met the 
protocol-specified criteria for noninferiority. One of the 419 treated subjects in the three direct-
acting antiviral agents and ribavirin arm experienced on-treatment virologic failure. 
 
In Study M14-002, 305 subjects were randomized and received at least one dose of study drug. 
The SVR12 rates for treatment-naïve subjects with HCV genotype 1a-infection who received 
three  direct-acting  antiviral  agents  either  with  or  without  ribavirin  for  12  weeks  in  Study 
PEARL-IV were 97.0% and 90.2%, respectively. The SVR
12 rate in the 3-DAA arm did not 
achieve noninferiority to the 3-DAA and ribavirin arm. Virologic failure was noted in 2/100 
(2.0%) subjects (on treatment virologic failure: n = 1; relapse: n = 1) in the ribavirin-containing 
regimen and 16/205 (7.8%) subjects (on treatment virologic failure: n = 6; relapse: n = 10) in 
the ribavirin-free regimen. The difference between arms demonstrates that ribavirin contributes 
to the efficacy in genotype 1a-infected patients and suggests that three direct-acting antiviral 
agents and ribavirin is the optimal regimen for these patients. 
1.3 
Phase 3 Study in Cirrhotics:  Study TURQUOISE-II 
Study  TURQUOISE-II  is  a  randomized,  multicenter,  open-label  trial  in  treatment-naïve 
subjects  or  subjects  previously  treated  with  pegylated-interferon/ribavirin  with  chronic 
hepatitis C virus genotype 1-infection with compensated cirrhosis (Child-Pugh A, score l< 6). 
The  
three  direct-acting  antiviral  agents  and  
ribavirin  were  administered  
for  either  12  or  24 
weeks of treatment. 
 
A total of 380 subjects were randomized and received at least one dose of study drug, of which 
68.7% had hepatitis C virus genotype 1a, 31.3% had hepatitis C virus genotype 1b, 42.1% were 
treatment-naïve,  36.1%  were  prior  pegylated-interferon/ribavirin  (pegIFN/RBV)  null 
responders,  8.2%  were  prior  pegIFN/RBV  partial  responders,  and  13.7%  were  prior 
pegIFN/RBV relapsers. 
 
The  SVR12 rates  for  subjects  with  compensated  cirrhosis treated  with  three  direct-acting 
antiviral  agents  and  ribavirin  for  12  or  24  weeks  were  91.8%  and  95.9%,  respectively. 
Virologic failure was noted in 13/208 (6.3%) subjects (on treatment virologic failure: n = 1; 
relapse:  n  =  12)  receiving  the  12  week  regimen  and  4/172  (2.3%)  subjects  (on  treatment 
virologic failure: n = 3; relapse: n = 1) receiving the 24 week regimen. 
 
Analyses of subgroups suggest that the overall difference in SVR12 rates was driven largely by 
a  lower  SVR
12 rate  among  genotype  1a  prior  null  responders  who  received  12  weeks  of 
treatment,  while  other  subgroups  had  comparable  
response  
rates  when  
treated  
for  12  or  24 
weeks. 


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1.4 
Integrated Safety Results 
A summary of treatment-emergent adverse events from the combined analyses of data from 
the Phase 3 studies is presented in Table 2. A majority of subjects experienced at least one 
event, but most subjects experienced events that were mild in severity. Rates of severe adverse 
events and adverse events leading to discontinuation were low across studies but numerically 
higher in the study of subjects with cirrhosis. 
 
Table 2: Overview of Treatment-Emergent Adverse Events (AE) 
 
Placebo-Controlled 
Regimen-Controlled 
Cirrhotics 
12-Week 
3-DAA + 
RBV 
12-Week 
PBO 
12-Week 
3-DAA + 
RBV 
12-Week 3-
DAA 
12-Week 
3-DAA + 
RBV 
24-Week 
3-DAA + 
RBV 
Events, % 
N = 770 
N = 255 
N = 401 
N = 509 
N = 208 
N = 172 
Subjects ≥ 1 AE 
89.0 
76.9 
82.8 
75.0 
91.8 
90.7 
Severe AE 
3.5 
0.4 
1.0 
1.2 
6.7 
7.6 
Grade 3 or 4 AE 
3.9 
0.8 
3.0 
2.0 
7.7 
8.1 
Serious AE 
2.1 
0.4 
2.2 
1.4 
6.3 
4.7 
AE leading to 
discontinuation  
0.8 
0.4 
0.5 
0.4 
1.9 
2.3 
Deaths  
0.1a 
0 
0 
0 
0 
0 
DDA = Direct-Acting Antiviral; PBO: Placebo; 
aLung Cancer 
The most common adverse events regardless of causality are listed in Table 3. Adverse events 
that  occurred  at  ≥  5%  
incidence  
in  
the  3-DAA  and  RBV  
regimen  versus  
the  placebo  were 
considered to be adverse drug reactions related to the study treatment. These include fatigue, 
nausea, pruritus, insomnia, asthenia, and anemia. The frequency of these events was generally 
lower in the arm treated without ribavirin. In general, rates of adverse events were similar in 
patients with cirrhosis versus those without. 
 
Table 3: Treatment-Emergent Adverse Events with >/= 10% Frequency in at Least 
One Arm of the Analysis and Rates of Key Post-Baseline Lab Abnormalities 
 
Placebo-Controlled 
Regimen-Controlled 
Cirrhotics 
12-Week 
3-DAA + 
RBV 
12-Week 
PBO 
12-Week 
3-DAA + 
RBV 
12-Week 3-
DAA 
12-Week 
3-DAA + 
RBV 
24-Week 
3-DAA + 
RBV 
Treatment-
emergent Adverse 
Events, % 
N = 770 
N = 255 
N = 401 
N = 509 
N = 208 
N = 172 
Headache 
34.3 
29.8 
24.4 
25.1 
27.9 
30.8 
Fatigue 
34.2 
26.3 
29.9 
26.5 
32.7 
46.5 


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Placebo-Controlled 
Regimen-Controlled 
Cirrhotics 
12-Week 
3-DAA + 
RBV 
12-Week 
PBO 
12-Week 
3-DAA + 
RBV 
12-Week 3-
DAA 
12-Week 
3-DAA + 
RBV 
24-Week 
3-DAA + 
RBV 
Nausea 
22.3 
14.9 
15.7 
8.4 
17.8 
20.3 
Pruritus 
15.7 
4.3 
12.0 
6.1 
18.3 
19.2 
Insomnia 
14.0 
7.5 
12.2 
5.1 
15.4 
18.0 
Diarrhea 
13.5 
9.0 
8.7 
11.4 
14.4 
16.9 
Asthenia 
13.5 
6.7 
9.0 
3.9 
13.9 
12.8 
Rash 
10.0 
5.9 
6.2 
3.7 
11.1 
14.5 
Cough 
8.7 
5.1 
6.7 
4.7 
11.5 
11.0 
Irritability 
5.3 
4.7 
3.2 
3.1 
7.2 
12.2 
Anemia 
5.3 
0 
7.5 
0.2 
7.7 
10.5 
Dyspnea 
9.7 
5.5 
4.7 
2.2 
5.8 
12.2 
Laboratory Events, 
% 
N = 765 
N = 254 
N = 401 
N = 509 
N = 208 
N = 172 
Hemoglobin 
    < 10 g/dL (Gr 2) 
5.5 
0 
6.2 
0 
7.2 
11.0 
    < 8.0 g/dL (Gr 3) 
0.1 
0 
0.5 
0 
1.4 
0.6 
ALT 
   > 5 × ULN (Gr 3) 
1.2 
3.9 
0.7 
0.2 
2.9 
0 
Bilirubin 
   > 3 × ULN (Gr 3) 
2.6 
0 
5.7 
0.4 
13.5 
5.2 
DDA = Direct-Acting Antiviral; PBO: placebo; Percentages of laboratory events based on the number of subjects 
with at least one post-baseline value 
Transient  elevations  
in  
total  
(predominantly  
indirect)  bilirubin  may  occur  due  
to  ABT-450 
inhibition  of  the  bilirubin  transporters  OATP1B1  and  OATP1B3,  and  ribavirin-induced 
hemolysis.  The  elevations  generally  peaked  by  weeks  1 - 2,  declined  through  the  end  of 
treatment,  and  
returned  
to  within  
the  normal  
range  by  
four  weeks  post-treatment.  Rates  of 
hyperbilirubinemia were lower in subjects treated with three direct-acting antiviral (3-DAA) 
agents  without  ribavirin  compared  to  3-DAA  with  ribavirin.  The  rates  and  degree  of 
hyperbilirubinemia were higher in patients with cirrhosis, but the temporal pattern of elevation 
followed by resolution was similar and few were symptomatic (jaundice). Rates of ≥ Grade 2 
hemoglobin reductions were 6% among subjects without cirrhosis who received the 3-DAA 
and  ribavirin  regimen  for  12  weeks,  and  7%  and  11%  among  subjects  with  cirrhosis  who 
received  the  3-DAA  and  ribavirin  regimen  for  12  and  24  weeks,  respectively.  Grade  3 
hemoglobin values were rare. The decline in hemoglobin was largely managed with ribavirin 
dose  reductions;  use  of  hematologic  growth  factors  and  blood  transfusion  were  rare.  The 


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anemia reported in the clinical trials was primarily observed when the 3-DAA regimen was 
administered with ribavirin. 
 
Transient asymptomatic post-baseline serum alanine aminotransferase (ALT) elevations of > 
5 times upper limit of normal (ULN) occurred at a frequency of 1% across active treatment 
arms  and  were  evaluated  by  an  external  hepatic  panel.  The  serum  (ALT)  elevations  were 
asymptomatic, usually occurred within the first four weeks of treatment and typically declined 
with ongoing treatment. A disproportionate number of the cases were in women on concurrent 
systemic  estrogen-containing  therapy  (i.e.  contraceptives  or  hormone  replacement)  and 
discontinuation of the hormonal therapy with continuation or brief interruption of the direct-
acting  antiviral  regimen  led  to  resolution  in  ALT  elevation.  Concomitant  use  of  systemic 
estrogen-containing  medications  
is  a  
risk  
factor  
for  
these  post-baseline  elevations  
in  serum 
alanine aminotransferase. No serum ALT elevations > 5 times ULN were observed in subjects 
receiving progestin only, or in subjects receiving topical vaginal estrogen preparations. Among 
the cases of serum ALT elevation, considered related to the direct-acting antiviral regimen, 
none resulted in hepatic dysfunction and they generally resolved or improved with ongoing 
treatment. All cases had resolved completely in the post-treatment follow-up. 
 
ABT-450/ritonavir,  ABT-267  
(ombitasvir)  
(and  
its  major,  
inactive  human  metabolites)  and 
ABT-333 (dasabuvir) had no effects on embryo-fetal development in rodent and/or non-rodent 
species at maximal feasible exposures that provided area under the curve (AUC) multiples at 
least  4-fold  higher  than  exposures  at  the  recommended  clinical  doses.  Clinical  studies  in 
women who are pregnant have not been conducted. 
 
In  summary,  the  three  direct-acting  antiviral  (3-DAA)  agents  regimen,  with  or  without 
ribavirin, was well tolerated with a low discontinuation rate. Adverse events were typically 
mild, and many of the adverse events and laboratory abnormalities observed were attributable 
to the presence of ribavirin. 
 
Transient, asymptomatic serum alanine aminotransferase (ALT) elevations were observed at a 
low rate, were not associated with hepatic dysfunction, and generally resolved with ongoing 
treatment. 
1.5 
Study Risks versus Benefits 
ABT-450/ritonavir, ABT-267 (ombitasvir) and ABT-333 (dasabuvir) with or without ribavirin 
have been well tolerated in the Phase 3 studies. Adverse events that are known, and those not 
previously described, may occur with the direct-acting antivirals or ribavirin as detailed in the 
informed  consent  for  this  study.  In  addition,  subjects  may  experience  inconvenience  or 
discomfort related to the study visits or study procedures.  
 
Risks associated with ABT-450/ritonavir/ABT-267 (ombitasvir) and ABT-333 (dasabuvir) co-
administered  with  or  without  
ribavirin,  
including  
the  
risks  of  
toxicity  and  virologic  
failure, 
appear  limited  and  manageable  based  on  the  results  from  the  Phase  3  studies.  Given  the 
potential high rate of cure in hepatitis C virus genotype 1-infected subjects, the risk-benefit 
comparison is favorable. 


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This study will evaluate outcomes with ABT-450/ritonavir/ABT-267 (ombitasvir) and ABT-
333  (dasabuvir)  with  or  without  ribavirin  for  treatment-naïve  and  interferon/ribavirin 
treatment-experienced  adults  with  chronic  HCV  genotype  1-infection without cirrhosis in a 
real world setting. A non-cirrhotic population will be evaluated as this is a group that is not 
considered of highest priority according to current national practice guidelines and therefore, 
largely unstudied in a large real world population. 
 
Until  recently,  the  treatment  of  genotype  1  chronic  HCV  infection  involved  complicated 
interferon-containing regimens associated with many side effects. Due to adverse events and 
patient dropout, outcomes in real world settings during and after treatment with these regimens 
have been inferior to those seen in controlled clinical trials. The cure rate (sustained virological 
response) and the effectiveness of treatment has been reported to be low in real world settings 
using interferon-based treatment regimens. In a Veterans Administration study by Kramer et 
al, only 39.9% of genotype 1 patients who completed treatment and only 23.6% of those who 
initiated  treatment  achieved  sustained  virological  response.  Importantly,  treatment 
effectiveness  (defined  as  the  proportion  of  the  viremic  cohort  who  achieved  sustained 
virological response) was very low at only 3.5%.[18]  
FDA Approval 
On December 19, 2014, the FDA Approved ABT-450/ritonavir, ABT-267 (ombitasvir) and 
ABT-333 (dasabuvir) 
as VIEKIRA PAK™ (ombitasvir, paritaprevir, and ritonavir tablets, 12.5 
mg/  75  mg/  50  mg;  dasabuvir tablets,  250  mg),  co-packaged  for  oral  use  with  or  without 
ribavirin  for  the  treatment  of  patients  with  genotype  1  chronic  hepatitis  C  virus  (HCV) 
infection including those with compensated cirrhosis. 
1.6 
Hypothesis 
Since the new treatment regimens do not cause the adverse events associated with the prior 
therapy, our hypothesis is that treatment with the VIEKIRA PAK (ombitasvir, paritaprevir/r, 
dasubuvir) with or without ribavirin will result in excellent outcomes in the real world setting 
and that the outcomes will be similar to those seen in the registration trials. 
2  
OBJECTIVES 
2.1 Primary Objective 
 
The primary objective of this open label study is to evaluate the rate of sustained virological 
response  rate  12  weeks  after  completion  of  treatment  (SVR12)  with VIEKIRA  PAK 
(ombitasvir, paritaprevir/r, dasubuvir), with or without ribavirin in a large real world setting. 
2.2 Secondary Objective  
The secondary objectives of the study are as follows: 


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• To  evaluate  sustained  virological  response  rate  4  weeks  after  completion  of  treatment 
(SVR4)  with VIEKIRA  PAK  (ombitasvir,  paritaprevir/r,  dasubuvir),  with  or  without 
ribavirin in a large real world setting 
• To evaluate patient adherence with VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir), 
with or without ribavirin in a real world setting  
3 
STUDY DESIGN 
3.1 Description of the Study 
This  is  a  Phase  IV,  open-label,  multi-center  study  to  evaluate  the  real  world  sustained 
virological response rate, subject adherence, and subject reported outcomes during and after 
treatment of non-cirrhotic genotype 1 chronic hepatitis C subjects aged 18  years and older, 
with the AbbVie 3 direct-acting antiviral (3-DAA) regimen of VIEKIRA PAK (ombitasvir, 
paritaprevir/r,  dasubuvir),  with  or  without  ribavirin. Subjects may  be  treatment-naïve  or 
treatment  experienced  with  pegylated-interferon  based  regimens  excluding  regimens  with 
direct-acting antiviral agents.   
 
The study will be conducted at multiple KPSC Medical Centers and will screen approximately 
275 subjects with an estimated 33% screen failure rate to enroll 200 subjects.      
3.2 Subject Population 
Subjects will be considered treatment-naïve if they have never received any antiviral treatment 
for HCV infection. 
 
Subjects will be considered treatment-experienced if they have received prior interferon-based 
therapy (including interferon or pegylated-interferon monotherapy; interferon and ribavirin; or 
pegylated-interferon  and  
ribavirin).  Treatment-experienced subjects with  prior  use  of  HCV 
DAA(s) are excluded from study participation. 
 
Subjects with documentation available to classify prior response to interferon and ribavirin, or 
pegylated-interferon and ribavirin treatment will be categorized as one of the following:
 
• Null-responder: did not achieve a 1 log10 IU/mL reduction in HCV RNA by week 4 or a 
2 log10 IU/mL reduction in HCV RNA by week 12 during a prior interferon and ribavirin, 
or pegylated-interferon and ribavirin treatment course 
• Partial-responder: achieved at least a 2 log
10 IU/mL reduction in HCV RNA by week 12 
during  a  prior  interferon  and  ribavirin  or  pegylated-interferon  and  ribavirin  treatment 
course, but failed to achieve HCV RNA undetectable at the end of treatment 
• Relapser: achieved undetectable HCV RNA at end of a prior interferon and ribavirin or 
pegylated-interferon  and  ribavirin  treatment  course,  but  HCV  RNA  was  detectable 
following therapy completion 
Subjects  with  a  less  well-characterized  IFN-based  treatment  experience,  including  those 
subjects with incomplete HCV RNA and treatment date documentation, will be categorized as 
one of the following:
 


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• Relapse/breakthrough: achieved  at  least  one  documented  result  of  HCV  RNA 
undetectable during a prior IFN and RBV ribavirin, or pegIFN and RBV treatment course 
• Non-responder: did not achieve a documented result of HCV RNA undetectable or HCV 
RNA was detected at the end of treatment during a prior IFN and RBV, or pegIFN and 
RBV  
treatment  course  with  
insufficient  data  available  
to  categorize  as  a  breakthrough, 
partial or null responder 
• Interferon intolerant:  did not meet any of the above definitions of treatment-failure and 
discontinued IFN and RBV, or pegIFN and RBV therapy due to IFN intolerability 
• Interferon experienced-other:  Includes IFN, or pegIFN and RBV monotherapy; IFN and 
RBV,  or  pegIFN  and  RBV  experienced  subjects;  Includes  subjects  who  do  not  have 
adequate  documentation  of  response.  Subjects  receiving  interferon  or  peginterferon 
monotherapy must be categorized as 
'Interferon experienced-other
'. 
3.3 Treatment Arms 
Subjects who meet all eligibility criteria and provide written informed consent will be enrolled 
in the study and assigned to one of two treatment groups.  
 
Genotype 1a: VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) + RBV (ribavirin) 
Genotype 1b: VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) 
 
See Section 4.4 for more information. 
3.4 Study Duration 
Study Discontinuation 
Southern California Permanente Medical Group (SCPMG) reserves the right to terminate this 
study at any time due to the incidence or severity of adverse events in this study that indicate 
a potential health hazard to subject or partner. 
4 
STUDY PRODUCT INFORMATION 
For complete information on VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir), refer to the 
VIEKIRA PAK Package Insert version 12/2014. Select information from the document is available 
below. 
 
For  complete  
information  on ribavirin,  refer  
to  
the  Ribavirin  Package  Insert version  08/2011. 
Select information from the document is available below. 
4.1 Description 
4.1.1   
VIEKIRA PAK (ombitasvir, paritaprevir/r, dasubuvir) 
VIEKIRA  PAK  is  ombitasvir,  paritaprevir,  ritonavir  fixed  dose  combination  tablets 
copackaged with dasabuvir tablets.  


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Ombitasvir, paritaprevir, ritonavir fixed dose combination tablet includes a hepatitis C virus 
NS5A inhibitor (ombitasvir), a hepatitis C virus NS3/4A protease inhibitor (paritaprevir), and 
a  CYP3A  inhibitor  (ritonavir)  that  inhibits  CYP3A  mediated  metabolism of  paritaprevir, 
thereby providing increased plasma concentration of paritaprevir. Dasabuvir is a hepatitis C 
virus non-nucleoside NS5B palm polymerase inhibitor, which is supplied as separate tablets in 
the copackage. Both tablets are for oral administration.  
 
Ombitasvir  
The chemical name of ombitasvir is Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-
diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-
diyl]})biscarbamate hydrate. The molecular formula is C50H67N7O8•4.5H
2O (hydrate) and the 
molecular weight for the drug substance is 975.20 (hydrate). The drug substance is white to 
light yellow to light pink powder, and is practically insoluble in aqueous buffers but is soluble 
in ethanol. Ombitasvir has the following molecular structure: 
 
Paritaprevir  
The chemical name of paritaprevir is (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-
6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-
a][1,4]diazacyclopentadecine-14a(5H)-carboxamide  dihydrate.  The  molecular  formula  is 
C40H43N7O7S•2H2O  
(dihydrate)  and  
the  molecular  weight  
for  
the  drug  substance  
is  801.91 
(dihydrate). The drug substance is white to off-white powder with very low water solubility. 
Paritaprevir has the following molecular structure: 
 
Ritonavir  
The  chemical  name  of  ritonavir  is  [5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-
methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-
tetraazatridecan-13-oic acid,5-thiazolylmethyl ester. The molecular formula is C
37H48N6O5S2 


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and the molecular weight for the drug substance is 720.95. The drug substance is white to off 
white to light tan powder practically insoluble in water and freely soluble in methanol and 
ethanol. Ritonavir has the following molecular structure: 
 
Ombitasvir, Paritaprevir, Ritonavir Fixed-Dose Combination Tablets  
Ombitasvir, paritaprevir, and ritonavir film-coated tablets are co-formulated immediate release 
tablets. The tablet contains copovidone, K value 28, vitamin E polyethylene glycol succinate, 
propylene glycol monolaurate Type I, sorbitan monolaurate, colloidal silicon dioxide/colloidal 
anhydrous  silica,  sodium  stearyl  fumarate,  polyvinyl  alcohol,  polyethylene  glycol 
3350/macrogol 3350, talc, titanium dioxide, and iron oxide red. The strength for the tablet is 
12.5 mg ombitasvir, 75 mg paritaprevir, 50 mg ritonavir.  
 
Dasabuvir  
The  chemical  name  of  dasabuvir  is  Sodium  3-(3-tert-butyl-4-methoxy-5-{6-
[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-
ide  hydrate  
(1:1:1).  The  molecular  
formula  
is  C
26H26N3O5S•Na•H2O  
(salt,  hydrate)  and  
the 
molecular weight of the drug substance is 533.57 (salt, hydrate). The drug substance is white 
to pale yellow to pink powder, slightly soluble in water and very slightly soluble in methanol 
and isopropyl alcohol. Dasabuvir has the following molecular structure: 
 
Dasabuvir  is  formulated  as  a  250  mg  film-coated,  immediate  release tablet  containing 
microcrystalline  cellulose  (D50-100  um),  microcrystalline  cellulose  (D50-50  um),  lactose 
monohydrate, copovidone, croscarmellose sodium, colloidal silicon dioxide/anhydrous colloidal 
silica,  magnesium  stearate,  polyvinyl  alcohol,  titanium  dioxide,  polyethylene  glycol 
3350/macrogol 3350, talc, and iron oxide yellow, iron oxide red and iron oxide black. Each tablet 
contains 270.3 mg dasabuvir sodium monohydrate equivalent to 250 mg dasabuvir. 
4.1.2 
Ribavirin 
Ribavirin is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin 
is 1-β-D-ribofuranosyl-1H -1,2,4-triazole-3-carboxamide and has the following structural formula: 


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Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in 
anhydrous alcohol. The empirical formula is C8 H
12 N
4 O
5 and the molecular weight is 244.21. 
 
Ribavirin capsules  USP  consist  of  a  white  powder  in  a  white,  opaque,  gelatin  capsule.  Each 
capsule, for oral administration, contains 200 mg ribavirin. In addition, each capsule contains the 
following  inactive  ingredients:  corn  starch,  croscarmellose  sodium,  hypromellose,  magnesium 
stearate, mannitol and povidone. The capsule shell consists of gelatin and titanium dioxide. The 
capsule is printed with edible blue pharmaceutical ink which is made of FD&C Blue #2 aluminum 
lake, propylene glycol, shellac and titanium dioxide. 
4.2 Acquisition and Accountability 
VIEKIRA  PAK  is  manufactured by  AbbVie  Inc.,  North  Chicago,  IL  60064. Ribavirin  is 
manufactured by Sandoz, Inc., Broomfield, CO 80020. 
 
The investigational products are for investigational use only and are to be used only within the 
context  of  this  study.  The  study  drugs  supplied  for  this  study  must  be  maintained  under 
adequate security  and stored under the conditions specified on the label until dispensed for 
subject use, returned to the Sponsor, or destroyed per local regulations. 
4.3 Formulation, Packaging, Labeling, and Storage  
4.3.1 
VIEKIRA PAK 
VIEKIRA PAK is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly 
carton contains four weekly cartons. Each weekly carton contains seven daily dose packs. Each 
child resistant daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir, paritaprevir, 
ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need to be taken in 
the morning and evening. The NDC number is NDC 0074-3093-28.  
 
Ombitasvir,  paritaprevir,  ritonavir  12.5/75/50  mg  
tablets  are  pink-colored,  film-coated,  oblong 
biconvex shaped, debossed with “AV1” on one side. Dasabuvir 250 mg tablets are beige-colored, 
film-coated, oval-shaped, debossed with “AV2” on one side. 
Store at or below 30°C (86°F). 
4.3.2 
Ribavirin 
Ribavirin capsules USP, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) 
RIBAVIRIN over 200 mg on cap and GG 608 on body. Dispense in a tight container as defined 
in the USP. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) 




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commonly reported adverse reactions (greater than or equal to 5% of subjects) were nausea, 
pruritus and insomnia. Refer to the VIEKIRA PAK Package Insert for more information. 
4.6.2 
Ribavirin 
The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin 
therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial 
infarctions.  Patients  with  a  history  of  significant  or  unstable  cardiac  disease  should  not  be 
treated with ribavirin. 
 
Significant teratogenic and embryocidal effects have been demonstrated in all animal species 
exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it 
may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy 
is contraindicated in women, who are pregnant and in the male partners of women who are 
pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months 
after completion of treatment in both female patients and in female partners of male patients 
who are taking ribavirin therapy. At least two reliable forms of effective contraception must 
be utilized during treatment and during the 6-month post-treatment follow-up period. 
Refer to the Ribavirin Package Insert for more information. 
4.7 Prohibited Medication 
Estrogen-containing  hormonal  contraceptives,  
including  oral,  
injectable,  
implantable,  patch 
and ring varieties, may not be used during study drug treatment. 
 
Participants  must  not  
receive  contraindicated  medication  prior  
to  study  drug  administration 
including, but not limited to those listed in Table 4, or medications contraindicated for ritonavir 
or ribavirin per FDA label. For those that receive ribavirin, contraindicated medications must 
be discontinued at least 2 weeks or 10 half-lives prior to study drug administration, whichever 
is longer. 
 
Table 5. Medications Contraindicated for Use with Study Drug Regimen 
Alfuzosin 
Astemizole  
Carbamazepine 
Dihydroergotamine 
Efavirenz  
Ergotamine 
Ergonovine 
Estrogen-containing 
Medications for Systemic Use 
Fusidic Acid  
Gemfibrozil 
Lovastatin 
Methylergonovine  
Midazolam (oral) 
Phenobarbital 
Phenytoin 
Pimozide  
Rifampin 
Sildenafil** 
Simvastatin 
St. John
's Wort 
Terfenadine 
Triazolam 
*   Not all medications contraindicated with VIEKIRA PAK, ritonavir, and ribavirin are listed above. 
Refer to the most current package inserts or product labeling for each drug for a complete list of 
contraindicated medications. 
** When used for the treatment of pulmonary arterial hypertension 


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5  
SELECTION OF SUBJECTS 
5.1 Inclusion Criteria 
To participate in this study the subject must meet all of the following inclusion criteria: 
1. Male or female at least 18 years of age at time of screening. 
2. Subject voluntarily signed the Informed Consent Form for the study. 
3. Subject is able to adhere to study visit/ procedure schedule and protocol requirements 
4. Subject, if female must not use estrogen-containing hormonal contraception including oral, 
injectable, implantable, patch and ring varieties during study drug treatment 
5. Subject, if female must meet at least one of the following: 
• Subject of childbearing potential must agree to either 
o practice  2    effective  contraceptive  methods1 for  study  duration,  starting 
Screening through 30 days after stopping study drug if not receiving ribavirin, 
6 months/or as directed by ribavirin label if receiving ribavirin 
o practice  total  abstinence  from  sexual  intercourse  (minimum  1  complete 
menstrual cycle) 
o be sexually active with female partner only 
• Postmenopausal defined as age appropriate amenorrhea for > 2 years prior to screening 
and post-menopausal state confirmed by follicle-stimulating hormone (FSH) level 
• Surgically  sterile  defined  as  bilateral  tubal  ligation  or  bilateral  oophorectomy  or 
hysterectomy 
• Has male sexual partner with vasectomy 
6. Subject, if male, who is not surgically sterile and is sexually active with female partner of 
childbearing potential must agree to practice 2 effective contraceptive methods2 for study 
duration, starting at Screening through 30 days after stopping study drug if not receiving 
ribavirin, 7 months/or as directed by ribavirin label if receiving ribavirin  
7. Subject must  have  at  
least  one  of  
the  following  
indicators  of  chronic  hepatitis  C  virus 
infection prior to study enrollment: 
• Positive anti-HCV antibody or HCV RNA > 10,000 IU/mL at least 6 months before 
screening, and positive for HCV RNA at the time of screening  
• HCV RNA > 10,000 IU/mL at screening and liver biopsy consistent with chronic HCV 
infection 
• Credible evidence of chronic hepatitis C as per  
the  
investigator  and HCV RNA  > 
10,000 IU/mL at the time of screening. 
8. Subject has a screening laboratory result indicating HCV genotype 1-infection. Historical 
genotype within 6 months of screening may be used at the discretion of the investigator. 
                                                 
1 Effective contraceptive methods outlined in informed consent form, subject information sheet, and other subject documents 
2 
Effective contraceptive methods outlined in informed consent form, subject information sheet, and other subject documents 


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5.2 Exclusion Criteria 
To participate in this study the subject must not meet any of the following exclusion criteria: 
1. Subject declined to sign the Informed Consent Form for the study. 
2. Subject, if female is pregnant or is breastfeeding, or if male, with a partner who is currently 
pregnant.  
3. Subject has positive test result for hepatitis B surface antigen or confirmed positive anti-
HIV antibody test 
4. Subject received study contraindicated medications including but not limited to those listed 
in Table 5, or medications contraindicated for ritonavir or ribavirin per FDA label prior to 
the study drug administration and unwilling to discontinue prior to starting the study drug. 
For those that receive ribavirin, contraindicated medications must be discontinued at least 
2 weeks or 10 half-lives prior to study drug administration, whichever is longer. 
5. Use  of  known  strong  
inducers  of  cytochrome  P450  3A  
(CYP3A)  or  strong  
inducers  of 
cytochrome P450 2C8 (CYP2C8) or strong inhibitors of CYP2C8 within 2 weeks of the 
respective medication/supplement prior to initial dose of study drug (see Table 5). 
6. Clinically  significant  abnormalities  or  co-morbidities,  other  
than  HCV  
infection  
that  
in 
opinion of the investigator makes subject unsuitable for this study or drug regimen 
7. Current enrollment in another interventional clinical study or prior or current use of any 
investigational  or  commercially  available  anti-HCV  agents  other  than  interferon  or 
ribavirin including previous exposure to ABT450 (paritaprevir), ABT-267 (ombitasvir) or 
ABT-333  (dasabuvir)  or  
receipt  of  any  
investigational  product  within  6  weeks  prior  
to 
study drug administration 
8. Prior treatment of chronic HCV infection with a direct acting antiviral agent(s): telaprevir, 
boceprevir, sofosbuvir, simeprevir, or other direct acting antiviral 
9. History of solid organ transplant 
10. Screening laboratory analyses shows any of the following abnormal laboratory results: 
• Glomerular filtration rate < 30 mL/min as estimated by the Cockcroft-Gault equation19 
• Hemoglobin < 12 gram per deciliter for male 
• Hemoglobin < 11 gram per deciliter for female 
11. Evidence of cirrhosis, documented by one of the following:  
• Liver biopsy histologic diagnosis: Metavir Score > 3 (includes 3 - 4 or 3/4) or Ishak 
score > 4  
• In the absence of liver biopsy: a FibroScan score > 12.5 kPa 
• In the absence of a FibroScan: an APRI score > 1.5 
• In the judgment of the investigator clinical findings  are  consistent with cirrhosis.  
In 
general,  a non-cirrhotic result from a Fibroscan will supersede evidence  of cirrhosis 
based on APRI and a liver biopsy not showing cirrhosis will superseded both Fibroscan 
and APRI. 
12. History of liver decompensation: ascites noted on a physical exam, imaging or other test; 
variceal bleeding; hepatic encephalopathy 


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13. Confirmed  presence  of  hepatocellular  carcinoma  indicated  on  computed  tomography, 
magnetic resonance, or other imaging techniques within 3 months prior to screening 
14. HCV  genotype  performed  during  screening  
indicates  
infection  with  any  genotype  other 
than genotype 1 
15. Recent history of active drug or alcohol abuse that could, in the opinion of the investigator, 
affect adherence to the study protocol 
6  
STUDY ASSESSMENTS 
The study procedures to be performed are outlined in Appendix A: Study Visit/ Procedures Table 
and  discussed  
in  detail  
in  
this  section.  All  study  data  will  be  recorded  
in  
the  subject
's  source 
documentation and appropriate case report form(s). 
6.1 Study Procedures 
6.1.1 Informed Consent  
The study and the associated risks and benefits of participating in the study will be outlined in 
detail by the investigator. Signed study-specific informed consent will be obtained from the 
subject  before  any  
study  procedures  are  performed.  Details  
regarding the informed consent 
process and documentation are provided in Section 13.1.  
6.1.2 Eligibility Review 
An eligibility review will be documented at Screening and confirmed at Baseline/Day 1. 
6.1.3 Medical History 
A review of medical history will be done at screening and baseline (before treatment). 
6.1.4 Complete Physical Examination 
A  complete  physical  examination  will  be  conducted  at  the Screening Visit.  The  physical 
examination performed at the screening visit will serve as the baseline physical examination 
for clinical assessment. 
 
Additional physical exam(s) may be performed at the discretion of investigator per standard of 
care. If available, data related to changes from baseline, adverse events, and participant follow-
up resulting from the symptom-directed physical exam will be documented as appropriate. 
6.1.5 Liver Fibrosis Assessment 
Liver fibrosis  assessment  
is  comprised  of aspartate  aminotransferase to  platelet  
ratio  
index 
(APRI), liver FibroScan, liver biopsy, and/or clinical finding consistent with cirrhosis.  


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6.1.6 Vital Signs, Weight, and Height 
Body  
temperature,  blood  pressure,  pulse,  body  weight,  and  height  will  be  measured  at  
the 
screening visit. Optional, obtain vital signs (temperature, blood pressure, pulse), weight and 
height  at  
the Baseline  Visit  may  be  done  at  
the discretion  of  
the  
investigator for  Ribavirin 
dosing calculations. 
6.1.7 Pregnancy Test 
Pregnancy  
tests  are  not  required  for  female  subjects  with  documented  prior  bilateral tubal 
ligation,  bilateral  oophorectomy,  or  hysterectomy,  or  
for  subjects  who  are  confirmed  
to  be 
postmenopausal.  Confirmation  of  post-menopausal  status  measured  by  follicle-stimulating 
hormone (FSH) will be obtained at the screening visit only for all female subjects. 
 
For females of childbearing potential: 
● A serum pregnancy test will be performed at the screening visit only and sent to the local 
laboratory for analysis. 
● Pregnancy testing will be performed 
on site during the study visits 
as specified in Appendix 
A: Study Visit/ Procedures Table regardless  of  
treatment  
regimen. If  a  urine  pregnancy 
result is positive, a confirmatory serum human chorionic gonadotropin (β-hCG) test will 
be collected and sent to the local lab for processing. 
● Subjects that receive a ribavirin-containing regimen will have pregnancy tests performed 
in accordance with the protocol while participating in the study. Otherwise, subjects are 
recommended to have monthly pregnancy test throughout the treatment period and for a 
minimum  of  7  months  after  
the  discontinuation  of  ribavirin,  or  according  
to  
the  FDA 
approved ribavirin label and/or standard of care. 
 
For  females  of  childbearing  potential,  and  males  with  a  female  partner  of  child-bearing 
potential: 
● Upon completion of the study, subjects will be counseled regarding pregnancy at their last 
study visit with instructions to contact their healthcare provider right away in the event that 
they or their female partner becomes pregnant. 
 
For subjects with positive pregnancy test during the course of the study, refer to Section 6.3.4. 
6.1.8 
Clinical Laboratory Samples 
The  
following  
laboratory  samples  will  be  obtained  as  outlined  
in Appendix  A.  Laboratory 
samples will be managed, processed, and resulted in accordance with KPSC standards. 
6.1.8.1 Hepatitis and HIV Screen 
Hepatitis  B  surface  antigen (HBsAg),  anti-hepatitis  C  antibody  (anti-HCV  Ab),  and  anti-
human  
immunodeficiency  virus  antibody  
(anti-HIV  Ab)  will  be  performed  at  screening.  A 
positive anti-HIV Ab test result must be confirmed. The site will report these results per local 
regulations, if necessary. 


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6.1.8.2 Hepatitis C Virus Genotype and Subtype 
Plasma samples for HCV genotype and subtype will be collected at screening. Historical HCV 
genotype  and  subtype within  6  months  of the  Screening  Visit is  permitted and  may  be 
substituted  
for  
the  screening  plasma  sample  collection at  
the  discretion  of  
the  
investigator. 
Genotype  and  subtype  will  be  assessed  using  the  standard  assay  per  Kaiser  Permanente 
regional laboratory. 
6.1.8.3 Hepatitis C Virus RNA 
Plasma  samples  
for  HCV  RNA  
levels  will  be  collected  as  
indicated  
in Appendix  A:  Study 
Visit/ Procedures Table. Plasma HCV RNA levels will be determined using the standard assay 
per Kaiser Permanente laboratory.  
6.1.8.4 Safety Monitoring Labs 
CBC  with  differential,  creatinine,  and liver  panel  lab  tests (total  bilirubin,  alanine 
aminotransferase  (ALT),  and  alkaline  phosphatase  
levels  (AlkPhos)) will  be  performed  as 
indicated in Appendix A: Study Visit/ Procedures Table. 
6.1.8.5 Additional Labs 
At the discretion of the treating investigator, additional laboratory tests may be ordered with 
the study labs. If available, results from the following labs will also be collected in the study: 
coagulation panel (PT, PTT), INR, reticulocyte count, direct bilirubin, and electrolytes. 
 
Consistent with standard practice, clinically significant laboratory tests must be repeated and 
monitored to a satisfactory clinical resolution.  
6.1.9 Concomitant Medication Assessment 
Subject’s  use  of concomitant medications,  prescription and  over-the-counter  including 
vitamins and herbal supplements, administered from the time of signing the consent through 
30  days  after  
last  dose  of  study  drug  administration  will  be collected.  The  
investigator  or 
authorized designee should review concomitant medication  
label(s)  and  assess  
for  potential 
drug interactions.  
6.1.10 Adverse Event (AE) Assessment 
Clinical outcome events that occur during the treatment period through post-treatment week 12 will 
be recorded  and  documented in the  case report  
form as an AE or Serious  Adverse  Event  
(SAE). 
Refer to Section 9 Assessment of Safety for more information. 
6.1.11 Study Drug Dispensing 
Study  drugs  will  be  dispensed  at  the  visits  as  indicated Appendix  A. At  each  visit,  any 
remaining study drug from the previous visit will be re-dispensed to the subject. 
 
Subjects  
receiving  
ribavirin  will  be  provided  with  
the  Ribavirin  Medication  Guide  at  
their 
Baseline Visit. 


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6.1.12 Study Drug Accountability/ Compliance Review 
At each visit noted in Appendix A, study drug dispensation and administration reconciliation 
will  be  
recorded  according  
to  
the  number(s)  of: VIEKIRA  PAK™ and  
ribavirin  
tablets  
(if 
applicable) available at each study visit. Study drug dosing will be reviewed at each study visit. 
Subject adherence to study protocol and study drug treatment will be monitored each visit.  
6.2 STUDY VISITS 
6.2.1 Screening Visit Procedures (- 28 days to Baseline/Day 1) (Visit 1) 
The following assessments/procedures will be performed in-clinic: 
 
• Obtain signed informed consent 
• Eligibility review  
• Complete medical history  
• Complete physical examination 
• Liver fibrosis assessment  
• Obtain vital signs (temperature, blood pressure, pulse), weight and height 
• Obtain Pregnancy Test, serum β-hCG
1  
• Obtain HCV Genotype and Subtype2 
• Obtain the following labs. Note: Laboratory results obtained within three (3) months of 
Screening Visit may be used at the discretion of the investigator. 
o HBsAg and anti-HCV Ab 
o Anti-HIV Ab  
o HCV RNA 
o CBC with differential 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications 
6.2.2 Baseline/Day 1 Procedures (Visit 2) 
The following assessments/procedures will be performed in-clinic: 
 
• Confirm inclusion and exclusion criteria to determine eligibility 
• Review Medical History 
                                                 
1 Pregnancy  
test  not  required  for  female  subject  with  documented  bilateral  tubal ligation,  bilateral oophorectomy,  or 
hysterectomy
, or for postmenopausal subjects as confirmed by FSH test 
2 Medical record documentation of HCV genotype and subtype within the last 6 months may be substituted for the screening 
plasma sample collection 


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• Optional, obtain vital signs (temperature, blood pressure, pulse), weight and height at the 
discretion of the investigator 
• Pregnancy Test, Serum or Urine 
• Additional labs as determined by the investigator 
• Review concomitant medications 
• Review for AEs 
• Study Enrollment/Treatment assignment 
• Dispense study drug by providing the subject with a ne two week supply of Viekira Pak, 
and if applicable, provide subject with the Ribavirin Medication Guide. Subjects should be 
instructed to have their first dose same day that they can take a full day course of the study 
drug (e.g. subject seen in the afternoon should be instructed to take their first dose the next 
day) 
• Study drug accountability 
6.2.3 Treatment Period 
Treatment visits should be based on the subject’s Baseline Visit date.  
 
If  a  subject  discontinues  or  withdraws  from the  study during  
the  
treatment  period,  he/she 
should be encouraged to complete the End of Treatment (EOT) Procedures (Section 6.2.3.3) 
and the Early Termination Visit (Section 6.2.4.2) within 14 days of the last study treatment 
dose. In the event that subject is unable to complete the visit(s) but willing to provide survival 
status, the study site staff should contact the subject within 14 days to collect the information.  
6.2.3.1 Week 2 (Visit 3) 
The following assessments/procedures will be performed in-clinic: 
• Obtain labs: 
o HCV RNA 
o CBC with differential, only required for subjects receiving ribavirin (Genotype 1a) 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications 
• Review for AEs 
• Dispense study drug by providing the subject with a new two week supply of Viekira Pak 
and re-dispensing the remaining RBV 
• Study drug accountability 
6.2.3.2 Week 4 (Visit 4) and Week 8 (Visit 5)  
The following assessments/procedures will be performed in-clinic: 


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• Pregnancy Test, Serum or Urine  
• Obtain labs: 
o CBC with differential 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications  
• Review for AEs 
• Dispense study drug  
• Study drug accountability 
6.2.3.3  Week 12 (Visit 6) - End of Treatment (EOT) Procedures 
The following assessments/procedures will be performed in-clinic: 
• Pregnancy Test, Serum or Urine  
• Obtain labs: 
o HCV RNA 
o CBC with differential 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications 
• Review for AEs 
• Study drug accountability 
6.2.4 Post-Treatment (PT) Period 
Post-treatment visits should be based on the subject’s last dose of the study drug. 
 
If a subject discontinues or withdraws from the study during the post-treatment period, he/she 
should be encouraged to complete the Early Termination Visit (Section 6.2.4.2) except when 
the reason for discontinuation is confirmed virologic failure as described in Section 6.3.3. If a 
subject is unable to complete the Early Termination visit but willing to provide survival status, 
the study site staff should contact the subject to collect the information. 
6.2.4.1 Post-Treatment (PT) Week 4 (Visit 7) 
The following assessments/procedures will be performed 
either 
in-clinic, or remotely by phone 
with labs collected at the subject’s nearest laboratory facility:
 
• Pregnancy Test, Serum or Urine  
• Obtain labs: 


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o HCV RNA 
o CBC with differential 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications 
• Review for AEs 
6.2.4.2 Post-Treatment (PT) Week 12 (Visit 8) - End of Study/ Early 
Termination (ET) 
The End of Study Post-Treatment Week 12 visit will be completed at the conclusion of the 
post-treatment period.  
 
Early Termination Visit should be completed when a subject discontinues or withdraws from 
the  study  during either  the  Treatment  or  Post-treatment, except  when  the  reason  for 
discontinuation is confirmed virologic failure (Section 6.3.3). 
 
If  a  subject  discontinues  or  withdraws  from the  study during  
the  
treatment  period,  he/she 
should be encouraged to complete the End of Treatment (EOT) Procedures (Section 6.2.3.3) 
and the Early Termination Visit (Section 6.2.4.2) within 14 days of the last study treatment 
dose. In the event that subject is unable to complete the visit(s) but willing to provide survival 
status, the study site staff should contact the subject within 14 days to collect the information. 
 
If a subject discontinues or withdraws from the study during the post-treatment period, he/she 
should be encouraged to complete the Early Termination Visit (Section 6.2.4.2) except when 
the reason for discontinuation is confirmed virologic failure as described in Section 6.3.3. If a 
subject is unable to complete the Early Termination visit but willing to provide survival status, 
the study site staff should contact the subject to collect the information. 
 
The following assessments/procedures will be performed in-clinic, or remotely by phone with 
labs collected at the subject’s nearest laboratory facility: 
• Pregnancy Test, Serum or Urine  
• Obtain labs: 
o HCV RNA 
o CBC with differential 
o Creatinine 
o Liver panel (ALT, Alkaline Phosphatase, Total Bilirubin), AST and Direct Bilirubin 
o Additional labs as determined by the investigator 
• Review concomitant medications 
• Review for AEs 


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6.2.4.3 Unscheduled Visits and Labs  
Unscheduled visits and labs may be done as determined by the investigator to protect the safety 
of the subject, such as in the case of AEs.  
6.2.4.4 Unscheduled Drug Dispensing 
Unscheduled drug dispensing to prevent treatment interruption requires prior approval from 
the Sponsor-Investigator or designee. 
6.3 
Subject Discontinuation 
6.3.1 
Subject Initiated Discontinuation 
Each subject has the right to withdraw from the study at any time for any reason. Subjects who 
discontinue from the study regardless of cause should be encouraged to complete the Early 
Termination  Visit  within  14  days  of  the  last  treatment dose. Ideally  for  study  drug 
discontinuation, this should occur on the day of study drug discontinuation, and prior to the 
initiation of any other anti-hepatitis C virus therapy. However, these procedures should not 
interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator 
feels are necessary to treat the subject
's condition.   
 
In the event that subject is unable to complete the visit but willing to provide survival status, 
the study site staff should contact the patient within 14 days of the last study dose to collect 
the information. 
 
Following discontinuation of study drug, the subject will  be  
treated in accordance with the 
investigator
's  best  clinical  judgment.  The  last  dose  of  any  study  drug  and  reason  for 
discontinuation from the treatment period will be recorded in the case report form. 
 
Withdrawal of consent for the study will be  documented  
in the subject’s study records and 
reported to the PI and/or designee.  
6.3.2 
Investigator Initiated Discontinuation 
The investigator may also discontinue a subject from the study at any time for the following 
reasons: 
•  Subject or subject’s partner experiences AE or toxicity from the study drug that warrants 
discontinuation, or 
•  Subject is noncompliant (e.g. missed treatment doses, or missed visits) with the protocol, 
or 
• If  a  subject  has  an  ongoing AE or  an  unresolved  
laboratory  result  
that  
is  significantly 
outside of the reference range at the time of study drug discontinuation, the investigator 
will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory 
result or AE is resolved. 


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6.3.3 
Discontinuation of Subjects Meeting Virologic Failure Criteria 
The following criteria will be considered evidence of virologic failure: 
• Confirmed  
increase  from  nadir  
in  HCV  RNA,  defined  as  
two  consecutive  HCV  RNA 
measurements > 1 log10 IU/mL above nadir, at any time point during treatment 
• Confirmed HCV RNA ≥ lower limit of quantification, defined as two consecutive HCV 
RNA measurements ≥ lower limit of quantification, at any point after HCV RNA less than 
lower limit of quantification 
Confirmatory testing for the above criteria should be completed. Subjects receiving study drug 
treatment should remain on treatment until the virologic failure has been confirmed.  
 If  any  of  
the  above  criteria  are  confirmed  
for  subjects  during  study  drug  
treatment,  
the 
subject will discontinue treatment.  
 If any of the above criteria are confirmed for subjects during the post-treatment phase of 
the study, the subject will be discontinued from the study. 
6.3.4 
Pregnancy 
In the  event that a positive result is  obtained on a pregnancy test for  a subject or a subject 
reports  becoming  pregnant  during  the  treatment  period,  the  administration  of  ribavirin  (if 
applicable)  to  that  subject  must  be  discontinued  immediately. The  investigator  is  also 
encouraged to report the pregnancy information to the voluntary ribavirin pregnancy registry, 
if applicable. 
 
Direct-acting antiviral agents may be continued at the Sponsor-investigator
's discretion after 
discussion with the subject, if the benefit of continuing direct acting antiviral agents is felt to 
outweigh the potential risk. Subjects will be monitored for sustained virological response in 
the post-treatment period per protocol.  
7 
DATA COLLECTION AND MONITORING 
7.1 Data Management and Record Keeping 
The data will be collected and reported on paper case report forms and/or in electronic medical 
record. Each site will be responsible for data entry into system. In the event of discrepant data, 
research  personnel  at  each  site  will  resolve items. KPSC will  be  responsible  for  the  data 
management of this study, including quality checking of the data by conducting an internal 
audit review. 
7.2 Data Monitoring Plan 
Remote  and  on-site monitoring visits will be conducted at each site in  accordance  with  
the 
study monitoring plan that includes at a minimum, a review of signed ICFs, review of subject 
eligibility, AE reporting  and  data  integrity.  Visits  will  occur  approximately  during  the 
screening period, after start of study treatment, and at the end of study. 
 


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Monitoring  visits  will  be  performed  by  a  Kaiser  Permanente  employee  approved  by  the 
Department of Research & Evaluation. In addition, this employee will have been trained and 
met criteria under applicable KPSC Clinical Trials Standard Operating Procedures.   
 
During the monitoring visits, any finding that pose as an actual or potential risk to the health, 
safety,  welfare,  or  privacy  of  a  research  participant  or  the  integrity  of  the  study  may  be 
disclosed to the KPSC IRB by the monitor. 
 
Investigators will permit national and local health authorities, KPSC IRB, KPSC Research & 
Evaluation,  U.S.  FDA,  Department  of  Health  and  Human  Services,  along  with  other 
governmental agencies with responsibilities for the safety of drugs and studies. 
7.3 Data Safety Monitoring Board (DSMB) 
There will be no Data Safety Monitoring Board (DSMB) for this clinical trial since the study 
drugs used in this study  
is FDA approved and is being used in accordance to the approved 
indication. Additionally, all study procedures are considered standard of care. 
7.4 Retention of Study Record 
Records and documents pertaining to the conduct of this study, including Informed Consent 
Forms,  case  report  forms,  Patient  Reported  Outcome  data,  drug  accountability  logs,  IRB 
submissions, approvals and correspondence, and any regulatory documents, must be retained 
by  
the Sponsor-Investigator  
for  at  
least  15  years  after  completion  or  discontinuation  of  
the 
study, or for the length of time required by relevant Federal or local regulations, whichever is 
longer. After this time period, study documents may be destroyed per local regulations after 
receipt  of  written  approval  by  
the Sponsor-Investigator  and  KPSC  Research  &  Evaluation. 
Written  notification  must  be  provided  to  the Sponsor-Investigator  and  KPSC  Research  & 
Evaluation  prior  
to  moving  
records  
to  another  
location  or  when  
transferring  any  
records  
to 
another party. 
8 
STATISTICAL CONSIDERATIONS 
This is an open label, non-randomized, study with one study arm. Descriptive statistics will be 
used to describe the observed sustained virological response rate and patient adherence to the 
treatment regimen. The primary analysis, to evaluate SVR12, will occur after all subjects have 
completed or prematurely discontinued the study. 
 
The intent-to-treat population will consist of all enrolled subjects in this study. The primary 
efficacy analysis on clinical outcomes will be performed on all subjects in the intent-to-treat 
population. The modified intent-to-treat population will include all who receive at least one 
dose of study drug.  
 
No data will be imputed for any efficacy or safety analyses except for analyses of the HCV 
RNA endpoints.  
 


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HCV RNA values will be selected for the SVR4 and SVR12 analysis based on the defined visit 
windows. The visit window for analysis of SVR4 is post-treatment days 2-56, and the visit 
window for analysis of SVR12 is post-treatment days 57-168. 
 The latest available value within 
each window will be used to define the SVR 4 or SVR12 result.  
8.1 Demographics 
Demographics and baseline characteristics will be summarized for all subjects in the intent to 
treat  population.  Demographics  
include  age,  weight,  height,  and  body  mass  
index,  and  
the 
frequency of gender, race, and ethnicity.  
 
Baseline characteristics will include:  
• HCV  genotype  1  subtype  (1a,  1b);  interferon  treatment  history  (treatment-naïve 
[interferon-eligible, interferon-ineligible] or interferon-based treatment experienced [null 
responder,  partial  responder,  relapse,  prior  relapse/breakthrough,  prior  nonresponder, 
interferon intolerant and interferon experienced-other]);  
• Baseline HCV RNA levels [(continuous) ≤ 800,000 IU/ or > 800,000 IU/mL], baseline.  
 
Summary statistics (number, mean, median, standard deviation and range) will be generated 
for continuous variables for example, age, and body mass index. The number and percentage 
of subjects will be presented for categorical variables for example, gender, and race. 
8.2 Safety Outcome Measures 
The  following  safety  evaluations  will  be  analyzed  during  
the  study: AEs  monitoring,  and 
laboratory test assessments. Potential AEs that will be captured include those most commonly 
reported  in  the  registration  trials  including  headache,  fatigue,  nausea,  pruritus,  insomnia, 
diarrhea, asthenia, rash, cough, irritability, anemia and dyspnea.  
 
All subjects who receive at least one dose of study drug will be included in the safety analyses. 
8.3 
Efficacy Analysis 
The primary efficacy analysis on clinical outcomes will be performed on all subjects in the 
intent to treat population. All other efficacy analyses will be performed on the modified intent 
to treat population 
8.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is to assess SVR12 in two subgroups of HCV (genotype 1a or 
1b). The simple percentage of subjects achieving SVR12 will be calculated and a two-sided 
95% confidence interval of the percentage will be computed based on Wilson
's score method. 
We cannot know a priori how the 200 patients will be split into the two subgroups, but we 
expect  each  group  
to  have  approximately  100 patients (presumably  between  80  and  120). 
Assuming a subgroup size of 100 each, the lower bound of the 95% confidence interval will 


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be within 7 percentage points of the observed SVR12 rate. 
Once the groups are fixed, the actual 
lower bound of the 95% confidence interval can be computed. 
 
The observed SVR12 rate and confidence interval will be discussed in the context of results 
from randomized clinical trials, such as the SAPPHIRE-I/II trials and PEARL-II/III/IV trials 
described in the Background section.  While formal statistical inference comparing results of 
this study to those of the randomized clinical trials will not be conducted, the point estimates 
and confidence intervals will be compared to assess the degree to which results from the real 
world setting are similar to or different from those in the randomized clinical trial setting. 
Results by prior treatment experience and response may be summarized if appropriate, based 
on the number of subjects enrolled in each subgroup. No subgroup sample size targets have 
been established. 
8.3.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are: 
• To assess SVR4. The simple percentage of subjects achieving SVR4 will be calculated and 
a two-sided 95% confidence interval of the percentage will be computed based on Wilson
's 
score method. 
• Patient adherence with the VIEKIRA PAK regimen will be evaluated by review of study 
drug  
returned for drug reconciliation and/or compilation of patient reported compliance 
information.  
9 
ASSESSMENT OF SAFETY 
9.1 Safety Parameter and Definitions 
9.1.1 
Adverse Event (AE) 
An  adverse  event  
(AE)  
is  any  undesirable  experience  associated  with  
the  use  of  a  medical 
product in a subject and includes the following: 
• AE not  previously  observed  in  the  subject  during  the  protocol-specified AE reporting 
period, limited to signs or symptoms associated with Genotype 1 Chronic Hepatitis C and 
effects of study drug 
• Complications that occur as a result of protocol-mandated activities 
• AEs that occur prior to study treatment assignment that are related to a protocol-mandated 
activity 
• Pre-existing medical conditions determined by investigator to have worsened in frequency 
or severity during the protocol-specified AE reporting period 
9.1.2 
Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is any adverse event that is any of the following: 
• Fatal 


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• Life-threatening 
• Requires initial or prolonged hospitalization 
• Disability or permanent damage 
• A  congenital  anomaly/birth  defect  in  a  neonate/infant  that  is  suspect  
to  exposure  to  a 
medical product prior to conception or during pregnancy 
• A significant medical event determined by the investigator that may jeopardize the subject 
or may require medical or surgical intervention to prevent one of the outcomes listed above 
9.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory  abnormalities  without  clinical  significance  are  not  recorded  as  AEs  or  SAEs, 
However, in the event that the abnormalities require medical or surgical intervention, or lead 
to interruption, modification or discontinuation of either of the investigational drug, they must 
be recorded as an AE, and if applicable as an SAE. When reporting the AE, the event should 
be based on the syndrome or diagnosis, and not the lab result.  
9.2 Methods and Timing for Capturing Safety Parameters 
The investigator is responsible for ensuring that all potential AEs (defined in Section 9.1.1) or 
SAEs (defined in Section 9.1.2) that occurred after subject provides written informed consent, 
but prior to initiation of study medication that are caused by protocol-mandated interventions 
will be collected and reported.  
 
After initiation of study treatment, all AE and SAE probably related or possibly related to the 
study treatment or study-related procedures will be collected and reported until the end of study 
visit, or Early Termination.  
9.2.1 
Timing of Adverse Event (AE) Reporting 
All AEs  occurring  after  
the  
initiation  of  study  
treatment that  are considered expected,  and 
possibly or  definitely related  to  the  study  (e.g.  treatment)  must  be documented,  and 
subsequently  reported  to  the Sponsor-Investigator or  designee at  the  end  of  the  subject’s 
participation in the study.  
 
All AEs that are considered unanticipated, and possibly or definitely related to the study (e.g. 
treatment) must be reported to the Sponsor-Investigator or designee within 72 hours. 
 
All unanticipated SAEs considered possibly or definitely related to the study (e.g. treatment) 
must be reported to the Sponsor-Investigator or designee within 24 hours of discovery. 
 
Any AEs identified as occurring prior to the study treatment will be considered as part of the 
subject’s medical history. 


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9.2.1 
Reportable Adverse Event (AE) or Serious Adverse Event (SAE) 
All  
reportable AEs  or SAE will  be  
recorded  
in  source  documents  and  
reported  
to IRB per 
reporting guidelines. Additionally, any AEs that meet the criteria for MedWatch reporting will 
be submitted accordingly. 
9.2.2 
Assessment of Serious, Severity, Causality and Unexpectedness 
Investigators are required to assess all AEs occurring after the initiation of study treatment for 
seriousness, severity, and causality as defined below. 
 
Serious refers to events that pose a threat to a subject’s life or vital functions and is based on 
subject or event outcome or action criteria. An AE that does not meet any criteria for serious, 
as defined in Section 9.1.2 should be regarded as “non-serious” AE.  
 
Severity refers to intensity of an AE as “mild,” “moderate,” or “severe”:  
• Mild: Symptom(s) that do not interfere with subject’s usual social and functional activities 
• Moderate:  Symptom(s)  that  interfere  to  some  extent  with  subject’s  usual  social  and 
functional activities 
• Severe: Symptom(s) that interfere significantly with subject’s usual social and functional 
activities 
Causality refers to a reasonable possibility that the AE is related to the study medication or 
study-related procedure. If AE is not related to study medication or study-related procedure, 
investigators will assess the most likely cause of AE. 
 
Unexpected refers  
to  whether  or  not  
the AE is  described  as  a  
risk  
in  
the  package  
insert  or 
investigator’s brochure for the study drug(s), the protocol or in the informed consent form. 
10 ADMINISTRATIVE STRUCTURE 
This  study  
is a  collaborative  effort  between AbbVie Inc. and  Southern  California  Permanente 
Medical  Group (SCPMG) with Sponsor-Investigator,  Lisa  Nyberg,  MD  as the  Principal 
Investigator. Multiple KPSC Medical Centers will be participating in the study with a lead site 
investigator delegated by the PI to supervise local activities. 
 
Data collected in this study will be managed in accordance to the signed contract.  
11 REGISTRATION GUIDELINE 
11.1 No randomization 
11.2 Forms and Records for Registration  
A screening number will be assigned for each subject that signs the study informed consent. 
Once  deemed  eligible,  
the  subject  will  be  assigned  a  unique  study  ID  
that  will  be  used  
to 
identify the subject for registration and enrollment.    


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12 BIOHAZARD CONTAINMENT 
Biohazard materials will be discarded according to standard guidelines. 
13 COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full compliance with the KPSC IRB, International Conference on 
Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), principles of the Declaration 
of Helsinki, and applicable United States Food and Drug Administration (FDA), state, and local 
laws, policies, and guidelines. 
13.1 Informed Consent  
The Informed Consent Form (ICF) will contain all the required elements for informed consent 
as indicated in 21 CFR Part 50.25, and will be approved by KPSC IRB prior to distribution to 
prospective subjects. Written informed consent will be obtained in accordance to 21 CFR Part 
50 and KPSC IRB applicable requirements. 
 
The study ICF and Privacy Rule Authorization Form, will be signed and dated by the subject 
or the subject
's legally authorized representative before participating in any study procedures. 
A copy of the signed Informed Consent Form and Privacy Rule Authorization Form, and a 
copy of the Experimental Subject
's Bill of Rights will be provided to the subject or the subject’s 
legally authorized representative. The investigator will 
document the informed consent process 
in the subject’s medical record.  
 
All  original signed ICFs will  be  maintained  at  
the  site  with  
the  subject’s  study  chart,  and 
available for study monitoring at any time. 
Non-English Speaking Subject 
In the case that a non-English speaking subject is eligible in the study, the informed consent 
process will involve the use of the KPSC IRB-approved Short Form as described in 21 CFR 
50.27(2). Every effort will be made to have subsequent informed consents translated in the 
subject’s language. 
13.2 Institutional Review Board (IRB) 
This study protocol, the Informed Consent Forms, any information intended for distribution to 
subjects,  and  any  relevant  supporting  
information  will  be  submitted  
to  KPSC  IRB  by  
the 
Principal Investigator and reviewed and approved by KPSC IRB prior to initiation of the study. 
 
The  Principal  
Investigator  
is  
responsible  
for  submitting  all  
reportable  events  as  defined  by 
KPSC IRB SOP 502 to KPSC IRB within the appropriate reporting periods. 


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Page 45 of 54 
 
13.3 Confidentiality 
KPSC maintains confidentiality standards by coding each subject in the study with a subject 
identification number. As a result, subjects’ name  and  medical  
record  number  are  
removed 
from data sets, and subject is identified by subject identification number.  
 
Results  of  
this  study  may  be  published  or  presented  at  scientific  conference  or  committee 
meetings as aggregated data. 
13.4 Conflict of Interest 
All  
investigators  
involved  
in  
this  study  
that  has  a  conflict  of  
interest  with  
this  study  must 
provide information about this conflict to KPSC IRB for review. 
 
 


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Page 46 of 54 
 
14  PROTOCOL SIGNATURE PAGE 
The study  will  be  conducted  in compliance  with  the  protocol,  International  Conference on 
Harmonization, Good Clinical Practice guidelines and applicable regulatory requirements. 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, and scientific 
information necessary to conduct this study
. I will personally conduct the study as described. 
 
I will  provide  copies  of  
the  protocol  
to all physicians,  nurses and  other  professional  personnel 
responsible to me who will participate in the study
.  
I understand that all information concerning 
the study supplied to me in connection with this study and not previously published is considered 
confidential information. 
 
I am aware that this protocol must be approved by the KPSC IRB. I understand that any changes 
to the protocol must be approved by 
the KPSC IRB. I attest that I have read, understood, and agree 
to abide by all conditions, instructions and restrictions contained in the above protocol. 
 
 
 
Lisa M. Nyberg, MD, MPH 
 
Kaiser Permanente San Diego 
Sponsor-Investigator Name (print name) 
 
Study Site 
 
 
Signature on file 
 
03/01/2016 
Sponsor-Investigator Signature 
 
Date 
 


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Real World Study: Genotype 1 Chronic HCV Treatment and Evaluation of Real World SVR and PROs 
 
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Page 47 of 54 
APPENDIX A: STUDY VISIT/ PROCEDURES TABLE 
 
Screening 
Treatment Period 
Post-Treatment (PT)  
-28 Days 
Baseline 
Day 1 
Week 2  
Week 4  
Week 8  
EOT1/ 
Week 12  
PT2 
Week 4  
PT 
Week 12/ 
ET3  
Visit Window 
 
 
± 5 days ± 5 days ± 5 days ± 5 days 
± 5 days 
± 5days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
Liver fibrosis assessment4  
X 
 
 
 
 
 
 
 
Vital Signs5, Weight and Height 
X 
X6  
 
 
 
 
 
 
Pregnancy test7 
X 
X 
 
X 
X 
X 
X 
X 
HBsAg, anti-HCV Ab 
X8 
 
 
 
 
 
 
 
Anti-HIV Ab 
X8 
 
 
 
 
 
 
 
HCV Genotype and Subtype9 
X 
 
 
 
 
 
 
 
HCV RNA Samples 
X8 
 
X 
 
 
X 
X 
X 
                                                 
1 EOT = End of Treatment. See 6.2.33 Week 12 (Visit 6) – End of Treatment (EOT) Procedures 
2 PT = Post Treatment, can be done in-clinic or remotely by phone with labs collected at the subject’s nearest laboratory facility 
3 ET = Early Termination. See 6.2.4.2 Post-Treatment (PT) Week 12 (Visit 8) – End of Study/ Early Termination (ET). 
4 
Liver fibrosis assessment: aspartate aminotransferase to platelet ratio index (APRI); Liver FibroScan; Liver Biopsy, and/or clinical finding consistent with cirrhosis 
5 Blood Pressure, Pulse and Temperature 
6 Optional assessment at the discretion of the investigator 
7 Pregnancy test is not required for female subject with documented bilateral tubal ligation, bilateral oophorectomy, or hysterectomy, or for postmenopausal subjects 
as confirmed by FSH test. Serum pregnancy test at screening; urine or serum pregnancy test at subsequent visits 
8 Laboratory results obtained within three (3) months of the Screening Visit may be used at the discretion of the investigator 
9 Historical HCV genotype and subtype within 6 months of the Screening Visit is permitted with medical record documentation at the discretion of the investigator 
 


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Page 48 of 54 
 
 
Screening 
Treatment Period 
Post-Treatment (PT)  
-28 Days 
Baseline 
Day 1 
Week 2  
Week 4  
Week 8  
EOT1/ 
Week 12  
PT2 
Week 4  
PT 
Week 12/ 
ET3  
Visit Window 
 
 
± 5 days ± 5 days ± 5 days ± 5 days 
± 5 days 
± 5days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
CBC with differential 
X8 
 
X10 
X 
X 
X 
X 
X 
Creatinine 
X8 
 
X 
X 
X 
X 
X 
X 
Liver panel11, AST, Direct Bilirubin 
X8 
 
X 
X 
X 
X 
X 
X 
Additional labs as determined by 
the investigator
12 
X8 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
Enrollment/treatment assignment 
 
X 
 
 
 
 
 
 
Study Drug Dispense 
 
X13 
X14 
X 
X 
 
 
 
Ribavirin Medication Guide15 
 
X 
 
 
 
 
 
 
Study Drug Accountability 
 
X 
X 
X 
X 
X 
 
 
                                                 
10 Only required for subjects receiving ribavirin (Genotype 1a) 
11 ALT, Alkaline Phosphatase, and Total Bilirubin 
12 Consider Coagulation Panel (PT, PTT); INR, Reticulocyte Count; Direct Bilirubin, Electrolytes 
13 Subject is dispensed a new two week supply of Viekira Pak and one bottle of RBV  
14 Subject is dispensed a new two week supply of Viekira Pak and re-dispensed their remaining RBV  
15 Applicable only to subjects receiving Ribavirin as part of their study treatment. 


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Page 49 of 54 
APPENDIX B: REFERENCES 
1. 
Weekly Epidemiological Record. No. 41, 7 October 2011, WHO. 
2. 
Freeman  AJ,  Dore  GJ,  Law  MG,  et  al.  Estimating  progression  to  cirrhosis  in  chronic 
hepatitis C virus infection. Hepatology. 2001;34(4 Pt 1):809-16. 
3. 
Sangiovanni A., Prati GM, Fasani P, et al. The natural history of compensated cirrhosis due 
to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology. 2006;43 (6):1303-
10. 
4. 
El-Serag  HB.  Hepatocellular  carcinoma:  recent  trends  in  the United  States. 
Gastroenterology. 2004;127(5 Suppl 1):S27-34. 
5. 
Serfaty L, Aumaitre H, Chazouilleres O, et al. Determinants of outcome of compensated 
hepatitis C virus-related cirrhosis. Hepatology. 1998;27(5):1435-40. 
6. 
Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis 
type  C:    a  retrospective  follow-up  study  of  384  patients. 
Gastroenterology.1997;112(2):463-72. 
7. 
Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the 
natural  history  of  compensated  cirrhosis:  a  cohort  study  of  297  patients.  Am  J 
Gastroenterol. 2002;97(11):2886-95. 
8. 
Wasley  A,  Alter  MJ.  Epidemiology  of  hepatitis  C:  geographic  differences  and  
temporal 
trends. Semin Liver Dis. 2000;20(1):1-16. 
9. 
Backus LI, Boothroyd DB, Phillips BR, et al. A sustained virologic response reduces risk 
of  all-cause  mortality  in  patients  with  hepatitis  C.  Clin  Gastroenterol  Hepatol. 
2011;9(6):509-516.e1. 
10. Veldt  BJ,  Heathcote  EJ,  Wedemeyer  H,  et  al.  Sustained  virologic  
response  and  clinical 
outcomes in  patients  with  chronic  hepatitis  C  and  advanced  fibrosis.  Ann  Intern  Med. 
2007;147(10):677-84. 
11. Everson  GT,  Balart  L,  Lee  SS,  et  al.  Histological  benefits  of  virological  response  to 
peginterferon  alfa-2a  monotherapy  
in  patients  with  hepatitis  C  and  advanced  
fibrosis  or 
compensated cirrhosis. Aliment Pharmacol Ther. 2008;27(7):542-51. 
12. Poynard  T,  McHutchison  J,  Manns  M,  et  al.  
Impact  of  pegylated  
interferon  alfa-2b  and 
ribavirin  on  liver  fibrosis  in  patients  with  chronic  hepatitis  C.  Gastroenterology. 
2002;122(5):1303-13. 
13. Shiffman  ML,  Hofmann  CM,  Thompson  EB,  et  al.  Relationship  between  biochemical, 
virologic  and  histologic  response  during  interferon  treatment  of  chronic  hepatitis  C. 
Hepatology. 1997;26:780-5. 
14. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha 
is  associated  with  improved  outcome  in  HCV-related  cirrhosis:  a  retrospective  study. 
Hepatology. 2007;45(3):579-87. 
15. Di  Bisceglie  AM,  Everson  GT,  Linsay  KL,  et  al.  Prolonged  antiviral  therapy  with 
peginterferon to prevent complications of advanced liver disease associated with hepatitis 


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Page 50 of 54 
 
C:  results of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. 
Hepatology. 2007;46:ALB1-ALB1. 
16. Camma C, Di Bona D, Schepis F, et al. Effect of peginterferon alfa-2a on liver histology in 
chronic hepatitis C: a meta-analysis of individual patient data. Hepatology. 2004;39:333-
42 
17. Shiffman ML, Morishima C, Dienstag JL, et al; HALT-C Trial Group. Effect of HCV RNA 
suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the 
HALT-C trial. Gastroenterology. 2009;137(6):1986-94. 
18. Kramer  J,  Kanwal  F,  Richardson  P,  Mei  M,  El-Serag  H.  Gaps  in  the  achievement  of 
effectiveness of HCV treatment in national VA practice. J Hepatol 2012;56:320-325. 
19. Khatri A, Dutta S, Marbury T, et al. The Pharmacokinetics and Safety of the Direct Acting 
Antiviral  Regimen  of  ABT-450/r,  Ombitasvir  with/without  Dasabuvir  in  Subjects  with 
Mild, Moderate and Severe Renal Impairment Compared to Subjects with Normal Renal 
Function. Hepatology 2014;60(4)238.  
 
 
 
 


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APPENDIX C: SITE LEAD INVESTIGATOR SIGNATURE PAGE 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization, Good Clinical Practice guidelines and applicable regulatory requirements. 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, and 
scientific information necessary to conduct this study
. I will personally conduct the study 
as described. 
 
I  will  provide  copies  of  the  protocol  to all  physicians,  nurses  and  other  professional 
personnel  responsible  to me  who  will  participate  in  the  study
.  I  understand  that  all 
information  concerning  
the  study supplied  
to  me  
in  connection  with  
this  study and  not 
previously published is considered confidential information. 
 
I am aware that this protocol must be approved by the KPSC IRB. I understand that any 
changes  to  the  protocol  must  be  approved  in writing  by the  Primary  Investigator  and 
approved by the KPSC IRB. I attest that I have read, understood, and agree to abide by all 
conditions, instructions and restrictions contained in the above protocol. 
 
 
 
 
Site Lead Investigator Name (print name) 
 
Study Site 
 
 
 
 
 
Site Lead Investigator Signature 
 
Date 
 
 






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