Real World Evidence of the Effectiveness of Paritaprevir/r - Ombitasvir, ± Dasabuvir, ± Ribavirin in Patients With Chronic Hepatitis C - An Observational Study in Hungary - VERITAS
Conditions: Chronic Hepatitis C
Sponsor: AbbVie

Paritaprevir/r + ombitasvir and dasabuvir
P15-709 Protocol (Affiliate study tracking no HU15-01)
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Title Page  
Title
Real World Evidence of the Effectiveness of Paritaprevir/r –
Ombitasvir, ± Dasabuvir, ± Ribavirin in Patients with Chronic 
Hepatitis C - An Observational Study in Hungary - VERITAS
Protocol Version 
Identifier
Protocol Version 1.0 (10 August 2015)
Date of Last Version of 
Protocol
n.a.
Research Question and 
Objectives
What is the effectiveness and, patient reported outcome of the 
interferon-free regimen of Paritaprevir/r + Ombitasvir, ± 
Dasabuvir, ± Ribavirin in patients with CHC in a real life setting 
across clinical practice patient populations? Further objective is
to collect information about co-morbidities and concomitant 
medication, work productivity and the contribution of the patient 
support program (PSP) of PTV/r+OBV±DSV±RBV treatment.
Country(-ies) of Study
Hungary
Main Author
MD.
Marketing Authorization
Holder(s)
AbbVie Pharmaceuticals Ltd.
This study will be conducted in compliance with this protocol and all applicable 
local regulatory requirements 
NCT02636608

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1.0 
Table of Contents 
1.0 
Table of Contents ..................................................................... 2 
2.0 
Abbreviations ........................................................................... 5 
3.0 
Responsible Parties .................................................................. 8 
4.0 
Abstract .................................................................................... 9 
5.0 
Amendments and Updates .................................................... 14 
6.0 
Milestones ............................................................................... 14 
7.0 
Rationale and Background ................................................... 14 
7.1 
Background .............................................................................................. 14 
7.2 
Rationale .................................................................................................. 19 
8.0 
Research Question and Objectives ...................................... 20 
8.1 
Research Question ................................................................................... 20 
8.2 
Objectives ................................................................................................ 21 
8.2.1 
Primary Objective .................................................................................... 21 
8.2.2 
Secondary Objectives ............................................................................... 21 
9.0 
Research Methods ................................................................. 21 
9.1 
Study Design ............................................................................................ 21 
9.2 
Setting ...................................................................................................... 22 
9.2.1 
Target Population ..................................................................................... 23 
9.2.2 
Study Duration ......................................................................................... 23 
9.2.3 
Termination Criteria ................................................................................. 23 
9.2.4 
Investigator Selection Criteria ................................................................. 24 
9.3 
Variables .................................................................................................. 24 
9.3.1 
Primary Variable ...................................................................................... 24 
9.3.2 
Secondary Variables ................................................................................ 24 
9.4 
Data Sources ............................................................................................ 25 
9.4.1 
Data to be Documented ............................................................................ 25 
9.4.1.1 
Inclusion Documentation ......................................................................... 26 
9.4.1.2 
During Treatment Documentation ........................................................... 27 
9.4.1.3 
Post-Treatment Documentation ............................................................... 28 
9.4.1.4 
HCV RNA Sample ................................................................................... 30 
9.4.1.5 
Concomitant Medication .......................................................................... 31 

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9.4.1.6 
Standardized Assessment Tools ............................................................... 31 
9.5 
Study Size ................................................................................................ 33 
9.6 
Data Management .................................................................................... 33 
9.6.1 
Electronic Case Report Forms ................................................................. 33 
9.6.2 
Assignment of Preferred Terms ............................................................... 34 
9.7 
Data Analysis ........................................................................................... 35 
9.7.1 
Analysis Population, Time Windows and Handling of Missing 
Data .......................................................................................................... 35 
9.7.2 
Demographics and Disease Characteristics ............................................. 36 
9.7.3 
Effectiveness Analysis ............................................................................. 37 
9.7.3.1 
Primary Effectiveness Endpoint .............................................................. 37 
9.7.3.2 
Secondary Effectiveness Endpoints ......................................................... 37 
9.7.3.3 
Statistical Methods for Analysis of Effectiveness Variables ................... 38 
9.7.4 
Clinical Laboratory Data .......................................................................... 39 
9.7.5 
Patient Questionnaires ............................................................................. 40 
9.7.6 
Tolerability Analysis ................................................................................ 41 
9.7.7 
Interim Assessments ................................................................................ 42 
9.8 
Quality Control ........................................................................................ 42 
9.9 
Limitations of the Research Methods ...................................................... 42 
10.0 
Protection of Human Subjects .............................................. 43 
11.0 
Management and Reporting of Adverse 
Events/Adverse Reactions ..................................................... 43 
11.1 
Adverse Event Definition and Serious Adverse Event Categories .......... 44 
11.2 
Severity .................................................................................................... 45 
11.3 
Relationship to Pharmaceutical Product .................................................. 45 
11.4 
Serious Adverse Event Collection Period ................................................ 46 
11.5 
Serious and non-serious Adverse Event Reporting.................................. 46 
11.6 
Pregnancy Reporting ................................................................................ 46 
12.0 
Plans for Disseminating and Communicating Study 
Results ..................................................................................... 47 
13.0 
References ............................................................................... 48 
Annex 1. 
EQ5D-5L ................................................................................. 52 
Annex 2. 
WPAI ...................................................................................... 54 

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2.0 
Abbreviations 
 
Paritaprevir/r 
Paritaprevir/ritonavir 
 
AE 
adverse event 
 
APRI 
AST to platelet ratio index 
 
AFP 
alfa fetoprotein 
 
ALT 
alanine-aminotransferase 
 
AST 
aspartate-aminotransferase 
 
PTV/r+OBV±DSV±RBV Paritaprevir/ritonavir + ombitasvir ± dasabuvir ± 
ribavirin 
 
ANCOVA 
analysis of covariance 
 
BMI 
body mass index 
 
CA 
competent authority 
 
CD4 
cluster of differentiation 4 
 
CHC 
chronic hepatitis C 
 
CI 
confidence interval 
 
CNI 
calcineurin 
 
CP 
core population 
 
CPFSU 
core population with sufficient follow-up data 
 
CT 
computer tomography 
 
DAA 
direct-acting antiviral agent 
 
DDI 
drug-drug interaction 
 
EC 
ethics committee 
 
EDC 
electronic data capture 
 
eCRF 
electronic case report form 
 
EMA 
European Medicines Agency 
 
EoT 
end of treatment 
 
EQ-5D-5L 
EuroQol 5 dimension 5 level 
 
FDA 
Food and Drug Administration 
 
FIB-4 
Fibrosis-4 Score/Index 

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γ-GT 
gamma-glutamyltransferase 
 
HCC 
hepatocellular carcinoma 
 
HCP 
health care provider 
 
Hb 
hemoglobin 
 
HbA1c 
hemoglobin A1c 
 
HBV 
hepatitis B virus 
 
HCV 
hepatitis C virus 
 
HDL 
high-density lipoprotein 
 
HIV 
human immunodeficiency virus 
 
HOMA 
homeostasis model assessment 
 
HVPG 
hepatic venous pressure gradient 
 
ICMJE 
International Committee of Medical Journal Editors
 
IEC/IRB 
independent ethics committee/- review board 
 
IgA 
Immunoglobulin A 
 
IgG 
Immunoglobulin G 
 
IgM 
Immunoglobulin M 
 
INN 
international non-proprietary name 
 
INR 
international normalized ratio 
 
LDL 
low-density lipoprotein 
 
LLoD 
lower limit of detection 
 
LLoQ 
lower limit of quantification 
 
MAH 
Marketing Authorization Holder 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MLR 
multiple logistic regression 
 
MRI 
magnetic resonance imaging 
 
NCP 
non-core population 
 
NS3/NS4A 
nonstructural protein 3/nonstructural protein 4A 
 
NS5A 
nonstructural protein 5A 
 
NS5B 
nonstructural protein 5B 

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OATP 
organic anion-transporting polypeptide 
 
OLT 
orthotopic liver transplant 
 
PAM-13 
Patient Activation Measure 13 
 
PCR 
polymerase chain reaction 
 
pegIFN 
pegylated interferon 
 
PRO 
patient reported outcome 
 
PSP 
patient support program 
 
PT 
preferred term 
 
RBV  
ribavirin 
 
RF 
rheumatoid factor 
 
RNA 
ribonucleic acid 
 
SAE 
serious adverse event 
 
SAP 
statistical analysis plan 
 
SD 
standard deviation 
 
SDP 
study designated physician 
 
SNP 
single nucleotide polymorphism 
 
SOC 
system organ class 
 
SP 
safety population 
 
SVR 
sustained virological response 
 
SVR12 
SVR at 12 weeks after EoT 
 
SVR24 
SVR at 24 weeks after EoT 
 
TAI 
total activity impairment 
 
TP 
target population 
 
TWP 
total work productivity impairment 
 
VAS 
visual analogue scale 
 
WHO 
World Health Organization 
 
WPAI 
work productivity and activity impairment 
 
WPAI-GH 
WPAI as general health measure 
 
WPAI-SHP 
WPAI modified for specific health condition 

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3.0 
Responsible Parties  
Study Designated Physician (SDP): 
x
 
 
Protocol Authors: 
x
Vendor: 
x 
IST GmbH, Soldnerstrasse 1, D-68219 Mannheim, Germany 
www.istgmbh.com 

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4.0 
Abstract  
Title: 
 
Real World Evidence of the Effectiveness of Paritaprevir/r + Ombitasvir, ± Dasabuvir, ± 
Ribavirin in Patients with Chronic Hepatitis C 
An Observational Study in Hungary 
  
Rationale and Background: 
The interferon-free combination regimen of Paritaprevir/r + ombitasvir with or without dasabuvir 
(PTV/r+OBV±DSV) ± ribavirin (RBV) for the treatment of chronic hepatitis C (CHC) has been 
shown to be safe and effective in randomized controlled clinical trials with strict inclusion and 
exclusion criteria under well controlled conditions.  
The PTV/r+OBV±DSV±RBV is expected to be first available in Hungary for the treatment of 
CHC in 2015.  
The rationale for this observational study is to determine how the efficacy and safety of the 
PTV/r+OBV±DSV±RBV as demonstrated in pivotal trials translates into real world everyday 
clinical settings, which means evaluating its effectiveness. Whereas efficacy can be defined as 
a measure of the capacity of a treatment to produce the desired effect in a controlled 
environment, such as in a randomized controlled trial, effectiveness is the extent to which a drug 
achieves its intended effect in the usual clinical setting. Effectiveness trials typically have limited 
exclusion criteria and will involve the broader patient populations in routine clinical practice and 
per local label which might include patients with heterogeneous compliance patterns and 
patients with significant comorbid conditions and could be used to model and disseminate best 
practices. Effectiveness research allows for external patient-, provider-, and system-level factors 
and can therefore be more relevant for health-care decisions by both providers in practice and 
policy-makers. 
This observational study is the first effectiveness research examining the 
PTV/r+OBV±DSV±RBV, used according to local label, under real world conditions in Hungary in 
a clinical practice patient population.  
During the last decade when dual therapy with pegylated interferon (pegIFN) plus RBV was 
standard of care for the treatment of CHC, the discovery of predictive factors for virological 
response and the subsequent development of treatment algorithms marked a milestone in 
patient care for CHC. As a consequence, treatment could be effectively targeted to patients 
most likely to respond. Interestingly, many of the now well established predictors of response to 
pegIFN/RBV and first generation direct acting antivirals (DAAs) in combination with pegIFN/RBV 
were not predictive of outcome in the development trials of the PTV/r+OBV±DSV±RBV. This 
observational study may play an important part in bridging the data gaps. It may help identify 
predictive factors of response that are important in real world treatment settings and thus, could 
assist in further optimizing treatment with the interferon-free PTV/r+OBV±DSV±RBV in the 
future. 
The label of the PTV/r+OBV±DSV±RBV will vary according to hepatitis C virus (HCV) 
genotype/subtype and stage of liver disease. It is therefore relevant to understand the pattern of 

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use and outcome in daily clinical practice. In addition, this study will provide data on the impact 
of adherence on treatment outcomes in everyday settings, which may help treating physicians 
to improve the management of patients under their care. 
The aim of this observational study is to provide evidence of the effectiveness, patient reported 
outcome and to collect information about co-morbidities and concomitant medication, work 
productivity and the contribution of the patient support program (PSP)  of the 
PTV/r+OBV±DSV±RBV in a real world setting across clinical practice patient populations. 
Research Question and Objectives: 
What is the effectiveness and patient reported outcome of the interferon-free regimen of 
Paritaprevir/r + Ombitasvir, ± Dasabuvir, ± Ribavirin in patients with CHC in a real life setting 
across clinical practice patient populations? Further objective is to collect information about co-
morbidities and concomitant medication, work productivity and the contribution of the patient 
support program (PSP) of PTV/r+OBV±DSV±RBV treatment. 
 
Primary Objective 
1. To describe in routine clinical practice the effectiveness of the interferon-free 
PTV/r+OBV±DSV±RBV in patients with CHC as evidenced by sustained virological 
response at 12  weeks after end of treatment (SVR12) 
Secondary Objectives 
2. To describe in routine clinical practice the effectiveness of the interferon-free 
PTV/r+OBV±DSV±RBV in patients with CHC as evidenced by sustained virological 
response at 24 weeks after end of treatment (SVR24) 
3. To provide real world evidence for predictive factors of virological response 
4. To describe the pattern of real world use of the PTV/r+OBV±DSV±RBV with respect 
to different patient and treatment characteristics  
5. To evaluate the influence of adherence on treatment outcome in routine clinical 
practice 
6. To collect information on co-morbidities and concomitant medication in the 
Hungarian population 
7. To describe the tolerability of the PTV/r+OBV±DSV±RBV 
8. To document the effect of the PTV/r+OBV±DSV±RBV on PROs and work 
productivity in the Hungarian population  
9. To evaluate the contribution of the patient support program (PSP) to disease 
control, treatment continuation over time, patient satisfaction and PSP utilization 
 
Study Design:  
This is a prospective, multi-center observational study in patients receiving the interferon-free 
PTV/r+OBV±DSV±RBV.  
The prescription of a treatment regimen is at the discretion of the physician in accordance with 
local clinical practice and label, is made independently from this observational study and 
precedes the decision to offer the patient the opportunity to participate in this study. 
Target Population: 
Patients are eligible for observation in this cohort if the following applies: 
x 
Treatment-naïve or -experienced adult male or female patients with confirmed CHC, 

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genotype 1 or 4, receiving combination therapy with the interferon-free 
PTV/r+OBV±DSV±RBV according to standard of care and in line with the current local 
label 
x 
If RBV is co-administered with the PTV/r+OBV±DSV±RBV, it has been prescribed in 
line with the current local label (with special attention to contraception requirements and 
contraindication during pregnancy)  
x 
Patients must voluntarily sign and date Subject Information Form and Inform Consent 
Form prior to inclusion into the study 
x 
Patient must not be participating or intending to participate in a concurrent interventional 
therapeutic trial  
Variables: 
Primary Variable 
x 
The percentage of patients achieving SVR12 (HCV RNA <50 IU/mL 12 weeks[i.e. ≥70 
days after the last actual dose of the PTV/r+OBV±DSV±RBV) 
Secondary Variables 
x 
The percentage of patients achieving SVR 24  (HCV RNA <50 IU/mL 24 weeks [i.e. 
≥141 days] after the last actual dose of the ABBVIE REGIMENPTV/r+OBV±DSV±RBV) 
x 
Type of treatment regimen (PTV/r+OBV±DSV±RBV, intended and actual combination, 
dose and duration) 
x 
Adherence 
o 
Percentage of the DAA dose taken in relation to the target dose of DAA 
(cumulative dose taken divided by target dose in percent) 
o 
Percentage of the RBV dose taken in relation to the target dose of RBV 
(cumulative dose taken divided by target dose in percent)  
o 
Percentage of missed RBV treatment days in relation to the target number of 
RBV treatment days 
x 
Co-morbidities and concomitant medication 
x 
Serious and non-serious adverse events and pregnancy occurrences  
x 
Questionnaires on PROs: e.g. EuroQol 5 dimension 5 level (EQ-5D-5L) questionnaire 
and work productivity and activity impairment (WPAI) questionnaire prior to treatment 
initiation, at EoT as well as 12 and 24 weeks after EoT 
x 
PAM-13, PSP satisfaction and utilization questionnaires  
 
Data Sources: 
Source documents are defined as original documents. The investigator will document patient 
data in his/her own patient files which will serve as source data for the study.  
Study Size:  
 In phase III studies investigating the interferon-free PTV/r+OBV±DSV±RBV, SVR12 rates of at 
least 90% were observed, even in difficult-to-treat CHC patients (e.g. cirrhotic G1a treatment 
experienced patients). To describe in routine clinical practice the effectiveness of 
PTV/r+OBV±DSV±RBV in patients with CHC, a precise estimate of the SVR12 rates in the core 
population of this study should be achieved (see Data Analysis for the definition of the core 
population). 
If the SVR12 rate is at least 90% then with 241 evaluable patients the width of the 95% 
confidence interval (CI) based on Clopper-Pearson method will not be wider than 8%. If the 

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SVR12 rate is at least 95%, then 140 patients are sufficient for a width of 8%, and the width of 
the 95%CI will be ≤ 6% if at least 238 evaluable patients can be included. Taken into 
consideration that about 5% of the patients enrolled, might be not evaluable in the core 
population 255 patients should be enrolled during the planned inclusion period of 12 months. 
 
Data Analysis: 
The core population (CP) is defined as all patients of the target population (TP) (definition see 
above), who have started the treatment combination recommended in the current local label for 
their disease characteristics. Patients not receiving the treatment recommended in the local 
label will be summarized in the non-core population (NCP). In addition, the core population with 
sufficient follow-up data (CPSFU) is defined as all CP patients, who have (i) evaluable HCV 
RNA data ≥70 days after the last actual dose of the PTV/r+OBV±DSV±RBV or (ii) a HCV RNA 
value ≥50 IU/mL at the last measurement or (iii) had HCV RNA <50 IU/mL at the last 
measurement, but no HCV RNA measurement  ≥ 70 days after the last actual dose of the 
PTV/r+OBV±DSV±RBV due to reasons related to safety (e.g. dropped out due to adverse 
event) or incomplete efficacy information (e.g. virological failure such as relapse is reported in 
the electronic case report form (eCRF) but date and value of the corresponding HCV RNA test 
is missing). The safety population (SP) is defined as all patients who received at least one dose 
of the PTV/r+OBV±DSV±RBV. 
Descriptive and exploratory statistical methods will be used to analyze the data of the study. All 
baseline and disease characteristics will be summarized for the CP stratified by the CP analysis 
groups (based on genotype 1 subtype, fibrosis status, treatment experienced or naïve), which 
are relevant for scheduled treatment combination (PTV/r+OBV±DSV±RBV) and duration (12 or 
24 weeks). In addition, baseline summaries will be repeated for the SP and TP without 
stratification into subgroups. Further details of analysis populations and the CP analysis groups 
will be specified in the statistical analysis plan (SAP).  
The primary effectiveness analysis will be performed for CP patients, stratified by the CP 
analysis groups. Response rates (i.e. SVR12 rate, end of treatment [EoT] response rate, 
relapse rate, viral breakthrough) will be determined for the various CP analysis groups. The 
relapse rates will be estimated in patients of the CP analysis groups with EoT response and 
sufficient HCV RNA measurements post treatment. Viral breakthrough rates will be estimated in 
all patients of the CP analysis groups, who have at least one undetectable HCV RNA 
measurement on treatment and at least one on-treatment or EoT measurement thereafter. For 
all rates specified above 95%-confidence intervals (CIs) will be determined using the Pearson-
Clopper method. 
Univariate and multiple logistic regression (MLR) methods will be used to investigate the impact 
of various explanatory covariates (e.g. demographic and disease characteristics, co-morbidities, 
type of treating institution, and prior treatment for CHC and response outcome in treatment 
experienced patients) on SVR12. These analyses will be of exploratory nature, data driven, and 
will be performed for various CP analysis groups since not each covariate might be predictive in 
each patient group. Furthermore, the fact that treatment regimens will differ in the various 
patient groups has to be taken into account, when selecting the patient groups for each MLR 
analysis. Backward selection procedures will be applied to generate the final MLR models which 
will consider only covariates in the selection procedure with a p-value <0.25 in the 
corresponding univariate logistic regression analysis. A p-value <0.05 will be used for the 

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covariates to stay in the model in a backward elimination step. Logistic regression methods will 
also be used to investigate the impact of treatment adherence on SVR12.  
All safety variables will be summarized for patients in the SP using descriptive statistical 
methods stratified by the type of combination treatment and scheduled treatment duration.  
Milestones:  
Start of Data Collection:  
November 2015 
End of Data Collection:  
November 2017 
Final Report of Study Results:        October 2018 

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5.0 
Amendments and Updates 
x 
None 
 
6.0 
Milestones 
x 
Start of Data Collection:  
 
November 2015 
x 
End of Data Collection:   
 
November 2017 
x 
Final Report of Study Results: 
October 2018 
 
7.0 
Rationale and Background 
7.1 
Background 
Infection with the hepatitis C virus (HCV) is associated with considerable morbidity and 
mortality [1] and is a leading cause of chronic liver disease, cirrhosis, and hepatocellular 
carcinoma (HCC), as well as the most common indication for liver transplantation in 
many countries [2]. Around 60-85% of subjects exposed to HCV do not clear the virus 
and go on to develop chronic disease [3] [4]. Chronic hepatitis C (CHC) affects an 
estimated 2-3% of the world’s population - equaling approximately 130-210 million 
individuals [5] [6]. The prevalence varies markedly from one geographic area to another 
ranging from 0.1-1% in Western Europe to 1-2% in Latin America and up to 4.9% in 
some regions of Eastern Europe [7] [8] [9] [10]. 
HCV demonstrates a high degree of genetic variability and has been classified into seven 
major genotypes (and a large number of subtypes) the distribution of which varies 
globally [11]. Genotypes 1 through 3 are found worldwide; the other genotypes have a 
more restricted distribution, genotype 4 is found predominantly in the Middle East, 
Central Africa, and Egypt; genotype 5 in South Africa; and genotype 6 mainly in Asia. 
HCV genotypes 1a and 1b are the most common forms, accounting for 60% of HCV 
infections worldwide [12] [13] [14] [15]. 
HCV is primarily transmitted by parenteral exposures to contaminated blood, most 
frequently by injection drug use, exposures in health-care settings and inadequate 
infection-control practices (tattoo, piercing). Occupational, perinatal and sexual exposure 
can also result in transmission of HCV [16] [17]. Since the early 1990’s routine blood 
screening protocols have been introduced in most countries and as a consequence 

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transmission of the virus is rarely seen following receipt of blood, blood products or 
through organ transplants. 
The natural course of CHC leads to progressive fibrosis and can eventually lead to 
cirrhosis of the liver over the course of 20-30 years in approximately 15-30% of infected 
individuals [18]. Once patients become cirrhotic, around 6% per year are expected to 
develop hepatic decompensation (ascites, encephalopathy, variceal hemorrhage, 
hepatorenal syndrome, or hepatic synthetic dysfunction) and around 3% per year will 
develop HCC [19]. Over the same time frame, between 4 and 5% of patients can be 
expected to require liver transplantation or die [19] [20]. Progression is not necessarily a 
linear process and can be accelerated by a number of factors including the age of the 
patient, duration of HCV infection, male gender, alcohol consumption and co-infection 
with other viruses such as hepatitis B virus (HBV) and human immunodeficiency virus 
(HIV) [4] but also by concomitant steatosis and obesity. Comorbid conditions can impact 
CHC treatment eligibility, safety, tolerability and efficacy of therapy [21] [22].  
The burden of advanced liver disease varies widely across countries and is dependent 
upon several factors including chronic HCV prevalence and age distribution (and duration 
of infection) of those infected [23]. Due to an aging cohort of patients and an associated 
increase in the incidence of severe liver disease, the burden of CHC will continue to 
increase. In persons 30–49 years of age, the prevalence of the disease is 3–fold higher 
than in other age groups. By 2020, the rates of HCC and liver-related deaths among 
individuals with CHC are expected to increase by 81% and 180%, respectively [24]. 
The eradication of the virus, defined as the absence of HCV ribonucleic acid (RNA) in 
serum (as shown by a sensitive test) at the end of treatment (EoT) and 24 weeks later 
(sustained virological response [SVR]), is the therapeutic goal of CHC treatment [25] [26] 
[27] and is generally accepted as a virological cure, thus, eventually preventing the 
aforementioned complications [26] [27]. 
Achieving an SVR was associated with significant reduction in all-cause death compared 
to patients who did not achieve SVR (5-year mortality rate in HCV genotype 1-infected 
patients: 6.7% vs 14.4%, respectively) [28]. In another study the 10-year cumulative all-
cause mortality rate was 8.9% in patients with SVR and 26.0% without SVR (p<0.001), 
the liver-related mortality or transplantation was 1.9% with SVR and 27.4% without SVR 
(p<0.001), the rate of HCC was 5.1% with and 21.8% without SVR (p<0.001), and the 
rate of patients experiencing liver failure was 2.1% with and 29.9% (p<0.001) without 
SVR [29]. Patients with SVR following treatment with pegylated interferon (pegIFN) with 
or without RBV have also shown improvement in liver histology and a reduction in liver-
related death in several studies [30] [31] [32]. Moreover, patients with compensated 

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cirrhosis who achieve SVR essentially eliminate their subsequent risk of 
decompensation, may achieve histologic regression, and decrease their risk of HCC by 
two-thirds [33] [34] [35].  
In the 1980’s and 1990’s interferon alfa was the first drug to show activity against HCV. 
However, the effectiveness of interferon monotherapy in the treatment of CHC infection 
was generally unsatisfactory resulting in an overall SVR rate across genotypes of <20% 
[36] [37]. Combination therapy with interferon plus ribavirin (RBV) improved SVR rates 
but still overall rates across genotypes remained below 50% [38] [39]. Following the 
introduction of long-acting interferons (peginterferon alfa-2a and peginterferon alfa-2b 
[i.e. pegIFNs]) in combination with RBV more than a decade ago, further advances have 
been made in efficacy with overall rates of SVR up to 54-63% [39] [40] [41]. SVR rates 
vary substantially by HCV genotype with genotype 1 being the most difficult-to-treat, thus 
requiring longer treatment periods to obtain SVR with interferon-based dual therapy. SVR 
rates up to around 50% can be achieved in patients with genotype 1 whereas for 
genotypes 2 and 3 cure rates of up to 80% can be achieved [41]. 
Treatment with pegIFN and RBV is associated with considerable, often treatment-limiting 
toxicities including cytopenias, neuro-psychiatric disorders and influenza-like symptoms. 
In 2011 the first direct-acting antivirals (DAAs), specifically the protease inhibitors 
boceprevir and telaprevir, have been approved by the US Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) for treatment of HCV genotype 1. 
These two protease inhibitor drugs are available and financed for a segment of 
Hungarian patients since May 2013. These first generation DAAs have significantly 
improved efficacy with rates of SVR reported as high as 63-75% among treatment-naïve 
HCV genotype 1 individuals [42] [43] [44]. However, these DAAs must be used in 
combination with pegIFN and RBV as triple combination therapy and the tolerability 
profile is further impaired by additional DAA specific adverse effects such as rash, 
pruritus, dysgeusia and anemia [42] [43] [44]. Treatment regimens with these DAAs are 
rather complicated with the necessity of futility rules and a response guided therapy 
duration of up to 48 weeks in selected patients.  
Since 2014, new direct acting antivirals have been registered for the IFN-free treatment 
of chronic hepatitis C in different combinations with a potential efficacy over 90% 
(sofosbuvir+simeprevir, sofosbuvir+daclatasvir, ledipasvir+sofosbuvir, 
PTV/r+OBV±DSV±RBV). These new interferon-free regimens offer a new standard of 
care for chronic HCV infected patients. 
AbbVie's interferon-free regimen for the treatment of CHC includes 3 DAAs targeting 
different steps in HCV replication. Paritaprevir is a NS3/4A protease inhibitor with 

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nanomolar potency in vitro and is co-administered with low-dose ritonavir, an inhibitor of 
the cytochrome P-450 enzyme CYP3A4. As a pharmacologic enhancer of Paritaprevir, 
ritonavir co-administration with Paritaprevir (Paritaprevir/r) results in higher drug 
exposures than administration of Paritaprevir alone [45]. Ombitasvir (ABT-267) is a 
nonstructural protein 5A (NS5A) inhibitor with picomolar potency in vitro, and dasabuvir 
(ABT-333) is a NS5B non-nucleoside polymerase inhibitor with nanomolar potency in 
vitro.  
The 3 DAA combination of Paritaprevir/r – ombitasvir plus dasabuvir with or without RBV 
has been initially evaluated in 6 Phase III studies with genotype 1 infected patients 
(SAPPHIRE-I [46], SAPPHIRE-II [47], PEARL-II [48], PEARL-III [49], PEARL-IV [49], 
TURQUOISE-II [50]).  
Therapy for 12 weeks with the above regimen in non-cirrhotic patients resulted in the 
following SVR rates 12 weeks after EoT (SVR12):  
Table 1 - SVR12 rates in clinical trials: 
Population 
and 
treatment 
duration 
Genotype SVR12 
PTV/r+OBV±DSV±RBV 
SVR12 
PTV/r+OBV±DSV alone 
Non-
cirrhotic, 
treatment-
naïve 
(12 weeks) 
1a 
95-97%  
(SAPPHIRE-I, PEARL-IV) 
90%  
(PEARL-IV) 
1b 
98-99.5% 
(SAPPHIRE-I, PEARL-III) 
99% 
(PEARL-III) 
Non-
cirrhotic, 
treatment-
experienced 
(12 weeks) 
1a 
96% 
(SAPPHIRE-II) 
n.a. 
1b 
97% 
(SAPPHIRE-II, PEARL-II) 
100% 
(PEARL-II) 
 
These results suggest that the PTV/r+OBV±DSV with RBV is the optimal regimen for 
genotype 1a infected patients, while non-cirrhotic patients with genotype 1b do not 
require RBV. 
The TURQUOISE-II [50] study explored the efficacy of the PTV/r+OBV±DSV±RBV in the 
traditionally most difficult-to-treat cirrhotic patients. This large study enrolled exclusively 

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genotype 1 infected patients with cirrhosis, including treatment-naïve and treatment-
experienced individuals. All patients received the PTV/r+OBV±DSV with RBV and were 
randomized to 12 or 24 weeks of therapy. Overall 92% and 96% of patients achieved 
SVR following treatment for 12 or 24 weeks, respectively. Analysis of subgroups 
demonstrated that the small difference in SVR between treatment arms was due largely 
to the subgroup of genotype 1a treatment-experienced prior null responders treated for 
12 weeks who achieved an SVR of 80%. This subgroup of patients achieved an SVR of 
93% when treated for 24 weeks. Among genotype 1a infected patients, partial 
responders and relapsers had higher SVR rates than null responders in the 12 week 
treatment group, while similar SVR rates were seen among the null responders, partial 
responders and relapsers treated for 24 weeks, suggesting that the longer duration of 24 
weeks is required only for cirrhotic genotype 1a null responders. SVR rates were very 
high across all subgroups in genotype 1b treatment-experienced patients treated for 12 
and 24 weeks.  
The PTV/r+OBV±DSV±RBV has been studied with and without RBV in over 2,300 
patients in Phase III trials across a variety of patient populations including those with 
compensated cirrhosis. Based on Phase III data, the PTV/r+OBV±DSV, with or without 
RBV, was well tolerated with a low discontinuation rate. Adverse events (AEs) were 
typically mild, and many of the AEs and laboratory abnormalities reported were 
attributable to the presence of RBV. However, these AEs were much milder than 
observed when RBV was given in combination with interferon. 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. A 
disproportionate number of the cases were in women on concurrent ethinyl estradiol-
containing therapy (i.e., contraceptives or hormone replacement) and discontinuation of 
the hormonal therapy with continuation or brief interruption of the PTV/r+OBV±DSV±RBV 
led to resolution in serum ALT elevation. Transient elevations in serum bilirubin 
(predominantly indirect) were observed in subjects receiving the PTV/r+OBV±DSV with 
RBV, related to the inhibition of the bilirubin transporters, organic anion-transporting 
polypeptides (OATPs) 1B1/1B3, by Paritaprevir and RBV-induced hemolysis. Bilirubin 
elevations occurred after initiation of treatment, peaked by study Week 1, and generally 
resolved with ongoing therapy. Bilirubin elevations were not associated with 
aminotransferase elevations. The frequency of indirect bilirubin elevations was lower 
among subjects who did not receive RBV.  
Response of CHC genotype 4 was assessed in the phase II study PEARL-I in which 86 
treatment-naïve patients were randomized to the 2 DAA combination of Paritaprevir/r – 

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ombitasvir with vs. without RBV for 12 weeks. The SVR was 100% with RBV vs. 91% 
without RBV [51]. No serious SAEs or AEs leading to discontinuation were reported. 
These results from pivotal studies are encouraging and the new interferon-free regimens 
might provide physicians with the armamentarium to cure the vast majority of patients 
infected with CHC. However, the medical community is expecting data which show how 
these results translate into routine clinical practice particularly after the experience with 
the first protease inhibitors which were available to physicians and where the outcome in 
everyday life and especially the tolerability was far less favorable in certain difficult-to-
treat patient subgroups than expected from the development trials [52] [53]. 
7.2 
Rationale 
The PTV/r+OBV±DSV±RBV for the treatment of CHC has been shown to be safe and 
effective in randomized controlled clinical trials with strict inclusion and exclusion criteria 
under well controlled conditions.  
The PTV/r+OBV±DSV±RBV is expected to be first available in Hungary for the treatment 
of CHC in 2015. 
The rationale for this observational study is to determine how the efficacy and safety of 
the PTV/r+OBV±DSV±RBV as demonstrated in pivotal trials translates into real world 
everyday clinical settings, evaluating its effectiveness. Whereas efficacy can be defined 
as a measure of the capacity of a treatment to produce the desired effect in a controlled 
environment, such as in a randomized controlled trial, effectiveness is ‘the extent to 
which a drug achieves its intended effect in the usual clinical setting’ [54]. Effectiveness 
trials typically have limited exclusion criteria and will involve the broader patient 
populations in routine clinical practice, treated per local label, which might include 
patients with heterogeneous compliance patterns and patients with significant comorbid 
conditions and could be used to model and disseminate best practices. Effectiveness 
research allows for external patient-, provider-, and system-level factors and can 
therefore be relevant for health-care decisions by both providers in practice and policy-
makers [55].  
This observational study is the first effectiveness research examining the 
PTV/r+OBV±DSV±RBV, used according to local label, under real world conditions in 
Hungary in clinical practice patient population.  
During the last decade when dual therapy with pegIFN plus RBV was standard of care for 
the treatment of CHC, management of patients and clinical outcome were improved 
following the discovery of predictive factors of virological response, often in observational 
studies with large data bases [56]. Thus treatment could be targeted to patients most 

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likely to respond and futile treatment stopped in patients with a low likelihood of 
virological cure. HCV genotype and subtype, baseline viral load, fibrosis stage, age, 
treatment exposure and on-treatment virological response proved to be useful predictors 
for the eradication of HCV in everyday clinical practice [27]. More recently the discovery 
of a genetic disposition of the Interleukin 28B (IL28B) single nucleotide polymorphism 
(SNP) contributed further to our understanding of virological responses to treatment [57]. 
For new interferon-free treatment regimens knowledge of predictive factors of virological 
response is extremely sparse and several of the now well established predictors of 
response were not initially identified through analyses of the development trials. This 
observational study may play an important part in bridging the data gaps and could help 
identify predictive factors of virological response in everyday clinical settings which were 
not detected in interventional trials and which could be used to further optimize treatment 
with the interferon-free PTV/r+OBV±DSV±RBV in the future. 
The label of the PTV/r+OBV±DSV±RBV will vary according to HCV genotype/subtype 
and stage of liver disease. It is therefore relevant to understand the pattern of use and 
outcome in daily clinical practice. In addition, this study will provide data on the impact of 
adherence on treatment outcomes in everyday settings, which may help treating 
physicians to improve the management of patients under their care.  
The aim of this observational study is to provide evidence of the effectiveness, patient 
reported outcome and to collect information about co-morbidities and concomitant 
medication, work productivity and the contribution of the patient support program (PSP) 
of the PTV/r+OBV±DSV±RBV in a real world setting across clinical practice patient 
populations. 
 
8.0 
Research Question and Objectives 
8.1 
Research Question 
What is the effectiveness and patient reported outcome of the interferon-free regimen of 
Paritaprevir/r + Ombitasvir, ± Dasabuvir, ± Ribavirin in patients with CHC in a real life 
setting across clinical practice patient populations? Further objective is to collect 
information about co-morbidities and concomitant medication, work productivity and the 
contribution of the patient support program (PSP) of PTV/r+OBV±DSV±RBV treatment. 

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8.2 
Objectives 
8.2.1 
Primary Objective 
1. To describe in routine clinical practice the effectiveness of the interferon-free 
PTV/r+OBV±DSV±RBV in patients with CHC as evidenced by SVR12 
8.2.2 
Secondary Objectives 
2. To describe in routine clinical practice the effectiveness of the interferon-free 
PTV/r+OBV±DSV±RBV in patients with CHC as evidenced by sustained virological 
response at 24  weeks (≥141 days) after end of treatment (SVR24) 
3. To provide real world evidence for predictive factors of virological response 
4. To describe the pattern of real world use of the PTV/r+OBV±DSV±RBV with 
respect to different patient and treatment characteristics  
5. To evaluate the influence of adherence on treatment outcome in routine clinical 
practice  
6. To collect information on co-morbidities and concomitant medication in the 
Hungarian population 
7. To describe the tolerability of the PTV/r+OBV±DSV±RBV  
8. To document the effect of the PTV/r+OBV±DSV±RBV on PROs and work 
productivity in the [country] population 
9. To evaluate the contribution of the patient support program (PSP) to disease 
control, treatment continuation over time, patient satisfaction and PSP utilization  
 
 
9.0 
Research Methods 
9.1 
Study Design  
This is a prospective, multi-center observational study in patients receiving the interferon-
free PTV/r+OBV±DSV with or without RBV. The prescription of a treatment regimen is at 
the discretion of the physician in accordance with local clinical practice and label, is made 
independently from this observational study and precedes the decision to offer the patient 
the opportunity to participate in this study.  
Adult patients chronically infected with HCV, receiving the interferon-free 
PTV/r+OBV±DSV±RBV will be offered the opportunity to participate in this study during a 
routine clinical visit at the participating sites. 
After written Subject Information Form and Informed Consent Form has been obtained, 
patient data including demographic data, HCV disease characteristics, co-morbidities, co-
medication, treatment details, and laboratory assessments as recorded in the patient's 

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medical records (source documentation) will be documented in the electronic case report 
form (eCRF). Patients will be observed for the duration of the PTV/r+OBV±DSV±RBV 
therapy and for up to 24 weeks after treatment completion. No patient identifiable 
information will be captured, a unique patient number will be automatically allocated by 
the web based eCRF system once the investigator or designee creates a new patient file. 
This study is focusing on collecting real-world data. Follow-up visits, treatment, 
procedures and diagnostic methods will follow physicians’ routine clinical practice. The 
observational study period entails the following data collection schemes, data 
documented will be those closest to the time windows as indicated in Figure 1: 
x 
12-week treatment regimen: four visits plus two interim data collection windows 
x 
24-week treatment regimen: four visits plus three interim data collection windows 
This schedule is based on the anticipated regular follow-up for patients undergoing 
treatment for CHC. 
Figure 1 - Study Flowchart  
 
 
9.2 
Setting 
For overall research design and observational documentation schedule refer to Sections 
9.1 and 9.4.1 as well as to Figure 1. 

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9.2.1 
Target Population 
Patients are eligible for observation in this cohort if the following applies: 
x 
Treatment-naïve or -experienced adult male or female patients with confirmed 
CHC, genotype 1 and 4, receiving combination therapy with the interferon-free 
PTV/r+OBV±DSV±RBV according to standard of care and in line with the current 
local label  
x 
If RBV is co-administered with the PTV/r+OBV±DSV±RBV, it has been prescribed 
in line with the current local label (with special attention to contraception 
requirements and contraindication during pregnancy) 
x 
Patients must voluntarily sign and date Subject Information Form and Informed 
Consent Form prior to inclusion into the study 
x 
Patient must not be participating or intending to participate in a concurrent 
interventional therapeutic trial 
x 
Patient has been started on PTV/r+OBV±DSV±RBV therapy no more than one (1) 
month prior to the study enrolment 
 
9.2.2 
Study Duration 
This is a prospective, observational study. The inclusion period will be approximately 12 
months and the observational period of the study will be from baseline visit until 24 
weeks post-treatment. 
The observational period for patients receiving 12 weeks of PTV/r+OBV±DSV±RBV will 
be max. 36 weeks (12 weeks treatment and 24 weeks post-treatment observation) and 
for patients receiving 24 weeks of PTV/r+OBV±DSV±RBV the observational period will 
be max. 48 weeks (24 weeks treatment and 24 weeks post-treatment observation). 
 
9.2.3 
Termination Criteria 
For patients who terminate the PTV/r+OBV±DSV±RBV prematurely for whatever reason 
the EoT eCRF page should be filled in and the reason for treatment discontinuation 
should be documented. If the reason for PTV/r+OBV±DSV±RBV discontinuation is due to 
an SAE, the event must be reported to AbbVie within 24 hours of physician awareness 
(see Section 11.5). 

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If, in such patients, there is evidence of virological response during therapy or at EoT, the 
SVR12 (Post-Treatment Week 12 data) and SVR 24 (Post-treatment week 24 data) 
pages should be completed if respective data is available.  
 
9.2.4 
Investigator Selection Criteria 
University centers and outpatient clinics qualified by training and experience in the 
management of patients with CHC will be selected to participate in this study. The 
AbbVie Affiliate Medical Director will ensure that sites participating in the study are 
representative of the medical practice in the country, have the ability to conduct the study 
and their availability of the target patient population. The type of the participating treating 
institute will be documented in the eCRF. 
 
9.3 
Variables  
9.3.1 
Primary Variable 
x 
The percentage of patients achieving SVR12 (HCV RNA <50 IU/mL 12 weeks 
[i.e. ≥70 days]after the last actual dose of the PTV/r+OBV±DSV±RBV)  
 
9.3.2 
Secondary Variables 
x 
The percentage of patients achieving SVR 24  (HCV RNA <50 IU/mL 24 
weeks [i.e. ≥141 days] after the last actual dose of the ABBVIE 
REGIMENPTV/r+OBV±DSV±RBV) 
x 
Type of treatment regimen (PTV/r+OBV±DSV±RBV, intended and actual 
combination, dose and duration) 
x 
Adherence 
o Percentage of the DAA dose taken in relation to the target dose of DAA 
(cumulative dose taken divided by target dose in percent)  
o Percentage of the RBV dose taken in relation to the target dose of RBV 
(cumulative dose taken divided by target dose in percent) 
o Percentage of missed RBV treatment days in relation to the target number 
of RBV treatment days 
x 
Co-morbidities and concomitant medication 
x 
Serious and non-serious adverse events and pregnancy occurrences 
x 
Questionnaires on PROs: e.g. EuroQol 5 dimension 5 level (EQ-5D-5L) 
questionnaire and work productivity and activity impairment (WPAI) questionnaire 
prior to treatment initiation, at EoT as well as 12 and 24 weeks after EoT  

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x 
PAM-13, PSP satisfaction and utilization questionnaires 
 
9.4 
Data Sources  
Source documents are defined as original documents. The investigator will document 
patient data in his/her own patient files which will serve as source data for the study. Data 
are collected from the source documents for each patient in the study, consisting of 
medical records containing demographic data, medical, treatment and diagnostic 
documentation and laboratory assessments.  
The investigator(s)/institution(s) will permit study-related monitoring, audits, independent 
ethics committee/- review board (IEC/IRB) review, and regulatory inspection(s), providing 
direct access to source data documents. 
 
9.4.1 
Data to be Documented 
This observational study covers three documentation periods, see Figure 1. An overview 
on data to be collected throughout the study is summarized in  

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o Year of diagnosis and mode of infection 
o Stage of liver fibrosis 
x 
CHC treatment history 
o Naïve or experienced 
o If experienced, most recent prior therapy and outcome 
x 
Relevant medical history, co-morbidities and co-infections 
x 
Concomitant medication, see 9.4.1.5 
x 
PTV/r+OBV±DSV±RBV  
x 
Laboratory data 
Key clinical chemistry 
Remarks 
 
ALT 
(alanine-aminotransferase) 
including upper limit of normal (ULN), 
 
AST 
(aspartate-aminotransferase) 
including ULN,  
AST to platelet ratio index (APRI) and Fibrosis-4 Score/Index 
(FIB-4)* will be calculated  
 
γ-GT 
(gamma-glutamyltransferase) 
 
Total bilirubin 
 
Albumin 
 
Creatinine 
 
AFP 
creatinine clearance# will be calculated 
Key hematology 
 
Hb (Hemoglobin) 
 
Platelets 
 
Prothrombin time 
or international normalized ratio (INR) 
Virology 
 
HCV genotype and subtype 
 
HCV RNA 
quantitative/ qualitative HCV RNA by polymerase chain 
reaction (PCR) test, see 9.4.1.4 
HIV-infected patients only 
 
CD 4 count 
(cluster of differentiation 4) 
most recent assessment 
 
HIV RNA 
in copies/mL 
*derived from patient’s age, ALT, AST and platelets 
#by Cockcroft-Gault-Formula based on creatinine, gender, age and weight 
 
x 
Patient questionnaires, see 9.4.1.6 
x 
PAM-13 
 
9.4.1.2 
During Treatment Documentation 
Follow-up visits are scheduled by the physician per routine clinical practice. Likewise 
treatment, procedures and diagnostic methods will follow physicians’ routine clinical 
practice. 

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The following will be documented:  
x 
Laboratory data 
Key clinical chemistry 
Remarks 
 
ALT 
including ULN 
 
AST 
including ULN,  
APRI and FIB-4 will be calculated  
 
γ-GT 
 
Total bilirubin 
 
Creatinine 
creatinine clearance will be calculated  
Key hematology 
 
Hb 
 
Platelets  
Virology 
 
HCV RNA 
quantitative/ qualitative HCV RNA PCR test, see 9.4.1.4 
HIV-infected patients only 
 
CD 4 count 
most recent assessment 
 
HIV RNA 
in copies/mL 
 
x 
Concomitant medication, see 9.4.1.5 
x 
Adherence to PTV/r+OBV±DSV±RBV (% of target dose taken and RBV Y/N)  
x 
Tolerability (sAEs and AEs, see 11.5) and pregnancies (see 11.6) 
x 
Patient questionnaires see Table 2 and  9.4.1.6 
x 
PSP satisfaction and utilization questionnaires, PAM-13: only at EoT/premature 
discontinuation 
 
9.4.1.3 
Post-Treatment Documentation 
Follow-up visits are scheduled by the physician per routine clinical practice. Likewise 
treatment, procedures and diagnostic methods will follow physicians’ routine clinical 
practice. 

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The following will be documented:  
x 
Laboratory data 
Key clinical chemistry 
Remarks 
 
ALT 
including ULN 
 
AST 
including ULN,  
APRI and FIB-4, will be calculated  
 
γ-GT 
 
Total bilirubin 
 
Albumin 
 
Creatinine 
creatinine clearance will be calculated  
Key hematology 
 
Hb 
 
Platelets 
 
Prothrombin time 
or INR 
Virology 
 
HCV RNA 
quantitative/ qualitative HCV RNA PCR test, see 9.4.1.4 
HIV-infected patients only 
 
CD 4 count 
most recent assessment 
 
HIV RNA 
in copies/mL 
 
x 
Tolerability (sAEs, see 11.4) and pregnancies (see 11.6) 
x 
Patient questionnaires see Table 2 and  9.4.1.6 
x 
PSP Satisfaction and utilization questionnaires 
 
 
 
Table 2 - Data Documentation Schedule 

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o Test name and result in IU/mL  
o Lower limit of detection (LLoD) in IU/mL and lower limit of quantification 
(LLoQ) in IU/mL 
 
x 
Qualitative HCV RNA by PCR test  
o Test name and result (positive/negative) 
o LLoD in IU/mL 
 
9.4.1.5 
Concomitant Medication  
Concomitant medication - the following will be documented: 
x 
Concomitant medication used from the time when the decision is made to initiate 
treatment with the PTV/r+OBV±DSV±RBV until after the last dose  
It should be verified by the treating physician that concomitant medication can be safely 
administered with the PTV+OBV±DSV (including ritonavir) and RBV. Some medications 
may be contra-indicated, some may require dose adjustments due to potential for drug-
drug interactions (DDIs). The investigator or qualified designee should review the 
concomitant medication(s) labels and screen concomitant medications at each visit for 
potential DDIs.  
 
9.4.1.6 
Standardized Assessment Tools  
This study will assess quality of life and work productivity using PRO instruments: EQ-
5D-5L and WPAI Hep C. Validated translations of these patient questionnaires will be 
administered. 
Assessment of general quality of life - EQ-5D-5L  
The EQ-5D-5L is a health state utility instrument that evaluates preference for health 
status (utility). The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 5 
levels of severity. Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies. Patients also rate their 
perception of their overall health on a separate visual analogue scale (VAS).  
The EQ-5D-5L should require approximately 5 minutes to complete and is presented in 
Annex 1. 
 

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Assessment of work productivity and activity impairment – WPAI Hep C V2.0  
The WPAI questionnaire will be used to measure work absenteeism, work presenteeism, 
and daily activity impairment. The WPAI questionnaire was created as a patient-reported 
quantitative assessment of both reduced productivity at work and non-work activities. 
WPAI has been validated as a general health measure (WPAI-GH) and can be easily 
modified for specific health condition, disease or problem (WPAI-SHP). WPAI Hep C 
V2.0 is the HCV specific questionnaire that will be used in this study). Respondents are 
asked about time missed from work and time while at work during which productivity was 
impaired in the past seven days. Results of WPAI are expressed as a percentage of 
impairment from 0 to 100, with higher percentages indicating greater impairment and less 
productivity:  
x 
% Presenteeism – percentage of impairment while working due to health problem 
x 
% Absenteeism – percentage of work time missed due to health problem 
x 
% Total work productivity impairment (TWP) – percentage of overall work 
impairment due to health problem 
x 
% Total activity impairment (TAI) – percentage of general (non-work) activity 
impairment due to health problem 
The WPAI Hep C should require approximately 5 minutes to complete and is presented 
in Annex 2. 
PRO data are not considered a potential source of adverse reactions. However, 
participating sites should review the PRO data and if a possible product-related event 
(including a suspected adverse reaction) is noted, the health care provider (HCP) must 
determine whether the event is related to  PTV/r+OBV±DSV (or any other AbbVie 
authorized product) and if so, it should be reported to AbbVie. The relevant AbbVie 
Pharmacovigilance contact details are specified in Section 11.0. 
Patient Activation Measure – (PAM-13) 
PAM 13 is a measure used to assess the patient knowledge, skill, and confidence for 
self-management. It should require approximately 7 minutes to complete and is 
presented in Annex 3. 
Patient Support Program (PSP) Questionnaire 
The PSP utilization and satisfaction assessment will evaluate the frequency of utilization 
and patient’s overall satisfaction with their respective Patient Support Program. 
The PSP questionnaire should require approximately 2-5 minutes to complete and is 
presented in Annex 4-5. 

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9.5 
Study Size  
In phase III studies investigating the interferon-free ABBVIE REGIMEN ± RBV, SVR12 
rates of at least 90% were observed, even in difficult-to-treat CHC patients (e.g. cirrhotic 
G1a treatment experienced patients). To describe in routine clinical practice the 
effectiveness of the ABBVIE REGIMEN ± RBV in patients with CHC, a precise estimate 
of the SVR12 rates in the core population of this study should be achieved (see Section 
Error! Reference source not found. for the definition of the core population). 
As obvious from Table 3, if the SVR12 rate is at least 90%, then with 241 evaluable 
patients the width of the 95% confidence interval (CI) will not be wider than 8%. If the 
SVR12 rate is at least 95%, then 140 patients are sufficient for a width of 8%, and the 
width of the 95%CI will be ≤ 6% if at least 238 evaluable patients can be included. Taken 
into consideration that about 5% of the patients enrolled might be not evaluable in the 
core population 255 patients should be enrolled during the planned inclusion period of 12 
months.  
Table 3 
Width of 95% Confidence Interval for SVR12 
Number of 
patients 
SVR12 rates 
95% Confidence Interval* 
Lower Limit 
Upper Limit 
Width  
241 
90% 
85.50 
93.48 
7.98% 
140 
95% 
89.97 
97.97 
8.00% 
238 
95% 
91.41 
97.40 
5.99% 
* exact two-sided 95% confidence interval according Clopper-Pearson  
 
9.6 
Data Management 
9.6.1 
Electronic Case Report Forms 
Data for this study will be recorded in English by each participating center via an 
electronic data capture (EDC) system using a web-based eCRF. Examinations, 
diagnostic measures, laboratory assessments, findings and observations routinely 
performed in patients with CHC included in this cohort, will be transcribed by the 
investigator or designee from the source documents into the eCRF. Only data specified 
in the protocol will be entered into the eCRF. For each enrolled patient, the investigator 
or designee will create a new patient file in the eCRF and a unique patient number will be 
automatically allocated by the system. 

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A comprehensive data validation program utilizing front-end checks in the eCRF will 
validate the data. Automated checks for data consistency will be implemented, 
discrepancies need to be solved by the researcher in the eCRF before the module can 
be completed.  
Follow-up on eCRF data for medical plausibility will be done by AbbVie personnel (or 
their representatives). Queries will be generated in the eCRF for online resolution at the 
site. The investigator or an authorized member of the investigator's staff will make any 
necessary data corrections to the eCRF. All change information, including the date and 
person performing the corrections, will be available via the audit trail, which is part of the 
EDC system. The principal investigator of each site will finally review the eCRFs for 
completeness and accuracy of available data and provide his or her electronic signature 
and date to the eCRFs as evidence thereof. 
Access to the EDC system will be provided for the duration of the study through a 
password-protected method of internet access. Such access will be removed from 
investigator sites at the end of the site's participation in the study. Data from the EDC 
system will be archived on appropriate data media (e.g. CD-ROM) and provided to the 
investigator as a durable record of the site's eCRF data.  
Original Questionnaires will be sent from the participating site to: 
Name:  
Krisztina Török / CRA 
Address: AbbVie Pharmaceuticals Ltd. 
 
 
 
Lechner Ödön fasor 7., 1095 Budapest, Hungary 
Tel.: 
 
+ 36 1 455 8600 
Fax: 
 
+ 36 1 544 8699 
 
9.6.2 
Assignment of Preferred Terms 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
will be tabulated by primary MedDRA system organ class (SOC) and preferred term (PT). 
For treatments, surgical and medical procedures the international non-proprietary name 
(INN) Drug Terms and Procedures Dictionary will be used. 

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9.7 
Data Analysis 
9.7.1 
Analysis Population, Time Windows and Handling of 
Missing Data  
 
The target population (TP) is defined as all patients who fulfill the criteria specified in 
Section 9.2.1. The core population (CP) is defined as all patients of the TP, who have 
started the treatment combination recommended in the current local label for their 
disease characteristics. Patients not receiving the treatment recommended in the local 
label will be summarized in the non-core population (NCP). In addition, the core 
population with sufficient follow-up data (CPSFU) is defined as all CP patients, who fulfil 
one of the following criteria:  
(1) evaluable HCV RNA data ≥70 days after the last actual dose of the 
PTV/r+OBV±DSV±RBV (i.e. data within the SVR12 time window) 
 
(2) a HCV RNA value ≥50 IU/mL at the last measurement post-baseline (i.e. no 
virological response achieved at the last measurement on-treatment or post-
treatment) 
(3) HCV RNA <50 IU/mL at the last measurement post-baseline, but no HCV RNA 
measurement ≥70 days after the last actual dose of the PTV/r+OBV±DSV±RBV 
due to reasons related to safety (e.g. dropped out due to AE) or incomplete 
efficacy information (e.g. virological failure such as relapse is reported in the 
eCRF but date and value of the corresponding HCV RNA test is missing). This 
means only patients who had virological response at their last on-treatment or 
post-treatment measurement, but had no HCV RNA measurements ≥70 days 
post-treatment for reasons not related to safety or effectiveness (e.g. lost-to-
follow-up or patient not willing to perform an additional HCV RNA test ≥70 days 
post-treatment will be excluded from this analysis. 
The Safety Population (SP) is defined as all patients who received at least one dose of 
the PTV/r+OBV±DSV±RBV.  
In accordance with the non-interventional nature of the study all HCV RNA 
measurements will be performed at the sole discretion of the physician and all HCV RNA 
measurements have to be entered into the eCRF. All recorded HCV RNA values will be 
assigned to appropriate time points (baseline, on-treatment visits, EoT visit, post-

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treatment visits). The time windows for the assignments will be specified in the statistical 
analysis plan (SAP).  
No data will be imputed for any effectiveness or safety analyses except for the analyses 
of the HCV RNA endpoints. When there is no HCV RNA value in a visit time window 
post-baseline, but prior to EoT, the closest values before and after the window, 
regardless of the value chosen for the subsequent and preceding window, will be used 
for the flanking imputation described below. If a patient has a missing HCV RNA value at 
a post-baseline visit prior to EoT but has undetectable HCV RNA (with LLoD ≤50 IU/mL) 
or unquantifiable, but detectable HCV RNA levels (with LLoQ ≤50 IU/mL) at both the 
preceding and succeeding measurements, the HCV RNA level will be considered 
undetectable or unquantifiable, respectively, at this visit for this patient. In addition, if a 
patient has an unquantifiable HCV RNA level at the preceding measurement and an 
undetectable HCV RNA level at the succeeding measurement, or vice versa, the HCV 
RNA level will be imputed as unquantifiable at this visit for this patient. For virological 
response at EoT a corresponding backward imputation approach will be applied. This 
means if HCV RNA is missing at EoT, then unquantifiable or undetectable will be 
assumed for EoT, if the succeeding HCV RNA value is undetectable or unquantifiable. 
For SVR12 the single last available HCV RNA measurement ≥70 days post-treatment will 
be used. For SVR24 the single last available HCV RNA measurement at 24 weeks (≥141 
days) post-treatment will be used.  Subsequent to this flanking and backward imputation, 
if the HCV RNA value remains missing at a specific time point, then the patients will 
considered as virological failure at this time point (i.e. not undetectable or unquantifiable). 
 
9.7.2 
Demographics and Disease Characteristics  
All baseline and disease characteristics will be summarized for the CP stratified by the 
CP analysis groups (i.e. based on genotype 1 subtype, fibrosis status, treatment 
experienced or naïve), which are relevant for scheduled treatment combination 
(PTV/r+OBV±DSV±RBV ) and duration (12 and 24 weeks). In addition, baseline 
summaries will be repeated for the SP and the TP without stratification into subgroups. 
Summary statistics (n, mean, median, standard deviation [SD], and range) will be 
generated for continuous variables (e.g. age and body mass index [BMI]). The number 
and percentage of patients will be presented for categorical variables (e.g. gender and 
race). Further details of analysis populations and the CP analysis groups will be specified 
in the SAP, taking into account the PTV/r+OBV±DSV±RBV recommended in the current 
local label for various patient groups. 
 

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9.7.3 
Effectiveness Analysis 
The primary effectiveness analysis on clinical outcomes will be performed on all patients 
in the CP stratified by the CP analysis groups. Due to the non-interventional nature of this 
study several different methods for determination of the HCV RNA value can be applied. 
For the purpose of the statistical analysis, a HCV RNA measurement is considered ≤50 
IU/mL, 
• 
if a PCR test was used 
• 
and the test result is undetectable and the LLoD of the test is ≤50 IU/mL or the 
test result is unquantifiable and the LLoQ is ≤50 IU/mL 
 
9.7.3.1 
Primary Effectiveness Endpoint 
The percentage of patients achieving SVR12 (single last HCV RNA <50 IU/mL 12 
weeks[i.e. at least 70 days] after the last actual dose of the PTV/r+OBV±DSV±RBV) is 
the primary effectiveness endpoint. 
 
9.7.3.2 
Secondary Effectiveness Endpoints 
The secondary effectiveness endpoints are: 
x 
The percentage of patients achieving SVR24 (single last HCV RNA <50 IU/mL 
24 weeks [i.e. at least 141 days] after the last actual dose of 
PTV/r+OBV±DSV±RBV)  
x 
The percentage of patients with virological response (HCV RNA <50 IU/mL) at 
EoT 
x 
The percentage of patients with relapse (defined as HCV RNA <50 IU/mL at 
EoT followed by HCV RNA ≥50 IU/mL) 
x 
The percentage of patients with breakthrough (defined as at least one 
documented HCV RNA <50 IU/mL followed by HCV RNA ≥50 IU/mL during 
treatment).  
x 
The number and percentage of patients meeting each and any of the following 
SVR12 non-response categories: 
o On-treatment virological failure (breakthrough [defined as above ] or 
failure to suppress [each measured on-treatment HCV RNA value ≥50 
IU/mL]) 

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o Relapse (defined as HCV RNA <50 IU/mL at EoT or at the last on-
treatment HCV RNA measurement followed by HCV RNA ≥50 IU/mL 
post-treatment) 
o Premature study drug discontinuation with no on-treatment virological 
failure 
o Missing SVR12 data and/or none of the above criteria 
 
9.7.3.3 
Statistical Methods for Analysis of Effectiveness Variables 
The simple percentage of patients achieving SVR12 will be calculated and an exact two-
sided 95% confidence interval (CI) of the percentage will be computed based on the 
Pearson Clopper method.  
Corresponding methods will be used for other response rates (EoT response rate, 
relapse rate, viral breakthrough). The relapse rates will be estimated in patients of the CP 
analysis groups with EoT response and sufficient HCV RNA measurements post-
treatment. Viral breakthrough rates will be estimated in all patients of the CP analysis 
groups, who have at least one undetectable HCV RNA measurement on-treatment and at 
least one on-treatment or EoT measurement thereafter.  
Univariate and multiple logistic regression (MLR) methods will be used to investigate the 
impact of the following explanatory covariates on SVR12 and SVR 24: 
x 
Key demographic information  
x 
Mode of CHC infection 
x 
HCV RNA level at baseline 
x 
Most recent stage of liver fibrosis 
x 
HCV genotype and subtype (if available)  
x 
Type of treating institute 
x 
Liver and/or CHC related co-morbidities 
x 
Key clinical chemistry and hematology laboratory variables at baseline  
x 
In treatment experienced patients only:  
o Most recent prior treatment for CHC 
o Outcome of most recent prior CHC treatment 
 
Further details and additional covariates will be specified in the SAP. 
These analyses will be of exploratory nature, data driven, and will be repeatedly 
performed for various CP Analysis Groups, since not each covariate might be predictive 
in each patient group. Furthermore, the fact that treatment regimens will differ in the 

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various patient groups has to be taken into account, when selecting the patient groups for 
each MLR analysis. Backward selection procedures will be applied to generate the final 
MLR models which consider only covariates in the selection procedure with a p-value 
<0.25 in the corresponding univariate logistic regression analysis. A p-value <0.05 will be 
used for the covariates to stay in the model in a backward elimination step. Logistic 
regression methods will also be used to investigate the impact of treatment adherence on 
SVR12 and SVR 24.  
9.7.4 
Clinical Laboratory Data 
All reported clinical laboratory test results will be assigned to one of the time points using 
the time windows specified in the table below. 
Table 4 - Analysis Time Windows 
Phase 
Time point 
Time Window 
Pre-Treatment 
Baseline 
Last value prior to start of study treatment 
(i.e. dstudy day 1) 
 
 
Study day during treatment period 
(Study day 1 = first treatment day) 
Treatment Weeks 
4 (day 29) 
15 - 42 
 
8 (day 57) 
43 - 70 
 
12 (day 85) 
71 - 98 
 
16 (day 113) 
99 - 126 
EoT  
Actual EoT 
Study day of last dose 
(28 days prior to EoT - 14 days post EoT) 
Post Treatment  
4 weeks 
(day 29 post EoT) 
15 – 56 post EoT 
 
12 weeks  
(day 85 post EoT) 
57 – 112 post EoT 
 
24 weeks 
(day 169 post EoT) 
141 – 196 post EoT 
Mean changes from baseline to each post-baseline visit will be summarized descriptively. 
Laboratory data values collected during the treatment period will be categorized as low, 
normal, or high based on reference ranges used in this study. The number and percent of 
patients who experience post-baseline shifts during treatment in clinical laboratory values 
from low/normal to high and high/normal to low based on the reference range will be 
summarized. 

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Additional details of the analyses of clinical laboratory data will be specified in the SAP. 
 
9.7.5 
Patient Questionnaires 
The EQ-5D-5L is a health state utility instrument that evaluates preference for health 
status (utility). The EQ-5D-5L comprises 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression) each of which are rated on 5 levels of 
severity (1: indicating no problem, 2: indicating slight problems, 3: indicating moderate 
problems, 4: indicating severe problems, 5: indicating extreme problems), and a separate 
VAS. 
Patients’ responses to the EQ-5D-5L will be combined into a unique health state using a 
5-digit code with one digit from each of the 5 dimensions representing the level of 
severity. These EQ-5D-5L states will be converted into a single preference-weighted 
health utility index score by applying country-specific weights (if available) or US weights 
(if not available). 
No imputation will be performed for missing items, and in case of missing items no index 
score will be calculated.  
A summary table will show descriptive statistics (n, mean, median, SD, minimum and 
maximum) of the index score values and for the VAS values for baseline and the post-
baseline time points, as well as changes from baseline both for the index score values 
and for the VAS values. In addition analysis of covariance (ANCOVA) will be applied to 
investigate the effect of the different PTV/r+OBV±DSV (± RBV and duration) on EQ-5D-
5L endpoints using the corresponding EQ-5D-5L baseline values as covariates. Further 
details will be specified in the SAP.  
Assessments of work productivity and activity impairment as assessed by the WPAI Hep 
C v2.0 will be evaluated according to the WPAI-SHP scoring manual. The WPAI yields 
four types of scores, the results of which will be presented as percentage of impairment 
from 0 to 100. Higher percentages indicate greater impairment: 
1. % absenteeism: percentage of work time missed due to hepatitis C 
2. % presenteeism: percentage of impairment while working due to hepatitis C 
3. % TWP: percentage of overall work impairment due to hepatitis C 
4. % TAI: percentage of general (non-work) activity impairment due to hepatitis C 
The WPAI Hep C v2.0 consists of 6 questions aimed at the following targets: 
Q1. currently employed (yes, no) 
Q2. hours missed due to hepatitis C in the last seven days 

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Q3. hours missed due to other reasons in the last seven days 
Q4. hours actually worked in the last seven days 
Q5. degree hepatitis C affected productivity while working 
Q6. degree hepatitis C affected regular activities 
The four scores will be derived as follows: 
1. % absenteeism: 
100*Q2/(Q2+Q4) 
2. % presenteeism: 100*Q5/10 
3. % TWP: 
100*{Q2/(Q2+Q4) + [Q4/(Q2+Q4)]* Q5/10} 
4. % TAI: 
100*Q6/10 
A score will be set to missing if one or more of the items Q1-Q6 that are needed for the 
calculation of the score are missing. No imputation will be performed for missing items. 
The summary table will present the absolute and relative frequencies of employed and 
unemployed patients and descriptive statistics for the four scores. Further details of the 
analysis will be specified in the SAP.  
 
9.7.6 
Tolerability Analysis 
All tolerability variables will be summarized using descriptive statistical methods for the 
SP stratified by type of combination treatment and scheduled treatment duration.  
All SAEs, non-serious AEs and pregnancy occurrences are to be reported for patients 
included in the study (see Section 11.0). AEs will be coded using MedDRA. The number 
and percentage of patients with treatment-emergent AEs (i.e. any reported event that 
begins or worsens in severity after initiation of study drug through 30 days post-study 
drug dosing) will be tabulated by primary MedDRA SOC and PT. Corresponding 
summary tables will be provided for all serious treatment-emergent AEs. The tabulation 
of the number of patients with treatment-emergent AEs by severity and relationship to 
study drug will also be provided. Patients reporting more than one AE for a given 
MedDRA PT will be counted only once for that term using the most severe incident for 
the severity summary table and the most related for the relationship summary table. 
Patients reporting more than one type of event within a SOC will be counted only once 
for that SOC. 
Additional details of the analysis of AEs will be specified in the SAP.  
 

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9.7.7 
Interim Assessments  
An interim analysis is planned when the first 100 patient with 12 weeks treatment 
duration have completed the treatment. The focus of the interim analysis will be a 
description of the patient characteristics, the study status, adherence to treatment and 
safety, while the analysis of efficacy endpoints is not planned. Further details will be 
specified in the SAP. 
 
9.8 
Quality Control 
The sites will be instructed in the protocol, the functionality and handling of the eCRF, 
and the requirement to maintain source documents for each patient in the study (see 
Section 9.4).  
A comprehensive data validation program utilizing front-end checks in the eCRF will 
validate the data. Automated checks for data consistency will be implemented, 
discrepancies need to be solved by the researcher in the eCRF before the module can 
be completed. Follow-up on eCRF data for medical plausibility will be done by AbbVie 
personnel (or their representatives). The principal investigator of each site will finally 
review the eCRFs for completeness and accuracy of available data and provide his or 
her electronic signature and date to eCRFs as evidence thereof.  
Continuous monitoring of the study and frequent site telephone contacts will be done by 
AbbVie or a CRO working on behalf of AbbVie. 
 
9.9 
Limitations of the Research Methods 
The limitations of observational studies, such as uncontrolled confounding by lack of 
randomization, and difficulties to clearly interpret treatment effects in the context of 
missing data are well known. Their validity can be increased by accurate outcome 
measurements, documentation of the most common confounders, sufficient length of 
follow-up and by activities to obtain complete recording of available data as well as by 
searches for missing key data.  
The most important outcome measure in this study is HCV RNA. Missing or unrecorded 
follow-up HCV RNA data can in particular lead to an underestimation of the real SVR rate 
as compared to the SVR rate of interventional trials. Highly sensitive and quantitative 
diagnostic tests are required to measure HCV RNA levels in blood. In an observational 
study each center will be using its own test – either commercially available or so-called 

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“home-brew” tests – which might change from one visit to the next within a patient data 
set. The challenge is to accurately and consistently document test properties such as the 
LLoD and the LLoQ to put the results into perspective of prior outcomes from randomized 
controlled trials with (usually) central laboratory assessments for all trial participants. 
10.0 
Protection of Human Subjects 
This observational study will be run in compliance with local laws and regulations. 
Notification/submission to the responsible regulatory authorities, Ethics Committee (EC) 
and/or Competent Authorities (CAs) will be done as required by local laws and 
regulations. 
The investigator is responsible to ensure that written Subject Information Form and
Informed Consent Form will be obtained prior to patient inclusion  
To maintain patient confidentiality, no demographic data that can identify the patient will 
be collected (e.g. initials, date of birth) - only the patient age will be collected. In order to 
protect patient identity, a unique number will be assigned to each patient and related 
study recording. 
11.0 
Management and Reporting of Adverse 
Events/Adverse Reactions 
PRO data are not considered a potential source of adverse reactions. However, 
participating sites should review the PRO data and if a possible product-related event 
(including a suspected adverse reaction) is noted, the HCP must determine whether the 
event is related to the PTV/r+OBV±DSV±RBV (or any other AbbVie authorized product) 
and if so, it should be reported to AbbVie.  
Medication errors (this refers to any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in control of the HCP, patient or consumer) ,
AEs, SAEs should be reported by the HCP to AbbVie. 
The relevant AbbVie Pharmacovigilance contact details are specified below: 
Name:  
Address: AbbVie Pharmaceutical Ltd. 

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Tel.: 
 
Fax: 
 
11.1 
Adverse Event Definition and Serious Adverse Event 
Categories 
An adverse event (AE) is defined as any untoward medical occurrence in a patient, which 
does not necessarily have a causal relationship with their treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not the event is considered causally related to the use of the product. 
Such an event can result from use of the drug as stipulated in the labeling, as well as 
from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening 
of a pre-existing condition or illness is considered an AE. 
If an AE meets any of the following criteria, it is considered a serious adverse event 
(SAE): 
Death of Patient:
An event that results in the death of a patient.
Life-Threatening:
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical 
intervention had not been taken. This does not 
include an event that would have been fatal if it had 
occurred in a more severe form.
Hospitalization:
An event that results in an admission to the hospital 
for any length of time. This does not include an 
emergency room visit or admission to an outpatient 
facility.
Prolongation of 
Hospitalization:
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay.
Congenital Anomaly:
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss.
Persistent or Significant 
Disability/Incapacity:
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
patient. Disability is not intended to include 
experiences of relatively minor medical significance 

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such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained 
ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome: 
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e. death of patient, life threatening, 
hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
11.2 
Severity 
The following definitions will be used to rate the severity for any AE being collected as an 
endpoint/data point in the study and for all SAEs. 
Mild: 
The AE is transient and easily tolerated by the patient. 
Moderate: 
The AE causes the patient discomfort and interrupts the patient's 
usual activities. 
Severe: 
The AE causes considerable interference with the patient's usual 
activities and may be incapacitating or life threatening. 
 
11.3 
Relationship to Pharmaceutical Product 
The following definitions will be used to assess the relationship of the AE to the use of 
product: 

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Reasonable Possibility 
An AE where there is evidence to suggest a causal 
relationship between the product and the AE. 
No Reasonable 
Possibility 
An AE where there is no evidence to suggest a causal 
relationship between the product and the AE. 
If no reasonable possibility of being related to product is given, an alternate etiology must 
be provided for the AE. 
 
11.4 
Serious Adverse Event Collection Period 
SAEs will be reported to AbbVie from the time the physician obtains the Subject 
Information Form and Informed Consent Form until 30 days or 5 half-lives following the 
intake of the last dose of physician-prescribed treatment. 
 
11.5 
Serious and non-serious Adverse Event Reporting 
In the event of an SAE, the physician will: 
● For events from patients using the PTV/r+OBV±DSV±RBV (or any other 
AbbVie authorized product) report to AbbVie within 24 hours of the physician 
becoming aware of the event by using the eCRF system or notifying the 
AbbVie contact person identified in Section 11.0.  
● For events from patients using a non-AbbVie product - notify the Marketing 
Authorization Holder (MAH) of the product within 24 hours of the physician 
becoming aware of the event. 
In the event of a non-serious AE, the physician will:  
● For events from patients using the PTV/r+OBV±DSV±RBV report to AbbVie 
by using the eCRF system.  
 
11.6 
Pregnancy Reporting 
Patients and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the HCV treatment and for 30 days after the end of 
treatment with DAAs only, or for 7 months after the last dose of RBV (or per local RBV 
label) and/or consistent with local treatment guidelines for RBV. 

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In the event of a pregnancy occurrence in the patient, the physician will report to AbbVie 
within 24 hours of the physician becoming aware of the pregnancy by using the eCRF 
system or notifying the AbbVie contact person identified in Section 11.0.  
The investigator is encouraged to report the pregnancy information to the voluntary RBV 
Pregnancy Registry, if RBV is included within the regimen. 
 
12.0 
Plans for Disseminating and Communicating Study 
Results 
At the end of this observational study, a report will be written by AbbVie or a CRO 
working on behalf of AbbVie. The required standard study report template will be 
followed. This report will contain a description of the objectives of the study, the 
methodology and its results and conclusions. The completed eCRFs, patient 
questionnaires, the final study output and study report are the confidential property of 
AbbVie and may not be released to unauthorized people in any form (publications or 
presentations) without express written approval from AbbVie. The study results will be 
submitted to local authorities by the participating countries per local laws and regulations. 
The results of this study will be made publicly available on one of the primary registries in 
the World Health Organization (WHO) Registry Network which meet the requirements of 
the ICMJE (International Committee of Medical Journal Editors) and through scientific 
publications. Authorship will be in line with ICMJE’ authorship requirements [58].  
 
 
 

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13.0 
References 
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peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or 
compensated cirrhosis. Aliment Pharmacol Ther 2008; 27: 542-51. 
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and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 
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Shiffman M, 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. 

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[33] 
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: 579-87. 
[34] 
Di Bisceglie AM, Shiffman M, Everson GT, et al. Prolonged antiviral therapy with 
peginterferon to prevent complications of advanced liver disease associated with 
hepatitis C: results of the hepatitis C antiviral long-term treatment against cirrhosis 
(HALT-C) trial. Hepatology 2007; 46 (Suppl S1): 290A. 
[35] 
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. 
[36] 
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in 
combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis 
Interventional Therapy Group. NEJM 1998; 339: 1485-92. 
[37] 
Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon α-2a in patients with chronic 
hepatitis C. NEJM 2000; 343: 1666-72. 
[38] 
Poynard T, McHutchison JG, Goodman Z, Ling MH, Albrecht J. Is an “à la carte” 
combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment 
in patients with chronic hepatitis C? Hepatology 2000; 31: 211-8. 
[39] 
Fried MW, Shiffman M, Reddy KR, et al (for the PEGASYS® International Study 
Group). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. 
NEJM 2002; 347: 975-82. 
[40] 
Manns M, McHutchison JG, Gordon SC et al. PegInterferon alfa-2b plus ribavirin 
compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis 
C: a randomized trial. Lancet 2001; 358: 958-65. 
[41] 
Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha 2a and ribavirin 
combination therapy in chronic hepatitis C: a randomized study of treatment duration 
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[42] 
Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with 
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phase 3 ADVANCE study. Hepatology 2010; 52 (Suppl S1): 427A. 
[43] 
Sherman KE, Flamm SL, Afdhal NH et al. Telaprevir in combination with peginterferon 
alfa2b and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients 
who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE 
study. Hepatology 2010; 52 (Suppl S1): 401A. 
[44] 
Poordad F, McCone J, Bacon BR et al. Boceprevir (BOC) combined with peginterferon 
alfa-2b/ribavirin (P/R) for treatment-naive patients with hepatitis C (HCV) genotype 1: 
SPRINT-2 final results. Hepatology 2010; 52 (Suppl S1): 402A. 
[45] 
Menon RM, Klein CE, Lawal AA, et al. Pharmacokinetics and tolerability of the HCV 
protease inhibitor ABT-450 following single ascending doses in healthy adult 
volunteers with and without ritonavir. Abstract of HepDART 2009, Kohala Coast, 
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[46] 
Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r ombitasvir 
and dasabuvir with ribavirin. NEJM 2014; 370: 1594-603. 

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[47] 
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-
ombitasvir and dasabuvir with ribavirin. NEJM 2014; 370: 1604-14. 
[48] 
Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and 
dasabuvir achieves 97% and 100% sustained virologic response with or without 
ribavirin in treatment-experienced patients with HCV genotype 1b infection. 
Gastroenterology 2014; doi: 10.1053/j.gastro.2014.04.045 (Epub ahead of print). 
[49] 
Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or 
without ribavirin for HCV. NEJM 2014; 370: 1983-92.  
[50] 
Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin 
for hepatitis C with cirrhosis. NEJM 2014; 370: 1973-82. 
[51] 
Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PEARL-I study: 
interferon-free regimens of ABT-450/R + ABT-267 with or without ribavirin in patients 
with HCV genotype 4 infection. J Hepatol 2014; 60 (Suppl 1): S24. 
[52] 
Hezode C, Fontaine H, Dorival C et al. Effectiveness of telaprevir or boceprevir in 
treatment-experienced patients with HCV genotype 1 infection and cirrhosis. 
Gastroenterology 2014; 147: 132-42. 
[53] 
Colombo M, Fernández I, Abdurakhmanov D, et al. Safety and on-treatment efficacy of 
telaprevir: the early access programme for patients with advanced hepatitis C. Gut 
2014; 63: 1150-8. 
[54] 
Marley J. Efficacy, effectiveness, efficiency. Aust Prescr 2000; 23: 114-5. 
[55] 
Singal AG, Higgins PDR, Waljee AK. A primer on effectiveness and efficacy trials. Clin 
Trans Gastroenterol 2014; 5 (e45): 1-4. 
[56] 
Marcellin P, Cheinquer H, Curescu M, et al. High sustained virologic response rates in 
rapid virologic response patients in the large real-world PROPHESYS cohort confirm 
results from randomized clinical trials. Hepatology 2012; 56: 2039-50. 
[57] 
Thompson AJ, Muir AJ, Sulkowski MS, et al. IL28B polymorphism improves viral 
kinetics and is the strongest pre-treatment predictor of SVR in HCV-1 patients. 
Gastroenterology 2010; 139: 120-9. 
[58] 
International Committee of Medical Journal Editors. Available at 
http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-
role-of-authors-and-contributors.html; accessed July 07, 2014. 

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Annex 1. 
EQ5D-5L  
 
 
 
 

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Annex 2. 
WPAI 
Work Productivity and Activity Impairment Questionnaire Hepatitis C, V2.0 
(WPAI: Hepatitis C) 
 
 
 
 
 
 

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WPAI: HepC V2.0 (English - United Kingdom) 
 
 

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Annex 3. 
PAM-13 Questionnaire Sample  
 

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Annex 4. 
Patient Support Program (PSP) Utilization 
Questionnaire 
 
 
 

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Annex 5. 
Patient Support Program (PSP) Utilization and 
Satisfaction Questionnaire 
 
 
 

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Annex 6. 
Child-Pugh Classification of Severity of Cirrhosis 
  
Parameter 
Points Assigned for Observed Findings 
1 
2 
3 
Total bilirubin, μmol/L 
(mg/dL) 
<34.2  
(<2) 
34.2 – 51.3  
(2 – 3) 
>51.3 
(>3) 
Serum albumin, g/L (g/dL) 
>35 
(>3.5) 
28 – 35  
(2.8 – 3.5) 
<28 
(<2.8) 
INR 
<1.7 
1.7 – 2.3 
>2.3 
Ascites* 
None 
Slight 
Moderate to severe 
Hepatic encephalopathy** 
None 
Grade 1 or 2  
(or suppressed with 
medication) 
Grade 3 or 4 
(or refractory) 
* 
None. 
 
Slight ascites = Ascites detectable only by ultrasound examination. 
 
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen. 
 
Severe ascites = Large or gross ascites with marked abdominal distension. 
 
** 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram. 
 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves. 
 
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves. 
 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity