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

NCT02618928

 
Paritaprevir/r – ombitasvir and dasabuvir 
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study tracking no 10711) 
 
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1.0 
Table of Contents 
 
2.0 
Abbreviations ............................................................................ 5 
3.0 
Responsible Parties ................................................................... 8 
4.0 
Abstract ..................................................................................... 9 
5.0 
Amendments and Updates ..................................................... 13 
6.0 
Milestones ............................................................................... 14 
7.0 
Rationale and Background ..................................................... 14 
7.1 
Background .............................................................................................. 14 
7.2 
Rationale .................................................................................................. 20 
8.0 
Research Question and Objectives ........................................ 21 
8.1 
Research Question ................................................................................... 21 
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 ...................................................................................................... 23 
9.2.1 
Target Population ..................................................................................... 23 
9.2.2 
Study Duration ......................................................................................... 23 
9.2.3 
Termination Criteria ................................................................................. 24 
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 ............................................................................................ 24 
9.4.1 
Data to be Documented ........................................................................... 25 
9.4.1.1 
Inclusion documentation ......................................................................... 25 
9.4.1.2 
During Treatment Documentation .......................................................... 26 
9.4.1.3 
Post-Treatment Documentation .............................................................. 27 
9.4.1.4 
HCV RNA Sample ...................................................................................... 29 
9.4.1.5 
Concomitant Medication ......................................................................... 29 
9.4.1.6 
Standardized Assessment Tools ............................................................... 29 
9.5 
Study Size ................................................................................................. 31 
9.6 
Data Management ................................................................................... 32 

 
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9.6.1 
Electronic Case Report Forms .................................................................. 32 
9.6.2 
Assignment of Preferred Terms ............................................................... 33 
9.7 
Data Analysis ............................................................................................ 33 
9.7.1 
Analysis Population, Time Windows and Handling of Missing Data ....... 33 
9.7.2 
Demographics and Disease Characteristics ............................................. 34 
9.7.3 
Effectiveness Analysis .............................................................................. 35 
9.7.3.1 
Primary Effectiveness Endpoint ............................................................... 35 
9.7.3.2 
Secondary Effectiveness Endpoints ......................................................... 35 
9.7.3.3 
Statistical Methods for Analysis of Effectiveness Variables .................... 35 
9.7.4 
Clinical Laboratory Data ........................................................................... 37 
9.7.5 
Patient Questionnaires ............................................................................ 37 
9.7.6 
Resource Utilization ................................................................................. 39 
9.7.7 
Tolerability Analysis ................................................................................. 40 
9.7.8 
Co-morbidities and Concomitant Medication ......................................... 40 
9.7.9 
Interim Assessments ................................................................................ 40 
9.8 
Quality Control ......................................................................................... 41 
9.9 
Limitations of the Research Methods ...................................................... 41 
10.0 
Protection of Human Subjects ................................................ 41 
11.0 
Management and Reporting of Complaints .......................... 42 
11.1 
Medical Complaints ................................................................................. 42 
11.1.1 
Adverse Event Definition and Serious Adverse Event Categories .......... 42 
11.1.2 
Severity .................................................................................................... 44 
11.1.3 
Relationship to Pharmaceutical Product .................................................. 44 
11.1.4 
Serious Adverse Event Collection Period ................................................ 44 
11.1.5 
Serious and non-serious Adverse Event Reporting .................................. 44 
11.1.6 
Pregnancy Reporting ................................................................................ 45 
11.2 
Product Complaints .................................................................................. 45 
11.2.1 
Definition ................................................................................................. 45 
11.2.2 
Reporting .................................................................................................. 45 
12.0 
Plans for Disseminating and Communicating Study 
Results ..................................................................................... 46 
13.0 
References ............................................................................... 47 
Annex 1. 
EQ5D-5L ................................................................................... 52 
Annex 2. 
WPAI ........................................................................................ 54 
Annex 3. 
PAM-13 Questionnaire Sample .............................................. 56 
Annex 4. 
Beliefs Medication Questionnaire ......................................... 57 

 
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Annex 5. 
Fatigue Impact Scale ............................................................... 59 
Annex 6. 
Child-Pugh Classification of Severity of Cirrhosis .................. 61 
14.0 
Protocol Signature Page ......................................................... 62 
 
 

 
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2.0 
Abbreviations 
 
AE 
adverse event
 
APRI 
AST to platelet ratio index
 
AFP 
alfa fetoprotein
 
ALT 
alanine-aminotransferase
 
AST 
aspartate-aminotransferase
 
ABBVIE REGIMEN 
Paritaprevir/r – ombitasvir ± dasabuvir
 
ANCOVA 
analysis of covariance
 
BMI 
body mass index
 
BMQ 
beliefs medication questionnaire
 
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
 
FIS 
Fatigue Impact Scale
 
γ-GT 
gamma-glutamyltransferase

 
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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
 
OATP 
organic anion-transporting polypeptide
 
OLT 
orthotopic liver transplant

 
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PAM-13 
Patient Activation Measure 13
 
PCR 
polymerase chain reaction
 
pegIFN 
pegylated interferon
 
PRO 
Patient reported outcome
 
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
 
SPC 
Summary of Product Characteristics
 
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): 
 
Protocol Authors: 
Vendor (for Statistics) : 
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 France - OPALE 
Rationale and Background: 
The interferon-free combination regimen of Paritaprevir/r – ombitasvir with or without dasabuvir 
(ABBVIE REGIMEN) ± 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 ABBVIE REGIMEN is expected to be first available in France for the treatment of CHC in 2015.  
The rationale for this observational study is to determine how the efficacy and safety of the ABBVIE 
REGIMEN 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 
heterogenous 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 ABBVIE REGIMEN ± RBV, used 
according to local label, under real world conditions in France in clinical practice patient populations.  
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 ABBVIE REGIMEN ± 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 
ABBVIE REGIMEN ± RBV in the future. 
The label of the ABBVIE REGIMEN ± 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 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 of the ABBVIE REGIMEN ± 
RBV in a real world setting across clinical practice patient populations. 
Research Question and Objectives: 
What is the effectiveness of the interferon-free ABBVIE REGIMEN ± RBV in patients with CHC in a real 
life setting across clinical practice patient populations? 
 
 
 

 
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Primary Objective 
1. To describe in routine clinical practice the effectiveness of the interferon-free ABBVIE 
REGIMEN ± RBV in patients with CHC as evidenced by sustained virological response at 12 
weeks after end of treatment (SVR12)  
Secondary Objectives 
2. To describe the pattern of real world use of the ABBVIE REGIMEN ± RBV with respect to 
different patient and treatment characteristics  
3. To describe the tolerability of the ABBVIE REGIMEN ± RBV 
4. To document the effect of the ABBVIE REGIMEN ± RBV on PROs and work productivity in 
the French population  
5. To determine the impact of the ABBVIE REGIMEN ± RBV on healthcare resource utilization  
 
Study Design:  
This is a prospective, multi-center observational study in patients receiving the interferon-free ABBVIE 
REGIMEN ± 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: 
Inclusion criteria 
x 
A patient must be at least 18 years of age to be considered eligible to participate. 
x 
Treatment-naïve or -experienced adult male or female patients with confirmed CHC, genotype 
1 or 4, receiving combination therapy with the interferon-free ABBVIE REGIMEN ± RBV 
according to standard of care and in line with local label.  
x 
If RBV is co-administered with the ABBVIE REGIMEN, it has been prescribed in line with the 
current local label (with special attention to contraception requirements and contraindication 
during pregnancy) 
Patients must voluntarily sign and date a patient informed consent prior to inclusion into the study. 
Exclusion criteria 
x 
Patient must not be participating or intending to participate in a concurrent interventional 
therapeutic trial 
Variables: 
Primary Variable 
The percentage of patients achieving SVR12 (HCV RNA <50 IU/mL 12 weeks [i.e. ≥70 days] after the last 
actual dose of the ABBVIE REGIMEN) 
Secondary Variables 
x 
Type of treatment regimen (± Dasabuvir, ± RBV, intended and actual combination, dose and 
duration)  
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, work 
productivity and activity impairment (WPAI) questionnaire and fatigue (FIS) questionnaire prior 
to treatment initiation, at EoT as well as 12 and 24 weeks after EoT  
x 
Healthcare Resource Utilization 
x 
PAM-13, BMQ  
 

 
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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 ABBVIE REGIMEN ± RBV, SVR12 rates of at least 90% were observed, 
even in difficult-to-treat patients (e.g. cirrhotic G1a treatment experienced patients). To describe in 
routine clinical practice the effectiveness of the interferon-free 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 
below for the definition of the core population). It is expected, that during the planned recruitment 
period of 18 months between 500 to 700 patients with ABBVIE REGIMEN ± RBV can be included into this 
observational study. If the SVR12 rate is at least 90%, then with 600 patients in the core population the 
width of the 95% confidence interval (CI) will be not wider than 5%. Even in the case, that only 500 
patients are available in the core population, the 95% CI will have a width of less than 5.5% for a SVR12 
rate of at least 90% and about 4% for a SVR12 rate of 95%. In summary, a sample size of 500 to 700 
evaluable patients will provide sufficient precision for the estimation of the SVR12 rates. It is 
furthermore, expected, that the number of patients to excluded from the core population will be not 
higher than 5%, which means that about 25 additional patients should be enrolled to achieve at least 
500 evaluable patients in the core population. This assumption will be verified after the enrollment of 
about 300 patients. 
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 who have started the treatment more than one month after the recruitment 
period end date will be excluded from the target population. 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 ABBVIE REGIMEN 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 ABBVIE REGIMEN due to reasons 
related to safety (e.g. dropped out due to adverse event) or incomplete efficacy information (e.g. 
virologic 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 ABBVIE REGIMEN. 
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 ABBVIE REGIMEN arms (based 
on genotype 1 subtype, fibrosis status, treatment experienced or naïve), which are relevant for 
scheduled treatment combination (± dasabuvir, ± RBV) and duration (8, 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 ABBVIE REGIMEN arms will be specified in the statistical analysis 
plan (SAP).  
The primary effectiveness analysis will be performed for CP patients, stratified by the ABBVIE REGIMEN 
arms. Response rates at other time points (i.e. SVR12 rate, end of treatment [EoT] response rate, 
relapse rate, viral breakthrough) will also be determined for the various ABBVIE REGIMEN arms. The 
relapse rates will be estimated in patients of the ABBVIE REGIMEN arms with EoT response and 
sufficient HCV RNA measurements post treatment. Viral breakthrough rates will be estimated in all 
patients of the ABBVIE REGIMEN arms, 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. 

 
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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 ABBVIE REGIMEN arms 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 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 ABBVIE REGIMEN arms.  
Descriptive statistics will be used to summarize all other secondary variables stratified by ABBVIE 
REGIMEN arms. In addition, exploratory statistical method will be applied for the analysis of patient 
questionnaires (ANCOVA).   
Milestones:  
Start of Data Collection:  
Dec 2015 
End of Data Collection:  
Mar 2018 
Final Report of Study Results:  
                 Feb 2019 

 
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5.0 
Amendments and Updates 
x 
 Administrative Change N°1 :  
o ABT-450 replaced by Paritaprevir 
o Study designatred physician updated : Rachel BLUM replaced by Anne 
DILLENSCHNEIDER 
o Update of the planned milestones of the study 
o Update of the Patient Support Program Utilization and Satisfaction questionnaire 
(annex 6 and 7) 
o Update of Table 1 - Data Documentation Schedule regarding patients 
questionnaire administration. 
x 
Administrative Change N°2 :  
Product complaints text added 
Management and Reporting of Product Complaints need to be available at the protocol. That’s 
why the section “Management and Reporting of Adverse Events/Adverse Reactions” was 
changed to “Management of Complaints” and language for Product Complaints was added. 
x 
Amendment N°1 : 
o Modification of the follow-up period duration. SVR48 visit deleted as long term 
follow-up is generally not performed in the current practice, 
o Deletion of the secondary criteria regarding the Patient Support Program 
evaluation as this program was not initiated, 
o Addition of analysis regarding 8 weeks treatment duration, 
o Update of the planned milestones of the study, 
o Addition that patient who started treatment more than one months after the 
recruitment period end date will be excluded from the target population, 
o Update of the background paragraph, addition of study result conducting to a 
modification of the practice during the study. 
 
 

 
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6.0 
Milestones 
x 
Start of Data Collection: 
 
Dec 2015 
x 
End of Data Collection:   
 
Mar 2018 
x 
Final Report of Study Results: 
Feb 2019 
 
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 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 

 
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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 12-24 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 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 

 
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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 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 the new standard of care for genotype 1 is pegIFN and RBV combined with either the 
nonstructural protein 3/nonstructural protein 4A (NS3/4A) protease inhibitor simeprevir or the 
nucleotide nonstructural protein 5B (NS5B) polymerase inhibitor sofosbuvir [45] [46]. 
Simeprevir is a NS3/4A protease inhibitor which was approved by the FDA at the end of 2013 and 
by the EMA in May 2014. In the phase III studies QUEST 1 and 2 treatment-naïve patients with 
genotype 1 yielded SVR rates of 80%, around 90% of these patients were eligible for truncated 
therapy of 24 weeks in a response guided treatment setting [47] [48]. Very similar results were 
reported for patients with prior relapse in the PROMISE trial [49]. In the ATTAIN study 771 
treatment-experienced partial and null-responder patients were randomized to either simeprevir 
plus pegIFN and RBV or telaprevir plus pegIFN and RBV. Although efficacy rates were similar (SVR 
was 55% and 54%, respectively) the safety profile of simeprevir was significantly improved, in 
particular with regards to anemia (13% vs. 37%) and pruritus (31% vs. 43%), while serious adverse 
events 
(SAEs) 
were 
reported 
by 
2% 
and 
9% 
of 
patients, 
respectively 
[50]. 
Notably, among patients infected with HCV genotype 1a the presence of a common pre-existing 
Q80K polymorphism (pre-existing resistance-associated variant or not) results in significantly 
reduced response rates and thus, it is recommended that patients infected with HCV genotype 1a 
are screened for this mutation, and if the respective variant is present, consideration is given to 
selecting an alternative therapy [51]. 
Sofosbuvir acts as an RNA chain terminator within the catalytic site of the NS5B polymerase. It was 
approved by the FDA in December 2013 and by the EMA in January 2014 for treatment of 
genotype 1, 4, 5, and 6 along with pegIFN plus RBV and in genotype 2 and 3 patients as an 
interferon-free regimen with RBV only.  

 
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In the NEUTRINO phase III trial with sofosbuvir plus pegIFN/RBV in 326 treatment-naïve genotype 
1, 4, 5 and 6 patients, the overall SVR was 90% (92% in genotype 1a and 82% in genotype 1b; 80% 
in cirrhotic patients) with a tolerability profile similar to pegIFN plus RBV. One further advantage of 
this triple treatment regimen is the treatment duration of just 12 weeks [52]. 
Data on the interferon-free combination of sofosbuvir plus RBV in treatment-naïve patients with 
genotype 1 are only available from small trials and results are somewhat inconsistent. When given 
for a duration of 24 weeks SVR rates of 50-68% have been reported and this regimen is currently 
only recommended for patients who cannot take pegIFN [45] [46] [53] [54]. 
Thus, currently available approved treatment regimens are not optimal for many patients and 
there is a clear unmet need for effective anti-HCV compounds which can increase the likelihood of 
successful treatment and/or decrease the need for pegIFN as components of CHC therapy, ideally 
with shorter treatment duration. 
Combinations of multiple DAAs targeting different steps of viral replication have the potential to 
significantly improve CHC treatment compared to current therapies by increasing SVR rates, 
eliminating interferon as a component of therapy, increasing the safety and tolerability of 
treatment, shortening duration of therapy and simplifying the treatment algorithm. In addition, 
wider application of DAA therapy and better responses with combination DAA regimens could 
significantly reduce the public health burden of this disease. 
AbbVie's interferon-free regimen for the treatment of CHC includes 3 DAAs targeting different 
steps in HCV replication. Paritaprevir (ABT-450), is a NS3/4A protease inhibitor with 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 
paritaprvir (paritaprevir/r) results in higher drug exposures than administration of paritaprevir 
alone [55]. 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 [56], 
SAPPHIRE-II [57], PEARL-II [58], PEARL-III [59], PEARL-IV [59], TURQUOISE-II [60]).  
Therapy for 12 weeks with the above regimen in non-cirrhotic patients resulted in the following 
SVR rates 12 weeks after EoT (SVR12):  
Table 2 - SVR12 rates in clinical trials: 
Population and 
treatment duration 
Genotype 
SVR12
3D + RBV 
SVR12
3D alone 
Non-cirrhotic, 
1a 
95-97% 
90% 

 
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treatment-naïve 
(12 weeks) 
(SAPPHIRE-I, PEARL-IV)
(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 ABBVIE REGIMEN with RBV is the optimal regimen for genotype 1a 
infected patients, while patients with genotype 1b do not require RBV. 
The TURQUOISE-II [60] study explored the efficacy of the ABBVIE REGIMEN in the traditionally 
most difficult-to-treat cirrhotic patients. This large study enrolled exclusively genotype 1 infected 
patients with cirrhosis, including treatment-naïve and treatment-experienced individuals. All 
patients received the ABBVIE REGIMEN 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 ABBVIE REGIMEN 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 ABBVIE REGIMEN, 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 ABBVIE REGIMEN led to resolution in serum 
ALT elevation. Transient elevations in serum bilirubin (predominantly indirect) were observed in 

 
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subjects receiving the ABBVIE REGIMEN 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-
naīve patients were randomized to the 2 DAA combination of paritaprevir/r – ombitasvir with vs. 
without RBV for 12 weeks. The SVR was 100% with RBV vs. 91% without RBV [61]. 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 [62] [63]. 
In complement of the pivotal studies, several studies were conducted to evaluate the interferon-
free regimen in specific populations. 
The results from the TURQUOISE III study (M14-490 showed that the HCV regimen of 
ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12 weeks achieved 100% 
SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that 
this 12-week ribavirin-free regimen is sufficient in this population [70]. 
The results from the AGATE I study (M11-665) (randomised, open-label study to evaluate the 
safety and efficacy of ombitasvir/ABT-450/ritonavir co-administered with ribavirin in adults with 
genotype 4 chronic hepatitis C virus infection and cirrhosis) showed that a decrease in treatment 
duration of 12 weeks for patients with compensated cirrhosis and infected with genotype 4 is 
justified. The efficacy results observed showed a high response rate and none of the patients 
experienced a relapse despite the shortened treatment duration. There were no new safety signals 
in this study. Adverse events reported were in line with the known safety profile of Viekirax. 
Consequently a decrease in treatment duration of 12 weeks in genotype 4 cirrhotic patients is 
recommended [71]. 
The results from the GARNET study (M15-684) showed that treatment duration of 8 weeks with 
the 3 DAA combination of paritaprevir/r – ombitasvir plus dasabuvir may be considered in 
previously untreated genotype 1b-infected patients with minimal to moderate fibrosis [72].  
The results of these 3 studies conducted to an update of the Marketing Authorization. 

 
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7.2 
Rationale 
The ABBVIE REGIMEN ± (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 ABBVIE REGIMEN is expected to be first available in France for the treatment of CHC in 2015. 
The rationale for this observational study is to determine how the efficacy and safety of the 
ABBVIE REGIMEN 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’[64]. 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 heterogenous 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 [65].  
This observational study is the first effectiveness research examining the ABBVIE REGIMEN ± RBV, 
used according to local label, under real world conditions in France in clinical practice patient 
populations.  
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 [66]. Thus treatment could be targeted to patients most 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 [67]. 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 ABBVIE REGIMEN in the future. 
The label of the ABBVIE REGIMEN 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 

 
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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 of the ABBVIE 
REGIMEN ± 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 of the interferon-free ABBVIE REGIMEN ± RBV in patients with CHC in a 
real life setting across clinical practice patient populations? 
8.2 
Objectives 
8.2.1 
Primary Objective 
1. To describe in routine clinical practice the effectiveness of the interferon-free ABBVIE 
REGIMEN ± RBV in patients with CHC as evidenced by SVR 12 
8.2.2 
Secondary Objectives 
2. To describe the pattern of real world use of the ABBVIE REGIMEN ± RBV with respect to 
different patient and treatment characteristics  
3. To describe the tolerability of the ABBVIE REGIMEN ± RBV 
4. To document the effect of the ABBVIE REGIMEN ± RBV on PROs and work productivity in 
the French population  
5. To determine the impact of the ABBVIE REGIMEN ± RBV on healthcare resource utilization  
 
 
9.0 
Research Methods 
9.1 
Study Design  
This is a prospective, multi-center observational study in patients receiving the interferon-free 
ABBVIE REGIMEN 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.  

 
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Adult patients chronically infected with HCV, receiving the interferon-free ABBVIE REGIMEN will be 
offered the opportunity to participate in this study during a routine clinical visit at the participating 
sites. 
After written patient informed consent 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 medical records (source documentation) will be 
documented in the electronic case report form (eCRF) Patients will be observed for the duration of 
the ABBVIE REGIMEN 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 
8-week treatment regimen: four visits plus two interim data collection windows 
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  
 
 

 
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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. 
9.2.1 
Target Population 
Patients are eligible for observation in this cohort if the following applies: 
9.2.1.1 Inclusion criteria 
x 
A patient must be at least 18 years of age to be considered eligible to participate. 
x 
Treatment-naïve or -experienced adult male or female patients with confirmed CHC, 
genotype 1 or 4, receiving combination therapy with the interferon-free ABBVIE REGIMEN 
± RBV according to standard of care and in line with local label.  
x 
If RBV is co-administered with the ABBVIE REGIMEN, it has been prescribed in line with the 
current local label (with special attention to contraception requirements and 
contraindication during pregnancy) 
Patients must voluntarily sign and date a patient informed consent prior to inclusion into the 
study. 
9.2.1.2 Exclusion criteria 
x 
Patient must not be participating or intending to participate in a concurrent interventional 
therapeutic trial 
 
9.2.2 
Study Duration 
This is a prospective, observational study. The inclusion period will be approximately 18 months 
and the observational period of the study will be from baseline visit until 24 weeks post-treatment. 
The observational period for patients receiving 8 weeks of ABBVIE REGIMEN will be max 32 weeks 
(8 weeks treatment and 24 weeks post treatment observation), for patients receiving 12 weeks of 
ABBVIE REGIMEN the observational period will be max. 36 weeks (12 weeks treatment and 24 
weeks post-treatment observation) and for patients receiving 24 weeks of ABBVIE REGIMEN the 
observational period will be max. 48 weeks (24 weeks treatment and 24 weeks post-treatment 
observation). 
 

 
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9.2.3 
Termination Criteria 
For patients who terminate the ABBVIE REGIMEN 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 ABBVIE REGIMEN discontinuation is due to an SAE, the event must be reported to 
AbbVie within 24 hours of physician awareness (see Section 11.1.5). 
If; in such patients, there is evidence of virological response during therapy or at EoT, the SVR12 
and SVR24 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 ABBVIE REGIMEN)  
 
9.3.2 
Secondary Variables 
x 
Type of treatment regimen (± Dasabuvir, ± RBV, intended and actual combination, dose 
and duration)  
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, fatigue (FIS) 
questionnaire prior to treatment initiation, at EoT as well as 12 and 24 weeks after EoT  
x 
Healthcare Resource Utilization 
x 
PAM-13, BMQ  
 
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 

 
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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 Table 2.  
After the patient has signed the patient informed consent, the following data will be documented 
in the eCRF, if available from the patient charts based on assessments done in physicians’ routine 
clinical practice. 
 
9.4.1.1 
Inclusion documentation 
The following will be documented: 
x 
Demographic information 
o IL28B genotypes    
x 
CHC disease characteristics 
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 
ABBVIE REGIMEN ± 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 
 

 
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 
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 
Metabolic profile: Fasting glucose, fasting insulin (HOMA score will be calculated by eCRF 
based on fasting insulin and glucose), HbA1c, fasting high-density lipoprotein (HDL), fasting 
low-density lipoprotein (LDL), fasting cholesterol and fasting triglycerides  
x 
More extensive laboratory: direct bilirubin, indirect bilirubin, AFP, Fibrotest, cryoglobulin 
presence, microglobulin B2, porphyrins, drug monitoring of calcineurin (CNI) inhibitors (for 
OLT patients only)  
x 
Patient questionnaires, see table 2 and 9.4.1.6  
x 
PAM-13, BMQ 
x 
Treatment related health care resource utilization  
 
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. 
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 

 
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 
HIV RNA 
in copies/mL 
 
x 
Concomitant medication, see 9.4.1.5 
x 
Adherence to ABBVIE REGIMEN ± RBV: Subjects will maintain a daily diary to be shared 
with physician during visits (morning and/or evening dose taken – Yes/No). Physician will 
calculate the % of target dose taken for ABBVIE REGIMEN and RBV. The % of target dose 
taken for ABBVIE REGIMEN ± RBV will be entered into the eCRF. A period of 7 days in a 
row of missed intake of the ABBVIE Regimen during the time between documented first 
dose and last dose will issue a medication error report. 
x 
Tolerability (sAEs and AEs, see 11.1.5) and pregnancies (see 11.1.6) 
x 
Metabolic profile: Fasting glucose, fasting insulin (HOMA score will be calculated by eCRF 
based on fasting insulin and glucose), HbA1c, HDL, LDL, fasting cholesterol and fasting 
triglycerides  
x 
More extensive laboratory: direct bilirubin, indirect bilirubin, AFP, Fibrotest, cryoglobulin 
presence, microglobulin B2, porphyrins, drug monitoring of CNI inhibitors (for OLT patients 
only)  
x 
Patient questionnaires see table 2 and 9.4.1.6  
x 
 (PAM-13 and BMQ only at EoT/premature discontinuation) 
x 
Treatment related health care resource utilization  
 
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. 
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 11.1.4) and pregnancies (see 11.1.6) 

 
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9.4.1.4 
HCV RNA Sample 
HCV RNA sample – the following needs to be documented: 
x 
Quantitative HCV RNA by PCR test  
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 ABBVIE REGIMEN until after the last dose  
It should be verified by the treating physician that concomitant medication can be safely 
administered with the ABBVIE REGIMEN (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, work productivity and fatigue using PRO instruments: EQ-5D-
5L, WPAI Hep C and FIS. 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. 
Assessment of Fatigue – FIS Mapi Research Institute ID-2115 
The Fatigue Impact Scale (FIS) questionnaire will be used to assess the impact of fatigue on the 
quality of life of patients and to examine the relationship between the severity of fatigue and 
various parameters of the disease. The FIS questionnaire was developed to obtain validated, 
reliable fatigue specific measures.  
There are 40 items, each of which is scored 0 (no problem) to 4 (extreme problem), providing a 
continuous scale of 0-160. It is composed of three subscales that describe how fatigue impacts 
upon cognitive, physical and psychosocial functioning [68]. 
The FIS should require approximately 3 minutes to complete and is presented in Annex 5. 
 
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 
paritaprevir/r – ombitasvir ± dasabuvir (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, 
 
 

 
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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. 
Beliefs Medication Questionnaire – (18-item BMQ) 
The 18-item BMQ consists of 18 questions used to screen for patients’ beliefs, attitudes and 
concerns about their medication.  
The BMQ should require approximately 10 minutes to complete and is presented in Annex 4. 
 
9.5 
Study Size  
In phase III studies investigating the ABBVIE REGIMEN ± RBV, SVR12 rates of at least 90% were 
observed, even in difficult-to-treat patients (e.g. cirrhotic G1a treatment experienced patients). To 
describe in routine clinical practice the effectiveness of the interferon-free 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 9.2.1 for the definition of the core population). It is expected, that 
during the planned recruitment period of 18 months between 500 to 700 patients with ABBVIE 
REGIMEN ± RBV can be included into this observational study. As obvious from Table 3, if the 
SVR12 rate is at least 90%, then with 600 patients in the core population the width of the 95% 
confidence interval (CI) will be not wider than 5%. Even in the case, that only 500 patients can be 
included, the 95% CI will have a width of less than 5.5% for a SVR12 rate of at least 90% and about 
4% for a SVR12 rate of 95%. 
Table 3 Width of 95% Confidence Interval for SVR12 
Number of 
patients 
SVR12 rates 
95% Confidence Interval* 
Lower Limit 
Upper Limit 
Width  
700 
95% 
93.11
96.49
3.38%
700 
90% 
87.53
92.12
4.59%
600 
95% 
92.94
96.60
3.66%
600 
90% 
87.32
92.28
4.97%
500 
95% 
92.71
96.74
4.03%
500 
90% 
87.03
92.49
5.46%
* exact two-sided 95% confidence interval according Pearson Clopper  
 
Assuming, that in total 600 patients can be enrolled, and larger subgroups consist of at least 25% 
of the entire group (ie. ≥150 patients), then the width of the 95% CI will ≤10.25% for a SVR12 rate 
of 90% and ≤7.70% for a SVR12 rate of 95%, which is also considered sufficiently precise for 
subgroup analyses. In summary, a sample size of 500 to 700 evaluable patients will provide 

 
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sufficient precision for the estimation of the SVR12 rates, both in the core population as well as for 
subgroups of at least 25% of the core population. It is furthermore, expected, that the number of 
patients to be excluded from the core population will be not higher than 5%, which means that 
about 25 additional patients should be enrolled to achieve at least 500 evaluable patients in the 
core population. This assumption will be verified after the enrollment of about 300 patients. 
 
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. 
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:  AbbVie 
Address: 10 rue d’Arcueil, 94528 RUNGIS CEDEX 

 
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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. 
 
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 who 
have started the treatment more than one month after the recruitment period end date will be 
excluded from the target population. 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 ABBVIE REGIMEN (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 ABBVIE REGIMEN due to reasons 
related to safety (e.g. dropped out due to AE) or incomplete efficacy information (e.g. 
virologic 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 ABBVIE 
REGIMEN.  
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 

 
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entered into the eCRF. All recorded HCV RNA values will be assigned to appropriate time points 
(baseline, on-treatment visits, EoT visit, post-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. 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 (including IL28B polymorphism, co-infections, liver and/or 
CHC related co-morbidities and alcohol consumption, and most recent prior treatment for CHC 
plus outcome to prior treatment) will be summarized for the entire CP and stratified by ABBVIE 
REGIMEN arms (i.e. based on genotype 1 subtype, fibrosis status, treatment experienced or naīve), 
which are relevant for scheduled treatment combination (ABBVIE REGIMEN ± RBV) and duration 
(8, 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 ABBVIE REGIMEN arms will be specified in the 
SAP, taking into account the ABBVIE REGIMEN 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 
and stratified by the ABBVIE REGIMEN arms. 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 ABBVIE REGIMEN) is the primary effectiveness endpoint.  
 
9.7.3.2 
Secondary Effectiveness Endpoints 
In addition to the primary endpoint, the following secondary effectiveness endpoints will be 
analyzed: 
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 virologic failure (breakthrough [defined as above ] or failure to 
suppress [each measured on-treatment HCV RNA value ≥50 IU/mL]) 
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 virologic 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.  

 
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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 ABBVIE REGIMEN arms 
with EoT response and sufficient HCV RNA measurements post-treatment. Viral breakthrough 
rates will be estimated in all patients of the ABBVIE REGIMEN arms, 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: 
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 regarding predictive factors of virological response will be of exploratory nature, 
data driven, and will be repeatedly performed for various ABBVIE REGIMEN arms, 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 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 the backward elimination procedure. Logistic regression 
methods will also be used to investigate the impact of treatment adherence on SVR12.  
 

 
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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. 
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. 

 
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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 ABBVIE 
REGIMENS arms on EQ-5D-5L endpoints using the corresponding EQ-5D-5L baseline values as 
covariates.  
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 
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. 

 
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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.  
Assessment of fatigue will be performed using the FIS questionnaire. Each question will be scored 
from 0 (no problem) to 4 (extreme problem), the 3 sub-scales and the total score will be 
calculated. The same methods as specified above for EQ-5D-5L will be applied for the FIS subscales 
and the total score. Further details of the analysis will be specified in the SAP. 
 
The Patient Activation Measure (PAM) 13 item scale is a measure used to assess the patient 
knowledge, skill, and confidence for self-management (see Section 8.2.2 secondary objective no 6). 
Each of the 13 items can be answered with one of four possible response options, which are 
“disagree strongly” (1), “disagree” (2), “agree” (3), “agree strongly” (4). A fifth  
Based on responses to the 13-item measure, the score is calculated by adding up the raw scores 
(range of the sum: 13 – 52) and mapping up the value onto a scale of 0–100 indicating strength of 
agreement with the 13 items (100 *(sum - 13) / (52 - 13)).The final score can be assigned to one of 
the four levels of activation. A higher score indicates that the patient is likely to participate more 
actively in health care processes and takes more responsibility for his or her health. 
In case of missing item values, the mean value of the available items will be used for replacement. 
However, if there are less than nine items answered, no summary score will be calculated.  
The same methods as specified above for EQ-5D-5L will be applied for the PAM summary score. 
The 18-item Beliefs Medication Questionnaire (BMQ) consists of 18 questions used to screen for 
patients’ beliefs, attitudes and concerns about their medication. The 18 items are rated on a Likert 
scale from 1=strongly disagree to 5 = strongly agree and the 18 items are summarized into 4 scale 
scores: necessity of their medication, medication-related concerns, general medication-related 
harm and general medication overuse. The total score of each BMQ subscale will be calculated.   
The same methods as specified above for EQ-5D-5L will be applied for the BMQ subscales.  
 
9.7.6 
Resource Utilization 
Data of resource utilization will be captured separately with regard to outpatient consultations. 
Only the number of hospitalizations during the period will be collected. 
Descriptive analysis will be used to present the number of consultations and their particularities. 
 

 
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9.7.7 
Tolerability Analysis 
All tolerability variables will be summarized using descriptive statistical methods for the SP 
stratified by ABBVIE REGIMEN arms .  
All SAEs, non-serious AEs and pregnancy occurrences are to be reported for patients included in 
the study (see Section 11.0 and 9.2.3). 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.  
 
9.7.8 
Co-morbidities and Concomitant Medication  
All co-morbidities reported at baseline and the concomitant diseases reported on the CRF pages 
regarding concomitant/prior medication will be summarized for the SP stratified by ABBVIE 
REGIMEN arms.  
Concomitant and prior medications have to be recorded from the time when the decision is made 
to initiate treatment with the ABBVIE REGIMEN until after the last dose of the ABBVIE REGIMEN. 
For each of these medications recorded, a pre-specified treatment profile has to be ticked by the 
investigator (e.g. discontinued prior to start of the ABBVIE REGIMEN and re-introduced after 
discontinuation of the ABBVIE REGIMEN) and it has to be recorded whether the treatment profile 
was chosen due to ABBVIE REGIMEN management (e.g. it was contra-indicated).  
The association between the various concomitant medications and the treatment profiles together 
with the causality to the ABBVIE REGIMEN arms will be investigated by appropriate frequency 
tables for the different ABBVIE REGIMEN arms. More details will be provided in the SAP.  
 
9.7.9 
Interim Assessments  
Interim assessments are planned, details will be specified in the SAP. 
 

 
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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 remote 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 “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 informed consent will be obtained prior to 
patient inclusion  

 
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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 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 

 
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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. 
11.1.2 
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. 
11.1.3 
Relationship to Pharmaceutical Product 
The following definitions will be used to assess the relationship of the AE to the use of product: 
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. 
11.1.4 
Serious Adverse Event Collection Period 
SAEs will be reported to AbbVie from the time the physician obtains the patient's authorization to 
use and disclose information (or the patient's informed consent) until 30 days or 5 half-lives 
following the intake of the last dose of physician-prescribed treatment. 
11.1.5 
Serious and non-serious Adverse Event Reporting 
In the event of an SAE, the physician will: 
● For events from patients using the ABBVIE REGIMEN ± 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.  

 
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● 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 ABBVIE REGIMEN ± RBV report to AbbVie by using 
the eCRF system.  
11.1.6 
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. 
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. 
 
11.2 
Product Complaints 
11.2.1 
Definition 
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the drug or 
drug component of the product or to the medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or packaging, 
product 
appearance 
whose 
color/markings 
do 
not 
match 
the 
labeling, 
labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), missing 
components/product, device not working properly, or packaging issues. 
11.2.2 
Reporting 
The relevant AbbVie Product Complaint contact details are specified below:  
Name:   
 
 
AbbVie regulatory department 
 

 
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Product Complaints concerning the ABBVIE REGIMEN must be reported to the Sponsor within 24 
hours of the study site's knowledge of the event via local Product Complaint reporting practices.  
Product Complaints occurring during the study will be followed-up to a satisfactory conclusion.  All 
follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor.  Product Complaints associated with adverse 
events will be reported in the study summary.  All other complaints will be monitored on an 
ongoing basis. 
Product complaints involving a non-Sponsor investigational product and/or device should be 
reported to the identified contact or manufacturer, as necessary per local regulations. 
Product Complaints may require return of the product with the alleged complaint condition.  In 
instances where a return is requested, every effort should be made by the investigator to return 
the product within 30 days.  If returns cannot be accommodated within 30 days, the site will need 
to provide justification and an estimated date of return. 
The description of the complaint is important for AbbVie in order to enable AbbVie to investigate 
and determine if any corrective actions are required. 
 
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, interim assessments 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 ICMJEs’ authorship requirements [69].  
 
 
 

 
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13.0 
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plus ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a 
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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 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