Real World Evidence of the Effectiveness of Paritaprevir/r - Ombitasvir, ± Dasabuvir, ± Ribavirin and Patient Support Program in Patients With Chronic Hepatitis C - An Observational Study in Israel (CITRINE STUDY)
Conditions: Chronic Hepatitis C
Sponsor: AbbVie

Paritaprevir/r – ombitasvir and dasabuvir 
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Title Page  
Title
Real World Evidence of the Effectiveness of Paritaprevir/r –
Ombitasvir, ± Dasabuvir, ± Ribavirin and Patient Support 
Program in Patients with Chronic Hepatitis C -
An Observational Study in Israel (CITRINE STUDY)
Protocol Version 
Identifier
Protocol Version 1, 16 Mar 2016
Date of Last Version of 
Protocol
Not Applicable
Research Question and 
Objectives
What is the effectiveness of the interferon-free regimen of 
Paritaprevir/r – Ombitasvir, ± Dasabuvir, ± Ribavirin and
Patient Support Program and its influence on patients with 
CHC in a real life setting across clinical practice patient
populations?
Country(-ies) of Study
Israel
Main Author
Marketing Authorization
Holder(s)
AbbVie Ltd.
This study will be conducted in compliance with this protocol and all applicable 
local regulatory requirements 
NCT02803138

 
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1.0 
Table of Contents 
1.0 
Table of Contents ................................................................. 2 
2.0 
Abbreviations ........................................................................... 5 
3.0 
Responsible Parties .................................................................. 8 
4.0 
Abstract .................................................................................... 9 
5.0 
Amendments and Updates .................................................... 13 
6.0 
Milestones ............................................................................... 13 
7.0 
Rationale and Background ................................................... 13 
7.1 
Background .............................................................................................. 13 
7.2 
Rationale .................................................................................................. 19 
8.0 
Research Question and Objectives ...................................... 20 
8.1 
Research Question ................................................................................... 20 
8.2 
Objectives ................................................................................................ 20 
8.2.1 
Primary Objective .................................................................................... 20 
8.2.2 
Secondary Objectives ............................................................................... 21 
9.0 
Research Methods ................................................................. 21 
9.1 
Study Design ............................................................................................ 21 
9.2 
Setting ...................................................................................................... 22 
9.2.1 
Target Population ..................................................................................... 22 
9.2.2 
Study Duration ......................................................................................... 23 
9.2.3 
Termination Criteria ................................................................................. 23 
9.2.4 
Investigator Selection Criteria ................................................................. 23 
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 ............................................................................ 24 
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 ................................................................................... 28 
9.4.1.5 
Concomitant Medication .......................................................................... 29 

 
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9.4.1.6 
Standardized Assessment Tools ............................................................... 29 
9.5 
Study Size ................................................................................................ 30 
9.6 
Data Management .................................................................................... 30 
9.6.1 
Electronic Case Report Forms ................................................................. 30 
9.6.2 
Assignment of Preferred Terms ............................................................... 31 
9.7 
Data Analysis ........................................................................................... 32 
9.7.1 
Analysis Population, Time Windows and Handling of Missing 
Data .......................................................................................................... 32 
9.7.2 
Demographics and Disease Characteristics ............................................. 33 
9.7.3 
Effectiveness Analysis ............................................................................. 34 
9.7.3.1 
Primary Effectiveness Endpoint .............................................................. 34 
9.7.3.2 
Secondary Effectiveness Endpoints ......................................................... 34 
9.7.3.3 
Statistical Methods for Analysis of Effectiveness Variables ................... 35 
9.7.4 
Clinical Laboratory Data .......................................................................... 36 
9.7.5 
PSP and PAM .......................................................................................... 37 
9.7.6 
Tolerability Analysis ................................................................................ 37 
9.7.7 
Interim Assessments ................................................................................ 38 
9.8 
Quality Control ........................................................................................ 38 
9.9 
Limitations of the Research Methods ...................................................... 38 
10.0 
Protection of Human Subjects .............................................. 39 
11.0 
Management and Reporting of Complaints ........................ 39 
11.1 
Medical Complaints ................................................................................. 40 
11.1.1 
Adverse Event Definition and Serious Adverse Event Categories .......... 40 
11.1.2 
Severity .................................................................................................... 42 
11.1.3 
Relationship to Pharmaceutical Product .................................................. 42 
11.1.4 
Serious Adverse Event Collection Period ................................................ 42 
11.1.5 
Serious and non-serious Adverse Event Reporting.................................. 43 
11.1.6 
Pregnancy Reporting ................................................................................ 43 
11.2 
Product Complaint ................................................................................... 43 
11.2.1 
Definition ................................................................................................. 43 
11.2.2 
Reporting .................................................................................................. 44 
12.0 
Plans for Disseminating and Communicating Study 
Results ..................................................................................... 45 

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13.0 
References ...............................................................................46 
Annex 1. 
 
  
................................................................................................. 51 
Annex 2. 
Patient Support Program (PSP) Utilization 
Questionnaire.........................................................................52 
Annex 3. 
Patient Support Program (PSP) Utilization and Sa-
tisfaction Questionnaire........................................................53 
Annex 4. 
Child-Pugh Classification of Severity of Cirrhosis ............55 
14.0 
Protocol Signature Page ........................................................56 

 
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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 
 
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 
 
FDA 
Food and Drug Administration 
 
FIB-4 
Fibrosis-4 Score/Index 
 
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

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

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3.0 
Responsible Parties  
Study Designated Physician (SDP): 
Protocol Authors: 
  
Vendor: 
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 
and Patient Support Program in Patients with Chronic Hepatitis C  
An Observational Study in Israel (CITRINE STUDY) 
 
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 available in Israel for the treatment of CHC since 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 Israel in a clinical practice 
patient population.  
During the last decade when dual therapy with pegylated interferon (pegIFN) plus RBV was 
standard of care for the treatment of CHC, the discovery of predictive factors for virological 
response and the subsequent development of treatment algorithms marked a milestone in 
patient care for CHC. As a consequence, treatment could be effectively targeted to patients 
most likely to respond. Interestingly, many of the now well established predictors of response to 
pegIFN/RBV and first generation direct acting anitvirals (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 

 
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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 interferon-
free regimen of Paritaprevir/r – Ombitasvir, ± Dasabuvir, ± Ribavirin and PSP and its influence 
on patients with CHC in a real world setting across clinical practice patient populations. 
Research Question and Objectives: 
What is the effectiveness  of the interferon-free regimen of Paritaprevir/r – Ombitasvir, ± 
Dasabuvir, ± Ribavirin and Patient Support Program and its influence on patients with CHC in a 
real life setting across clinical practice patient populations? 
 
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 provide real world evidence for predictive factors of virological response 
3. To describe the pattern of real world use of the ABBVIE REGIMEN ± RBV with 
respect to different patient and treatment characteristics  
4. To evaluate the contribution of the patient support program (PSP) to disease 
control, treatment continuation over time, patient satisfaction and PSP utilization  
5. To describe the effect of the ABBVIE REGIMEN ± RBV on metabolic profile  
6. To evaluate the effect of the ABBVIE REGIMEN ± RBV on extrahepatic 
manifestations and associated diseases like cryoglobulinemia/cutaneous vasculitis 
or porphyria cutanea tarda  
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: 
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 the current 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)  
x 
Patients must voluntarily sign and date an informed consent form to use and/or disclose 
his/her anonymized health data prior to inclusion into the study 
x 
Patient must not be participating or intending to participate in a concurrent interventional 
therapeutic trial  
Variables: 
Primary Variable 

 
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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) 
Secondary Variables 
x 
Type of treatment regimen (± Dasabuvir, ± RBV, intended and actual combination, dose 
and duration)  
x 
PAM-13, PSP satisfaction and utilization questionnaires  
x 
Metabolic laboratory profile (see section  9.4.1.1) prior to treatment initiation, and at all 
subsequent visits  
x 
Cryoglobulins, immunoglobulins and porphyrin prior to treatment initiation, and at all 
subsequent visits  
Data Sources: 
Source documents are defined as original documents. The investigator will document patient 
data in his/her own patient files which will serve as source data for the study.  
Study Size:  
In phase III studies investigating the interferon-free ABBVIE REGIMEN ± RBV, SVR12 rates of 
at least 90% were observed, even in difficult-to-treat CHC patients (e.g. cirrhotic G1a treatment 
experienced patients). To describe in routine clinical practice the effectiveness of the ABBVIE 
REGIMEN ± RBV in patients with CHC, a precise estimate of the SVR12 rates should be 
achieved. 
It is expected, that during the planned inclusion period of 8 months about 250 patients treated 
with the ABBVIE REGIMEN ± RBV can be included. It is furthermore, expected, that the number 
of patients to exclude from the core population will be not higher than 5-10%. With 235 
evaluable patients the width of the 95% confidence interval (CI) will be 7.7% and 5.7% for 
SVR12 rates of 90% and 95%, respectively. If only 200 patients can be evaluated, the 95% CI 
will have a width of less than 8.4% for a SVR12 rate of at least 90% and less than 6.2% for a 
SVR12 rate of at least 95%.  
 
Data Analysis: 
The core population (CP) is defined as all patients of the target population (TP) (definition see 
above), who have started the treatment combination recommended in the current local label for 
their disease characteristics. Patients not receiving the treatment recommended in the local 
label will be summarized in the non-core population (NCP). In addition, the core population with 
sufficient follow-up data (CPSFU) is defined as all CP patients, who have (i) evaluable HCV 
RNA data ≥70 days after the last actual dose of the 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 CP analysis 
groups (based on genotype and fibrosis status), which are relevant for the scheduled treatment 

 
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combination. In addition, baseline summaries will be repeated for the SP and TP. Further details 
of analysis populations and the CP analysis groups will be specified in the statistical analysis 
plan (SAP).  
The primary effectiveness analysis will be performed for CP patients, stratified by the CP 
analysis groups. Response rates (i.e. SVR12 rate, end of treatment [EoT] response rate, 
relapse rate, viral breakthrough) will be determined for the various CP analysis groups. The 
relapse rates will be estimated in patients of the CP analysis groups with EoT response and 
sufficient HCV RNA measurements post treatment. Viral breakthrough rates will be estimated in 
all patients of the CP analysis groups, who have at least one undetectable HCV RNA 
measurement on treatment and at least one on-treatment or EoT measurement thereafter. For 
all rates specified above 95%-confidence intervals (CIs) will be determined using the Wilson 
Score method. 
Univariate and multiple logistic regression (MLR) methods will be used to investigate the impact 
of various explanatory covariates (e.g. demographic and disease characteristics, co-morbidities, 
type of treating institution, and prior treatment for CHC and response outcome in treatment 
experienced patients) on SVR12. These analyses will be of exploratory nature, data driven, and 
could be performed for various CP analysis groups since not each covariate might be predictive 
in each patient group. Furthermore, the fact that treatment regimens will differ in the various 
patient groups has to be taken into account, when selecting the patient groups for each MLR 
analysis. Backward selection procedures will be applied to generate the final MLR models and 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 type of combination treatment.  
Milestones:  
Start of Data Collection:  
Jun 2016 
End of Data Collection:  
Jan 2018 
Final Report of Study Results:                Dec 2018 

 
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5.0 
Amendments and Updates 
x 
None 
 
6.0 
Milestones 
x 
Start of Data Collection:  
 
June 2016 
x 
End of Data Collection:   
 
Jan 2018 
x 
Final Report of Study Results: 
Dec 2018 
 
7.0 
Rationale and Background 
7.1 
Background 
Infection with the hepatitis C virus (HCV) is associated with considerable morbidity and 
mortality  [1] and is a leading cause of chronic liver disease, cirrhosis, and hepatocellular 
carcinoma (HCC), as well as the most common indication for liver transplantation in 
many countries  [2]. Around 60-85% of subjects exposed to HCV do not clear the virus 
and go on to develop chronic disease  [3]  [4]. Chronic hepatitis C (CHC) affects an 
estimated 2-3% of the world’s population - equaling approximately 130-210 million 
individuals  [5]  [6]. The prevalence varies markedly from one geographic area to another 
ranging from 0.1-1% in Western Europe to 1-2% in Latin America and up to 4.9% in 
some regions of Eastern Europe  [7]  [8]  [9]  [10]. 
HCV demonstrates a high degree of genetic variability and has been classified into seven 
major genotypes (and a large number of subtypes) the distribution of which varies 
globally  [11]. Genotypes 1 through 3 are found worldwide; the other genotypes have a 
more restricted distribution, genotype 4 is found predominantly in the Middle East, 
Central Africa, and Egypt; genotype 5 in South Africa; and genotype 6 mainly in Asia. 
HCV genotypes 1a and 1b are the most common forms, accounting for 60% of HCV 
infections worldwide  [12]  [13]  [14]  [15]. 
HCV is primarily transmitted by parenteral exposures to contaminated blood, most 
frequently by injection drug use, exposures in health-care settings and inadequate 
infection-control practices (tattoo, piercing). Occupational, perinatal and sexual exposure 
can also result in transmission of HCV  [16]  [17]. Since the early 1990’s routine blood 
screening protocols have been introduced in most countries and as a consequence 

 
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transmission of the virus is rarely seen following receipt of blood, blood products or 
through organ transplants. 
The natural course of CHC leads to progressive fibrosis and can eventually lead to 
cirrhosis of the liver over the course of 20-30 years in approximately 15-30% of infected 
individuals  [18]. Once patients become cirrhotic, around 6% per year are expected to 
develop hepatic decompensation (ascites, encephalopathy, variceal hemorrhage, 
hepatorenal syndrome, or hepatic synthetic dysfunction) and around 3% per year will 
develop HCC  [19]. Over the same time frame, between 4 and 5% of patients can be 
expected to require liver transplantation or die  [19]  [20]. Progression is not necessarily a 
linear process and can be accelerated by a number of factors including the age of the 
patient, duration of HCV infection, male gender, alcohol consumption and co-infection 
with other viruses such as hepatitis B virus (HBV) and human immunodeficiency virus 
(HIV)  [4] but also by concomitant steatosis and obesity. Comorbid conditions can impact 
CHC treatment eligibility, safety, tolerability and efficacy of therapy  [21]  [22].  
The burden of advanced liver disease varies widely across countries and is dependent 
upon several factors including chronic HCV prevalence and age distribution (and duration 
of infection) of those infected  [23]. Due to an aging cohort of patients and an associated 
increase in the incidence of severe liver disease, the burden of CHC will continue to 
increase. In persons 30–49 years of age, the prevalence of the disease is 3–fold higher 
than in other age groups. By 2020, the rates of HCC and liver-related deaths among 
individuals with CHC are expected to increase by 81% and 180%, respectively  [24]. 
The eradication of the virus, defined as the absence of HCV ribonucleic acid (RNA) in 
serum (as shown by a sensitive test) at the end of treatment (EoT) and 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 

 
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cirrhosis who achieve SVR essentially eliminate their subsequent risk of 
decompensation, may achieve histologic regression, and decrease their risk of HCC by 
two-thirds  [33]  [34]  [35].  
In the 1980’s and 1990’s interferon alfa was the first drug to show activity against HCV. 
However, the effectiveness of interferon monotherapy in the treatment of CHC infection 
was generally unsatisfactory resulting in an overall SVR rate across genotypes of 
<20%  [36]  [37]. Combination therapy with interferon plus ribavirin (RBV) improved SVR 
rates but still overall rates across genotypes remained below 50%  [38]  [39]. Following the 
introduction of long-acting interferons (peginterferon alfa-2a and peginterferon alfa-2b 
[i.e. pegIFNs]) in combination with RBV more than a decade ago, further advances have 
been made in efficacy with overall rates of SVR up to 54-63%  [39]  [40]  [41]. SVR rates 
vary substantially by HCV genotype with genotype 1 being the most difficult-to-treat, thus 
requiring longer treatment periods to obtain SVR with interferon-based dual therapy. SVR 
rates up to around 50% can be achieved in patients with genotype 1 whereas for 
genotypes 2 and 3 cure rates of up to 80% can be achieved  [41]. 
Treatment with pegIFN and RBV is associated with considerable, often treatment-limiting 
toxicities including cytopenias, neuro-psychiatric disorders and influenza-like symptoms. 
In 2011 the first direct-acting antivirals (DAAs), specifically the protease inhibitors 
boceprevir and telaprevir, have been approved by the US Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) for treatment of HCV genotype 1. 
These 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 

 
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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 
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.  
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 

 
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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 paritaprevir (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 1 - SVR12 rates in clinical trials: 
Population and 
treatment duration 
Genotype 
SVR12 
ABBVIE REGIMEN + RBV 
SVR12 
ABBVIE REGIMEN alone 
Non-cirrhotic, 
treatment-naïve 
(12 weeks) 
1a 
95-97%  
(SAPPHIRE-I, PEARL-IV) 
90%  
(PEARL-IV) 
1b 
98-99.5% 
(SAPPHIRE-I, PEARL-III) 
99% 
(PEARL-III) 
Non-cirrhotic, 
treatment-
experienced 
(12 weeks) 
1a 
96% 
(SAPPHIRE-II) 
n.a. 
1b 
97% 
(SAPPHIRE-II, PEARL-II) 
100% 
(PEARL-II) 
 
These results suggest that the 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 

 
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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 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. 

 
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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]. 
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 available in Israel for the treatment of CHC since 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 Israel in 
clinical practice patient population.  
During the last decade when dual therapy with pegIFN plus RBV was standard of care for 
the treatment of CHC, management of patients and clinical outcome were improved 
following the discovery of predictive factors of virological response, often in observational 
studies with large data bases  [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 

 
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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 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 
interferon-free regimen of Paritaprevir/r – Ombitasvir, ± Dasabuvir, ± Ribavirin and 
Patient Support Program and its influence on patients with CHC 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 regimen of Paritaprevir/r – Ombitasvir, ± 
Dasabuvir, ± Ribavirin and PSP and its influence on 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 SVR12 

 
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8.2.2 
Secondary Objectives 
 
2. To provide real world evidence for predictive factors of virological response 
3. To describe the pattern of real world use of the ABBVIE REGIMEN ± RBV with 
respect to different patient and treatment characteristics  
4. To evaluate the contribution of the patient support program (PSP) to disease 
control, treatment continuation over time, patient satisfaction and PSP utilization  
5. To describe the effect of the ABBVIE REGIMEN ± RBV on metabolic profile  
6. To evaluate the effect of the ABBVIE REGIMEN ± RBV on extrahepatic 
manifestations and associated diseases like cryoglobulinemia/cutaneous 
vasculitis or porphyria cutanea tarda  
 
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.  
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 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: 

 
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x 
12-week treatment regimen: four visits plus two interim data collection windows 
x 
24-week treatment regimen: four visits plus three interim data collection windows 
This schedule is based on the anticipated regular follow-up for patients undergoing 
treatment for CHC. 
Figure 1 - Study Flowchart  
 
  
9.2 
Setting 
For overall research design and observational documentation schedule refer to 
Sections  9.1 and  9.4.1 as well as to Figure 1. 
9.2.1 
Target Population 
Patients are eligible for observation in this cohort if the following applies: 
x 
Treatment-naïve or -experienced adult male or female patients with confirmed 
CHC, genotype 1 or 4, receiving combination therapy with the interferon-free 
ABBVIE REGIMEN ± RBV according to standard of care and in line with the 
current 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) 

 
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x 
Patients must voluntarily sign and date an informed consent form prior to 
inclusion into the study 
x 
Patient must not be participating or intending to participate in a concurrent 
interventional therapeutic trial 
 
9.2.2 
Study Duration 
This is a prospective, observational study. The inclusion period will be approximately 8 
months and the observational period of the study will be from baseline visit until 24 
weeks post-treatment. 
The observational period for patients receiving 12 weeks of ABBVIE REGIMEN 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). 
 
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 
Medical 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. 
 

 
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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 
PAM-13, PSP satisfaction and utilization questionnaires  
x 
Metabolic laboratory profile (see section  9.4.1.1) prior to treatment initiation, and 
at all subsequent visits  
x 
Cryoglobulins, immunoglobulins and porphyrin prior to treatment initiation, and at 
all subsequent visits  
9.4 
Data Sources  
Source documents are defined as original documents. The investigator will document 
patient data in his/her own patient files which will serve as source data for the study. Data 
are collected from the source documents for each patient in the study, consisting of 
medical records containing demographic data, medical, treatment and diagnostic 
documentation and laboratory assessments.  
The investigator(s)/institution(s) will permit study-related monitoring, audits, independent 
ethics committee/- review board (IEC/IRB) review, and regulatory inspection(s), providing 
direct access to source data documents. 
 
9.4.1 
Data to be Documented 
This observational study covers three documentation periods, see Figure 1. An overview 
on data to be collected throughout the study is summarized in Table 2.  
After the patient has signed the informed consent form, the following data will be 
documented in the eCRF, if available from the patient charts based on assessments 
done in physicians’ routine clinical practice. 
 

 
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9.4.1.1 
Inclusion Documentation 
The following will be documented: 
x 
Demographic information 
o Interleukin 28B (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 
 
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 

 
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lipoprotein (HDL), fasting low-density lipoprotein (LDL), fasting cholesterol and 
fasting triglycerides  
x 
More extensive laboratory: direct bilirubin, indirect bilirubin, AFP, Fibrotest, 
cryoglobulin presence, cryocrit, IgG, IgA, IgM, rheumatoid factor (RF), 
complement components, proteinuria, microscopic hematuria, cutaneous 
vasculitis score, plasma and urinary porphyrin, ferritin, drug monitoring of 
calcineurin (CNI) inhibitors (for OLT patients only)  
x 
PAM-13  
9.4.1.2 
During Treatment Documentation 
Follow-up visits are scheduled by the physician per routine clinical practice. Likewise 
treatment, procedures and diagnostic methods will follow physicians’ routine clinical 
practice. 
The following will be documented:  
x 
Laboratory data 
Key clinical chemistry 
Remarks 
 
ALT 
including ULN 
 
AST 
including ULN,  
APRI and FIB-4 will be calculated  
 
γ-GT 
 
Total bilirubin 
 
Creatinine 
creatinine clearance will be calculated  
Key hematology 
 
Hb 
 
Platelets  
Virology 
 
HCV RNA 
quantitative/ qualitative HCV RNA PCR test, see  9.4.1.4 
HIV-infected patients only 
 
CD 4 count 
most recent assessment 
 
HIV RNA 
in copies/mL 
 
x 
Concomitant medication, see  9.4.1.5 
x 
Adherence to ABBVIE REGIMEN ± RBV (ABBVIE REGIMEN - % of target dose 
taken and RBV Y/N)  
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, cryocrit, IgG, IgA, IgM, RF, complement components, 
proteinuria, microscopic hematuria, cutaneous vasculitis score, plasma and 
urinary porphyrin, ferritin, drug monitoring of CNI inhibitors (for OLT patients only)  

 
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x 
PSP satisfaction and utilization questionnaires; PAM-13  
 
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) 
 
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, cryocrit, IgG, IgA, IgM, RF, complement components, 
proteinuria, microscopic hematuria, cutaneous vasculitis score, plasma and 
urinary porphyrin, ferritin, drug monitoring of CNI inhibitors (for OLT patients only)  
x 
PSP Satisfaction and utilization questionnaires  
 

 
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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  
 
Patient Activation Measure – (PAM-13) 
PAM 13 is a measure used to assess the patient knowledge, skill, and confidence for 
self-management. It should require approximately 7 minutes to complete and is 
presented in Annex 3. 
  
Patient Support Program (PSP) Questionnaire 
The PSP utilization and satisfaction assessment will evaluate the frequency of utilization 
and patient’s overall satisfaction with their respective Patient Support Program. 
The PSP questionnaire should require approximately 2-5 minutes to complete and is 
presented in Annex 5-6. 

 
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9.5 
Study Size  
In phase III studies investigating the interferon-free ABBVIE REGIMEN ± RBV, SVR12 
rates of at least 90% were observed, even in difficult-to-treat CHC patients (e.g. cirrhotic 
G1a treatment experienced patients). To describe in routine clinical practice the 
effectiveness of the ABBVIE REGIMEN ± RBV in patients with CHC, a precise estimate 
of the SVR12 rates should be achieved. 
It is expected, that during the planned inclusion period of 8 months about 250 patients 
treated with the ABBVIE REGIMEN ± RBV can be included. It is furthermore, expected, 
that the number of patients to exclude from the core population will be not higher than 5-
10%. With 235 evaluable patients the width of the 95% confidence interval (CI) will be 
7.7% and 5.7% for SVR12 rates of 90% and 95%, respectively. If only 200 patients can 
be evaluated, the 95% CI will have a width of less than 8.4% for a SVR12 rate of at least 
90% and less than 6.2% for a SVR12 rate of at least 95%. See for further details. 
Table 3- Width of 95% Confidence Interval for SVR12 
Number of 
patients 
SVR12 rates 
95% Confidence Interval* 
Lower Limit 
Upper Limit 
Width  
200 
90% 
85.1 
93.4 
8.4% 
200 
95% 
91.0 
97.3 
6.2% 
225 
90% 
85.4 
93.3 
7.9% 
225 
95% 
91.3 
97.2 
5.8% 
235 
90% 
85.6 
93.2 
7.7% 
235 
95% 
91.4 
97.1 
5.7% 
* two-sided 95% confidence interval according the Wilson Score method  
9.6 
Data Management 
9.6.1 
Electronic Case Report Forms 
Data for this study will be recorded in English by each participating center via an 
electronic data capture (EDC) system using a web-based eCRF. Examinations, 
diagnostic measures, laboratory assessments, findings and observations routinely 
performed in patients with CHC included in this cohort, will be transcribed by the 
investigator or designee from the source documents into the eCRF. Only data specified 
in the protocol will be entered into the eCRF. For each enrolled patient, the investigator 
or designee will create a new patient file in the eCRF and a unique patient number will be 
automatically allocated by the system. 

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

 
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9.7 
Data Analysis 
9.7.1 
Analysis Population, Time Windows and Handling of 
Missing Data  
The target population (TP) is defined as all patients who fulfill the criteria specified in 
Section  9.2.1. The core population (CP) is defined as all patients of the TP, who have 
started the treatment combination recommended in the current local label for their 
disease characteristics. Patients not receiving the treatment recommended in the local 
label will be summarized in the non-core population (NCP). In addition, the core 
population with sufficient follow-up data (CPSFU) is defined as all CP patients, who fulfil 
one of the following criteria:  
(1) evaluable HCV RNA data ≥70 days after the last actual dose of the 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 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).  

 
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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 within 70 -126 days post-
treatment will be used. For SVR analysis, if there is no value in this time window, but 
there is an HCV RNA value after the window, then it will be imputed into the SVR 
window. Subsequent to this flanking and backward imputation, if the HCV RNA value 
remains missing at a specific time point, then the patients will considered as virological 
failure at this time point (i.e. not undetectable or unquantifiable). 
 
9.7.2 
Demographics and Disease Characteristics  
All baseline and disease characteristics will be summarized for the CP stratified by the 
CP analysis groups (i.e. based on genotype and fibrosis status), which are relevant for 
scheduled treatment combination (ABBVIE REGIMEN ± RBV). In addition, baseline 
summaries will be repeated for the SP and the TP. Summary statistics (n, mean, median, 
standard deviation [SD], and range) will be generated for continuous variables (e.g. age 
and body mass index [BMI]). The number and percentage of patients will be presented 
for categorical variables (e.g. gender and race). Further details of analysis populations 
and the CP analysis groups will be specified in the SAP, taking into account the 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 stratified by the CP analysis groups. Due to the non-interventional nature of this 
study several different methods for determination of the HCV RNA value can be applied. 
For the purpose of the statistical analysis, a HCV RNA measurement is considered ≤50 
IU/mL, 
• 
if a PCR test was used 
• 
and the test result is undetectable and the LLoD of the test is ≤50 IU/mL or the 
test result is unquantifiable and the LLoQ is ≤50 IU/mL 
 
9.7.3.1 
Primary Effectiveness Endpoint 
The percentage of patients achieving SVR12 (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 
The secondary effectiveness endpoints are: 
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) 

 
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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 a two-sided 
95% confidence interval (CI) of the percentage will be computed based on the Wilson 
score method.  
Corresponding methods will be used for other response rates (EoT response rate, 
relapse rate, viral breakthrough). The relapse rates will be estimated in patients of the CP 
analysis groups with EoT response and sufficient HCV RNA measurements post-
treatment. Viral breakthrough rates will be estimated in all patients of the CP analysis 
groups, who have at least one undetectable HCV RNA measurement on-treatment and at 
least one on-treatment or EoT measurement thereafter.  
Univariate and multiple logistic regression (MLR) methods will be used to investigate the 
impact of the following explanatory covariates on SVR12: 
x 
Key demographic information  
x 
Mode of CHC infection 
x 
HCV RNA level at baseline 
x 
Most recent stage of liver fibrosis 
x 
HCV genotype and subtype (if available)  
x 
Type of treating institute 
x 
Liver and/or CHC related co-morbidities 
x 
Key clinical chemistry and hematology laboratory variables at baseline  
x 
In treatment experienced patients only:  
o Most recent prior treatment for CHC 
o Outcome of most recent prior CHC treatment 
 
Further details and additional covariates will be specified in the SAP. 
These analyses will be of exploratory nature, data driven, and will be repeatedly 
performed for various CP Analysis Groups, since not each covariate might be predictive 
in each patient group. Furthermore, the fact that treatment regimens will differ in the 
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 and a p-value <0.05 will be used for the covariates to stay in the model in a 

 
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backward elimination step. Logistic regression methods will also be used to investigate 
the impact of treatment adherence on SVR12.  
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 – 126 post EoT 
 
24 weeks 
(day 169 post EoT) 
127 – 252 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. 
 

 
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9.7.5 
PSP and PAM 
The contribution of the patient support program (PSP) to disease control, treatment 
continuation over time, patient satisfaction and PSP utilization will be analyzed using 
descriptive and exploratory statistical methods. Appropriate frequency tables will 
summarize all corresponding variables of the PSP questionnaires (see ANNEX 2 and 3) 
over time stratified by ABBVIE REGIMEN arms. In addition, multiple logistic regression 
(MLR) analysis will be performed to investigate the association between the use of the 
PSP, the patient satisfaction variables of the PSP questionnaires with the probability to 
treatment completion. These MLRs will be performed similar to the MLRs for SVR12 (see 
Section Error! Reference source not found.). Additional details 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. 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). 
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. 
A summary table will show descriptive statistics (n, mean, median, SD, minimum and 
maximum) of the score for baseline and EoT, as well as change from baseline. In 
addition analysis of covariance (ANCOVA) will be applied to investigate the effect of the 
different ABBVIE REGIMENS (± RBV) on the activation score using the corresponding 
score at baseline as covariate. Further details will be specified in the SAP. 
9.7.6 
Tolerability Analysis 
All tolerability variables will be summarized using descriptive statistical methods for the 
SP stratified by type of combination treatment.  
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. 

 
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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.  
 
9.7.7 
Interim Assessments  
 
No interim assessments are planned. 
 
9.8 
Quality Control 
The sites will be instructed in the protocol, the functionality and handling of the eCRF, 
and the requirement to maintain source documents for each patient in the study (see 
Section  9.4).  
A comprehensive data validation program utilizing front-end checks in the eCRF will 
validate the data. Automated checks for data consistency will be implemented, 
discrepancies need to be solved by the researcher in the eCRF before the module can 
be completed. Follow-up on eCRF data for medical plausibility will be done by AbbVie 
personnel (or their representatives). The principal investigator of each site will finally 
review the eCRFs for completeness and accuracy of available data and provide his or 
her electronic signature and date to eCRFs as evidence thereof.  
Continuous monitoring of the study and frequent site telephone contacts will be done by 
AbbVie or a CRO working on behalf of AbbVie. 
 

 
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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 patient informed consent will be 
obtained prior to patient inclusion  
 
To maintain patient confidentiality, no demographic data that can identify the patient will 
be collected (e.g. initials, date of birth) - only the patient age will be collected. In order to 
protect patient identity, a unique number will be assigned to each patient and related 
study recording. 
 
11.0 
Management and Reporting of Complaints 
 

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A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of the ABBVIE REGIMEN must be reported 
to the Sponsor (11.2.2).
For adverse events, please refer to Sections 11.1.1 through 11.1.6.  For product 
complaints, please refer to Section 11.2. 
11.1 
Medical Complaints 
PRO data are not considered a potential source of adverse reactions. However, 
participating sites should review the PRO data and if a possible product-related event 
(including a suspected adverse reaction) is noted, the HCP must determine whether the 
event is related to the ABBVIE REGIMEN ± RBV (or any other AbbVie authorized 
product) and if so, it should be reported to AbbVie.  
Medication errors (this refers to any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in control of the HCP, patient or consumer) 
should be reported by the HCP to AbbVie. 
The relevant AbbVie Pharmacovigilance contact details are specified below:
Name: 
Address: 
Tel.: 
Fax: 
Email: 
11.1.1 
Adverse Event Definition and Serious Adverse Event 
Categories 
An adverse event (AE) is defined as any untoward medical occurrence in a patient, which 
does not necessarily have a causal relationship with their treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not the event is considered causally related to the use of the product. 

 
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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 

 
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spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
11.1.2 
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 
informed consent until 30 days or 5 half-lives following the intake of the last dose of 
physician-prescribed treatment. 

 
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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.  
● 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 Complaint 
11.2.1 
Definition 
A Product Complaint is any Complaint (see Section Error! Reference source not 
found. for the definition) related to the drug or drug component of the product. 

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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, or packaging issues. 
11.2.2 
Reporting 
The relevant AbbVie Product Complaint contact details are specified below:
Name: 
Address: 
Tel.:
Fax:
Email: 
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. 

 
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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 ICMJE’ authorship requirements  [68].  

 
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13.0 
References 
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Van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological 
response and all-cause mortality among patients with chronic hepatitis C and 
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Everson GT, Balart L, Lee SS, et al. Histological benefits of virological response to 
peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or 
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and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 
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Shiffman M, Hofmann CM, Thompson EB, et al. Relationship between biochemical, 
virologic and histologic response during interferon treatment of chronic hepatitis C. 
Hepatology 1997; 26: 780-5. 

 
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[33] 
Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-
alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective 
study. Hepatology 2007; 45: 579-87. 
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Di Bisceglie AM, Shiffman M, Everson GT, et al. Prolonged antiviral therapy with 
peginterferon to prevent complications of advanced liver disease associated with 
hepatitis C: results of the hepatitis C antiviral long-term treatment against cirrhosis 
(HALT-C) trial. Hepatology 2007; 46 (Suppl S1): 290A. 
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histology in chronic hepatitis C: a meta-analysis of individual patient data. Hepatology 
2004; 39: 333-42. 
[36] 
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in 
combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis 
Interventional Therapy Group. NEJM 1998; 339: 1485-92. 
[37] 
Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon α-2a in patients with chronic 
hepatitis C. NEJM 2000; 343: 1666-72. 
[38] 
Poynard T, McHutchison JG, Goodman Z, Ling MH, Albrecht J. Is an “à la carte” 
combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment 
in patients with chronic hepatitis C? Hepatology 2000; 31: 211-8. 
[39] 
Fried MW, Shiffman M, Reddy KR, et al (for the PEGASYS® International Study 
Group). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. 
NEJM 2002; 347: 975-82. 
[40] 
Manns M, McHutchison JG, Gordon SC et al. PegInterferon alfa-2b plus ribavirin 
compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis 
C: a randomized trial. Lancet 2001; 358: 958-65. 
[41] 
Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha 2a and ribavirin 
combination therapy in chronic hepatitis C: a randomized study of treatment duration 
and ribavirin dose. Ann Intern Med 2004; 140: 346-55. 
[42] 
Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with 
peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of 
phase 3 ADVANCE study. Hepatology 2010; 52 (Suppl S1): 427A. 
[43] 
Sherman KE, Flamm SL, Afdhal NH et al. Telaprevir in combination with peginterferon 
alfa2b and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients 
who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE 
study. Hepatology 2010; 52 (Suppl S1): 401A. 
[44] 
Poordad F, McCone J, Bacon BR et al. Boceprevir (BOC) combined with peginterferon 
alfa-2b/ribavirin (P/R) for treatment-naive patients with hepatitis C (HCV) genotype 1: 
SPRINT-2 final results. Hepatology 2010; 52 (Suppl S1): 402A. 
[45] 
EASL Recommendations on Treatment of Hepatitis C 2014. J Hepatol 2014; doi: 
10.1016/j.jhep.2014.05.001 (Epub ahead of print). 
[46] 
AASLD. Recommendations for Testing, Managing, and Treating Hepatitis C. 2014: 1-
50. Available at http://www.hcvguidelines.org/sites/default/files/full_report.pdf. 

 
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[47] 
Jacobson IM, Dore G, Foster G et al. Simeprevir with pegylated interferon alfa 2a plus 
ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection 
(QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 
2014; doi: 10.1016/S0140-6736(14)60494-3 (Epub ahead of print). 
[48] 
Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 
2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 
infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. 
Lancet 2014; doi: 10.1016/S0140-6736(14)60538-9 (Epub ahead of print). 
[49] 
Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with Peginterferon and ribavirin leads 
to high rates of SVR in patients with HCV genotype 1 who relapsed after previous 
therapy: a phase 3 trial. Gastroenterology. 2014; 146: 1669-79. 
[50] 
Reddy KR, Zeuzem S, Zoulim F, et al. A Phase III randomised, double-blind study to 
evaluate the efficacy, safety and tolerability of simeprevir vs telaprevir in combination 
with pegylated interferon and ribavirin in chronic hepatitis C virus genotype 1 
treatment-experienced patients: the ATTAIN study. Abstract APASL 2014 Brisbane, 
Australia. Available at http://www.natap.org/2014/APASL/APASL_20.htm. 
[51] 
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http://www.olysio.com/shared/product/olysio/prescribing-information.pdf; accessed 
February 09, 2014. 
[52] 
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic 
hepatitis C infection. NEJM 2013; 368: 1878-87. 
[53] 
Lalezari L, Nelson D, Hyland R, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 
weeks in treatment-naive patients with HCV infection: the QUANTUM study. J Hepatol 
2013; 58 (Suppl 1): S346. 
[54] 
Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C 
genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical 
trial. JAMA 2013; 310: 804-11. 
[55] 
Menon RM, Klein CE, Lawal AA, et al. Pharmacokinetics and tolerability of the HCV 
protease inhibitor ABT-450 following single ascending doses in healthy adult 
volunteers with and without ritonavir. Abstract of HepDART 2009, Kohala Coast, 
Hawaii, USA. Available at http://www.natap.org/2009/hepDART/hepDART_03.htm. 
[56] 
Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r ombitasvir 
and dasabuvir with ribavirin. NEJM 2014; 370: 1594-603. 
[57] 
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-
ombitasvir and dasabuvir with ribavirin. NEJM 2014; 370: 1604-14. 
[58] 
Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and 
dasabuvir achieves 97% and 100% sustained virologic response with or without 
ribavirin in treatment-experienced patients with HCV genotype 1b infection. 
Gastroenterology 2014; doi: 10.1053/j.gastro.2014.04.045 (Epub ahead of print). 
[59] 
Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or 
without ribavirin for HCV. NEJM 2014; 370: 1983-92.  
[60] 
Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin 
for hepatitis C with cirrhosis. NEJM 2014; 370: 1973-82.

 
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[61] 
Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PEARL-I study: 
interferon-free regimens of ABT-450/R + ABT-267 with or without ribavirin in patients 
with HCV genotype 4 infection. J Hepatol 2014; 60 (Suppl 1): S24. 
[62] 
Hezode C, Fontaine H, Dorival C et al. Effectiveness of telaprevir or boceprevir in 
treatment-experienced patients with HCV genotype 1 infection and cirrhosis. 
Gastroenterology 2014; 147: 132-42. 
[63] 
Colombo M, Fernández I, Abdurakhmanov D, et al. Safety and on-treatment efficacy of 
telaprevir: the early access programme for patients with advanced hepatitis C. Gut 
2014; 63: 1150-8. 
[64] 
Marley J. Efficacy, effectiveness, efficiency. Aust Prescr 2000; 23: 114-5. 
[65] 
Singal AG, Higgins PDR, Waljee AK. A primer on effectiveness and efficacy trials. Clin 
Trans Gastroenterol 2014; 5 (e45): 1-4. 
[66] 
Marcellin P, Cheinquer H, Curescu M, et al. High sustained virologic response rates in 
rapid virologic response patients in the large real-world PROPHESYS cohort confirm 
results from randomized clinical trials. Hepatology 2012; 56: 2039-50. 
[67] 
Thompson AJ, Muir AJ, Sulkowski MS, et al. IL28B polymorphism improves viral 
kinetics and is the strongest pre-treatment predictor of SVR in HCV-1 patients. 
Gastroenterology 2010; 139: 120-9. 
[68] 
International Committee of Medical Journal Editors. Available at 
http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-
role-of-authors-and-contributors.html; accessed July 07, 2014. 
 
 
 
 
 
 
 
 
 
 
 
 

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Annex 1  
PAM-13 Questionnaire Sample  

 
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Annex 2. 
Patient Support Program (PSP) Utilization 
Questionnaire  
12 weeks treatment: At Interim early post-treatment visit 
24 weeks treatment: At Interim mid treatment visit and Interim early post-treatment visit 
 
Since the last visit, have you utilized any components from the AbbVie Patient 
Support Program? 
 
 No 
Please ignore questions below and return questionnaire to your physician or study 
nurse 
 
 Yes  
 
Please specify service(s) used: 
 
    Personal support (e.g. Care Coach)  
 
    Educational and information material (e.g. magazines, leaflets, diaries)  
 
 Printed 
Please specify how often used:   Usually daily 
 
 
 
 
 
 
 
 
 
 
 
 Several times per week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Usually once weekly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Less than once weekly 
 
 Additional digital and mobile resources  
 
 Reminders  
 
 

 
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Please specify your level of satisfaction:  Very good 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Good 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Satisfactory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Poor 
 
 Additional digital and mobile resources  
 
 
 Reminders  
 
Please specify your level of satisfaction:  Very good 
 
 
 
 
 
  
 
 
 
 
 
 
 
 Good 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 Satisfactory 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 Poor 
 
 

 
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Annex 4. 
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