Clinical trial NCT02517528
Conditions: Chronic Hepatitis C Virus (HCV)
Keywords: HCV Infection Compensated Cirrhosis
Sponsor: AbbVie
Start date: 2015-07-20; Completion date: 2017-03-16
Enrollment: 104 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, open-label, multicenter study evaluating the efficacy and safety of ABT-450/r/ ABT-267 and ABT-333 coadministered with RBV for 12 weeks in HCV genotype 1b, treatment naïve and Interferon (IFN) (alpha, beta or pegIFN) plus RBV treatment-experienced Asian adults with compensated cirrhosis.

Detailed description:

Arms: arm 1: ABT-450/r/ABT-267 once daily + ABT-333 twice daily + weight-based RBV divided twice daily for 12 weeks
Interventions: intervention 1: ABT-450/r/ABT-267 intervention 2: ABT-333 intervention 3: ribavirin
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Tablet

Protocol documents:
Prot_000.pdf: 
ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
1
1.0
Title Page
Clinical Study Protocol M14-491
An Open-Label Study to Evaluate the Safety and 
Efficacy of ABT-450/Ritonavir/ABT-267
(ABT-450/r/ABT-267) and ABT-333 Coadministered 
with Ribavirin (RBV) in Treatment-Naïve and 
Treatment-Experienced Asian Adults with 
Genotype 1b Chronic Hepatitis C Virus (HCV) 
Infection and Compensated Cirrhosis
AbbVie Investigational
  Product:
ABT-450/r/ABT-267, ABT-333
Date:
11 February 2015
Development Phase:
3
Study Design:
This is an open-label combination drug study.
Investigator:
Multicenter.  Investigator information is on file at AbbVie 
Sponsor:
AbbVie
Sponsor/Emergency
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie
/$5


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
2
1.1
Synopsis
AbbVie Inc.
Protocol Number:  M14-491
Name of Study Drug:  ABT-450, ritonavir, 
ABT-267, ABT-333
Phase of Development:  3
Name of Active Ingredient:  
ABT-450
ritonavir
ABT-267
ABT-333 
Date of Protocol Synopsis:  11 February 2015
Protocol Title:  An Open-Label Study to Evaluate the Safety and Efficacy of ABT-450/Ritonavir/ 
ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in 
Treatment-Naïve and Treatment-Experienced Asian Adults with Genotype 1b Chronic Hepatitis C Virus 
(HCV) Infection and Compensated Cirrhosis
Objectives:  
The primary objectives of this study are to assess the safety and to compare the percentage of subjects 
achieving SVR12 rate (the percentage of subjects achieving a 12 week sustained virologic response, 
SVR12, [HCV ribonucleic acid (RNA), < lower limit of quantification (LLOQ), 12 weeks following 
therapy] and the percentage of subjects achieving SVR24 [HCV RNA < LLOQ, 24 weeks following 
therapy] (SVR24 for China only) following 12 weeks of treatment with co-formulated ABT-450, ritonavir 
and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with ribavirin to the historical SVR 
rate of telaprevir plus pegIFN and RBV therapy in HCV genotype 1b-infected cirrhotic adults.  
The secondary objectives of this study are to demonstrate the effect of the DAA combination regimen on 
HCV RNA levels during and after treatment as measured by on-treatment virologic failure and 
post-treatment relapse, respectively.
Investigator:  Multicenter trial:  Investigator information is on file at AbbVie.
Study Sites:  Approximately 18 sites.
Study Population:  Treatment-naïve and previous IFN (alpha, beta or pegIFN) with RBV therapy 
treatment-experienced HCV genotype 1b Chinese, Korean, and Taiwanese adults with compensated 
cirrhosis, aged 18 to 70 years of age, inclusive.
Number of Subjects to be Enrolled:  Approximately 100 subjects; 60 from China, 20 from South Korea 
and 20 from Taiwan.
Methodology:  
This is a Phase 3, open-label, multicenter study evaluating the efficacy and safety of ABT 450/r/ 
ABT-267 and ABT-333 coadministered with ribavirin for 12 weeks in HCV genotype 1b, 
treatment-naïve and IFN (alpha, beta or pegIFN) plus RBV treatment-experienced Asian adults with 
compensated cirrhosis.
Treatment will consist of:  ABT-450/r/ABT-267 150/100/25 mg once daily (QD) + ABT-333 250 mg 
twice daily (BID) + RBV* for 12 weeks.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
3
Methodology (Continued):
*
RBV will be administered weight-based 1000 – 1200 mg divided to twice daily.
Subjects meeting the eligibility criteria will be enrolled and begin the 12-week treatment period.  
Approximately 100 subjects are will be enrolled.  A minimum of 35 treatment-naïve and 
35 treatment-experienced subjects will be enrolled.
The treatment-experienced subjects are defined as follows: 
!
Non-responder:  Received at least 12 weeks of IFN (alpha, beta or pegIFN) with RBV therapy 
for the treatment of HCV and failed to achieve undetectable HCV RNA (HCV RNA < LLOD) at 
the end of treatment, or 
!
Relapser:  Received IFN (alpha, beta or pegIFN) with RBV therapy for the treatment of HCV 
and was undetectable at or after the end of treatment, but subsequently had detectable HCV 
RNA within 24 weeks of treatment follow-up; or
!
IFN (alpha, beta or pegIFN) with RBV therapy Intolerant:  treatment of HCV was discontinued 
during the treatment period due to intolerance to any of the components of the IFN based 
therapy.
This study will consist of a Treatment Period and a Post-Treatment (PT) Period.  All subjects dosed with 
study drug who complete or prematurely discontinue study drug will be followed for 48 weeks in the 
Post-Treatment Period, to monitor safety, HCV RNA level, the emergence and persistence of viral 
variants and assessment of patient reported outcomes (PROs). 
Visits will occur during the treatment period at Day 1, Weeks 1, 2, 4, 6, 8, 10, and 12 and Post-Treatment 
Weeks 2, 4, 8, 12, 24, 36, and 48 for all subjects on study.
The safety data will be reviewed by the sponsor, as this is an open-label study, and by an independent 
Data Monitoring Committee (DMC) during the Treatment Period of the study.
Virologic Failure Criteria – The following criteria will be considered evidence of virologic failure.  
!
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA 
measurements of > 1 log10 IU/mL above nadir) at any time point during treatment;
!
Failure to achieve HCV RNA < LLOQ by Week 6; or
!
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements ≥ LLOQ) 
at any point after HCV RNA < LLOQ during treatment.
Confirmatory testing should be completed as soon as possible.  If any of the above criteria are met for a 
subject in the Treatment Period, study drug will be discontinued.
The Sponsor will evaluate efficacy throughout the Treatment and Post-Treatment Periods in this 
open-label study.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female of Chinese, South Korean, and Taiwanese descent with full Chinese, South Korean, 
and Taiwanese parentage between the ages of 18 and 70 years, inclusive, at the time of Screening.
2.
Chronic HCV-infection prior to study enrollment.  Chronic HCV-infection is defined as one of the 
following:


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
4
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
!
Positive for anti-HCV antibody (Ab) or HCV RNA > 1000 IU/mL at least 6 months before 
Screening, and positive for HCV RNA and anti-HCV Ab at the time of Screening; or 
!
Positive for HCV RNA > 1000 IU/mL at the time of Screening with a liver biopsy consistent 
with chronic HCV-infection (or a liver biopsy performed prior to enrollment with evidence of 
chronic hepatitis C disease).
3.
Screening laboratory result indicating HCV genotype 1b-infection.
4.
Compensated cirrhosis defined as a Child-Pugh Score of ≤ 6 at Screening.
5.
Per local standard practice, documentation of cirrhosis by one of the following methods:  
!
Diagnosis on previous liver biopsy or liver biopsy conducted during screening e.g., Metavir 
Score of > 3 (including 3/4 or 3 – 4), Ishak score of > 4 or,
!
FibroScan score ≥ 14.6 kPa within 6 months of Screening or during the Screening Period.
Main Exclusion:  
1.
HCV genotype performed during screening indicating unable to genotype or infection with any other 
HCV genotype.
2.
Positive test result at Screening for Hepatitis B surface antigen (HBsAg), or HBV DNA > LLOQ if 
HBsAg negative, or anti-Human Immunodeficiency virus antibody (HIV Ab).
3.
Use of known strong inducers of cytochrome P450 3A (CYP3A) or strong inhibitors of CYP2C8 
within 2 weeks or within 10 half-lives, whichever is longer, of the respective medication/supplement 
prior to study drug administration.
4.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical history of liver 
decompensation including ascites (noted on physical exam), variceal bleeding, or hepatic 
encephalopathy.
5.
Serum Alpha-Fetoprotein (sAFP) > 100 ng/mL at Screening.
6.
Confirmed presence of hepatocellular carcinoma (HCC) indicated on imaging techniques such as 
computed tomography (CT) scan or magnetic resonance imaging (MRI) within 3 months prior to 
Screening or on an ultrasound performed at Screening (a positive ultrasound result should be 
confirmed with CT scan or MRI.)
7.
Any primary cause of liver disease other than chronic HCV-infection, including but not limited to 
the following:
!
Hemochromatosis
!
Alpha-1 antitrypsin deficiency
!
Wilson's disease
!
Autoimmune hepatitis
!
Alcoholic liver disease
!
Drug-related liver disease
Steatosis and steatohepatitis on a liver biopsy coincident with HCV-related changes would not 
be considered exclusionary unless the steatohepatitis is considered to be the primary cause of the 
liver disease.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
5
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
8.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Alanine aminotransferase (ALT) > 7 × upper limit of normal (ULN)
!
Aspartate aminotransferase (AST) > 7 × ULN
!
Estimated Glomerular filtration rate adjusted for the Asian population (eGFR) 
< 50 mL/min/1.73m2 as estimated by the C-MDRD method, modified for the Asian population, 
according to the following formula:  eGFR = 175 × (Serum Creatinine) –1 234 × (Age) –0 179 × 
(0.79 if Female)
!
Albumin < 2.8 g/dL
!
International normalized ratio (INR) > 2.3.  Subjects with a known inherited blood disorder and 
INR > 2.3 may be enrolled with permission of the AbbVie Study Designated Physician
!
Hemoglobin < LLN
!
Platelets < 60,000 cells per mm3
!
Absolute neutrophil count (ANC) < 1200 cells/μL 
!
Total bilirubin ≥ 3.0 mg/dL
Investigational Products:
!
ABT-450/Ritonavir/ABT-267 75 mg/50 mg/12.5 mg tablet
!
ABT-333 250 mg tablet
!
Ribavirin 200 mg tablet (for Korea and Taiwan)
!
Ribavirin 100 mg tablet (for China)
Doses:
!
ABT-450/Ritonavir/ABT-267 150/100/25 mg QD
!
ABT-333 250 mg BID
!
Ribavirin weight-based dosing 1000 to 1200 mg divided twice daily
Mode of Administration:
Oral
Duration of Treatment:  
Subjects will receive ABT-450/Ritonavir/ABT-267 and ABT-333 co-administered with RBV for 
12 weeks.
Criteria for Evaluation:
Efficacy:  
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
Patient Reported Outcomes (PROs):
The change in general and disease-specific Health Related Quality of Life (HRQoL) will be assessed 
using the SF-36v2 (Short Form 36-Version 2) and HCV Patient Reported Outcomes (HCVPRO) 
instruments, respectively.  Health State Utility will be measured using the EuroQol-5 Dimensions-5 
Level (EQ-5D-5L).


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
6
Criteria for Evaluation (Continued):  
Resistance:  
For subjects receiving study drugs who experience virologic failure, the amino acid variants at signature 
resistance-associated amino acid positions by population nucleotide sequencing at baseline compared to 
the prototypic reference sequence, the amino acid variants by population nucleotide sequencing at 
available post-baseline time points compared to baseline, and the amino acid variants at signature 
resistance-associated positions by population nucleotide sequencing compared to the prototypic reference 
sequence will be tabulated and summarized.  In addition, a listing of amino acid variants that emerge in 
isolates from at least 2 subjects will be provided, and the persistence of viral resistance-associated amino 
acid variants will be summarized.
Pharmacokinetic:  
Plasma concentrations for ABT-450, possible ABT-450 metabolites, ritonavir, ABT-267, ABT-267 
metabolites ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites and RBV will be 
determined at each study visit up to the end of treatment.
Values for the pharmacokinetic parameters of ABT-450, ABT-267, ritonavir, ABT-333, ABT-333 M1 
metabolite, and ribavirin including the Cmax, Tmax, Ctrough, and AUC will be determined by 
non-compartmental methods using data from subjects who participate in intensive pharmacokinetic 
sampling in the study.  Additional parameters or summaries may be determined if useful in the 
interpretation of the data.
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-Lead ECGs and vital signs.
Statistical Methods:  
Efficacy:  
For South Korea and Taiwan, the primary efficacy endpoint is:
A1. SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN and RBV therapy –
lower confidence bound of 2-sided 95% confidence interval (LCB) for the percentage of 
subjects with SVR12 must exceed 67% to achieve superiority. 
For China, the primary efficacy endpoints are as follows.  In order to control the Type 1 error rate of 
0.05, a fixed-sequence testing procedure will be used to proceed through the primary endpoints in the 
order numbered below. 
B1.
SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN and RBV therapy –
lower confidence bound of 2-sided 95% confidence interval (LCB) for the percentage of 
subjects with SVR12 must exceed 67% to achieve superiority.
B2.
SVR24:  Superiority to the historical SVR rate for telaprevir plus pegIFN and RBV therapy –
lower confidence bound of 2-sided 95% confidence interval (LCB) for the percentage of 
subjects with SVR24 must exceed 67% to achieve superiority.
To test each hypothesis that the percentage of treatment-naïve and IFN based treatment experienced HCV 
genotype 1b-infected Asian subjects with compensated cirrhosis treated with ABT 450/r/ABT 267 + 
ABT-333 + RBV for 12 weeks who achieve SVR12/SVR24 is superior to a clinically meaningful threshold 
based on historical SVR rates for the HCV genotype 1b-infected population treated with telaprevir plus 
pegIFN and RBV.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
7
Statistical Methods (Continued):  
Efficacy (Continued):  
The percentage of subjects with SVR12/SVR24 will be calculated with a 2-sided 95% CI using Wilson 
score method, and the LCB will be compared to the defined threshold.  The LCB of the 95% CI of 
SVR12/SVR24 must be greater than 67% in order for the regimen to be considered superior.
The secondary endpoints are:
!
The percentage of subjects with on treatment virologic failure (defined as confirmed HCV RNA 
≥ the lower limit of quantitation (LLOQ) (defined as 2 consecutive HCV RNA measurements 
≥LLOQ) at any point during treatment after HCV RNA < LLOQ, confirmed increase from 
nadir in HCV RNA (two consecutive HCV RNA measurements > 1 log10 IU/mL above nadir) at 
any time point during treatment or HCV RNA ≥ LLOQ persistently during treatment with at 
least 6 weeks (≥ 36 days) of treatment
!
The percentage of subjects with  relapse by Post-Treatment Week 12 (defined as confirmed 
HCV RNA ≥ LLOQ between end of treatment and 12 weeks after the last dose of study drugs 
among subjects completing treatment and with HCV RNA < LLOQ at the end of treatment) and,
!
The percentage of subjects with relapse by Post-Treatment Week 24 (defined as confirmed HCV 
RNA ≥ LLOQ between end of treatment and 24 weeks after the last dose of study drugs among 
subjects completing treatment and with HCV RNA < LLOQ at the end of treatment).
The percentages (with 2-sided 95% confidence intervals using the Wilson Score method to the binomial 
distribution) of the subjects with on treatment virologic failure and post-treatment relapse will be 
calculated and summarized.
Resistance:
The following resistance information will be provided for subjects receiving active study drugs who 
experience virologic failure (who have HCV RNA ≥ 1000 IU/mL):  1) the amino acid variants at baseline 
at signature resistance-associated positions identified by population nucleotide sequencing and 
comparison to the prototypic reference sequence, 2) the amino acid variants in available post-baseline 
samples identified by population nucleotide sequencing and comparison to the baseline sequence, and 
3) the amino acid variants in available post-baseline samples at signature resistance-associated positions 
identified by population nucleotide sequencing and comparison to the prototypic reference sequence.  
In addition, a listing of amino acid variants that emerge in isolates from at least 2 subjects will be 
provided, and the persistence of viral resistance-associated amino acid variants will be summarized.
Pharmacokinetic:  
Plasma concentrations for ABT-450, possible ABT-450 metabolites, ritonavir, ABT-267, ABT-267 
metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites and RBV will be 
tabulated and summarized at each study visit through the end of the Treatment Period.
Values for the pharmacokinetic parameters of ABT-450, ABT-267, ritonavir, ABT-333, ABT-333 M1 
metabolite, and ribavirin including the Cmax, Tmax, Ctrough, and AUC will be summarized and tabulated.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
8
Statistical Methods (Continued):
Safety:  
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term.  The 
number and percentage of subjects with serious treatment-emergent adverse events and the number and 
percentage of subjects with treatment-emergent adverse events leading to study drug discontinuation will 
also be provided.
Tabulations will also be provided in which the number of subjects reporting an adverse event (MedDRA 
preferred term) is presented by grading and relationship to study drug(s). 
Change from baseline in laboratory tests and vital sign measurements to each time point of collection will 
be summarized descriptively.  Laboratory test and vital sign values that are potentially clinically 
significant, according to predefined criteria, will be identified and the number and percentage of subjects 
with potentially clinically significant values during treatment will be calculated.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
9
1.2
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
ABT-450/r/ABT-267
ABT-450 co-formulated with ritonavir and ABT-267
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
AUC
Area Under the Concentration Curve
BID
Twice Daily
BMI
Body mass index
BOC
Boceprevir
BUN
Blood urea nitrogen
CL/F
Apparent Oral Clearance
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed Tomography
CYP2C8
Cytochrome P450 2C8
CYP3A
Cytochrome P450 3A
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
EOTR
End of treatment response
EU
European Union


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
10
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Health State Instrument 
GCP
Good Clinical Practice
GCSF
granulocyte colony stimulating factor 
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HCVPRO
Hepatitis C Virus Patient Reported Outcomes Instrument
Hemoglobin A1c
Glycated hemoglobin
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
HRQoL
Health Related Quality of Life
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
IL28B
Interleukin 28B
IMP
Investigational Medical Product
INR
International normalized ratio
IP-10
Interferon gamma-induced protein 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to Treat
IU
International units
IUD
Intrauterine device
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
MID
Minimally Important Difference
MRI
Magnetic Resonance Imaging


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
11
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
PCR
Polymerase Chain Reaction
PCS
Physical Component Summary
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PK
Pharmacokinetic
POR
Proof of Receipt
PRO
Patient Reported Outcomes
PT
Post-Treatment
QD
Once daily
QTc
QT interval corrected for heart rate
QTcF
QTc using Fridericia's correction formula
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
ROC
Receiver Operating Characteristic
RT-PCR
Reverse transcriptase PCR
RVR
Rapid virologic response
SAE
Serious adverse event
sAFP
Serum Alpha-Fetoprotein
SAS
Statistical Analysis System
SD
Standard Deviation
SF-36 V2
Short Form 36-Version 2
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
SVR4
Sustained virologic response 4 weeks post dosing
SVR12
Sustained virologic response 12 weeks post dosing
SVR24
Sustained virologic response 24 weeks post dosing
TP
Treatment Period


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
12
TVR
Telaprevir
ULN
Upper limit of normal
VAS
Visual analogue scale
V/F
Apparent Volume of distribution
WBC
White blood cells
Definition of Terms
Non-responder
Received at least 12 weeks of IFN (alpha, bet or pegIFN) with RBV 
therapy for the treatment of HCV and failed to achieve undetectable 
HCV RNA (HCV RNA < LLOD) at the end of treatment
Relapser
Received IFN-based therapy (IFN [alpha, beta or pegIFN] with RBV 
therapy) for the treatment of HCV and was undetectable at or after the 
end of treatment, but subsequently had detectable HCV RNA within 
24 weeks of treatment follow-up
IFN-based therapy (IFN 
[alpha, beta, or pegIFN] with 
RBV therapy) Intolerant
Treatment of HCV was discontinued during the treatment period due to 
intolerance to any of the components of the IFN RBV therapy.
Study Drug
ABT-450/r/ABT-267, ABT-333, RBV
Study Day 1
First day of study drug dosing 
Treatment Period
Baseline/Day 1 through the day of last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 48 or 
the day of Post-Treatment Discontinuation


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
13
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Synopsis .....................................................................................................2
1.2
List of Abbreviations and Definition of Terms..........................................9
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................35
3.2
Benefits and Risks....................................................................................35
4.0
Study Objectives....................................................................36
4.1
Primary Objectives...................................................................................36
4.2
Secondary Objectives...............................................................................36
5.0
Investigational Plan...............................................................37
5.1
Overall Study Design and Plan:  Description ..........................................37
5.1.1
Screening..................................................................................................38
5.1.1.1
Rescreening..............................................................................................38
5.1.2
Treatment Period (TP) .............................................................................39
5.1.3
Post-Treatment (PT) Period .....................................................................41
5.2
Selection of Study Population..................................................................42
5.2.1
Inclusion Criteria .....................................................................................42
5.2.2
Exclusion Criteria ....................................................................................45
5.2.3
Prior and Concomitant Therapy...............................................................48
5.2.3.1
Prior HCV Therapy..................................................................................49
5.2.3.2
Concomitant Therapy...............................................................................49
5.2.3.3
Prohibited Therapy...................................................................................50
5.3
Efficacy, Pharmacokinetic, Optional Pharmacogenetic and Safety 
Assessments/Variables.............................................................................51
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................51
5.3.1.1
Study Procedures .....................................................................................58
5.3.1.2
Meals and Dietary Requirements.............................................................70
5.3.1.3
Blood Samples for Pharmacogenetic Analysis ........................................70
5.3.2
Drug Concentration Measurements .........................................................71
5.3.2.1
Collection of Samples for Analysis .........................................................71


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
14
5.3.2.2
Handling/Processing of Samples .............................................................71
5.3.2.3
Disposition of Samples ............................................................................71
5.3.2.4
Measurement Methods.............................................................................72
5.3.3
Efficacy Variables....................................................................................72
5.3.3.1
Primary Variable......................................................................................72
5.3.3.2
Secondary Variable(s)..............................................................................72
5.3.3.3
Resistance Variables ................................................................................72
5.3.4
Safety Variables .......................................................................................73
5.3.5
Pharmacokinetic Variables ......................................................................73
5.3.6
Pharmacogenetic Variables......................................................................73
5.4
Removal of Subjects from Therapy or Assessment .................................74
5.4.1
Discontinuation of Individual Subjects....................................................74
5.4.1.1
Virologic Failure Criteria.........................................................................75
5.4.2
Discontinuation of Entire Study...............................................................76
5.5
Treatments................................................................................................76
5.5.1
Treatments Administered.........................................................................76
5.5.2
Identity of Investigational Product...........................................................78
5.5.2.1
Packaging and Labeling...........................................................................78
5.5.2.2
Storage and Disposition of Study Drugs..................................................79
5.5.3
Method of Assigning Subjects to Treatment ...........................................79
5.5.4
Selection and Timing of Dose for Each Subject......................................79
5.5.5
Blinding....................................................................................................80
5.5.5.1
Data Monitoring Committee ....................................................................80
5.5.6
Treatment Compliance.............................................................................80
5.5.7
Drug Accountability.................................................................................82
5.6
Discussion and Justification of Study Design..........................................83
5.6.1
Discussion of Study Design and Choice of Control Groups....................83
5.6.2
Appropriateness of Measurements...........................................................83
5.6.3
Justification of Primary Endpoint Success Criteria .................................83
5.6.4
Suitability of Subject Population .............................................................87
5.6.5
Selection of Doses in the Study ...............................................................87
6.0
Adverse Events.......................................................................92
6.1
Definitions................................................................................................92


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6.1.1
Adverse Event..........................................................................................92
6.1.2
Serious Adverse Events ...........................................................................93
6.2
Adverse Event Severity............................................................................94
6.3
Relationship to Study Drug......................................................................95
6.4
Adverse Event Collection Period.............................................................95
6.5
Adverse Event Reporting.........................................................................96
6.6
Pregnancy.................................................................................................98
6.7
Toxicity Management ..............................................................................99
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events ........................................................................................99
6.7.2
Grades 3 or 4 Laboratory Abnormalities and Severe or Serious 
Adverse Events ......................................................................................100
6.7.3
Management of Hemoglobin Decreases ................................................101
6.7.4
Management of Transaminase Elevations .............................................102
6.7.5
Management of eGFR Decreases...........................................................103
7.0
Protocol Deviations..............................................................104
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................105
8.1
Statistical and Analytical Plans..............................................................105
8.1.1
Demographics ........................................................................................107
8.1.2
Efficacy..................................................................................................107
8.1.2.1
Primary Efficacy Endpoints...................................................................108
8.1.2.2
Secondary Efficacy Endpoints...............................................................109
8.1.2.3
Sensitivity Analyses for the Primary Endpoint......................................110
8.1.2.4
Subgroup Analysis .................................................................................111
8.1.2.5
Additional Efficacy Endpoints...............................................................112
8.1.3
Patient Reported Outcomes....................................................................113
8.1.4
Resistance Analyses...............................................................................114
8.1.5
Safety .....................................................................................................116
8.1.5.1
Adverse Events ......................................................................................116
8.1.5.2
Clinical Laboratory Data........................................................................116
8.1.5.3
Vital Signs Data .....................................................................................117
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................117


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8.2
Determination of Sample Size ...............................................................119
9.0
Ethics.....................................................................................120
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................120
9.2
Ethical Conduct of the Study .................................................................121
9.3
Subject Information and Consent...........................................................121
10.0
Source Documents and Case Report Form 
Completion ...........................................................................121
10.1
Source Documents .................................................................................121
10.2
Case Report Forms.................................................................................122
11.0
Data Quality Assurance......................................................123
12.0
Use of Information...............................................................123
13.0
Completion of the Study .....................................................123
14.0
Investigator's Agreement....................................................125
15.0
References.............................................................................126
List of Tables
Table 1.
SVR12 Rates (Intent-to-Treat, Missing = Failure) in Phase 3 by 
Subpopulation of Subtype, Prior Treatment History, and Presence 
or Absence of Cirrhosis ...........................................................................27
Table 2.
Overview of Treatment-Emergent Adverse Events (AE)........................32
Table 3.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline 
Lab Abnormalities ...................................................................................33
Table 4.
Medications Contraindicated for Use with the Study Drug 
Regimen ...................................................................................................47
Table 5.
Study Activities – Treatment Period (TP)................................................52
Table 6.
Study Activities – Post-Treatment (PT) Period .......................................56
Table 7.
Clinical Laboratory Tests.........................................................................61
Table 8.
Child-Pugh Classification of Severity of Cirrhosis .................................65
Table 9.
Identity of Investigational Products .........................................................78
Table 10.
Estimated SVR Rates for Telaprevir Plus PegIFN and RBV in 
Cirrhotic Subjects.....................................................................................84


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Table 11.
SVR Rates for Telaprevir Plus pegIFN and RBV Therapy in 
Treatment-Naïve Subjects by Subgenotype.............................................85
Table 12.
Estimated SVR Rates for Telaprevir-Based Therapy in Treatment 
Experienced Subjects by Subgenoytpe ....................................................86
Table 13.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases ..........................................................................102
Table 14.
Management of Confirmed ALT Elevations .........................................103
Table 15.
Dosing of RBV in Subjects with Renal Impairment..............................104
List of Figures
Figure 1.
Worldwide Distribution of HCV Genotypes ...........................................19
Figure 2.
HCV Genotypes Distributions in China ..................................................21
Figure 3.
Adverse Event Collection ........................................................................96
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................133
Appendix B.
List of Protocol Signatories....................................................................135
Appendix C.
Clinical Toxicity Grades ........................................................................136


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with over 170 million 
individuals chronically infected worldwide.1  Cirrhosis is a common sequelae of HCV 
infection occurring in approximately 20% of patients.2  Complications of cirrhosis include 
hepatic decompensation (ascites, encephalopathy, variceal hemorrhage, hepatorenal 
syndrome, or hepatic synthetic dysfunction) and hepatocellular carcinoma ensue at a rate 
of about 3% per year.3-6  Without liver transplantation, decompensated cirrhosis leads to 
death in 50% to 72% of patients after 5 years.7  As a result of the high prevalence of HCV 
infection and resultant complications, HCV is the leading indication for liver
transplantation in the United States and the world as a whole.8
World Geographical Distribution of HCV Genotypes
HCV can be classified into 6 major genotypes based on sequence divergence of 30%.  In 
North America and Western Europe, HCV genotype 1 (subgenotypes 1a and 1b) is the 
most prevalent, causing > 75% of all infections in some countries (Figure 1).9  In Asia, 
genotypes 1 (subgenotype 1b), 2, 3, and 6 are the most common types of HCV 
infections.10


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Figure 1.
Worldwide Distribution of HCV Genotypes
Epidemiology of HCV in China
Chronic HCV infection is recognized as an important cause of chronic hepatitis, cirrhosis, 
and hepatocellular carcinoma in China.11  Epidemiological studies in the mid-1990s 
reported a national prevalence of 3.2%,12 but other reports suggested a prevalence ranging 
from 0.29% to 9.6%.13
These studies showed that the frequency of HCV infection in China varied by 
geographical region within the country, age, and population groups and also between rural 
and metropolitan areas.  With the Yangtze River as the boundary, the prevalence rate in 
northern China (3.6%) was higher than southern China (2.9%).12  Anti-HCV positive rates 
were reported to increase gradually with age, from 2% in 1 year old to 3.9% in 50 to 
59 year old groups, respectively.12  A study of individuals > 55 years old in the rural 


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Henan province found a prevalence of 9.6%,14 while Liu et al., documented a prevalence 
of 0.9% in persons 25 to 65 years old in Anyang.15
In 2006, the National Nutritional Survey estimated that the overall national prevalence is 
approximately 0.43%, which represents approximately 5.1 million Chinese infected with 
HCV.16  A recent study reported that 25 million Chinese were infected with HCV 
chronically and advance liver diseases were frequently detected.17  Among human 
immunodeficiency virus (HIV)-positive Chinese patients, it is estimated that 60% to 90% 
are coinfected with HCV.16  Among patients with chronic hepatitis B, it is estimated that 
11% to 15% are coinfected with HCV.18,19  In addition, 50% of the patients receiving
dialysis in China are reported to be infected with HCV.16  Together, these data suggest 
that a significant number of Chinese patients are at risk for the morbidity and mortality 
associated with HCV infection.
An important epidemiologic feature of HCV infections in China is the distribution of 
genotypes (Figure 2).  HCV subgenotype 1b is the most common genotype in China with 
a prevalence of 66%,20 but it has been reported to be as high as 90% in some areas of 
southern China.16  HCV genotype 2 is the second most common genotype, with a 
prevalence of 14%,20 increasing gradually from southern to northern China (Figure 2).16  
Other HCV genotypes include genotype 6, which is detected in approximately 10% of 
cases, especially in the south region of China; and genotype 3 which is reported in 
approximately 4.3% of the cases in China (Study M14-491).20  Majority of these chronic 
HCV-infected patients in China have IL28B CC genotype.17


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Figure 2.
HCV Genotypes Distributions in China
In summary, the current epidemiology data indicate that HCV infections are an important 
public health problem in China and that the most prevalent genotypes in the general 
population countrywide are HCV subgenotype 1b and genotype 2.  HCV genotypes 3 and 
6 are detected in the southern region of China, but their frequency is reported to be 
increasing in recent years.
Epidemiology of HCV in South Korea
South Korea is a relatively low prevalence area for HCV, while known as a high 
prevalence area for HBV infection.  For this reason less attention has been given to HCV 
related liver diseases and few studies have been focused in the analyses of clinical and 
epidemiological characteristics of HCV-infection in Korea.21  A recent nationwide 
seroprevalence survey showed that the age, sex, and area-adjusted prevalence of 


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anti-HCV antibody in Korean adults in 2009 was 0.78%,22 whereas the nationwide 
seroprevalence of HBsAg in persons aged > 10 years in 2009 was 3.2% according to the 
results of the National Health and Nutrition Examination Survey.23  In Korea, chronic 
liver disease is caused by HCV in approximately 10 – 15% of patients and by HBV in 
65% to 75% of patients.  Few studies have reported the prevalent HCV genotypes in 
Korea.24,25  An assessment of anti-HCV antibodies detection performed in blood donor
revealed that genotype 1b and 2a/c are dominant in Korea and genotypes 4 and 6 were 
identified in a small proportion of the tested population.26
However, after the launch of new therapeutics such as DAA in 2011, the importance of 
HCV infection as a cause of liver disease has been increasingly recognized in 
South Korea.
A recent evaluation of a large multicenter cohort of 1,173 anti-HCV antibody positive 
adult patients shown that the mean age of the HCV patients is around 55 years old, and 
half of the infected people were women.27  The large majority presented with chronic 
hepatitis (66%) as the clinical diagnosis, followed by cirrhosis of the liver (15%), and 
HCC (10%).  In patients with HCC, cirrhosis was present in 87% of the patients.  The 
proportion of patients with Child class B or C decompensated liver cirrhosis was 8.1%.  
Comparison of clinical and epidemiological characteristics between patients with 
subgenotype 1b and those with non-1b genotypes (genotypes 2, 3, 4, and 6) showed that 
advanced liver disease such as cirrhosis of the liver or HCC was more prevalent in the 
subgenotype 1b group than in non-1b genotypes (29.4% versus 22.5%, respectively; 
P = 0.02).27
Antiviral therapy was initiated in 43% of patients, which is a higher proportion than that 
reported in studies conducted in the US and Europe.27-29  The patients who had received
antiviral therapy included those with chronic hepatitis (73.2%), cirrhosis of the liver 
(15.2%), HCC (8.0%), and acute hepatitis (3.6%).  Currently, most HCV patients were 
treated with a combination of pegIFN/RBV (65%), and the remainder were treated with
conventional interferon (15%), or a combination of conventional interferon alpha and 
RBV (17%), or pegIFN alone (3%).  The duration of treatment is 48 weeks.27


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Epidemiology of HCV in Taiwan
Similar to the case in China, the frequency of HCV infection in Taiwan varied by 
geographical region within the country, age, and population groups.  There is a wide 
geographic variation in HCV seroprevalence in Taiwan.  The seroprevalence of anti-HCV 
varied from 1.7% to 57.9% in different townships in different studies reported over the 
period from 1992 to 2003.  In the HCV hyperendemic areas, transmission may partly be 
related to the iatrogenic routes.  People acquired HCV infection when they received 
medical or dental procedures, blood transfusion, medical injections, hemodialysis, 
acupuncture, and similar procedures.30,31
In Taiwan, the prevalence of HCV is estimated at 4% to 10% in the general 
population,30,32 however increases dramatically in some subpopulations.  The prevalence 
of HCV goes up to 30% to 56% in HIV-positive patients in studies that included different 
proportions of injecting drug users (IDUs)31,33,34 and up to 90% in hemophilic patients.35  
After an outbreak of HIV infection occurred among IDUs in Taiwan between 2003 and 
2007, HCV seropositivity was 95% to 97% among HIV-positive IDUs.36  A 
seroprevalence of anti-HCV positivity also increases gradually with age, from 4.3% in 
subjects with 60 to 69 years old, 6.3% in subjects with 70 to 79 years old, and 8.8% in 
subjects with > 80 years old group.30,37
In regards to HCV subtype distribution, a difference is observed between the north and 
south regions.  The most common subtype in the south are 1b and genotype 2, while 1b 
alone is the most common genotype observed in the north regions.38
HCV infection is highly associated to mortality due progressive liver diseases (liver 
cancer, and cirrhosis).  However, chronic hepatitis C has been also associated with an 
increased mortality from extra-hepatic diseases, including circulatory diseases renal 
diseases, and extra-hepatic cancers.39  Currently, the local standard of care treatment has 
been pegINF/RBV for 24 – 48 weeks pending on patients' clinical and virological 
characteristics.


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In summary, the prevalence of HCV in China, South Korea, and Taiwan varies depending 
on the research and region from less that 1% to 10%.  Most patients with Chronic HCV 
are middle-age.  Subgenotype 1b is the predominant serotype detected in more than 60% 
of the patients followed by genotype 2.  The current standard of care (SoC) for the 
treatment of chronic HCV infection in these countries is pegIFN combined with RBV.  
SVR rates vary from 50% to 70% among subgenotype 1b, however the pegIFN-RBV 
regimen carries a well described burden of toxicity (e.g., severe anemia, and depression) 
and cumbersome weekly injections.  Therefore, the treatment for chronic HCV in Asian 
could be improved by a regimen that requires shorter treatment duration, provides higher 
SVR rates and a convenient all oral PegIFN-free regimen.
Treatment in HCV Patients with Cirrhosis
Patients with compensated cirrhosis who receive treatment and achieve an SVR (sustained 
virologic response) essentially eliminate their subsequent risk of decompensation, may 
achieve histologic regression, and decrease their risk of hepatocellular carcinoma by 
two-thirds.40-42
While the introduction of the protease inhibitors, telaprevir (TVR) or boceprevir (BOC), 
have increased SVR rates, current treatment is less than optimal as the protease inhibitors 
must be used in combination with pegIFN/RBV, two agents with considerable treatment 
limiting toxicities and treatment may extend for up to 48 weeks.  Furthermore, regardless 
of a patient's treatment history, treatment of HCV infected patients with underlying 
cirrhosis with either telaprevir or boceprevir in combination with pegIFN/RBV results in 
lower rates of SVR when compared to overall response rates:  treatment-naïve patients 
treated with TVR (62% response rate in cirrhotics versus 79% overall response rate in the
ADVANCE study),43,44 prior partial responders treated with TVR (34% response rate in 
cirrhotics versus 59% overall response rate in the REALIZE study),45,46 prior null 
responders treated with TVR (14% response rate in cirrhotics versus 32% overall response 
rate in the REALIZE study),45,46 treatment-naïve patients treated with BOC (31% to 42% 
response rate in cirrhotics versus 62% to 66% overall response in the SPRINT-2 study),47


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and treatment-experienced patients treated with BOC (35% response in cirrhotics versus 
59% overall response rate in the RESPOND-2 study).47
Combinations of multiple DAAs (direct-acting antiviral agent) have the potential of 
further improving HCV treatment by increasing SVR rates, eliminating interferon (IFN), 
increasing the safety and tolerability of treatment, shortening duration of therapy and 
simplifying the treatment algorithm.  In addition, wider application of DAA therapy and 
better responses with combination DAA regimens could significantly reduce the public 
health burden of this disease.
Promising short-term antiviral efficacy results have been reported from IFN-free 
combinations (either with or without RBV) of a protease inhibitor with a nucleoside 
polymerase inhibitor,48 a non-nucleoside polymerase inhibitor,49 or a nonstructural protein 
5A (NS5A) inhibitor.50  Twelve-week SVR (SVR12) rates of 36% (4/11) in HCV genotype 
1-infected null responders and 90% (9/10) in HCV genotype 1b-infected null responders 
have been observed in subjects treated with the combination of a protease inhibitor and 
NS5A inhibitor (BMS 650032 and BMS-790052) for 24 weeks.51,52  Additionally, a recent 
descriptive sub-analysis from the SOUND-C2 study, a Phase 2b study evaluating IFN-free 
treatment with BI 201335 and BI 207127 plus RBV, reported SVR12 rates of 54% (20/37) 
in genotype 1, treatment-naive patients with compensated liver cirrhosis, regardless of IL 
28B allele status.53  Recently, preliminary data from ELECTRON Phase 2 study revealed 
that sofobuvir/ledipavir combination with or without ribavirin for 12 weeks delivered 
100% (11/11) and 70% (7/10) SVR12 in cirrhotic genotype 1 HCV patients respectively.54  
LONESTAR trial also demonstrated 100% (11/11) and 91% (11/11) SVR12 in 
sofobuvir/ledipavir with or without RBV in treatment-experienced cirrhotic HCV 
genotype 1 patients.55
Together, these safety and efficacy data suggest that interferon-free DAA combinations 
may address patient's needs and further advance HCV therapy by increasing SVR rates 
even in difficult-to-treat populations, improving safety and tolerability of treatment, 
reducing duration, and simplifying treatment.


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AbbVie IFN-Free Regimen
AbbVie's IFN-free regimen for the treatment of chronic HCV genotype 1 infection 
includes 3 DAAs targeting different steps in HCV replication.  ABT-450 is a 
nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease inhibitor 
coadministered with the pharmacokinetic enhancer, ritonavir (ABT-450/r); ABT-267 is a 
NS5A inhibitor, and ABT-333 is a NS5B non-nucleoside polymerase inhibitor.  The 
3-DAA regimen has been studied with and without ribavirin in over 2,300 patients in 
Phase 3 trials across a variety of patient populations including compensated cirrhosis.  
Based on Phase 3 data, the regimen with or without RBV is safe, well tolerated and 
efficacious in treatment-naïve and treatment-experienced HCV genotype 1-infected 
subjects.  The overall efficacy results (intent-to-treat) from the Phase 3 studies are listed in 
Table 1.


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Table 1.
SVR12 Rates (Intent-to-Treat, Missing = Failure) in Phase 3 by 
Subpopulation of Subtype, Prior Treatment History, and Presence 
or Absence of Cirrhosis
Subpopulation
3-DAA
12 Weeks 
SVR12
3-DAA + RBV
12 Weeks
SVR12
3-DAA + RBV
24 Weeks
SVR12
Genotype 1b non-cirrhotics
     Naïve
99.0
98.0, 99.5
--
     Null
100
93.5, 94.9
--
     Partial
100
96.0, 100
--
     Relapser
100
97.2, 100
--
Genotype 1a non-cirrhotics
     Naïve
90.2
95.3, 97.0
--
     Null
--
95.4
--
     Partial
--
100
--
     Relapser
--
94.0
--
Genotype 1b cirrhotics
     Naïve
--
100
100
     Null
--
100
100
     Partial
--
85.7*
100
     Relapser
--
100
100
Genotype 1a cirrhotics
     Naïve
--
92.2
92.9
     Null
--
80.0
92.9
     Partial
--
100
100
     Relapser
--
93.3
100
*
Based on N = 7; 6/7 achieved SVR.
Phase 3 Placebo-Controlled Studies:  Studies M11-646 and M13-098 
Study M11-646 and Study M13-098 are randomized, placebo-controlled studies to assess 
the safety and efficacy of 12 weeks therapy with 3-DAA + RBV in HCV genotype 
1-infected treatment-naïve (Study M11-646) and prior pegIFN/RBV non-responders 
(Study M13 098) without cirrhosis.  ABT-450/r/ABT-267 with ABT-333 was given for 


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12 weeks of treatment in combination with RBV.  Subjects randomized to the placebo arm 
received placebo for 12 weeks, after which they received open-label ABT-450/r/ABT-267 
with ABT-333 in combination with RBV for 12 week. 
In Study M11-646, treated subjects (N = 631) had a median age of 52 years (range:  18 to 
70); 54.5% of the subjects were male; 5.4% were black and 5.1% were Hispanic or 
Latino; 16.2% had a body mass index (BMI) greater than or equal to 30 kg/m2; 79.1% had 
baseline HCV RNA levels ≥ 800,000 international units (IU)/mL; 8.7% had bridging 
fibrosis (F3); 67.7% had HCV GT1a; 32.3% had HCV GT1b, and 69.3% had IL28B 
non-CC genotype. 
The SVR12 rate for treatment-naïve subjects receiving 3-DAA + RBV for 12 weeks in 
Study M11-646 was 96.2%.  Virologic failure was noted in 7/322 (2.2%) GT1a subjects 
(on-treatment virologic failure:  n = 1; relapse:  n = 6) and 1/151 (0.7%) GT1b subjects 
(relapse).
In Study M13-098, treated subjects (N = 394) had a median age of 54 years (range:  19 to 
71); 57.6% of the subjects were male; 8.1% were black and 6.3% were Hispanic or 
Latino; 19.8% had a BMI greater than or equal to 30 kg/m2; 87.1% had baseline HCV 
RNA levels ≥ 800,000 IU/mL; 14.5% had bridging fibrosis; 58.4% had HCV GT1a; 
41.4% had HCV GT1b; 89.6% had IL28B non-CC genotype; 49.0% were prior 
pegIFN/RBV null responders; 21.9/% were prior pegIFN/RBV partial responders, and 
29.2% were prior pegIFN/RBV relapsers.  The SVR12 rate for treatment-experienced 
subjects receiving 3-DAA + RBV for 12 weeks was 96.3% in Study M13-098.  Virologic 
failure (all relapse) was noted in 5/173 (2.9%) GT1a subjects and 2/123 (1.6%) GT1b 
subjects.
Phase 3 Regimen-Controlled Studies:  Studies M13-389, M13-961, and M14-002
Studies M13-389, M13-961, and M14-002 are randomized, regimen-controlled studies to 
assess the safety and efficacy of 12 weeks of treatment with 3-DAA + RBV versus 
3-DAA without RBV.  Study M13-961 and Study M14-002 are placebo-controlled 


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studies, while Study M13-389 is an open-label study.  The patient population was 
different in each of the 3 studies.  Study M13-389 enrolled G1b-infected subjects with 
prior non-response to PegIFN/RBV, Study M13-961 enrolled G1b-infected subjects who 
were treatment-naïve, and Study M14-002 enrolled G1a-infected subjects who were 
treatment naïve.  All three studies excluded subjects with cirrhosis.
In Study M13-389, treated subjects (N = 186) had a median age of 57 years (range:  26 to 
70); 54.8% of the subjects were male; 4.8% were black and 3.2% were Hispanic or 
Latino; 21.5% had a BMI greater than or equal to 30 kg/m2; 87.6% had baseline HCV 
RNA levels ≥ 800,000 IU/mL; 14.5% had bridging fibrosis; 90.9% had IL28B non-CC 
genotype; 34.9% were prior pegIFN/RBV null responders; 28.5% were prior 
pegIFN/RBV partial responders, and 36.6% were prior pegIFN/RBV relapsers. 
The SVR12 rates were 96.6% in the 3-DAA + RBV arm and 100% in the 3-DAA without 
RBV arm in Study M13-389.  The 3-DAA regimen without RBV demonstrated 
noninferiority in SVR12 rates compared to 3-DAA + RBV, as the lower bound of the 
95% confidence interval for the difference in response rates was 3.4%, which was above 
the prespecified noninferiority threshold of –10.5%.  No subject in either arm experienced 
on treatment virologic failure or post-treatment relapse. 
In Study M13-961, treated subjects (N = 419) had a median age of 50 years (range:  19 to 
70); 45.8% of the subjects were male; 4.8% were black and 1.7% were Hispanic or 
Latino; 16.5% had a BMI greater than or equal to 30 kg/m2; 73.3% had baseline HCV 
RNA ≥ 800,000 IU/mL; 10.0% had bridging fibrosis; and 79.0% had IL28B non-CC 
genotype. 
The SVR12 rates for treatment-naïve subjects with HCV GT1b infection who received 
either 3-DAA + RBV or 3-DAA without RBV for 12 weeks in Study M13-961 were 
99.5% and 99.0%, respectively.  The 3-DAA regimen demonstrated noninferiority in 
SVR12 rates compared to 3-DAA + RBV, as the lower bound of the 95% confidence 
interval for the difference in response rates was –2.1%, which was above the prespecified 


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noninferiority threshold of –10.5%.  One of the 419 treated subjects (3-DAA + RBV arm) 
experienced on-treatment virologic failure.  
In Study M14-002, treated subjects (N = 305) had a median age of 54 years (range:  19 to 
70); 65.2% of the subjects were male; 11.8% were black and 9.2% were Hispanic or 
Latino; 19.7% had a BMI greater than or equal to 30 kg/m2; 86.6% had baseline HCV 
RNA levels ≥ 800,000 IU/mL; 17.7% had bridging fibrosis; and 69.2% had IL28B 
non-CC genotype. 
The SVR12 rates for treatment-naïve subjects with HCV GT1a infection who received 
either 3-DAA + RBV or 3-DAA without RBV for 12 weeks in Study M14-002 were 
97.0% and 90.2%, respectively.  The SVR12 rate in the 3-DAA arm did not achieve 
noninferiority to the 3-DAA + RBV arm since the lower bound of the 95% confidence 
interval for the difference between arms was –12.0%, below the prespecified –10.5% 
noninferiority margin.  Virologic failure was noted in 2/100 (2.0%) subjects (on treatment 
virologic failure:  n = 1; relapse:  n = 1) in the RBV-containing regimen and 16/205 
(7.8%) subjects (on treatment virologic failure:  n = 6; relapse:  n = 10) in the RBV-free 
regimen.  The difference between arms demonstrates that RBV contributes to the efficacy 
in GT1a-infected patients and suggests that 3-DAA + RBV is the optimal regimen for 
these patients.
A Phase 3 Study in Cirrhotics:  Study M13-099
Study M13-099 is a randomized, multicenter, open-label trial in treatment-naïve subjects 
or subjects previously treated with pegIFN/RBV with chronic HCV GT1-infection with 
compensated (Child-Pugh A, score ≤ 6) cirrhosis.  ABT-450/r/ABT-267 with ABT-333 in 
combination with RBV was administered for either 12 or 24 weeks of treatment.
Treated subjects (N = 380) had a median age of 58 years (range:  21 to 71); 70.3% of the 
subjects were male; 3.2% were black and 11.8% were Hispanic or Latino; 28.4% had a 
BMI greater than or equal to 30 kg/m2; 14.7% had platelet counts of < 90,000 × 109/L, 
86.1% had baseline HCV RNA levels of 800,000 IU/mL or greater; 68.7% had HCV 


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GT1a, 31.3% had HCV GT1b, 81.8% had IL28B non-CC genotype; 42.1% were 
treatment-naïve, 36.1% were prior pegIFN/RBV null responders; 8.2% were prior 
pegIFN/RBV partial responders, and 13.7% were prior pegIFN/RBV relapsers. 
The SVR12 rates for subjects with compensated cirrhosis treated with 3-DAA + RBV for 
12 or 24 weeks were 91.8% and 95.9%, respectively.  Virologic failure was noted in 
13/208 (6.3%) subjects (on treatment virologic failure:  n = 1; relapse:  n = 12) receiving 
the 12-week regimen and 4/172 (2.3%) subjects (on treatment virologic failure:  n = 3; 
relapse:  n = 1) receiving the 24-week regimen.
Analyses of subgroups suggest that the overall difference in SVR12 rates was driven 
largely by lower SVR12 rate among genotype 1a prior null responders who received.  The 
SVR12 for the treatment-naïve and treatment-experienced genotype 1b patients were both 
99%.  Therefore, a 12-week treatment regimen is recommended for all patients with 
cirrhosis with the exception of GT1a prior null responders for whom 24 weeks of 
treatment provides a higher SVR.
Integrated Safety Results
A summary of treatment-emergent adverse events from the pooled analyses of data from 
the Phase 3 studies is presented in Table 2.  A majority of subjects experienced at least 
one event, but most subjects experienced events that were mild in severity.  Rates of 
severe adverse events and adverse events leading to discontinuation were low across 
studies but numerically higher in the study of subjects with cirrhosis.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
32
Table 2.
Overview of Treatment-Emergent Adverse Events (AE)
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-Week 
3-DAA + 
RBV
12-Week 
PBO
12-Week 
3-DAA + 
RBV
12-Week 
3-DAA
12-Week 
3-DAA + 
RBV
24-Week 
3-DAA + 
RBV
Events, %
N = 770
N = 255
N = 401
N = 509
N = 208
N = 172
Subjects ≥ 1 AE
89.0
76.9
82.8
75.0
91.8
90.7
Severe AE
3.5
0.4
1.0
1.2
6.7
7.6
Grade 3 or 4 AE
3.9
0.8
3.0
2.0
7.7
8.1
Serious AE
2.1
0.4
2.2
1.4
6.3
4.7
AE leading to 
discontinuation 
0.8
0.4
0.5
0.4
1.9
2.3
Deaths 
0.1a
0
0
0
0.5b
0
PBO = Placebo
a.
Lung cancer.
b.
Metformin toxicity, lactic acidosis, multi-organ system failure.
The most common adverse events regardless of causality are listed in Table 3.  Adverse 
events that occurred at a ≥ 5% incidence in the 3-DAA + RBV regimen versus the placebo 
were considered to be adverse drug reactions related to the study treatment.  These include 
fatigue, nausea, pruritus, insomnia, asthenia, and anemia.  These events were mostly 
attributable to ribavirin as the rates were lower in the RBV-free arm, and were similar to 
the placebo rates observed in the placebo-controlled cohorts.  In general, rates of adverse 
events were similar in patients with cirrhosis versus patients without cirrhosis.  Patients 
with cirrhosis had a higher frequency of bilirubin elevations.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
33
Table 3.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline Lab 
Abnormalities
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-Week 
3-DAA + 
RBV
12-Week 
PBO
12-Week 
3-DAA + 
RBV
12-Week 
3-DAA
12-Week 
3-DAA + 
RBV
24-Week 
3-DAA + 
RBV
Treatment-emergent 
Adverse Events, %
N = 770
N = 255
N = 401
N = 509
N = 208
N = 172
Headache
34.3
29.8
24.4
25.1
27.9
30.8
Fatigue
34.2
26.3
29.9
26.5
32.7
46.5
Nausea
22.3
14.9
15.7
8.4
17.8
20.3
Pruritus
15.7
4.3
12.0
6.1
18.3
19.2
Insomnia
14.0
7.5
12.2
5.1
15.4
18.0
Diarrhea
13.5
9.0
8.7
11.4
14.4
16.9
Asthenia
13.5
6.7
9.0
3.9
13.9
12.8
Rash
10.0
5.9
6.2
3.7
11.1
14.5
Cough
8.7
5.1
6.7
4.7
11.5
11.0
Irritability
5.3
4.7
3.2
3.1
7.2
12.2
Anemia
5.3
0
7.5
0.2
7.7
10.5
Dyspnea
9.7
5.5
4.7
2.2
5.8
12.2
Laboratory Events, %
N = 765
N = 254
N = 401
N = 509
N = 208
N = 172
Hemoglobin
     < 10 g/dL (Gr 2)
5.5
0
6.2
0
7.2
11.0
     < 8.0 g/dL (Gr 3)
0.1
0
0.5
0
1.4
0.6
ALT
     > 5 × ULN (Gr 3)
1.2
3.9
0.7
0.2
2.9
0
Bilirubin
     > 3 × ULN (Gr 3)
2.6
0
5.7
0.4
13.5
5.2
PBO = Placebo 
Note:
Percentages of laboratory events are based on the number of subjects with at least one post-baseline value.
Transient elevations in total (predominantly indirect) bilirubin may occur due ABT-450 
inhibition of OATP1B1, an enzyme involved in bilirubin transport, accentuated by 
RBV-induced hemolysis.  The elevations generally peaked by Weeks 1 – 2 and declined 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
34
after wards.  Rates of hyperbilirubinemia were lower in subjects treated with 3-DAA 
without RBV.  Rates and degree of hyperbilirubinemia were higher in patients with 
cirrhosis, but the temporal pattern of elevation followed by resolution was similar and few 
were symptomatic (jaundice).  All bilirubin elevations resolved completely after treatment 
was discontinued.  
Rates of ≥ grade 2 hemoglobin reductions were 5% to 7% across the 12-week arms among 
subjects who received the RBV-containing regimen, and 11% with the 24-week arm.  
Grade 3 hemoglobin events were rare.  Anemia observed during the clinical trials was 
attributable to the presence of RBV as it was not observed when the 3-DAA regimen was 
administered without RBV.
Transient asymptomatic post baseline serum ALT elevations of > 5 × ULN occurred at a 
frequency of 1% across active treatment arms and were evaluated by an external hepatic 
panel.  The ALT elevations were asymptomatic, usually occurred within the first 4 weeks 
of treatment and typically declined with ongoing treatment.  A disproportionate number of 
the cases were in women on concurrent estrogen-containing therapy (i.e., contraceptives 
or hormone replacement) and discontinuation of the hormonal therapy with continuation 
or brief interruption of the DAA regimen led to resolution in serum ALT elevation.  
Among the cases of serum ALT elevation thought to be related to the DAA regimen, none 
resulted in hepatic dysfunction and they resolved or improved with ongoing treatment.  
All cases had resolved completely in the post-treatment follow-up.
Thirty Asian subjects were enrolled in these Phase 3 studies.  Overall, no data in the 
37 Asian subjects suggest a difference in efficacy or safety.
In summary, the 3-DAA regimen, with or without RBV, was well tolerated with a low 
discontinuation rate.  Adverse events were typically mild, and the main adverse events 
and laboratory abnormalities observed were mainly due to the presence of RBV.  
Transient, asymptomatic serum ALT elevations were observed at a low rate, were not 
associated with hepatic dysfunction and generally resolved with ongoing treatment.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
35
Study M12-536 is an ongoing Phase 2, multicenter, randomized, dose and duration 
ranging, open-label study evaluating the antiviral activity, safety and pharmacokinetics of 
two doses of ABT450/r (100/100 mg or 150/100 mg) with ABT 267 25 mg for 12 or 
24 weeks for treatment-experienced HCV subgenotype 1b-infected Japanese subjects and 
for 12 weeks for treatment-experienced HCV genotype 2-infected Japanese subjects.  A 
preliminary analysis shows that among subjects infected with HCV subgenotype 1b, 
SVR24 rates from 88.9% to 100% were achieved in the 12 week treatment arms, and 
SVR12 rates of 100% were achieved in the 24-week treatment arms.  The most common 
treatment-emergent adverse events (AEs) were nasopharyngitis, headache, back pain, 
hypertension, gastroenteritis, pruritus, and rash.  One serious AE (fluid retention) was 
deemed as having a reasonable possibility of being related to study drug; this AE led to 
study drug discontinuation.
The current study is intended to examine the safety and efficacy of the combination of 
ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin for 12 weeks in 
treatment-naïve and pegIFN-containing regimen treatment experienced Asian adults with 
chronic HCV GT1b infection and compensated cirrhosis.
3.1
Differences Statement
The combination of ABT-450/r, ABT-267 and ABT-333 coadministered with RBV for 12 
and 24 weeks was explored in treatment-naïve and treatment-experienced genotype 1 
HCV subjects with compensated cirrhosis in Study M13-099 globally except in Asia.  
This is a study to evaluate ABT 450/r/ABT 267 and ABT-333 coadministered with RBV 
for 12 weeks in HCV genotype 1b-infected Asian subjects with compensated cirrhosis.
3.2
Benefits and Risks
This is a single arm study with ABT-450/r/ABT-267 and ABT-333 coadministered with 
RBV for 12 weeks to treat HCV genotype 1b-infected patients with compensated cirrhosis 
in an Asian population. 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
36
The likelihood of successfully demonstrating high SVR12 in an Asian cirrhotic population 
in the current study is high.  Based on data from Study M13-099, the SVR12 rates for the 
same regimen in treatment-naïve and treatment-experience genotype 1b patients with 
compensated cirrhosis were 100% and 98%, respectively.  The regimen was well tolerated 
with < 2% treatment discontinuation rate due to adverse events. 
Risks associated with ABT-450/r/ABT-267 and ABT-333 co-administered with RBV, 
including the risks of toxicity and virologic failure, appear limited and manageable based 
on the results of the ongoing Phase 3 trials discussed above.  Given the potential high rate 
of cure in this population of HCV-infected subjects, the risk-benefit comparison is 
favorable.
4.0
Study Objectives
4.1
Primary Objectives
The primary objectives of this study are to assess the safety and to compare SVR 12 (the 
percentage of subjects achieving a 12-week sustained virologic response, SVR12, [HCV 
ribonucleic acid {RNA},< lower limit of quantification {LLOQ}, 12 weeks following 
therapy]) and SVR24 (the percentage of subjects achieving a 24-week sustained virologic 
response, SVR24 [HCV RNA < LLOQ, 24 weeks following therapy]) of 12 weeks of
treatment with co-formulated ABT-450, ritonavir and ABT-267 (ABT-450/r/ABT-267) 
and ABT-333 coadministered with ribavirin to the historical SVR rate of telaprevir plus 
pegIFN and RBV therapy in HCV genotype 1b-infected cirrhotic adults.
4.2
Secondary Objectives
The secondary objectives of this study are to demonstrate the effect of the DAA 
combination regimen on HCV RNA levels during and after treatment as measured by on 
treatment virologic failure and post-treatment relapse, respectively.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
37
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, open-label, multicenter study evaluating the efficacy and safety of 
ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin for 12 weeks in HCV 
genotype 1b, treatment-naïve and IFN based therapy (IFN [alpha, beta or pegIFN] with 
RBV) treatment-experienced adults with compensated cirrhosis.
Treatment will consist of:  ABT-450/r/ABT-267 150/100/25 mg once daily (QD) + 
ABT-333 250 mg twice daily (BID) + RBV* for 12 weeks.
*
RBV will be administered weight-based 1000 – 1200 mg divided to twice daily.
Approximately 100 subjects will be enrolled (approximately 60 subjects from sites in 
China and 20 subjects each from sites in S. Korea and Taiwan).  At least 
35 treatment-naïve and 35 treatment-experienced subjects will be enrolled.
This study will consist of a Treatment Period and a Post-Treatment (PT) Period.
During the Treatment Period, subjects will receive treatment with ABT-450/r/ABT-267 
and ABT-333 co-administered with RBV for 12 weeks.
Upon completing the Treatment Period or premature discontinuation of the Treatment 
Period, subjects will enter the 48-week Post-Treatment Period.  Safety evaluations will 
also occur by a Data Monitoring Committee (DMC); see Section 5.5.5.1. 
As this is an open-label study, safety and efficacy evaluations will occur throughout the 
Treatment and Post-Treatment Periods.  Safety evaluations will also occur by a Data 
Monitoring Committee (DMC); see Section 5.5.5.1.
A primary analysis will occur after all subjects have completed the Treatment Period 
through Post-Treatment Week 24 of the Post-Treatment Period or prematurely 
discontinued from the study.  An interim analysis will occur after all subjects at sites in 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
38
South Korea and Taiwan have completed the Treatment Period through Post-Treatment 
Week 12 of the Post-Treatment Period or prematurely discontinued from the study.  This 
interim analysis is planned to also support regulatory submission activities in S. Korea 
and Taiwan.
5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures, will receive a unique subject number via the 
Interactive Response Technology (IRT) system and will undergo the study procedures 
identified in Section 5.3.1.1 associated with the Screening Visit.  The investigator will 
evaluate whether the subject meets all of the eligibility criteria specified in Section 5.2.1
and Section 5.2.2 during the period from the Screening Visit through Study Day 1 prior to 
dosing and record the results of this assessment and the details of the informed consent 
process in the subject's medical records.  Eligible subjects have up to 35 days following 
the Screening Visit to enroll into the study.
Subjects who meet all eligibility criteria with the exception of their initial non-invasive 
assessment of liver cirrhosis by FibroScan may undergo a liver biopsy.
Liver biopsy should only be performed during the Screening Period if all inclusion criteria 
and none of the exclusion criteria are met (see Section 5.3.1.1 for exception regarding 
FibroScan).
The study is designed to enroll approximately 100 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
5.1.1.1
Rescreening
Subjects who meet all eligibility criteria with the exception of up to three exclusionary 
laboratory parameters may rescreen once within the 35-day screening period without prior 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
39
AbbVie approval.  However, subjects with any of the following exclusionary values will 
not be allowed to rescreen: exclusionary HCV genotype, a positive hepatitis B surface 
antigen, positive human immunodeficiency virus (HIV) antibody, confirmed pregnancy, 
or positive drug screening results without a prescription nor medical justification 
confirmed by the investigator on over the counter medication.  Subjects with more than 
three exclusionary laboratory results will require approval from the AbbVie Study 
Designated Physician prior to rescreening.  Subjects being rescreened because of 
exclusionary laboratory parameter(s) must have the related panel(s) repeated 
(e.g., exclusionary ALT requires a repeat chemistry panel) within the same screening 
period. 
Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol 
screen, may have only the urine alcohol screen repeated. If the repeat urine alcohol screen 
is negative, the subject may be considered eligible.
Subjects who fail to enroll within 35 days of Screening, regardless of the reason for 
falling outside the 35-day screening window, may be allowed to rescreen only once
without approval of the AbbVie Study Designated Physician.  These subjects must be 
rescreened for all laboratory and eligibility criteria, not just those that were exclusionary 
at the first screening attempt (with the exception of HCV genotype, IL28B genotype, 
FibroTest, FibroScan, liver biopsy, Follicle stimulating hormone [FSH], and hemoglobin 
Apolipoprotein A1 [AIC] which do not need to be repeated).
For subjects who do not meet the study eligibility criteria, the site personnel must register 
the subject as a screen failure in both IRT and electronic data capture (EDC) systems.
5.1.2
Treatment Period (TP)
After meeting the eligibility criteria, approximately 100 treatment-naïve and IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) treatment-experienced subjects will be 
enrolled via IRT and assigned to 12 weeks of treatment.  Approximately 100 subjects will 
be enrolled (approximately 60 subjects at sites in China and 20 subjects each at sites in 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
40
South Korea and Taiwan).  At least 35 treatment-naïve subjects and 
35 treatment-experienced subjects will be enrolled.  Subjects will be administered study 
drugs at the site on Study Day 1.  Subjects will receive instructions about the study drugs 
and the dosing schedule at the Day 1 Visit.  ABT-450/r/ABT-267 will be administered 
orally once daily and ABT-333 and RBV will be dosed orally twice daily as described in 
Section 5.5.1.  The doses are as follows:
●
ABT-450/r/ABT-267 150/100/25 mg QD
●
ABT-333 250 mg BID
●
RBV weight based, 1000 mg to 1200 mg daily divided BID per local label 
(e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg daily 
divided BID)
Subjects will be administered the first doses of study drugs at the site on Study Day 1 
(ABT-450/r/ABT-267, ABT-333, and RBV).  Plasma samples for pharmacokinetic 
analysis and HCV RNA analysis will be collected on Study Day 1 prior to dose and at 
2 hours post dose and at the additional visits detailed in Table 5 and Table 6.
All subjects will continue to return to the site on an outpatient basis up to 12 weeks for the 
study procedures identified in Section 5.3.1.1.  Sites should ensure that subjects adhere to 
the study visits listed in Table 5.  Subjects who cannot complete their study visit per the 
visit schedule should ensure they do not run out of study drug prior to their next study 
visit.  Compliance is critical to ensure adequate drug exposure.
Safety and tolerability of the treatments will be assessed throughout the study.  Laboratory 
testing will include chemistry, hematology, and urinalysis (Section 5.3.1.1).  Blood 
samples for optional pharmacogenetic analysis, will be collected as detailed in 
Section 5.3.1.3.  Patient Reported Outcomes (PROs) will also be assessed at the visits 
listed in Table 5 and Table 6.  Virologic failure criteria will be evaluated and applied by 
the Investigator as detailed in Section 5.4.1.1 and ongoing review of the data is planned in 
order to determine if subjects meet the virologic failure criteria (Section 5.4.1.1).


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
41
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in and as 
described in Section 5.4.1.
Ideally, this should occur on the day of study drug discontinuation, but should be no later 
than 2 days after their final dose of study drug and prior to the initiation of any other 
anti-HCV therapy if applicable.  Subjects who complete or discontinue treatment will be 
monitored for safety, HCV RNA, the emergence and persistence of resistant viral variants 
and assessment of PROs in the 48-week Post-Treatment Period as detailed in 
Section 5.4.1.
5.1.3
Post-Treatment (PT) Period
All subjects who receive at least one dose of DAA in the Treatment Period and either 
complete treatment or prematurely discontinue study drug will be monitored in the 
Post-Treatment Period for safety, HCV RNA, the emergence and persistence of resistant 
viral variants and assessment of PROs for an additional 48 weeks following the last dose 
of study drug.
The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.  Subjects with HCV RNA < LLOQ at the end of treatment and who have a 
confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements 
≥LLOQ) at any point in the Post-Treatment Period will be considered to have relapsed.  
Confirmation of an HCV RNA ≥ LLOQ in the Post-Treatment Period should be 
completed as soon as possible.
Subjects who prematurely discontinue the Post-Treatment Period should return to the site 
for a Post-Treatment discontinuation visit as outlined in Table 6.
All subjects who receive at least one dose of DAA and who do not achieve and maintain 
virologic suppression (HCV RNA < LLOQ), or who relapse post DAA therapy, should 
discuss the future treatment options with the investigators.


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
42
5.2
Selection of Study Population
The study population consists of HCV genotype 1b-infected adult subjects with 
compensated cirrhosis who are either treatment-naïve or (IFN [alpha, beta or pegIFN] 
with RBV) based treatment-experienced adults.  Refer to Section 5.2.1 for details 
regarding required documentation for prior IFN-based treatment failures.
Subjects who meet the inclusion criteria and who do not meet any of the exclusion criteria 
will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
1.
Male or female of Chinese, South Korean, and Taiwanese descent with full 
Chinese, South Korean, and Taiwanese parentage between the ages of 18 and 
70 years of age, inclusive, at time of screening.
2.
Chronic HCV-infection prior to study enrollment.  Chronic HCV-infection is 
defined as one of the following:
●
Positive for anti-HCV antibody (Ab) or HCV RNA > 1000 IU/mL at least 
6 months before Screening, and positive for HCV RNA and anti-HCV Ab at 
the time of Screening; or
●
Positive HCV RNA > 1000 IU/mL at the time of Screening with a liver biopsy 
consistent with chronic HCV-infection (or a liver biopsy performed prior to 
enrollment with evidence of chronic hepatitis C disease).
3.
Screening laboratory result indicating HCV genotype 1b-infection.
4.
Per local standard practice, documentation of cirrhosis by one of the following 
methods:
●
Diagnosis on previous liver biopsy or liver biopsy conducted during screening, 
e.g., Metavir Score of > 3 (including 3/4 or 3-4), Ishak score of > 4 or,
●
FibroScan score ≥ 14.6 kPa within 6 months of Screening or during the 
Screening Period.
Subjects with a non-qualifying FibroScan result may only be enrolled if they have 
a qualifying liver biopsy diagnosis. 


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
43
5.
Compensated cirrhosis defined as Child-Pugh score of ≤ 6 at Screening.
6.
Subject has never received antiviral treatment including IFN based therapy (IFN 
[alpha, beta or pegIFN] with or without RBV) for hepatitis C infection 
(treatment-naïve subject), or subject must have documentation that they meet the 
definition of one of the following categories (treatment-experienced subject):
●
Non responder:  received at least 12 weeks of IFN based therapy (IFN [alpha, 
beta or pegIFN] with RBV) for the treatment of HCV and failed to achieve 
undetectable HCV RNA (HCV RNA < LLOD) at the end of treatment; or
●
Relapser:  Received IFN based therapy (IFN [alpha, beta or pegIFN] with 
RBV) for the treatment of HCV and was undetectable (HCV RNA < LLOD) at 
or after the end of treatment, but subsequently had detectable HCV RNA 
within 24 weeks of treatment follow-up; or 
●
IFN based therapy (IFN [alpha, beta or pegIFN] with RBV) Intolerant: 
treatment of HCV was discontinued during the treatment period due to 
intolerance to any of the components of the IFN based therapy (IFN [alpha, 
beta or pegIFN] with RBV) therapy.
HCV RNA levels that serve as documentation to support the type of prior 
non-response should have been obtained in relation to the previous IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) treatment.  IFN based therapy 
(IFN [alpha, beta or pegIFN] with RBV) must have been completed no less than 
2 months prior to the Screening visit.
7.
Female who is:
●
practicing total abstinence from sexual intercourse (minimum 1 complete 
menstrual cycle)
●
sexually active with female partners only
●
not of childbearing potential and sexually active with male partner(s);
○
postmenopausal for at least 2 years prior to screening (defined as 
amenorrheic for longer than 2 years, age appropriate, and confirmed by a 
follicle stimulating hormone [FSH] level indicating a postmenopausal 
state) or


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
44
○
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy 
or hysterectomy) or has a vasectomized partner(s)
●
of childbearing potential and sexually active with male partner(s):
○
currently using at least one effective method of birth control at the time of 
screening and 
○
agree to using two effective methods of birth control while receiving study 
drugs (as outlined in the subject information and consent form or other 
subject information documents), starting with Study Day 1 and for 
7 months after stopping study drug or as directed by the local ribavirin 
label.  
8.
Males who are not surgically sterile who are sexually active with female partner(s) 
of childbearing potential must agree to practice two effective forms of birth control 
(as outlined in the subject informed consent or other subject information 
documents) throughout the course of the study, starting with Day 1 and for 
7 months after stopping study drug or as directed by the local ribavirin label.  
9.
Body Mass Index (BMI) is from ≥ 18 to < 38 kg/m2 at the time of screening.  BMI 
is calculated as weight measured in kilograms (kg) divided by the square of height 
measured in meters (m).
10.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements and must voluntarily sign and date an informed 
consent form, approved by an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) prior to the initiation of any screening or study specific 
procedures.
Rationale for Inclusion Criteria
1 – 6
To select the appropriate subject population with sufficient disease 
severity for evaluation
7, 8
For the safety of study subjects
10
In accordance with harmonized Good Clinical Practice (GCP)


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
45
5.2.2
Exclusion Criteria
1.
HCV genotype performed during screening indicating unable to genotype or 
subtype infection with any other HCV genotype or subtype.
2.
Positive test result at Screening for hepatitis B surface antigen (HBsAg), or 
HBV-DNA > LLOQ if HBsAg negative, or anti-human immunodeficiency virus 
antibody (HIV Ab).
3.
Any current or past clinical evidence of Child-Pugh B or C Classification or 
clinical history of liver decompensation including ascites (noted on physical exam), 
variceal bleeding or hepatic encephalopathy.
4.
Serum Alpha-Fetoprotein (sAFP) > 100 ng/mL at Screening.
5.
Confirmed presence of hepatocellular carcinoma indicated on imaging techniques 
such as computed tomography (CT) scan or magnetic resonance imaging (MRI) 
within 3 months prior to Screening or on an ultrasound performed at Screening (a 
positive ultrasound result should be confirmed with CT scan or MRI.)
6.
Any primary cause of liver disease other than chronic HCV-infection, including but 
not limited to the following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Drug-related liver disease
Steatosis and steatohepatitis on a liver biopsy coincident with HCV-related 
changes would not be considered exclusionary unless the steatohepatitis is 
considered to be the primary cause of the liver disease.
7.
Screening laboratory 
●
ALT > 7 × upper limit of normal (ULN)


ABT-450/r/ABT-267, ABT-333
M14-491 Protocol
46
●
Aspartate aminotransferase (AST) > 7 × ULN
●
Estimated Glomerular filtration rate adjusted for the Asian population (eGFR) 
< 50 mL/min/1.73 m2 as estimated by the C-MDRD method, modified for the 
Asian population, according to the following formula:  eGFR = 175 × (Serum 
Creatinine) –1.234 × (Age) –0.179 × (0.79 if female)
●
Albumin < 2.8 g/dL
●
International normalized ratio (INR) > 2.3.  Subjects with a known inherited 
blood disorder and INR > 2.3 may be enrolled with permission of the AbbVie 
Study Designated Physician
●
Hemoglobin < LLN
●
Platelets < 60,000 cells per mm3
●
Absolute neutrophil count (ANC) < 1200 cells/μL
●
Total bilirubin ≥ 3.0 mg/dL
8.
Females who are pregnant or plan to become pregnant, or breastfeeding, or males 
whose partners are pregnant or planning to become pregnant within 7 months (or 
per local RBV label) after their last dose of study drug/RBV.
●
Female subjects with a borderline hCG at Screening and/or Day 1 may enroll 
into the study if they either:
○
Have a documented history of bilateral tubal ligation, hysterectomy, 
bilateral oophorectomy; or
○
Are confirmed to be postmenopausal defined as amenorrheic for longer 
than 2 years, age appropriate, and confirmed by a follicle-stimulating 
hormone (FSH) level indicating a postmenopausal state at Screening.
9.
Use of known strong inducers of cytochrome P450 3A (CYP3A) 
(e.g.,phenobarbital, rifampin, carbamazepine, St. John's Wort), or strong CYP2C8 
inhibitors within 2 weeks or within 10 half-lives, whichever is longer, of the 
respective medication/supplement, prior to the initial dose of study drug.  
10.
Use of any medication listed below, as well as those that are contraindicated for 
ritonavir and RBV, within 2 weeks or 10 half-lives of the medication whichever is 
longer, to study drug administration including but not limited to:


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Table 4.
Medications Contraindicated for Use with the Study Drug Regimen
Alfuzosin
Amiodarone
Astemizole
Bepredil
Carbamazepine 
Cisapride
Clorazepate
Clozapine
Diazepam
Efavirenz
Encainide Ergot
Derivatives
(ergotamine, dihydroergotamine, 
ergonovine, methylergonovine)
Estazolam
Flecainide
Flurazepam
Fusidic acid
Gemfibrozil
Hormonal contraceptives
Lovastatin
Midazolam (oral)
Pethidine
Phenobarbital
Phenytoin
Pimozide
Piroxicam
Propafenone
Propoxyphene
Quindine
Rifabutin
Rifampin
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
Voriconazole
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with ritonavir and ribavirin are listed above.  Refer to the most current 
package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated 
medications.
11.
History of uncontrolled seizures, uncontrolled diabetes as defined by a glycated 
hemoglobin (hemoglobin A1C) level > 8.5% at the Screening Visit, active or 
suspected malignancy or history of malignancy (other than basal cell skin cancer or 
carcinoma in situ) in the past 5 years.
12.
History of solid organ transplant.
13.
Clinical significant abnormal ECG, or ECG with QT interval corrected for heart 
rate (QTc) using Fridericia's correction formula (QTcF) > 470 msec at Screening or 
Study Day 1 (Baseline, prior to dosing).
14.
Clinically significant abnormalities or comorbidities, other than HCV-infection, 
that make the subject an unsuitable candidate for this study in the opinion of the 
investigator.
15.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol.


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16.
Positive result of a urine drug screen at the Screening Visit for opiates, barbiturates, 
amphetamines, cocaine, benzodiazepines, phencyclidine, propoxyphene, or 
alcohol, with the exception of a positive result associated with documented short 
term use or chronic stable use of a prescribed or over-the-counter medication.  In 
the case of a positive urine drug screen attributed to an over-the-counter 
medication, there must be documented medical justification for its use confirmed 
by the Investigator.  Single positive results on urine screen for alcohol are 
discussed in Section 5.1.1.1, Rescreening.
17.
Current enrollment in another interventional clinical study, previous enrollment in 
this study, or previous use of any protease inhibitor, non-nucleoside polymerase 
inhibitor, or Ns5A inhibitor, either investigational or experimental (including 
previous exposure to ABT-450, ABT-267 or ABT333).  Receipt of any 
investigational produce within 6 weeks prior to study drug administration. 
Rationale for Exclusion Criteria
1 – 8, 11 – 13, 15
To ensure safety of the subjects throughout the study
9, 10, 16
To avoid bias for the evaluation of efficacy and safety by 
concomitant use of other medications
14, 17
To avoid bias for the evaluation of efficacy and safety
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, traditional medicines, and/or herbal supplements) that the subject is receiving 
from the time of signing the consent through the Treatment Period and 30 days after study 
drugs are stopped, must be recorded in the electronic case report form (eCRF) along with 
the reason for use, date(s) of administration including start and end dates, and dosage 
information including dose, route and frequency.  The investigator should review all 
concomitant medications for any potential interactions.


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During the Post-Treatment Period, all medications will be collected until 30 days 
following the last dose of study drugs.  Only medications associated with HCV treatment 
or a serious adverse event (SAE) will be collected thereafter.
The AbbVie Study Designated Physician should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).
5.2.3.1
Prior HCV Therapy
Treatment-naïve subjects must not have prior or current use of any investigational or 
commercially available anti-HCV agents, including IFN, pegIFN, telaprevir, boceprevir or 
RBV.  Subjects who previously participated in trials of direct-acting antiviral agents for 
treatment of HCV may be enrolled with the approval of the AbbVie Study Designated 
Physician if they can provide documentation that they received placebo.
Treatment-experienced subjects must have previously received IFN based therapy (IFN 
[alpha, beta or pegIFN] with RBV) and failed treatment.  These subjects should have 
documentation of IFN based therapy (IFN [alpha, beta or pegIFN] with RBV) treatment 
history, including start and stop dates and HCV RNA levels to document the type of 
non-response or the reason for discontinuation of therapy to document intolerance in the 
source document.
Treatment-experienced subjects must have discontinued IFN based therapy (IFN [alpha, 
beta or pegIFN] with RBV) at least 2 months prior to the Screening Visit and IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) was the last therapy received in order to 
be eligible for the study.
5.2.3.2
Concomitant Therapy
The investigator should confirm that concomitant medication can be administered with 
DAAs (including ritonavir).  Some medications may require dose adjustments due to 
potential for drug-drug interactions.  The investigator should also review the label(s) for 
the concomitant medication(s) for additional information.


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The use of hepatoprotective medication (e.g., Sho-saiko-to, Milk thistle, ursodeoxycholic 
acid, glycyrrhizin acid, SAMe, etc.) is allowed, provided that the drug does not meet any 
other exclusion criterion.  While the subject is using hepatoprotective medication, the 
dose should be kept stable.
During the Post-Treatment Period, investigators should reassess concomitant medications 
and subjects may resume previously prohibited medications or revert to pre-study doses, 
2 weeks following discontinuation of study drugs, if applicable.
5.2.3.3
Prohibited Therapy
In addition to the medications listed above in Table 4, use of known strong inducers of 
CYP3A or strong inhibitors of CYP2C8 are prohibited within 2 weeks or within 
10 half-lives, whichever is longer, prior to the initial dose of study drugs and through the 
first 2 weeks after the subject has completed active study drugs in the Treatment Period.
Refer to the ritonavir and RBV labeling for a list of prohibited medications.  Anti-HCV 
medications other than those specified in the protocol will not be allowed during the 
Treatment Period of the study.
Hormonal contraceptives (including oral, topical, injectable or implantable varieties) may 
not be used from 2 weeks prior to the first dose of study drug until 2 weeks after the end 
of study drug dosing.  Post-menopausal hormone replacement therapy may be used at the 
discretion of the Investigator.
Management of hematologic growth factor therapy is the responsibility of the 
Investigator; growth factors will not be provided by AbbVie, and AbbVie will not 
reimburse for the expense of growth factors or their use.
Investigators should refer to the package inserts for erythropoiesis stimulating agents for 
additional information regarding their use.


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5.3
Efficacy, Pharmacokinetic, Optional Pharmacogenetic and 
Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart


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Table 5.
Study Activities – Treatment Period (TP)
Activity
Treatment Period (TP)
Treatment Visits – All Subjects
Screening
Day1/ 
Baselinea
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12 
(EOT)b
Premature 
D/Cb
Informed Consentc
X
Provide RBV Medication Guided and 
Partner Risk Fact Sheet 
X
Medical History
X
Xe
Physical Exam
X
X
X
X
Vital Signs, Weight, Height
Xf
X
X
X
X
X
X
X
X
X
ECG
X
Xg
X
X
Hematology/Chemistry/Urinalysis/ 
Coagulation Panel
X
X
X
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s, u)
X (s, u)
X (u)
X (u)
X (u)
X (u)
Urine Albumini
X
FSH (all females), HbA1c 
X
HBsAg, Anti-HCV Ab, Anti-HIV Ab, 
HBV-DNA if HBsAg Negative
X
Drug/Alcohol Screen
X
Total Insulin
X
X
X
HCV Genotype and Subgenotype
X
IL28B Sample
X


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Table 5.
Study Activities – Treatment Period (TP) (Continued)
Activity
Treatment Period (TP)
Treatment Visits – All Subjects
Screening
Day1/ 
Baselinea
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12 
(EOT)b
Premature 
D/Cb
Screening:  Liver Biopsy or Fibroscanj
X
Longitudinal FibroTest  
Xk
Child-Pugh Score
X
X
X
Clinical Assessment of Hepatic 
Decompensation
Xl
HCC Screening: Liver Ultrasound and 
Alpha Fetoproteinm
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes 
Instruments (PROs)n
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
X
Study Drugs Dispensed
X
X
X
HCV RNA Samples
X
Xo
X
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
X
X
Pharmacokinetic Sample
Xp
X
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X


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Table 5.
Study Activities – Treatment Period (TP) (Continued)
Activity
Treatment Period (TP)
Treatment Visits – All Subjects
Screening
Day1/ 
Baselinea
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12 
(EOT)b
Premature 
D/Cb
Archive Serum Sample
X
X
X
X
X
X
X
X
X
X
Interferon Gamma-Induced Protein 
10 (IP-10) Sample
X
X
X
X
X
Pharmacogenetic Sample (optional)q
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
a.
All procedures, including pharmacokinetic sample collection, to be performed prior to first dose with the exception of the 2-hour post-dose pharmacokinetic and HCV RNA 
samples.
b.
Subjects should begin the Post-Treatment Period after the subject completes study drug treatment or prematurely discontinues Treatment Period.
c.
Subjects will need to sign an informed consent for the study (prior to performing any screening or study-specific procedures) and the optional Pharmacogenetic sample(s), if 
applicable.
d.
Where applicable/locally available.
e.
Medical history will be updated at the Day 1 Visit.  This updated medical history will serve as the Baseline for clinical assessment.
f.
Height will be measured at Screening only.
g.
Evaluate the Day 1 ECG prior to dosing to determine eligibility.
h.
Urine pregnancy testing is not required after the Screening Visit for female subjects with a documented history of bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy or who are confirmed to be post-menopausal. A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for 
additional details.) 
i.
Done at Day 1/Baseline and collected for decrease in eGFR as defined in Section 5.3.1.1.
j.
Subjects who do not have a qualifying historical liver biopsy, but who otherwise meet all of the inclusion criteria and none of the exclusion criteria will undergo a liver 
biopsy.  
k.
Longitudinal FibroTest measured for exploratory analysis of fibrosis over time.  Day 1 results will be blinded to the investigator/site.


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Table 5.
Study Activities – Treatment Period (TP) (Continued)
l.
Clinical assessment of Hepatic encephalopathy and ascites at Day 1 prior to dosing. 
m.
Liver Ultrasound and alpha fetoprotein to be performed at Screening.  Subjects with a historical negative Liver Ultrasound, CT or MRI (within 3 months prior to screening) 
are not required to have a screening Ultrasound performed.  If additional Liver Ultrasound testing is required it should be completed as an unscheduled visit.  A positive 
Ultrasound result suspicious for HCC will be confirmed with CT scan or MRI.
n.
SF-36v2, EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L), and Hepatitis C Virus Patient Reported Outcomes Instrument (HCVPRO), should be 
administered before any study procedures and in the following order:  SF-36v2, EQ-5D-5L and HCVPRO.
o.
HCV RNA will be collected at 0-hour (immediately prior to the morning dose) and at 2 hours post-dose.
p.
Blood Sample(s) for pharmacokinetic assay as described in Section 5.3.2.1 will be collected as follows:
!
Day 1:  0-hr (immediately prior to the morning dose), and at 2 hours post-dose.
!
A single pharmacokinetic sample will be collected at all other Treatment Study Visits without regard to the time of dosing asdetailed in Section 5.3.2.1 above.  
Additional intensive PK samples will be collected at a single visit on or after the Week 2 study visit.  Samples will be collected at predose and approximately 2, 4, 6 and 
at 24 hours post DAA dose.  Subjects may opt out of intensive PK sampling. On the day of intensive blood sampling, subjects will take their morning dose of DAAs and 
ribavirin onsite in the presence of study site personnel and the time of administration will be noted.
q.
If the optional pharmacogenetic sample is not collected at Day 1, it may be collected at any other visit during the study.


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Table 6.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48 
or PT D/Ca
Vital Signs and Weight
X
X
X
X
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
X
X
X
X
X
X
Monthly Pregnancy Test (females)b
X
X
(Weeks 12, 16, 20, 24, 28)
Longitudinal FibroTest
X
X
Child-Pugh Score
X
HCC Screening: Liver Ultrasound and Alpha 
Fetoproteinc
X
X
PRO Instrumentsd
X
X
X
X
Concomitant Medication Assessmente
X
X
X
X
X
X
X
Adverse Event Assessmentf
X
X
X
X
X
X
X
HCV RNAg
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
Archive Serum Sample
X
X
X
X
X
X
X
IP-10 Sample
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit 
b.
Urine pregnancy testing is not required after TP Day 1 visit for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or 
who are confirmed post-menopausal.  At PT Weeks 16, 20 and 28, subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home 
with test kits provided by the site.  Additional testing may be required per local RBV label.


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Table 6.
Study Activities – Post-Treatment (PT) Period (Continued)
c.
Liver ultrasound and alpha fetoprotein to be performed at PT Week 12 and PT Week 36.  A positive Ultrasound result suspicious for HCC will be confirmed with CT scan or 
MRI.
d.
PRO instruments should be administered before any study procedures and in the order listed below. 
!
PT Week 4:  SF-36v2, EQ-5D-5L and HCVPRO
!
PT Week 12:  SF-36v2, EQ-5D-5L and HCVPRO
!
PT Week 24:  SF-36v2, EQ-5D-5L and HCVPRO
!
PT Week 48 or D/C:  SF-36v2, EQ-5D-5L and HCVPRO
e.
Only medications related to the treatment of HCV and medications prescribed in association with a SAE will be collected after 30 days post-dosing.
f.
Only SAEs will be collected after 30 days post-dosing.
g.
Confirmation of an HCV RNA ≥ LLOQ in the post-treatment period should be completed as soon as possible per Section 5.1.3.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 5 and Table 6 are discussed in detail in this 
section with the exception of the assessment of concomitant medications (Section 5.2.3.3), 
the collection of blood samples for optional pharmacogenetic analysis (Section 5.3), the 
collection of blood samples for pharmacokinetic analysis (Section 5.3.2), the monitoring 
of treatment compliance (Section 5.5.6), and the collection of adverse event information 
(Section 6.0).  All study data will be recorded in the subject's source documentation and 
then on the appropriate eCRFs, with the exception of laboratory data which will be 
provided to the Sponsor electronically from the individual laboratorie(s).
Informed Consent and RBV Information
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  All subjects will be given the RBV Medication Guide (where 
applicable/locally available).  Male subjects will be given an additional copy of the RBV 
Medication Guide (where applicable/locally available) and a RBV Partner Risk Fact Sheet 
to share with their female partner(s).  Details about how informed consent will be 
obtained and documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco, alcohol use and injection drug 
use will be taken from each subject during the Screening Visit.  The subject's medical 
history will be updated at the Day 1 Visit (Treatment Period).  This updated medical 
history will serve as the baseline for clinical assessment.
Physical Examination
A complete physical examination will be performed at visits indicated in Table 5, or upon 
subject discontinuation.  A symptom-directed physical examination may be performed at 
any other visit, when necessary.


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The physical examination performed on Day 1 of the Treatment Period will serve as the 
baseline physical examination for clinical assessment.  Any significant physical 
examination findings after the first dose will be recorded as adverse events.
Vital Signs, Weight, Height
Body temperature (oral or tympanic), blood pressure, pulse, and body weight will be 
measured at the visits indicated in Table 5 and Table 6.  Blood pressure and pulse rate will 
be measured after the subject has been sitting for at least 3 minutes.  The vital signs 
performed on Day 1 will serve as the baseline for clinical assessment.  The subject should 
wear lightweight clothing and no shoes during weighing.  Height will only be measured at 
Screening; the subject will not wear shoes.
12-lead Electrocardiogram
A 12-lead resting ECG will be obtained at the visits indicated in Table 5 or upon subject 
discontinuation from the Treatment Period (or as clinically needed).  The Day 1 
(Treatment Period) reading will serve as the baseline assessment.  The ECG should be 
performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.  


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The QT interval measurement (corrected by Fridericia formula, QTcF) will be 
documented in the eCRF only if the local reader's assessment is "prolonged QT."
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 7
at the visits indicated in Table 5 and Table 6.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast (with the exception of the Screening Visit, which may be non-fasting).  Subjects 
whose visits occur prior to the morning dose of study drug should be instructed to fast 
after midnight.  Subjects whose visits occur following the morning dose of study drug 
should be instructed to fast after breakfast until the study visit occurs.  At the Day 1 study 
visit, a fasting blood sample is to be collected prior to the first dose of study drug which is 
administered at the Day 1 study visit.  Subjects should be reminded to eat prior to their 
first dose of study drug (e.g., suggest they bring a light snack).  Blood samples should still 
be drawn if the subject did not fast for at least 8 hours.  Fasting status will be recorded in 
the source documents and on the laboratory requisition.  The baseline laboratory test 
results for clinical assessment for a particular test will be defined as the last measurement 
prior to the initial dose of study drug.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Information on the location of the lab where samples will be 
sent will be found in the lab manual.


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Table 7.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Additional Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
ANC
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Reticulocyte count
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubina,b
Direct and indirect bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT) 
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumina
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)b
Creatinine clearance (Cockcroft 
Gault calculation)
eGFRe
Alpha2-macroglobulinb
Haptoglobinb
Apolipoprotein A1b
Alpha fetoprotein
HBV DNAg
HBsAgc
Anti-HCV Abc
Anti-HIV Abc
FSH (all females)c
Opiatesc
Barbituratesc
Amphetaminesc
Cocainec
Benzodiazepinesc
Alcoholc
Phencyclidinec
Propoxyphenec
Methadonec
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG) females)d
Total insulin
HCV RNA
Hepatitis B Panelf
Hepatitis A Antibody, Totalf
Hepatitis E Virus IgGf
Hepatitis E Virus IgMf
Hemoglobin A1Cc
IP-10
IL28Bc
HCV genotype and subtypec
Pharmacogenetic sample (optional)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
Albumini
Urine Archive Specimenh
a.
Also a component of the Child-Pugh Assessment.
b.
Also a component of FibroTest.
c.
Performed only at Screening.
d.
Urine pregnancy testing is not required after Day 1 of the Treatment Period for female subjects who are confirmed 
to be post-menopausal or who have a documented history of prior bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy.
e.
eGFR calculated by the MDRD formula, modified for the Chinese population.
f.
Performed for management of transaminase elevations.  See Section 6.7.4 for details.
g.
Only performed if HBsAg is negative.
h,
Performed if eGFR level is < 50 mL/minute.  See Section 6.7.5 Management of eGFR decreases for details.
i.
Collected at Day 1 and if eGFR level < 50 mL/minute.  See Section 6.7.5 Management of eGFR decreases for 
details.


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For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug or requires a subject to receive treatment will be recorded 
as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.7. 
Pregnancy Test
A urine pregnancy test will be performed for all female subjects at all the visits indicated 
in Table 5 and Table 6 except for those female subjects with a documented history of 
bilateral tubal ligation, bilateral oophorectomy or hysterectomy or who are confirmed to 
be post-menopausal.  In addition, a serum pregnancy test will be performed at Screening 
and Day 1 and analyzed by the central laboratory.  All urine pregnancy tests will be 
performed on-site during the study visit if there is a scheduled visit, as indicated in 
Table 5 and Table 6 and monthly for a minimum of 7 months after the discontinuation of 
RBV, or according to the local RBV label and/or local treatment guidelines for RBV.  A 
positive urine pregnancy test requires a confirmatory serum test.  Urine pregnancy tests 
are not required after Day 1 for female subjects with a documented history of bilateral 
tubal ligation, hysterectomy, bilateral oophorectomy, or for subjects who are confirmed to 
be postmenopausal.  Confirmation of postmenopausal status will be determined during the 
Screening period, based on the subject's history and on the FSH level.
During post-treatment where there is not a scheduled study visit, female subjects of 
childbearing potential may either have pregnancy testing performed at the site as an 
unscheduled study visit using an unscheduled test kit or a urine pregnancy test may be 
conducted by the subject at home with a pregnancy test kit provided by the site; site 


ABT-450/r/ABT-267, ABT-333
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personnel should contact these female study subjects to capture the results of any study 
related pregnancy tests performed at home.  The at home pregnancy test results will only 
be recorded in the subject's source records.
If the subject elects to return to the study site for an unscheduled visit for pregnancy 
testing, the results of the urine pregnancy test will be captured in the eCRF, unless serum 
pregnancy is elected.  Serum pregnancy testing will be completed by the central 
laboratory.
Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCV Ab, anti-HIV Ab and HBV-DNA (only if 
HBsAg is negative) will be performed at Screening.  The Investigator must discuss any 
local reporting requirements to local health agencies with the subject.  The site will report 
these results per local regulations, if necessary.  The HBsAg and/or HBV DNA results 
will be reported by the central laboratory to the clinical database.
Urine Screens for Drugs of Abuse
Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse.  
The panel for drugs of abuse will minimally include the drugs listed in Table 7.  A 
positive screen is exclusionary, with the exception of a positive screen associated with 
documented short-term use or chronic stable use of a prescribed medication in that class.
Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol 
screen, may have only the urine alcohol screen repeated as described in Section 5.1.1.  If 
the repeat urine screen is negative, and all other eligibility criteria have been met, the 
subject may be considered eligible for study participation.
These analyses will be performed by the certified central laboratory chosen for the study.


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Screening:  Liver Biopsy or FibroScan
To be eligible, subjects must have a diagnosis of cirrhosis by one of the following 
methods, per local standard practice:
●
Diagnosis on liver biopsy, e.g., Metavir Score of > 3 (including 3/4), Ishak 
score of > 4; or
●
FibroScan score ≥ 14.6 kPa within 6 months of Screening or during the 
Screening Period;
●
Subjects with a non-qualifying FibroScan result may only be enrolled if they 
have a qualifying liver biopsy.
Longitudinal FibroTest 
In addition to the assessments of cirrhosis performed during the Screening Period, all 
subjects will have FibroTest performed at baseline (Day 1) and throughout the 
Post-Treatment Period as indicated in Table 5 and Table 6 for the purpose of assessing 
changes in liver fibrosis over time.  Day 1 results will be blinded to the investigator/site.
Child-Pugh Score and Category
The Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters 
and 2 clinical assessments).  Child-Pugh score will be determined at the visits indicated in 
Table 8.


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Table 8.
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.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Day 1 
prior to dosing to confirm the subject has not progressed to hepatic decompensation since 
Screening.
Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
In order to monitor for the presence of hepatocellular carcinoma (HCC), alpha fetoprotein 
will be assayed and an ultrasound of the liver will be performed as indicated in Table 5
and Table 6.
A positive Ultrasound result suspicious for HCC at screening will be confirmed with CT 
scan or MRI during the screening period.  Suspicious ultrasound lesions confirmed by CT 
or MRI are exclusionary.


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A positive Ultrasound result suspicious for HCC during the treatment or Post-Treatment 
Period will be confirmed with CT scan or MRI.  Confirmatory results should be discussed 
with the AbbVie Study Designated Physician as appropriate.
Concomitant Medication Assessment
Use of medications (prescription or over-the-counter, including vitamins and herbal 
supplements) from the time of signing the consent through 30 days after last dose of study 
drug will be recorded in the eCRF at each study visit indicated in Table 5.
During the Post-Treatment Period, antiviral therapies related to the treatment of HCV and 
medications prescribed in association with an SAE will be recorded in the eCRF at the 
visits indicated in Table 6.
Assignment of Subject Numbers
All screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet the eligibility criteria will proceed to enrollment via the IRT system on Day 1 
(Treatment Period).
Subject numbers will be unique 4-digit numbers and will begin with 1001 with the 
first two digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their subject number assigned at the 
Screening Visit.
Study Drug Diary
Subjects will be provided self-administration instructions and study drug diaries to record 
the exact date, time and number of tablets of study drug administration.  On Study Day 1,
the time of dosing will be recorded to the nearest minute by the site staff.  The exact date, 
time and number of tablets of study drug taken will be recorded daily by the subjects 
between study visits.  In the event the study drug diary is not available, the site may 
obtain dosing information via patient interview and record this information in the source 
notes.


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Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments (where allowed per local 
regulatory guidelines) on the study days indicated in Table 5 and Table 6.  Subjects will 
be instructed to follow the instructions provided with each instrument and to provide the 
best possible response to each item.  Site personnel shall not provide interpretation or 
assistance to subjects other than encouragement to complete the tasks.  Subjects who are 
functionally unable to read or understand any of the instruments may have site personnel 
read the questionnaires to them.  Site personnel will encourage completion of each 
instrument at all visits and will ensure that a response is entered for all items.
In this study, PRO instruments should be consistently presented so that subjects complete 
the SF-36v2 instrument first, followed by the EQ-5D-5L and followed by the HCVPRO.  
PRO instruments should be completed prior to drug administration (on Day 1) and prior to 
any discussion of adverse events or any review of laboratory findings, including HCV 
RNA levels.
Short Form 36 – Version 2 Health Status Survey
The SF-36v2 is a general Health Related Quality of Live (HRQoL) instrument with 
extensive use in multiple disease states.  The SF-36v2 instrument comprises 36 total items 
(questions) targeting a subject's functional health and well-being in 8 dimensions 
(physical functioning, role physical, bodily pain, general health, vitality, social 
functioning, role emotional and mental health).  Scoring is totaled into a Physical 
Component Summary and a Mental Component Summary.  Higher SF-36v2 scores 
indicate a better state of health.  Completion of the SF-36v2 should require approximately 
10 minutes to complete.
EuroQol-5 Dimensions-5 Level (EQ-5D-5L)
The EQ-5D-5L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 


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5 levels of severity.  Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) using country-specific based weights, where available.  
Subjects also rate their perception of their overall health on a separate visual analogue 
scale (VAS).  The EQ-5D-5L should require approximately 5 minutes to complete.
HCV Patient Report Outcomes (HCVPRO) Instrument
The HCVPRO has been developed specifically to capture the function and wellbeing 
impact of HCV conditions and treatment.  This instrument has been preliminarily 
validated and further validation is ongoing.  The HCVPRO contains 16 items important to 
HCV patients; items are totaled to a summary score.  Higher HCVPRO score indicates a 
better state of health.  Completion of the HCVPRO should require approximately 
5 minutes.
Study Drug Compliance for Kits
Study drug compliance will be recorded per kit in the IRT system.  Study drugs will be 
collected at each drug dispensation visit after Day 1, as indicated Section 5.5.6.  The 
number of tablets of ABT-450/r/ABT-267, ABT-333, and of RBV remaining in each 
bottle will be recorded in the source and transferred to the IRT system along with the date 
of reconciliation.
HCV Genotype and Subgenotype 
Plasma samples for HCV genotype and subgenotype will be collected at Screening.  
Genotype and subgenotype will be assessed using the Versant® HCV Genotype Inno 
LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, 
NY).
HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Table 5 and 
Table 6.  Plasma HCV RNA levels will be determined for each sample collected by the 


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central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test 
v. 2.0. For this assay, the lower limit of quantification (LLOQ) is 15 IU/mL.
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected at 0-hour (prior to dose) and 
2 hours post dose on Day 1 and at the study visits, indicated in Table 5 and Table 6.  
Specific instructions for preparation and storage of HCV RNA and HCV resistance 
samples will be provided by the central laboratory, the Sponsor, or its designee.
Archive Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Table 5 and 
Table 6.  Archive plasma samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, viral load, 
safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and other 
possible predictors of response, as determined by the Sponsor.
Specific instructions for preparation and storage of archive samples will be provided by
the central laboratory, the Sponsor, or its designee.
Archive Serum Sample 
Archive serum samples will be collected at the study visits, indicated in Table 5 and 
Table 6.  Archive serum samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, viral load, 
safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and other 
possible predictors of response, as determined by the Sponsor.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, the Sponsor, or its designee.


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Interferon Gamma-Induced Protein 10 (IP-10) Levels
A plasma sample for IP-10 testing will be collected at the study visits indicated in Table 5
and Table 6.  Specific instructions for preparation and storage of IP-10 samples will be 
provided by the central laboratory, the Sponsor, or its designee.
5.3.1.2
Meals and Dietary Requirements
All study drugs should be dosed together and administered with food, i.e., the AM dose of 
ABT-450/r/ABT-267, ABT-333 and RBV should be taken together with food and the PM 
dose of ABT-333 and RBV should be taken together with food. 
5.3.1.3
Blood Samples for Pharmacogenetic Analysis
IL28B Sample
One (required) whole blood sample for DNA isolation will be collected from each subject 
Day 1 for Interleuken 28B (IL28B) pharmacogenetic analysis.  This sample will not be 
used for any testing other than IL28B genotypes.
Optional Sample for Pharmacogenetic Analysis
A separate (optional) whole blood sample for DNA isolation will be collected on Day 1 
(Treatment Period) from each subject who consents to provide the optional sample for 
pharmacogenetic analysis.  If the optional pharmacogenetic sample is not collected at 
Day 1, it may be collected at any other visit during the study.  The procedure for obtaining 
and documenting informed consent is discussed in Section 9.3.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, the Sponsor, or its designee.
Samples will be stored in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on ABT-450, ABT-267 and 
ABT-333 (or drugs for the treatment of HCV) continues but no longer than 10 years.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of ABT-450, possible ABT-450 metabolites, 
ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other 
possible ABT-333 metabolites, as well as ritonavir and RBV will be collected by 
venipuncture at each study visit, including at Day 1, for the 0-hour and 2-hour PK sample 
collection.  Intensive PK samples will be collected from at least 30 subjects at a visit on or 
after 2 weeks of the beginning of the treatment with DAAs.  Samples will be collected at 
predose and approximately 2, 4, 6, and at 24 hours post DDA dose.  Subjects may opt out 
of intensive PK sampling. 
The date and time of the first dose of each drug will be recorded in the source documents 
and the eCRF.  The time that each blood sample is collected will be recorded to the 
nearest minute.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-450, possible 
ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 
M1 metabolite, other possible ABT-333 metabolites, ritonavir and RBV will be provided 
by the central laboratory, the Sponsor, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of ABT-450, possible 
ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 
M1 metabolite, other possible ABT-333 metabolites, ritonavir, RBV and archive plasma 
samples will be packed in dry ice sufficient to last during transport, and transferred from 
the study site to the central laboratory.  Specific instructions for shipping to the analytical 
lab from the central laboratory will be provided by the central laboratory, the Sponsor, or 
its designee. 


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5.3.2.4
Measurement Methods
Plasma concentrations of ABT-450, ritonavir, ABT-267, ABT-333, ABT-333 
M1 metabolite, and RBV will be determined using validated assay methods under the 
supervision of the Drug Analysis Department at AbbVie.  Plasma concentrations of 
possible metabolites of ABT-450 and ABT-267, and other metabolites of ABT-333 may 
also be determined using non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by HCV RNA in IU/mL at various time points from 
Day 1 through 48 weeks after completion of treatment.
5.3.3.1
Primary Variable
The primary endpoints are the percentage of subjects with SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug) and the percentage of subjects with 
SVR24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drug).
5.3.3.2
Secondary Variable(s)
The secondary endpoints are: 
●
The percentage of subjects with on-treatment virologic failure;
●
The percentage of subjects with relapse by post treatment Week 12;
●
The percentage of subjects with relapse by post treatment Week 24.
5.3.3.3
Resistance Variables
The following resistance analyses will be performed for subjects receiving study drugs 
who experience virologic failure (who have HCV RNA ≥ 1000 IU/mL):  
1.
the amino acid variants at baseline at signature resistance-associated positions 
identified by population nucleotide sequencing and comparison to the prototypic 
reference sequence,


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2.
the amino acid variants in available post-baseline samples identified by population 
nucleotide sequencing and comparison to the baseline sequence, 
3.
the amino acid variants in available post-baseline samples at signature resistance 
associated positions identified by population nucleotide sequencing and 
comparison to the prototypic reference.
5.3.4
Safety Variables
The following safety evaluations will be analyzed during the study:  adverse event 
monitoring and vital signs, physical examination, ECG, and laboratory tests assessments.  
5.3.5
Pharmacokinetic Variables
Values for the pharmacokinetic parameters of ABT-450, ABT-267, ritonavir, ABT-333, 
ABT-333 M1 metabolite, and RBV including the Cmax, Tmax, Ctrough, and AUC will be 
determined by noncompartmental methods using data from subjects who participate in the 
intensive pharmacokinetic sampling.  Additional parameters or summaries may be 
determined if useful in the interpretation of the data.
Individual plasma concentrations and pharmacokinetic parameters of ABT-450, 
ABT-267, ritonavir, ABT-333, ABT-333 M1 metabolite, ribavirin and possible 
metabolites of ABT-450, ABT-267, and ABT-333 (other than ABT-333 M1) will be 
tabulated and summarized.
5.3.6
Pharmacogenetic Variables
IL28B genotypes are associated with response to pegIFN/RBV.  IL28B status will be 
determined for each subject and analyzed as a factor contributing to the subject's response 
to study treatment.  These IL28B genotype results may be analyzed as part of a 
multi-study assessment of IL28B and response to ABT-450, ABT-267, ABT-333, or 
drugs of these classes.  The results may also be used for the development of diagnostic 


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tests related to IL28B and study treatment, or drugs of these classes.  The results of 
additional pharmacogenetic analyses may not be reported with the clinical study report.
Additional parameters or summaries may be determined if useful in the interpretation of 
the data.
DNA samples from subjects who separately consent for additional pharmacogenetic 
analysis may be analyzed for genetic factors contributing to the subject's response to study 
treatment, in terms of pharmacokinetics, pharmacodynamics, efficacy, tolerability and 
safety.  Such genetic factors may include genes for drug metabolizing enzymes, drug 
transport proteins, genes within the target pathway, or other genes believed to be related 
to drug response (including IL28B).  Some genes currently insufficiently characterized or 
unknown may be understood to be important at the time of analysis.  Pharmacogenetic 
analyses will be limited to studying response to HCV therapy; no other analyses will be 
performed.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If, during the course of study drug administration, the subject prematurely discontinues 
during the Treatment Period or the Post-Treatment Period, the procedures outlined for the 
applicable Premature D/C Visit should be completed as defined in Table 5 and Table 6.  
  Ideally this should occur on the day of study drug discontinuation, but no later than 2 
days after their final dose of study drug and prior to the initiation of any other anti-HCV 
therapy.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the Investigator feels are necessary to treat the 
subject's condition.  Following discontinuation of study drug, the subject will be treated in 


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accordance with the Investigator's best clinical judgment.  The last dose of any study drug 
and reason for discontinuation from the Treatment Period will be recorded in the EDC 
(electronic data capture) system.  The subject should then begin the Post-Treatment Period 
where the subject will be monitored for 48 weeks for safety, HCV RNA, the emergence 
and persistence of resistant viral variants and PROs.
If a subject is discontinued from study drug (Treatment Period) or the Post-Treatment 
Period with an ongoing adverse event or an unresolved laboratory result that is 
significantly outside of the reference range, the Investigator will attempt to provide 
follow-up until a satisfactory clinical resolution of the laboratory result or adverse event is 
achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of study drug 
(including RBV) to that subject must be discontinued immediately.  Specific instructions 
regarding subject pregnancy can be found in Section 6.6.  Subjects will be monitored for 
SVR in the Post-Treatment Period as described in Section 5.1.3.  The Investigator is also 
encouraged to report the pregnancy information to the voluntary RBV Pregnancy 
Registry.
5.4.1.1
Virologic Failure Criteria
The following criteria will be considered evidence of virologic failure.  Subjects 
demonstrating any of the following will be discontinued from study drug:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurements of > 1 log10 IU/mL above nadir) at any time point during 
treatment;
●
Failure to achieve HCV RNA < LLOQ by Week 6 (≥36 days of treatment); or
●
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA 
measurements ≥ LLOQ) at any point after HCV RNA < LLOQ during 
treatment.


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Confirmatory testing should be completed as soon as possible.  Subjects should remain on 
study treatment until the virologic failure has been confirmed.
If any of the above criteria are met for subjects on DAA therapy, the subject will 
discontinue study treatment (Section 5.4.1).  Subjects with HCV RNA < LLOQ at the end 
of treatment and who have a confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive 
HCV RNA measurements ≥ LLOQ) at any point in the Post-Treatment Period will be 
considered to have relapsed.  Confirmation of an HCV RNA ≥ LLOQ in the 
Post-Treatment Period should be completed as soon as possible.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of study drug (ABT-450/r/ABT-267, ABT-333 and RBV) will be dispensed in 
the form of tablets at the visits listed in Table 6. 
ABT-450/r/ABT-267 will be provided by the Sponsor as 75 mg/50 mg/12.5 mg tablets.  
ABT 450/r/ABT-267 will be taken orally as 2 tablets once daily which corresponds to a 
150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.
ABT-333 will be provided by the Sponsor as 250 mg tablets.  ABT-333 will be taken 
orally as 1 tablet twice daily, which corresponds to a 250 mg dose BID.


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RBV will also be provided by the Sponsor to the Investigator for use in this study.  RBV 
will be provided as 200 mg tablets for Korea and Taiwan sites.  RBV will be provided as 
100 mg tablets for China sites.  RBV has weight-based dosing 1000 to 1200 mg divided 
twice daily per local label.  (For example, for Korea and Taiwan subjects weighing less 
than 75 kg, 200 mg RBV may be taken orally as 2 tablets in the morning and 3 tablets in 
the evening which corresponds to a 1000 mg total daily dose.  Or for subjects weighing 
75 kg or more, 200 mg RBV may be taken orally as 3 tablets in the morning and 3 tablets 
in the evening which corresponds to a 1200 mg total daily dose.  For example, for Chinese 
subjects weighing less than 75 kg, RBV 100 mg tablets may be taken orally as 
five 100 mg tablets in the morning and five 100 mg tablets in the evening which 
corresponds to a 1000 mg total daily dose.  Or for Chinese subjects weighing 75 kg or 
more, RBV 100 mg tablets may be taken orally as six 100 mg tablets in the morning and 
six 100 mg tablets in the evening which corresponds to a 1200 mg total daily dose.)
At Day 1 subjects will be administered study drugs by the study site personnel and receive 
instructions for self-administration of all study drugs from Study Day 2 through Study 
Week 12 of the Treatment Period.  
On the day of intensive PK subjects will take their morning dose of DAAs and RBV 
onsite in the presence of study site personnel and the time of administration will be noted.
Subjects will be instructed to take study medication at the same time(s) every day.  All 
compounds should be taken with food.
Following enrollment, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits indicated in Section 5.5.7.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  At the end of the Treatment Period 
or at the Premature D/C Visit from the Treatment Period, the site will contact the IRT 
system to provide visit date information and study drug return information for each kit 
(Section 5.5.7).


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All subjects who receive at least one dose of DAA and who fail to achieve virologic 
suppression, or who experience virologic breakthrough on DAA therapy will be 
discontinued from treatment.  Resistance monitoring will continue in the Post-Treatment 
Period regardless whether subjects opt for alternative post-study treatment.
5.5.2
Identity of Investigational Product
Information about the study drugs to be used in this study is presented in Table 9.
Table 9.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
ABT-450/ 
Ritonavir/ABT-267
AbbVie
Oral
Tablet
75 mg/50 mg/ 
12.5 mg
ABT-333
AbbVie
Oral
Tablet
250 mg
Ribavirin for Korea and 
Taiwan
Roche or Generic 
Manufacturer
Oral
Tablet
200 mg
Ribavirin for China
Shanghai Sine 
Tianping 
Pharmaceutical 
Co., Ltd.
Oral
Tablet
100 mg
5.5.2.1
Packaging and Labeling
ABT-450/r/ABT-267 tablets will be supplied in bottles containing 64 tablets.  ABT-333 
will be supplied in bottles containing 64 tablets.  Ribavirin 200 mg will be supplied in 
bottles containing 168 tablets each for Korea and Taiwan.  Ribavirin 100 mg will be 
supplied in cartons for China.  Each Ribavirin 100 mg carton will contain a blister pack of 
24 tablets for China.
Each bottle or carton will be labeled as required per country requirements.  
The labels must remain affixed to the bottles or cartons.  All blank spaces should be 
completed by site staff prior to dispensing to subject.


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5.5.2.2
Storage and Disposition of Study Drugs
Study Drug
Storage Conditions
ABT-450/Ritonavir/ABT-267 bottles
15° to 25°C (59° to 77°F)
ABT-333 bottles
15° to 25°C (59° to 77°F)
Ribavirin 200 mg bottles 
Ribavirin 100 mg cartons 
15° to 25°C (59° to 77°F) 
15° to 25°C (59° to 77°F)
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the Sponsor.  Upon receipt of study drugs, 
the site will acknowledge receipt within the IRT system.
5.5.3
Method of Assigning Subjects to Treatment 
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive unique study drug kit numbers.  The study drug 
kit numbers will be assigned according to schedules computer-generated before the start 
of the study by the AbbVie Statistics Department.  Upon receipt of study drug, the site 
will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site. 
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.5.  Study drug dosing will 
be initiated at the Study Day 1 Visit.  


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ABT-450/r/ABT-267 will be dosed QD; ABT-333 and RBV will be dosed BID.  Thus 
with normal dosing, 2 ABT-450/r/ABT-267 tablets, 1 ABT-333 tablet, should be taken in 
the morning, and 1 ABT-333 tablet should be taken in the evening. 
RBV should be dosed BID, e.g., 2 to 3 tablets taken in the morning, and 3 RBV tablets 
taken in the evening for subjects in Korea and Taiwan, or 5 to 6 tablets taken in the 
morning and 5 to 6 tablets taken in the evening for subjects in China.
All study drugs should be dosed together and administered with food i.e., the AM dose of 
ABT-450/r/ABT-267, ABT-333 and RBV should be taken together with food and the PM 
dose of ABT-333 and RBV should be taken together and with food.
5.5.5
Blinding
This is an open-label study.
5.5.5.1
Data Monitoring Committee 
An independent DMC will review safety data and provide recommendations to the 
Sponsor as per the DMC charter.  The charter also describes DMC membership, which 
will include individuals with experience in the management of patients with chronic HCV 
infection, and member responsibilities.  The DMC will receive interim summaries of 
safety data according to a schedule and format specified in the charter.  After each review, 
the DMC will communicate its recommendations to the Sponsor.  The Sponsor will retain 
sole responsibility for study management, communication with study sites and regulatory 
authorities.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.  All study drugs will be dispensed to subjects by study-site personnel under the 
direction of the Investigator.


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At the start of the study, each subject should receive counseling regarding the importance 
of dosing adherence with the treatment regimen with regard to virologic response and 
potential development of resistance.  Subjects will be administered study drugs at the site 
at the Day 1 Visit.  The start and stop dates of all study drugs will be recorded in the 
source documents and eCRFs.  Subjects will be provided self-administration instructions 
and study drug diaries to record the exact date, time and number of tablets of study drug 
administration each day between study visits. 
Subjects will be instructed to return all bottles of ABT-450/r/ABT-267 and ABT 333 (full, 
partial, or empty) and bottles and/or blister packs or cartons of RBV (full, partial or 
empty) to the study site at each visit indicated in Table 3.  At every study visit, during the 
Treatment Period, study site personnel will inspect the contents of the bottles and record 
the status of each one as well as the exact number of remaining tablets of 
ABT-450/r/ABT-267 and ABT-333 or tablets of RBV in IRT at the dispensing visits and 
in the source at all other Treatment Period visits (Weeks 1, 2, 6, and 10).  Study drugs 
may be re-dispensed at Treatment Period Weeks 1, 2, 6 and 10 therefore, Reconciliation 
in IRT should occur only when the bottles are returned to the site at the dispensation visits 
during the Treatment Period in Table 2.  If poor adherence is noted, the subject should be 
counseled and this should be documented in the subject's source.
Study drugs should not be interrupted for toxicity management or any other reason for 
more than 7 days consecutively.  If study drugs need to be interrupted for more than 
7 days consecutively, the Study Designated Physician should be contacted and 
consideration should be given to discontinue the subject.
At Day 1, for the 0-hour and 2-hour PK sample collection, the date and time of the 
first dose of each drug will be recorded in the source documents and the eCRF.  The date 
of last dose of all study drugs will be recorded in the source documents and the 
appropriate eCRF. 


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5.5.7
Drug Accountability
The Investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the Investigator and 
will include lot number, POR number, number of tablets dispensed, subject number, 
initials of person who dispensed study drug and date dispensed for each subject.  An 
overall accountability of the study drug will be performed and verified by the AbbVie 
monitor throughout the Treatment Period.  The monitor will review study drug 
accountability on an ongoing basis.  Final accountability will be verified by the monitor at 
the end of study drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug bottle, the 
IRT system must be contacted and informed of the misplaced or damaged study drug.  If 
the bottle is damaged, the subject will be requested to return the remaining study drug to 
the site.  Replacement study drug may only be dispensed to the subject by contacting the 
IRT system.  Study drug replacement(s) and an explanation of the reason for the 
misplaced or damaged study drug(s) will be documented within the IRT system.  Study 
drug start dates for each drug and the last dose of the regimen will be documented in the 
subject's source documents and recorded on the appropriate eCRF.  The status of bottle, 
number of each type of tablets remaining in each one returned, and the date of 
reconciliation will be documented in the IRT system.  The monitor will review study drug 
accountability on an ongoing basis.
Upon completion of or discontinuation from the Treatment Period, all original study drug 
bottles (containing unused study drugs) will be returned to the Sponsor (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  The number of tablets of each type of study drug returned in each bottle will 
be noted in the IRT system or on a drug accountability log (if appropriate).  Labels must 
remain attached to the containers.


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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The Phase 3 Study M13-099 demonstrated a high SVR12 of 99% with ABT-450/r/ 
ABT-267 + ABT-333 with ribavirin for 12 weeks treatment in subjects infected with 
HCV genotype 1 and with compensated cirrhosis except those with HCV genotype 1a 
who were prior null responders.  Study M13-099 was conducted globally except Asia.  
The current single arm study is evaluating the safety and efficacy of the same regimen in 
Asian subjects infected with HCV genotype 1b and with compensated cirrhosis.  No 
control arm is required per design.
The regulatory requirements for the primary endpoint differ for countries participating in 
this trial.  Currently SVR12 is accepted as the primary endpoint by health authorities in 
S. Korea and Taiwan but not in China.  Therefore, for S. Korea and Taiwan, superiority of 
the SVR12 rate to the historical SVR rate for telaprevir plus pegIFN/RBV therapy is 
specified as a primary endpoint.  For China, superiority of the SVR 12 and SVR24 rates to 
the historical SVR rate for telaprevir plus pegIFN/RBV therapy in genotype 1 HCV
infected patients with cirrhosis is specified as the primary endpoints.  
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.  Clonal and population 
sequencing methods are experimental.  The SF-36v2 and EQ 5D 5L instruments are 
standard in the literature and thoroughly validated.  The HCVPRO is preliminarily 
validated and has demonstrated excellent responsiveness in patients with HCV.
5.6.3
Justification of Primary Endpoint Success Criteria
The current study is a Asian study examining the combination of ABT-450/r/ABT-267 
and ABT-333 administered with RBV for 12 weeks in treatment-naïve and IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) treatment-experienced HCV genotype 
1-infected subjects with compensated cirrhosis.  This is a similar trial design as in AbbVie 


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Study M13-099.  In Study M13-099, the SVR12 rate for each treatment arm was compared 
to an historical SVR rate for telaprevir plus pegIFN and RBV (54%, see Table 10).  A 
weighted average of the corresponding SVR rates among treatment-naïve and 
treatment-experienced (prior relapsers, partial responders and null responders) in HCV 
genotype 1 infected cirrhotic subjects was calculated to reflect the population expected to 
enroll in Study M13-099.  The historical rate of 54% was defined conservatively as the 
upper bound of the 95% confidence interval for the telaprevir-based rate. 
Table 10.
Estimated SVR Rates for Telaprevir Plus PegIFN and RBV in 
Cirrhotic Subjects
Telaprevir-Treated 
Subjects with 
Cirrhosis n/N (%)
Projected Enrollment 
in Study M13-099 (%)
Population-Based 
Weighted Average % 
[95% CI]
Meta Analysis of ADVANCE57 and ILLUMINATE57 Studies
Naïve Subjects
(56)
53
REALIZE57
Prior relapsers
48/57 (84)
12
47 [41, 54]
Prior partial responders
11/32 (34)
12
Prior null responders
7/50 (14)
23
Consistent with Study M13-099, the SVR12 and SVR24 rates from the current study will 
be compared to a clinically relevant threshold based on historical SVR rates for telaprevir 
plus pegIFN/RBV.  However, since the historical SVR rate used in Study M13-099 is 
based on a population that included HCV genotype 1a-infected cirrhotic subjects as well 
as HCV genotype 1b-infected cirrhotic subjects, a higher threshold will be used in this 
study to account for a genotype 1b only population.  
Because data are not available on the subpopulation of HCV genotype 1b-infected 
subjects with cirrhosis treated with telaprevir plus pegIFN/ RBV, the SVR rates in HCV 
genotype 1a and genotype 1b-infected, non-cirrhotic subjects treated with telaprevir plus 
pegIFN/RBV were used to determine an appropriate adjustment factor to increase the 
historical rate used in Study M13-099.  An appropriate adjustment factor was determined 
based on the relative failure rate between the HCV genotype 1b and genotype 1a 


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populations in the telaprevir ADVANCE, ILLUMINATE, and REALIZE studies Table 11
and Table 12).  For treatment-naïve subjects, the SVR failure rate in genotype 1b subjects 
was reduced by a relative 29% (from 28% to 20%) from the SVR rate for genotype 1a 
subjects (Table 11).  For treatment-experienced subjects, the SVR failure rate in genotype 
1b was also reduced by a relative 29% (from 41% to 29%) from the SVR rate for 
genotype 1a subjects (Table 12).  Since the SVR rate for the genotype 1a cirrhotic 
subjects is not available and SVR rate for all cirrhotic patients would be higher than that 
for genotype 1a cirrhotic subjects, it would be more conservative to estimate the SVR rate 
for the genotype 1b cirrhotic subjects by taking 29% reduction from the combined data 
from genotype 1a + genotype 1b cirrhotic subjects together.  Therefore, to account for the 
exclusion of HCV genotype 1a-infected subjects in the current study, the historical SVR 
failure rate of 46% used in Study M13-099 for genotype 1 was reduced by a relative 29%, 
resulting in a 33% failure rate (or 67% SVR rate) for genotype 1b.  The rate of 67% 
should be conservative because the 54% was based on a population that was a mix of 
genotype 1a and 1b and the expectation is that the SRV rate for genotype 1a subjects 
would be lower than the SVR rate for the mix population of genotype 1a and 1b subjects.
Hence, for this current study, for a regimen to be considered superior to a clinically 
meaningful threshold based on SVR rates for telaprevir plus pegIFN/RBV, the lower 
confidence bound of the SVR rate must exceed 67%.  The value of 67% used for the 
superiority comparison represents the 54% historical genotype 1 SVR rate plus a relative 
29% adjustment factor for the exclusion of genotype 1a subjects.
Table 11.
SVR Rates for Telaprevir Plus pegIFN and RBV Therapy in 
Treatment-Naïve Subjects by Subgenotype
Telaprevir Studies
ADVANCE
ILLUMINATE
Meta Analysis
T12/PR n/N (%)
T12/PR n/N (%)
T12/PR % [95% CI]
Treatment-naïve GT1a 
subjects 
162/217 (75)57
273/388 (70)58
72 [68, 75]
Treatment-naïve GT1b 
subjects
119/142 (84)57
112/149 (75)59
80 [75, 84]
GT1a = genotype 1a; GT1b = genotype 1b


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Table 12.
Estimated SVR Rates for Telaprevir-Based Therapy in Treatment Experienced Subjects by Subgenoytpe
REALIZE†‡
GT1a 
(Pooled T12/PR48) 
n/N (%)
With Increase for 
Excluding Cirrhotics 
(%)
GT1b
(Pooled T12/PR48) 
n/N (%)
With Increase for 
Excluding Cirrhotics 
(%)
Population-Based 
Weighted Average* % 
[95% CI]
Relapsers
119/142 (83.8)
84.3
123/140 (87.9)
88.4
GT1a
59 [53, 65]
GT1b
71 [64, 77]
Partial responders
26/55 (47.3)
59.3
27/40 (67.5)
79.5
Null responders
24/88 (27.3)
36.5
22/59 (37.3)
46.5
GT1a = genotype 1a; GT1b = genotype 1b
†
US Prescribing Information for INCIVEK™ (telaprevir).  Vertex Pharmaceuticals Incorporated; Cambridge, MA.
‡
Zeuzem S, Andreone P, Pol S, et al.  REALIZE trial final results:  telaprevir-based regimen for GT1 hepatitis c virus infection in patients with prior null response, partial 
response or relapse to peginterferon/ribavirin.  J Hepatol.  2011;54Suppl:S3.
*
Based on a population of 30% relapsers, 35% partial responders, 35% null responders.


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5.6.4
Suitability of Subject Population 
This study plans to enroll both HCV treatment-naïve and treatment-experienced 
(pegIFN/RBV) subjects with genotype 1b chronic HCV and compensated cirrhosis.
The selection of subject population is based on the results from the Phase 3 trial 
Study M13-099.  Study M13-099 demonstrated high SVR12 100% and 98% with a 
12-week regimen of ABT-450/r/ABT-267 + ABT-333 with ribavirin in the treatment of 
naïve and treatment-experienced subjects infected with HCV genotype 1b and with 
compensated cirrhosis.  Study M13-099 was conducted globally except Asia and Russia.  
The goal of the current study is to confirm the results form Study M13-099 in Asian 
subjects infected with genotype 1b chronic HCV and compensated cirrhosis.
5.6.5
Selection of Doses in the Study
Doses of the three DAAs to be used in this study have shown significant antiviral activity 
and have been shown to be generally safe and well tolerated both as monotherapy, in 
combination with pegIFN + RBV, and in combination with each other and RBV in 
western studies.  Of note, coadministration of ABT-450/r, ABT-267 and ABT-333 at the 
doses planned for use in this study do not clinically significantly impact plasma exposures 
compared to administration as single agents thus dose adjustments based on drug 
interactions are not required.
ABT-450/r
An ABT-450 dose of 150 mg QD using the ABT-450/r/ABT-267 co-formulated tablet has 
been selected to for Phase 3 studies.  The same dose and formulation was used in western 
Phase 3 studies.
The ABT-450/r doses of 100/100 and 150/100 mg evaluated in the western Phase 2 
studies using the ABT-450 SDD tablet provided high ITT SVR12 rates in treatment-naïve 
(100% and 95%, respectively) and treatment-experienced (91% and 95.5%, respectively) 
subjects when dosed with ABT-333 and ABT-267 + RBV.  The higher ABT-450 dose of 
150 mg, administered with 100 mg ritonavir has been selected to advance into western 


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Phase 3 studies as it provides an optimal balance between safety and suppression of 
resistant variants.
In combination with other DAAs ± RBV, the highly fit, moderately resistant R155K viral 
variant was observed in a lower fraction of patients who had virologic failure at the 
150/100 and 200/100 mg ABT-450/r dose (SDD tablet of ABT-450) compared to the 
100/100 mg ABT-450/r dose.  This finding is consistent with monotherapy data for 
ABT-450/r where the higher 200/100 mg dose of ABT-450/r selected fewer resistant 
variants including R155K as compared to the lower 50/100 and 100/100 mg doses of 
ABT-450/r.  Higher doses were also associated with higher SVR24 rates when combined 
with pegIFN and RBV.  Thus based on resistance profile and SVR24 data with pegIFN + 
RBV, higher doses provide better efficacy.  However, ABT-450 doses of 200/100 and 
250/100 mg (SDD tablet) were associated with a greater incidence of grade 3+ ALT 
elevations (4% to 5% at doses ≥ 200/100 versus 0.3% to 0.5% at lower doses) suggesting 
that doses ≤ 200/100 mg SDD tablet might have a more favorable safety profile.  In 
western subjects, the ABT-450 150 mg dose from the ABT-450/r/ABT-267 co-formulated 
tablets planned for this study has a ~60% higher exposure compared to the 150/100 mg 
SDD tablet but the exposure is ~50% lower than that from the 200/100 mg SDD 
formulation.  The 150 mg ABT-450 dose from the co-formulation will hence provide a 
good balance between minimize the incidence of asymptomatic, transient grade 3 ALT 
elevations while maximizing virologic suppression.
ABT-450 exposures from the ABT-450/r/ABT-267 co-formulated tablets are comparable 
between Chinese and Western subjects.  Thus, same dose of ABT-450 is hence 
recommended in Western and Chinese subjects.
ABT-333
An ABT-333 dose of 250 mg BID using the optimized tablet formulation that is expected 
to provide exposures comparable to the 400 mg BID dose used in Phase 2 studies has 
been selected to for Phase 3 studies.  The same dose and formulation was used in western 
Phase 3 studies.  This is based on comparable efficacy and better safety profile compared 


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to exposures at higher ABT-333 doses.  Comparable viral load decline following 
monotherapy (approximately 1 log10 IU/mL) was observed at exposures greater than that 
achieved with the 400 mg BID dose evaluated in western Phase 2 studies.  Additionally, 
the 400 and 800 mg BID doses resulted in identical SVR rates (63%) when combined 
with pegIFN and RBV for 12 weeks followed by 36 weeks of pegIFN + RBV, indicating 
that increasing ABT-333 dose > 400 mg BID did not improve efficacy.  Furthermore, 
available data from the Phase 2b study indicates that when ABT-333 400 mg BID dose is 
combined with ABT-450, ABT-267 and RBV for 12 weeks, very high SVR12 rates were 
observed in treatment-naïve and treatment-experienced subjects (> 90%).  While both the 
400 mg BID and 800 mg BID doses of ABT-333 in combination with pegIFN and RBV 
were well tolerated by HCV-infected subjects for 12 weeks, the 800 mg BID dose was 
associated with a greater mean hemoglobin reduction compared to the 400 mg BID dose 
and compared to placebo plus pegIFN and RBV.  Therefore, 400 mg ABT-333 in tablet 
formulation is favored.
In the western subjects, the 250 mg optimized tablet used in the current study has 
comparable bioavailability to the 400 mg tablet formulation used in western Phase 2 
studies.  Hence, the ABT-333 250 mg optimized tablet dosed BID was selected as the 
Phase 3 formulation as it provides exposures that maximizes efficacy and a superior safety 
profile compared to higher ABT-333 doses.
The ABT-333 250 mg optimized tablet, alone or in combination, has not been evaluated 
in Chinese subjects.  However, ABT-333 400 mg tablet (which is bioequivalent to the 
ABT-333 250 mg optimized tablet) was evaluated as a part of the 3-DAA regimen, 
ABT-450/r + AB-267 + ABT-333, in Chinese and Western subjects (Study M12-221).  
Following administration of the 3-DAA combination (ABT-450/r 150/100 mg QD + 
ABT-267 25 mg QD + ABT-333 400 mg BID) for 21 day, ABT-333 exposures in Chinese 
subjects were comparable to Caucasian subjects with this 400mg tablet formulation.  
Thus, same dose of ABT-333, 250 mg optimized tablet, can be used in Chinese and 
Western subjects.


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ABT-267
An ABT-267 dose of 25 mg QD using the ABT-450/r/ABT-267 co-formulated tablet has 
been selected to for Phase 3 studies.  The same dose and formulation was used in Western 
Phase 3 studies.
Compared to higher doses, the 25 mg QD dose provided comparable viral load decline 
following monotherapy and lower potential to decrease ABT-450 exposures.  In Western 
subjects, following 2 to 3 days of ABT-267 monotherapy at doses of 1.5 mg to 200 mg 
QD, the 25 mg dose of ABT-267 showed viral load decline comparable to higher doses 
with none of the rebound between doses seen at lower doses.  Resistance analysis 
following monotherapy suggests that doses significantly greater than 25 mg would be 
needed to improve the resistance profile as a variety of NS5A resistant mutants were 
observed following monotherapy with doses of 5 mg to 200 mg.  In addition, higher 
ABT-267 doses have been associated with decreases in ABT-450 exposures; the ABT-267 
200 mg dose resulted in ~80% lower ABT-450 exposures when ABT-450 250 mg was 
dosed with 100 mg ritonavir.  Hence, doses > 25 mg could decrease the exposures of the 
"anchor" molecule ABT-450, without providing significant benefit in terms of improved 
efficacy.  Additionally, available data from the Phase 2b study indicates that when 
ABT-267 25 mg QD dose is combined with ABT-450, ABT-333 and RBV for 12 weeks, 
very high SVR12 rates were observed in treatment-naïve and treatment experienced 
subjects (> 90%).
In Western subjects, the co-formulated ABT-450/r/ABT-267 formulation used in the 
current study has ABT-267 bioavailability comparable to the ABT-267 25 mg tablet used 
in Phase 2 studies.  In addition, ABT-450 exposures from the ABT-450/r/ABT-267 
co-formulated tablets are comparable between Chinese and Western subjects.  Thus, same 
dose of ABT-450 can be used in Chinese and Western subjects.
Hence, the ABT-267 dose in the current study is the 25 mg dose, as it provides exposures 
that maximizes efficacy without compromising ABT-450 exposures.


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RBV
The daily dose of RBV selected in Western Phase 2 and 3 studies is 1000 mg to 1200 mg, 
divided twice daily, and based on subject weight.  This dose was chosen as it was the 
approved dose for treatment of adult patients with chronic hepatitis C infection in 
combination with pegIFN.  The same dose is selected for this study because its safety 
profile has been well characterized when administered with pegIFN, including the 
incidence of hemolytic anemia, and there are well-defined dose reduction criteria in the 
event of RBV-induced anemia.  In addition, this dose was studied in the absence of 
pegIFN in subjects with chronic hepatitis C infection in Studies M12-267, M12-746, 
M12-998 and M11-652 and was found to be generally safe and well-tolerated and resulted 
in high SVR rates.
In Chinese subjects, the recommended dose of RBV with an IFN-based regimen is weight 
based, 1000 mg daily in subjects with a body weight of less than 75 kg, and 1200 mg 
daily in subjects with a body weight of greater than or equal to 75 kg, per the Chinese 
HCV Treatment Guidelines.59  Hence, for the Regional Phase 3 studies, the proposed 
RBV dose is weight-based 1000 mg or 1200 mg.
Doses comparable to, and higher than, the DAA doses to be administered in this study 
have been studied in single- and multiple-dose healthy volunteer studies and administered 
to western HCV-infected subjects as monotherapy or in combination with pegIFN/RBV 
and found to be generally safe and well tolerated.  In addition, the pharmacokinetics of 
ABT-450, ABT-267 and ritonavir when given in combination to western subjects with 
mild hepatic impairment were comparable to or slightly lower than in subjects with 
normal hepatic function.  The area under the concentration curve (AUC) of ABT-450 and 
ABT-267 were comparable (≤ 30% change) in subjects with mild hepatic impairment 
compared to healthy controls.  The AUC for ritonavir was 34% lower in subjects with 
mild hepatic impairment.  Additionally, based on the package insert for RBV, dose 
adjustments are not required in subjects with mild hepatic impairment.


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Based on these data, no dose adjustment is required for Chinese subjects with 
compensated cirrhosis taking the DAA combination in this study.  The doses of ABT-267, 
ABT-333 and ABT-450/r chosen for this study in compensated cirrhotic subjects are the 
same that was used in Phase 3 studies for the IFN-free 3-DAA Study in Western subjects 
(Study M13-099).
The maximum dose of ABT-450/r/ABT-267 75 mg/50 mg/12.5 mg tablets will not exceed 
150 mg/100 mg/25 mg per day for 12 weeks.  The maximum dose of ABT-333 250 mg 
tablets administered in this study will not exceed 500 mg per day for 12 weeks.  The 
maximum RBV dose administered in this study will not exceed 1200 mg, divided 
twice daily for 12 weeks.
6.0
Adverse Events
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 


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necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or 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 adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.7 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
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.


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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
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 
subject.  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 subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life 
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:


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Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of DAAs (ABT-450/r/ABT-267 and ABT-333), and RBV:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of the event must be provided by the investigator for the serious 
adverse event.
6.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events will be 
collected from the time the subject signed the study-specific informed consent until study 
drug administration. From the time of study drug administration until 30 days after last 
administration AEs and SAEs will be collected whether solicited or spontaneously 


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reported by the subject. From 30 days after last dose until the end of study, SAEs will be 
collected.  
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
6.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system or if RAVE is not operable s should use the SAE 
non-CRF paper forms and send them to Clinical Pharmacovigilance within 24 hours of 
the site being aware of the serious adverse event.
FAX to:  
Email:  


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For safety concerns, contact the Antiviral Safety Team at:
For any subject safety concerns, please contact the Primary Study Designated Physician 
listed below:
In case of subject safety concerns or medical emergencies when the Primary Study 
Designated Physician is unavailable, please call the following central back-up number:
Phone:  


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The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.  
6.6
Pregnancy
Subjects and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the study, starting with Day 1 and for 7 months after 
the last dose of RBV (or per local RBV label) and/or consistent with local treatment 
guidelines for RBV.
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who report a positive pregnancy test during 
the Treatment Period must be notified to stop RBV immediately.  Subjects will be 
monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.  
Administration of DAAs may be continued at the investigator's discretion, if the benefit of 
continuing therapy is felt to outweigh the risk.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 7 months (or per local RBV 
label) after the last dose of RBV for treatment with DAAs plus RBV.  The investigator is 
encouraged to report the pregnancy information to the voluntary RBV Pregnancy 
Registry, if RBV is included within the regimen.
Subjects who discontinue study medications due to pregnancy will be monitored for SVR 
in the Post-Treatment Period as described in Section 5.1.3.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to the Sponsor within 24 hours of 
the site becoming aware of the event.


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6.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the Investigator.  A table of Clinical 
Toxicity Grades for evaluating laboratory abnormalities is provided in Appendix C.  This 
table should be used in determination of the appropriate toxicity management as discussed 
in  Section 6.7.1 and Section 6.7.5.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the Investigator or the Sponsor as having a "reasonable possibility"
of being related to the study drug (Section 6.3).  A toxicity is deemed "clinically 
significant" based on the medical judgment of the Investigator.  Laboratory abnormalities 
will be managed as deemed clinically appropriate by the investigator until resolved.
Investigators should avoid interrupting study drugs for more than 7 consecutive days.  The 
Investigator should ensure that any study drug interruptions or RBV dose modifications 
and associated adverse events are promptly entered into the appropriate eCRFs.
The toxicity management guidelines below should be followed throughout the Treatment 
Period of the study.
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or 
Moderate Adverse Events
Subjects who develop a mild or moderate adverse event or Grade 1 or 2 laboratory 
abnormality, other than those discussed separately in Section 6.7.4 and Section 6.7.5, may 
continue study drugs with follow-up per study protocol and in accordance with local 
standard of care.


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6.7.2
Grades 3 or 4 Laboratory Abnormalities and Severe or 
Serious Adverse Events
Grade 3 – 4 Laboratory Abnormalities
With the exception of Grade 3 or higher abnormalities of total bilirubin, uric acid, 
phosphorus, total cholesterol, triglycerides, or glucose (in subjects with a history of 
diabetes), if a subject experiences a Grade 3 or greater abnormal laboratory parameter 
during the Treatment Period, the abnormal laboratory test should be repeated.  If the 
Grade 3 or greater abnormality is confirmed, the investigator should assess whether the 
abnormality can be managed medically without interruption of study drug, or whether 
study drugs should be interrupted and the laboratory parameter followed until it improves.  
If study drugs are interrupted and restarted and the abnormality recurs, then study drugs 
should be permanently discontinued. 
Decreases in serum hemoglobin or elevations of serum ALT should be managed 
according to the guidance in Section 6.7.4 and Section 6.7.5 below.  Grade 3 or greater 
abnormalities of total bilirubin, uric acid, phosphorus, total cholesterol, triglycerides or 
glucose (in subjects with a history of diabetes) should be managed medically as 
appropriate and do not require confirmation or study drug interruption unless deemed 
necessary by the investigator.
Severe Adverse Event or Serious Adverse Events
If a subject experiences a severe adverse event or a serious adverse event that the 
investigator considers to be a reasonable possibility of relationship to study drug, 
investigator should assess whether the adverse event can be managed medically without 
interruption of study drug, or whether study drugs should be interrupted until it improves, 
or study drugs should be permanently discontinued.  If study drugs are interrupted and 
restarted and the adverse event recurs, then study drugs should be permanently 
discontinued. 


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If a subject experiences a severe adverse event or serious adverse event that is considered 
unrelated (no reasonable possibility) to the study drugs, it is not necessary to interrupt 
study drugs unless an interruption is required because of the nature of the event 
(e.g., unable to take oral medications).  If an interruption is required, it should not exceed 
7 days.
The investigator should ensure that all serious adverse events are reported to AbbVie 
within 24 hours of awareness.  Serious adverse event follow-up information, including 
associated dose interruptions (or discontinuations), must be reported to AbbVie within 
24 hours of awareness by entering updated SAE information into the appropriate eCRFs. 
Severe adverse events and any associated dose interruptions (or discontinuations) should 
be entered into the appropriate eCRFs.
6.7.3
Management of Hemoglobin Decreases
Reductions in hemoglobin are a well characterized side effect of ribavirin exposure.  If a 
subject experiences a hemoglobin decrease meeting one of the criteria outlined in 
Table 13, a confirmatory test should be performed.  If the hemoglobin decrease is 
confirmed, the management guidelines in Table 13 should be followed.  Management will 
be different for subjects without a history of known cardiac disease and subjects with 
known cardiac disease. 
Use of hematologic growth factors (such as erythropoietin or filgrastim) or blood 
transfusions are permitted at the discretion of the Investigator.  Management of 
hematologic growth factor therapy is the responsibility of the Investigator, and growth 
factors will not be provided by AbbVie.
Alternate management of hemoglobin decreases outside of these criteria requires approval 
of the AbbVie Study Designated Physician.


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Table 13.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases
Hemoglobin Value
Intervention
All subjects
< 10 g/L and ≥ 8.5 g/dL for 
subjects without cardiac disease
< 12 g/L and ≥ 8.5 g/dL for 
subjects with cardiac disease
Reduce RBV dose*.  Study drugs may be continued.  If hemoglobin 
increases to ≥ 10 g/dL for subjects without cardiac disease or to 
12g/dL for subjects with cardiac disease.  RBV dose may be 
increased gradually in 200 mg increments towards original dose.
< 8.5 g/dL
Interrupt ribavirin.  Manage the subject as medically appropriate.
Investigator should evaluate if RBV discontinuation is warranted.
If subsequent hemoglobin results are improved to ≥ 10 g/dL for 
subjects without cardiac disease or 12 g/dL for subjects with cardiac 
disease RBV, may be restarted.
Additional guidance for subjects with history of stable cardiac disease
Hemoglobin decrease of ≥ 2 g/dL 
during any 4-week treatment 
period
Reduce RBV dose*.  If a subsequent hemoglobin result is greater 
than the level that triggered the dose reduction, RBV dose may be 
increased gradually in 200 mg increments 
< 12 g/dL after a 4-week RBV 
dose reduction
Interrupt ribavirin.  Manage the subject as medically appropriate.
Investigator should evaluate if RBV discontinuation is warranted.
If subsequent hemoglobin results are improved to ≥ 12g/dL, RBV 
may be restarted.
*
1st dose reduction of ribavirin is to 600 mg/day.  If needed, 2nd dose reduction of ribavirin is by an additional 
200 mg/day.  Subjects whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg tablet in the morning 
and two 200 mg tablets in the evening.
6.7.4
Management of Transaminase Elevations
Transient asymptomatic Grades 3 – 4 ALT elevations have been observed in 
approximately 1% of subjects receiving ABT-450/r-containing regimens.  If a subject 
experiences an increase in ALT to > 10 × ULN, or to > 5 × ULN which was increased 
from previous measurement, the subject should have a confirmatory ALT measurement 
performed in a timely fashion.  If the ALT increase is confirmed, the management 
guidelines in Table 14 should be followed.  Subjects using an estrogen-containing product 
should discontinue use of that product.  Alternate management of ALT increases is 
permitted with approval of the AbbVie Study Designated Physician.


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Table 14.
Management of Confirmed ALT Elevations
ALT ≥ 20 × ULN
!
Permanently discontinue study drugs.
!
Manage the subject as medically appropriate.
ALT ≥ 10 × ULN 
or
ALT ≥ 5 × ULN and increased 
from previous measurement with 
symptoms and signs of hepatitis 
present
!
If using an estrogen-containing product:  Discontinue 
estrogen-containing product and repeat ALT testing, 
preferably within 1 week. 
!
Repeat ALT, AST, total and fractionated bilirubin, alkaline 
phosphatase and INR, preferably within 1 week.
!
Evaluate for alternative etiology of ALT elevation:  update 
medical history and concomitant medications eCRF (if 
applicable), and obtain additional testing as appropriate.
!
Manage the subject as medically appropriate.
!
Permanently discontinue study drugs for any of the following:  
ALT level increases to 20 × ULN, increasing direct bilirubin, 
increasing INR, or new symptoms/signs of hepatitis.
ALT ≥ 5 × ULN and increased 
from previous measurement but 
< 10 × ULN and without 
symptoms or signs of hepatitis
!
Continue study drugs.
!
As soon as possible, measure ALT, AST, total and 
fractionated bilirubin, alkaline phosphatase and INR.  Repeat 
liver chemistries as indicated until resolution. Evaluate for 
alternative etiology of ALT elevation:  update medical history 
and concomitant medications eCRF (if applicable), and obtain 
additional testing as appropriate.
!
Manage the subject as medically appropriate.
!
Permanently discontinue study drugs for any of the following:  
ALT level increases to 20 × ULN, increasing direct bilirubin, 
increasing INR, or symptoms/signs of hepatitis.
6.7.5
Management of eGFR Decreases
If calculated eGFR is confirmed to have decreased to < 50 mL/minute, medical evaluation 
should include a full review of current medications, including those taken on an as needed 
basis, those which are sold over the counter and any dietary and herbal supplements, and 
appropriate dose reduction or discontinuation based on impaired renal function should be 
done (if applicable).  Ribavirin dose should be adjusted as in Table 15.  Alternative 
management of RBV dose in the setting of reduced renal function will require approval of 
the AbbVie Study Designated Physician.


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The investigator should also consider whether drug-drug interactions with concomitant 
medications may have contributed to the decrease in eGFR, and whether discontinuation 
of substitution of the possible interacting drug should be considered.  For example, drug 
interactions between DAAs and some antihypertensive medications could potentially 
increase exposures of the antihypertensive and may reduce renal function.  If 
anti-hypertensive medications are adjusted, vital signs must be monitored to ensure 
appropriate blood pressure control.  Refer to Section 5.2.3.3 for additional information 
regarding drug-drug interactions.
If eGFR improves, the site should perform all necessary readjustment of any dose 
modifications that have been made. 
The Investigator should ensure that any concomitant medication changes, RBV dose 
reductions, and study drug discontinuations, as well as consequent related adverse events 
are entered into the appropriate eCRFs.
Table 15.
Dosing of RBV in Subjects with Renal Impairment
eGFR Value
RBV Dose
30 – 50 mL/min
Alternating doses of 200 mg with 400 mg every other day
< 30 mL/min
200 mg daily
Hemodialysis
200 mg daily
7.0
Protocol Deviations
The investigator should not implement any deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects.  When a deviation from the 
protocol is deemed necessary for an individual subject, the investigator must contact the 
following AbbVie personnel:


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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
An interim analysis will occur after all enrolled subjects from S. Korea and Taiwan have 
completed the Treatment Period through Post-Treatment Week 12 of the Post-Treatment 
Period or prematurely discontinued from the study.  This interim analysis is planned to 
support regulatory submission activities in S. Korea and Taiwan.  The primary analysis 
will occur after all subjects have completed PT Week 24 or prematurely discontinued the 
study.  All remaining data through PT Week 48 will be summarized in the end of study 
analysis.
SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All confidence intervals will be 2-sided with an α level of 0.05.  Descriptive 
statistics will be provided, such as the number of observations (N), mean, and standard 
deviation (SD) for continuous variables and counts and percentages for discrete variables.  


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Efficacy, safety, and demographic analyses will be performed on the intent-to-treat (ITT) 
population which will consist of all enrolled subjects who receive at least one dose of 
study drug.  Additional summaries will be provided by geographic region (China, 
S. Korea, Taiwan).
No data will be imputed for any efficacy or safety analyses except for the PRO 
questionnaires and for analyses of the HCV RNA endpoints of RVR, EOTR, and all SVR 
endpoints.  If a respondent answers at least 50% of the items in a multi-item scale of the 
SF-36v2, the missing items will be imputed with the average score of the answered items 
in the same scale.  In cases where the respondent did not answer at least 50% of the items, 
the score for that domain will be considered missing.  The Mental and Physical 
Component Summary measures will not be computed if any domain is missing.  If a 
respondent answers at least 12 of the 16 items on the HCVPRO, the missing items will be 
imputed with the mean score of the answered items.  In cases where the respondent did 
not answer five or more items, the HCVPRO total score will be considered missing.  For 
EQ-5D-5L index and VAS scores, no imputation will be performed for missing items.
HCV RNA values will be selected for the analyses of HCV RNA endpoints of RVR, 
EOTR, and all SVR endpoints based on the defined visit windows.  When there is no 
HCV RNA value in a visit window based on defined visit windows, 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 subject has a missing HCV RNA value at a post-baseline visit but with undetectable 
or unquantifiable HCV RNA levels at both the preceding value and succeeding value, the 
HCV RNA level will be considered undetectable or unquantifiable, respectively, at this 
visit for this subject.  Subsequent to this flanking imputation, if a subject is missing a 
value for the visit window associated with the analysis, the subject will be imputed as a 
visit failure (i.e., not undetectable or unquantifiable).  For SVR analyses (e.g., SVR4, 
SVR12, SVR24) if after performing the flanking imputation there is no value in the 
appropriate window but there is an HCV RNA value after the window, then it will be 
imputed into the SVR window.


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8.1.1
Demographics
Demographics and baseline characteristics will be summarized for the ITT population.  
Demographics include age, weight, and BMI, and the frequency of gender, race, ethnicity, 
age category ([< 55 years or ≥ 55 years] and [< 65 or ≥ 65 years]) and BMI category 
(< 30 kg/m2 or ≥ 30 kg/m2).  Baseline characteristics will include IL28B genotype ([CC, 
CT, or TT] and [CC or non-CC]), IFN based therapy (IFN [alpha, beta or pegIFN] with 
RBV) treatment history (treatment-naïve or treatment-experienced) non-responder {null 
responder, partial responder, or other non-responder} or relapser or IFN based therapy 
intolerant, baseline HCV RNA levels ([continuous] and [< 800,000 IU/mL or 
≥800,000 IU/mL]), baseline IP-10 ([continuous] and [< 600 pg/mL or ≥ 600 pg/mL]), 
baseline HOMA-IR (< 3 mU × mmol/L2 or ≥ 3 mU × mmol/L2), Child-Pugh score at 
Screening (5 or 6), baseline Child-Pugh score (5, 6, or > 6), baseline longitudinal 
FibroTest score (continuous), baseline platelet counts [(continuous) and (< 60, 60 to < 90, 
90 to < 120, or ≥ 120 × 109/L)],baseline albumin [(continuous) and (< 28, 28 to < 33, 
33 to < 40, 40 to 49, and > 49 g/L), baseline alpha fetoprotein (continuous), presence of 
hepatic steatosis at baseline (yes, no), hepatoprotective drug use at baseline (yes, no), 
tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) 
status, former injection drug user (yes, no, unknown), history of bleeding disorders (yes, 
no), history of diabetes (yes, no), history of depression or bipolar disorder (yes, no), and 
geographic region (China, S. Korea and Taiwan).  Summary statistics (N, mean, median, 
Standard Deviation [SD], and range) will be generated for continuous variables (e.g., age 
and BMI).  The number and percentage of subjects will be presented for categorical 
variables (e.g., gender and race). 
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population. 
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS TaqMan® real-time reverse transcriptase-PCR (RT 
PCR) assay version 2.0.  For this assay, the lower limit of detection (LLOD) is 15 IU/mL 


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and lower limit of quantification (LLOQ) is 25 IU/mL.  HCV RNA results that are 
detectable but not quantifiable are reported as "< 25 IU/ML HCV RNA detected" and 
those that are undetectable are reported as "HCV RNA not detected" in the database.
8.1.2.1
Primary Efficacy Endpoints
For South Korea and Taiwan the primary endpoint is: 
A1.
SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN/RBV 
therapy; the LCB of the 95% CI for the percentage of subjects with SVR12
must exceed 67% to achieve superiority.
For China, the primary endpoints are:
B1.
SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN/RBV 
therapy; the LCB of the 95% CI for the percentage of subjects with SVR12 
must exceed 67% to achieve superiority.
B2.
SVR24:  Superiority to the historical SVR rate for telaprevir plus pegIFN/RBV 
therapy; the LCB of the 95% CI for the percentage of subjects with SVR24
must exceed 67% to achieve superiority.
For China, in order to control the Type I error rate at 0.05, a fixed-sequence testing 
procedure will be used to proceed through the primary efficacy endpoints.  That is, only if 
success has been demonstrated for the primary endpoint of superiority of SVR12 rate to 
the historical rate for telaprevir plus pegIFN and RBV therapy (B1) will the testing 
continue to the second primary endpoint of superiority of the SVR24 rate to the historical 
rate for telaprevir plus pegIFN and RBV therapy (B2).
To test the hypothesis that the percentage of treatment-naïve and IFN based therapy (IFN 
[alpha, beta or pegIFN] with RBV) treatment-experienced HCV genotype 1b infected 
Asian subjects with compensated cirrhosis treated with ABT-450/r/ABT-267 + ABT-333 
+ RBV for 12 weeks who achieve SVR12 is superior to a clinically meaningful threshold 


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based on the historical SVR rates for the HCV genotype 1 infected population treated with 
telaprevir plus pegIFN/RBV, the percentage of subjects with SVR12 will be calculated 
with a 2-sided 95% CI using Wilson score method, and the LCB will be compared to the 
defined threshold.  The LCB of the 95% CI of SVR12 must be greater than 67% in order 
for the regimen to be considered superior.
Similarly, to test the hypothesis that the percentage of treatment-naïve and IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) treatment-experienced HCV genotype 1b 
infected Asian subjects with compensated cirrhosis treated with ABT-450/r/ABT-267 + 
ABT-333 + RBV for 12 weeks who achieve SVR24 is superior to a clinically meaningful 
threshold based on historical SVR rates for the HCV genotype 1 infected population 
treated with telaprevir plus pegIFN and RBV, the percentage of subjects with SVR24 will 
be calculated with a 2-sided 95% CI using Wilson score method, and the LCB will be 
compared to the defined threshold.  The LCB of the 95% CI of SVR24 must be greater 
than 67% in order for the regimen to be considered superior.
The value of 67% used in the endpoints as the historical SVR rate for telaprevir plus 
pegIFN/RBV is described in Section 5.6.3.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment virologic failure defined as the 
occurrence of at least one of the following:
○
confirmed HCV RNA ≥ the lower limit of quantitation (LLOQ) (defined as 
2 consecutive HCV RNA measurements ≥ LLOQ) at any point during 
treatment after HCV RNA < LLOQ, or
○
confirmed increase from nadir in HCV RNA (defined as 2 consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point 
during treatment, or
○
Failure to achieve HCV RNA < LLOQ by Week 6 with ≥ 36 days of 
treatment.


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●
The percentage of subjects with  relapse by Post-Treatment Week 12 
(confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
the last dose of study drug among subjects completing treatment and with 
HCV RNA < LLOQ at the end of treatment).  
●
The percentage of subjects with relapse by Post-Treatment Week 24 
(confirmed HCV RNA ≥ LLOQ between end of treatment and 24 weeks after 
the last dose of study drug among subjects completing treatment and with 
HCV RNA < LLOQ at the end of treatment).  
The percentages (with 2-sided 95% confidence intervals using the Wilson Score method 
to the binomial distribution) of the subjects with on treatment virologic failure and 
post-treatment relapse will be calculated and summarized.
8.1.2.3
Sensitivity Analyses for the Primary Endpoint
In addition to presenting the primary efficacy endpoints with HCV RNA and SVR 12 and 
SVR24 imputed as described in Section 8.1, SVR12 and SVR24 will be presented using the 
following other methods to impute missing post-treatment virologic results:
●
Imputing any missing HCV RNA values in the SVR12/SVR24 window by 
carrying forward the last non-missing (post-baseline) HCV RNA value prior to 
the SVR12/SVR24 window;
●
Imputing as described in Section 8.1 but exclude the subjects who were 
categorized as "prematurely discontinued study drug with no on-treatment 
virologic failure" and "missing follow-up data in the PT Period."
For each of these, the simple percentage of subjects with SVR12/SVR24 will be presented 
along with a 2-sided 95% CI using Wilson score method.
As a sensitivity analysis, comparisons of the SVR12 and SVR24 rates may be made to 
geographic region-specific SVR rates with IFN based therapy (IFN [alpha, beta or 
pegIFN] with RBV) treatment.


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8.1.2.4
Subgroup Analysis
The percentage (with 2-sided 95% confidence intervals) of subjects with SVR12 and 
SVR24 will be presented for the following subgroups:
●
Treatment-naïve versus previous IFN based therapy (IFN [alpha, beta or 
pegIFN] with RBV) treatment-experienced subjects;
○
For treatment-experienced subjects, type of response to previous IFN based 
therapy (non-responder, relapser, or (IFN based therapy intolerant);
○
For non-responders to previous IFN based therapy, type of response (null 
responder, partial responder, or other non-responder);
○
Geographic region/previous HCV treatment status (China/treatment-naïve, 
China/treatment-experienced, S. Korea/treatment-naïve, 
S. Korea/treatment-experienced, Taiwan/treatment-naïve, 
Taiwan/treatment-experienced). 
●
IL28B genotype (CC or non-CC), (CC, CT, or TT);
●
Baseline HCV RNA level (< 800,000 IU/mL or ≥ 800,000 IU/mL);
●
Baseline IP-10 (< 600 pg/mL or ≥ 600 pg/mL);
●
Baseline HOMA-IR (< 3 or ≥ 3 mU × mmol/L2);
●
Sex (male versus female);
●
Age (< 55 versus ≥ 55 years), (< 65 versus ≥ 65 years);
●
BMI (< 30 or ≥ 30 kg/m2);
●
Subjects with RBV dose modifications (yes/no);
●
Presence of hepatic steatosis at Baseline (yes/no);
●
Hepatoprotective drug use at baseline (yes/no);
●
History of Diabetes (yes/no);
●
History of Bleeding Disorders (yes/no);
●
History of Depression or Bipolar Disorder (yes/no);
●
Former injection drug user (yes/no);
●
Baseline Child-Pugh Score ( 5, 6, or > 6);
●
Baseline platelets (< 90 or ≥ 90 × 109cells/L);


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●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline alpha fetoprotein [AFP] (< 20 or ≥ 20 ng/mL).
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized and analyzed, as 
specified:
●
The percentage of subjects with rapid virologic response (RVR) (HCV RNA 
< LLOQ at Week 4);
●
The percentage of subjects with end of treatment response (EOTR) (HCV 
RNA < LLOQ at Week 12;
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using only subjects with data in each visit window, 
i.e., no imputation for missing data);
●
The number of subjects with virologic rebound at each protocol-specified visit 
(confirmed HCV RNA ≥ LLOQ after HCV RNA < LLOQ during treatment, or 
confirmed increase from nadir in HCV RNA (two consecutive HCV RNA 
measurements > 1 log10 IU/mL above nadir) at any time point during 
treatment.  A single rebound value (≥ LLOQ or >1 log10 IU/mL above nadir) 
followed by lost to follow-up will be considered a rebound);
●
The percentage of subjects who failed to have confirmed suppression of HCV 
RNA (never achieving HCV RNA < LLOQ) during the Treatment Period and 
have received at least 6 weeks of treatment (study drug duration ≥ 36 days);
●
Time to suppression of HCV RNA (defined as the study day of the 
first occurrence of HCV RNA < LLOQ) during the Treatment Period;
●
the percentage of subjects achieving SVR4;
●
The percentage of subjects who complete treatment (defined as a study drug 
duration ≥ 77 days) with HCV RNA < LLOQ at Final Treatment Visit who 
relapsed post-treatment within 4 weeks after the last actual dose of study drug 
(up to and including the SVR4 assessment time point);
●
The percentage of subjects who complete treatment (defined as a study drug 
duration ≥ 77 days) with HCV RNA < LLOQ at Final Treatment Visit who 


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relapsed between end of treatment and up to and including the last HCV RNA 
measurement collected in the PT Period; 
●
The percentage of subjects who achieved SVR24 who subsequently relapsed;
●
Time to relapse at any time post-treatment for subjects who complete treatment 
with HCV RNA < LLOQ at Final Treatment Visit;
●
The percentage of subjects with SVR12 weeks after the last planned dose of 
study drug (SVR12planned);
●
The percentage of subjects with SVR24 (South Korea and Taiwan);
●
The percentage of subjects with SVR24 weeks after the last planned dose of 
study drug (SVR24planned);
●
Mean change from baseline in liver function tests (e.g., PT/INR, Fibrotest) to 
each applicable post-baseline time point.
In the above analyses for RVR, EOTR, and SVR, the percentage of responders and 
2-sided 95% confidence intervals using Wilson score method will be calculated.  From 
HCV RNA levels, the time to suppression on treatment and time to relapse post-treatment 
will be displayed graphically using Kaplan-Meier curves.
8.1.3
Patient Reported Outcomes
The following exploratory analyses of patient reported outcomes (PROs) will be 
performed:
●
mean change from baseline in HCVPRO total score to each applicable 
post-baseline time point;
●
mean change from baseline in EQ-5D-5L health index score and VAS score to 
each applicable post-baseline time point;
●
mean change from baseline in the SF-36v2 Mental Component Summary 
(MCS) and Physical Component Summary (PCS) scores to each applicable 
post-baseline time point.


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Summary statistics (n, mean, SD, median, minimum and maximum) at each visit and for 
change from baseline to each visit will be provided for the HCVPRO total score, the 
EQ-5D-5L health index and VAS scores, and the SF-36v2 PCS and MCS scores.
For HCVPRO total score, a continuous plot by treatment arm will be provided with 
percent change from baseline on the horizontal axis and the cumulative percent of subjects 
experiencing up to that change on the vertical axis.  These plots will be used to show 
change from Baseline to Final Treatment Visit, and change from Baseline to 
Post-Treatment Week 12 and change from Baseline to Post-Treatment Week 24.
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
Resistance Analyses
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo population 
sequence analysis in order to allow accurate assessment of the products of amplification.  
For subjects who experience virologic failure, the sample closest in time after failure with 
an HCV RNA level ≥ 1000 IU/mL will be used if the HCV RNA level at the time of 
failure is < 1000 IU/mL.  The prototypic reference strain with its associated GenBank 
Accession ID for sequence analyses is 1b-Con1 (AJ238799).
For each DAA target, resistance-associated signature amino acid variants will be 
identified by AbbVie Clinical Virology.  Amino acid positions where 
resistance-associated variants have been identified in vitro and/or in vivo in genotype 1b 
are 1) for ABT-450:  56, 155, 156, and 168 in NS3; 2) for ABT-267:  28, 29, 30, 31, 32, 
58, and 93 in NS5A; and 3) for ABT-333:  316, 368, 411, 414, 445, 448, 553, 556, 558, 
and 559 in NS5B.
The following definitions will be used in the resistance analyses:
●
Baseline sample:  sample collected before the first dose of DAA study drug.
●
Baseline variant:  a variant (by population sequencing) in a baseline sample 
determined by comparison of the amino acid sequence of the baseline sample 


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to the appropriate prototypic reference amino acid sequence for a given DAA 
target (NS3, NS5A, or NS5B).
●
Post-baseline variant by population sequencing:  an amino acid variant in a 
post-baseline time point sample that was not detected at baseline in the subject 
and is detectable by population sequencing.
●
Emerged variant by population sequencing:  a post-baseline variant that is 
observed in 2 or more subjects of the same subgenotype by population 
sequencing.
●
Linked variant by population sequencing:  2 or more signature or emerged 
amino acid variants identified within a sample by population sequencing where 
at least one of the variants is at a signature position, and no mixture of amino 
acids is detected at either position.
For those samples evaluated, a listing by subject of all baseline variants relative to the 
prototypic reference sequence at signature resistance-associated amino acid positions will 
be provided for each DAA target (NS3, NS5A, and/or NS5B).  Furthermore, the HCV 
amino acid sequence at post-baseline time points with an HCV RNA level of 
≥1000 IU/mL that are analyzed will be compared to the baseline and prototypic reference 
amino acid sequences.  A listing by subject and time point of all post-baseline variants 
relative to the baseline amino acid sequences will be provided for each DAA target (NS3, 
NS5A, and/or NS5B).  In addition, a listing by subject and time point of all post-baseline 
variants at signature resistance-associated amino acid positions relative to the prototypic 
reference amino acid sequences will be provided.  Furthermore, the number and 
percentage of subjects with emerged variants by amino acid position and variant within a 
DAA target as compared to baseline will be summarized.
The number and percentage of subjects with linked variants by population sequencing 
within a DAA target will be summarized.  In addition a listing of linked variants by 
subject and time point will be provided for each DAA target (NS3, NS5A, and NS5B).
The persistence of resistance-associated substitutions that emerged for each target (NS3, 
NS5A, and NS5B) will be assessed by population sequencing at selected post-treatment 


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time points.  Listings by subject and time point of all post-baseline variants relative to the 
baseline amino acid sequence will be provided for each DAA target (NS3, NS5A, and 
NS5B). 
8.1.5
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.
8.1.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (defined as any event that begins or worsens in severity after initiation of active 
study drugs through 30 days after the last dose of study drugs) will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term (PT).  The tabulation of 
the number of subjects with treatment-emergent adverse events by severity rating and 
relationship to study drug will be provided.  In addition, the number and percentage of 
subjects with serious treatment-emergent adverse events and the number and percentage 
of subjects with treatment-emergent adverse events leading to study drug discontinuation 
will also be provided.  
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term using the most severe incident for the severity rating 
table and the most related for the relationship to study drug table.  Subjects reporting more 
than one type of event within a SOC will be counted only once for that SOC.
Additional analyses will be performed if useful and appropriate.
8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last measurement prior to the initial dose of study drug.  Mean changes from baseline to 
each Post-Baseline Visit will be summarized. 


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Laboratory data values collected during the Treatment Period will be categorized as low, 
normal, or high based on reference ranges of the laboratory used in this study.  The 
number and percent of subjects who experience post-baseline shifts during treatment in 
clinical laboratory values from low/normal to high and high/normal to low based on the 
normal range will be summarized.
In addition, the number and percentage of subjects with post-baseline values meeting pre 
specified criteria for Potentially Clinically Significant laboratory values during treatment 
will be summarized.
Additional analyses will be performed if useful and appropriate.
8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each Post-Baseline Visit will be summarized.  Frequencies and 
percentages of subjects with post-baseline values meeting pre-defined criteria for 
Potentially Clinically Significant vital signs values during treatment will be summarized.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations and pharmacokinetic parameters of ABT-450, possible ABT-450 
metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 
metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated 
and summarized and summary statistics will be computed for each time and visit.
In addition, plasma concentration data from this study may be combined with data from 
other studies and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VI, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 


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volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of 
major interest in the NONMEM analyses.  If necessary, other parameters, including the 
parameters describing absorption characteristics, may be fixed if useful in the analysis.  
The evaluation criteria described below will be used to examine the performance of 
different models.
●
The objective function of the best model is significantly smaller than the 
alternative model(s).
●
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept 
and a slope of one) than the alternative model(s).
●
Visual inspection of model fits, standard errors of model parameters and 
change in inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates CL/F and V/F values with only 
potentially physiologically relevant or clinically meaningful covariates (such as subject 
age, sex, body weight, concomitant medications, laboratory markers of hepatic or renal 
function, etc.) will be explored using either stepwise forward selection method, or 
generalized additive method (GAM) or another suitable regression/smoothing method at a 
significance level of 0.05.  After identification of all relevant covariates, a stepwise 
backward elimination of covariates from the full model will be employed to evaluate the 
significance (at P < 0.005, corresponding to an increase in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
In general, all continuous covariates will be entered in the model, initially in a linear 
fashion, with continuous covariates centered around the median value.  Linear or 
non-linear relationships of primary pharmacokinetic parameters with various covariates 
may also be explored.  For example:


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TVCLi = + Theta(2) (Comedication [1,2,…] + Theta(3) (WTi-median value) + Theta(4) 
(AGEi – median value).
Where TVCLi = Typical value of clearance for an individual i1, Theta(1) is the intercept 
and Theta(2) – (4) are regression parameters relating the fixed effects (weight and age 
centered on the median value) to clearance.
Relationship between exposure and clinical observations (antiviral activity) will be 
explored.  Exposure-response relationships for primary and secondary efficacy variables 
and/or some safety measures of interest may also be explored. 
The relationship between exposure (e.g., population pharmacokinetic model predicted 
concentrations over time or average concentrations or AUC or trough concentrations of 
the individual model-predicted pharmacokinetic profiles, or some other appropriate 
measure of exposure) and antiviral activity will be explored.  Exposure response 
relationships will be explored using a semi-mechanistic viral dynamic model and/or 
logistic regression analyses. 
Logistic regression analyses will explore the relationship between exposure and one or 
more virologic endpoints (e.g., RVR, EVR, SVR4, SVR12, relapse following end of 
treatment and breakthrough on treatment).
Additionally, relationship between exposure and safety endpoints of interest may also be 
explored.
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
It is planned to enroll approximately 100 subjects (60 from China, 20 from South Korea 
and 20 from Taiwan).  All subjects will receive ABT-450/r/ABT-267 + ABT-333 
coadministered with RBV for 12 weeks.  With a total sample size of about 100 subjects 
and assuming that 94% of the subjects will achieve SVR12, this study has greater than 


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90% power to demonstrate SVR12 superiority with a 2-sided 95% lower confidence bound 
greater than 67% (based on the normal approximation of a single binomial proportion in a 
one-sample test for superiority using EAST 6.2).  The SVR24 rate is anticipated to be very 
similar to the SVR12 rate and thus the power should still be at least 90%.  No adjustment 
for dropout is applicable because subjects who do not have data at Post-Treatment 
Week 12 (after imputing) are counted as failures for SVR12 and SVR24.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Additional pharmacogenetic analyses will only be performed if the subject has voluntarily 
signed and dated the IRB/IEC approved pharmacogenetic informed consent after the 
nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The subject must provide consent specific to pharmacogenetic before the 
pharmacogenetic testing is performed.  If the subject does not consent to the additional 
pharmacogenetic testing, it will not impact the subject's participation in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 


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automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary 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.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 


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principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
11.0
Data Quality Assurance
Medidata will provide access to the EDC system for the duration of the trial 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 (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.  
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  


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Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-450, ABT-267, 
ABT-333 and the product labeling for ritonavir and RBV.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-Label Study to Evaluate the Safety and Efficacy of 
ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 
Coadministered with Ribavirin (RBV) in Treatment-Naïve and 
Treatment-Experienced Asian Adults with Genotype 1b Chronic 
Hepatitis C Virus (HCV) Infection and Compensated Cirrhosis
Protocol Date:
11 February 2015
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
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Cohort Profile:  the Swiss Hepatitis C cohort Study (SCCS).  Int J Epidemiol.  
2007;36(4):731-7.
29.
Hansen N, Obel N, Christensen PB, et al; DANHEP group.  Predictors of antiviral 
treatment initiation in hepatitis C virus-infected patients:  a Danish cohort study.  J 
Viral Hepat.  2009;16(9):659-65.
30.
Chen CH, Yang PM, Huang GT, et al.  Estimation of seroprevalence of hepatitis B 
virus and hepatitis C virus in Taiwan from a large-scale survey of free hepatitis 
screening participants.  J Formos Med Assoc.  2007;106(2):148-55.
31.
Lee HC, Ko NY, Lee NY, et al.  Seroprevalence of viral hepatitis and sexually 
transmitted disease among adults with recently diagnosed HIV infection in 
Southern Taiwan, 2000 – 2005:  upsurge in hepatitis C virus infections among 
injection drug users.  J Formos Med Assoc.  2008;107(5):404-11.
32.
Yang JF, Lin CI, Huang JF, et al.  Viral hepatitis infections in southern Taiwan:  a 
multicenter community-based study.  Kaohsiung J Med Sci.  2010;26:461-9.


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33.
Chu FY, Chiang SC, Su FH, et al.  Prevalence of human immunodeficiency virus 
and its association with hepatitis B, C, and D virus infections among incarcerated 
male substance abusers in Taiwan.  J Med Virol.  2009;81:973-8.
34.
Sun HY, Lee HC, Liu CE, et al.  Factors associated with isolated anti-hepatitis B 
core antibody in HIV positive patients:  impact of compromised immunity.  J Viral 
Hepat.  2010;17:578-87.
35.
Chen DS, Kuo GC, Sung JL, et al.  Hepatitis C virus infection in an area 
hyperendemic for hepatitis B and chronic liver disease:  the Taiwan experience.  
J Infect Dis.  1990;162(4):817-22.
36.
Tseng YT, Sun HY, Chang SY, et al.  Seroprevalence of hepatitis virus infection in 
men who have sex with men aged 18 – 40 years in Taiwan.  J Formos Med Assoc.  
2012;111(8):431-8.
37.
Huang CF, Chuang WL, Yu ML.  Chronic hepatitis C infection in the elderly.  
Kaohsiung J Med Sci.  2011;27(12):533-7.
38.
Yu ML, Chuang WL, Chen SC, et al.  Changing prevalence of hepatitis C virus 
genotypes:  molecular epidemiology and clinical implications in the hepatitis C 
virus hyperendemic areas and a tertiary referral center in Taiwan.  J Med Virol.  
2001:65(1):58-65.
39.
Lee MH, Yang HI, Lu SN, et al; R.E.V.E.A.L.-HCV Study Group.  Chronic 
hepatitis C virus infection increases mortality from hepatic and extrahepatic 
diseases:  a community-based long-term prospective study.  J Infect Dis.  
2012;206(4):469-77.
40.
Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to 
interferon-alpha is associated with improved outcome in HCV-related cirrhosis:  a 
retrospective study.  Hepatology.  2007;45(3):579-87.
41.
Di Bisceglie AM, Everson GT, Linsay KL, 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:ALB1-ALB1.


ABT-450/r/ABT-267, ABT-333
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42.
Camma C, Di Bona D, Schepis F, et al.  Effect of peginterferon alfa-2a on liver 
histology in chronic hepatitis C:  a meta-analysis of individual patient data.  
Hepatology.  2004;39(2):333-42.
43.
Jacobson IM, McHutchison JG, Dusheiko G, 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:S427.
44.
Jacobson IM, Catlett I, Marcellin P, et al.  Telaprevir substantially improved SVR 
rates across all IL28B genotypes in the ADVANCE trial.  J Hepatol.  
2011a;54:S542-3.
45.
Pol S, Aerssens J, Zeuzem S, et al.  Similar SVR rates in IL28b cc, ct or tt prior 
relapser, partial- or null-responder patients treated with 
telaprevir/peginterferon/ribavirin:  retrospective analysis of the REALIZE study.  J 
Hepatol.  2011a;54:S6-S7.
46.
Pol S, Roberts SK, Andreone P, et al.  Efficacy and safety of telaprevir-based 
regimens in cirrhotic patients with HCV genotype 1 and prior 
peginterferon/ribavirin treatment failure:  subanalysis of the REALIZE phase III 
study.  Hepatology.  2011b;54:374A-5A.
47.
Bruno S, Vierling JM, Esteban R, et al.  Boceprevir in addition to standard of care 
enhanced SVR in hepatitis c virus (HCV) genotype-1 with advanced 
fibrosis/cirrhosis:  subgroup analysis of SPRINT-2 and RESPOND-2 studies.  J 
Hepatol.  2011;54:S4-4.
48.
Gane EJ, Roberts SK, Stedman CA, et al.  Oral Presentation at:  60th AASLD, 
Boston 2009. Oral Presentation No. 193.
49.
Zeuzem S, Asselah T, Angus PW, et al.  Strong antiviral activity and safety of IFN 
sparing treatment with the protease inhibitor BI 201335, the HCV polymerase 
inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C.  Hepatology.  
2010;52 (Suppl):876A.


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50.
Lok AS, Gardiner DF, Lawitz E, et al.  Combination therapy with BMS-790052 
and BMS-650032 alone or with PegIFN and RBV results in undetectable HCV 
RNA through 12 weeks of therapy in HCV genotype 1 null responders [Abstract].  
Hepatology.  2010;52 (Suppl):877A.
51.
Zeuzem S, Andreone P, Pol S, et al.  Realize Trial final results:  Telaprevir based 
regimen for genotype 1 hepatitis C virus infection in patients with prior null 
response, partial response or relapse to pegInterferon/Ribavirin.  J Hepatol.  
2011;54(1):S3.
52.
Chayama K, Takahashi S, Kawakami Y, et al.  Dual Oral Combination Therapy 
with the NS5A Inhibitor BMS-790052 and the NS3 Protease Inhibitor BMS 
650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 
1b-Infected Null Responders.  Paper Presented at:  62nd Annual Meeting of the 
American Association for the Study of Liver Disease (AASLD 2011).  
November 4 – 8, 2011; San Francisco, CA.  Abstract LB-4.
53.
Soriano V, Gane E, Angus P, et al.  The efficacy and safety of the interferon-free 
combination of BI 201335 and BI 207127 in genotype 1 HCV patients with 
cirrhosis:  interim analysis from SOUND-C2.  Poster Presented at:  International 
Liver Congress™, the 47th Annual Meeting of the European Association of the 
Study of the Liver (EASL 2012).  2012 Apr 18 – 22; Barcelona, Spain].
54.
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Association for the Study of Liver Disease; November 1-5, 2013; Washington, DC, 
Abstract 73, 2013.
55.
Everson et al, Abstract LBI, 2013 AASLD.
56.
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Pharmaceuticals Inc., 2012.
57.
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from:  the European Public Assessment 
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_Summary_for_the_public/human/002313/WC500115507.pdf.


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58.
Sherman K, Flamm S, Afdhal N, et al; ILLUMINATE Study Team.  Response 
guided telaprevir combination treatment for hepatitis C virus infection.  N Engl J 
Med.  2011;365(11):1014-24.
59.
Xie R, Fan X, Yang S, et al.  Expert consensus for antiviral treatment of chronic 
hepatitis C.  Chinese J Exp Clinic Infect Dis (Electronic Edition). 
2009;3(3):343-52.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees [e.g., independent ethics committee (IEC) or 
institutional review board (IRB)] review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Clinical
Pharmacokinetics
Statistics
Global Drug Supply Management


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Appendix C.
Clinical Toxicity Grades


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SAP_001.pdf: 
ABT-450/Ritonavir/ABT-267 and ABT-333
M14-491 – Statistical Analysis Plan
Version 1.0 – 29 June 2016
1
1.0
Title Page
Statistical Analysis Plan
Study M14-491
An Open-Label Study to Evaluate the Safety and 
Efficacy of ABT-450/Ritonavir/ABT-267
(ABT-450/r/ABT-267) and ABT-333 Coadministered 
with Ribavirin (RBV) in Treatment-Naïve and 
Treatment-Experienced Asian Adults with 
Genotype 1b Chronic Hepatitis C Virus (HCV) 
Infection and Compensated Cirrhosis
29 June 2016
/$5


ABT-450/Ritonavir/ABT-267 and ABT-333
M14-491 – Statistical Analysis Plan
Version 1.0 – 29 June 2016
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................7
4.1
Objectives ..................................................................................................7
4.2
Design Diagram .........................................................................................7
4.3
Sample Size................................................................................................8
4.3.1
Justification of Primary Endpoint Success Criteria ...................................9
4.4
Planned Analysis......................................................................................13
4.5
Unplanned Interim Analysis ....................................................................14
5.0
Analysis Populations .............................................................15
5.1
Definition for Analysis Populations.........................................................15
5.2
Variables Used for Stratification of Randomization................................16
6.0
Analysis Conventions ............................................................16
6.1
Definition of Baseline and Final Values ..................................................16
6.2
Definition of Analysis Windows .............................................................17
6.3
Missing Data Imputation..........................................................................23
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............24
7.1
Demographic and Baseline Characteristics .............................................25
7.2
Medical History .......................................................................................28
7.3
Previous Treatment and Concomitant Medications .................................28
8.0
Subject Disposition................................................................28
9.0
Study Drug Exposure and Compliance...............................30
9.1
Exposure ..................................................................................................30
9.2
Compliance ..............................................................................................30
10.0
Efficacy Analysis....................................................................31
10.1
General Considerations............................................................................31
10.2
Handling of Multiplicity ..........................................................................35
10.3
Primary Efficacy Analysis .......................................................................36
10.4
Secondary Efficacy Analyses...................................................................37


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10.5
Sensitivity Analyses for the Primary Efficacy Endpoint .........................38
10.5.1
Assessment of Homogeneity Across Geographic Regions......................39
10.6
Additional Efficacy Analyses ..................................................................40
10.7
Efficacy Subgroup Analysis ....................................................................43
10.8
Resistance Analyses.................................................................................44
10.9
Patient Reported Outcomes......................................................................46
11.0
Safety Analysis.......................................................................49
11.1
General Considerations............................................................................49
11.2
Analysis of Adverse Events .....................................................................49
11.2.1
Treatment-Emergent Adverse Events ......................................................49
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events..............................50
11.2.2
Listings of Adverse Events ......................................................................54
11.3
Analysis of Laboratory Data....................................................................54
11.3.1
Variables and Criteria Defining Abnormality..........................................54
11.3.2
Statistical Methods...................................................................................58
11.4
Analysis of Vital Signs and Weight.........................................................61
11.4.1
Variables and Criteria Defining Abnormality..........................................61
11.4.2
Statistical Methods...................................................................................62
12.0
Summary of Changes............................................................62
12.1
Summary of Changes Between the Latest Version of the Protocol 
and Version 1 of the SAP.........................................................................62
13.0
References...............................................................................64
List of Tables
Table 1.
Estimated SVR Rates for Telaprevir Plus PegIFN and RBV in 
Cirrhotic Subjects.......................................................................................9
Table 2.
SVR Rates for Telaprevir Plus pegIFN and RBV Therapy in 
Treatment-Naïve Subjects by Subgenotype.............................................11
Table 3.
Estimated SVR Rates for Telaprevir-Based Therapy in 
Treatment-Experienced Subjects by Subgenoytpe ..................................12
Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period) ...................................................................................19


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Table 5.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)...........................................................................20
Table 6.
Analysis Time Windows for PRO Instruments........................................21
Table 7.
Laboratory Data and Vital Sign Visit Windows ......................................22
Table 8.
Child-Pugh Classification of Severity of Cirrhosis .................................27
Table 9.
Adverse Events of Special Interest ..........................................................52
Table 10.
Criteria for Potentially Clinically Significant Hematology Values .........56
Table 11.
Criteria for Potentially Clinically Significant Chemistry Values ............57
Table 12.
Definitions of CTCAE Grades 1, 2, 3, and 4 ...........................................60
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Values.............61


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3.0
Introduction
This statistical analysis plan (SAP) for Study M14-491 is based on the study protocol 
dated 23 November 2015, incorporating Administrative Change 1.  Study M14-491 
examines the safety and efficacy of co-formulated ABT-450, ritonavir and ABT-267 
(ABT-450/r/ABT-267) and ABT-333 co-administered with ribavirin (RBV) for 12 weeks 
in adults with genotype 1b chronic hepatitis C virus (HCV) infection and compensated 
cirrhosis.  Throughout the SAP, the combination of direct-acting antiviral agents (DAAs) 
with RBV, ABT-450/r/ABT-267 and ABT-333 plus RBV, will be denoted as "DAA 
combination regimen" for simplicity.
The protocol specifies that the primary analysis of efficacy (including resistance and 
Patient Reported Outcomes [PROs]) and safety data will occur after all subjects have 
completed the Post-Treatment Week 24 Visit or prematurely discontinued the study and 
that the primary analysis will summarize data collected through Post-Treatment Week 24.  
All remaining data through Post-Treatment Week 48 will be summarized in the end of 
study analysis.
Per agreement with the Center for Drug Evaluation (CDE)/China Food and Drug 
Administration (CFDA), an interim analysis that was not specified in the protocol will 
occur after all subjects have completed the Post-Treatment Week 12 Visit or prematurely 
discontinued the study.  This interim analysis will include analyses of SVR12 (HCV 
ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following 
therapy), which is the primary endpoint for South Korea and Taiwan and the first element 
of the primary endpoints (SVR12 and SVR24, HCV RNA < LLOQ 24 weeks following 
therapy) in the fixed-sequence testing procedure specified for China (see Section 10.2).  
The interim analysis will be conducted once SVR12 data for all subjects are available, 
rather than at the time specified in the protocol (i.e., once SVR24 data are available).  The 
primary endpoints of the study for China (SVR12 and SVR24), South Korea (SVR12), and 
Taiwan (SVR12) remain unchanged; only the timing of when SVR12 will be analyzed has 
changed.  The interim analysis will allow each element of the primary endpoint to be 


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analyzed when data for the endpoint are available.  Also, the hierarchy in the fixed-
sequence testing procedure for the primary endpoints will be maintained.  For these 
reasons, the Type I error rate for each primary endpoint will be preserved at 0.05.  
Furthermore, the interim analysis will not compromise the study integrity or results, will 
not affect the study sample size/power or study procedures, and will not pose a risk to 
subjects as subjects will have completed treatment at the time of the analysis.  The interim 
analysis will include analyses of the endpoints specified in the protocol and this SAP for 
data collected through this time point.  This interim analysis will support regulatory 
submission activities in China, South Korea, and Taiwan.
A previously planned interim analysis to support regulatory submission activities in South 
Korea and Taiwan was specified in the protocol.  The planned interim analysis was to 
include all efficacy (including resistance and Patient Reported Outcomes [PRO]) and 
safety data through Post-Treatment Week 12 and was to occur after all subjects from 
South Korea and Taiwan completed the Treatment Period through Post-Treatment 
Week 12 or prematurely discontinued from the study.  The planned interim analysis was 
not going to include hypothesis testing for the HCV RNA endpoints.  The planned interim 
analysis will not be conducted, but will be replaced with the unplanned interim analysis, 
which will include hypothesis testing.
The SAP provides details to guide the analyses for baseline, efficacy, and safety variables 
and describes the populations and variables that will be analyzed and the statistical 
methods that will be utilized.  Analyses will be performed using SAS® Version 9.3 (SAS 
Institute, Inc., Cary, NC) or a later version under the UNIX operating system.
Any deviations from the planned statistical analysis will be described and justified in the 
clinical study report, as appropriate.
This is the first version of the SAP for Protocol M14-491.


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4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of  this study are to assess the safety and to compare SVR 12 and 
SVR24 following 12 weeks of treatment with the DAA combination regimen to the 
historical SVR rate of telaprevir plus pegIFN and RBV therapy in HCV genotype 1b 
infected adults with compensated cirrhosis.
The secondary objectives of this study are to demonstrate the effect of the DAA 
combination regimen on HCV RNA levels during and after treatment as measured by on-
treatment virologic failure and post-treatment relapse, respectively.
4.2
Design Diagram
This is a Phase 3, open-label, single-arm, multicenter study evaluating the efficacy and 
safety of the DAA combination regimen for 12 weeks in HCV genotype 1b, treatment-
naïve and IFN based therapy (IFN [alpha, beta or pegIFN] with RBV) treatment-
experienced adults with compensated cirrhosis.
The study is designed to enroll approximately 100 subjects (approximately 60 subjects 
from sites in China and 20 subjects each from sites in South Korea and Taiwan).  At least 
35 treatment naïve and 35 treatment-experienced subjects will be enrolled.
Treatment will consist of:  ABT-450/r/ABT-267 150/100/25 mg once daily (QD) + 
ABT-333 250 mg twice daily (BID) + RBV* for 12 weeks.
*
RBV will be administered weight-based 1000 – 1200 mg divided to twice daily.
The study consists of a Treatment Period and a Post-Treatment Period.  During the 
Treatment Period, all enrolled subjects will receive 12 weeks of treatment.  All subjects 
administered study drug will be followed for 48 weeks post-treatment to test for durability 
of SVR and emergence or persistence of DAA resistance associated variants.  The 
duration of the study will be 60 weeks, not including a screening period of up to 35 days.


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Treatment Period
Subjects meeting eligibility criteria will be enrolled via Interactive Response Technology 
(IRT) and will receive ABT-450/r/ABT-267 orally QD and ABT-333 with RBV orally 
BID.  Subjects will be administered the first doses of study drugs at the site on Study 
Day 1.
Post-Treatment Period
All subjects who receive at least one dose of DAA in the Treatment Period and either 
complete treatment or prematurely discontinue study drug will be monitored in the Post-
Treatment Period for safety, HCV RNA, the emergence and persistence of resistant viral 
variants and assessment of PROs for an additional 48 weeks following the last dose of 
study drug.
The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.
4.3
Sample Size
It is planned to enroll approximately 100 subjects (60 from China, 20 from South Korea 
and 20 from Taiwan).  With a total sample size of about 100 subjects and assuming that 
94% of the subjects will achieve SVR12, this study has greater than 90% power to 
demonstrate SVR12 superiority with a 2-sided 95% lower confidence bound greater than 
67% (based on the normal approximation of a single binomial proportion in a one-sample 
test for superiority using EAST 6.2).  The SVR24 rate is anticipated to be very similar to 
the SVR12 rate and thus the power should still be at least 90%.  No adjustment for dropout 
is applicable because subjects who do not have data at Post-Treatment Week 12 and Post-
Treatment Week 24 (after imputing) are counted as failures for SVR12 and SVR24, 
respectively.


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4.3.1
Justification of Primary Endpoint Success Criteria
The current study is an Asian study examining the combination of ABT-450/r/ABT-267 
and ABT-333 administered with RBV for 12 weeks in treatment-naïve and IFN based 
therapy (IFN [alpha, beta or pegIFN] with RBV) treatment-experienced HCV 
genotype 1b-infected subjects with compensated cirrhosis.  This is a similar trial design as 
in AbbVie Study M13-099.  In Study M13-099, the SVR12 rate for each treatment arm 
was compared to an historical SVR rate for telaprevir plus pegIFN and RBV (54%, see 
Table 1).  A weighted average of the corresponding SVR rates among treatment-naïve and 
treatment-experienced (prior relapsers, partial responders and null responders) in HCV 
genotype 1 infected cirrhotic subjects was calculated to reflect the population expected to 
enroll in Study M13-099.  The historical rate of 54% was defined conservatively as the 
upper bound of the 95% confidence interval for the telaprevir-based rate.
Table 1.
Estimated SVR Rates for Telaprevir Plus PegIFN and RBV in 
Cirrhotic Subjects
Telaprevir-Treated 
Subjects with 
Cirrhosis n/N (%)
Projected 
Enrollment in 
Study M13-099 (%)
Population-Based 
Weighted Average % 
[95% CI]
Meta Analysis of ADVANCE1 and ILLUMINATE1 Studies
Naïve Subjects
(56)
53
REALIZE1
Prior relapsers
48/57 (84)
12
47 [41, 54]
Prior partial responders
11/32 (34)
12
Prior null responders
7/50 (14)
23
Consistent with Study M13-099, the SVR12 and SVR24 rates from the current study will 
be compared to a clinically relevant threshold based on historical SVR rates for telaprevir 
plus pegIFN/RBV.  However, since the historical SVR rate used in Study M13-099 is 
based on a population that included HCV genotype 1a-infected cirrhotic subjects as well 
as HCV genotype 1b-infected cirrhotic subjects, a higher threshold will be used in this 
study to account for a genotype 1b only population.


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Because data are not available on the subpopulation of HCV genotype 1b-infected 
subjects with cirrhosis treated with telaprevir plus pegIFN/ RBV, the SVR rates in HCV 
genotype 1a and genotype 1b-infected, non-cirrhotic subjects treated with telaprevir plus 
pegIFN/RBV were used to determine an appropriate adjustment factor to increase the 
historical rate used in Study M13-099.  An appropriate adjustment factor was determined 
based on the relative failure rate between the HCV genotype 1b and genotype 1a 
populations in the telaprevir ADVANCE, ILLUMINATE, and REALIZE studies (Table 2
and Table 3).  For treatment-naïve subjects, the SVR failure rate in genotype 1b subjects 
was reduced by a relative 29% (from 28% to 20%) from the SVR rate for genotype 1a 
subjects (Table 2).  For treatment-experienced subjects, the SVR failure rate in 
genotype 1b was also reduced by a relative 29% (from 41% to 29%) from the SVR rate 
for genotype 1a subjects (Table 3).  Since the SVR rate for the genotype 1a cirrhotic 
subjects is not available and SVR rate for all cirrhotic patients would be higher than that 
for genotype 1a cirrhotic subjects, it would be more conservative to estimate the SVR rate 
for the genotype 1b cirrhotic subjects by taking 29% reduction from the combined data 
from genotype 1a + genotype 1b cirrhotic subjects together.  Therefore, to account for the 
exclusion of HCV genotype 1a-infected subjects in the current study, the historical SVR 
failure rate of 46% used in Study M13-099 for genotype 1 was reduced by a relative 29%, 
resulting in a 33% failure rate (or 67% SVR rate) for genotype 1b.  The rate of 67% 
should be conservative because the 54% was based on a population that was a mix of 
genotype 1a and 1b and the expectation is that the SRV rate for genotype 1a subjects 
would be lower than the SVR rate for the mix population of genotype 1a and 1b subjects.  
Hence, for this current study, for a regimen to be considered superior to a clinically 
meaningful threshold based on SVR rates for telaprevir plus pegIFN/RBV, the lower 
confidence bound of the SVR rate must exceed 67%.  The value of 67% used for the 
superiority comparison represents the 54% historical genotype 1 SVR rate plus a relative 
29% adjustment factor for the exclusion of genotype 1a subjects.


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Table 2.
SVR Rates for Telaprevir Plus pegIFN and RBV Therapy in 
Treatment-Naïve Subjects by Subgenotype
ADVANCE
ILLUMINATE
Meta Analysis
Telaprevir Studies
T12/PR n/N (%)
T12/PR n/N (%)
T12/PR % [95% CI]
Treatment-Naïve GT1a Subjects
162/217 (75)1
273/388 (70)2
72 [68, 75]
Treatment-Naïve GT1b Subjects
119/145 (84)1
112/149 (75)3
80 [75, 84]
CI = confidence interval; GT1a = genotype 1a; GT1b = genotype 1b


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Table 3.
Estimated SVR Rates for Telaprevir-Based Therapy in Treatment-Experienced Subjects by Subgenoytpe
REALIZE†‡
GT1a
(Pooled T12/PR48)
n/N (%)
With Increase for 
Excluding Cirrhotics 
(%)
GT1b
(Pooled T12/PR48)
n/N%
With Increase for 
Excluding Cirrhotics 
(%)
Population-Based 
Weighted Average* % 
[95% CI]
Relapse
119/142 (83.8)
84.3
123/140 (87.9)
88.4
GT1a 59 [53, 65]
Partial responders
26/55 (47.3)
59.3
27/40 (67.5)
79.5
GT1b 71 [64, 77]
Null responders
24/88 (27.3)
36.5
22/59 (37.3)
46.5
CI – confidence interval; GT1a = genotype 1a; GT1b = genotype 1b
†
US Prescribing Information for INCIVEK™ (telaprevir).  Vertex Pharmaceuticals Incorporated; Cambridge, MA.
‡
Zeuzem S, Andreone P, Pol S, et al.  REALIZE trial final results: telaprevir-based regimen for GT1 hepatitis c virus infection in patients with prior null response, partial 
response or relapse to peginterferon/ribavirin.  J Hepatol.  2011;54 Suppl:S3.
*
Based on a population of 30% relapsers, 35% partial responders, 35% null responders.


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Furthermore, as the primary endpoints combine data from the three geographical regions 
(China, South Korea, and Taiwan), it was necessary to set one threshold for each primary 
endpoint.
In general, the SVR rate for telaprevir/pegIFN/RBV is greater than that of the standard of 
care of pegIFN/RBV in each of the geographic regions participating in this study.  
Additionally, this regimen has demonstrated superiority to pegIFN/RBV in a global 
Phase 3 program.  The reported SVR rates for pegIFN/RBV vary significantly from report 
to report and are different in each of the 3 geographic regions.  The SVR rates for 
telaprevir/pegIFN/RBV are 80% in cirrhotic and non-cirrhotic treatment-naïve GT1b-
infected patients and 69% to 71% in cirrhotic and non-cirrhotic treatment-experienced 
GT1a-infected patients.4  In China, South Korea, and Taiwan the pegIFN/RBV SVR rates 
range from 10% to 44%,5 20.8%6 and 60.7%,7 respectively.  Therefore, AbbVie believes 
that demonstrating the superiority of the DAA combination regimen to the SVR with 
telaprevir/pegIFN/RBV will ensure the superiority of the DAA combination regimen to 
the SVR achieved locally with pegIFN/RBV treatment.  However, as sensitivity analyses 
(see Section 10.5), comparisons of the SVR12 and SVR24 rates will be made to geographic 
region-specific SVR rates with pegIFN/RBV treatment as appropriate.
4.4
Planned Analysis
The primary analysis of SVR24 data will occur after all subjects have completed the Post-
Treatment Week 24 Visit or prematurely discontinued the study.  All remaining data 
through Post-Treatment Week 48 will be summarized in the end of study analysis.
For each analysis specified above, the data will be locked after performing appropriate 
data cleaning.
All analyses will be conducted by statisticians or programmers at AbbVie (or their 
designees) according to the methodologies specified in this SAP.


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4.5
Unplanned Interim Analysis
An interim analysis that was not specified in the protocol will occur after all subjects have 
completed the Post-Treatment Week 12 Visit or prematurely discontinued the study.  This 
interim analysis will include SVR12, which is the primary endpoint for South Korea and 
Taiwan and the first element of the primary endpoints (SVR12 and SVR24) in the fixed-
sequence testing procedure specified for China (see Section 10.2).  The interim analysis 
will be conducted once SVR12 data are available, rather than at the time specified in the 
protocol (i.e., once SVR24 data are available).  The primary endpoints of the study for 
China (SVR12 and SVR24), South Korea (SVR12), and Taiwan (SVR12) remain unchanged; 
only the timing of when SVR12 will be analyzed has changed.  The interim analysis will 
allow each element of the primary endpoint to be analyzed when data for the endpoint are 
available.  Also, the hierarchy in the fixed-sequence testing procedure for the primary 
endpoints will be maintained.  For these reasons, the Type I error rate for each primary 
endpoint will be preserved at 0.05.  Furthermore, the interim analysis will not compromise 
the study integrity or results, will not affect the study sample size/power or study 
procedures, and will not pose a risk to subjects as subjects will have completed treatment 
at the time of the analysis.  The interim analysis will include analyses of the endpoints 
specified in the protocol and this SAP for data collected through this time point.  This 
interim analysis will support regulatory submission activities in China, South Korea, and 
Taiwan.
For the interim analysis, the data will be locked after performing appropriate data 
cleaning.  Data collected after this lock will be added to a new version of the database.  
All analyses will be conducted by statisticians or programmers at AbbVie (or their 
designees) according to the methodologies specified in this SAP.  There is no intention of 
shortening the follow-up time of subjects based on efficacy findings from the interim 
analysis.  The intention is to follow all subjects who receive study drug for 48 weeks 
following treatment.  There will be no statistical adjustment employed due to the interim 
analysis.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
Intent-to-Treat (ITT) Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
ITT population.  The ITT Population will be used for efficacy, PROs, and resistance 
analyses.
Modified Intent-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 and SVR24 will be performed on the modified ITT –
Genotype (mITT – GT), modified ITT – Genotype and SVR12 Virologic Failure (mITT –
GT + VFSVR12), and modified ITT – Genotype and SVR24 Virologic Failure (mITT – GT 
+ VFSVR24) populations as specified in Section 10.5.
The mITT-GT population includes subjects who receive at least 1 dose of study drug but 
excludes the subjects who do not have HCV genotype 1b infection.  The mITT-GT 
population is used to reduce the risk of bias that could occur due to the enrolled 
population deviating from the population intended to be treated with the regimen assigned 
in this study.
The mITT-GT + VFSVR12 and mITT-GT + VFSVR24 populations include all subjects who 
receive at least 1 dose of study drug but excludes the subjects who do not have HCV 
genotype 1b infection and the subjects who were not categorized as virologic failures 
(i.e., on-treatment virologic failure or non-infection relapse by Post-Treatment Week 12 
for mITT-GT + VFSVR12, and on-treatment virologic failure or non-infection relapse by 
Post-Treatment Week 24 for mITT-GT + VFSVR24).  The mITT-GT + VFSVR12 and 
mITT-GT + VFSVR24 populations are used to reduce the risk of bias that could occur due 
to either discordant HCV genotype or failures unrelated to study drug.


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Safety Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
Safety Population.  Demographics, baseline characteristics, medical history, 
previous/concomitant medications, subject disposition, exposure, compliance, and safety 
analyses will be performed on the Safety Population, unless otherwise noted.  The Safety 
Population will be the same as the ITT Population. 
5.2
Variables Used for Stratification of Randomization
There is no randomization for this study.
6.0
Analysis Conventions
6.1
Definition of Baseline and Final Values
Definition of Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.  All assessments, except for HCV RNA, on Study 
Day 1 should be performed prior to administering the first dose of study drug per 
protocol.  The baseline value is therefore determined by the last non-missing measurement 
collected on or before the first day of study drug administration.  For HCV RNA, samples 
will be collected on Day 1 prior to dosing and 2 hours after dosing.  Therefore, the 
baseline HCV RNA value will be determined by the last non-missing measurement 
collected prior to dosing.
If multiple measurements are recorded on the same day, the last measurement recorded 
prior to dosing will be used as the baseline value.  If these multiple measurements occur at 
the same time or time is not available, then the average of these measurements (for 
continuous data) or the worst among these measurements (for categorical data) will be 
considered as the baseline value.  This same baseline value will be used for the Treatment 
and PT Periods.


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Safety assessments that are related to a serious adverse event that occurs on the first dose 
day are excluded when applying this algorithm.
Definition of Study Days (Days Relative to the First Dose of Study Drug)
Study Days are calculated for each time point in the Treatment Period relative to the 
first dose of study drug.  Study Days are negative values when the time point of interest is 
prior to the first study drug dose day.  Study Days are positive values when the time point 
of interest is after the first study drug dose day.  There is no Study Day 0.  Study Day 1 is 
the day of the first dose of study drug.
Definition of Study Drug End Days (Days Relative to the Last Dose of Study Drug)
For all subjects who receive at least one dose of study drug, study drug end days are 
calculated relative to the last dose of study drug.  The last day of study drug is defined as 
Study Drug End Day 0.  Days before it have negative study drug end days, and days after 
it have positive study drug end days. 
Definition of Final Treatment Value
The final treatment value for each subject is the last non-missing measurement collected 
after Study Day 1 and on or before Study Drug End Day 2.
Definition of Final Post-Treatment Value
The final post-treatment value for each subject is the last non-missing measurement 
collected after Study Drug End Day 2.
6.2
Definition of Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 4
and Table 5 describe how efficacy data are assigned to protocol-specified time points 
during the Treatment and PT Periods, respectively.  All time points and corresponding 
time windows are defined based on the blood sample collection date.


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The visit windows used for analyses of health-related quality of life (QoL) patient 
reported outcomes (PROs) collected throughout the study are described in Table 6.
For laboratory data and vital signs, the time windows specified in Table 7 describe how 
data are assigned to protocol-specified time points.
Except for analyses of SVR (e.g., SVR4, and SVR12), if more than one assessment is 
included in a time window, the assessment closest to the nominal time will be used.  If 
there are two observations equally distant to the nominal time, the latest one will be used 
in analyses.  For analyses of SVR, the last value in the window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used in analyses.  For summaries of 
shifts from baseline and potentially significant values, multiple values on the same day 
will not be averaged; all values will be considered for these analyses.


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Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period)
Scheduled Visit
Nominal Day/
Time (Study Day)
Time Window
(Study Days Range)
Baselinea
--
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 35
Week 6
42
36 to 49
Week 8
56
50 to 63
Week 10 
70
64 to 77
Week 12
84
78 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
SVR12planned
c
168
141 to 210
SVR24planned
c,d
252
211 to 294
a.
HCV RNA values on Day 1 must also be before the time of the first study drug administration. 
b.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of the 
Final Treatment Visit window is Study Drug End Day 2.
c.
For SVR windows, the last value in the window will be used.
d.
Not included in interim analysis.
Note:
Except for Final Treatment Visit and SVR windows, the result closest to the scheduled time point (nominal 
day/time) will be used.  For visits through Week 12, data must also occur before or on Study Drug End Day 2.


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Table 5.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 2
14
3 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24a
168
127 to 210
Post-Treatment Week 36a
252
211 to 294
Post-Treatment Week 48a
336
295 to 378
SVR4
28
3 to 56
SVR12
84
57 to 126
SVR24
a
168
127 to 210
a.
Not included in interim analysis.
Note:
For Post-Treatment visits the results closest to the scheduled time point (nominal day) will be used.  For SVR 
windows the last value in the window will be used.  For all windows, the data must also occur after Study 
Drug End Day 2.


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Table 6.
Analysis Time Windows for PRO Instruments
Scheduled Visit
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baselinea
1
≤ 1
Week 4
28
2 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24c
168
127 to 252
Post-Treatment Week 48c
336
253 to 378
Final Post-Treatment Visitd
> 2 days after last dose of study drug
a.
A value is considered to be baseline if it is the last non-missing value on or before Study Day 1.
b
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final Treatment Visit window is Study Drug End Day 2.
c.
Not included in interim analysis.
d.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment Visit 
value.  The lower bound of this Final Post-Treatment Visit window is Study Drug End Day 3 with no upper bound.
Note:
Except for Final Treatment Visit and Final Post-Treatment Visit, the result closest to the scheduled time point 
(nominal day) will be used.  For visits through Week 12, data must also occur before or on Study Drug End 
Day 2.  For Post-Treatment visits, data must also occur after Study Drug End Day 2 for all windows.


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Table 7.
Laboratory Data and Vital Sign Visit Windows
Scheduled Visit
Nominal Day/Time
(Study Day)
Time Window
(Study Days Range)
Day 1/Baselinea
1
≤ 1
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 35
Week 6
42
36 to 49
Week 8
56
50 to 63
Week 10 
70
64 to 77
Week 12 
84
78 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 2
14
3 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24c
168
127 to 210
Post-Treatment Week 36c
252
211 to 294
Post-Treatment Week 48c
336
295 to 378
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
A value is considered to be baseline if it is the last non-missing value on or before Study Day 1.
b.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final Treatment Visit window is Study Drug End Day 2.
c.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment Visit 
value.  The lower bound of this Final Post-Treatment Visit window is Study Drug End Day 3 with no upper bound.
Notes:
Except for Final Treatment Visit and Final Post-Treatment Visit, the result closest to the scheduled time point 
will be used.  For visits through Week 12, data must also occur before or on Study Drug End Day 2.  For Post-
Treatment visits, data must also occur after Study Drug End Day 2 for all windows.
IP-10 is measured at Baseline, Weeks 4, 8, and 12, PT Week 12, and PT Week 48.  Total Insulin is measured 
at Baseline and Week 12.  Child-Pugh classification is collected at Screening, Week 12, and PT Week 12.  
Clinical assessments of ascites and hepatic encephalopathy for calculation of Child-Pugh classification are 
collected on Day 1 prior to dosing.  FibroTest samples are collected at Baseline, PT Week 12, and PT 
Week 48.  Analyses of these variables will use the visit windows as defined above.


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6.3
Missing Data Imputation
Data will be imputed for HCV RNA analyses of RVR, EOTR, and SVR and for analyses 
of PRO questionnaires.
HCV RNA
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.2.  When there is no HCV RNA value in a defined visit window, the closest 
values before and after the window will be used for the flanking imputation, regardless of 
the values chosen for the subsequent and preceding windows.
For the flanking imputation, if a subject has a missing HCV RNA value at a post-baseline 
visit but with undetectable or unquantifiable HCV RNA levels at both the preceding value 
and the succeeding value, then the HCV RNA level will be imputed as undetectable or 
unquantifiable, respectively, at this visit for this subject.  In addition, if a subject has an 
unquantifiable HCV RNA level at the preceding value and an undetectable HCV RNA 
level at the succeeding value, or vice versa, the HCV RNA level will be imputed as 
unquantifiable at this visit for this subject.
For analyses of RVR, subjects still missing a value for the visit after flanking imputation 
will be imputed as a failure.  For analyses of SVR, subjects still missing visit values after 
flanking imputation will have backward imputation applied.  For backward imputation, if 
the nearest HCV RNA value after the SVR window is unquantifiable or undetectable, then 
it will be used to impute the HCV RNA value in the SVR window.
If a subject starts another treatment for HCV, then all HCV RNA values for this subject 
measured on or after the start date of the new HCV treatment will be excluded from 
analyses.  The subject will be considered a failure for summaries of viral response at all 
time points after the start of the new HCV treatment.


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HCV RNA < LLOQ Analyses for RVR, EOTR, and SVR
If a subject is missing an HCV RNA value for the visit window associated with the 
analysis of RVR, EOTR, or SVR after performing the imputations described above, then 
this value will be imputed with an HCV RNA value from a local laboratory if present; 
otherwise, the HCV RNA value for this visit will be missing.  Subjects with missing HCV 
RNA data in the analysis window, after imputations, will be imputed as failures.
HCV RNA Analyses for Relapse and Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure.
PRO Questionnaires
If more than 4 items of the 16-item HCV-PRO are missing responses, then the total score 
is set to missing.  When four or fewer items are missing, the mean of the non-missing 
items will be used to impute the responses for the missing item(s) and a total score will be 
calculated.
For EQ-5D-5L, no imputation will be performed for missing items.
For SF-36 Health Survey version 2, if a respondent answers at least 50% of the items in a 
multi-item scale of SF-36v2, the missing items will be imputed with the average score of 
the answered items in the same scale.  In cases where the respondent did not answer at 
least 50% of the items, the score for that domain will be considered missing.  The Mental 
and Physical Component measure will not be computed if any domain is missing.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
Demographics, baseline characteristics, medical history and previous/concomitant 
medications will be summarized by geographic region (China, South Korea, Taiwan) and 


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overall for all subjects in the safety population and all subjects in the mITT-GT and 
mITT-GT+VF populations, if applicable.
7.1
Demographic and Baseline Characteristics
Demographics include age, weight, and body mass index (BMI) as continuous variables, 
and sex, race, ethnicity, type of Asian descent (Chinese, Korean, or Taiwanese), 
geographic region (China, South Korea, or Taiwan), age category (< 55 or ≥ 55 years; 
< 65 or ≥ 65 years), BMI category (< 30 or ≥ 30 kg/m2), and women of childbearing 
potential (females between the ages of 18 and 55 years, inclusive [yes or no]).
Baseline characteristics will include prior IFN-based therapy (IFN [alpha, beta or pegIFN] 
with RBV) treatment history (treatment-naïve or treatment-experienced; non-responder 
[null responder, partial responder, or other non-responder], relapser, or IFN-based therapy 
intolerant), IL28B genotype (CC, CT, or TT; CC or non-CC), screening HCV RNA 
(≤1000, > 1000 to 10,000, or > 10,000 IU/mL), baseline log10 HCV RNA level 
(continuous), baseline HCV RNA level (< 800,000 or ≥ 800,000 IU/mL), baseline IP-10 
(continuous; < 600 or ≥ 600 ng/L), baseline HOMA-IR (< 3 or ≥ 3 mU × mmol/L2), 
Child-Pugh score at Screening (5 or 6), baseline Child-Pugh score (5, 6, or > 6), baseline 
longitudinal FibroTest score (continuous), baseline platelet counts (continuous; < 60, 60 
to < 90, 90 to < 120, or ≥ 120 × 109/L), baseline albumin (continuous; (< 28, 28 to < 33, 
33 to < 40, 40 to 49, or > 49 g/L; < 35 or ≥ 35 g/L), baseline alpha fetoprotein 
(continuous), presence of hepatic steatosis at baseline (yes or no), hepatoprotective drug 
use at baseline (yes or no), tobacco and alcohol use status (current, former, never), former 
injection drug user (yes, no, or unknown), stable opiate substitution use (yes or no), 
history of bleeding disorders (yes or no), history of diabetes (yes or no), history of 
depression or bipolar disorder (yes or no), history of hypertension (yes or no), and history 
of cardiovascular disease (yes or no).
If the IL28B genotype result is not available from a sample collected during the Screening 
period, then a result available from a sample collected at any time during the study will be 


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used to summarize IL28B genotype.  IL28b rs12979860 will be resulted as C/C, C/T, T/T, 
or Unable to Assign Genotype by the central laboratory.
HOMA-IR is defined as fasting glucose (mmol/L) × fasting insulin (μIU/mL) ÷ 22.5.  
Subjects who do not have a fasting glucose value and/or a fasting insulin value at Baseline 
will be excluded from the summary of baseline HOMA-IR.
Histories of diabetes, depression or bipolar disorder, bleeding disorders, hypertension, and 
cardiovascular disease will be based on the Medical History (MH) eCRF.  History of 
diabetes is defined as presence of "Metabolic/Diabetes mellitus" on the MH eCRF.  
History of depression or bipolar disorder is defined as presence of "Neurologic and 
Psychiatric System/Depression" or "Neurologic and Psychiatric System/Bipolar Disorder" 
on the MH eCRF.  All medical history terms within "Clotting/bleeding problems" or 
"Other" under the "Blood" body system on the MH eCRF will be reviewed to identify 
subjects with a history of bleeding disorders (e.g., hemophilia).  History of hypertension is 
defined as presence of "Cardiovascular/Hypertension" on the MH eCRF.  History of 
cardiovascular disease is defined as conditions or diagnoses of "Angina," "Myocardial 
infarction," "Congestive heart failure," and "Coronary artery disease" under the 
"Cardiovascular" body system.  Medical history terms within "Other Body System" or any 
condition/diagnosis of "Other" may be reviewed for all baseline characteristics 
determined by the MH eCRF.
Baseline Child-Pugh score is calculated using the Day 1 assessment of ascites and hepatic 
encephalopathy along with the baseline values of total bilirubin, serum albumin, and INR.  
The Child-Pugh score is the sum of the points assigned for each of the five observed 
findings as defined in Table 8.  Child-Pugh score at all other visits will be based on the 
total score automatically calculated on the eCRF.


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Table 8.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
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.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central laboratory and/or from phylogenetic analysis of the full length 
NS3/4A, NS5A, and/or NS5B sequences performed by AbbVie.  If the phylogenetic 
analysis is available it will be used to determine the subject's HCV genotype and subtype.  
If it is not available, then the Inno-LiPA 2.0 assay result will be used to categorize the 
subject.
Categorical variables will be summarized with the number and percentage of subjects in 
each category.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum, and 
maximum).


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7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be calculated.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.
7.3
Previous Treatment and Concomitant Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug.  A concomitant medication is defined as any medication that started prior to 
the date of the first dose of study drug and continued to be taken on or after the first dose 
of study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug.  A Post-Treatment medication 
for the treatment of HCV is defined as any medication taken on or after the last dose of 
study drug and entered as "Post-treatment HCV medications" on the eCRF.
The number and percentage of subjects taking prior medications, concomitant medications 
and post-treatment HCV medications will be calculated by generic drug name based on 
the WHO Drug Dictionary. Additionally, hepatoprotective medications taken at baseline 
will be summarized by generic drug name. The prior HCV medications taken by the 
treatment-experienced subjects will be summarized separately from other prior 
medications.
8.0
Subject Disposition
Disposition data will be summarized for the set of all subjects in the safety population 
overall and separately for each geographic region.


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The number of subjects for each of the following categories will be calculated overall and 
by investigator:
●
Subjects enrolled to this study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who discontinued from study drug; 
●
Subjects who discontinued from the study;
●
Subjects who completed the study;
●
Subjects ongoing in the Post-Treatment Period at the time of the primary 
analysis.
The number and percentage of subjects who discontinued study drug will be calculated by 
reason (all reasons) and by primary reason (per eCRF) for all subjects and for women of 
childbearing potential.  Similar summaries will be provided for discontinuations from the 
study.
A table that lists reasons for discontinuation of study drug will be provided for women of 
childbearing potential who discontinued study drug.
The number and percentage of subjects will be calculated for:
●
Subjects with interruptions of all study drugs for toxicity management;
●
Subjects with any RBV dose modification;
○
Subjects with RBV dose modification due to decrease in hemoglobin;
○
Subjects with RBV dose modification due to decrease in eGFR;
○
Subjects with RBV dose modification due to other reasons;
●
Subjects with any RBV dose modification to 0 mg (i.e., RBV interruptions).
Reasons for study drug interruptions and RBV dose modifications will be presented in the 
listings.


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The number and percentage of screened subjects who screen failed will be calculated, and 
the reasons for screen failure (inclusion/exclusion criteria, withdrew consent, lost to 
follow-up, and/or other) will be summarized.  A listing of reasons for screen failure will 
be provided for all subjects who screen failed.
9.0
Study Drug Exposure and Compliance
9.1
Exposure
The duration of exposure to study drug will be summarized for the set of all subjects in 
the safety population and for each geographic region (China, South Korea, Taiwan).  
Duration of exposure is defined for each subject as the last study drug dose date minus the 
first study drug dose date plus 1 day.
Descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) 
will be presented.  Study drug duration also will be summarized with frequencies and 
percentages using the following categories:  1 to 15 days, 16 to 30 days, 31 to 45 days, 46 
to 60 days, 61 to 75 days and > 75 days.
9.2
Compliance
At each protocol-specified visit during the Treatment Period, the total number of tablets 
dispensed and returned is recorded for each type of study drug.  The compliance for each 
study drug (ABT-450/r/ABT-267, ABT-333, and RBV) within the Treatment Period will 
be calculated as the percentage of tablets taken relative to the total tablets expected to be 
taken.  The total number of tablets prescribed will be equal to the total number of tablets 
that should have been taken per the protocol for the duration that the subject was in the 
Treatment Period (date of last dose – date of first dose + 1 day).  Study drug interruptions 
due to an adverse event or other planned interruptions recorded on the eCRF will be 
subtracted from the duration.  For compliance to RBV, RBV dose modifications due to 
adverse events, toxicity management, or weight changes as recorded on the RBV Dose 
Modifications eCRF will be used to modify the total number of tablets that should have 
been taken.


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A subject is considered to be compliant if the percentage is between 80% and 120%.  
Compliance will be calculated for each study drug for each subject in the safety 
population and summarized with the N, mean, median, standard deviation, minimum, and 
maximum for each geographic region (China, South Korea, Taiwan) and overall.  In 
addition, the percentage of compliant subjects will be calculated for each study drug by 
geographic region and overall.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
Efficacy analyses will be performed on the ITT population, unless otherwise noted.
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of RVR, EOTR and SVR and the PRO questionnaires.  Except for the local 
laboratory imputation for RVR, EOTR and SVR that is described in Section 6.3, HCV 
RNA values will be limited to those obtained from the central laboratory.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v. 2.0.  
For this assay, the lower limit of quantification (LLOQ) is 15 IU/mL.  HCV RNA results 
that are detectable but not quantifiable are reported as "< 15 IU/ML HCV RNA 
DETECTED" and results that are not detectable are reported as "NO HCV RNA 
DETECTED."
Definitions for Efficacy Endpoints
Note that a confirmed quantifiable post-treatment value is defined as two consecutive 
post-treatment HCV RNA measurements ≥ LLOQ.  During treatment, a confirmed 
quantifiable value is defined as any two consecutive HCV RNA values ≥ LLOQ, either 
both during treatment or at the final treatment measurement and the next consecutive post-
treatment measurement.


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Failure to suppress = never achieved HCV RNA < LLOQ during at least 6 weeks of 
treatment (study drug duration ≥ 36 days).
Rebound = confirmed increase from nadir in HCV RNA (two consecutive HCV RNA 
measurements > 1 log10 IU/mL above nadir) at any time point during treatment or 
confirmed HCV RNA ≥ LLOQ after HCV RNA < LLOQ during treatment.  A single 
rebound value (≥ LLOQ or > 1 log10 above nadir) followed by lost to follow-up would be 
considered a rebound (i.e., will not require confirmation). 
On-treatment virologic failure = rebound or failure to suppress during treatment (all on-
treatment values of HCV RNA ≥ LLOQ) with at least 6 weeks (defined as study drug 
duration ≥ 36 days) of treatment.
RVR (rapid virologic response) = HCV RNA < LLOQ in the Week 4 window.
EOTR (end of treatment response) = HCV RNA < LLOQ in the Week 12 window.
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12planned = HCV RNA < LLOQ in the SVR12planned window (12 weeks after the last 
planned dose of study drug [i.e., Week 24]) without any confirmed quantifiable (≥ LLOQ) 
post-treatment value before or during that SVR window.
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.  This will not be included in the interim analysis.


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SVR24planned = HCV RNA < LLOQ in the SVR24planned window (24 weeks after the last 
planned dose of study drug [i.e., Week 36]) without any confirmed quantifiable (≥ LLOQ) 
post-treatment value before or during that SVR window.  This will not be included in the 
interim analysis.
Relapse4 = confirmed HCV RNA ≥ LLOQ between end of treatment and 4 weeks after 
last actual dose of study drug (up to and including the SVR4 assessment time point) for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completes treatment.
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of study drug (up to and including the SVR12 assessment time point) for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completes treatment.
Relapse24 = confirmed HCV RNA ≥ LLOQ within the SVR24 window for a subject who 
achieved SVR12 and has HCV RNA data available in the SVR24 window.  This will not be 
included in the interim analysis.
Relapselate = confirmed HCV RNA ≥ LLOQ at any time after the SVR24 assessment time 
point for a subject who achieved SVR24 and has post-SVR24 HCV RNA data available.  
This will not be included in the interim analysis.
Relapseoverall = confirmed HCV RNA ≥LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completes treatment.
For relapse analyses, the completion of treatment is defined as a study drug duration 
≥77 days.  If the last available post-treatment value is ≥ LLOQ, then the subject will be 
considered a relapse (i.e., will not require confirmation).  Relapse analyses will exclude 
subjects who do not have any post-treatment HCV RNA values.
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the post 
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baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B gene 
sequences.  Reinfection in the case of the same HCV subtype is defined as a clade switch, 
as indicated by the lack of clustering between the baseline and post-treatment sequences 
by phylogenetic analysis.  If phylogenetic analysis is not possible due to technical 
difficulties, HCV reinfection may be determined with a confirmed HCV genotype or 
subtype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0.
Post-treatment non-reinfection relapse is defined as relapse was described earlier 
(Relapse4, Relapse12, Relapse24, Relapselate, Relapseoverall), but with no genotype, subtype, 
or clade switch compared with baseline as determined by phylogenetic analysis of the 
NS3 or NS5A gene sequences.  If phylogenetic analysis is not possible due to technical 
difficulties, the subject will be defined as having a post-treatment non-reinfection relapse 
unless an HCV genotype or subgenotype switch is confirmed by the Versant HCV 
Genotype Inno-LiPA Assay v2.0.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
Relapse (defined according to the Relapse12 definition for subjects who complete 
treatment) with further breakdown by non-reinfection relapse versus reinfection;
3.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
(duration < 77 days) and did not meet the On-treatment virologic failure
definition);
4.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], or [3]);


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5.
Other (defined as any SVR12 non-responder not meeting the definitions of [1] – [4], 
such as a subject with a single quantifiable value within the SVR12 window 
followed by an undetectable value beyond the SVR12 window).
Reasons for SVR24 Non-Response (Not Included in the Interim Analysis)
Subjects who do not achieve SVR24 (SVR24 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
Relapse12, with further breakdown by non-reinfection relapse versus reinfection;
3.
Relapse24, with further breakdown by non-reinfection relapse versus reinfection;
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
(duration < 77 days) and did not meet the On-treatment virologic failure, 
Relapse12, or Relapse24 definitions);
5.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR24 non-responder not meeting the definitions of [1] –
[5]).
10.2
Handling of Multiplicity
Because of local regulatory requirements in China, both SVR12 and SVR24 are specified as 
primary endpoints.  In order to control the Type I error rate at 0.05, a fixed-sequence 
testing procedure8 will be used to proceed through the primary endpoints specified for 
China in the order numbered below for each.  That is, for China, only if success has been 
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rate (B1) will the testing continue to the second primary endpoint of superiority of the 
SVR24 to the historical rate (B2) specified in Section 10.3.
For South Korea and Taiwan, only SVR12 is specified as a primary endpoint.  Therefore 
no multiplicity adjustment will be made.
10.3
Primary Efficacy Analysis
For South Korea and Taiwan the primary endpoint is:
A1.
SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN/RBV 
therapy; the lower confidence bound (LCB) of the 95% CI for the percentage 
of subjects with SVR12 must exceed 67% to achieve superiority.
For China, the primary endpoints are:
B1.
SVR12:  Superiority to the historical SVR rate for telaprevir plus pegIFN/ 
RBV therapy; the LCB of the 95% CI for the percentage of subjects with 
SVR12 must exceed 67% to achieve superiority.
B2.
SVR24:  Superiority to the historical SVR rate for telaprevir plus pegIFN/RBV 
therapy; the LCB of the 95% CI for the percentage of subjects with SVR24
must exceed 67% to achieve superiority.
For China, in order to control the Type I error rate at 0.05, a fixed-sequence testing 
procedure will be used to proceed through the primary efficacy endpoints as specified in 
Section 10.2.
To test the hypothesis that the percentage of treatment-naïve and IFN based therapy (IFN 
[alpha, beta or pegIFN] with RBV) treatment-experienced HCV genotype 1b infected 
Asian subjects with compensated cirrhosis treated with the DAA treatment regimen for 
12 weeks who achieve SVR12 is superior to a clinically meaningful threshold based on the 
historical SVR rates for the HCV genotype 1 infected population treated with telaprevir 
plus pegIFN/RBV, the percentage of subjects with SVR12 will be calculated with a 
2-sided 95% CI using the Wilson score method,9 and the LCB will be compared to the 


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defined threshold.  The LCB of the 95% CI of SVR12 must be greater than 67% in order 
for the regimen to be considered superior.
Similarly, to test the hypothesis that the percentage of treatment-naïve and IFN based 
therapy treatment-experienced HCV genotype 1b infected Asian subjects with 
compensated cirrhosis treated with the DAA treatment regimen for 12 weeks who achieve 
SVR24 is superior to a clinically meaningful threshold based on historical SVR rates for 
the HCV genotype 1 infected population treated with telaprevir plus pegIFN and RBV, 
the percentage of subjects with SVR24 will be calculated with a 2-sided 95% CI using the 
Wilson score method, and the LCB will be compared to the defined threshold.  The LCB 
of the 95% CI of SVR24 must be greater than 67% in order for the regimen to be 
considered superior.
The value of 67% used in the endpoints as the historical SVR rate for telaprevir plus 
pegIFN/RBV is described in Section 4.3.1.
10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment virologic failure during the 
Treatment Period;
●
The percentage of subjects with post-treatment relapse (defined as Relapse12), 
with further breakdown by non-reinfection relapse versus reinfection based on 
HCV population sequencing;
●
The percentage of subjects with relapse by Post-Treatment Week 24 
(confirmed HCV RNA ≥ LLOQ between end of treatment and 24 weeks after 
the last dose of study drug among subjects completing treatment and with 
HCV RNA < LLOQ at the end of treatment), with further breakdown by non-
reinfection relapse versus reinfection based on HCV population sequencing.


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The percentages (with two-sided 95% confidence intervals using the Wilson score 
method) of the subjects with virologic failure during treatment and post-treatment relapse 
will be calculated.
10.5
Sensitivity Analyses for the Primary Efficacy Endpoint
Sensitivity analyses of the primary endpoints specified in Section 10.3 using the 
imputation methods described in Section 6.3 will be performed by geographic region on 
the ITT population and by geographic region and overall on the mITT-GT population, the 
mITT-GT + VFSVR12 population, and the mITT-GT + VFSVR24 population defined in 
Section 5.1.
Additionally, the percentage of subjects achieving SVR12 and SVR24 will be summarized 
for the ITT population by geographic region and overall using the following alternative 
imputation methods to impute missing post-treatment virologic results:
●
Impute as described in Section 6.3 but exclude subjects who were categorized 
for SVR12 (or SVR24) non-response as "prematurely discontinued study drug 
with no on-treatment virologic failure," "missing follow-up data in the SVR12
(or SVR24) window" or "other;"
●
Impute any missing HCV RNA values in the SVR12 (or SVR24) window by 
carrying forward the last non-missing (post-baseline) HCV RNA value prior to 
the SVR12 (or SVR24) window;
●
no imputation such that all missing HCV RNA values will be treated as 
failures;
●
impute as described in Section 6.3 but exclude local laboratory HCV RNA 
data.
An additional sensitivity analysis will be performed for SVR12 and SVR24 in which the 
LLOQ will be replaced with 25 IU/mL; this analysis will be performed by geographic 
region and overall for the ITT population.


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For each of these, the simple percentage of subjects with SVR12 (or SVR24) will be 
presented along with a two-sided 95% CI using the Wilson score method.
As a sensitivity analysis, comparisons of the SVR12 and SVR24 rates will be made to 
geographic region-specific SVR rates with IFN based therapy (IFN with RBV).  The rates 
of 44% from China, 20.8% from South Korea, and 60.7% from Taiwan will be used for 
comparisons (references provided in Section 4.3).  The SVR12 and SVR24 rates for the 
overall ITT population will be compared to each of these rates, and the SVR12 and SVR24
rates for the ITT population from each geographic region will be compared to the 
geographic region-specific IFN-based therapy rate.
10.5.1
Assessment of Homogeneity Across Geographic Regions
Heterogeneity across the three geographic regions will be examined for the primary 
efficacy endpoints of SVR12 and SVR24 using the chi-square test of homogeneity.  The 
three strata are China, South Korea, and Taiwan.
A confidence interval based on a stratum-weighted variance will be calculated using the 
equations below.  The variance of ps will be estimated by:
and the 2-sided 95% confidence interval will be calculated as ps ± z √Var(ps), where z is 
the 1-α/2 point of the standard normal distribution.  Note that N represents the number of 
subjects in the ITT population, Nh represents the number of subjects in stratum h, 
Wh = Nh/N, ph = the proportion of subjects achieving SVR12 (or SVR24) in stratum h, and 
ps = the proportion of subjects with SVR12 (or SVR24) among N subjects, which can be 
defined as:
!
∀
#
#
∀
H
h
h
h
h
h
s
N
p
p
W
p
Var
1
2
1
)
1(
)
(
!
∀
∀
H
h
h
h
s
p
W
p
1


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10.6
Additional Efficacy Analyses
As additional efficacy analyses, the secondary endpoints will also be summarized for each 
geographic region (China, South Korea, Taiwan).
The following additional efficacy endpoints will be summarized on the ITT population by 
geographic region and overall.
●
mean change from baseline in FibroTest score to each applicable post-baseline 
time point.
●
the percentage of subjects with unquantifiable HCV RNA at each post-baseline 
visit throughout the Treatment Period (using data from the central laboratory 
as observed, i.e., no imputation for missing data);
●
the percentage of subjects with "failure to suppress;"
●
the number of subjects with virologic rebound at each protocol-specified visit 
in the Treatment Period;
●
the percentage of subjects with RVR;
●
the percentage of subjects with EOTR;
●
time to suppression of HCV RNA (defined as the study day of the 
first occurrence of HCV RNA < LLOQ) during the Treatment Period;
●
the percentage of subjects achieving SVR4;
●
the percentage of subjects with Relapse4, with further breakdown by non-
reinfection relapse versus reinfection based on HCV population sequencing;
●
the percentage of subjects achieving SVR12planned;
●
the percentage of subjects achieving SVR24planned;
●
the percentage of subjects with Relapse24, with further breakdown by non-
reinfection relapse versus reinfection based on HCV population sequencing;
●
the percentage of subjects with Relapselate, with further breakdown by non-
reinfection relapse versus reinfection based on HCV population sequencing;
●
the percentage of subjects with Relapseoverall, with further breakdown by non-
reinfection relapse versus reinfection based on HCV population sequencing;


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●
time to relapse at any time post-treatment (defined in text below with 
additional relapse analyses);
For the change from baseline to each post-baseline time point in FibroTest score, 
descriptive statistics (N, mean, SD, median, minimum, and maximum) will be calculated.
For HCV RNA virologic response, the number and percentage of subjects with RVR, 
EOTR, SVR, on-treatment virologic failure, and post-treatment relapse will be calculated 
along with two-sided 95% confidence intervals using the Wilson score method; missing 
data will be imputed as described in Section 6.3.  All other endpoints will be presented 
using data as observed, i.e., not performing any missing data imputations.
The number and percentage of subjects who do not achieve SVR12 (or SVR24) by reason 
for non-response (defined in Section 10.1) will be calculated, and the non-responders will 
be presented in a listing.
The subjects who fail to suppress HCV RNA and received at least 6 weeks of treatment 
(study drug duration ≥ 36 days) will be presented in a listing.  The subjects who rebound 
at any time during treatment and within each protocol-specified visit (defined in Table 4) 
will be presented in a listing displaying the subject numbers at the first occurrence of 
breakthrough.
The number of completers (defined as study drug duration ≥ 77) with final on-treatment 
HCV RNA < LLOQ who relapse at any time post-treatment and within each SVR window 
will be calculated along with a corresponding listing displaying the first occurrence of 
relapse.  A similar table and listing will be provided of Preterm Relapses for subjects who 
do not complete treatment (defined as study drug duration < 77 days) with HCV RNA 
< LLOQ at Final Treatment Visit.  These summaries will include data collected after Post-
Treatment Week 12.
From HCV RNA levels, the time to relapse post-treatment will be calculated for each 
subject treated with study drug and displayed graphically using a Kaplan-Meier (KM) 


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curve.  For time to relapse analyses, time to event will be measured as the number of days 
from the last dose of active study drug to event or censoring time.  The time of relapse 
post-treatment is defined as the first of two consecutive HCV RNA values ≥ LLOQ 
between the end of the treatment period and end of the Post-Treatment Period amongst 
subjects who completed study drug with HCV RNA < LLOQ at the Final Treatment Visit.  
Subjects who do not relapse will be censored at the date corresponding to the last 
available HCV RNA value within the Post-Treatment Period.  Time to relapse will be 
performed only for subjects with HCV RNA < LLOQ at Final Treatment Visit who 
completed study drug, defined as a study drug duration ≥ 77 days.
The time to suppression on treatment will be calculated for each subject treated with study 
drug and displayed graphically using a KM curve.  For time to suppression analyses, time 
to event will be measured as the number of days from the first dose of study drug to event 
or censoring time.  The time of suppression is defined as the first occurrence of HCV 
RNA values < LLOQ during a treatment period.  Subjects who do not suppress will be 
censored at the date of the last HCV RNA value within the corresponding treatment 
period.
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and by the positive predictive value (PPV) and negative predictive 
value (NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is a 
percentage defined as the number of subjects achieving both SVR12 and SVR24 and the 
number of subjects not achieving both SVR12 and SVR24 out of all subjects in the ITT 
population.  The PPV of SVR12 on SVR24 is the proportion of subjects who achieve 
SVR24 out of all subjects who achieved SVR12.  The NPV of SVR12 on SVR24 is the 
proportion of subjects who do not achieve SVR24 out of all subjects who did not achieve 
SVR12.


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10.7
Efficacy Subgroup Analysis
Analyses will be performed for the primary efficacy variables of SVR12 and SVR24 on the 
ITT population by geographic region (China, South Korea, Taiwan) and overall using the 
following subgroups:
●
Previous HCV treatment status (Treatment-naïve versus previous IFN-based 
therapy [IFN (alpha, beta or pegIFN) with RBV] treatment-experienced;
○
For treatment-experienced subjects, type of response to previous IFN-
based therapy (non-responder, relapser, or IFN-based therapy intolerant);
○
For non-responders to previous IFN-based therapy, type of response (null 
responder, partial responder, or other non-responder);
●
IL28B genotype (CC or non-CC) and (CC, CT, or TT);
●
Sex (male or female);
●
Age (< 55 or ≥ 55 years) and (< 65 or ≥ 65 years);
●
BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 800,000 or ≥ 800,000 IU/mL);
●
Baseline IP-10 (< 600 or ≥ 600 ng/L);
●
Baseline HOMA-IR (< 3 or ≥ 3 mU × mmol/L2);
●
Baseline Child-Pugh Score (5, 6 or > 6);
●
Baseline platelets (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline alpha fetoprotein [AFP] (< 20 or ≥ 20 ng/mL);
●
Any of platelets < 90 × 109/L, albumin < 35 g/L, or alpha fetoprotein 
≥20 ng/mL, or none of the three;
●
RBV dose modifications (yes/no);
●
History of Depression or Bipolar Disorder (yes/no);
●
History of Diabetes (yes/no);
●
History of Bleeding Disorders (yes/no);
●
Presence of hepatic steatosis at Baseline (yes/no);
●
Hepatoprotective drug use at Baseline (yes/no);


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●
Former injection drug use (yes/no).
The numbers and percentages of subjects achieving SVR12 and SVR24 within each 
subgroup will be provided.  If there are 10 or more subjects within the subgroup level, 
then a two-sided 95% confidence interval will be calculated using the Wilson score 
method.
A logistic regression model will be used to explore the associations between the subgroup 
variables and SVR12 (or SVR24) on all subjects in the ITT population.  A stepwise logistic 
regression approach will be used to assess the strength of each subgroup variable in 
predicting SVR12 (or SVR24), with P values of 0.10 to enter and remain in the model.  
Subgroup variables may be changed to be continuous to prevent separation.  A similar 
analysis will be performed to explore the associations between each of the subgroup 
variables and virologic failure (on treatment virologic failure or Relapse12 for SVR12; on 
treatment virologic failure or Relapse12 or Relapse24 for SVR24).
10.8
Resistance Analyses
If possible, subjects who do not achieve SVR12 (or SVR24) will have resistance testing 
conducted if (1) they have on-treatment rebound; (2) they have a study drug duration 
≥77 days and then experience post-treatment relapse; or (3) they have at least 6 weeks of 
treatment and fail to suppress by Week 6.  Subjects meeting one of these criteria will be 
considered to have experienced virologic failure and will be referred to as subjects in the 
primary virologic failure (PVF) population; a listing by subject that includes reason for 
SVR12 (or SVR24) non-response, time point(s) sequenced as closest to time of VF, and 
HCV RNA value at the VF time point(s) will be produced for these subjects.  In addition, 
all listings described below will display reason for SVR12 (or SVR24) non-response in the 
subject identifier for each subject.  A separate listing will delineate all subjects in the PVF 
population for whom no sequencing was performed (e.g., lost to follow-up while HCV 
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Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo population 
sequence analysis in order to allow accurate assessment of the products of amplification.  
For subjects who experience virologic failure, the sample closest in time after failure with 
an HCV RNA level ≥ 1000 IU/mL will be used if the HCV RNA level at the time of 
failure is < 1000 IU/mL.  The prototypic reference strain with its associated GenBank 
Accession ID for sequence analyses is 1b-Con1 (AJ238799).
For each DAA target, resistance-associated signature amino acid variants will be 
identified by AbbVie Clinical Virology.  Amino acid positions where resistance-
associated variants have been identified in vitro and/or in vivo in genotype 1b are 1) for 
ABT-450:  55, 56, 155, 156, and 168 in NS3; 2) for ABT-267:  24, 28, 29, 30, 31, 32, 58, 
62, 92, and 93 in NS5A; and 3) for ABT-333:  316, 368, 411, 414, 445, 448, 553, 556, 
558, and 559 in NS5B.
The following definitions will be used in the resistance analyses:
●
Baseline sample: sample collected before the first dose of DAA study drug.
●
Baseline variant: a variant (by population sequencing) in a baseline sample 
determined by comparison of the amino acid sequence of the baseline sample 
to the appropriate prototypic reference amino acid sequence for a given DAA 
target (NS3, NS5A, or NS5B).
●
Post-baseline variant by population sequencing:  an amino acid variant in a 
post-baseline time point sample that was not detected at baseline in the subject 
and is detectable by population sequencing.
●
Emerged variant by population sequencing:  a post-baseline variant that is 
observed in 2 or more subjects by population sequencing.
For those samples evaluated, a listing by subject of all baseline variants relative to the 
prototypic reference sequence at signature resistance-associated amino acid positions will 
be provided for each DAA target (NS3, NS5A, and/or NS5B).  Furthermore, the HCV 
amino acid sequence at post-baseline time points with an HCV RNA level of 
≥1000 IU/mL that are analyzed will be compared to the baseline and prototypic reference 


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amino acid sequences.  A listing by subject and time point of all post-baseline variants 
relative to the baseline amino acid sequences will be provided for each DAA target (NS3, 
NS5A, and/or NS5B).  In addition, a listing by subject and time point of all post-baseline 
variants at signature resistance-associated amino acid positions relative to the prototypic 
reference amino acid sequences will be provided.  Furthermore, the number and 
percentage of subjects with emerged variants by amino acid position and variant within a 
DAA target as compared to baseline will be summarized.
The persistence of resistance-associated substitutions that emerged for each target (NS3, 
NS5A, and NS5B) will be assessed by population sequencing at selected post-treatment 
time points.  Listings by subject and time point of all post-baseline variants relative to the 
baseline amino acid sequence will be provided for each DAA target (NS3, NS5A, and 
NS5B).  The analysis of any resistance data from samples collected after Post-Treatment 
Week 24 will be summarized in the end of study analysis.
10.9
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  
HCV-PRO, EQ-5D-5L, and SF-36 version 2 (SF-36v2).  PROs will be collected at 
protocol-specified visits for all enrolled subjects.  The HCV-PRO, EQ-5D-5L, and SF-
36v2 will be collected at Baseline, Weeks 4, 8, and 12, and Post-Treatment Weeks 4, 12, 
24 and 48, or upon premature discontinuation of the Treatment or Post-Treatment Periods.  
Missing data for each instrument will be handled as described in Section 6.3.  PROs will 
be summarized on the ITT population by geographic region (China, South Korea, Taiwan) 
and overall.
The following analyses of PROs will be performed:
●
mean change from baseline in HCV-PRO total score to each applicable post-
baseline time point;
●
mean change from baseline in EQ-5D-5L health index score and VAS score to 
each applicable post-baseline time point;


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●
mean change from baseline to each applicable post-baseline time point in the 
SF-36v2 Mental Component Summary (MCS) and Physical Component 
Summary (PCS) measures;
●
continuous plots of the change from Baseline to Final Treatment Visit and PT 
Week 12 in the SF-36v2 PCS and MCS, HCV-PRO total score, EQ-5D-5L 
health index score and VAS on the horizontal axis and the cumulative percent 
of subjects experiencing up to that change on the vertical axis;
●
percentage of subjects without a decrease from Baseline to Final Treatment 
Visit in the SF-36v2 PCS and MCS that is greater than or equal to the 
minimally important difference (MID) of five points;
●
percentage of subjects without a decrease from Baseline to Final Treatment 
Visit in the EQ-5D-5L health index score that is greater than or equal to its 
study-defined MID;
●
percentage of subjects without a decrease from Baseline to Final Treatment 
Visit in the HCVPRO total score that is greater than or equal to its study-
defined MID.
The HCV-PRO consists of 16 items with 5 response choices (1, 2, 3, 4, or 5) that are 
recoded to 0, 1, 2, 3, or 4, respectively, when deriving the total score.  The total score is 
the sum of all 16 items and is converted to a score between 0 and 100 by 
ScaledScore=Sum*100/64.  Subject's responses to the self-administered HCV-PRO 
instrument will be assessed for the total score.  Subject's responses to the EQ-5D-5L will 
be combined into a unique health state using a 5-digit code with 1 digit from each of the 
5 dimensions.  The EQ-5D-5L states will be converted into a single preference-weighted 
health utility index score by applying country-specific weights (if available) or US 
weights (if not available).10,11  The VAS score will be measured separately.  The SF-36v2 
measures dimensions of a patient's functional health and well-being in 8 domains and also 
provides 2 summary scores that characterize a patient's mental (MCS) and physical (PCS) 
health status.  The score for each of the 8 domains ranges from 0 to 100 and will be 
normalized according to the user manual.12  The standardization of the normalized scores 
will provide the norm-based scores with a mean of 50 and a SD of 10.  The two summary 
scores are based on the norm-based scores.  Per the SF-36v2 instrument manual, score for 


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any item with multiple responses will be set to "missing."  Missing item responses will be 
handled as described in Section 6.3.  Subject's responses to the SF-36v2 will be 
summarized for the PCS and MCS measures.
Summary statistics (n, mean, SD, median, minimum and maximum) for the mean change 
from baseline to each applicable visit will be provided for the HCV-PRO total score, 
EQ-5D-5L index and VAS scores, and the SF-36v2 PCS and MCS scores.
An MID of –5 will be used for the change from Baseline to Final Treatment Visit in the 
SF-36v2 PCS and MCS.  The percentage of subjects with a change from Baseline to Final 
Treatment Visit > –5 will be presented along with 95% confidence intervals.
To calculate the MID for HCVPRO and EQ-5D-5L, a receiver operating characteristics 
(ROC) analysis will be performed from PROC LOGISTIC with each of the following 
anchors for the change from Baseline to Final Treatment Visit in the HCVPRO total score 
and in the EQ-5D-5L health index score:
●
Change from Baseline to Final Treatment Visit in SF-36 PCS > –5 [yes/no];
●
Change from Baseline to Final Treatment Visit in SF-36 MCS > –5 [yes/no].
Change from Baseline to Final is defined as the Final Score – Baseline Score within the 
Treatment Period for all subjects in the ITT population.  The point on the ROC curve that 
is closest to the upper left-hand corner (0, 1) yields the optimal sensitivity and specificity.  
This point will be determined by minimizing (1 – sensitivity)2 + (1 – specificity)2.  The 
cutoff point corresponding to the sensitivity and specificity values closest to (0, 1) for 
each anchor will be averaged and used as the MID.  The MID determined for the HCV-
PRO total score will be used for the change from baseline to Final Treatment Visit in 
HCV-PRO total score.  The MID determined for the EQ-5D-5L health index score will be 
used for the change from baseline to Final Treatment Visit in EQ-5D-5L health index 
score.  The percentage of subjects in each treatment group with a change from Baseline to 
Final Treatment Visit > MID will be presented along with 95% confidence intervals.  If, 
for example, the MID is determined to be –10 for the HCVPRO total score, then the 


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responders are subjects with an improvement from baseline and subjects with decreases 
between zero and 10 points in the change from Baseline to Final Treatment Visit in HCV-
PRO total score.
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed on the safety population.  For analyses of safety, data 
will be summarized by geographic region (China, South Korea, and Taiwan) and for the 
overall set of subjects.
11.2
Analysis of Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  Any worsening of a pre-
existing condition or illness is considered an AE.  Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) with the MedDRA version used 
for the study at the time of database lock.  The actual version of the MedDRA coding 
dictionary will be noted in the study report.
11.2.1
Treatment-Emergent Adverse Events
A treatment-emergent AE is defined as any AE with an onset date that is after the 
first dose of study drug and no more than 30 days after the last dose of study drug.  Events 
where the onset date is the same as the study drug start date are assumed to be treatment-
emergent.  If an incomplete onset date was collected for an adverse event, the event will 
be assumed to be treatment emergent, unless there is other evidence that confirms that the 
event was not treatment-emergent (e.g., the event end date was prior to the study drug 
start date).


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11.2.1.1
Tabulations of Treatment-Emergent Adverse Events
AE data will be summarized and presented using primary MedDRA system organ classes 
(SOCs) and preferred terms (PTs).  The SOCs will be presented in alphabetical order and 
the PTs will be presented in alphabetical order within each SOC.  Subjects reporting more 
than one AE for a given PT will be counted only once for that term (most severe incident 
for the severity tables and most related incident for the relationship tables).  Subjects 
reporting more than one AE within a SOC will be counted only once for that SOC.  
Subjects reporting more than one AE will be counted only once in the overall total.
Adverse Event Overview
An overview of adverse events will be presented consisting of the number and percentage 
of subjects experiencing at least one event for the following adverse event categories:
●
Any treatment-emergent adverse event;
●
Treatment-emergent AE with a reasonable possibility of being related to 
DAAs;
●
Treatment-emergent adverse events with a reasonable possibility of being 
related to RBV;
●
Severe treatment-emergent adverse events;
●
Moderate or severe treatment-emergent adverse events;
●
Serious treatment-emergent adverse events;
●
Grade 3 or 4 (see definition below) treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modification;
●
Treatment-emergent adverse events leading to death;
●
Treatment-emergent adverse events leading to concomitant medication use 
(events with other action taken of "concomitant medication prescribed");
●
Deaths (any event after the first dose of study drug, regardless of how many
study days after the last dose of study drug).


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Adverse Events by SOC and PT
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV;
●
Serious treatment-emergent adverse events;
●
Moderate or severe treatment-emergent adverse events;
●
Severe treatment-emergent adverse events;
●
Grade 3 or 4 (see definition below) treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modification;
●
Treatment-emergent adverse events leading to death;
●
Treatment-emergent adverse events leading to concomitant medication use 
(events with other action taken of "concomitant medication prescribed").
A listing of treatment-emergent adverse events grouped by SOC and PT with subject 
numbers will be created.
Adverse Events by PT
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated according to PT and sorted by overall frequency.  Similar summaries 
will be provided for moderate to severe treatment-emergent adverse events and treatment 
emergent adverse events with a "reasonable possibility" of being related to DAAs and 
RBV.


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Adverse Events of Special Interest
Specific treatment-emergent adverse events of special interest, which will be searched 
using Standardized or Company MedDRA Queries, will be summarized.  The search 
criteria for each of the adverse events of interest are summarized in Table 9.
Table 9.
Adverse Events of Special Interest
Adverse Event of Special Interest
Search Criteria
Hepatotoxicity-related events
SMQ "Drug-related hepatic disorders – severe events only" 
(broad search)
Bilirubin-related events
SMQ "Cholestasis and jaundice of hepatic origin" (broad search)
Anemia
SMQ "Haematopoietic erythropenia" (broad search) plus the 
following preferred terms:
∃
Haemolytic anaemia,
∃
Coombs negative haemolytic anaemia,
∃
Coombs positive haemolytic anaemia
Drug-induced rash events
CMQ "Drug induced rash" (latest CMQ version based on 
MedDRA version used at time of analysis)
Severe cutaneous reactions
SMQ "Severe cutaneous adverse reactions" (narrow search)
For each adverse event of interest, the number and percentage of subjects experiencing at 
least one treatment-emergent adverse event in the search for the event of interest will be 
presented by SOC and PT.
A listing of treatment-emergent adverse events for subjects meeting the search criterion 
will be provided for each adverse event of special interest.
Adverse Events by Maximum Severity
Treatment-emergent adverse events and treatment-emergent adverse events with a 
"reasonable possibility" of being related to DAAs will be summarized by maximum 
severity of each PT.  If a subject has an adverse event with unknown severity, then the 
subject will be counted in the severity category of "unknown," even if the subject has 
another occurrence of the same event with a severity present.  The only exception is if the 


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subject has another occurrence of the same adverse event with the most extreme severity –
"Severe."  In this case, the subject will be counted under the "Severe" category.
Adverse Events by Maximum Severity Grade Level
Treatment-emergent adverse events will be summarized by maximum severity grade level 
of each PT.  Each PT will be assigned to a grade level based on severity and seriousness, 
adapted from the Division of AIDS (DAIDS) table for grading severity of adverse events.  
All serious adverse events will be categorized as Grade 4.  Nonserious adverse events 
categorized by the investigators as mild, moderate or severe will be categorized as 
Grade 1, Grade 2, or Grade 3, respectively.  If a subject has a nonserious adverse event 
with unknown severity and does not have another occurrence of the same event that is 
marked serious or severe, then the subject will be counted in the severity grade level 
category of "unknown," even if the subject has another nonserious occurrence of the same 
event with a severity present.  If the subject has another occurrence of the same adverse 
event with the most extreme severity for nonserious events ("Severe") and does not have 
another occurrence of the same event that is marked serious, then the subject will be 
counted under the "Grade 3" category.  If the subject has another occurrence of the same 
adverse event that is marked serious, then the subject will be counted under the "Grade 4" 
category.
Adverse Events by Maximum Relationship
Treatment-emergent adverse events will be summarized by maximum relationship of each 
PT to DAA and by maximum relationship to RBV, as assessed by the Investigator.  If a 
subject has an AE with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same AE with a relationship assessment of "Reasonable Possibility."  In 
this case, the subject will be counted under "Reasonable Possibility."


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11.2.2
Listings of Adverse Events
The following listings of adverse events will be prepared:
●
All serious adverse events (from the time the subject signed the study-specific 
informed consent through the end of the study);
●
Treatment-emergent serious adverse events;
●
Treatment-emergent adverse events leading to death;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to study drug interruption;
●
Treatment-emergent adverse events leading to RBV dose modification;
●
Treatment-emergent adverse events in each of the adverse events of special 
interest categories.
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.
11.3.1
Variables and Criteria Defining Abnormality
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, absolute neutrophil count (ANC), reticulocyte count, 
prothrombin time (PT), international normalized ratio (INR), and activated partial 
thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, serum glutamic pyruvic transaminase (SGPT/ALT), serum glutamic 
oxaloacetic transaminase (SGOT/AST), alkaline phosphatase, sodium, potassium, 
calcium, inorganic phosphorus, uric acid, cholesterol, total protein, glucose, triglycerides, 
albumin, chloride, bicarbonate, magnesium, gamma glutamyl transferase (GGT), 
creatinine clearance (Cockcroft-Gault calculation), calculation of estimated glomerular 


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filtration rate (eGFR) adjusted for the Asian population using the Chinese modification of 
diet in renal disease (C-MDRD) equation as defined below, alpha2-macroglobulin, 
haptoglobin, apolipoprotein A1, and alpha fetoprotein.
Urinalysis variables include:  specific gravity, ketones, pH, protein, blood, glucose, 
urobilinogen, bilirubin, leukocyte esterase, albumin, and microscopic (reflex performed if 
other variables are abnormal).
Additional variables include:  total insulin and IP-10.
The following calculation is used by the central lab for eGFR by C-MDRD, where serum 
creatinine is measured in mg/dL and age is measured in years:
eGFR (mL/min/1.73 m2) = 175 × Serum Creatinine(–1.234) × Age(–0.179) × 0.79 (if Female).
The Criteria for Potentially Clinically Significant (PCS) Laboratory Findings are 
described in Table 10 and Table 11.


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Table 10.
Criteria for Potentially Clinically Significant Hematology Values
Test/Units (if applicable)
Very Low (VL)
Very High (VH)
Hemoglobin
(mmol/L)
< 4.9
(g/dL)
< 8.0
(g/L)
< 80
Platelets Count
(cells/mm3)
< 50,000
(cells/L)
< 50 × 109
White Blood Cell Count
(cells/mm3)
< 2000
> 20,000
(cells/L)
< 2.0 × 109
> 20 × 109
Absolute Neutrophil Count
(cells/mm3)
< 1000
(cells/L)
< 1 × 109
Lymphocyte Count
(cells/mm3)
< 500
(cells/L)
< 0.5 × 109
Eosinophil Count
(cells/mm3)
> 5000
(cells/L)
> 5 × 109
aPTT
> 2 × ULN
International Normalized Ratio
> 2 × ULN
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.


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Table 11.
Criteria for Potentially Clinically Significant Chemistry Values
Test/Units (if applicable)
Very Low (VL)
Very High (VH)
ALT/SGPT
> 5 × ULN and ≥ 2 × baseline
AST/SGOT
> 5 × ULN and ≥ 2 × baseline
Alkaline Phosphatase
> 1.5 × ULN
Total Bilirubin
≥ 2.0 × ULN
Creatinine
(mcmol/L)
≥ 132.605
(mg/dL)
≥ 1.5
Creatinine Clearance (mL/min)
< 50
eGFR using C-MDRD (mL/min/1.73 m2)
< 50
BUN
> 5 × ULN
Uric Acid
(mcmol/L)
> 713.817
(mg/dL)
> 12.0
Phosphate
(mmol/L)
< 0.6
(mg/dL)
< 2.0
Calcium, Serum
(mmol/L)
< 1.75
> 3.1
(mg/dL)
< 7.0
> 12.5
Sodium (mmol/L)
< 130
> 155
Potassium (mmol/L)
< 3.0
> 6.0
Magnesium
(mmol/L)
< 0.4
> 1.23
(mg/dL)
< 0.9
> 3.0
Glucose
(mmol/L)
< 2.2
> 13.9
(mg/dL)
< 40
> 250
Albumin
(g/L)
< 20
(g/dL)
< 2


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Table 11.
Criteria for Potentially Clinically Significant Chemistry Values 
(Continued)
Test/Units (if applicable)
Very Low (VL)
Very High (VH)
Protein 
(g/L)
< 50
(g/dL)
< 5.0
Cholesterol
(mmol/L)
> 10.34
(mg/dL)
> 400
Triglycerides
(mmol/L)
> 5.7
(mg/dL)
> 500
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.
11.3.2
Statistical Methods
Clinical laboratory tests will be summarized at each protocol-specified visit.  The baseline 
value will be the last measurement on or before the day of the first dose of study drug.  
This same baseline value will be used for all change from baseline tables in the Treatment 
Period and Post-Treatment Period.
At each protocol-specified post-baseline visit, including applicable post-treatment visits, 
protocol-specified hematology, clinical chemistry, insulin, IP-10, and urinalysis pH and 
specific gravity parameters will be summarized with the baseline mean; visit mean; and 
change from baseline mean, standard deviation, minimum, maximum, and median.
Laboratory data values will be categorized as low, normal, or high based on normal 
ranges of the laboratory used in this study.  Shift tables from baseline to minimum value, 
maximum value, and final values during the Treatment Period (Study Drug End Day ≤ 2) 
will be created.  The shift tables will cross tabulate the frequency of subjects with baseline 
values below/within/above the normal range versus minimum/maximum/final values 
below/within/above the normal range.


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The number and percentage of subjects with post-baseline values during the Treatment 
Period meeting the specified criteria for Potentially Clinically Significant (PCS) 
laboratory values (defined in Table 10 and Table 11) will be calculated.  A post-baseline 
value must be more extreme than the baseline value to be considered a PCS finding.  A 
separate listing will be provided that presents all laboratory values for the subjects 
meeting PCS criteria during treatment.
Hemoglobin and the liver function tests (LFTs) of ALT, AST, alkaline phosphatase, and 
total bilirubin will be assigned a CTCAE Grade of 1, 2, 3, or 4 as defined in Table 12.  
The number and percentage of subjects with a maximum CTCAE Grade of 1, 2, 3 or 4 at 
any post-baseline visit during the Treatment Period (regardless of the baseline value) will 
be calculated.  All LFT summaries will also include the number and percentage of 
subjects with at least a Grade 2 and at least a Grade 3 laboratory abnormality.  The 
hemoglobin table will include a summary row for the number and percentage of subjects 
with at least a Grade 2 laboratory abnormality.  A separate listing of all ALT, AST, total, 
indirect and direct bilirubin, and alkaline phosphatase values will be provided for each 
subject who had at least a Grade 3 ALT, AST, alkaline phosphatase, or total bilirubin.  A 
similar listing of all hemoglobin values will be provided for each subject who had at least 
a Grade 2 hemoglobin value.  The listing for hemoglobin will include all hemoglobin, 
total neutrophils, platelet count and white blood cell count values.
The hemoglobin by maximum CTCAE grade table, described above, also will be provided 
for subjects with and without treatment-emergent adverse events of dyspnea (defined by 
PTs of "dyspnoea" or "dyspnoea exertional").
For subjects with a Grade 3 or higher total bilirubin elevation, a listing of treatment-
emergent events will be provided that includes all events with PTs in the "Cholestasis and 
jaundice of hepatic origin" SMQ (broad search) after excluding PTs within the 
"Investigations" SOC.


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Table 12.
Definitions of CTCAE Grades 1, 2, 3, and 4
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin decreased
< LLN – 100 g/L
< 100 – 80 g/L
< 80 – 65 g/L
< 65 g/L
The number and percentage of subjects meeting the following criteria during the 
Treatment Period will be calculated:
●
ALT ≥ 3 × ULN and total bilirubin value ≥ 2 × ULN;
●
ALT ≥ 3 × ULN and total bilirubin value < 2 × ULN;
●
ALT > 5 × ULN (equivalent to Grade 3 or higher) and total bilirubin value 
< 2 × ULN;
●
ALT < 3 × ULN and total bilirubin ≥ 2 × ULN.
A subject or event will be counted if the post-baseline laboratory values meet the above 
criteria regardless of the baseline laboratory value (i.e., the post-baseline laboratory value 
does not need to be worse than the baseline laboratory value).  The maximum value will 
be compared to the ULN to determine if a subject meets the criteria listed above.  The 
maximum values do not have to be concurrent when determining if a subject met the 
criteria above.
For subjects meeting the ALT ≥ 3 × ULN and total bilirubin value ≥ 2 × ULN criterion 
during the Treatment Period, a corresponding listing of all ALT, AST, alkaline 
phosphatase, and total, direct, and indirect bilirubin values will be provided.
For subjects meeting the criterion of ALT < 3 × ULN and total bilirubin ≥ 2 × ULN, the 
number and percentage of subjects with a total bilirubin value in the categories of ≤ ULN, 
> ULN – < 2 × ULN, and ≥ 2 × ULN at the Final Treatment Visit will be calculated.  A 
similar summary will be provided for Post-Treatment Week 4.


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In addition, for subjects meeting the criterion of ALT < 3 × ULN and total bilirubin 
≥2 × ULN (based on the maximum value relative to the ULN), the ratio of indirect 
bilirubin to total bilirubin will be calculated.  The following summary statistics will be 
presented for the ratio at baseline and for the ratio associated with the peak total bilirubin 
value during the Treatment Period:  sample size, mean, standard deviation, minimum, 
maximum, and median.  In addition, the number and percentage of subjects with a ratio 
< 0.75 and < 0.50 will be presented for baseline and peak.
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality
Vital sign variables are body temperature, sitting systolic blood pressure, sitting diastolic 
blood pressure, sitting pulse rate, and body weight.
The Criteria for Potentially Clinically Significant vital sign findings are presented in 
Table 13.
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic blood pressure
≤ 90 mmHg AND
A decrease of ≥ 20 mmHg from 
baseline
≥ 180 mmHg AND
An increase of ≥ 20 mmHg from 
baseline
Diastolic blood pressure
≤ 50 mmHg AND
A decrease of ≥ 15 mmHg from 
baseline
≥ 105 mmHg AND
An increase of ≥ 15 mmHg from 
baseline
Pulse rate
≤ 50 bpm AND
A decrease of ≥ 15 bpm from 
baseline
≥ 120 bpm AND
An increase of ≥ 15 bpm from 
baseline
Weight
A decrease of ≥ 15% from baseline
An increase of ≥ 15% from baseline
Temperature
> 38.3°C AND
An increase of ≥ 1.1°C from baseline


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11.4.2
Statistical Methods
Vitals signs will be summarized at each visit.  The baseline value will be the last 
measurement on or before the day of the first dose of study drug.  The same baseline 
value will be used for all change-from-baseline tables in the Treatment and Post-
Treatment Periods.
At each protocol-specified post-baseline visit, including applicable post-treatment visits, 
vital sign parameters will be summarized with the baseline mean; visit mean; and change 
from baseline mean, standard deviation, minimum, maximum, and median.
The number and percentage of subjects with post baseline values during the Treatment 
Period meeting Criteria for Potentially Clinically Significant vital signs values (Table 13) 
will be calculated.  A post-baseline value must be more extreme than the baseline value to 
be considered as a PCS finding.  A separate listing will be provided that presents all of the 
vital sign values for the subjects meeting the PCS vital sign criteria during treatment.
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and Version 1 of the SAP
●
Added unplanned interim analysis including all subjects to allow for 
submission to the CFDA at the time of SVR12 analysis.
●
Deleted planned interim analysis, which was to be conducted after all South 
Korean and Taiwanese subjects completed the Post-Treatment Week 12 Visit, 
because the unplanned interim analysis was added.
●
Added references for geographic region-specific pegIFN/RBV SVR rates for 
use in sensitivity analyses of the primary endpoints (Section 4.3) and specified 
the rates (Section 10.5) to provide details for the sensitivity analyses pre-
specified in the protocol.
●
Added modified ITT Genotype (mITT-GT) population and modified ITT-
Genotype and SVR12 Virologic Failure (mITT-GT + VFSVR12) population and 
modified ITT-Genotype and SVR24 Virologic Failure (mITT-GT + VFSVR24) 


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population as populations for sensitivity analyses to exclude SVR failures due 
to reasons other than virologic failure (Section 5.1 and Section 10.5).
●
Added additional summaries of demographics, baseline characteristics, 
medical history, and previous/concomitant medications by geographic region 
to provide geographic region-specific information (Section 7.1).
●
Provided algorithm for determining a subject's HCV genotype and subtype 
based on phylogenetic analyses and/or Inno-LiPA 2.0 to guide programming 
(Section 7.1).
●
Changed the unit for IP-10 from pg/mL to ng/L (units are equivalent) to align 
with the global studies (Section 7.1 and Section 10.7).
●
Added summary of hepatoprotective medications taken at baseline to provide 
additional information on the types of hepatoprotective medications used
(Section 7.3).
●
Corrected the HCV RNA LLOQ to be 15 IU/mL (Section 10.1).
●
Added re-infection definition and further breakdown of Relapse by non-
reinfection relapse versus reinfection in Reasons for SVR12 non-Response to 
distinguish between reinfection and true virologic failure due to relapse 
(Section 10.1).
●
Added Modified ITT Genotype (mIA-GT) population and Modified ITT-
Genotype and SVR12 Virologic Failure (mIA-GT + VFSVR12) population and 
Modified ITT-Genotype and SVR24 Virologic Failure (mIA-GT + VFSVR24) 
population as populations for sensitivity analyses to exclude SVR failures due 
to reasons other than virologic failure (Section 10.5).
●
Excluded subjects who were categorized as "other" for SVR12 (or SVR24) non-
response in the alternative imputation methods for sensitivity analyses in order 
to exclude all subjects without virologic failure (Section 10.5).
●
Moved the analysis of the primary endpoints by geographic region from the 
subgroup analysis section (Section 10.7) to the sensitivity analysis section to 
align with the Study M13-767 SAP (Section 10.5). 
●
Added additional sensitivity analysis for SVR12 and SVR24 in which the LLOQ 
will be replaced with 25 IU/mL to align with the LLOQ used in the global 
studies (Section 10.5).


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●
Added test for homogeneity to align with the global studies (Section 10.5.1).
●
Added summaries of secondary efficacy endpoints by geographic region as 
additional efficacy analyses to provide information by geographic region 
(Section 10.6).
●
Specified that subgroup analyses of SVR12 and SVR24 would also be 
performed by geographic region to provide geographic region-specific 
information (Section 10.7).
●
Added a subgroup analysis of SVR12 and SVR24 for "any of platelets 
< 90 × 109/L, albumin < 35 g/L, or alpha fetoprotein ≥ 20 ng/mL, or none of 
the three" to provide additional information (Section 10.7).
●
Updated the resistance analyses to guide programming (Section 10.8).
●
Added eGFR using C-MDRD in Criteria for Potentially Clinically Significant 
Chemistry Values because this parameter is more applicable to the study's 
population than calculated creatinine clearance (Section 11.3.1).
●
Moved analyses of mean change from baseline in liver function tests (other 
than Fibrotest) from Additional Efficacy Analyses (Section 10.6) to Analysis 
of Laboratory Data (Section 11.3) because the parameters are safety 
parameters.
●
Added summaries of hemoglobin and LFTs by CTCAE grade and summaries 
of ALT and total bilirubin with respect to the ULN to align with the global 
studies (Section 11.3.2).
13.0
References
1.
EU Summary of Product Characteristics for INCIVO® (telaprevir).  Available 
from:  the European Public Assessment Report:  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/002313/WC500115507.pdf.
2.
Sherman K, Flamm S, Afdhal N, et al; ILLUMINATE Study Team.  Response 
guided telaprevir combination treatment for hepatitis C virus infection.  N Engl J 
Med.  2011;365(11):1014-24.


ABT-450/Ritonavir/ABT-267 and ABT-333
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3.
Xie R, Fan X, Yang S, et al.  Expert consensus for antiviral treatment of chronic 
hepatitis C.  Chinese J Exp Clinic Infect Dis (Electronic Edition).  
2009;3(3):343-52.
4.
INCIVO® (telaprevir) [Summary of Product Characteristics].  Belgium; 
Janssen-Cilag International NV, 2013.
5.
Vezali E, Aghemo A, Colombo M.  A review of the treatment of chronic 
hepatitis C virus infection in cirrhosis.  Clinical Therapeutics.  
2010;32(13):2117-38.
6.
Korean Association for the Study of the Liver (KASL.  KASL clinical practice 
guidelines:  management of hepatitis C.  Clinical Molecular Hepatology.  
2014;20(2):89-136.
7.
Huang JF, Yu ML, Huang CF, et al.  The efficacy and safety of pegylated 
interferon plus ribavirin combination therapy in chronic hepatitis C patients with 
hepatocellular carcinoma post curative therapies – a multicenter prospective trial.  
J Hepatol.  2011;54(2):219-26.
8.
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures.  J Stat Plan Inference.  2001;99:25-40.
9.
Newcombe RG.  Two-sided confidence intervals for the single proportion:  
comparison of seven methods.  Stat Med.  1998;17(8):857-72.
10.
Szende A, Williams A, editors.  Measuring self-reported population health:  an 
international perspective based on EQ-5D-5L.  EuroQol Group Monographs 
Volume 1.  SpringMed, 2004.
11.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L User Guide:  Basic information on 
how to use the EQ-5D-5L instrument, version 1.0.  April 2011.
12.
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's manual for the SF-36v2 health 
survey.  2nd Edition.  Lincoln, RI:  QualityMetric Incorporated; 2007.




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16.1__9.2
CMQ Preferred Terms
The AbbVie drug-induced rash company MedDRA query included the following 
preferred terms:
Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Actinic prurigo
Acute generalised exanthematous pustulosis
Administration site abscess sterile
Administration site dryness
Administration site erosion
Administration site exfoliation
Administration site induration
Administration site irritation
Administration site macule
Administration site nodule
Administration site pallor
Administration site papule
Administration site plaque
Administration site pustule
Administration site rash
Administration site scab
Administration site vasculitis
Application site abscess sterile
Application site acne
Application site erythema
Application site hypersensitivity
Application site macule
Application site papules
Application site plaque
Application site pruritus
Application site pustules
Application site rash
Application site urticaria
Application site vasculitis


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Application site vesicles
Atopy
Biopsy skin
Biopsy skin abnormal
Bullous impetigo
Butterfly rash
Capillaritis
Catheter site rash
Catheter site urticaria
Chronic pigmented purpura
Conjunctivitis
Corneal exfoliation
Cutaneous lupus erythematosus
Cutaneous symptom
Cutaneous vasculitis
Dermatitis
Dermatitis acneiform
Dermatitis allergic
Dermatitis atopic
Dermatitis bullous
Dermatitis contact
Dermatitis diaper
Dermatitis exfoliative
Dermatitis exfoliative generalised
Dermatitis infected
Dermatitis papillaris capillitii
Dermatitis psoriasiform
Device allergy
Diffuse vasculitis
Drug cross-reactivity
Drug eruption
Drug hypersensitivity
Drug reaction with eosinophilia and systemic symptoms


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Dyshidrotic eczema
Eczema
Eosinophilic pustular folliculitis
Eosinophilic pustulosis
Epidermal necrosis
Epidermolysis
Epidermolysis bullosa
Eruptive pseudoangiomatosis
Erythema
Erythema multiforme
Erythrodermic psoriasis
Exfoliative rash
Fixed drug eruption
Generalised erythema
Genital ulceration
Granulomatous rosacea
Haemorrhagic urticaria
Hand dermatitis
Henoch-Schonlein purpura
Henoch-Schonlein purpura nephritis
Hypersensitivity
Hypersensitivity vasculitis
Idiopathic urticaria
Impetigo
Implant site erosion
Implant site exfoliation
Implant site pustules
Implant site rash
Implant site urticaria
Implant site vesicles
Incision site dermatitis
Incision site rash
Incision site ulcer


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Incision site vesicles
Infusion site abscess sterile
Infusion site dermatitis
Infusion site discharge
Infusion site discolouration
Infusion site dryness
Infusion site erosion
Infusion site erythema
Infusion site exfoliation
Infusion site hypersensitivity
Infusion site induration
Infusion site inflammation
Infusion site irritation
Infusion site macule
Infusion site nodule
Infusion site pallor
Infusion site papule
Infusion site plaque
Infusion site pruritus
Infusion site pustule
Infusion site rash
Infusion site reaction
Infusion site urticaria
Infusion site vesicles
Infusion site warmth
Injection site dermatitis
Injection site discolouration
Injection site erosion
Injection site erythema
Injection site exfoliation
Injection site hypersensitivity
Injection site induration
Injection site inflammation


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Injection site irritation
Injection site macule
Injection site papule
Injection site pruritus
Injection site pustule
Injection site rash
Injection site reaction
Injection site urticaria
Injection site vasculitis
Injection site vesicles
Injection site warmth
Lip exfoliation
Lupus vasculitis
Lupus-like syndrome
Medical device site dermatitis
Medical device site discharge
Medical device site discolouration
Medical device site dryness
Medical device site eczema
Medical device site erosion
Medical device site erythema
Medical device site exfoliation
Medical device site hypersensitivity
Medical device site induration
Medical device site inflammation
Medical device site irritation
Medical device site macule
Medical device site nodule
Medical device site pallor
Medical device site papule
Medical device site plaque
Medical device site pruritus
Medical device site pustule


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Medical device site rash
Medical device site scab
Medical device site scar
Medical device site sterile abscess
Medical device site vasculitis
Medical device site vesicles
Microscopic polyangiitis
Mouth ulceration
Mucocutaneous rash
Mucocutaneous ulceration
Mucosal exfoliation
Mucosal necrosis
Mucosal ulceration
Nikolsky's sign
Nodular rash
Ocular vasculitis
Oculomucocutaneous syndrome
Oral mucosal eruption
Oral mucosal exfoliation
Oropharyngeal blistering
Pain of skin
Palmar-plantar erythrodysaesthesia syndrome
Palpable purpura
Papulopustular rosacea
Pemphigoid
Pemphigus
Penile exfoliation
Penile ulceration
Photosensitivity reaction
Polymorphic light eruption
Pruritus
Pruritus allergic
Pruritus generalised


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Psoriasis
Purpura
Rash
Rash erythematous
Rash follicular
Rash generalised
Rash macular
Rash maculo-papular
Rash maculovesicular
Rash morbilliform
Rash neonatal
Rash papular
Rash papulosquamous
Rash pruritic
Rash pustular
Rash scarlatiniform
Rash vesicular
Rebound atopic dermatitis
Rebound eczema
Scleroderma-like reaction
Skin exfoliation
Skin irritation
Skin necrosis
Skin reaction
Skin toxicity
Stevens-Johnson syndrome
Stoma site extravasation
Stomatitis
Systemic lupus erythematosus rash
Tongue eruption
Tongue exfoliation
Toxic epidermal necrolysis
Toxic skin eruption


ABT-450/r/ABT-267, ABT-333
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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Transient neonatal pustular melanosis
Type I hypersensitivity
Type II hypersensitivity
Type III immune complex mediated reaction
Type IV hypersensitivity reaction
Urticaria
Urticaria contact
Urticaria vesiculosa
Urticarial vasculitis
Vaccination site dermatitis
Vaccination site discolouration
Vaccination site eczema
Vaccination site erosion
Vaccination site erythema
Vaccination site exfoliation
Vaccination site extravasation
Vaccination site hypersensitivity
Vaccination site hypertrichosis
Vaccination site induration
Vaccination site inflammation
Vaccination site irritation
Vaccination site macule
Vaccination site pallor
Vaccination site papule
Vaccination site plaque
Vaccination site pruritus
Vaccination site rash
Vaccination site reaction
Vaccination site urticaria
Vaccination site vasculitis
Vaccination site vesicles
Vaccination site warmth
Vaginal exfoliation


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Preferred Terms in the AbbVie Drug-Induced Rash Company MedDRA (Version 19.0) Query
Vaginal ulceration
Vasculitic rash
Vulval ulceration
Vulvovaginal rash