Clinical trial NCT03089944
Conditions: Hepatitis C Virus (HCV)
Keywords: Hepatitis C Virus (HCV) Glecaprevir Pibrentasvir Treatment Naïve Cirrhosis Compensated Cirrhosis Genotype (GT) 1-6 Pangenotypic Chronic Hepatitis C Virus (HCV)
Sponsor: AbbVie
Start date: 2017-04-28; Completion date: 2019-11-08
Enrollment: 343 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 3b, single arm, open-label, multicenter study in treatment naïve adults with chronic HCV infection and compensated cirrhosis to assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir and to demonstrate the efficacy of the sustained virologic response 12 weeks post dosing (SVR12) rates of 8 weeks of treatment with glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of treatment with glecaprevir/pibrentasvir.

Detailed description:

Arms: arm 1: Glecaprevir (GLE)/Pibrentasvir (PIB) 300 mg/120 mg once daily (QD) for 8 weeks.
Interventions: intervention 1: Glecaprevir/Pibrentasvir
Intervention descriptions: intervention 1: Tablet

Protocol documents:
Prot_000.pdf: 
Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
1
1.0
Title Page
Clinical Study Protocol M16-135
A Single Arm, Open-label Study to Evaluate the 
Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir 
(PIB) in Treatment Naïve Adults with Chronic 
Hepatitis C Virus (HCV) Genotype 1 - 6 Infection and 
Compensated Cirrhosis
Incorporating Amendments 1, 2 and 3
AbbVie Investigational
  Product:
Glecaprevir, Pibrentasvir
Date:
11 June 2018
Development Phase:
3b
Study Design:
This is an open-label, multicenter study
EudraCT Number:
2016-004967-38
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc. (AbbVie)*
Sponsor/Emergency 
  Contact:
, MD
Medical Director
Antiviral Clinical Project Team
1500 Seaport Blvd.
Redwood City, CA 94063
Phone:
Fax:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
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.
NCT03089944


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date 
Original
17 January 2017
Amendment 1
25 April 2017
Amendment 2
06 September 2017
The purpose of this amendment is to:
●
Update several sections of the protocol to allow for the enrollment of subjects 
infected with HCV Genotype 3
Rationale:  To evaluate the efficacy and safety of an 8-week treatment regimen 
in a treatment-naïve cirrhotic patient population inclusive of patients with 
HCV GT3 infection.
●
Update Section 5.2.3.3 Prohibited Therapy
Rationale:  To reflect most updated protocol guidance in the setting of 
marketing approval of GLE/PIB.
●
Update Sponsor/Emergency Contact
Rationale:  To reflect the new physician assuming the role of Primary 
Therapeutic Area Medical Director.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-135
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  11 June 2018
Protocol Title:  A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus (HCV) Genotype 1 
- 6 Infection and Compensated Cirrhosis
Objectives:
!
To demonstrate the efficacy of the SVR12 rates of 8 weeks of treatment with 
glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of treatment with 
glecaprevir/pibrentasvir in treatment naïve adults with chronic HCV infection and compensated 
cirrhosis.
!
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in treatment naïve 
adults with chronic HCV infection and compensated cirrhosis.
Investigators:  Multicenter
Study Sites:  Approximately 120 globally
Study Population:  Adults with chronic HCV genotype (GT) 1 - 6 infection, aged 18 years or older, 
with compensated cirrhosis, who are HCV treatment-naïve.
Number of Subjects to be Enrolled:  Approximately 330 subjects
Methodology:
This is a Phase 3b, single arm, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of glecaprevir/pibrentasvir in treatment-naïve subjects with chronic HCV GT 1 - 6 infection and 
compensated cirrhosis.  The study will initially enroll subjects with HCV GT 1, 2, 4, 5, and 6 infection 
followed by subjects with HCV GT3 infection.  Once enrollment of subjects with HCV GT3 infection 
begins, enrollment of subjects with HCV GT 1, 2, 4, 5 or 6 infection will be closed.
The study will consist of 3 periods:
Screening Period:
Subjects have up to 42 days following the Screening Visit to confirm eligibility and enroll into the study.
Treatment Period:
Eligible subjects will be enrolled to receive glecaprevir/pibrentasvir 300 mg/120 mg once daily (QD) for 
8 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, and 8.  Study 
procedures, including assessment of adverse events, vital signs, adherence, concomitant medications, 
HCV RNA, HCV resistance, pharmacokinetic assays, and clinical laboratory tests, will be conducted at 
each visit.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
4
Methodology (Continued):
Because subjects with GT 1, 2, 4, 5 or 6 infection will be enrolled first, separate treatment extension 
criteria will apply to subjects with GT 1, 2, 4, 5 or 6 infection versus subjects with GT3 infection, as 
described below.  However, if treatment is extended for all or a particular subgroup of subjects with GT 
1, 2, 4, 5 or 6 infection, then enrollment of subjects with GT3 infection will be terminated and all GT3-
infected subjects who are on treatment or have completed treatment within the previous 7 days will have 
their treatment extended to 12 weeks.
In subjects with HCV GT 1, 2, 4, 5, and 6 infection, an efficacy assessment will evaluate the post-
treatment relapse rate after the first 30 subjects reach Post-Treatment Week 4 and will be done 
periodically thereafter.  If more than 10% of subjects experience post-treatment relapse, an analysis will 
be conducted to determine if extension of treatment to 12 weeks is needed for all GT 1, 2, 4, 5, and 6-
infected subjects or for a particular subgroup of GT 1, 2, 4, 5, and 6-infected subjects who are on
treatment or have completed treatment within the previous 7 days.
In subjects with HCV GT3 infection, an efficacy assessment will evaluate the post-treatment relapse rate 
after the first 20 subjects reach Post-Treatment Week 4 and will be done periodically thereafter.  If more 
than 10% of subjects experience post-treatment relapse, an analysis will be conducted to determine if 
extension of treatment to 12 weeks is needed for all GT3-infected subjects or for a particular subgroup of 
GT3-infected subjects who are on treatment or have completed treatment within the previous 7 days.
Post-Treatment Period:
Subjects who complete or prematurely discontinue the Treatment Period will be followed for 24 weeks 
to monitor safety, HCV RNA levels and to evaluate efficacy and the emergence and persistence of 
resistance associated substitutions. 
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant virus will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female, at least 18 years of age at time of Screening;
2.
Screening laboratory result indicating HCV GT 1 - 6 infection;
3.
Positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening; 
4.
Treatment-naïve to any approved or investigational anti-HCV medication;
5.
Subject must be documented as cirrhotic, with a Child-Pugh score of ≤ 6.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study, or for approximately 30 days after the last dose of study drug;
2.
Any current or historical clinical evidence of decompensated cirrhosis, including any current or past 
evidence of Child-Pugh B or C classification, hepatic encephalopathy or variceal bleeding, 
radiographic evidence of small ascites, or empiric use of lactulose/rifaximin for neurologic 
indications.  The use of beta blockers is not exclusionary;  
3.
Current HBV or HIV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative HBsAg and Anti-
HBs), or;
!
A positive anti-human immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed by the central laboratory during screening indicating co-infection with 
more than one HCV genotype;
5.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Alanine aminotransferase ALT > 10 × ULN
!
Aspartate aminotransferase AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL
!
Calculated creatinine clearance (CrCl, Cockcroft-Gault method) of < 50 mL/min
!
Albumin < 2.8 mg/dL
!
Hemoglobin < 10 g/dL 
!
Platelets < 50,000 cells/mm3
Investigational Products:
Glecaprevir/Pibrentasvir:  100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir:  300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects will receive glecaprevir/pibrentasvir for 8 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-Lead ECGs and vital signs.


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M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
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Criteria for Evaluation (Continued):
Patient Reported Outcomes (PROs):
The Treatment Satisfaction Questionnaire-Medication (TSQM) will be used to assess subjects' 
satisfaction with the treatments efficacy and side effects.  The Short Form 36 Version 2 Health Status 
Survey (SF-36v2) will be used to assess the functional health and well-being of subjects.  The Fatigue 
Severity Scale (FSS) will be used to measure the severity of fatigue and its effect on lifestyle and 
activities.
Pharmacokinetic:
Individual plasma concentrations of glecaprevir and pibrentasvir will be tabulated and summarized.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the 
appropriate prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline 
substitutions relative to the corresponding baseline sequence in available samples.
Statistical Methods:
Efficacy:
The Intention-to-Treat (ITT) population includes all enrolled subjects who receive at least one dose of 
study drug.  The Per-Protocol (PP) population includes all enrolled subjects who receive at least 
one dose of study drug, with the exception of subjects who experience breakthrough, or prematurely 
discontinue treatment prior to Week 8, or have no HCV RNA value in the SVR12 visit window or later.
The primary efficacy endpoint is SVR12.  The following primary and key secondary efficacy analyses are 
the comparisons of the SVR12 rate of the 8-week treatment duration to a historical SVR12 rate for 
12 weeks in the Per-Protocol (PP) population and in the Intention-to-Treat (ITT) population.  The 
primary efficacy analyses will be conducted among HCV GT1, 2, 4, 5, and 6-infected subjects, and the 
two key secondary efficacy analyses will be conducted among all (HCV GT1 - 6) subjects.  The primary 
efficacy analyses are listed below and will be tested through a fixed-sequence testing procedure:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 4, 5, and 6-infected subjects in the 8-week treatment duration achieving 
SVR12 is greater than 94% in the PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 4, 5, and 6-infected subjects in the 8-week treatment duration achieving 
SVR12 is greater than 93% in the ITT population.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
7
Statistical Methods (Continued):
Efficacy (Continued):
The two key secondary efficacy analyses included in the fixed-sequence testing procedure are:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 3, 4, 5, and 6-infected subjects in the 8-week treatment duration 
achieving SVR12 is greater than 94% in the PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 3, 4, 5, and 6-infected subjects in the 8-week treatment duration 
achieving SVR12 is greater than 93% in the ITT population.
The primary and key secondary efficacy analyses will be tested using the hierarchical order outlined 
above to control the Type I error rate.  Only if success has been demonstrated for the first primary 
efficacy analysis of SVR12 based on the PP population in HCV GT1, 2, 4, 5, and 6-infected subjects will 
the testing proceed to the second primary efficacy analysis of SVR12 based on the ITT population in 
HCV GT1, 2, 4, 5, and 6-infected subjects.  And only if success has been demonstrated for the second 
primary efficacy analysis will the testing proceed to the first key secondary efficacy analysis of SVR12
based on the PP population in HCV GT1, 2, 3, 4, 5, and 6-infected subjects, and so on.  For all primary 
and key secondary efficacy analyses, the percentage of subjects achieving SVR12 and a two-sided 95% 
confidence interval will be calculated using the normal approximation to the binomial distribution, 
unless the number of subjects who failed to achieve SVR12 is less than 5, then the Wilson's score method 
will be used for the confidence interval instead.
The other secondary efficacy analyses are listed below and are not included in the fixed-sequence 
testing:
!
The percentage of HCV GT3-infected subjects in the PP population who achieve SVR12;
!
The percentage of HCV GT3-infected subjects in the ITT population who achieve SVR12;
!
The percentage of subjects with on-treatment virologic failure (OTVF) across genotypes, within 
HCV GT 1, 2, 4, 5, and 6-infected subjects combined, and within HCV GT3-infected subjects 
(based on ITT population);
!
The percentage of subjects with post-treatment relapse across genotypes, within HCV GT 1, 2, 
4, 5, and 6-infected subjects combined, and within HCV GT3-infected subjects (based on ITT 
population).
The number and percentage of subjects will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of OTVF and post-treatment relapse, separate summaries will be provided for all 
subjects across genotypes, within HCV GT1, 2, 4, 5, and 6-infected subjects combined, and within HCV 
GT3-infected subjects.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
8
Statistical Methods (Continued):
Safety:
All subjects who receive at least one dose of study drug will be included in the safety analyses.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The number 
and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug through 30 days post-study drug dosing) will be 
tabulated by MedDRA System Organ Class (SOC) and preferred term.  The tabulation of the number of 
subjects with treatment-emergent adverse events also will be provided by severity grade (Grades 1 – 5) 
and relationship to study drug.  Mean changes in clinical laboratory and vital sign data from baseline to 
each post-baseline visit will be summarized.  The number and percentage of subjects with post-baseline 
laboratory values meeting toxicity grades and meeting pre-defined criteria for laboratory parameters of 
interest during treatment will be summarized.  The number and percentage of subjects with post-baseline 
vital sign values during the Treatment Period meeting pre-specified criteria for potentially clinically 
significant vital sign values will be summarized.
Patient Reported Outcomes (PROs):
The mean change from baseline to each applicable post-baseline timepoint in the FSS total score and the 
SF-36v2 Mental Component Summary (SF-36-MCS) and Physical Component Summary SF-36-PCS 
scores will be summarized descriptively at each visit.  The TSQM subscales (global satisfaction, 
convenience, effectiveness, side effects) will be summarized descriptively at Weeks 2, 4, and 8 and the 
change from the baseline visit will be summarized at all on treatment timepoints.
Pharmacokinetic:
Plasma concentration of glecaprevir and pibrentasvir will be tabulated for each subject.  Plasma
concentrations of glecaprevir and pibrentasvir will be summarized based on last dosing time, sampling 
time and time since last dose.  Summary statistics will be computed for glecaprevir and pibrentasvir 
plasma concentrations binned by time since last dose.
Resistance:
For all subjects receiving study drug and with available samples, baseline polymorphisms at signature 
resistance-associated amino acid positions identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the corresponding 
baseline sequence, 2) the amino acid substitutions in available post baseline samples at signature 
resistance-associated positions identified by NGS, and comparison to the appropriate prototypic 
reference sequence, and 3) the persistence of viral substitutions by NGS.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
ADR
Study drug related AE
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
APRI
Aminotransferase/platelet ratio index
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
AUC
Area Under the Concentration Curve
BMI
Body Mass Index
BUN
Blood urea nitrogen
CL/F
Apparent Oral Clearance
CrCl
Creatinine clearance
CRF
Case report form
CT
Computed Tomography
CTEP
Cancer Therapy Evaluation Program
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMEA
European Agency for the Evaluation of Medicinal Products
EOT
End of treatment
EU
European Union
FSS
Fatigue Severity Scale
GAM
Generalized additive method
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLE
Glecaprevir


Glecaprevir/Pibrentasvir
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GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCC
Hepatocellular carcinoma
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
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
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention to treat
IU
International units
IUD
Intrauterine device
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NCI CTCAE 
National Cancer Institute Common Terminology Criteria
NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
OTVF
On-treatment virologic failure
PCS
Potentially clinically significant


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PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
PIB
Pibrentasvir
PK
Pharmacokinetic
POR
Proof of receipt
PP
Per-protocol
PRO
Patient Reported Outcome
PR
pegIFN/RBV
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
RTV or r
Ritonavir
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SF-36v2
Short Form 36 – Version 2 Health Survey
SF-36-MCS
Mental Component Summary
SF-36-PCS
Physical Component Summary
SOC
System Organ Class/Standard of Care
SOF
Sofosbuvir
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
TA MD
Therapeutic Area Medical Director
TN
Treatment naïve
TSQM
Treatment Satisfaction Questionnaire – Medication
ULN
Upper limit of normal
V/F
Apparent Volume of distribution


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WBC
White blood cells
WOCBP
Women of child bearing potential
Definition of Terms
Study Drug
glecaprevir/pibrentasvir (GLE/PIB)
Study Day 1
First day of study drug dosing
Treatment Period
Day 1 through last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 24 or 
Post-Treatment Discontinuation


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 3
1.3
List of Abbreviations and Definition of Terms........................................ 9
2.0
Table of Contents ................................................................ 13
3.0
Introduction......................................................................... 18
3.1
Differences Statement .......................................................................... 27
3.2
Benefits and Risks................................................................................ 28
4.0
Study Objective ................................................................... 30
4.1
Primary Objective ................................................................................ 30
4.2
Secondary Objectives ........................................................................... 30
5.0
Investigational Plan.............................................................30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.1.1
Screening ............................................................................................. 32
5.1.1.1
Rescreening.......................................................................................... 32
5.1.2
Treatment Period.................................................................................. 33
5.1.3
Post-Treatment Period.......................................................................... 34
5.2
Selection of Study Population............................................................... 34
5.2.1
Inclusion Criteria.................................................................................. 35
5.2.2
Exclusion Criteria................................................................................. 36
5.2.3
Prior and Concomitant Therapy............................................................ 38
5.2.3.1
Prior HCV Therapy .............................................................................. 39
5.2.3.2
Concomitant Therapy........................................................................... 39
5.2.3.3
Prohibited Therapy............................................................................... 39
5.2.4
Contraception Recommendations ......................................................... 40
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 41
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 41
5.3.1.1
Study Procedures.................................................................................. 41
5.3.1.2
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples................................................................................. 53


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5.3.1.3
Meals and Dietary Requirements.......................................................... 54
5.3.2
Drug Concentration Measurements....................................................... 54
5.3.2.1
Collection of Samples for Analysis....................................................... 54
5.3.2.2
Handling/Processing of Samples........................................................... 54
5.3.2.3
Disposition of Samples......................................................................... 55
5.3.2.4
Measurement Methods ......................................................................... 55
5.3.3
Efficacy Variables................................................................................ 55
5.3.3.1
Primary Variables................................................................................. 55
5.3.3.2
Secondary Variable .............................................................................. 55
5.3.3.3
HCV Resistance Variables.................................................................... 56
5.3.4
Safety Variables ................................................................................... 56
5.3.5
Pharmacokinetic Variables ................................................................... 56
5.3.6
Pharmacogenetic Exploratory Research Variables ................................ 57
5.4
Removal of Subjects from Therapy or Assessment ............................... 57
5.4.1
Discontinuation of Individual Subjects ................................................. 57
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 58
5.4.1.2
Treatment Extension Criteria................................................................ 59
5.4.2
Discontinuation of Entire Study............................................................ 60
5.5
Treatments ........................................................................................... 61
5.5.1
Treatments Administered...................................................................... 61
5.5.2
Identity of Investigational Products ...................................................... 61
5.5.2.1
Packaging and Labeling........................................................................ 62
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 62
5.5.3
Method of Assigning Subjects to Treatment Groups............................. 62
5.5.4
Selection and Timing of Dose for Each Subject .................................... 63
5.5.5
Blinding ............................................................................................... 63
5.5.6
Treatment Compliance ......................................................................... 63
5.5.7
Drug Accountability ............................................................................. 64
5.6
Discussion and Justification of Study Design........................................ 65
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 65
5.6.2
Appropriateness of Measurements........................................................ 66
5.6.3
Suitability of Subject Population .......................................................... 66
5.6.4
Selection of Doses in the Study ............................................................ 68


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5.6.4.1
Rationale for Dose Selections............................................................... 68
5.6.4.2
GLE and PIB Dose and Treatment Duration......................................... 68
5.6.4.3
Risk of Development of Resistance Mutations During 
Combination DAA Trials ..................................................................... 68
6.0
Complaints........................................................................... 69
6.1
Medical Complaints ............................................................................. 69
6.1.1
Definitions ........................................................................................... 70
6.1.1.1
Adverse Event...................................................................................... 70
6.1.1.2
Serious Adverse Events........................................................................ 71
6.1.2
Adverse Event Severity ........................................................................ 72
6.1.3
Relationship to Study Drug................................................................... 73
6.1.4
Adverse Event Collection Period.......................................................... 74
6.1.5
Adverse Event Reporting...................................................................... 74
6.1.6
Pregnancy............................................................................................. 76
6.1.7
Toxicity Management........................................................................... 76
6.1.7.1
Management of Transaminase Elevations............................................. 77
6.2
Product Complaint................................................................................ 78
6.2.1
Definition............................................................................................. 78
6.2.2
Reporting ............................................................................................. 78
7.0
Protocol Deviations ............................................................. 79
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 80
8.1
Statistical and Analytical Plans............................................................. 80
8.1.1
Demographics and Baseline Characteristics.......................................... 81
8.1.2
Efficacy................................................................................................ 82
8.1.2.1
Primary Efficacy Endpoints.................................................................. 82
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 83
8.1.2.2.1
Key Secondary Efficacy Endpoints....................................................... 83
8.1.2.2.2
Other Secondary Efficacy Endpoints .................................................... 84
8.1.2.3
Sensitivity Analysis.............................................................................. 85
8.1.2.4
Subgroup Analysis ............................................................................... 85
8.1.2.5
Additional Efficacy Endpoints.............................................................. 86
8.1.2.6
Multiplicity .......................................................................................... 87


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8.1.3
Patient Reported Outcomes .................................................................. 88
8.1.4
Resistance Analyses ............................................................................. 89
8.1.5
Safety................................................................................................... 93
8.1.5.1
Adverse Events..................................................................................... 93
8.1.5.2
Clinical Laboratory Data ...................................................................... 94
8.1.5.3
Vital Signs Data ................................................................................... 94
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................. 94
8.2
Determination of Sample Size .............................................................. 96
8.2.1
Justification of Success Criteria for SVR12............................................ 97
8.3
Randomization Methods....................................................................... 98
9.0
Ethics.................................................................................... 99
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 99
9.2
Ethical Conduct of the Study................................................................ 99
9.3
Subject Information and Consent.........................................................100
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 101
10.1
Source Documents...............................................................................101
10.2
Case Report Forms..............................................................................101
11.0
Data Quality Assurance .................................................... 102
12.0
Use of Information ............................................................ 102
13.0
Completion of the Study ................................................... 103
14.0
Investigator's Agreement.................................................. 104
15.0
Reference List.................................................................... 105
List of Tables
Table 1.
Overview of Clinical Studies by Subject Population ............................. 20
Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype –
GT1 –6 (ITT Population, Phase 2 and 3 Analysis Set) .......................... 22
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)........................................................................................ 25
Table 4.
Prohibited Medications and Supplements ............................................. 40


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Table 5.
Clinical Laboratory Tests ..................................................................... 45
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 48
Table 7.
Identity of Investigational Products ...................................................... 62
Table 8.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ...................................................................................... 90
List of Figures
Figure 1.
Study Schematic................................................................................... 32
Figure 2.
Adverse Event Collection..................................................................... 74
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................107
Appendix B.
List of Protocol Signatories .................................................................109
Appendix C.
Study Activities – Treatment Period ....................................................110
Appendix D.
Study Activities – Post-Treatment Period ............................................113
Appendix E.
Protocol Amendment:  List of Changes ...............................................115


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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 
184 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype 1 (GT1) being the most prevalent worldwide.  HCV genotypes 2 (GT2) and 
3 (GT3) infections are more common in Latin America (5% to 30%), Europe (20% to 
40%) and Asia (30% to 45%).2-4 HCV GT4 is commonly found in parts of Africa and the 
Middle East, particularly in Egypt, GT5 is primarily found in South Africa, GT6 is 
primarily found in south-east Asia, and GT7 has recently been described in Central 
Africa.5  
Depending on various risk factors, between 10% and 40% of all patients with chronic 
HCV infection will develop cirrhosis.6  Deaths related to the complications of cirrhosis 
may occur at an incidence of approximately 4% per year; hepatocellular carcinoma (HCC) 
occurs in this population at an estimated incidence of 1% to 5% per year.6  Patients 
diagnosed with hepatocellular carcinoma have a 33% probability of death during the 
first year.6  Successful treatment of HCV has been shown to significantly reduce the risk 
of disease progression and related mortality as well as the development of hepatocellular 
carcinoma.7,8
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF, simeprevir [SMV], daclatasvir [DCV], 
ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] + dasabuvir [DSV], elbasvir 
[ELB]/grazoprevir [GZV], and SOF/velpatasvir [VEL]).9,10  However, the approved and 
recommended regimens are not equally potent across all HCV genotypes and 
subpopulations.  Additional limitations of several current regimens include the 
requirement of ribavirin (RBV) for certain populations, significant drug to drug 
interactions, limited options for subjects with renal insufficiency, reduced efficacy in 
patients with baseline amino acid variants associated with reduced susceptibility to the 


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HCV nonstructural 5A (NS5A) inhibitors or NS3/NS4A protease inhibitors (PIs), and 
limited options for patients who have failed IFN-free treatment regimens.   
AbbVie has developed two next generation DAAs for use in combination for the 
treatment of HCV infection.  These next generation DAAs are glecaprevir (GLE, formerly 
known as ABT-493), an HCV NS3/4A PI and pibrentasvir (PIB, formerly known as 
ABT-530), an NS5A inhibitor.  Co-formulated GLE/PIB is now an approved treatment for 
infection with all six major HCV genotypes in patients without cirrhosis and with 
compensated cirrhosis.13,14  GLE and PIB each have potent in vitro antiviral activity 
against genotypes 1 through 6,11 and a high genetic barrier to resistance with no or little 
loss of potency against common resistant-associated substitutions.  Additive or synergistic 
in vitro anti-HCV activity has been demonstrated with the combination of GLE and PIB.  
GLE 100 mg and PIB 40 mg are co-formulated into a fixed-dose combination tablet 
(hereafter referred to as GLE/PIB), which provides patients with a convenient once-daily 
(QD), fixed-dose combination treatment regimen of three 100 mg/40 mg tablets QD to 
maximize treatment compliance.  
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data can be found in the Investigator's Brochure.12
GLE/PIB
Overview of GLE/PIB Registrational Program and Supportive Phase 2 Studies
The GLE/PIB registrational program included a broad subject population without 
cirrhosis or with compensated cirrhosis (defined by a Child Pugh A [CPA] score) across 
all genotypes using a single GLE/PIB dose of 300 mg/120 mg QD.  Supportive Phase 2 
studies used the Phase 2 formulation of separate GLE and PIB tablets, with each tablet 
containing 100 mg and 40 mg, respectively.  Treatment arms from these supportive 
Phase 2 studies using the regimen selected for registrational studies (GLE 300 mg plus 
PIB 120 mg) were pooled with arms from the registrational studies for analyses of 
efficacy and safety.  Treatment-naïve (TN) and treatment-experienced (TE) subjects to 
any combination of pegylated IFN (pegIFN), RBV, SOF, NS5A inhibitors, or PIs were 


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allowed in the program.  In addition, studies allowed subjects with human 
immunodeficiency virus (HIV) coinfection (Study M13-590), subjects with chronic 
kidney disease [CKD] Stages 4 and 5, including those on hemodialysis (Study M15-462), 
subjects with compensated cirrhosis (Studies M14-172, M15-462, and M14-868 Part 3) 
and subjects with or without cirrhosis who failed a previous regimen containing an NS5A 
inhibitor and/or an NS3/4A PI (Study M15-410).
A total of 2,376 subjects were randomized or enrolled in the registrational studies or 
supportive Phase 2 studies to take GLE 300 mg QD and PIB 120 mg QD without RBV.  
Of these, 2,369 subjects received at least 1 dose of study drug (Table 1).
Table 1.
Overview of Clinical Studies by Subject Population
Genotype
Clinical Study
Summary of Study Design
TN and TE Subjects Without Cirrhosis
GT1
M13-590
GLE/PIB 300 mg/120 mg QD for 8 (n = 351) or 12 weeks (n = 352)
M14-867
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 34)
GT2
M15-464
GLE/PIB 300 mg/120 mg QD (n = 202) or placebo (n = 100) for 
12 weeks
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 199) or 12 weeks 
(n = 25)
GT3
M13-594
GLE/PIB 300 mg/120 mg QD for 8 (n = 157) or 12 weeks (n = 233) 
or SOF 400 mg + DCV 60 mg QD for 12 weeks (n = 115) (all 
subjects in study were TN)
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 29; TN only), 
12 weeks (n = 76), or 16 weeks (n = 22; TE only)
GT4, 5, 6
M13-583
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 121)
M14-867
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 32)
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 58)
TN and TE Subjects with Cirrhosis
GT1, 2, 4, 5, 6
M14-172
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 146)
GT3
M14-868
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 64; TN only) or 
16 weeks (n = 51; TE only)
Subjects with CKD Stages 4 – 5 With or Without Cirrhosis
GT1 – 6
M15-462
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 104)
NS5A Inhibitor and/or PI-Experienced Subjects With or Without Cirrhosis
GT1, 4
M15-410
GLE/PIB 300 mg/120 mg QD for 12 (n = 66) or 16 weeks (n = 47)


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Table 1.
Overview of Clinical Studies by Subject Population (Continued)
CKD = chronic kidney disease; DCV = daclatasvir; GLE = glecaprevir; GT = genotype; 
NS5A = nonstructural viral protein 5A; PI = protease inhibitor; PIB = pibrentasvir; QD = once daily; SOF = sofosbuvir; 
TE = treatment-experienced; TN = treatment-naïve
Overall Efficacy on the GLE/PIB Registrational Program and Among TN GT 1 - 6-
Infected Subjects with Compensated Cirrhosis
In treatment-naïve (TN) or interferon, pegylated interferon, ribavirin, and/or sofosbuvir 
treatment experienced (TE-PRS) subjects, the pooled overall SVR12 rates with GLE/PIB 
were > 97% across GT1, 2, 4, 5 and 6 regardless of treatment experience, treatment 
duration, including any degree of renal impairment, presence of cirrhosis, or HIV-1 
coinfection (Table 2).  
Among subjects with GT3 infection, the pooled SVR12 rates across durations were 95.2% 
among all subjects, 96.6% among cirrhotic subjects, and 100% among subjects with CKD 
Stages 4 – 5.  The SVR12 rates among subjects previously treated with a PI and/or NS5A 
inhibitor were ≥ 89.0% for GT1 and GT4.


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Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 –
6 (ITT Population, Phase 2 and 3 Analysis Set)
Genotype
TN n/N 
(%) 95% 
CIa
TE-PRS 
n/N (%) 
95% CIa
TN + TE-PRS
TE-NS5A 
and/or PIs 
n/N (%) 
95% CIa
Overall 
n/N (%) 
95% CIa
Alla
Cirrhotic 
n/N (%) 
95% CIb
CKD 4 – 5 
n/N (%) 
95% CIb
Phase 2 and 
3 Analysis 
Set
1604/1640 
(97.8)
97.1, 98.5
602/616 
(97.7)
96.6, 98.9
2206/2256 
(97.8)
97.2, 98.4
274/281 
(97.5)
95.7, 99.3
102/104 
(98.1)
95.4, 100.0
101/113 
(89.4)
83.7, 95.1
2307/2369 
(97.4)
96.7, 98.0
GT1
555/561 
(98.9)
98.1, 99.8
326/328 
(99.4)
98.5, 100.0
881/889 
(99.1)
98.5, 99.7
98/101 
(97.0)
93.7, 100.0
53/55 
(96.4)
91.4, 100.0
97/109 
(89.0)
83.1, 94.9
978/998c 
(98.0)
97.1, 98.8
GT2
365/369 
(98.9)
97.9, 100.0
95/97 
(97.9)
95.1, 100.0
460/466 
(98.7)
97.7, 99.7
35/35 
(100)
100.0, 
100.0
16/16 
(100)
100.0, 
100.0
N/A
460/466 
(98.7)
97.7, 99.7
GT3
499/521 
(95.8)
94.0, 97.5
113/122 
(92.6)
88.0, 97.3
612/643 
(95.2)
93.5, 96.8
112/116 
(96.6)
93.2, 99.9
11/11 (100)
100.0, 
100.0
N/A
612/643 
(95.2)
93.5, 96.8
GT4
119/122 
(97.5)
94.8, 100.0
55/56 
(98.2)
94.7, 100.0
174/178 
(97.8)
95.6, 99.9
20/20 
(100)
100.0, 
100.0
20/20 
(100)
100.0, 
100.0
4/4 (100) 
100.0, 
100.0
178/182 
(97.8)
95.7, 99.9
GT5
26/26 (100)
100.0, 
100.0
6/6 (100)
100.0, 
100.0
32/32 (100)
100.0, 
100.0
2/2 (100)
100.0, 
100.0
1/1 (100)
100.0, 
100.0
N/A
32/32 (100)
100.0, 
100.0
GT6
40/41 
(97.6)
92.8, 100.0
7/7 (100) 
100.0, 
100.0
47/48 
(97.9)
93.8, 100.0
7/7 (100)
100.0, 
100.0
1/1 (100)
100.0, 
100.0
N/A
47/48 
(97.9) 93.8, 
100.0
CI = confidence interval; CKD = chronic kidney disease; GT = genotype; HCV = hepatitis C virus; 
ITT = intention-to-treat; N/A = not applicable; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; 
PRS = regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic 
response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naïve; TE-NS5A and/or 
PI = TE with NS5A inhibitor and/or PI
a.
CI was calculated using a stratum-weighted proportion and variance.
b.
CI was calculated using the normal approximation to the binomial distribution.
c.
Eleven subjects were classified by the central laboratory and treated as GT2 but included here as GT1 due to being 
identified as such by phylogenetic analysis; all 11 subjects achieved SVR12.  
The rate of non-virologic failures in the GLE/PIB registrational program was 1.2% 
(29/2369).


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In the GLE/PIB registrational program, 117 treatment naïve subjects with compensated 
cirrhosis infected with GTs 1, 2, 4, 5, or 6 were treated with GLE/PIB for 12 weeks.  Of 
those, 2 subjects did not achieve SVR12 (one discontinued treatment early and the other 
had missing SVR12 data).  No virologic failure was observed.  Therefore, the SVR12 rate 
in a Per-Protocol population (PP), defined as subjects who receive at least one dose of 
study drug, with the exception of subjects who experience breakthrough, or prematurely 
discontinue treatment prior to Week 8, or have no HCV RNA value in the SVR12 visit 
window or later) was 100%.
In the registrational program, the SVR12 rate (ITT) was 98.5% (64/65) in HCV GT3-
infected, treatment-naïve subjects with compensated cirrhosis treated for 12 weeks.  No 
virologic failure was observed.  Therefore, the PP SVR12 rate in this population was 
100%.
Impact of Baseline Polymorphisms on Treatment Outcome
The association between baseline polymorphisms and treatment outcome in subjects who 
received GLE 300 mg QD with PIB 120 mg QD in the registrational or supportive 
Phase 2 studies was evaluated by conducting an integrated analysis of baseline sequence 
data.  Next-generation sequencing (NGS) was conducted on all baseline samples at 15% 
detection threshold at key amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 
31, 58, 92, and 93 in NS5A. 
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% 
(1/34) of subjects with HCV genotype 1, 2, 3, 4, 5 and 6 infection, respectively.  Baseline 
polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% 
(136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV 
genotype 1, 2, 3, 4, 5, and 6 infection, respectively.
The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1-, 2-, 4-, 5-, or 6-infected subjects.  Baseline polymorphisms in NS3 


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did not have an impact on SVR12 in GT3-infected subjects.  Among baseline 
polymorphisms in NS5A in GT3-infected subjects, Y93H did not have an impact on 
SVR12 rates except in treatment-experienced non-cirrhotic subjects receiving 12 weeks of 
treatment.  A30K in NS5A at baseline was associated with lower SVR12 rates among non-
cirrhotic treatment-naïve subjects receiving 8 weeks of treatment and treatment-
experienced subjects receiving 12 weeks of treatment, but had no impact on SVR12 rates 
in treatment-naïve non-cirrhotic subjects receiving 12 weeks of treatment.  The SVR12
rates in subjects with A30K at baseline were 77.8% (14/18), 25.0% (1/4), and 92.9% 
(13/14) among treatment-naïve subjects receiving 8 weeks, treatment-experienced 
subjects receiving 12 weeks, and treatment-naïve subjects receiving 12 weeks of 
treatment, respectively.  Given the A30K prevalence of 6.3% among GT3-infected 
subjects, the difference in SVR12 attributable to the impact of A30K between the 8 and 
12 weeks treatment duration is < 1%.  Among treatment-experienced non-cirrhotic or 
cirrhotic subjects receiving 16 weeks of treatment, the impact of A30K is unclear due to 
the low prevalence of the polymorphism in this arm of the study.
Integrated Safety Results
The clinical program enrolled a broad HCV population (n = 2,369), including subjects 
with and without cirrhosis, subjects with advanced renal disease, HIV coinfected subjects, 
and subjects who previously failed DAA-based regimens, including NS5A-experienced 
subjects. 
A summary of treatment-emergent adverse events (AEs) from pooled analyses of the 
registrational studies and supportive Phase 2 studies are presented in Table 3.  The 
severity of the underlying renal disease and its associated comorbidities in patients with 
CKD Stages 4 and 5, the frequency and severity of the AEs in subjects enrolled 
Study M15-462 were expected to be higher than in subjects enrolled in the other 
registrational studies.  Therefore, the summary of adverse events reported in Table 3 does 
not include the results of Study M15-462.  


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The adverse events occurring with a frequency ≥ 5.0% of subjects were headache, fatigue, 
nausea and diarrhea (Table 3).  The majority of subjects experienced an AE, which were 
mostly considered to be mild in severity by the investigator (Grade 1).  Rates of AEs that 
were serious, led to premature study drug discontinuation or had a severity Grade ≥ 3 
were low.  Including data from Study M15-462, there were 7 deaths, none of which were 
related to study drug, and the majority occurred several months after the last dose of study 
drug.  Adverse events in subjects without cirrhosis (n = 1,977) were similar in type, 
frequency, and severity compared with subjects with cirrhosis (n = 288).
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related 
Adverse Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade ≥ 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Termd
Headache
410 (18.1)
298 (13.2)
Fatigue
330 (14.6)
259 (11.4)
Nausea
208 (9.2)
172 (7.6)
Diarrhea
146 (6.4)
86 (3.8)
AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse
event
a.
Excludes Study M15-462.
b.
DAAs = GLE, PIB, or GLE/PIB.
c.
Includes nontreatment-emergent deaths.
d.
DAA-related AEs reported for ≥ 5.0% of subjects in the Phase 2 and 3 Analysis Set.


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The frequency and severity of hepatic-related AEs as well as liver chemistry 
abnormalities evaluating potential hepatotoxicity were low across the Phase 2 and 3 
studies.  Liver-related safety results indicated that:
●
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
○
ALT abnormalities in 3 of these 4 subjects were not clinically significant
○
One subject experienced concurrent ALT > 3 × ULN (increased from nadir 
grade) and total bilirubin ≥ 2 × ULN in the context of multiple gallstones 
and was not consistent to have drug-induced liver injury
●
Based on exposure-response analyses, no exposure-dependent ALT increases 
were observed in subjects with ALT abnormalities. 
●
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression.
●
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.  
●
A total of 6 (0.3%) subjects experienced a de novo event of HCC.  In all 
6 subjects, the events were considered related to subject's medical history of 
underlying liver disease and not to GLE/PIB.  
In summary, GLE/PIB demonstrated a favorable safety profile similar across durations of 
8, 12, and 16 weeks.  The regimen was well tolerated across a broad and diverse 
population of subjects, including subjects with cirrhosis, HIV coinfection, and CKD 
Stage 4 or 5. 
Common study drug-related AEs (ADRs) occurring in ≥ 5% of subjects were headache, 
fatigue, nausea.  ADRs were mostly Grade 1 (mild) in severity.  Serious AEs and AEs 
leading to premature study drug discontinuation were rare. 


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There were no hematological or blood chemistry findings of concern or considered likely 
related to treatment.  Unlike other protease inhibitors, no liver-related toxicities and no 
cases consistent with drug-induced liver injury were identified.  
Glecaprevir/Pibrentasvir (GLE/PIB) Viral Dynamic Modeling for Study M16-135
To determine the likelihood of success for Study M16-135, HCV modeling simulations 
were conducted using a viral dynamic model, including dynamics of hepatocytes, infected 
cells, wild type virus and mutants.  In vitro efficacy and resistance data was incorporated.  
Viral load and SVR data from GLE/PIB Phase 2 and 3 studies in non-cirrhotic and 
cirrhotic subjects receiving 8 to 16 week treatment durations were included in the 
modeling.  Additional internal and external efficacy data from treatments with different 
durations (4 to 24 weeks) were also taken into considerations in the modeling and 
simulations. 
For this analysis, HCV virus in treatment-naïve GT 1, 2, 4, 5 or 6 cirrhotic subjects were 
assumed to have comparable responses to the GLE/PIB combination and non-virologic 
failures were not accounted in the simulations.  The clinical trial simulation scenarios for 
an 8-week treatment duration in treatment-naïve subjects with compensated cirrhosis 
resulted in an SVR12 rate of approximately 98% in GT 1-, 2-, 4-, 5-, or 6-infected subjects 
and approximately 92% for GT3-infected subjects.
The objectives of this study are to evaluate the efficacy and safety of 8 weeks of GLE/PIB 
for the treatment of treatment-naïve subjects with chronic HCV GT 1 - 6 infection and 
compensated cirrhosis.
3.1
Differences Statement
The current Phase 3b Study M16-135 is the first study to evaluate the efficacy and safety 
of GLE/PIB in treatment-naïve adult subjects with chronic HCV GT 1 - 6 infection with 
compensated cirrhosis for 8 weeks.  In the registrational program, treatment naïve subjects 
with compensated cirrhosis were treated with GLE/PIB for 12 weeks and the observed 
SVR12 rates were high across genotypes.  


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3.2
Benefits and Risks
This Phase 3b study is a single arm study in which eligible HCV GT 1 - 6 infected 
subjects with compensated cirrhosis will receive GLE/PIB for 8 weeks.  The combination 
of GLE/PIB has been evaluated in six Phase 3 registration studies and three Phase 2b 
supportive studies.  The results of these studies, together with PK modeling based on the 
registrational data, suggest that the likelihood of demonstrating a high SVR12 rate with an 
8 week regimen in subjects with HCV GT 1 - 6 infection with compensated cirrhosis is 
high. 
As demonstrated in the registration studies, the benefits of treatment with GLE/PIB 
include:  pangenotypic antiviral activity, higher genetic barrier to development of drug 
resistance across genotypes compared to first generation HCV protease and NS5A 
inhibitors, no need for RBV, 8 or 12 weeks of treatment, and the convenience of a once 
daily regimen.  In a compensated cirrhotic population at risk for clinical events, a short 
duration DAA regimen with high SVR rates can be a favored option.  The GLE/PIB 
regimen is potent; according to a Phase 2 and 3 analysis, SVR12 rates in treatment naïve 
cirrhotics treated for 12 weeks were 97.2% (69/71) for GT 1 and 100% (46/46) for GT 2, 
4 – 6.  Overall, the SVR12 rate was 98.3% (115/117) for GT 1, 2, 4, 5, or 6.  The SVR12
rate in treatment naïve cirrhotics with GT3 infection treated for 12 weeks was 98.5% 
(64/65).
Risk of hepatic decompensation with jaundice, ascites, encephalopathy and/or variceal 
bleeding are possible, but are likely to occur as a result of the natural history of advanced 
liver disease rather than a DAA class effect.  No safety signals with respect to hepatic 
decompensation were observed on the Phase 2 and 3 studies of GLE/PIB in the 
compensated cirrhotic population.
Based on safety data from the registrational and supportive clinical trials where over 
2369 HCV-infected subjects were treated, the fixed-dose combination of GLE/PIB 
demonstrated a favorable safety profile.  The most frequent GLE/PIB AEs include 
headache, fatigue, nausea and diarrhea these were mostly Grade 1 in severity.  Serious 


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AEs and AEs leading to premature study drug discontinuation were rare.  Adverse events 
that are known, and those that may potentially occur with GLE/PIB are described in the 
informed consent form for this study.  In addition, subjects may experience inconvenience 
or discomfort related to the study visits or study procedures.  Additional safety data for 
each DAA alone and the combination of GLE/PIB are detailed in Section 3.0 and in the 
Investigator's Brochure.12
No significant trends in liver chemistry abnormalities have been observed in 
Phase 2 and 3 studies, including patients with compensated cirrhosis.
The overall rates of virologic failure for the GLE/PIB regimen in Phase 2 and 3 studies 
were low.  With the shortened duration of treatment in this study, higher rates of virologic 
failure may be observed.  In patients who experience virologic failure, amino acid 
substitution(s) in NS3 and/or NS5A conferring resistance to GLE and/or PIB, 
respectively, may emerge.  NS3 substitutions tend to revert back to wild type, while 
NS5A substitutions have been reported to persist for years.  Retreatment of subjects who 
experience virologic failure with the GLE/PIB regimen for 8 weeks will be offered in the 
AbbVie Study M15-942.  
An assessment of the post-treatment relapse rate occurring in this study in the non-GT3 
and in the GT3 population will be performed on a periodic basis in order to minimize 
exposure to a potentially suboptimal duration (see Section 5.4.1.2).
Based on results of Phase 1 pharmacokinetic studies clinically significant DDI's with 
GLE/PIB have been identified.  Monitoring of subjects, with dose adjustment of 
concomitant medications, as well as exclusion of subjects requiring the use of prohibited 
medications is expected to mitigate this risk.  Hepatitis B virus reactivation has been 
reported as a pharmacological class risk for DAAs.  This risk will be mitigated by proper 
screening and surveillance for HBV as described in the protocol. 


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Risks associated with GLE/PIB including the risks of toxicity, virologic failure, and 
development of resistant mutations substitutions (Section 5.6.4.3) appear to be limited and 
manageable based upon the available data.  
Overall, given the potential for achieving SVR12 with 8 weeks of treatment in this 
population of HCV GT 1 - 6 infected subjects with compensated cirrhosis, the risk-benefit 
assessment is considered favorable.
4.0
Study Objective
4.1
Primary Objective
The primary objectives of this study are:
●
To demonstrate the efficacy of the SVR12 rates of 8 weeks of treatment with 
glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of 
treatment with glecaprevir/pibrentasvir in treatment naïve adults with chronic 
HCV infection and compensated cirrhosis.  
●
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in 
treatment naïve adults with chronic HCV infection and compensated cirrhosis.
4.2
Secondary Objectives
The secondary objectives are:
●
To assess the percentage of subjects with on-treatment virologic failure 
(OTVF).
●
To assess the percentage of subjects with post-treatment relapse.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of GLE/PIB in HCV treatment-naïve adult subjects with chronic HCV GT 1 - 6 


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infection and compensated cirrhosis.  The study will initially enroll subjects with HCV 
GT 1, 2, 4, 5 and 6 infection followed by subjects with HCV GT3 infection.  Once 
enrollment of subjects with HCV GT3 infection begins, enrollment of subjects with HCV 
GT 1, 2, 4, 5 or 6 infection will be closed.  
This study will consist of 3 periods as follows:
Screening Period:  Subjects have up to 42 days following the Screening Visit to confirm 
eligibility and enroll into the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg 
once daily (QD) for 8 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, 
and 8.  Study procedures, including assessment of adverse events, vital signs, adherence, 
concomitant medications, HCV RNA, HCV resistance, pharmacokinetic assays, and 
clinical laboratory tests, will be conducted at each visit.
An assessment of the post-treatment relapse rate occurring in this study in the non-GT3 
and in the GT3 population will be performed on a periodic basis in order to minimize 
exposure to a potentially suboptimal duration (see Section 5.4.1.2).  
Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment 
Period will be followed for 24 weeks to monitor safety, HCV RNA levels and to evaluate 
efficacy and the emergence and persistence of resistance associated substitutions. 
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 
following completion of the Treatment Period.  Study procedures to monitor safety, HCV 
RNA, and the emergence and persistence of resistant virus will be conducted during these 
visits.
A study schematic is shown in Figure 1.


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Figure 1.
Study Schematic
The study is designed to enroll approximately 330 subjects (approximately 270 with GT1, 
2, 4, 5, or 6 infection and approximately 60 with GT3 infection) 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.
Analyses will occur after subjects have completed the Post-Treatment Week 12 Visit or 
prematurely discontinued from the study, starting with HCV GT1, 2, 4, 5, and 6-infected 
subjects.
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.  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 will 
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 42 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
A positive Hepatitis B surface antigen (HBsAg);


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●
A quantifiable HBV DNA;
●
A positive HIV test;
●
An exclusionary HCV genotype(s);
●
A positive serum pregnancy test (if female of childbearing potential);
●
Development of decompensated liver disease during the screening period, as 
defined in the Exclusion Criteria.
Otherwise, subjects may be retested or rescreened only once without approval of the 
AbbVie Therapeutic Area Medical Director (TA MD), as follows.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on all analytes of 
any panel that is repeated.  If the retest result(s) are also exclusionary, the subject may not 
be rescreened or retested again. 
Subjects who fail to enroll within the initial 42-day screening period, regardless of the 
reason for falling outside the 42-day screening window, may rescreen only once and must 
be rescreened for all laboratory and eligibility criteria (except for HBV, HIV, HCV 
genotype and subtype, and FibroScan/liver biopsy, which do not need to be retested), not 
just those that were exclusionary. 
For subjects who rescreen or subjects that do not meet the study eligibility criteria upon 
retest/rescreen, the site personnel must contact the IRT and identify the subject as a screen 
failure.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT.  Subjects will be 
administered study drugs at the site on Study Day 1, with dosing instructions.
Study visits and procedures during the Treatment Period are detailed in Appendix C.  
Safety and tolerability will be assessed throughout the study.  Laboratory testing will 


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include chemistry and hematology as specified in Table 5.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3.1.  Blood samples for optional pharmacogenetic analysis will be collected as 
detailed in Appendix C.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all the study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure that they do not run 
out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
HCV virologic failure criteria will be evaluated and applied by the investigator as detailed 
in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.4.1.
5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug, and either completed or 
prematurely discontinued treatment will be monitored in the Post-Treatment Period for 
24 weeks following the last dose of study drug for safety, HCV RNA, and the emergence 
and persistence of HCV resistance-associated viral substitutions.  The Post-Treatment 
Period will begin the day following the last dose of study drug.  Study visits during the 
Post-Treatment period are detailed in Appendix D and Section 5.3.1.1. 
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a Post-Treatment discontinuation visit as outlined in Appendix D.
5.2
Selection of Study Population
The study population consists of treatment-naïve male and female adults aged 18 years or 
older with chronic HCV GT 1 - 6 infection, with compensated cirrhosis.  Subjects who 


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meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
enrollment into the study.
5.2.1
Inclusion Criteria
1.
Male or female, at least 18 years of age at time of Screening.
2.
If female, subject must be either: 
●
Postmenopausal, defined as:
○
Age > 55 years with no menses for 12 or more months without an 
alternative medical cause.
○
Age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
●
Women of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at Study Day 1 
through at least 30 days after stopping study drug.  
3.
WOCBP must have a negative serum pregnancy test result at Screening, and a 
negative urine pregnancy test at Study Day 1.
Women of non-childbearing potential (either postmenopausal or permanently 
surgically sterile (as defined in the Inclusion Criteria) are not required to do 
pregnancy testing.
4.
Screening central laboratory result indicating HCV GT1 - 6-infection. 
5.
Subject has positive plasma HCV antibody and HCV RNA viral load 
≥1000 IU/mL at Screening Visit. 


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6.
Subject must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication). 
7.
Subject must be documented as cirrhotic, as specified in Section 5.3.1.1, with a 
Child-Pugh score of ≤ 6.
8.
Subject must have absence of hepatocellular carcinoma (HCC) as indicated by a 
negative ultrasound, computed tomography (CT) scan or magnetic resonance 
imaging (MRI) within 3 months prior to Screening or a negative ultrasound at 
Screening.  Subjects who have an ultrasound with results suspicious of HCC 
followed by a subsequent negative CT or MRI of the liver will be eligible for the 
study.
9.
Subject 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.
10.
Subject must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
Rationale for Inclusion Criteria
1, 4 – 8
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation
2, 3
The impact of GLE and PIB on human pregnancies has not been 
established.  However, assessment of the completed nonclinical 
reproductive toxicology studies indicates that there is no drug-related 
effect on teratogenicity/fetotoxicity.  In addition, the compounds are 
non-genotoxic
9, 10
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:


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1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
2.
HCV genotype performed by the central laboratory during screening indicating co-
infection with more than one HCV genotype.
3.
Current HBV or HIV infection on screening tests, defined as:
●
A positive HBsAg, or;
●
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative 
HBsAg and Anti HBs), or;
●
A positive anti human immunodeficiency virus antibody (HIV Ab).
4.
Requirement for and inability to safely discontinue the medications or supplements 
listed in Table 4 at least 14 days or 10 half-lives (whichever is longer) prior to the 
first dose of any study drug.
5.
Clinically significant abnormalities or co-morbidities, or recent (within 1 year prior 
to study drug administration) alcohol or drug abuse that make the subject an 
unsuitable candidate for this study in the opinion of the investigator. 
6.
Any current or historical clinical evidence of decompensated cirrhosis, including 
any current or past evidence of Child-Pugh B or C classification, hepatic 
encephalopathy or variceal bleeding, radiographic evidence of small ascites, or 
empiric use of lactulose/rifaximin for neurologic indications.  The use of beta 
blockers is not exclusionary.
7.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Alanine aminotransferase (ALT) > 10 × ULN
●
Aspartate aminotransferase  (AST) > 10 × ULN
●
Total Bililirubin > 3.0 mg/dL
●
Calculated creatinine clearance (CrCl, Cockcroft-Gault method) < 50 mL/min
●
Albumin < 2.8 mg/dL
●
Hemoglobin < 10 g/dL 


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●
Platelets < 50,000 cells/mm3
8.
Receipt of any investigational or commercially available anti-HCV agents, 
including direct acting antivirals (e.g., interferon, ribavirin, sofosbuvir, telaprevir, 
boceprevir, simeprevir, paritaprevir, grazoprevir, voxilaprevir daclatasvir, 
ledipasvir, ombitasvir, elbasvir, velpatasvir, or dasabuvir).
9.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
10.
Subject who cannot participate in the study per local law.
11.
History of solid organ transplantation, unless the implanted organ has since been 
removed, or is non-functional, and subject is no longer on immunosuppressive 
medication.  If the organ is non-functional, the subject must be clinically stable off 
of immunosuppressive medication for a minimum of 6 months prior to screening.
12.
History of suspected or confirmed hepatocellular carcinoma.
Rationale for Exclusion Criteria
1 – 4, 6 – 7, 9 – 12
In order to ensure safety of the subjects throughout the study
5, 8
In order to avoid bias for the evaluation of efficacy and safety, 
including concomitant use of other medications
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
the consent through the Treatment Period and 30 days after the last dose of study drugs, 
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 taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in EDC. 
The AbbVie Primary Therapeutic Area Medical Director (TA MD) should be contacted if 
there are any questions regarding concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
Subjects must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication).
5.2.3.2
Concomitant Therapy
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions.  
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drugs, if applicable.
5.2.3.3
Prohibited Therapy
Medications or supplements prohibited to be administered with GLE/PIB are listed in 
Table 4.  For subjects in the study in countries where GLE/PIB has received marketing 
authorization, any medications in the local label that are contraindicated to be 
administered with GLE/PIB are also considered to be prohibited medications.  Subjects 
must be able to safely discontinue any prohibited medications or supplements at least 
14 days or 10 half-lives (whichever is longer) prior to the first dose of GLE/PIB and not 
use these during the entire Treatment Period and for 14 days following discontinuation of 


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study drug.  The Informed Consent Form must be signed and dated prior to discontinuing 
any prohibited medications or supplements.
Table 4.
Prohibited Medications and Supplements
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Tipranavir/r, atazanavir, efavirenz
Ethinyl estradiol
Dabigatran
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drug.  After signing the consent form, subjects receiving these statins should either (a) switch to 
pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug 
or (b) may interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of study drug and until 14 days after the last dose of study drug, based 
on investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to either 
1) reduce the pravastatin or rosuvastatin dose in accordance with the GLE/PIB approved local product label (if 
approved in the country); or 2) reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD 
when taking with the study drug if GLE/PIB is not yet approved in the respective location.
Contraceptives and/or hormonal replacement therapies containing only progestins (such as 
those containing norethindrone, desogestrel, or levonorgestrel) or those containing 
progestins with non-ethinyl estradiol estrogens (e.g., esterified or conjugated) may be 
used with GLE/PIB at the discretion of the Investigator.
5.2.4
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of each) OR a Women of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.
●
Progestogen-only hormonal contraception (oral, injectable, implantable), 
initiated at least 1 month prior to Study Day 1.


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●
Bilateral tubal occlusion/ligation (if via hysteroscopy [i.e., Essure], provided 
that a hysterosalpingogram confirms success of the procedure)
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.
●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
For male study subjects, no contraception is required.  
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C and Appendix D.
5.3.1.1
Study Procedures
Informed Consent
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.


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Medical History 
A complete medical history, including history of tobacco, alcohol and drug use, will be 
taken from each subject at Screening Visit.  The subject's medical history will be updated 
at the Study Day 1 Visit.  This update medical history will serve as the baseline for 
clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 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.
Height will be measured only at Screening.  The subject will not wear shoes. 
Vital Signs and Weight
Body temperature, blood pressure, pulse, and body weight will be measured at each study 
visit as specified in Appendix C and Appendix D.  Blood pressure and pulse rate should 
be measured after the subject has been sitting for at least 3 minutes.  The subject should 
wear lightweight clothing and no shoes during weighing.  The vital signs performed on 
Day 1 of the Treatment Period will serve as the baseline for clinical assessment.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at the visits indicated in Appendix C.  The ECG 
should be performed prior to blood collection.
The ECG 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 


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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.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 5
at the visits indicated in Appendix C and Appendix D.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast prior to study drug intake (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 until the blood sample is collected in the morning and 
thereafter take their study medications with food.  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 Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug.  Blood samples should still be drawn if the subject did not fast 
for at least 8 hours.  Fasting or non-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.


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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.  Samples may be sent to the following addresses:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA (For sites in North America)
Covance
7 rue Moise-Marcinhes
1217 Geneva
Meyrin Switzerland
(For sites in Europe)
Covance (Asia) Pte Ltd
1 International Business Park
No. 01-01 The Synergy
Singapore 609917
(For sites in Asia Pacific)


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Table 5.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other 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)
Reticulocyte count 
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Creatinine clearance (Cockcroft-
Gault calculation)
eGFR (MDRD method)
Total bilirubina,b
Direct and indirect bilirubin
Alanine aminotransferase 
(ALT)b
Aspartate aminotransferase
(AST) 
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Cholesterol
Total protein
Glucose
Triglycerides
Albumina
Chloride
Bicarbonate
Magnesium 
Gamma-glutamyl transferase 
(GGT)b
Anti-HCV Abc
HIV Abc
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG)d
FSH (females only)
HCV RNA 
Hepatitis B Panel (Anti-HBc 
Total, Anti-HBs and 
HBsAg)e
Anti-HAV IgMf
Anti_ HAV Totalf
Anti-HEV IgGf
Anti-HEV IgMf
HEV RNAf
Anti-HBc IgMf
HBV DNAg
IL28Bh
HCV genotype and subtypec
Pharmacogenetic sample 
(optional)
Alpha2-macroglobulinb
Haptoglobinb
Apolipoprotein A1b
Urine Drug/Alcohol Screenc
Opiates 
Barbiturates
Amphetamines
Cocaine
Benzodiazepines 
Phencyclidine
Propoxyphene
Alcohol
a.
Also a component of Child-Pugh Assessment.
b.
Also a component of FibroTest.
c.
Performed only at Screening.
d.
Required only for females of childbearing potential.
e.
Performed at Screening for all subjects and also performed for management of transaminase elevation 
(Section 6.1.7.1).
f.
Performed for management of transaminase elevation (Section 6.1.7.1).
g.
Performed at Screening for subjects who have occult HBV infection (positive Anti-HBcAg with negative HBsAg 
and Anti-HBs) and also performed for management of transaminase elevation (Section 6.1.7.1).
h.
Performed only at Baseline.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:


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●
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 6.1.7.
Pregnancy Testing
●
WOCBP must have a negative serum pregnancy test result at Screening, and a 
negative urine pregnancy test at Study Day 1.
●
If urine pregnancy test is positive at any time, a serum pregnancy test should 
be performed.
●
Monthly pregnancy testing should be performed during treatment, including at 
the last dose and until 30 days of last study drug dose, as indicated in 
Appendix C and Appendix D. 
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in the inclusion criteria) at Screening do not 
require pregnancy testing.
Concomitant Medication Assessment
Please refer to Section 5.2.3.
Hepatitis B and C Virus and HIV Screen
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab 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 


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necessary.  The HIV results will not be reported by the central laboratory to the clinical 
database.
Urine Screens for Drugs of Abuse and Alcohol
Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse 
and alcohol.  The panel for drugs of abuse will minimally include the drugs listed in 
Table 5.  The results of these tests will be available to the Investigator to help determine 
the suitability of the subject for participation in this study.   
These analyses will be performed by the certified central laboratory chosen for the study.
Liver Diagnostic Testing
Subject must be documented as having cirrhosis at any time previous to or at Screening, 
by meeting one of the following criteria:
●
Histologic diagnosis of cirrhosis on a liver biopsy e.g., a METAVIR, Batts 
Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3 or Ishak 
fibrosis score of > 4; or 
●
A screening FibroTest score of ≥ 0.75 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) > 2;
○
Subjects with discordant FibroTest and APRI results (e.g., FibroTest 
≥0.75, but APRI ≤ 2) must have a qualifying FibroScan® or liver biopsy
●
FibroScan score ≥ 14.6 kPa.
The result of the liver biopsy supersedes the results of FibroScan and FibroTest/APRI and 
result of FibroScan supersedes the results of FibroTest/APRI.  At Screening, it is 
recommended that subjects should otherwise meet all other inclusion criteria and none of 
the exclusion criteria before undergoing a liver biopsy.
FibroTest will also be conducted at Day 1 and PT Week 12 and 24 for all subjects.


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Child-Pugh Score and Category
All subjects will have Child-Pugh scores assessed.  The Child-Pugh score uses 
five clinical measures of liver disease (3 laboratory parameters and 2 clinical assessments) 
as shown in Table 6.  Child-Pugh score will be determined at the visits indicated in 
Appendix C and Appendix D.
Table 6.
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)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points.
*
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 decompensation, as defined in the Exclusion Criteria, 
will be performed in all subjects at Study Day 1 prior to dosing, to confirm that the 
subject has not progressed to hepatic decompensation during Screening.  


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Hepatocellular Carcinoma Screening Liver Ultrasound
Hepatocellular carcinoma (HCC) screening will be required as a protocol-specified study 
procedure only at the Screening Study Visit and at the last Post-Treatment Study Visit, as 
indicated in Appendix C and Appendix D, for all enrolled subjects.  Between those visits, 
HCC screening should be performed according to standard of care.
At the Screening Study Visit and at the last Post-Treatment Study Visit, subjects will be 
required to perform a liver ultrasound to screen for HCC, unless the subject has a 
historical liver ultrasound (US), CT or MRI performed for HCC screening within 
3 months prior to those visits, in which case the result of the historical US, CT or MRI 
will be used as the result for the Study Visit assessment.  A positive ultrasound result 
suspicious of HCC will be confirmed with CT scan or MRI.  Alternate methods of 
screening for HCC (i.e., MRI or CT) at a study visit should be discussed with the study 
designated physician.
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments (where allowed per local 
regulatory guidelines) on the study visits specified in Appendix C and Appendix D.  
Subjects should 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 any of the instruments may have site 
personnel read the questionnaires to them.  Site personnel should encourage completion of 
each instrument at all specified visits and should ensure that a response is entered for all 
items.
Treatment Satisfaction Questionnaire – Medication (TSQM)
Subjects will complete the TSQM questionnaire at the designated study visits listed 
in Appendix C.  The TSQM is a 14-item instrument and includes assessments of 
satisfaction with a medication's effectiveness (Effectiveness, three items), lack of 


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side effects (Side Effects; five items), convenience (three items) and the subject's 
global satisfaction (Global Satisfaction; three items). 
The subject should complete the questionnaire before site personnel perform any 
clinic assessments and before any interaction with the site personnel has occurred 
to avoid biasing the subject's response.  TSQM scores range from 0 – 100 with 
higher scores indicating better satisfaction.  The TSQM should require 
approximately 5 minutes to complete.
Short Form 36 – Version 2 Health Survey
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use broad variety of health conditions and is the standard in literature for 
HCV.  The SF-36v2 instrument comprises 36 total items (questions) targeting a 
subject's functional health and well-being in 8 domains (physical functioning, role 
physical, bodily pain, general health, vitality, social functioning, role emotional and 
mental health).  Domain scores are also aggregated into a Physical Component 
Summary score and a Mental Component Summary score.  Higher SF-36v2 scores 
indicate a better state of health.  The SF-36v2 should require approximately 
10 minutes to complete.
Fatigue Severity Scale (FSS)
The FSS measures the impact of fatigue over the past week on specific types of 
functioning (e.g., motivation, exercise, physical functioning, carrying out duties, 
interfering with work, family, or social life).  The survey consists of 9 questions 
using a 7-point Likert scale.  A total score is calculated as the average of the 
individual item responses.  The scale's psychometric properties have been 
confirmed in chronic hepatitis C and other diseases.  The FSS should require 
approximately 5 minutes to complete.
PRO instruments should be consistently presented prior to any discussion of adverse 
events or any review of laboratory findings, including HCV RNA levels at each visit 


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where PROs are required throughout the study and in the following order:  the TSQM 
(when applicable), the SF-36v2 and FSS.  The Day 1 SF-36v2 and FSS questionnaires 
should be completed prior to drug administration on Day 1.
Enrollment and Assignment of Subject Numbers
All Screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet all the Inclusion Criteria and none of the Exclusion Criteria at Screening will 
proceed to enrollment via the IRT system on Study Day 1.
Subject numbers will be unique 6-digit numbers and will begin with 100001 with the 
first three digits representing the investigative site, and the last three digits representing 
the subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  Subject will be enrolled on Study Day 1 as described in Section 5.5.3.
Study Drug Compliance for Kits
Individual bottles of GLE/PIB will be provided for subject dosing to the site.  Each 
subject will have compliance documented by the site in the subject's source notes for 
GLE/PIB.  At each Study Drug Accountability Visit in Appendix C the overall number of 
tablets of GLE/PIB remaining in each bottle will be recorded and entered in the IRT 
system along with the date of reconciliation.
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subtype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
sample, its genotype and subtype will be determined by a Sanger sequencing assay of a 
region of the NS5B gene by the central laboratory.


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
Appendix D.  Plasma HCV RNA levels will be determined for each sample collected by 
the central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV 
Quantitative Test, v2.0.  The lower limit of detection (LLOD) and lower limit of 
quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Day 1 
and at the study visits indicated in Appendix C and Appendix D.  Specific instructions for 
preparation and storage of HCV RNA and HCV resistance samples will be provided by 
the central laboratory, AbbVie, or its designee.
Archive Serum and Plasma Samples
Archive serum and plasma samples will be collected at the study visits, indicated in 
Appendix C and Appendix D.  Archive samples are being collected for possible additional 
analyses, including but not limited to, study drug or metabolite measurements, HCV RNA 
levels, safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and 
other possible predictors of response, as determined by AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.
Study Drug Dosing Card
Subjects will be provided with self-administration instructions and study drug dosing 
cards to record the exact date, time (record to the nearest minute) and number of tablets of 
study drug administration (GLE/PIB) for the last 2 doses taken prior to the scheduled 
pharmacokinetic sample collection during the Treatment Period.


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The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes and the 
eCRF.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
●
The Investigator or designee should make sure the subject is given the dosing 
card at the visits listed in Appendix C.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.
5.3.1.2
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples
Specific instructions for collection, storage and shipment of pharmacogenetic samples will 
be provided by the central laboratory, AbbVie, or its designee.
IL28B Sample
One (required) whole blood sample for DNA isolation will be collected from each subject 
at Study Day 1 for Interleukin 28B (IL28B) pharmacogenetic analysis.  If the IL28B 
pharmacogenetic sample is not collected on Day 1, it may be collected at any other visit 
during the study.  This sample will not be used for any testing other than IL28B 
genotypes.
Optional Samples for Pharmacogenetic Exploratory Research
Optional whole blood samples for DNA and RNA isolation will be collected on Day 1, 
EOT Week 8 (or EOT Week 12 if extended for treatment extension criteria), and PT 
Week 12 from each subject who consents to provide samples for exploratory research.


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AbbVie (or people or companies working with AbbVie) will store the optional 
pharmacogenetic exploratory research samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
GLE/PIB (or drugs of this class) or this disease and related conditions continues, but for 
no longer than 20 years after study completion.  The procedure for obtaining and 
documenting informed consent for exploratory research samples is discussed in 
Section 9.3.
5.3.1.3
Meals and Dietary Requirements
Study drug (GLE/PIB) tablets should be dosed together and taken with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of GLE and PIB will be collected by 
venipuncture at each study visit indicated below and in Appendix C.
●
At all Treatment-Period visits, except for Study Day 1:  a single sample (3 mL) 
will be collected without regard to the time of dosing.  The date and time of 
blood sample collection and the two previous doses of the study drug will be 
recorded to the nearest minute in the source documents.  Additionally, the date 
and time of the two previous doses of the study drug will be recorded to the 
nearest minute on the eCRF.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of plasma samples for the pharmacokinetic assays of GLE, and PIB will be 
provided by the central laboratory, the Sponsor, or its designee.


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5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of GLE, PIB, and archive 
samples will be packed in dry ice sufficient to last during transport, and transferred from 
the study site to the central laboratory.
The central laboratory will then ship the GLE, and PIB samples to the reference 
laboratories following separately provided instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of GLE and PIB will be determined using a validated method by 
the Bioanalysis Department at AbbVie.  Plasma concentrations of possible metabolites of 
any analytes listed above may also be determined using either validated or non-validated 
methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Screening through 24 weeks after completion or discontinuation of treatment.
5.3.3.1
Primary Variables
The primary efficacy variable is the percentage of subjects achieving SVR12 (HCV RNA 
< LLOQ 12 weeks after the last actual dose of study drug).  
5.3.3.2
Secondary Variable
The secondary efficacy variables are:
●
The percentage of subjects with OTVF.
●
The percentage of subjects with post-treatment relapse.


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5.3.3.3
HCV Resistance Variables
For all subjects receiving study drug, baseline polymorphisms at signature resistance-
associated amino acid positions identified by next generation sequencing (NGS) will be 
compared to the appropriate prototypic reference sequence.
The following resistance information will be analyzed for subjects receiving study drug 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the corresponding baseline sequence, 2) the amino 
acid substitutions in available post-baseline samples at signature resistance-associated 
positions identified by NGS and comparison to the appropriate prototypic reference 
sequence, and 3) the persistence of viral substitutions by NGS.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, ECG, and laboratory tests assessments.
5.3.5
Pharmacokinetic Variables
Plasma concentration of glecaprevir and pibrentasvir will be tabulated for each subject.  
Plasma concentrations of glecaprevir and pibrentasvir will be summarized based on last 
dosing time, sampling time and time since last dose.  Summary statistics will be computed 
for glecaprevir and pibrentasvir plasma concentrations binned by time since last dose.  
Values for the pharmacokinetic parameters of GLE and PIB, including apparent oral 
clearance (CL/F) and apparent volume of distribution (V/F) will be estimated using 
population pharmacokinetic modeling procedures if population pharmacokinetic analysis 
is conducted.  Additional parameters may be calculated if useful in the interpretation of 
the data.


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5.3.6
Pharmacogenetic Exploratory Research Variables
IL28B status will be determined for each subject and analyzed as a factor contributing to 
the subject's response to study treatment.  These IL28B GT results may be analyzed as 
part of a multi-study assessment of IL28B and response to study drug or drugs of a similar 
class.  The results may also be used for the development of diagnostic tests related to 
IL28B and study treatment, or drugs of a similar class.  The results of additional 
pharmacogenetic IL28B analyses may not be reported with the clinical study report.  
Optional pharmacogenetic samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to, nucleic acids, proteins, lipids, or metabolites.  The samples may be 
analyzed as part of a multi-study assessment of factors influencing the subjects' response 
to the study drug (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods, or technologies.  The results 
from these analyses are exploratory in nature, may not be included with the study report, 
and may be performed by a non-GLP laboratory.
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, 
the procedures outlined for the applicable Premature D/C Visit should be completed as 
defined in Appendix C and Appendix D.  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 


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investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  The last dose of any study drug and reason for discontinuation 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 24 weeks for HCV RNA 
and the emergence and persistence of resistant viral substitutions.
If a subject is discontinued from study drug or in 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 
may be continued at the Principal Investigator's discretion after discussion with the 
subject, if the benefit of continuing study drug is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  If a 
subject is discontinued, subject will be monitored for SVR in the Post-Treatment Period 
as described in Section 5.1.3.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of OTVF, for the purposes of subject 
management, leading to discontinuation of study drug:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment; or
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.


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Confirmatory testing should be completed as soon as possible and the subject should 
remain on study drug treatment until the OTVF criterion has been confirmed.  Subjects 
with confirmed OTVF will be discontinued from study drug and will continue to be 
followed in the Post-Treatment Period for the emergence and persistence of resistant viral 
substitutions until 24 weeks post-treatment.
Post-treatment relapse is defined as confirmed HCV RNA ≥ LLOQ (defined as 
2 consecutive HCV RNA measurements ≥LLOQ) between end of treatment and 
12 weeks after the last dose of study drug (up to and including the SVR12 assessment time 
point), for a subject who completed treatment (defined as study drug duration ≥ 52 days 
for subjects assigned to 8 weeks of treatment) and had HCV RNA < LLOQ at final 
treatment visit, excluding cases of reinfection.
Subjects who completed treatment with HCV RNA < LLOQ at the end of treatment who 
experience potential virologic failure (HCV RNA ≥ LLOQ) in the post-treatment period 
should have confirmatory testing completed as soon as possible to determine if the subject 
relapsed.
5.4.1.2
Treatment Extension Criteria
Because subjects with GT 1, 2, 4, 5 or 6 infection will be enrolled first, separate treatment 
extension criteria will apply to subjects with GT 1, 2, 4, 5 or 6 infection versus subjects 
with GT3 infection, as described below.  However, if treatment is extended for all or a 
particular subgroup of subjects with GT 1, 2, 4, 5 or 6 infection, then enrollment of 
subjects with GT3 infection will be terminated and all GT3-infected subjects who are on 
treatment or have completed treatment within the previous 7 days will have their 
treatment extended to 12 weeks.
In subjects with GT 1, 2, 4, 5, or 6 infection, an efficacy assessment will evaluate the 
post-treatment relapse rate when the first 30 subjects reach Post-Treatment Week 4 and 
will be done periodically thereafter.  If more than 10% of subjects experience post-
treatment relapse, an analysis will be conducted to determine if extension of treatment to 


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12 weeks is needed for all GT 1, 2, 4, 5, and 6-infected subjects or for a particular 
subgroup of GT 1, 2, 4, 5, and 6-infected subjects who are on treatment or have completed 
treatment within the previous 7 days.
The enrollment of additional GT 1, 2, 4, 5, or 6-infected subjects in this study will be 
terminated if extension of treatment is needed for all GT 1, 2, 4, 5, or 6-infected subjects.  
If the extension is needed for a particular subgroup of GT 1, 2, 4, 5, or 6-infected subjects, 
then the enrollment will be terminated for this particular subgroup but other subgroups 
will continue to be allowed to enroll in the study with 8 weeks treatment duration. 
In subjects with GT3 infection, an efficacy assessment will evaluate the post-treatment 
relapse rate after the first 20 subjects reach Post-Treatment Week 4 and will be done 
periodically thereafter.  If more than 10% of subjects experience post-treatment relapse, 
an analysis will be conducted to determine if extension of treatment to 12 weeks is needed 
for all GT3-infected subjects or for a particular subgroup of GT3-infected subjects who 
are on treatment or have completed treatment within the previous 7 days.
The enrollment of additional GT3-infected subjects in this study will be terminated if 
extension of treatment is needed for all GT3-infected subjects.  If the extension is needed 
for a particular subgroup of GT3-infected subjects, then the enrollment will be terminated 
for this particular subgroup but other subgroups will continue to be allowed to enroll in 
the study with 8 weeks treatment duration.  Retreatment of subjects who experience 
virologic failure with the GLE/PIB regimen for 8 weeks will be offered retreatment in the 
AbbVie Study M15-942.
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 


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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
GLE/PIB will be dispensed in the form of film-coated co-formulated tablets at the visits 
listed in Appendix C.  Subjects will be instructed to take study drug at the same time 
every day with food.  Please refer to Section 5.3.1.1 and Section 5.3.2.1 for more details.
GLE/PIB will be provided by AbbVie as 100 mg/40 mg film-coated tablets.  GLE/PIB 
will be taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) 
QD and with food.
Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  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.  The site will also contact the IRT 
system to provide study drug return information for each kit at the visits specified in 
Appendix C.  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 the discontinuation visit 
date information and study drug return information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the HCV virologic 
failure criteria defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drug to be used in this study is presented in Table 7.


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Table 7.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode
Dosage Form
Strength
Glecaprevir/Pibrentasvir
AbbVie
Oral
Film-coated tablet
100 mg/40 mg
5.5.2.1
Packaging and Labeling
All study drug will be supplied in bottles.
Each bottle will be labeled as required per country requirements.
The labels must remain affixed to the bottles.  All blank spaces should be completed by 
site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drugs
Study Drug
Storage Conditions
Glecaprevir/Pibrentasvir bottles
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 AbbVie (or designee).
5.5.3
Method of Assigning Subjects to Treatment Groups
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.


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Contact information and user guidelines for IRT use will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.
All tablets of GLE/PIB will be dosed together (three tablets once daily).  All subjects 
should take all doses of study medications with food.
5.5.5
Blinding
This is an open-label study.
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.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing compliance with the treatment regimen with regard to HCV virologic response 
and potential development of resistance due to poor compliance.
At each study visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial, or empty) for the site to review adherence.  At 
Study Drug Accountability visits denoted in Appendix C, study site personnel will assess 
subject compliance by inspecting the contents of the bottles and record the status of each 
one, as well as the exact number of remaining tablets of GLE/PIB in IRT.  Treatment 
compliance will be based on the number of tablets dispensed, as recorded in IRT, and the 
number of remaining tablets.  If poor compliance is noted, the subject should be counseled 
and this should be documented in the subject's source.


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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, kit 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.  
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 of 
GLE/PIB 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.  
The study drug start date 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 each 
bottle, number 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 drug) will be returned to AbbVie (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 current study (Study M16-135) is a multicenter, single-arm, open-label, Phase 3b 
study evaluating the efficacy and safety of the co-formulated combination regimen of 
GLE 300 mg and PIB 120 mg QD administered for 8 weeks in treatment-naïve subjects 
with chronic HCV GT 1 - 6 infection and compensated cirrhosis.  
The 12-week regimen of GLE/PIB was studied in adults with chronic HCV GT 1, 2, 4, 5, 
or 6 infection and compensated cirrhosis in Study M14-172 and studied in adults with 
chronic HCV GT3 infection and compensated cirrhosis in Study M14-868.  Other Phase 3 
studies also enrolled a few cirrhotic subjects.  The integrated analysis of the registrational 
studies will serve as the historical control and reference point for the design of the current 
trial. 
In the registrational program, 117 treatment naïve subjects with compensated cirrhosis 
infected with GTs 1, 2, 4, 5, or 6 were treated with GLE/PIB for a 12 weeks.  Of those, 
2 subjects did not achieve SVR12 (one discontinued treatment early and the other had 
missing SVR12 data).  No virologic failure was observed.  Hence, the historical SVR12 rate 
based on PP population is 100% for GT1, 2, 4, 5, and 6-infected subjects.  Similarly, the 
historical SVR12 rate based on a PP population is 100% for GT1-6-infected subjects, as 
65 treatment naïve subjects with compensated cirrhosis infected with GT3 were treated 
with GLE/PIB for 12 weeks. Of those, 1 subject did not achieve SVR12 due to missing 
SVR12 data.  No virologic failure was observed.
The observed rate of non-virologic failure in the overall GLE/PIB registrational program 
was 1.2% (29/2369).  For this reason, this study assumes that the historical SVR12 rate for 
the ITT population for GT1, 2, 4, 5, and 6-infected and for GT1-6-infected subjects will 
be 99% (assuming 1% of non-virologic failures). The observed SVR rates for the 
GLE/PIB 12 weeks duration in the Phase 2/3 development program is very high (> 97%) 
for the treatment naïve GT 1, 2, 3, 4, 5, or 6-infected cirrhotic subjects.  Given such a high 
SVR rate, an active control arm does not provide value in establishing the efficacy of the 


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new regimen.  That is, the efficacy of the new regimen can be established via an absolute 
criterion (comparison to a threshold) rather than a relative criterion (non-inferiority to an 
active control).  Hence, the observed SVR rate from Phase 2/3 program will be used as 
historical control to provide a comparator for assessment of efficacy for the 8-week arm in 
this study for the treatment naïve cirrhotic patients. 
A threshold for the primary and key secondary efficacy analyses of the 8 weeks GLE/PIB 
regimen to the historical control is determined by subtracting a margin of 6% from the 
historical SVR12 rate of 100% or 99% (for PP or ITT population, respectively) for 
GLE/PIB for 12 weeks. 
A margin of 6% is selected to be used in this study to ensure a minimal loss of efficacy of 
the 8-week arm relative to the historical SVR12 rate for 12-week arm, and is in alignment 
with the GLE/PIB registrational program.
Thus, to establish efficacy of 8 weeks GLE/PIB to the 12 weeks GLE/PIB in treatment 
naïve cirrhotic subjects, the lower bound of the 95% CI for the SVR12 rate in the 8-week 
arm must exceed 94% or 93% for the PP and ITT populations, respectively.
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.
5.6.3
Suitability of Subject Population
HCV GT3-infected patients are known to be a more difficult to treat population for DAA-
based regimens.  Therefore, subjects infected with HCV GT1, 2, 4, 5 and 6 were enrolled 
first in this trial, while subjects infected with HCV GT3 were initially excluded.  The 
protocol was later amended to include GT3-infected subjects based on the following 
registrational clinical data:


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●
SVR12 rate (ITT) of 98.5% (64/65) in treatment-naïve GT3-infected subjects 
with compensated cirrhosis treated for 12 weeks of GLE/PIB, with no 
virologic failures observed; the PP SVR12 rate was 100% (64/64).
●
SVR12 rate (ITT) of 95.2% (177/186) and 95.6% (258/270) in treatment-naïve 
GT3-infected subjects without cirrhosis treated for 8 and 12 weeks of 
GLE/PIB, respectively; PP SVR12 rates were 97.3% (177/182) and 98.9% 
(258/261) for 8 and 12 weeks of GLE/PIB, respectively.15
●
GLE/PIB for 8 weeks in treatment-naïve GT3-infected subjects without 
cirrhosis was determined to be non-inferior to GLE/PIB for 12 weeks in 
Study M13-594 (ENDURANCE-3).16
This subject population will include treatment-naïve subjects only.  While high SVR12
rates with 8 weeks of GLE/PIB are expected, the ultrashort nature of this study risks an 
increase of post-treatment relapse or EOT failure in treatment-experienced patients. 
This study will exclude subjects with HIV/HCV coinfection, as this sub-population is 
currently being evaluated in Study M14-730 (EXPEDITION-2).17
Child Pugh B and C patients are also excluded from Study M16-135, since GLE/PIB has 
not been studied in this patient population. 
The pharmacokinetics of GLE/PIB has been evaluated in subjects with hepatic 
impairment.  In non-HCV infected subjects with mild hepatic impairment, exposures were 
higher for GLE (increase of 33%) compared to healthy subjects (Study M13-604).  GLE 
exposures are higher (increase to ~2-fold) in HCV-infected subjects with compensated 
cirrhosis than in subjects without cirrhosis (R&D/16/0234).  PIB exposures were 
comparable across populations.  No GLE/PIB dose adjustment is recommended in 
patients with compensated cirrhosis (Module 2, Section 2.7.2.3.4.4).
HCV-infected subjects with chronic HCV infection have moderate stable elevations of 
AST and ALT levels and are considered representative of the population who will receive 
anti-HCV therapy.  The age range selected for this study, 18 years of age or older, is also 
intended to be representative of the target population.  Similarly, a substantial portion of 


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the HCV infected population has a relatively high BMI, and given the acceptable safety 
and pharmacokinetic profiles of GLE and PIB in previous studies, this protocol will enroll 
subjects without a BMI restriction.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The doses of 300 mg GLE and 120 mg PIB were selected to optimize efficacy of the 
combination while maintaining an acceptable safety profile, and to be consistent with the 
dose selection for GLE and PIB in the currently on-going AbbVie HCV Phase 3 studies.
5.6.4.2
GLE and PIB Dose and Treatment Duration
GLE/PIB 300 mg/120 mg QD regimens with 8-week and 12-week durations were 
evaluated in non-cirrhotic subjects in registrational trials.  Efficacy of 8-week treatment 
duration is established for GT1-, GT2- and GT3- infected non-cirrhotic subjects 
[R&D/16/0144, R&D/15/1230].  Fifty-two non-cirrhotic GTs 4, 5, or 6-infected subjects 
received 8-weeks of GLE/PIB and no virologic failure was observed.  Overall, these 
results conclude that 8-weeks of GLE/PIB 300 mg/120 mg dose is efficacious for non-
cirrhotic GT 1 - 6-infected subjects.  
Based on modeling and simulations, assuming no subjects experience non-virologic 
failures, following 8 weeks of GLE/PIB in treatment-naïve HCV-infected subjects with 
compensated cirrhosis, the predicted SVR12 rate is approximately 98% for GT1, 2, 4, 5, 
and 6-infected subjects, and approximately 92% for GT3-infected subjects.
5.6.4.3
Risk of Development of Resistance Mutations During 
Combination DAA Trials
In subjects treated with a DAA, amino acid substitution(s) in the targeted protein 
conferring resistance to the DAA can be selected.  It is expected that PIB, an NS5A 
inhibitor, will be able to suppress the appearance of virus containing resistance-associated 
substitutions in NS3 that confer resistance to GLE, because there should not be any cross-


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resistance in substitutions resistant to DAAs targeting different proteins.  The converse is 
expected to be true as well – GLE should be able to suppress the appearance of virus 
containing NS5A substitutions conferring resistance to PIB.  In addition, in vitro resistant 
colony selection studies in HCV replicon cells containing GT1 – 6 NS5A demonstrated 
that PIB had a high genetic barrier to resistance – very few colonies were selected, and 
most of those that were selected contained NS5A substitutions that conferred only modest 
levels of resistance to PIB.  Based on accumulated clinical and in vitro data to date, the 
risk of development of resistant substitutions during GLE and PIB combination trials is 
reduced when compared to treatment with first generation protease and NS5A inhibitors.  
The combination of PIB and GLE achieved high SVR rates with few virologic failures in 
subjects with HCV GT1 – 6 infection in Phase 2 and 3 studies.  These results support the 
prediction that the risk of development of resistance-associated substitutions with GLE 
and PIB combination treatment is low.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.1.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
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 


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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.
6.1.1
Definitions
6.1.1.1
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 
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, (see Section 6.1.7 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.


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6.1.1.2
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.
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).


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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.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4).
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.03" is available from the Cancer Therapy 
Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
and is to be used in the grading of adverse events.  Below are the general grading 
categories.  However, the investigator should always search NCI CTC AE for a given 
diagnostic/symptomatic AE term to identify and apply specific grading details for that AE 
entity.
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).


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Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL*
Grade 3
Severe or medically significant but not life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient 
evidence (information) to suggest a causal relationship.
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.


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If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at liver biopsy site) 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 following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
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 


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having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:
FAX to
For safety concerns, con Antiviral Safety Team at:
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
 MD
Medical Director
1500 Seaport Blvd.
Redwood City, CA 94063
Telephone Contact Information:
Office:
Mobile:
eFAX:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 


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Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  
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.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 
investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).  If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.7
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.  All adverse events and 
laboratory abnormalities will be managed and followed to a satisfactory clinical 
resolution.  A toxicity is deemed "clinically significant" based on the medical judgment of 


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the investigator.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03" is to be used in the grading of 
adverse events and laboratory abnormalities, which is available on the Cancer Therapy 
Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Specific toxicity management guidelines apply to the instances of increases in ALT 
(Section 6.1.7.1).
6.1.7.1
Management of Transaminase Elevations
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also 
> 2 × baseline value, the subject should have a confirmatory ALT measurement 
performed.
If, the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Complete hepatic questionnaire.
●
Evaluate for alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain Anti-HAV IgM, Anti-HAV IgG, Anti-HBc IgM, Anti-HBc Total, 
Anti-HBs, HBV DNA, HBsAg, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, as appropriate. 
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drug if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis.
○
At the discretion of the investigator.


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Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director (TA MD).
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.


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The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow protocol waivers, or intentional/prospective deviations from the 
protocol unless when necessary to eliminate an immediate hazard to study subjects.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) and the following AbbVie Clinical Monitors:
Primary Contact:
1 North Waukegan Rd.
North Chicago, IL 60064
Office:
Fax:
Alternate Contact:
41-45 Marinou Antypa Street
14121 N. Irakleio
Athens, Greece
Office:
Fax:
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 and whether any 
instances of protocol non-compliance should be reported to regulatory authorities as a 
serious breach of GCP and the protocol.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Analyses will occur after subjects have completed the PT Week 12 Visit or prematurely 
discontinued study.  The first analysis will occur after all HCV GT1, 2, 4, 5, and 6-
infected subjects have completed the PT Week 12 Visit or prematurely discontinued 
study; the second analysis will occur after all HCV GT3-infected subjects have completed 
the PT Week 12 Visit or prematurely discontinued study; the third and final analysis will 
occur after all subjects have completed or prematurely discontinued from the study.
SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All confidence intervals will be two-sided with an alpha 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.
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.
Efficacy analyses will be performed on the intention-to-treat (ITT) population defined as 
all enrolled subjects who receive at least one dose of study drug, unless otherwise 
specified.  The Per-Protocol (PP) population includes all enrolled subjects who receive at 
least one dose of study drug, with the exception of subjects who experience breakthrough, 
or prematurely discontinue treatment prior to Week 8, or have no HCV RNA value in the 
SVR12 visit window or later. 
The primary and key secondary efficacy analyses will be performed on the PP and ITT 
populations, as specified.  The other secondary efficacy analyses will be performed on the 
ITT population, unless otherwise specified.  


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Sensitivity analyses of SVR12, when applicable, will be performed on the intention-to-
treat population modified to exclude subjects who were enrolled with ineligible genotypes 
(e.g., GT3 according to phylogenetic analyses for the group of non-GT3-infected subjects) 
(mITT-GT), and on the mITT-GT population modified to exclude subjects who did not 
achieve SVR12 for reasons other than virologic failure (mITT-GT-VF).
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data) and PRO questionnaires.  HCV RNA values will be selected 
for the analyses of all SVR endpoints (e.g., SVR4, SVR12, and SVR24) based on defined 
visit windows.  A backward imputation method will be used to impute missing responses 
for SVR analyses.  Imputation of missing responses on PRO questionnaires is described in 
Section 8.1.3.
8.1.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all subjects in the ITT 
population across genotypes.  Demographics include age, weight, height, BMI, sex, race, 
geographic region, and ethnicity.  Baseline characteristics will be summarized as 
continuous variables (where appropriate) and as categorical variables, including all 
subgroup variables defined in Section 8.1.2.4, in addition to HCV genotype and subtype, 
baseline Child-Pugh score, tobacco and alcohol use status.
All the demographics and baseline characteristics will be summarized as continuous or 
categorical variables where appropriate.  Summary statistics (N, mean, median, SD, and 
range) will be generated for continuous variables (e.g., age), and the number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).
Treatment compliance to study drug will be calculated based on the percentage of tablets 
taken relative to the total tablets expected to be taken.  A subject is considered to be 
compliant if the percentage is between 80% and 120%.  Compliance will be calculated for 
each subject and summarized with the mean, median, standard deviation, minimum, and 
maximum.  The percentage of compliant subjects will be summarized.


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8.1.2
Efficacy
The primary and key secondary efficacy analyses will be performed on both the PP and 
ITT populations, as specified.  The other secondary efficacy analyses will be analyzed 
based on ITT population, unless otherwise specified.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, regardless of whether the HCV RNA is detectable or not.  HCV RNA 
≥LLOQ are all quantifiable values.
IL28B rs12979860 will be resulted as C/C, C/T, or T/T by the central laboratory.
8.1.2.1
Primary Efficacy Endpoints
The two primary efficacy analyses are:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 4, 5, and 6-infected subjects 
in the 8-week treatment duration achieving SVR12 is greater than 94% in the PP 
population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 4, 5, and 6-infected subjects 
in the 8-week treatment duration achieving SVR12 is greater than 93% in the ITT 
population.
The two primary and two key secondary (defined in Section 8.1.2.2.1) efficacy analyses 
will be performed following a fixed-sequence testing procedure which is described in 
Section 8.1.2.6.


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Only if success has been demonstrated for the first primary efficacy analysis of SVR12
based on the PP population in HCV GT1, 2, 4, 5, and 6-infected subjects will the testing 
proceed to the second primary efficacy analysis of SVR12 based on the ITT population in 
HCV GT1, 2, 4, 5, and 6-infected subjects.  And only if success has been demonstrated 
for the second primary efficacy analysis will the testing proceed to the key secondary 
efficacy analyses described in Section 8.1.2.2.1.
For the first primary efficacy analysis, the PP population will be used.  The PP analysis is 
used to reduce the risk of bias toward no treatment difference that can occur due to 
dropouts or other measurement problems, since the subjects excluded in the PP population 
experience SVR failure for reasons that do not help in discriminating between treatment 
durations.  
For both primary efficacy analyses, the percentage of subjects achieving SVR12 and a 
two-sided 95% confidence interval will be calculated using the normal approximation to 
the binomial distribution, unless the number of subjects who failed to achieve SVR12 is 
less than 5, then the Wilson's score method will be used for the confidence interval 
instead. 
A summary of reason for SVR12 non-response (e.g., OTVF, post-treatment relapse, other) 
will be provided.
8.1.2.2
Secondary Efficacy Endpoints
8.1.2.2.1
Key Secondary Efficacy Endpoints
The two key secondary efficacy analyses included in the fixed-sequence are listed below:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 3, 4, 5, and 6-infected 
subjects in the 8-week treatment duration achieving SVR12 is greater than 94% in 
the PP population;


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2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 3, 4, 5, and 6-infected 
subjects in the 8-week treatment duration achieving SVR12 is greater than 93% in 
the ITT population.
Only if success was demonstrated for both primary efficacy analyses will testing proceed 
to the two key secondary efficacy analyses in the order listed above.  If success has been 
demonstrated for the first key secondary efficacy analysis of SVR12 based on the PP 
population in HCV GT1-6-infected subjects, then testing will proceed to the second key 
secondary efficacy analysis of SVR12 based on the ITT population in HCV GT1-6-
infected subjects.
8.1.2.2.2
Other Secondary Efficacy Endpoints
The other secondary efficacy analyses, which are not included in the fixed sequence, are 
listed below:
●
The percentage of HCV GT3-infected subjects in the PP population who 
achieve SVR12;
●
The percentage of HCV GT3-infected subjects in the ITT population who 
achieve SVR12;
●
The percentage of subjects with OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA 
≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment with at least 6 weeks of treatment), and 
●
The percentage of subjects with post-treatment relapse (Relapse12:  defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
the last dose of study drug [up to and including the SVR12 assessment time 
point] among subjects who completed treatment as planned [defined as study 
drug duration ≥ 52 days for subjects assigned to 8 weeks of treatment] with 
HCV RNA < LLOQ at the end of treatment; excluding subjects who have been 
shown to be reinfected).


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For the analyses of SVR12 among HCV GT3-infected subjects, the number and percentage 
of subjects achieving SVR12 will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of OTVF and post-treatment relapse, the number and percentage of 
subjects in the ITT population will be summarized along with a two-sided 95% 
confidence interval using Wilson's score method.  Separate summaries will be provided 
for all subjects across genotypes, within HCV GT1, 2, 4, 5, and 6-infected subjects 
combined, and within HCV GT3-infected subjects.
8.1.2.3
Sensitivity Analysis
As a sensitivity analysis, the percentage of subjects in the mITT-GT and mITT-GT-VF 
populations achieving SVR12, as applicable, will be summarized.
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated if applicable, as a sensitivity analysis for the primary and key secondary 
efficacy analyses of SVR12 based on the PP and ITT populations.
8.1.2.4
Subgroup Analysis
The subgroup analyses will be performed across genotypes based on ITT population.  The 
summary statistics of subjects with SVR12 will be provided for the following subgroups:
●
HCV genotype and subtype;
●
Sex;
●
Age;
●
Race;
●
BMI;
●
Baseline HCV RNA level;
●
Baseline platelet count;
●
Baseline albumin;


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●
Baseline APRI;
●
Baseline FibroTest;
●
Baseline FIB-4;
●
Baseline AST/ALT ratio;
●
Geographic region;
●
Baseline creatinine clearance;
●
Baseline eGFR;  
●
History of diabetes;  
●
Subject on stable opiate substitution.
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized across genotypes in the 
ITT population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR4 (HCV RNA < LLOQ 4 weeks 
after the last actual dose of study drug);
●
The percentage of subjects who achieve SVR24 (HCV RNA < LLOQ 24 weeks 
after the last actual dose of study drug);
●
The percentage of subjects who experience post-treatment relapse after 
achieving SVR12.
The number and percentage of subjects meeting each additional efficacy endpoint will be 
summarized along with a two-sided 95% confidence interval using the Wilson's score 
method.


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8.1.2.6
Multiplicity
In order to control family-wise Type I error rate, a fixed-sequence testing procedure will 
be used for the two primary and two key secondary efficacy analyses of SVR12 as listed 
below.  The fixed-sequence testing procedure will utilize the endpoint sequence of the 
first primary analysis followed by the second primary analysis, then the first key 
secondary analysis, and lastly the second key secondary analysis.  For example, only if 
success has been demonstrated for the first primary efficacy analysis of SVR12 based on 
the PP population, will the testing proceed to the second primary efficacy analysis of 
SVR12 based on the ITT population, and so on. 
The multiplicity controlled efficacy analyses will be tested sequentially in the following 
order:
1.
Primary 1:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on the PP population in HCV GT1, 
2, 4, 5, and 6-infected subjects:  If this endpoint is statistically significant, then 
proceed to the following efficacy endpoint.  If this endpoint is not statistically 
significant, then stop the testing procedure and declare that no endpoints in the 
study met statistical significance.  
3.
Primary 2:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on the ITT population in HCV 
GT1, 2, 4, 5, and 6-infected subjects:  If this endpoint is statistically significant, 
then declare the SVR12 endpoint is statistically significant on both the PP and ITT 
populations in HCV GT1, 2, 4, 5, and 6-infected subjects.  If not, then announce 
that SVR12 endpoint is statistically significant based on only the PP population in 
HCV GT1, 2, 4, 5, and 6-infected subjects and stop testing.
4.
Key Secondary 1:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on the PP population 
in HCV GT1, 2, 3, 4, 5, and 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both the 


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PP and ITT populations in HCV GT1, 2, 4, 5, and 6-infected subjects and on the PP 
population in HCV GT1-6-infected subjects.  If not, then announce that SVR12
endpoint is statistically significant based on only the preceding populations and
stop testing.
5.
Key Secondary 2:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on the ITT population 
in HCV GT1, 2, 3, 4, 5, and 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both the 
PP and ITT populations in HCV GT1, 2, 4, 5, and 6-infected subjects and on both 
the PP and ITT populations in HCV GT1-6-infected subjects.  If not, then 
announce that SVR12 endpoint is statistically significant based on only the 
preceding populations and stop testing.
8.1.3
Patient Reported Outcomes
The handling of missing data for patient reported outcomes (PROs) will be as follows.  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 missing item of the FSS questionnaire 
will be imputed with the average score of the answered items as long as more than 50% of 
the items on the FSS are answered.  
The mean change from baseline to each applicable post-baseline timepoint in the FSS 
total score and the SF-36v2 Mental Component Summary (SF-36-MCS) and Physical 
Component Summary SF-36-PCS scores will be summarized descriptively at each visit.  
The TSQM subscales (global satisfaction, convenience, effectiveness, side effects) will be 
summarized descriptively at Weeks 2, 4, and 8.  
The following analyses of patient reported outcomes (PROs) also will be performed:


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●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 3 points in the 
SF-36-MCS and SF-36-PCS;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 5 points in the 
SF-36-MCS and SF-36-PCS;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 5 points in the 
SF-36 domain scores;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 0.7 in the FSS 
total score;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 1 in the FSS 
total score.
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
Resistance Analyses
For all subjects, full length NS3/4A or NS5A from baseline samples will be sequenced by 
NGS.  For subjects who experience virologic failure (OTVF or post-treatment relapse), 
full length NS3/4A and NS5A genes from the first sample after virologic failure with 
HCV RNA ≥ 1000 IU/mL will be sequenced by NGS.  An appropriate subtype specific 
prototypic reference sequence will be used for comparison with sequences from samples.  
Subjects treated with study drug who do not achieve SVR12 due to reasons other than 
virologic failure but have a time point with HCV RNA ≥ 1000 IU/mL after treatment 
discontinuation will have the sample at that time point sequenced.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥ 1000 IU/mL will be used.  Included time 


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points for analyses on samples from subjects who do not achieve SVR12 are 1) the sample 
closest in time after failure/discontinuation with an HCV RNA level of ≥ 1000 IU/mL, 
and 2) 24 weeks post-DAA treatment, provided that resistance-associated substitutions 
were detected by NGS at the time of HCV virologic failure/treatment discontinuation.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions are listed in Table 8.  Appropriate subtype specific prototypic reference 
sequence will be used for comparison with sequences from samples.
Table 8.
Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 
NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 
92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 3, 4, 5, 6 
NS5A
24, 28, 29, 30, 31, 32, 58, 92, and 93
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in post-baseline sample at a signature amino acid position.


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●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post-baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution by NGS:  A post-baseline substitution or an 
enriched polymorphism.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
amino acid positions for each DAA target (NS3/4A and NS5A).
●
A listing of all baseline polymorphisms (15% detection threshold) at non-
signature amino acid positions for each DAA target (NS3/4A and NS5A) for 
subjects who experience virologic failure.
●
A by subject listing of baseline polymorphisms (15% detection threshold) at 
signature amino acid positions in subjects with polymorphisms across both 
NS3 and NS5A, or those with multiple baseline polymorphisms within any one 
target (NS3/4A or NS5A).
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total 
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared.  Analysis 
will be grouped by HCV subtype and DAA target (NS3/4A or NS5A).


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The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
●
Polymorphism at each non-signature amino acid position at a detection 
threshold of 15%.
Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 
amino acid positions at 15% detection threshold, the SVR12 rate will be calculated, and 
the rates with or without polymorphisms will be compared using Fisher's exact test.  
Analysis will be separated by HCV subtype.  The following tables will be provided:
●
Comparison of SVR12 rates by subtype, and total (include all subtypes)
●
Comparison of SVR12 rates by genotype, and total (include all subtypes)
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
●
Listings by subject and time point of all post-baseline substitution at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).


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HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LIPA assay 
results from the Central laboratory will be used to categorize the subject.  This 
information will be presented in summaries of efficacy subgroup analyses and resistance 
analyses.
8.1.5
Safety
Safety summaries will be provided across genotypes.  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 (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term.  The tabulation of the number of subjects with 
treatment-emergent adverse events by severity grade (Grades 1 – 5) and relationship to 
study drug 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 grade for the severity grade table and the most related for the relationship to study 
drug tables.  Subjects reporting more than one type of event within a SOC will be counted 
only once for that SOC.
Additional analyses will be described in the statistical analysis plan.


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8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last non-missing measurement prior to the initial dose of study drug.  Mean changes from 
baseline to each post-baseline visit, including Final Treatment Visit, will be summarized 
descriptively.  Summary of Child-Pugh score from baseline to each post-baseline visit, 
including applicable post treatment visits, will be provided.
Laboratory data values will be categorized as low, normal, or high based on reference 
ranges of the laboratory used in this study.  The number and percentage 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.
The number and percentage of subjects with post-baseline values meeting pre-specified 
criteria for toxicity grades and meeting pre-defined criteria for laboratory parameters of 
interest during treatment will be summarized.
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, including Final Treatment Visit, will be 
summarized descriptively.  The number and percentage of subjects with post-baseline 
values meeting pre-defined criteria for Potentially Clinically Significant (PCS) vital signs 
values during treatment will be summarized.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentration of GLE and PIB will be tabulated for each subject.  Plasma 
concentrations of GLE and PIB will be summarized based on last dosing time, sampling 
time and time since last dose.  Summary statistics will be computed for GLE and PIB 
plasma concentrations binned by time since last dose.  


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Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology for population pharmacokinetic 
analysis:
Population pharmacokinetic analysis 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 VII, 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 
volume of distribution (V/F) of the 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 


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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:
TVCLi = Theta(1) + Theta(2) (Comedication [1,2,…]) + Theta(3) (WTi-median value) + 
Theta(4) (AGEi – median value).
Where TVCLi = Typical value of clearance for an individual,1 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.
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 330 adult subjects with chronic HCV GT 1 - 6 
infection with compensated cirrhosis who are HCV treatment-naïve in the study.


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The study was initially designed to enroll about 270 non-GT3-infected subjects and 
amended to include GT3-infected subjects for a total of 330 GT1 - 6-infected (270 non-
GT3 and 60 GT3) subjects. 
With approximately 270 subjects with HCV GT1, 2, 4, 5, or 6 infection, this study has 
approximately 91% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on Per-Protocol (PP) population, assuming that 98% of the GT1, 2, 4, 5, and 
6-infected subjects receiving 8 weeks of treatment in PP population achieve SVR12.
With approximately 270 subjects with HCV GT1, 2, 4, 5, or 6 infection, this study has 
approximately 82% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on Intention-to-Treat (ITT) population, assuming that 97% of the GT1, 2, 4, 
5, and 6-infected subjects receiving 8 weeks of treatment in ITT population achieve 
SVR12.  
With approximately 330 subjects with HCV GT1 - 6 infection, this study has 
approximately 90% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on the PP population, assuming that 98% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the PP population achieve SVR12.
With approximately 330 subjects with HCV GT1-6 infection, this study has 
approximately 81% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on the ITT population, assuming that 97% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the ITT population achieve SVR12.
8.2.1
Justification of Success Criteria for SVR12
Efficacy for the 8-week regimen in this study is established by comparing the SVR12 rate 
from this study to the historical control regimen of GLE/PIB administered for 12 weeks.  


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The SVR12 rate of the historical control regimen is calculated, and a threshold is 
determined by subtracting a margin of 6% from the historical SVR12 rate.  Efficacy is 
established if the lower 95% confidence bound of the SVR12 rate in the 8-week regimen is 
greater than the threshold.
In the registrational program, 117 treatment naïve, compensated cirrhotic subjects, GT 1, 
2, 4, 5, or 6 subjects and 65 treatment naïve, GT3-infected subjects with compensated 
cirrhosis were treated with GLE/PIB for 12 weeks duration.  Three subjects did not 
achieve SVR12, one discontinued treatment early and two had missing SVR12 data.  No 
virologic failure was observed among these subjects which means SVR12 rate based on PP 
population is 100%.  Hence, for this study it assumed that the historical SVR12 rate for 
GT1 - 6-infected cirrhotic patients is 100%.  To establish efficacy to the historical control, 
a margin of 6% is applied to the historical control rate of 100%, resulting in a threshold of 
94%.
Historical SVR rate based on ITT population depends on the non-virologic failure in a 
study.  Study-to-study variability has been observed in non-virologic failure rates, and is 
typically around 1%.  The observed rate of non-virologic failure in the registrational 
program is 1.2% (29/2369).  For this reason, this study assumes that the historical SVR12
rate based on ITT population for cirrhotic patients is 99% (with 1% non virologic failure).  
To establish efficacy to the historical control, a margin of 6% is applied to the historical 
control rate of 99%, resulting in a threshold of 93%. 
A margin of 6% is selected to be used in this study to ensure a minimal loss of efficacy of 
the 8-week arm relative to the historical SVR12 rate for 12-week arm.
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be enrolled into a single arm.


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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 and all other 
applicable regulatory requirements.
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.
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.


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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.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected and testing performed for optional pharmacogenetic 
exploratory research.  The nature of the testing should be explained and the subject given 
an opportunity to ask questions.  If the subject does not consent to provide samples for the 
optional pharmacogenetic exploratory research, it will not impact their participation in the 
study.
In the event a subject withdraws from the main study, optional pharmacogenetic 
exploratory research samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for the optional samples.  If consent is withdrawn for the 
optional sampling, the subject must inform their study doctor, and once AbbVie is 
informed, the optional samples will be destroyed.  However, if the subject withdraws 
his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.


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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 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
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.


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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 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
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.
11.0
Data Quality Assurance
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 research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, 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 data from optional exploratory research 
may be provided to investigators and used in scientific publications or presented at 


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medical conventions.  Optional exploratory research 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.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator 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 submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory 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 Glecaprevir 
(GLE)/Pibrentasvir (PIB) Fixed-Dose Combination.
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:
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety 
of Glecaprevir (GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults 
with Chronic Hepatitis C Virus (HCV) Genotype 1 - 6 Infection and 
Compensated Cirrhosis
Protocol Date:
11 June 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of hepatitis 
C virus infection:  new estimates of age-specific antibody to HCV seroprevalence.  
Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al. A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
European Association for Study of Liver.  EASL Clinical Practice Guidelines:  
management of hepatitis C virus infection.  J Hepatol.  2014;60(2):392-420.
7.
Cardoso AC, Moucari R, Figueiredo-Mendes C, et al.  Impact of peginterferon and 
ribavirin therapy on hepatocellular carcinoma:  incidence and survival in hepatitis 
C patients with advanced fibrosis.  J Hepatol.  2010;52(5):652-7.
8.
Backus LI, Boothroyd DB, Phillips BR, et al.  A sustained virologic response 
reduces risk of all-cause mortality in patients with hepatitis C.  Clin Gastroenterol 
Hepatol.  2011;9(6):509-16.
9.
American Association for the Study of Liver Diseases.  Hepatitis C guidance:  
AASLD-IDSA recommendations for testing, managing, and treating hepatitis C.  
Available at:  http://www.hcvguidelines.org.  Updated:  24 February 2016.  
Changes made:  10 March 2016.


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10.
EPCLUSA® (sofosbuvir and velpatasvir) [US prescribing information].  Foster 
City, CA; Gilead Sciences, Inc., 2016.
11.
Ng T, Reisch T, Middleton T, et al.  ABT-493, a potent HCV NS3/4A protease 
inhibitor with broad genotype coverage.  Poster presented at:  21st Annual 
Conference on Retroviruses and Opportunistic Diseases.
12.
AbbVie.  ABT-530 (Glecaprevir/Pibrentasvir) Investigator's Brochure Edition 3.  
29 August 2017.
13.
Mavyret (glecaprevir and pibrentasvir tablets) [US package insert].  North Chicago, 
IL; AbbVie, 2017.
14.
Marivet (glecaprevir and pibrentasvir tablets) [SmPC].  Maidenhead, UK; AbbVie, 
2017.
15.
Puoti M, et al.  High SVR rates with eight and twelve weeks of pangenotypic 
glecaprevir/pibrentasvir:  integrated efficacy analysis of genotype 1-6 patients 
without cirrhosis.  Poster presentation at EASL 2017.
16.
Zeuzem S, Foster GR, Wang S, et al.  Glecaprevir-Pibrentasvir for 8 or 12 weeks in 
HCV genotype 1 or 3 infection.  N Engl J Med.  2018;378(4):354-69.
17.
Rockstroh JK, Lacombe K, Viani RM, et al.  Efficacy and safety of 
glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human 
immunodeficiency virus-1:  the EXPEDITION-2 study.  Clin Infect Dis.  
2018 Mar 16.  doi:  10.1093/cid/ciy220.  [Epub ahead of print]


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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:
6.
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.
7.
Personally conducting or supervising the described investigation(s).
8.
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.
9.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
10.
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).
11.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
12.
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.
13.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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14.
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.
15.
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
Bioanalysis
Statistics
Pharmacokinetics
Clinical


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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
EOT* or Premature D/C 
from Treatmentb,c
Informed Consentd
X
Medical Historye
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
Adverse Event Assessmentf
X
X
X
X
X
X
12 Lead ECG
X
X
X
Physical Exam 
X
X
X
Vital Signs, Weight, Heightg
X
X
X
X
X
X
Hematology/Chemistry/Coagulation Panel
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u, s)
X (u)
X (u)
Anti-HCV Ab, Anti-HIV Ab
X
Hepatitis B Panel
X
Drug/Alcohol Screen
X
FSH (all females)
X
HCV Genotype and Subgenotype 
X
Pharmacogenetic DNA and RNA Sample (optional)i
X
X
IL28B Samplei
X
FibroTest and APRI, FibroScan® or Liver Biopsyj
X
Xk
HCV RNA Samples
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X


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Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
EOT* or Premature D/C 
from Treatmentb,c
Archive Plasma and Serum Sample
X
X
X
X
X
X
Pharmacokinetic Samplesl
X
X
X
X
Child-Pugh Score
X
X
HCC Screening Liver Ultrasoundm
X
Clinical Assessment of Hepatic Decompensation
X
Patient Reported Outcomes Instruments (PROs)n
X
Xo
X
X
Study Drugs Dispensed
X
X
Dispense/Review Study Drug Dosing Card
X (Dispense only)
X
X
X
X (Review only)
Perform Study Drug Accountability and Review of 
Study Drug Adherencep
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit will be at either Week 8 or Week 12 depending on if Treatment Extension Criteria has been met.
a.
All procedures to be performed prior to first dose.
b.
Subjects who prematurely discontinue the Treatment Period should return to the site to complete the Premature D/C Visit Procedures (preferably prior to the initiation of any 
other anti-HCV therapy).
c.
If Treatment Extension Criteria has been met, subjects will receive treatment for 12 weeks and will have an additional visit at Week 8 which will include all procedures 
performed at Week 4.
d.
Subjects need to sign an IRB/IEC approved informed consent for the study (prior to performing any screening or study-specific procedures) and the optional pharmacogenetic 
sample(s), if applicable.
e.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
f.
See specific information regarding adverse event collection in Section 6.1.1.
g.
Height will be measured at the Screening Visit only. 
h.
Pregnancy testing is not required for females of non-childbearing potential as defined in the inclusion criteria.


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i.
If the IL28B is not collected at Study Day 1, it may be collected at any other visit during the study.
j.
For subjects who have not had a historical qualifying liver biopsy or a historical qualifying FibroScan®.
k.
On Day 1, only FibroTest will be conducted for all subjects.  Biopsy and FibroScan will not be conducted on Day 1.
l.
Detail regarding timing of samples is provided in Section 5.3.2.1.
m.
An HCC Screening assessment is required per protocol in the Screening Study Visit and at the PT Wk 24 or PT D/C Visit.  From Day 1 to EOT or premature D/C Study Visit, 
HCC screening should be performed as part of the Standard of Care for the subject.  Please refer to Section 5.3.1.1, item "Hepatocellular Carcinoma Screening" for details on 
this study procedure.
n.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.  TSQM is not administered at Day 1, only the FSS and SF-36 are collected at 
Day 1.
o.
TSQM is the only PRO that should be administered at Week 2.
p.
Subjects should bring all study drug to every visit for the site to review adherence.  However, the site will record the number of tablets returned only at the Study Drug 
Accountability Visits at Weeks 4, 8, (Week 12 due to Treatment Extension Criteria) or Premature D/C.


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Appendix D.
Study Activities – Post-Treatment Period
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Xb
Pregnancy Test (urine [u])c
X (u)
X (u)a
Concomitant Medication Assessmentd
X
Xd
Xd
Adverse Event Assessmente
X
Xe
Xe
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Pharmacogenetic DNA and RNA Sample (optional)
X
Archive Plasma and Serum Sample
X
X
X
FibroTest and APRI
X
X
Child-Pugh Score
X
X
Physical Examh
X
X
HCC Screening Liver Ultrasound
Xi
Patient Reported Outcomes Instruments (PROs)f,g
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 procedures.  Hematology/Chemistry/Coagulation 
Panel and Pregnancy Test are not required at PT Wk 24 but at PT D/C only if subject discontinues prior to PT Wk 4.
b.
Hematology/Chemistry/Coagulation Panel drawn at PT Wk 12 and PT Wk 24 are only conducted to support Child-Pugh assessment and/or FibroTest and APRI 
determination.  No other analytes will be resulted as part of the labs drawn at these timepoints.  
c.
Pregnancy testing is not required in the PT period for women that are not of childbearing potential. 
d.
Only medications taken for SAEs and for treatment of HCV will be collected after 30 days post-dosing.


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e.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  All spontaneously reported SAEs will be collected thereafter; nonserious AEs will not be collected 
(see Section 6.1.4).
f.
PROs should be administered before any study procedures and in the order listed in Section 5.3.1.1.
g.
TSQM should not be collected in the post-treatment period.
h.
An abbreviated Physical Exam should be conducted to assess Ascites, and potential hepatic encephalopathy required for the Child Pugh assessment score.
i.
Please refer to Section 5.3.1.1 item "Hepatocellular Carcinoma Screening Liver Ultrasound" for details on this study procedure.
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.


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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.0  Title Page
Protocol title previously read:
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus 
(HCV) Genotype 1, 2, 4, 5 or 6 Infection and Compensated Cirrhosis
Has been changed to read:
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus 
(HCV) Genotype 1 - 6 Infection and Compensated Cirrhosis
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
  Contact:
 MD
Associate Medical Director
Antiviral Clinical Project Team
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
Has been changed to read:
Sponsor/Emergency 
  Contact:
 MD
Medical Director
Antiviral Clinical Project Team
1500 Seaport Blvd.
Redwood City, CA 94063
Phone:
Fax:


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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M16-135
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  06 September 2017
Protocol Title:  A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus (HCV) Genotype 1, 
2, 4, 5 or 6 Infection and Compensated Cirrhosis
Objectives:  
!
To demonstrate the efficacy of the SVR12 rate of 8 weeks of treatment with  
glecaprevir/pibrentasvir compared to the historical SVR12 rate of 12 weeks of treatment with 
glecaprevir/pibrentasvir in treatment naïve adults with chronic HCV GT 1, 2, 4, 5 or 6 infection 
and compensated cirrhosis.  
!
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in treatment naïve 
adults with chronic HCV GT 1, 2, 4, 5 or 6 infection and compensated cirrhosis.
Investigators:  Multicenter
Study Sites:  Approximately 135 globally
Study Population:  Adults with chronic HCV genotype (GT) 1, 2, 4, 5 or 6 infection, aged 18 years or 
older, with compensated cirrhosis, who are HCV treatment-naïve.
Number of Subjects to be Enrolled:  Approximately 270 subjects
Methodology:  
This is a Phase 3b, single arm, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of glecaprevir/pibrentasvir in treatment-naïve subjects with chronic HCV GT 1, 2, 4, 5 or 6 
infection and compensated cirrhosis.
The study will consist of 3 periods:
Screening Period:
Subjects have up to 42 days following the Screening Visit to confirm eligibility and enroll into the study.
Treatment Period:  
Eligible subjects will be enrolled to receive glecaprevir/pibrentasvir 300 mg/120 mg once daily (QD) for 
8 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, and 8.  Study 
procedures, including assessment of adverse events, vital signs, adherence, concomitant medications, 
HCV RNA, HCV resistance, pharmacokinetic assays, and clinical laboratory tests, will be conducted at 
each visit.


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Methodology (Continued):
An efficacy assessment will evaluate the post-treatment relapse rate after the first 30 subjects reach 
Post-Treatment Week 4 and will be done periodically thereafter.  If more than 10% of subjects 
experience post-treatment relapse, an analysis will be conducted to determine if extension of treatment to 
12 weeks is needed for all subjects or for a particular subgroup of subjects who are on treatment or have 
completed treatment within the previous 7 days.
Post-Treatment Period:  
Subjects who complete or prematurely discontinue the Treatment Period will be followed for 24 weeks 
to monitor safety, HCV RNA levels and to evaluate efficacy and the emergence and persistence of 
resistance associated substitutions. 
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant virus will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female, at least 18 years of age at time of Screening;
2.
Screening laboratory result indicating HCV GT 1, 2, 4, 5 or 6 infection;
3.
Positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening; 
4.
Treatment-naïve to any approved or investigational anti-HCV medication;
5.
Subject must be documented as cirrhotic, with a Child-Pugh score of ≤ 6.
Main Exclusion:  
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study, or for approximately 30 days after the last dose of study drug;
2.
Any current or historical clinical evidence of decompensated cirrhosis, including any current or past 
evidence of Child-Pugh B or C classification, hepatic encephalopathy or variceal bleeding, 
radiographic evidence of small ascites, or empiric use of lactulose/rifaximin for neurologic 
indications.  The use of beta blockers is not exclusionary;  
3.
Current HBV or HIV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative HBsAg and Anti-
HBs), or;
!
A positive anti-human immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed by the central laboratory during screening indicating genotype 3 
infection or co-infection with more than one HCV genotype;


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
5.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Alanine aminotransferase ALT > 10 × ULN
!
Aspartate aminotransferase AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL
!
Calculated creatinine clearance (CrCl, Cockcroft-Gault method) of < 50 mL/min
!
Albumin < 2.8 mg/dL
!
Hemoglobin < 10 g/dL 
!
Platelets < 50,000 cells/mm3
Investigational Products:
Glecaprevir/Pibrentasvir:  100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir:  300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects will receive glecaprevir/pibrentasvir for 8 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-Lead ECGs and vital signs.
Patient Reported Outcomes (PROs):
The Treatment Satisfaction Questionnaire-Medication (TSQM) will be used to assess subjects' 
satisfaction with the treatments efficacy and side effects.  The Short Form 36 Version 2 Health Status 
Survey (SF-36v2) will be used to assess the functional health and well-being of subjects.  The Fatigue 
Severity Scale (FSS) will be used to measure the severity of fatigue and its effect on lifestyle and 
activities.
Pharmacokinetic:
Individual plasma concentrations of glecaprevir and pibrentasvir will be tabulated and summarized.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the 
appropriate prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline 
substitutions relative to the corresponding baseline sequence in available samples.


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Statistical Methods:
Efficacy:
The Intention-to-Treat (ITT) population includes all enrolled subjects who receive at least one dose of 
study drug.  The Per-Protocol (PP) population includes all enrolled subjects who receive at least 
one dose of study drug, with the exception of subjects who experience breakthrough, or prematurely 
discontinue treatment prior to Week 8, or have no HCV RNA value in the SVR12 visit window or later.
The two primary efficacy endpoints are the comparisons of the SVR12 rate of the 8-week treatment 
duration to a historical SVR12 rate for 12 weeks in the Per-Protocol (PP) population and in the Intention-
to-Treat (ITT) population.  The primary efficacy analyses will be performed across genotypes following 
a fixed-sequence testing procedure:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of subjects in the 8-week treatment duration achieving SVR12 is greater than 94% in the 
PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of subjects in the 8-week treatment duration achieving SVR12 is greater than 93% in the 
ITT population.
The primary efficacy endpoints will be tested using the hierarchical order outlined above to control the 
Type I error rate.  Only if success has been demonstrated for the first primary efficacy endpoint of 
SVR12 based on the PP population will the testing proceed to the second primary efficacy endpoint of 
SVR12 based on the ITT population.  For both primary efficacy endpoints, the percentage of subjects 
achieving SVR12 and a two-sided 95% confidence interval will be calculated using the normal 
approximation to the binomial distribution, unless the number of subjects who failed to achieve SVR12 is 
less than 5, then the Wilson's score method will be used for the confidence interval instead.
The secondary efficacy endpoints are:
!
The percentage of subjects with on-treatment virologic failure (OTVF) across genotypes (based 
on ITT population).
!
The percentage of subjects with post-treatment relapse across genotypes (based on ITT 
population).
The number and percentage of subjects will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.


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Statistical Methods (Continued):
Safety:
All subjects who receive at least one dose of study drug will be included in the safety analyses.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The number 
and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug through 30 days post-study drug dosing) will be 
tabulated by MedDRA System Organ Class (SOC) and preferred term.  The tabulation of the number of 
subjects with treatment-emergent adverse events also will be provided by severity grade (Grades 1 – 5) 
and relationship to study drug.  Mean changes in clinical laboratory and vital sign data from baseline to 
each post-baseline visit will be summarized.  The number and percentage of subjects with post-baseline 
laboratory values meeting toxicity grades and meeting pre-defined criteria for laboratory parameters of 
interest during treatment will be summarized.  The number and percentage of subjects with post-baseline 
vital sign values during the Treatment Period meeting pre-specified criteria for potentially clinically 
significant vital sign values will be summarized.
Patient Reported Outcomes (PROs):
The mean change from baseline to each applicable post-baseline timepoint in the FSS total score and the 
SF-36v2 Mental Component Summary (SF-36-MCS) and Physical Component Summary SF-36-PCS 
scores will be summarized descriptively at each visit.  The TSQM subscales (global satisfaction, 
convenience, effectiveness, side effects) will be summarized descriptively at Weeks 2, 4, and 8 and the 
change from the baseline visit will be summarized at all on treatment timepoints.  
Pharmacokinetic:
Plasma concentration of glecaprevir and pibrentasvir will be tabulated for each subject.  Plasma 
concentrations of glecaprevir and pibrentasvir will be summarized based on last dosing time, sampling 
time and time since last dose.  Summary statistics will be computed for glecaprevir and pibrentasvir 
plasma concentrations binned by time since last dose.  
Resistance:
For all subjects receiving study drug and with available samples, baseline polymorphisms at signature 
resistance-associated amino acid positions identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the corresponding 
baseline sequence, 2) the amino acid substitutions in available post baseline samples at signature 
resistance-associated positions identified by NGS, and comparison to the appropriate prototypic 
reference sequence, and 3) the persistence of viral substitutions by NGS.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M16-135
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  11 June 2018
Protocol Title:  A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus (HCV) Genotype 1 
- 6 Infection and Compensated Cirrhosis
Objectives:  
!
To demonstrate the efficacy of the SVR12 rates of 8 weeks of treatment with 
glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of treatment with 
glecaprevir/pibrentasvir in treatment naïve adults with chronic HCV infection and compensated 
cirrhosis.  
!
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in treatment naïve 
adults with chronic HCV infection and compensated cirrhosis.
Investigators:  Multicenter
Study Sites:  Approximately 120 globally
Study Population:  Adults with chronic HCV genotype (GT) 1 - 6 infection, aged 18 years or older, 
with compensated cirrhosis, who are HCV treatment-naïve.
Number of Subjects to be Enrolled:  Approximately 330 subjects
Methodology:  
This is a Phase 3b, single arm, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of glecaprevir/pibrentasvir in treatment-naïve subjects with chronic HCV GT 1 - 6 infection and 
compensated cirrhosis.  The study will initially enroll subjects with HCV GT 1, 2, 4, 5, and 6 infection 
followed by subjects with HCV GT3 infection.  Once enrollment of subjects with HCV GT3 infection 
begins, enrollment of subjects with HCV GT 1, 2, 4, 5 or 6 infection will be closed.  
The study will consist of 3 periods:
Screening Period:
Subjects have up to 42 days following the Screening Visit to confirm eligibility and enroll into the study.
Treatment Period:  
Eligible subjects will be enrolled to receive glecaprevir/pibrentasvir 300 mg/120 mg once daily (QD) for 
8 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, and 8.  Study 
procedures, including assessment of adverse events, vital signs, adherence, concomitant medications, 
HCV RNA, HCV resistance, pharmacokinetic assays, and clinical laboratory tests, will be conducted at 
each visit.


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Methodology (Continued):
Because subjects with GT 1, 2, 4, 5 or 6 infection will be enrolled first, separate treatment extension 
criteria will apply to subjects with GT 1, 2, 4, 5 or 6 infection versus subjects with GT3 infection, as 
described below.  However, if treatment is extended for all or a particular subgroup of subjects with GT 
1, 2, 4, 5 or 6 infection, then enrollment of subjects with GT3 infection will be terminated and all GT3-
infected subjects who are on treatment or have completed treatment within the previous 7 days will have 
their treatment extended to 12 weeks.
In subjects with HCV GT 1, 2, 4, 5, and 6 infection, an efficacy assessment will evaluate the post-
treatment relapse rate after the first 30 subjects reach Post-Treatment Week 4 and will be done 
periodically thereafter.  If more than 10% of subjects experience post-treatment relapse, an analysis will 
be conducted to determine if extension of treatment to 12 weeks is needed for all GT 1, 2, 4, 5, and 6-
infected subjects or for a particular subgroup of GT 1, 2, 4, 5, and 6-infected subjects who are on 
treatment or have completed treatment within the previous 7 days.
In subjects with HCV GT3 infection, an efficacy assessment will evaluate the post-treatment relapse rate 
after the first 20 subjects reach Post-Treatment Week 4 and will be done periodically thereafter.  If more 
than 10% of subjects experience post-treatment relapse, an analysis will be conducted to determine if 
extension of treatment to 12 weeks is needed for all GT3-infected subjects or for a particular subgroup of 
GT3-infected subjects who are on treatment or have completed treatment within the previous 7 days.
Post-Treatment Period:  
Subjects who complete or prematurely discontinue the Treatment Period will be followed for 24 weeks 
to monitor safety, HCV RNA levels and to evaluate efficacy and the emergence and persistence of 
resistance associated substitutions. 
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant virus will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female, at least 18 years of age at time of Screening;
2.
Screening laboratory result indicating HCV GT 1 - 6 infection;
3.
Positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening; 
4.
Treatment-naïve to any approved or investigational anti-HCV medication;
5.
Subject must be documented as cirrhotic, with a Child-Pugh score of ≤ 6.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study, or for approximately 30 days after the last dose of study drug;
2.
Any current or historical clinical evidence of decompensated cirrhosis, including any current or past 
evidence of Child-Pugh B or C classification, hepatic encephalopathy or variceal bleeding, 
radiographic evidence of small ascites, or empiric use of lactulose/rifaximin for neurologic 
indications.  The use of beta blockers is not exclusionary;  
3.
Current HBV or HIV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative HBsAg and Anti-
HBs), or;
!
A positive anti-human immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed by the central laboratory during screening indicating co-infection with 
more than one HCV genotype;
5.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Alanine aminotransferase ALT > 10 × ULN
!
Aspartate aminotransferase AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL
!
Calculated creatinine clearance (CrCl, Cockcroft-Gault method) of < 50 mL/min
!
Albumin < 2.8 mg/dL
!
Hemoglobin < 10 g/dL 
!
Platelets < 50,000 cells/mm3
Investigational Products:
Glecaprevir/Pibrentasvir:  100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir:  300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects will receive glecaprevir/pibrentasvir for 8 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-Lead ECGs and vital signs.


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Criteria for Evaluation (Continued):
Patient Reported Outcomes (PROs):
The Treatment Satisfaction Questionnaire-Medication (TSQM) will be used to assess subjects' 
satisfaction with the treatments efficacy and side effects.  The Short Form 36 Version 2 Health Status 
Survey (SF-36v2) will be used to assess the functional health and well-being of subjects.  The Fatigue 
Severity Scale (FSS) will be used to measure the severity of fatigue and its effect on lifestyle and 
activities.
Pharmacokinetic:
Individual plasma concentrations of glecaprevir and pibrentasvir will be tabulated and summarized.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the 
appropriate prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline 
substitutions relative to the corresponding baseline sequence in available samples.
Statistical Methods:
Efficacy:
The Intention-to-Treat (ITT) population includes all enrolled subjects who receive at least one dose of 
study drug.  The Per-Protocol (PP) population includes all enrolled subjects who receive at least 
one dose of study drug, with the exception of subjects who experience breakthrough, or prematurely 
discontinue treatment prior to Week 8, or have no HCV RNA value in the SVR12 visit window or later.
The primary efficacy endpoint is SVR12.  The following primary and key secondary efficacy analyses are 
the comparisons of the SVR12 rate of the 8-week treatment duration to a historical SVR12 rate for 
12 weeks in the Per-Protocol (PP) population and in the Intention-to-Treat (ITT) population.  The 
primary efficacy analyses will be conducted among HCV GT1, 2, 4, 5, and 6-infected subjects, and the 
two key secondary efficacy analyses will be conducted among all (HCV GT1 - 6) subjects.  The primary 
efficacy analyses are listed below and will be tested through a fixed-sequence testing procedure:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 4, 5, and 6-infected subjects in the 8-week treatment duration achieving 
SVR12 is greater than 94% in the PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 4, 5, and 6-infected subjects in the 8-week treatment duration achieving 
SVR12 is greater than 93% in the ITT population.


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Statistical Methods (Continued):
Efficacy (Continued):
The two key secondary efficacy analyses included in the fixed-sequence testing procedure are:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 3, 4, 5, and 6-infected subjects in the 8-week treatment duration 
achieving SVR12 is greater than 94% in the PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration 
will be demonstrated if the lower bound of the two-sided 95% confidence interval for the 
percentage of HCV GT1, 2, 3, 4, 5, and 6-infected subjects in the 8-week treatment duration 
achieving SVR12 is greater than 93% in the ITT population.
The primary and key secondary efficacy analyses will be tested using the hierarchical order outlined 
above to control the Type I error rate.  Only if success has been demonstrated for the first primary 
efficacy analysis of SVR12 based on the PP population in HCV GT1, 2, 4, 5, and 6-infected subjects will 
the testing proceed to the second primary efficacy analysis of SVR12 based on the ITT population in 
HCV GT1, 2, 4, 5, and 6-infected subjects.  And only if success has been demonstrated for the second 
primary efficacy analysis will the testing proceed to the first key secondary efficacy analysis of SVR12
based on the PP population in HCV GT1, 2, 3, 4, 5, and 6-infected subjects, and so on.  For all primary 
and key secondary efficacy analyses, the percentage of subjects achieving SVR12 and a two-sided 95% 
confidence interval will be calculated using the normal approximation to the binomial distribution, 
unless the number of subjects who failed to achieve SVR12 is less than 5, then the Wilson's score method 
will be used for the confidence interval instead.
The other secondary efficacy analyses are listed below and are not included in the fixed-sequence 
testing:
!
The percentage of HCV GT3-infected subjects in the PP population who achieve SVR12;
!
The percentage of HCV GT3-infected subjects in the ITT population who achieve SVR12;
!
The percentage of subjects with on-treatment virologic failure (OTVF) across genotypes, within 
HCV GT 1, 2, 4, 5, and 6-infected subjects combined, and within HCV GT3-infected subjects 
(based on ITT population);
!
The percentage of subjects with post-treatment relapse across genotypes, within HCV GT 1, 2, 
4, 5, and 6-infected subjects combined, and within HCV GT3-infected subjects (based on ITT 
population).
The number and percentage of subjects will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of OTVF and post-treatment relapse, separate summaries will be provided for all 
subjects across genotypes, within HCV GT1, 2, 4, 5, and 6-infected subjects combined, and within HCV 
GT3-infected subjects.


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Statistical Methods (Continued):
Safety:
All subjects who receive at least one dose of study drug will be included in the safety analyses.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The number 
and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug through 30 days post-study drug dosing) will be 
tabulated by MedDRA System Organ Class (SOC) and preferred term.  The tabulation of the number of 
subjects with treatment-emergent adverse events also will be provided by severity grade (Grades 1 – 5) 
and relationship to study drug.  Mean changes in clinical laboratory and vital sign data from baseline to 
each post-baseline visit will be summarized.  The number and percentage of subjects with post-baseline 
laboratory values meeting toxicity grades and meeting pre-defined criteria for laboratory parameters of 
interest during treatment will be summarized.  The number and percentage of subjects with post-baseline 
vital sign values during the Treatment Period meeting pre-specified criteria for potentially clinically
significant vital sign values will be summarized.
Patient Reported Outcomes (PROs):
The mean change from baseline to each applicable post-baseline timepoint in the FSS total score and the 
SF-36v2 Mental Component Summary (SF-36-MCS) and Physical Component Summary SF-36-PCS 
scores will be summarized descriptively at each visit.  The TSQM subscales (global satisfaction, 
convenience, effectiveness, side effects) will be summarized descriptively at Weeks 2, 4, and 8 and the 
change from the baseline visit will be summarized at all on treatment timepoints.  
Pharmacokinetic:
Plasma concentration of glecaprevir and pibrentasvir will be tabulated for each subject.  Plasma 
concentrations of glecaprevir and pibrentasvir will be summarized based on last dosing time, sampling 
time and time since last dose.  Summary statistics will be computed for glecaprevir and pibrentasvir 
plasma concentrations binned by time since last dose.  
Resistance:
For all subjects receiving study drug and with available samples, baseline polymorphisms at signature 
resistance-associated amino acid positions identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the corresponding 
baseline sequence, 2) the amino acid substitutions in available post baseline samples at signature 
resistance-associated positions identified by NGS, and comparison to the appropriate prototypic 
reference sequence, and 3) the persistence of viral substitutions by NGS.
Section 3.0  Introduction
Fourth paragraph, first, second and third sentence previously read:
AbbVie has developed two next generation DAAs for use in combination for the 
treatment of HCV.  These next generation DAAs are glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI and pibrentasvir (PIB, formerly known as ABT-530), 


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an NS5A inhibitor.  GLE and PIB each have potent in vitro antiviral activity against 
genotypes 1 through 6,11 and a high genetic barrier to resistance with no or little loss of 
potency against common resistant-associated substitutions.  
Has been changed to read:
AbbVie has developed two next generation DAAs for use in combination for the 
treatment of HCV infection.  These next generation DAAs are glecaprevir (GLE, formerly 
known as ABT-493), an HCV NS3/4A PI and pibrentasvir (PIB, formerly known as 
ABT-530), an NS5A inhibitor.  Co-formulated GLE/PIB is now an approved treatment for 
infection with all six major HCV genotypes in patients without cirrhosis and with 
compensated cirrhosis.13,14  GLE and PIB each have potent in vitro antiviral activity 
against genotypes 1 through 6,11 and a high genetic barrier to resistance with no or little 
loss of potency against common resistant-associated substitutions.  
Section 3.0  Introduction
Subsection GLE/PIB
Heading "Overall Efficacy on the GLE/PIB Registrational Program and Among TN 
GT 1-, 2-, 4-, 5- or 6-Infected Subjects with Compensated Cirrhosis"
Heading previously read:
Overall Efficacy on the GLE/PIB Registrational Program and Among TN GT 1-, 2-, 4-, 5-
or 6-Infected Subjects with Compensated Cirrhosis
Has been changed to read:
Overall Efficacy on the GLE/PIB Registrational Program and Among TN GT 1 - 6-
Infected Subjects with Compensated Cirrhosis


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Section 3.0  Introduction
Subsection GLE/PIB
Heading "Overall Efficacy on the GLE/PIB Registrational Program and Among TN 
GT 1-, 2-, 4-, 5- or 6-Infected Subjects with Compensated Cirrhosis"
Add:  new last paragraph
In the registrational program, the SVR12 rate (ITT) was 98.5% (64/65) in HCV GT3-
infected, treatment-naïve subjects with compensated cirrhosis treated for 12 weeks.  No 
virologic failure was observed.  Therefore, the PP SVR12 rate in this population was 
100%.
Section 3.0  Introduction
Subsection GLE/PIB
Heading "Impact of Baseline Polymorphisms on Treatment Outcome"
Second and third paragraph previously read:
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.2% (2/164), 41.9% (13/31), and 2.9% (1/34) of subjects 
with HCV genotype 1, 2, 4, 5 and 6 infection, respectively.  Baseline polymorphisms in 
NS5A were detected in 26.8% (225/841), 79.8% (331/415), 49.7% (80/161), 12.9% 
(4/31), and 54.1% (20/37) of subjects with HCV genotype 1, 2, 4, 5, and 6 infection, 
respectively.
The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1-, 2-, 4-, 5-, or 6-infected subjects.  
Has been changed to read:
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% 
(1/34) of subjects with HCV genotype 1, 2, 3, 4, 5 and 6 infection, respectively.  Baseline 
polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% 
(136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV 
genotype 1, 2, 3, 4, 5, and 6 infection, respectively.


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The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1-, 2-, 4-, 5-, or 6-infected subjects.  Baseline polymorphisms in NS3 
did not have an impact on SVR12 in GT3-infected subjects.  Among baseline 
polymorphisms in NS5A in GT3-infected subjects, Y93H did not have an impact on 
SVR12 rates except in treatment-experienced non-cirrhotic subjects receiving 12 weeks of 
treatment.  A30K in NS5A at baseline was associated with lower SVR12 rates among non-
cirrhotic treatment-naïve subjects receiving 8 weeks of treatment and treatment-
experienced subjects receiving 12 weeks of treatment, but had no impact on SVR12 rates 
in treatment-naïve non-cirrhotic subjects receiving 12 weeks of treatment.  The SVR12
rates in subjects with A30K at baseline were 77.8% (14/18), 25.0% (1/4), and 92.9% 
(13/14) among treatment-naïve subjects receiving 8 weeks, treatment-experienced 
subjects receiving 12 weeks, and treatment-naïve subjects receiving 12 weeks of 
treatment, respectively.  Given the A30K prevalence of 6.3% among GT3-infected 
subjects, the difference in SVR12 attributable to the impact of A30K between the 8 and 
12 weeks treatment duration is < 1%.  Among treatment-experienced non-cirrhotic or 
cirrhotic subjects receiving 16 weeks of treatment, the impact of A30K is unclear due to 
the low prevalence of the polymorphism in this arm of the study.
Section 3.0  Introduction
Subsection Glecaprevir/Pibrentasvir (GLE/PIB) PK Modeling for Study M16-135
Subsection title previously read:
Glecaprevir/Pibrentasvir (GLE/PIB) PK Modeling for Study M16-135
Has been changed to read:
Glecaprevir/Pibrentasvir (GLE/PIB) Viral Dynamic Modeling for Study M16-135


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Section 3.0  Introduction
Subsection Glecaprevir/Pibrentasvir (GLE/PIB) PK Modeling for Study M16-135
Second paragraph, last sentence previously read:
The clinical trial simulation scenarios for an 8-week treatment duration in non-cirrhotic, 
treatment-naïve subjects resulted in an SVR12 rate of approximately 98% in GT 1-, 2-, 4-, 
5-, or 6-infected subjects and approximately 92% for GT3-infected subjects.
Has been changed to read:
The clinical trial simulation scenarios for an 8-week treatment duration in treatment-naïve
subjects with compensated cirrhosis resulted in an SVR12 rate of approximately 98% in 
GT 1-, 2-, 4-, 5-, or 6-infected subjects and approximately 92% for GT3-infected subjects.
Section 3.0  Introduction
Subsection Glecaprevir/Pibrentasvir (GLE/PIB) PK Modeling for Study M16-135
Last paragraph previously read:
The objectives of this study are to evaluate the efficacy and safety of 8 weeks of GLE/PIB 
for the treatment of treatment-naïve subjects with chronic HCV GT 1, 2, 4, 5 or 6 
infection and compensated cirrhosis.
Has been changed to read:
The objectives of this study are to evaluate the efficacy and safety of 8 weeks of GLE/PIB 
for the treatment of treatment-naïve subjects with chronic HCV GT 1 - 6 infection and 
compensated cirrhosis.
Section 3.1  Differences Statement
First sentence previously read:
The current Phase 3b Study M16-135 is the first study to evaluate the efficacy and safety 
of GLE/PIB in treatment-naïve adult subjects with chronic HCV GT 1, 2, 4, 5, or 6 
infection with compensated cirrhosis for 8 weeks.  


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Has been changed to read:
The current Phase 3b Study M16-135 is the first study to evaluate the efficacy and safety 
of GLE/PIB in treatment-naïve adult subjects with chronic HCV GT 1 - 6 infection with 
compensated cirrhosis for 8 weeks.  
Section 3.1  Differences Statement
Delete:  third, fourth, fifth and sixth sentence
In the registrational program, 117 treatment naïve GT 1, 2, 4, 5 or 6 compensated cirrhotic 
subjects were treated with GLE/PIB for 12 weeks duration and 115 subjects achieved 
SVR12.  No virologic failure was observed.  Two subjects did not achieve SVR12:  one 
discontinued treatment early and another had missing SVR12 data.  Hence, the combined 
SVR12 rate for treatment naïve GT 1, 2, 4, 5, 6 compensated cirrhotic subjects was 100% 
(115/115), based on the PP population.
Section 3.2  Benefits and Risks
First paragraph, first sentence previously read:
This Phase 3b study is a single arm study in which eligible HCV GT 1, 2, 4, 5, or 6 
infected subjects with compensated cirrhosis will receive GLE/PIB for 8 weeks.  
Has been changed to read:
This Phase 3b study is a single arm study in which eligible HCV GT 1 - 6 infected 
subjects with compensated cirrhosis will receive GLE/PIB for 8 weeks.  
Section 3.2  Benefits and Risks
First paragraph, last sentence previously read:
The results of these studies, together with PK modeling based on the registrational data, 
suggest that the likelihood of demonstrating a high SVR12 rate with an 8 week regimen in 
subjects with HCV GT 1, 2, 4, 5 or 6 infection with compensated cirrhosis is high.


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Has been changed to read:
The results of these studies, together with PK modeling based on the registrational data, 
suggest that the likelihood of demonstrating a high SVR12 rate with an 8 week regimen in 
subjects with HCV GT 1 - 6 infection with compensated cirrhosis is high.
Section 3.2  Benefits and Risks
Second paragraph, last sentence previously read:
The GLE/PIB regimen is potent; according to a Phase 2 and 3 analysis SVR12 rates in 
treatment naïve cirrhotics treated for 12 weeks were 97.2% (69/71) for GT 1 and 100% 
(46/46) for GT 2, 4 – 6.  Overall, the SVR12 rate is 98.3% (115/117) for GT 1, 2, 4, 5, or 
6.
Has been changed to read:
The GLE/PIB regimen is potent; according to a Phase 2 and 3 analysis, SVR12 rates in 
treatment naïve cirrhotics treated for 12 weeks were 97.2% (69/71) for GT 1 and 100% 
(46/46) for GT 2, 4 – 6.  Overall, the SVR12 rate was 98.3% (115/117) for GT 1, 2, 4, 5, or 
6.  The SVR12 rate in treatment naïve cirrhotics with GT3 infection treated for 12 weeks 
was 98.5% (64/65).
Section 3.2  Benefits and Risks
Seventh paragraph previously read:
An assessment of the post-treatment relapse rate will be performed when the 
first 30 subjects reach Post-treatment Week 4 and will be done periodically thereafter, in 
order to minimize exposure to a potentially suboptimal duration.
Has been changed to read:
An assessment of the post-treatment relapse rate occurring in this study in the non-GT3 
and in the GT3 population will be performed on a periodic basis in order to minimize 
exposure to a potentially suboptimal duration (see Section 5.4.1.2).


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Section 3.2  Benefits and Risks
Last paragraph previously read:
Overall, given the potential for achieving SVR12 with 8 weeks of treatment in this 
population of HCV GT 1, 2, 4, 5 or 6 infected subjects with compensated cirrhosis, the 
risk-benefit assessment is considered favorable.
Has been changed to read:
Overall, given the potential for achieving SVR12 with 8 weeks of treatment in this 
population of HCV GT 1 - 6 infected subjects with compensated cirrhosis, the risk-benefit 
assessment is considered favorable.
Section 4.1  Primary Objective
Bullet list previously read:
●
To demonstrate the efficacy of the SVR12 rate of 8 weeks of treatment with 
glecaprevir/pibrentasvir compared to the historical SVR12 rate of 12 weeks of 
treatment with glecaprevir/pibrentasvir in treatment naïve adults with chronic 
HCV GT 1, 2, 4, 5 or 6 infection and compensated cirrhosis.  
●
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in 
treatment naïve adults with chronic HCV GT 1, 2, 4, 5 or 6 infection and 
compensated cirrhosis.
Has been changed to read:
●
To demonstrate the efficacy of the SVR12 rates of 8 weeks of treatment with 
glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of 
treatment with glecaprevir/pibrentasvir in treatment naïve adults with chronic 
HCV infection and compensated cirrhosis.  
●
To assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir in 
treatment naïve adults with chronic HCV infection and compensated cirrhosis.


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Section 5.1  Overall Study Design and Plan:  Description
First paragraph previously read:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of GLE/PIB in HCV treatment-naïve adult subjects with chronic HCV GT 1, 2, 4, 
5 or 6 infection and compensated cirrhosis.
Has been changed to read:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of GLE/PIB in HCV treatment-naïve adult subjects with chronic HCV GT 1 - 6 
infection and compensated cirrhosis.  The study will initially enroll subjects with HCV 
GT 1, 2, 4, 5 and 6 infection followed by subjects with HCV GT3 infection.  Once 
enrollment of subjects with HCV GT3 infection begins, enrollment of subjects with HCV 
GT 1, 2, 4, 5 or 6 infection will be closed.  
Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph previously read:
An efficacy assessment will evaluate the post-treatment relapse rate after the first 
30 subjects reach Post-Treatment Week 4 and will be done periodically thereafter.  If 
more than 10% of subjects experience post-treatment relapse, an analysis will be 
conducted to determine if extension of treatment to 12 weeks is needed for all subjects or 
for a particular subgroup of subjects who are on treatment or have completed treatment 
within the previous 7 days.
Has been changed to read:
An assessment of the post-treatment relapse rate occurring in this study in the non-GT3 
and in the GT3 population will be performed on a periodic basis in order to minimize 
exposure to a potentially suboptimal duration (see Section 5.4.1.2).  


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Section 5.1  Overall Study Design and Plan:  Description
Tenth paragraph, first sentence previously read:
The study is designed to enroll approximately 270 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Has been changed to read:
The study is designed to enroll approximately 330 subjects (approximately 270 with GT1, 
2, 4, 5, or 6 infection and approximately 60 with GT3 infection) to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Section 5.1  Overall Study Design and Plan:  Description
Last paragraph previously read:
The primary analysis will occur after all subjects have completed the Post-Treatment 
Week 12 Visit or prematurely discontinued from the study.
Has been changed to read:
Analyses will occur after subjects have completed the Post-Treatment Week 12 Visit or 
prematurely discontinued from the study, starting with HCV GT1, 2, 4, 5, and 6-infected 
subjects.
Section 5.2  Selection of Study Population
First sentence previously read:
The study population consists of treatment-naïve male and female adults aged 18 years or 
older with chronic HCV GT 1, 2, 4, 5, or 6 infection, with compensated cirrhosis.  
Has been changed to read:
The study population consists of treatment-naïve male and female adults aged 18 years or 
older with chronic HCV GT 1 - 6 infection, with compensated cirrhosis.  


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Section 5.2.1  Inclusion Criteria
Criterion 4 previously read:
Screening central laboratory result indicating HCV GT1, 2, 4, 5, or 6-infection.
Has been changed to read:
Screening central laboratory result indicating HCV GT1 - 6-infection.
Section 5.2.2  Exclusion Criteria
Criterion 2 previously read:
HCV genotype performed by the central laboratory during screening indicating 
genotype 3 infection or co-infection with more than one HCV genotype.
Has been changed to read:
HCV genotype performed by the central laboratory during screening indicating co-
infection with more than one HCV genotype.
Section 5.2.3.3  Prohibited Therapy
First paragraph previously read:
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 4 at least 14 days or 10 half-lives (whichever is longer) prior to the 
first dose of GLE/PIB and not use these during the entire Treatment Period and for 
14 days following discontinuation of study drug.
Has been changed to read:
Medications or supplements prohibited to be administered with GLE/PIB are listed in 
Table 4.  For subjects in the study in countries where GLE/PIB has received marketing 
authorization, any medications in the local label that are contraindicated to be 
administered with GLE/PIB are also considered to be prohibited medications.  Subjects 
must be able to safely discontinue any prohibited medications or supplements at least 
14 days or 10 half-lives (whichever is longer) prior to the first dose of GLE/PIB and not 


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use these during the entire Treatment Period and for 14 days following discontinuation of 
study drug.  The Informed Consent Form must be signed and dated prior to discontinuing 
any prohibited medications or supplements.
Table 4.  Prohibited Medications and Supplements
Add:  
Tipranavir/r, atazanavir, efavirenz
Table 4.  Prohibited Medications and Supplements
Table note "*" previously read:  
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) 
should not be taken with the study drug.  Subjects receiving these statins should either 
(a) switch to pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is 
longer) prior to the first dose of study drug or (b) interrupt statin therapy throughout the 
treatment period beginning at least 14 days or 10 half-lives (whichever is longer) prior to 
the first dose of study drug and until 14 days after the last dose of study drug, based on 
investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, it is 
recommended to either 1) reduce the pravastatin or rosuvastatin dose in accordance with 
the ABT-493/ABT-530 approved local product label; or 2) reduce the pravastatin dose by 
50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug if 
ABT-493/ABT-530 is not yet approved in the respective location.
Has been changed to read:
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) 
should not be taken with the study drug.  After signing the consent form, subjects 
receiving these statins should either (a) switch to pravastatin or rosuvastatin at least 
14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug or 
(b) may interrupt statin therapy throughout the treatment period beginning at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of study drug and until 14 
days after the last dose of study drug, based on investigator's judgment.  If switching to or 
continuing pravastatin or rosuvastatin, it is recommended to either 1) reduce the 


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pravastatin or rosuvastatin dose in accordance with the GLE/PIB approved local product 
label (if approved in the country); or 2) reduce the pravastatin dose by 50% or limit the 
rosuvastatin dose to 10 mg QD when taking with the study drug if GLE/PIB is not yet 
approved in the respective location.
Section 5.3.1.1  Study Procedures
Subsection HCV Genotype and Subgenotype
Subsection title previously read:
HCV Genotype and Subgenotype
Has been changed to read:
HCV Genotype and Subtype
Section 5.3.2.4  Measurement Methods
First sentence previously read:
Plasma concentrations of GLE and PIB will be determined using a validated method by 
the Drug Analysis Department at AbbVie.  
Has been changed to read:
Plasma concentrations of GLE and PIB will be determined using a validated method by 
the Bioanalysis Department at AbbVie.  
Section 5.4.1.2  Treatment Extension Criteria
Previously read:
An efficacy assessment will evaluate the post-treatment relapse rate when the first 
30 subjects reach Post-Treatment Week 4 and will be done periodically thereafter.  If 
more than 10% of subjects experience post-treatment relapse, an analysis will be 
conducted to determine if extension of treatment to 12 weeks is needed for all subjects or 
for a particular subgroup of subjects who are on treatment or have completed treatment 
within the previous 7 days.


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The enrollment of additional subjects in this study will be terminated if extension of 
treatment is needed for all subjects.  If the extension is needed for a particular subgroup of 
subjects, then the enrollment will be terminated for this particular subgroup but other 
subgroups will continue to be allowed to enroll in the study with 8 weeks treatment 
duration. 
Retreatment of subjects who experience virologic failure with the GLE/PIB regimen for 
8 weeks will be offered retreatment in the AbbVie Study M15-942.
Has been changed to read:
Because subjects with GT 1, 2, 4, 5 or 6 infection will be enrolled first, separate treatment 
extension criteria will apply to subjects with GT 1, 2, 4, 5 or 6 infection versus subjects 
with GT3 infection, as described below.  However, if treatment is extended for all or a 
particular subgroup of subjects with GT 1, 2, 4, 5 or 6 infection, then enrollment of 
subjects with GT3 infection will be terminated and all GT3-infected subjects who are on 
treatment or have completed treatment within the previous 7 days will have their 
treatment extended to 12 weeks.
In subjects with GT 1, 2, 4, 5, or 6 infection, an efficacy assessment will evaluate the 
post-treatment relapse rate when the first 30 subjects reach Post-Treatment Week 4 and 
will be done periodically thereafter.  If more than 10% of subjects experience post-
treatment relapse, an analysis will be conducted to determine if extension of treatment to 
12 weeks is needed for all GT 1, 2, 4, 5, and 6-infected subjects or for a particular 
subgroup of GT 1, 2, 4, 5, and 6-infected subjects who are on treatment or have completed 
treatment within the previous 7 days.
The enrollment of additional GT 1, 2, 4, 5, or 6-infected subjects in this study will be 
terminated if extension of treatment is needed for all GT 1, 2, 4, 5, or 6-infected subjects.  
If the extension is needed for a particular subgroup of GT 1, 2, 4, 5, or 6-infected subjects, 
then the enrollment will be terminated for this particular subgroup but other subgroups 
will continue to be allowed to enroll in the study with 8 weeks treatment duration. 


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In subjects with GT3 infection, an efficacy assessment will evaluate the post-treatment 
relapse rate after the first 20 subjects reach Post-Treatment Week 4 and will be done 
periodically thereafter.  If more than 10% of subjects experience post-treatment relapse, 
an analysis will be conducted to determine if extension of treatment to 12 weeks is needed 
for all GT3-infected subjects or for a particular subgroup of GT3-infected subjects who 
are on treatment or have completed treatment within the previous 7 days.
The enrollment of additional GT3-infected subjects in this study will be terminated if 
extension of treatment is needed for all GT3-infected subjects.  If the extension is needed 
for a particular subgroup of GT3-infected subjects, then the enrollment will be terminated 
for this particular subgroup but other subgroups will continue to be allowed to enroll in 
the study with 8 weeks treatment duration.  Retreatment of subjects who experience 
virologic failure with the GLE/PIB regimen for 8 weeks will be offered retreatment in the 
AbbVie Study M15-942.
Section 5.6.1  Discussion of Study Design and Choice of Control Groups
Previously read:
The current study (Study M16-135) is a multicenter, single-arm, open-label, Phase 3b 
study evaluating the efficacy and safety of the co-formulated combination regimen of 
GLE 300 mg and PIB 120 mg QD administered for 8 weeks in treatment-naïve subjects 
with chronic HCV GT 1, 2, 4, 5 or 6 infection and compensated cirrhosis.  
The 12-week regimen of GLE/PIB was studied in adults with chronic HCV GT 1, 2, 4, 5, 
or 6 infection and compensated cirrhosis in Study M14-172.  Other Phase 3 studies also 
enrolled a few cirrhotic subjects.  The integrated analysis of the registrational studies will 
serve as the historical control and reference point for the design of the current trial. 
In the registrational program, 117 treatment naïve subjects with compensated cirrhosis 
infected with GTs 1, 2, 4, 5, or 6 were treated with GLE/PIB for a 12 weeks.  Of those, 
2 subjects did not achieve SVR12 (one discontinued treatment early and the other had 
missing SVR12 data).  No virologic failure was observed.  Hence, the historical SVR12 rate 
based on PP population (defined as subjects who receive at least one dose of study drug, 


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with the exception of subjects who experience breakthrough, or prematurely discontinue 
treatment prior to Week 8, or have no HCV RNA value in the SVR12 visit window or 
later) is 100%.  The observed rate of non-virologic failure in the GLE/PIB registrational 
program was 1.2% (29/2369).  For this reason, this study assumes that the historical 
SVR12 rate for the ITT population will be 99% (assuming 1% of non-virologic failures). 
The observed SVR rates for the GLE/PIB 12 weeks duration in the Phase 2/3 
development program is very high (> 97%) for the treatment naïve GT 1, 2, 4, 5, or 6 
cirrhotic subjects.  Given such a high SVR rate, an active control arm does not provide 
value in establishing the efficacy of the new regimen.  That is, the efficacy of the new 
regimen can be established via an absolute criterion (comparison to a threshold) rather 
than a relative criterion (non-inferiority to an active control).  Hence, the observed SVR 
rate from Phase 2/3 program will be used as historical control to provide a comparator for 
assessment of efficacy for the 8-week arm in this study for the treatment naïve cirrhotic 
patients. 
A threshold for the primary efficacy endpoint of the 8 weeks GLE/PIB regimen to the 
historical control is determined by subtracting a margin of 6% from the historical SVR12
rate of 100% or 99% (for PP or ITT population, respectively) for GLE/PIB for 12 weeks. 
A margin of 6% is selected to be used in this study to ensure a minimal loss of efficacy of 
the 8-week arm relative to the historical SVR12 rate for 12-week arm, and is in alignment 
with the GLE/PIB registrational program.
Thus, to establish efficacy of 8 weeks GLE/PIB to the 12 weeks GLE/PIB in treatment 
naïve cirrhotic subjects, the lower bound of the 95% CI for the SVR12 rate in the active 
arm must exceed 94% or 93% for PP and ITT population, respectively.
Has been changed to read:
The current study (Study M16-135) is a multicenter, single-arm, open-label, Phase 3b 
study evaluating the efficacy and safety of the co-formulated combination regimen of 


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GLE 300 mg and PIB 120 mg QD administered for 8 weeks in treatment-naïve subjects 
with chronic HCV GT 1 - 6 infection and compensated cirrhosis.  
The 12-week regimen of GLE/PIB was studied in adults with chronic HCV GT 1, 2, 4, 5, 
or 6 infection and compensated cirrhosis in Study M14-172 and studied in adults with 
chronic HCV GT3 infection and compensated cirrhosis in Study M14-868.  Other Phase 3 
studies also enrolled a few cirrhotic subjects.  The integrated analysis of the registrational 
studies will serve as the historical control and reference point for the design of the current 
trial. 
In the registrational program, 117 treatment naïve subjects with compensated cirrhosis 
infected with GTs 1, 2, 4, 5, or 6 were treated with GLE/PIB for a 12 weeks.  Of those, 
2 subjects did not achieve SVR12 (one discontinued treatment early and the other had 
missing SVR12 data).  No virologic failure was observed.  Hence, the historical SVR12 rate 
based on PP population is 100% for GT1, 2, 4, 5, and 6-infected subjects.  Similarly, the 
historical SVR12 rate based on a PP population is 100% for GT1-6-infected subjects, as 65 
treatment naïve subjects with compensated cirrhosis infected with GT3 were treated with 
GLE/PIB for 12 weeks.  Of those, 1 subject did not achieve SVR12 due to missing SVR12
data.  No virologic failure was observed.
The observed rate of non-virologic failure in the overall GLE/PIB registrational program 
was 1.2% (29/2369).  For this reason, this study assumes that the historical SVR12 rate for 
the ITT population for GT1, 2, 4, 5, and 6-infected and for GT1-6-infected subjects will 
be 99% (assuming 1% of non-virologic failures).  The observed SVR rates for the 
GLE/PIB 12 weeks duration in the Phase 2/3 development program is very high (> 97%) 
for the treatment naïve GT 1, 2, 3, 4, 5, or 6-infected cirrhotic subjects.  Given such a high 
SVR rate, an active control arm does not provide value in establishing the efficacy of the 
new regimen.  That is, the efficacy of the new regimen can be established via an absolute 
criterion (comparison to a threshold) rather than a relative criterion (non-inferiority to an 
active control).  Hence, the observed SVR rate from Phase 2/3 program will be used as 
historical control to provide a comparator for assessment of efficacy for the 8-week arm in 
this study for the treatment naïve cirrhotic patients. 


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A threshold for the primary and key secondary efficacy analyses of the 8 weeks GLE/PIB 
regimen to the historical control is determined by subtracting a margin of 6% from the 
historical SVR12 rate of 100% or 99% (for PP or ITT population, respectively) for 
GLE/PIB for 12 weeks. 
A margin of 6% is selected to be used in this study to ensure a minimal loss of efficacy of 
the 8-week arm relative to the historical SVR12 rate for 12-week arm, and is in alignment 
with the GLE/PIB registrational program.
Thus, to establish efficacy of 8 weeks GLE/PIB to the 12 weeks GLE/PIB in treatment 
naïve cirrhotic subjects, the lower bound of the 95% CI for the SVR12 rate in the 8-week 
arm must exceed 94% or 93% for the PP and ITT populations, respectively.
Section 5.6.3  Suitability of Subject Population
First, second, and third paragraph previously read:
Results from the Registrational Program with GLE/PIB show that lower SVR12 rates were 
achieved in GT3-infected subjects (93.5%) than for other Genotypes (97.4 to 100%) 
(Table 2).  Exposure-viral load modeling and simulations were conducted and predicted  
lower SVR12 rate for treatment naïve GT3 subjects with cirrhosis (92%) compared to the 
rate in treatment naïve non-GT3 subjects (98%), without accounting for failures due to 
non-virologic reasons.  Therefore, subjects infected with GT3 were excluded from the 
population to be enrolled in this trial.
This subject population will include treatment-naïve subjects only.  While predictive 
models suggest high SVR12 rates with 8 weeks of GLE/PIB, the ultrashort nature of this 
study risks an increase of post-treatment relapse or EOT failure in treatment-experienced 
patients. 
This study will exclude subjects with HIV/HCV coinfection, as this sub-population is 
currently being evaluated in Study M14-730.


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Has been changed to read:
HCV GT3-infected patients are known to be a more difficult to treat population for DAA-
based regimens.  Therefore, subjects infected with HCV GT1, 2, 4, 5 and 6 were enrolled 
first in this trial, while subjects infected with HCV GT3 were initially excluded.  The 
protocol was later amended to include GT3-infected subjects based on the following 
registrational clinical data:
●
SVR12 rate (ITT) of 98.5% (64/65) in treatment-naïve GT3-infected subjects 
with compensated cirrhosis treated for 12 weeks of GLE/PIB, with no 
virologic failures observed; the PP SVR12 rate was 100% (64/64).
●
SVR12 rate (ITT) of 95.2% (177/186) and 95.6% (258/270) in treatment-naïve 
GT3-infected subjects without cirrhosis treated for 8 and 12 weeks of 
GLE/PIB, respectively; PP SVR12 rates were 97.3% (177/182) and 98.9% 
(258/261) for 8 and 12 weeks of GLE/PIB, respectively.15
●
GLE/PIB for 8 weeks in treatment-naïve GT3-infected subjects without 
cirrhosis was determined to be non-inferior to GLE/PIB for 12 weeks in 
Study M13-594 (ENDURANCE-3).16
This subject population will include treatment-naïve subjects only.  While high SVR12
rates with 8 weeks of GLE/PIB are expected, the ultrashort nature of this study risks an 
increase of post-treatment relapse or EOT failure in treatment-experienced patients. 
This study will exclude subjects with HIV/HCV coinfection, as this sub-population is 
currently being evaluated in Study M14-730 (EXPEDITION-2).17
Section 5.6.4.2  GLE and PIB Dose and Treatment Duration
Previously read:
GLE/PIB 300 mg/120 mg QD regimens with 8-week and 12-week durations were 
evaluated in non-cirrhotic subjects in registrational trials.  Efficacy of 8-week treatment 
duration is established for GT1- or GT2-infected non-cirrhotic subjects [R&D/16/0144, 
R&D/15/1230].  Fifty-two non-cirrhotic GTs 4, 5, or 6 subjects received 8-weeks of 
GLE/PIB and no virologic failure was observed.  Overall, these results conclude that 


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8-weeks of GLE/PIB 300 mg/120 mg dose is efficacious for non-cirrhotic GT 1, 2, 4, 5, or 
6 subjects.  
Based on modeling simulations, assuming no subjects experiencing non-virologic failures, 
the predicted SVR12 rate in treatment-naïve HCV GT1-, GT2-, GT4-, GT5- and 
GT6-infected subjects with 8 weeks of GLE/PIB is approximately 98%.
Has been changed to read:
GLE/PIB 300 mg/120 mg QD regimens with 8-week and 12-week durations were 
evaluated in non-cirrhotic subjects in registrational trials.  Efficacy of 8-week treatment 
duration is established for GT1-, GT2- and GT3- infected non-cirrhotic subjects 
[R&D/16/0144, R&D/15/1230].  Fifty-two non-cirrhotic GTs 4, 5, or 6-infected subjects 
received 8-weeks of GLE/PIB and no virologic failure was observed.  Overall, these 
results conclude that 8-weeks of GLE/PIB 300 mg/120 mg dose is efficacious for non-
cirrhotic GT 1 - 6-infected subjects.  
Based on modeling and simulations, assuming no subjects experience non-virologic 
failures, following 8 weeks of GLE/PIB in treatment-naïve HCV-infected subjects with 
compensated cirrhosis, the predicted SVR12 rate is approximately 98% for GT1, 2, 4, 5, 
and 6-infected subjects, and approximately 92% for GT3-infected subjects.
Section 6.1.5  Adverse Event Reporting
"Primary Therapeutic Area Medical Director:" previously read:
Associate Medical Director
1 North Waukegan Road
North Chicago, IL 60064 
Telephone Contact Information:
Office:
Mobile:
eFAX:
Email:


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Has been changed to read:
, MD
Medical Director
1500 Seaport Blvd.
Redwood City, CA 94063
Telephone Contact Information:
Office:
Mobile:
eFAX:
Email:
Section 8.1  Statistical and Analytical Plans
First paragraph previously read:
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued study.  The data for the primary analysis will be locked after 
data cleaning.  Data after PT Week 12 will be added to a new version of the database 
which will be cleaned and locked at the end of the study.
Has been changed to read:
Analyses will occur after subjects have completed the PT Week 12 Visit or prematurely 
discontinued study.  The first analysis will occur after all HCV GT1, 2, 4, 5, and 6-
infected subjects have completed the PT Week 12 Visit or prematurely discontinued 
study; the second analysis will occur after all HCV GT3-infected subjects have completed 
the PT Week 12 Visit or prematurely discontinued study; the third and final analysis will 
occur after all subjects have completed or prematurely discontinued from the study.
Section 8.1  Statistical and Analytical Plans
Sixth and seventh paragraph previously read:
The primary efficacy analyses will be performed on the PP and ITT populations.  The 
secondary efficacy analyses will be performed on the ITT population.  


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Sensitivity analyses of SVR12, when applicable, will be performed on the intention-to-
treat population modified to exclude subjects who were enrolled with ineligible genotypes 
(e.g., GT3 according to phylogenetic analyses) (mITT-GT), and on the mITT-GT 
population modified to exclude subjects who did not achieve SVR12 for reasons other than 
virologic failure (mITT-GT-VF).
Has been changed to read:
The primary and key secondary efficacy analyses will be performed on the PP and ITT 
populations, as specified.  The other secondary efficacy analyses will be performed on the 
ITT population, unless otherwise specified.  
Sensitivity analyses of SVR12, when applicable, will be performed on the intention-to-
treat population modified to exclude subjects who were enrolled with ineligible genotypes 
(e.g., GT3 according to phylogenetic analyses for the group of non-GT3-infected subjects) 
(mITT-GT), and on the mITT-GT population modified to exclude subjects who did not 
achieve SVR12 for reasons other than virologic failure (mITT-GT-VF).
Section 8.1.1  Demographics and Baseline Characteristics
First paragraph, last sentence previously read:
Baseline characteristics will be summarized as continuous variables (where appropriate) 
and as categorical variables, including all subgroup variables defined in Section 8.1.2.4, in 
addition to HCV genotype and subtype, baseline Child-Pugh score, tobacco and alcohol 
use status, history of bleeding disorders, history of depression or bipolar disorder, and 
history of cardiovascular disease.
Has been changed to read:
Baseline characteristics will be summarized as continuous variables (where appropriate) 
and as categorical variables, including all subgroup variables defined in Section 8.1.2.4, in 
addition to HCV genotype and subtype, baseline Child-Pugh score, tobacco and alcohol 
use status.


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Section 8.1.2  Efficacy
First paragraph previously read:
The primary efficacy analyses will be performed on both the PP and ITT populations and 
all the secondary efficacy endpoints will be analyzed based on ITT population.
Has been changed to read:
The primary and key secondary efficacy analyses will be performed on both the PP and 
ITT populations, as specified.  The other secondary efficacy analyses will be analyzed 
based on ITT population, unless otherwise specified.
Section 8.1.2.1  Primary Efficacy Endpoints
Previously read:
The two primary efficacy endpoints are comparisons of the SVR12 rate of the 8-week 
treatment duration to a historical SVR12 rate for 12 weeks in the Per-Protocol (PP) 
population and in the Intention-to-Treat (ITT) population.  The primary efficacy analyses 
will be performed across genotypes following a fixed-sequence testing procedure:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of subjects in the 8-week treatment duration 
achieving SVR12 is greater than 94% in the PP population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of subjects in the 8-week treatment duration 
achieving SVR12 is greater than 93% in the ITT population.
The primary efficacy endpoints will be tested using the hierarchical order outlined above 
to control the Type I error rate.  Only if success has been demonstrated for the 
first primary efficacy endpoint of SVR12 based on the PP population will the testing 
proceed to the second primary efficacy endpoint of SVR12 based on the ITT population. 


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For the first primary efficacy endpoint, the PP population will be used.  The PP analysis is 
used to reduce the risk of bias toward no treatment difference that can occur due to 
dropouts or other measurement problems, since the subjects excluded in the PP population 
experience SVR failure for reasons that do not help in discriminating between treatment 
durations.  
For both primary efficacy endpoints, the percentage of subjects achieving SVR12 and a 
two-sided 95% confidence interval will be calculated using the normal approximation to 
the binomial distribution, unless the number of subjects who failed to achieve SVR12 is 
less than 5, then the Wilson's score method will be used for the confidence interval 
instead. 
A summary of reason for SVR12 non-response (e.g., OTVF, post-treatment relapse, other) 
will be provided.
Has been changed to read:
The two primary efficacy analyses are:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 4, 5, and 6-infected subjects 
in the 8-week treatment duration achieving SVR12 is greater than 94% in the PP 
population.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 4, 5, and 6-infected subjects 
in the 8-week treatment duration achieving SVR12 is greater than 93% in the ITT 
population.


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The two primary and two key secondary (defined in Section 8.1.2.2.1) efficacy analyses 
will be performed following a fixed-sequence testing procedure which is described in 
Section 8.1.2.6.
Only if success has been demonstrated for the first primary efficacy analysis of SVR12
based on the PP population in HCV GT1, 2, 4, 5, and 6-infected subjects will the testing 
proceed to the second primary efficacy analysis of SVR12 based on the ITT population in 
HCV GT1, 2, 4, 5, and 6-infected subjects.  And only if success has been demonstrated 
for the second primary efficacy analysis will the testing proceed to the key secondary 
efficacy analyses described in Section 8.1.2.2.1.
For the first primary efficacy analysis, the PP population will be used.  The PP analysis is 
used to reduce the risk of bias toward no treatment difference that can occur due to 
dropouts or other measurement problems, since the subjects excluded in the PP population 
experience SVR failure for reasons that do not help in discriminating between treatment 
durations.  
For both primary efficacy analyses, the percentage of subjects achieving SVR12 and a 
two-sided 95% confidence interval will be calculated using the normal approximation to 
the binomial distribution, unless the number of subjects who failed to achieve SVR12 is 
less than 5, then the Wilson's score method will be used for the confidence interval 
instead. 
A summary of reason for SVR12 non-response (e.g., OTVF, post-treatment relapse, other) 
will be provided.
Section 8.1.2.2  Secondary Efficacy Endpoints
Previously read:
The secondary efficacy endpoints are:
●
The percentage of subjects with OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA 


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≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment with at least 6 weeks of treatment), and 
●
The percentage of subjects with post-treatment relapse (Relapse12:  defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
the last dose of study drug [up to and including the SVR12 assessment time 
point] among subjects who completed treatment as planned [defined as study 
drug duration ≥ 52 days for subjects assigned to 8 weeks of treatment] with 
HCV RNA < LLOQ at the end of treatment; excluding subjects who have been 
shown to be reinfected).
For the analysis of OTVF and post-treatment relapse, the number and percentage of 
subjects in the ITT population will be summarized along with a two-sided 95% 
confidence interval using Wilson's score method.
Has been changed to read:
8.1.2.2.1
Key Secondary Efficacy Endpoints
The two key secondary efficacy analyses included in the fixed-sequence are listed below:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 3, 4, 5, and 6-infected 
subjects in the 8-week treatment duration achieving SVR12 is greater than 94% in 
the PP population;
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT1, 2, 3, 4, 5, and 6-infected 
subjects in the 8-week treatment duration achieving SVR12 is greater than 93% in 
the ITT population.
Only if success was demonstrated for both primary efficacy analyses will testing proceed 
to the two key secondary efficacy analyses in the order listed above.  If success has been 


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demonstrated for the first key secondary efficacy analysis of SVR12 based on the PP 
population in HCV GT1-6-infected subjects, then testing will proceed to the second key 
secondary efficacy analysis of SVR12 based on the ITT population in HCV GT1-6-
infected subjects.
8.1.2.2.2
Other Secondary Efficacy Endpoints
The other secondary efficacy analyses, which are not included in the fixed sequence, are 
listed below:
●
The percentage of HCV GT3-infected subjects in the PP population who 
achieve SVR12;
●
The percentage of HCV GT3-infected subjects in the ITT population who 
achieve SVR12;
●
The percentage of subjects with OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA 
≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment with at least 6 weeks of treatment), and 
●
The percentage of subjects with post-treatment relapse (Relapse12:  defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
the last dose of study drug [up to and including the SVR12 assessment time 
point] among subjects who completed treatment as planned [defined as study 
drug duration ≥ 52 days for subjects assigned to 8 weeks of treatment] with 
HCV RNA < LLOQ at the end of treatment; excluding subjects who have been 
shown to be reinfected).
For the analyses of SVR12 among HCV GT3-infected subjects, the number and percentage 
of subjects achieving SVR12 will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of OTVF and post-treatment relapse, the number and percentage of 
subjects in the ITT population will be summarized along with a two-sided 95% 
confidence interval using Wilson's score method.  Separate summaries will be provided 


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for all subjects across genotypes, within HCV GT1, 2, 4, 5, and 6-infected subjects 
combined, and within HCV GT3-infected subjects.
Section 8.1.2.3  Sensitivity Analysis
Last paragraph previously read:
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated if applicable, as a sensitivity analysis for the primary endpoint of SVR12 based 
on both PP and ITT populations.
Has been changed to read:
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated if applicable, as a sensitivity analysis for the primary and key secondary 
efficacy analyses of SVR12 based on the PP and ITT populations.
Section 8.1.2.4  Subgroup Analysis
First bullet previously read:
HCV genotype and genotype 1 subtype;
Has been changed to read:
HCV genotype and subtype;
Section 8.1.2.4  Subgroup Analysis
Delete:  fourth bullet
IL28B genotype;
Section 8.1.2.6  Multiplicity
Previously read:
In order to control the Type I error rate, a fixed sequence testing procedure will be used 
for the SVR12 primary efficacy endpoints.  Only if success has been demonstrated for the 
first primary endpoint of SVR12 based on PP population, will the testing proceed to the 
second primary endpoint of SVR12 based on ITT population.


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The multiplicity controlled efficacy endpoints will be tested sequentially in the following 
order:
1.
Efficacy of the SVR12 rate of 8-week treatment duration compared to the historical 
12 week treatment duration based on PP population:  If this endpoint is statistically 
significant, then proceed to the following efficacy endpoint.  If this endpoint is not 
statistically significant then stop the testing procedure and declare that no endpoints 
in the study met statistical significance.  
2.
Efficacy of the SVR12 rate of 8-week treatment duration compared to the historical 
12 week treatment duration based on ITT population:  If this endpoint is 
statistically significant, then declare the SVR12 endpoint is statistically significant 
on both PP and ITT population.  If not, then announce that SVR12 endpoint is 
statistically significant based on only PP population.
Has been changed to read:
In order to control family-wise Type I error rate, a fixed-sequence testing procedure will 
be used for the two primary and two key secondary efficacy analyses of SVR12 as listed 
below.  The fixed-sequence testing procedure will utilize the endpoint sequence of the 
first primary analysis followed by the second primary analysis, then the first key 
secondary analysis, and lastly the second key secondary analysis.  For example, only if 
success has been demonstrated for the first primary efficacy analysis of SVR12 based on 
the PP population, will the testing proceed to the second primary efficacy analysis of 
SVR12 based on the ITT population, and so on. 
The multiplicity controlled efficacy analyses will be tested sequentially in the following 
order:
1.
Primary 1:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on the PP population in HCV GT1, 
2, 4, 5, and 6-infected subjects:  If this endpoint is statistically significant, then 
proceed to the following efficacy endpoint.  If this endpoint is not statistically 


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significant, then stop the testing procedure and declare that no endpoints in the 
study met statistical significance.  
2.
Primary 2:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on the ITT population in HCV 
GT1, 2, 4, 5, and 6-infected subjects:  If this endpoint is statistically significant, 
then declare the SVR12 endpoint is statistically significant on both the PP and ITT 
populations in HCV GT1, 2, 4, 5, and 6-infected subjects.  If not, then announce 
that SVR12 endpoint is statistically significant based on only the PP population in 
HCV GT1, 2, 4, 5, and 6-infected subjects and stop testing.
3.
Key Secondary 1:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on the PP population 
in HCV GT1, 2, 3, 4, 5, and 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both the 
PP and ITT populations in HCV GT1, 2, 4, 5, and 6-infected subjects and on the PP 
population in HCV GT1-6-infected subjects.  If not, then announce that SVR12
endpoint is statistically significant based on only the preceding populations and 
stop testing.
4.
Key Secondary 2:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on the ITT population 
in HCV GT1, 2, 3, 4, 5, and 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both the 
PP and ITT populations in HCV GT1, 2, 4, 5, and 6-infected subjects and on both 
the PP and ITT populations in HCV GT1-6-infected subjects.  If not, then 
announce that SVR12 endpoint is statistically significant based on only the 
preceding populations and stop testing.


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Table 8.  Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Previously read:
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 
92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
Has been changed to read:
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 
175 (GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 
62, 92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, and 93
Section 8.2  Determination of Sample Size
Previously read:
It is planned to enroll approximately 270 adult subjects with chronic HCV GT 1, 2, 4, 5 or 
6 infection with compensated cirrhosis who are HCV treatment-naïve in the study.
With approximately 270 subjects, this study has approximately 91% power to demonstrate 
efficacy of the 8-week treatment arm compared to the historical control SVR12 rate (i.e., a 
two-sided 95% lower confidence bound above 94%) based on Per-Protocol (PP) 
population, assuming that 98% of the subjects receiving 8 weeks of treatment in PP 
population achieve SVR12.


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With approximately 270 subjects, this study has approximately 82% power to demonstrate 
efficacy of the 8-week treatment arm compared to the historical control SVR12 rate (i.e., a 
two-sided 95% lower confidence bound above 93%) based on Intention-to-Treat (ITT) 
population, assuming that 97% of the subjects receiving 8 weeks of treatment in ITT 
population achieve SVR12.  
Has been changed to read:
It is planned to enroll approximately 330 adult subjects with chronic HCV GT 1 - 6 
infection with compensated cirrhosis who are HCV treatment-naïve in the study.
The study was initially designed to enroll about 270 non-GT3-infected subjects and 
amended to include GT3-infected subjects for a total of 330 GT1 - 6-infected (270 non-
GT3 and 60 GT3) subjects. 
With approximately 270 subjects with HCV GT1, 2, 4, 5, or 6 infection, this study has 
approximately 91% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on Per-Protocol (PP) population, assuming that 98% of the GT1, 2, 4, 5, and 
6-infected subjects receiving 8 weeks of treatment in PP population achieve SVR12.
With approximately 270 subjects with HCV GT1, 2, 4, 5, or 6 infection, this study has 
approximately 82% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on Intention-to-Treat (ITT) population, assuming that 97% of the GT1, 2, 4, 
5, and 6-infected subjects receiving 8 weeks of treatment in ITT population achieve 
SVR12.  
With approximately 330 subjects with HCV GT1 - 6 infection, this study has 
approximately 90% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on the PP population, assuming that 98% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the PP population achieve SVR12.


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With approximately 330 subjects with HCV GT1-6 infection, this study has 
approximately 81% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on the ITT population, assuming that 97% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the ITT population achieve SVR12.
Section 8.2.1  Justification of Success Criteria for SVR12
Second paragraph previously read:
In the registrational program, 117 treatment naïve, compensated cirrhotic subjects, GT 1, 
2, 4, 5, or 6 subjects were treated with GLE/PIB for 12 weeks duration.  Two subjects did 
not achieve SVR12, one discontinued treatment early and the other had missing SVR12
data.  No virologic failure was observed among these subjects which means SVR12 rate 
based on PP population is 100%.  Hence, for this study it assumed that the historical 
SVR12 rate for cirrhotic patients is 100%.  To establish efficacy to the historical control, a 
margin of 6% is applied to the historical control rate of 100%, resulting in a threshold of 
94%.
Has been changed to read:
In the registrational program, 117 treatment naïve, compensated cirrhotic subjects, GT 1, 
2, 4, 5, or 6 subjects and 65 treatment naïve, GT3-infected subjects with compensated 
cirrhosis were treated with GLE/PIB for 12 weeks duration.  Three subjects did not 
achieve SVR12, one discontinued treatment early and two had missing SVR12 data.  No
virologic failure was observed among these subjects which means SVR12 rate based on PP 
population is 100%.  Hence, for this study it assumed that the historical SVR12 rate for 
GT1-6-infected cirrhotic patients is 100%.  To establish efficacy to the historical control, 
a margin of 6% is applied to the historical control rate of 100%, resulting in a threshold of 
94%.


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Section 14.0  Investigator's Agreement
"Protocol Title:" previously read:
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus 
(HCV) Genotype 1, 2, 4, 5 or 6 Infection and Compensated Cirrhosis
Has been changed to read:
A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus 
(HCV) Genotype 1 - 6 Infection and Compensated Cirrhosis
Section 15.0  Reference List
Reference 12 previously read:
AbbVie.  ABT-530 (Glecaprevir/Pibrentasvir) Investigator's Brochure Edition 2.  06 
September 2016.
Has been changed to read:
12.
AbbVie.  ABT-530 (Glecaprevir/Pibrentasvir) Investigator's Brochure Edition 3.  
29 August 2017.
13.
Mavyret (glecaprevir and pibrentasvir tablets) [US package insert].  North 
Chicago, IL; AbbVie, 2017.
14.
Marivet (glecaprevir and pibrentasvir tablets) [SmPC].  Maidenhead, UK; AbbVie, 
2017.
15.
Puoti M, et al.  High SVR rates with eight and twelve weeks of pangenotypic 
glecaprevir/pibrentasvir:  integrated efficacy analysis of genotype 1-6 patients 
without cirrhosis.  Poster presentation at EASL 2017.  
16.
Zeuzem S, Foster GR, Wang S, et al.  Glecaprevir-Pibrentasvir for 8 or 12 weeks 
in HCV genotype 1 or 3 infection.  N Engl J Med.  2018;378(4):354-69.


Glecaprevir/Pibrentasvir
M16-135 Protocol Amendment 3
EudraCT 2016-004967-38
160
18.
Rockstroh JK, Lacombe K, Viani RM, et al.  Efficacy and safety of 
glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human 
immunodeficiency virus-1:  the EXPEDITION-2 study.  Clin Infect Dis.  
2018 Mar 16.  doi:  10.1093/cid/ciy220.  [Epub ahead of print]
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Bioanalysis
Statistics
Pharmacokinetics
Clinical
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Bioanalysis
Statistics
Pharmacokinetics
Clinical

SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-135 – Statistical Analysis Plan
Version 2.0 – 08 Aug 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-135
A Single Arm, Open-label Study to Evaluate the 
Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir
(PIB) in Treatment Naïve Adults with Chronic 
Hepatitis C Virus (HCV) Genotype 1 - 6 Infection and 
Compensated Cirrhosis 
Date:  08 Aug 2018
Version 2.0
NCT03089944


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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............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 6
4.3.1
Justification of Primary Endpoint Success Criteria.................................. 7
4.4
Planned Analyses ................................................................................... 8
4.4.1
Futility Analysis ..................................................................................... 8
4.4.2
Planned Analyses ................................................................................. 10
5.0
Analysis Populations ...........................................................11
5.1
Definition for Analysis Populations ...................................................... 11
5.1.1
Intention-to-Treat (ITT) Population ...................................................... 11
5.1.2
Per Protocol (PP) Population ................................................................ 11
5.1.3
Safety Population ................................................................................. 11
5.1.4
Modified Intention-to-Treat (mITT) Populations .................................. 11
5.2
Variables Used for Stratification of Randomization .............................. 12
5.3
Presentation of Summary Tables .......................................................... 12
6.0
Analysis Conventions ..........................................................13
6.1
Baseline and Final Value...................................................................... 13
6.1.1
Baseline................................................................................................ 13
6.1.2
Study Days........................................................................................... 13
6.2
Definition of Analysis Windows........................................................... 14
6.3
Missing Data Imputation ...................................................................... 17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications.........................................18
7.1
Demographic and Baseline Characteristics ........................................... 18
7.2
Medical History.................................................................................... 22
7.3
Prior, Concomitant and Post-Treatment Medications ............................ 22
8.0
Subject Disposition..............................................................23


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8.1
Disposition of Safety Population .......................................................... 23
9.0
Study Drug Exposure and Compliance..............................24
9.1
Exposure .............................................................................................. 24
9.2
Compliance .......................................................................................... 24
10.0
Efficacy Analysis .................................................................25
10.1
General Considerations......................................................................... 25
10.2
Handling of Multiplicity....................................................................... 29
10.3
Primary Efficacy Analysis.................................................................... 31
10.4
Secondary Efficacy Analyses ............................................................... 32
10.4.1
Key Secondary Efficacy Analyses ........................................................ 32
10.4.2
Other Secondary Efficacy Analyses...................................................... 33
10.5
Sensitivity Analyses ............................................................................. 34
10.5.1
Imputation Approaches......................................................................... 34
10.6
Efficacy Subgroup Analysis ................................................................. 34
10.7
Additional Efficacy Analyses ............................................................... 36
10.8
Resistance Analyses ............................................................................. 37
10.9
Patient Reported Outcomes .................................................................. 42
11.0
Safety Analysis.....................................................................44
11.1
General Considerations......................................................................... 44
11.2
Analysis of Adverse Events.................................................................. 44
11.2.1
Treatment-Emergent Adverse Events.................................................... 44
11.2.2
Tabulations of Treatment-Emergent Adverse Events ............................ 44
11.2.3
Listing of Adverse Event...................................................................... 47
11.3
Analysis of Laboratory Data................................................................. 48
11.3.1
Statistical Methods ............................................................................... 48
11.4
Analysis of Vital Signs and Weight ...................................................... 52
11.4.1
Variables and Criteria Defining Abnormality........................................ 52
11.4.2
Statistical Methods ............................................................................... 53
12.0
Summary of Changes ..........................................................53
12.1
Summary of Changes from SAP Version 1.0 ........................................ 53
13.0
References............................................................................54


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List of Tables
Table 1.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements and PRO Instruments 
(Treatment Period) ............................................................................... 15
Table 2.
Analysis Time Windows for HCV RNA Endpoints 
(Post-Treatment Period) ....................................................................... 16
Table 3.
Safety, Laboratory Data (Including FibroTest, APRI, Child-Pugh 
Score), Resistance, Vital Sign, and PRO Instruments Visit 
Windows (Post-Treatment Period)........................................................ 16
Table 4.
Child-Pugh Classification of Severity of Cirrhosis................................ 21
Table 5.
Medical History eCRF.......................................................................... 22
Table 6.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ...................................................................................... 38
Table 7.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 50
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Values............ 52
List of Figures
Figure 1.
Study Schematic..................................................................................... 6


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
AbbVie Statistics and Statistical Programming for Study M16-135.  
Study M16-135 examines the efficacy and safety of glecaprevir (GLE)/pibrentasvir (PIB) 
in treatment naïve adults with chronic Hepatitis C Virus (HCV) Genotype (GT) 1 - 6 
infection and compensated cirrhosis.  
This SAP (Version 2.0) incorporates Version 1.0 of the SAP dated 02 December 2017 and 
provides details to further elaborate statistical methods as outlined in Clinical Study 
Protocol M16-135 Amendment 3 dated 11 June 2018, and describes analysis conventions 
to guide the statistical programming work for the first analysis (after all HCV GT 1, 2, 4, 
5 and 6-infected subjects reach Post-Treatment [PT] Week 12 or discontinue the study), 
the second analysis (after all HCV GT3-infected subjects reach PT Week 12 or 
discontinue the study), and the end of study analysis (after all subjects reach PT Week 24 
or prematurely discontinue from the study).  Analyses will be performed using SAS 
Version 9.3 (SAS Institute, Inc., Cary, NC) or later under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to compare the SVR12 rates (12-week sustained 
virologic response, SVR12 [HCV ribonucleic acid {RNA} < lower limit of quantification 
{LLOQ} 12 weeks following treatment]) of 8 weeks of treatment with the GLE/PIB 
combination regimen to the historical SVR12 rate of 12 weeks of treatment with GLE/PIB 
in treatment naïve adults with chronic HCV infection and compensated cirrhosis and to 
assess the safety of 8 weeks of treatment with the GLE/PIB combination regimen in 
treatment naïve adults with chronic HCV infection and compensated cirrhosis.  
The secondary objectives of this study are to assess the percentage of subjects with on-
treatment virologic failure and the percentage of subjects with post-treatment relapse.


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4.2
Design Diagram
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
8 weeks of GLE/PIB in HCV treatment-naïve adult subjects with chronic HCV GT 1 - 6 
infection and compensated cirrhosis.  The study will initially enroll subjects with HCV 
GT 1, 2, 4, 5 and 6 infection followed by subjects with HCV GT3 infection. 
This study consists of a Screening Period, a Treatment Period, and a Post-Treatment (PT) 
Period.
The study is designed to enroll approximately 330 subjects (approximately 270 with GT1, 
2, 4, 5, or 6 infection and approximately 60 with GT3 infection) to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
scientific and ethical considerations.
Figure 1.
Study Schematic
4.3
Sample Size
It is planned to enroll approximately 330 adult subjects with chronic HCV GT 1 - 6 
infection with compensated cirrhosis who are HCV treatment-naïve in this study. 
The study was initially designed to enroll about 270 non-GT3-infected subjects and 
amended to include GT3-infected subjects for a total of 330 GT1 - 6-infected (270 non-
GT3 and 60 GT3) subjects.
With approximately 270 subjects with HCV GT 1, 2, 4, 5, or 6 infection, this study has 
approximately 91% power to demonstrate efficacy of the 8-week treatment arm compared 


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to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on the Per-Protocol (PP) population, assuming that 98% of the GT1, 2, 4, 5, 
and 6-infected subjects receiving 8 weeks of treatment in the PP population achieve 
SVR12.
With approximately 270 subjects with HCV GT 1, 2, 4, 5, or 6 infection, this study has 
approximately 82% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on the ITT population, assuming that 97% of the GT1, 2, 4, 5, and 6-infected 
subjects receiving 8 weeks of treatment in the ITT population achieve SVR12.
With approximately 330 subjects with HCV GT 1 - 6 infection, this study has 
approximately 90% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
94%) based on the PP population, assuming that 98% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the PP population achieve SVR12.
With approximately 330 subjects with HCV GT 1 - 6 infection, this study has 
approximately 81% power to demonstrate efficacy of the 8-week treatment arm compared 
to the historical control SVR12 rate (i.e., a two-sided 95% lower confidence bound above 
93%) based on the ITT population, assuming that 97% of the GT1 - 6-infected subjects 
receiving 8 weeks of treatment in the ITT population achieve SVR12.
4.3.1
Justification of Primary Endpoint Success Criteria 
Efficacy for the 8-week regimen in this study is established by comparing the SVR12 rate 
to the historical control regimen of GLE/PIB administered for 12 weeks.  The SVR12 rate 
of the historical control regimen is calculated, and a threshold is determined by 
subtracting a margin of 6% from the historical SVR12 rate.  Efficacy is established if the 
lower 95% confidence bound of the SVR12 rate in the 8-week regimen is greater than the 
threshold.


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A margin of 6% is selected to be used in this study to ensure a minimal loss of efficacy of 
the 8-week arm relative to the historical SVR12 rate for the 12-week treatment regimen.
In the registrational program, 117 treatment naïve, HCV GT 1, 2, 4, 5, or 6 subjects with 
compensated cirrhosis and 65 treatment naïve, GT3-infected subjects with compensated 
cirrhosis were treated with GLE/PIB for a planned duration of 12 weeks.  Three subjects 
did not achieve SVR12, one discontinued treatment early and two had missing SVR12 data.  
No virologic failure was observed among these subjects, which means that the SVR12 rate 
based on the PP population is 100%.  Hence, for this study it assumes that the historical 
SVR12 rate for GT 1 - 6-infected cirrhotic subjects is 100%.  To establish the efficacy 
compared to the historical control, a margin of 6% is applied to the historical control rate 
of 100%, resulting in a threshold of 94%.
Historical SVR rate based on ITT population depends on the number of non-virologic 
failures in a study.  Study-to-study variability has been observed in non-virologic failure 
rates, and is typically around 1%.  The observed rate of non-virologic failures in the 
registrational program was 1.2% (29/2369).  For this reason, this study assumes that the 
historical SVR12 rate based on ITT population for cirrhotic subjects is 99% (with 1% non 
virologic failure).  To establish the efficacy compared to the historical control, a margin of 
6% is applied to the historical control rate of 99%, resulting in a threshold of 93%. 
4.4
Planned Analyses
All analyses will be conducted by statisticians and programmers at AbbVie or designees 
according to the methodologies specified in this SAP.  There is no intention of stopping 
the study early based on efficacy findings from the futility analyses or the primary 
analyses.  The intention is to follow all subjects who receive study drug for 24 weeks 
following treatment.
4.4.1
Futility Analysis
Study M16-135 is the first study to evaluate GLE/PIB for 8 weeks in treatment-naïve 
HCV GT 1 - 6-infected subjects with compensated cirrhosis.  For that reason, virologic 


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futility rules are used in the protocol to minimize exposure to a potentially suboptimal 
duration.  The protocol described the futility rules as follows (Protocol Section 5.4.1.2, 
Treatment Extension Criteria):  
In subjects with GT 1, 2, 4, 5, or 6 infection, an efficacy assessment will evaluate the 
post-treatment relapse rate when the first 30 subjects reach Post-Treatment Week 4 
and will be done periodically thereafter.  If more than 10% of subjects experience 
post-treatment relapse, an analysis will be conducted to determine if extension of 
treatment to 12 weeks is needed for all GT 1, 2, 4, 5, or 6-infected subjects or for a 
particular subgroup of GT 1, 2, 4, 5, or 6-infected subjects who are on treatment or 
have completed treatment within the previous 7 days.
The enrollment of additional GT 1, 2, 4, 5, or 6-infected subjects in this study will be 
terminated if extension of treatment is needed for all GT 1, 2, 4, 5, or 6-infected 
subjects.  If the extension is needed for a particular subgroup of GT 1, 2, 4, 5, or 
6-infected subjects, then the enrollment will be terminated for this particular subgroup 
but other subgroups will continue to be allowed to enroll in the study with 8 weeks 
treatment duration. 
In subjects with GT3 infection, an efficacy assessment will evaluate the post-treatment 
relapse rate after the first 20 subjects reach Post-Treatment Week 4 and will be done 
periodically thereafter.  If more than 10% of subjects experience post-treatment 
relapse, an analysis will be conducted to determine if extension of treatment to 
12 weeks is needed for all GT3-infected subjects or for a particular subgroup of GT3-
infected subjects who are on treatment or have completed treatment within the 
previous 7 days.
The enrollment of additional GT3-infected subjects in this study will be terminated if 
extension of treatment is needed for all GT3-infected subjects.  If the extension is 
needed for a particular subgroup of GT3-infected subjects, then the enrollment will be 
terminated for this particular subgroup but other subgroups will continue to be 
allowed to enroll in the study with 8 weeks treatment duration.


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Subjects who experience virologic failure with the GLE/PIB regimen for 8 weeks in 
Study M16-135 will be allowed to be screened in the AbbVie Study M15-942.
Post-treatment relapse is defined as confirmed HCV RNA ≥ LLOQ (defined as 
2 consecutive HCV RNA measurements ≥ LLOQ) at any post-treatment visit, for a 
subjects who completed treatment (defined as study drug duration ≥ 52 days) and had 
HCV RNA < LLOQ at final treatment visit, excluding cases of reinfection.  HCV 
reinfection is defined in Section 10.1. 
Evaluations of virologic relapse rate will be performed on an ongoing basis until all 
subjects reach end of treatment.  There will be no statistical adjustment employed due to 
these futility analyses.
4.4.2
Planned Analyses
Analyses will occur after subjects have completed the PT Week 12 Visit or prematurely 
discontinued study.  The first analysis will occur after all HCV GT1, 2, 4, 5, or 6-infected 
subjects have completed the PT Week 12 Visit or prematurely discontinued from the 
study.  The second analysis will occur after all HCV GT3-infected subjects have 
completed the PT Week 12 Visit or prematurely discontinued from the study.  The third 
and final analysis will occur after all subjects have completed or prematurely discontinued 
from the study.
For each analysis, data will be locked after performing appropriate data cleaning.  
Results from the SVR12 analyses will be described in clinical study report(s) that are 
planned to be included as part of submissions to regulatory agencies to support possible 
labeling changes.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
Subjects who receive at least one dose of study drug will be included in the ITT 
population.  Efficacy analyses will be performed on the ITT population, unless otherwise 
specified. 
5.1.2
Per Protocol (PP) Population
All subjects who receive at least one dose of study drug, with the exception of subjects 
who experience breakthrough, or prematurely discontinue treatment prior to Week 8, or 
have no HCV RNA value in the SVR12 visit window or later will be included in the PP 
population.  In other words, the per protocol population includes all subjects in the ITT 
population, with the exception of subjects who prematurely discontinue prior to Week 8 
(subjects with treatment duration < 52 days), subjects who experience virologic failure 
prior to Week 8 (subjects with on-treatment virologic failure before Study Day 52), 
subjects without virologic failure who have no HCV RNA value in the SVR12 visit 
window or later, and subjects who are SVR12 non-responders due to re-infection.  Subjects 
who have HCV GT3 infection will be excluded from the PP analysis of HCV GT1, 2, 4, 
5, and 6-infected subjects. 
5.1.3
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population, which will be the same as the ITT population for this study. Safety and 
demographic analyses will be performed on the safety population.
5.1.4
Modified Intention-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 will be performed on the Modified Intention-to-Treat 
Genotype (mITT-GT) population and Modified Intention-to-Treat Genotype and 


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Virologic Failure (mITT-GT-VF) population, respectively, as defined below, when 
applicable.
The mITT-GT population includes subjects who receive at least 1 dose of study drug but 
excludes the subjects who were enrolled with ineligible genotypes (e.g., GT3 for the 
group of HCV GT 1, 2, 4, 5 or 6-infected subjects (final HCV genotype as defined in 
Section 10.8)).  
The mITT-GT-VF population includes all subjects in the mITT-GT population defined 
above by excluding subjects who did not achieve SVR12 for reasons other than virologic 
failure.
5.2
Variables Used for Stratification of Randomization
No stratification is used for this open-label single-arm study.
5.3
Presentation of Summary Tables
All tables (except safety analyses) will present data in separate columns for the GT 1, 2, 4, 
5 and 6-infected subjects, GT 3 subjects, and GT 1 - 6 infected subjects, if applicable.  
Tables of safety analyses will present data by overall for subjects dosed with GLE/PIB for 
8 weeks.  For the first analysis when only GT 1, 2, 4, 5 and 6 infected subjects have 
completed the PT Week 12 Visit or prematurely discontinued study, data will be 
presented in a single column of GT 1, 2, 4, 5 and 6-infected subjects.  
If a subset of subjects has treatment extended, the tables will present separate results for 
subjects assigned to GLE/PIB for 8 weeks (with a possible breakdown for the subset not 
requiring treatment extension), subjects assigned to GLE/PIB for 12 weeks following 
treatment extension, and overall.


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6.0
Analysis Conventions
6.1
Baseline and Final Value
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the first 
dose of study drug is received.  The protocol specifies that all Day 1 assessments are to be 
performed prior to administering the first dose of study drug.  Therefore, all Day 1 
assessments for which time is not collected will be assumed to be pre-dose and the 
baseline value will be the last non-missing measurement collected on or before the first 
day of study drug administration.
All Day 1 assessments with time available must be before the time of first dose to be 
considered baseline and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 
time or if time is not available, then the average of these measurements will be considered 
the baseline value.  The same baseline value will be used for analyses of the Treatment 
and Post-Treatment Periods.
Safety assessments that are related to a serious adverse event that occurred on the first 
dose day are excluded when applying this algorithm.
6.1.2
Study Days
Study days are calculated for each time point 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.


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Study Drug End Days (Days Relative to the Last Dose of Study Drug)
Study drug end days are calculated for each time point relative to the last dose of study 
drug.  The last day of study drug dosing 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.
Final Treatment Value
The final treatment value is defined as the last non-missing measurement collected after 
Study Day 1 and on or before Study Drug End Day 2.
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 and on or before Study Drug End Day 999.
6.2
Definition of Analysis Windows
For efficacy analyses of HCV RNA, the time windows specified in Table 1 and Table 2
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 date/time of blood sample collection.
For safety, laboratory data, resistance, vital signs and PRO measurements, the time 
windows specified in Table 1 and Table 3 describe how data are assigned to protocol 
specified time points.
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.  The only exception to this is for the SVR 
windows (e.g., SVR4, SVR12, and SVR24); for these windows, the last value in the 
window will be used.


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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.
Table 1.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements and PRO Instruments 
(Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12b
84
71 to 98
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
Week 12 is only applicable for the subjects who meet treatment extension criteria.  If the treatment extension 
criteria are not met, then there will be no Week 12 visit.
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  PRO instruments are collected at Day 1, Week 2, Week 4, and End of Treatment Visit. 


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Table 2.
Analysis Time Windows for HCV RNA Endpoints (Post-Treatment 
Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 999
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.
Table 3.
Safety, Laboratory Data (Including FibroTest, APRI, Child-Pugh 
Score), Resistance, Vital Sign, and PRO Instruments Visit Windows 
(Post-Treatment Period)
Scheduled Time
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 24
168
127 to 999
Final Post-Treatment Visita
> 2 days after last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
Vital signs are collected at every PT visit; hematology, chemistry, urinalysis, and coagulation panels are 
collected are collected at PTWk4, and not required at PTWk24 but PTDC only if subject discontinued prior to 
PT Wk4.  PRO instruments are collected at PTWk12 and PTWk24 (or PTDC) only.  FibroTest, APRI, and 
Child-Pugh scores are collected at PTWk12 and PTWk24 (or PTDC).  


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6.3
Missing Data Imputation
Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.2.
For analyses of SVR, subjects missing visit values will have backward imputation 
applied, if possible.  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 is missing an HCV RNA value within the 
appropriate SVR window after performing backward imputation, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value will be missing.  Subjects with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.
Regardless of the imputation method described above, 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.
Missing Data Imputation for 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.
Missing Data Imputation for PRO Questionnaires
The handling of missing data for patient reported outcomes (PROs) will be as follows.  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 


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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.  The missing items of 
the FSS questionnaire will be imputed with the average score of the answered items as 
long as more than 50% of the items on the FSS are answered.  For Treatment Satisfaction 
Questionnaire – Medication (TSQM), no imputation will be performed for missing items.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
Demographics, baseline characteristics, medical history, and previous, concomitant and 
post-treatment medications will be summarized for the safety population.
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum and minimum).  For categorical variables, the number of missing 
observations will be displayed, if applicable, on the summary tables.  Percentages will be 
calculated based on the number of non-missing observations.
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, race (using categories on the 
eCRF), black race (black or non-black, black will include any subject who marks 'Black 
or African American' for race on the Demographics eCRF), ethnicity, age category (< 65 
or ≥ 65 years; < 75 or ≥ 75 years), BMI category (< 30, or ≥ 30 kg/m2), country, and 
geographic region (North America, Europe, or rest of world [ROW]). 
When defining geographic region, sites in the United States, Canada and Puerto Rico will 
be grouped under North America; sites in Bulgaria, Czech Republic, France, Greece, 
Hungary, Ireland, Italy, Poland, Portugal, Romania, Russian Federation, Spain, and the 


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United Kingdom will be grouped under Europe; sites in Israel, Taiwan and Vietnam will 
be grouped together as ROW.
Continuous baseline characteristics include baseline log10 HCV RNA level, FibroTest 
score, FibroScan score, creatinine clearance, eGFR, platelet count, albumin, GGT, APRI, 
FIB-4, AST, ALT, total, direct, and indirect bilirubin for all subjects.
Categorical baseline characteristics include:
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (as determined by the 
central laboratory);
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (as determined by 
phylogenetic analysis);
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (final HCV genotype 
and subtype as defined in Section 10.8);
●
IL28B genotype (CC, CT, or TT; CC or non-CC);
●
Baseline HCV RNA level (< 800,000 or ≥ 800,000 IU/mL; < 1,000,000 or 
≥1,000,000 IU/mL);
●
Baseline platelet count (< 100 or ≥ 100 × 109/L; < 150 or ≥ 150 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Screening Child-Pugh score (5, 6, or > 6);
●
Baseline Child-Pugh score (5, 6, or > 6);
●
Baseline FibroTest (< 0.75 or ≥ 0.75);
●
Baseline APRI (≤ 1, > 1 to ≤ 2, or > 2);
●
Baseline FIB-4 (< 1.45, ≥ 1.45 to ≤ 3.25, or > 3.25);
●
Baseline AST/ALT ratio (≤ 1 or >1)
●
Baseline total bilirubin (< 34.2 or ≥ 34.2 μmol/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, or ≥ 90 mL/min);
●
Baseline eGFR (< 60, ≥ 60 to < 90, or ≥ 90 mL/min/1.73 m2);
●
History of diabetes (yes/no);


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●
Injection drug user (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Subject on stable opiate substitution (yes/no);
●
Tobacco user (current, former, never, or unknown);
●
Alcohol user (current, former, never, or unknown); 
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/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 
used to summarize IL28B genotype.
Baseline Child-Pugh score is determined by the Day 1 assessment of ascites and hepatic 
encephalopathy along with the baseline values of total bilirubin, serum albumin, and 
international normalized ratio (INR).  The Child-Pugh score is the sum of the point 
assigned for each of the five observed findings as defined in Table 4.


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Table 4.
Child-Pugh Classification of Severity of Cirrhosis
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, 
μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, 
g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic 
encephalopathy**
None
Grade 1 or 2 (or 
suppressed with 
medication)
Grade 3 or 4 (or 
refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
None:  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.
Baseline APRI and FIB-4 are calculated by the equations below.  Subjects who do not 
have concurrent AST and platelet values at baseline will be excluded from the summary 
of baseline APRI.  Age is defined in years at baseline.  Subjects who do not have 
concurrent baseline values of AST, ALT, and platelet count or subjects who are missing 
age will be excluded from the summary of FIB-4.
APRI =
AST Level (U/L)
AST (Upper Limit of Normal)(U/L)
Platelet Count (10!/L)
× 100
FIB −4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10!/L) × *ALT (U/L)


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Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.
History of diabetes will be based on the Medical History (MH) eCRF, as defined in 
Table 5.
Table 5.
Medical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Diabetes
Metabolic
Diabetes mellitus
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF.  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 summarized.  Subjects reporting more than one 
condition/diagnosis within a body system will be counted only once for that body system. 
7.3
Prior, Concomitant and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug (GLE/PIB).  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.


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The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.  
8.0
Subject Disposition
The number and percentage of subjects who screen failed for any reason, and for each 
screen fail reason, will be summarized for all subjects who screen failed.
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized overall 
and by investigator.
●
Subjects enrolled in this study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
●
Subjects ongoing in the PT Period at the time of the planned analysis.
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF).  Similar summaries will be 
provided for discontinuations from the study.
The number and percentage of subjects with reported study drug interruptions will be 
summarized.
Reasons for study drug interruptions will be presented in the CSR listings.


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9.0
Study Drug Exposure and Compliance
9.1
Exposure
The duration of exposure to study drug will be summarized in the safety population.  
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 (mean, standard deviation, median, minimum, and maximum) will 
be presented for exposure during the treatment period.
Study drug duration also will be summarized with frequencies and percentages using the 
following categories:
●
1 to 15 days, 16 to 35 days, 36 to 51 days, ≥ 52 days.
9.2
Compliance
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of tablets dispensed and returned is recorded.  The compliance for study drug 
(GLE/PIB) during 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 
expected to be taken 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 of study drug – date of first dose of study drug + 1).  Study drug interruptions 
recorded on the eCRF will not be subtracted from the duration.  
A subject is considered to be compliant if the percentage is between 80% and 120%.  
Compliance will be calculated for each subject and summarized with the mean, median, 
standard deviation, minimum, and maximum.  The percentage of compliant subjects will 
be summarized based on data as observed.  An additional summary of the percentage of 
compliant subjects will be provided where subjects who are missing study drug 
accountability records will be imputed as non-compliant.


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10.0
Efficacy Analysis
10.1
General Considerations
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® Quantitative HCV 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
IL28B rs12979860 will be resulted as C/C, C/T, or T/T by the central laboratory.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.


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Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-Treatment Virologic Failure = Breakthrough or EOT Failure.
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.
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.
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 completed treatment and 
has post treatment HCV RNA data available, excluding reinfection as described below.
Relapse24 = confirmed HCV RNA ≥ LLOQ during SVR24 window among subjects who 
achieved SVR12 and have HCV RNA data available during the SVR24 window, excluding 
reinfection as described below.


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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 completed treatment and has post 
treatment HCV RNA data available, excluding reinfection as described below.  
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For relapse analyses, the completion of treatment is defined as a 
study drug duration ≥ 52 days for subjects assigned to 8 weeks of treatment.  If the 
regimen is extended to 12 weeks for some subjects, then those subjects will be considered 
completers if they have a study 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).  
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-
treatment detection of a different HCV genotype, subtype, or clade compared with 
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 or Sanger assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and 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 relapse unless an HCV genotype or subtype switch is 
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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, if a 
subject meets both definitions of Breakthrough and EOT failure, he or she will 
be categorized as Breakthrough only);
2.
HCV reinfection (see definition described earlier);
3.
Relapse12 (see Relapse12 definition);
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects assigned to 8 weeks of treatment, and 
< 77 days for subjects extended to 12 weeks of treatment] and did not meet the On-
treatment virologic failure definition);
5.
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], [3], or [4]);
6.
Other (defined as any SVR12 non-responder not meeting the definitions of 
[1] – [5]).
Reasons for SVR24 Non-Response
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, if a 
subject meets both definitions of Breakthrough and EOT failure, he or she will 
be categorized as Breakthrough only);
2.
HCV reinfection (see definition described earlier);


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3.
Relapse12 (see Relapse12 definition);
4.
Relapsed after achieving SVR12 (see Relapse24 definition);
5.
Prematurely discontinued study drug with no on-treatment virologic failure and no 
relapse after achieving SVR12 (defined as any SVR24 non-responder who 
prematurely discontinued study drug [study drug duration < 52 days for subjects 
assigned to 8 weeks of treatment, and < 77 days for subjects extended to 12 weeks 
of treatment] and did not meet the On-treatment virologic failure or Relapse24
definitions);
6.
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], [4], or [5]);
7.
Other (defined as any SVR24 non-responder not meeting the definitions of 
[1] – [6]).
For the reasons for SVR12/SVR24 nonresponse defined above, subjects are only to be 
counted in 1 category.  For example, the categories of premature discontinuation and 
reinfection are mutually exclusive.  Thus, subjects who are SVR12/SVR24 nonresponders 
meeting the definition of HCV reinfection are counted in the reinfection category and not 
to be counted in any other category (as in the example, even if such a subject who was 
determined to be a case of reinfection appeared to meet the definition of prematurely 
discontinued study drug with no on-treatment virologic failure, the subject is to be 
counted in the reinfection category only).
10.2
Handling of Multiplicity
In order to control the Type I error rate at 0.05, a fixed sequence testing procedure will be 
used for the two primary and two key secondary efficacy analyses of SVR12 as listed 
below.  The fixed-sequence testing procedure will utilize the efficacy endpoint sequence 
of the first primary analysis followed by the second primary analysis, then the first key 
secondary analysis, and lastly the second key secondary analysis.  For example, only if 


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success has been demonstrated for the first primary efficacy analysis of SVR12 based on 
the PP population in HCV GT 1, 2, 4, 5 and 6-infected subjects will the testing proceed to 
the second primary efficacy analysis of SVR12 based on the ITT population in HCV GT 1, 
2, 4, 5 and 6-infected subjects.  And only if success has been demonstrated for the second 
primary efficacy analysis of SVR12 will the testing proceed to the first key secondary 
efficacy analysis of SVR12 based on the PP population in HCV GT 1 - 6-infected subjects, 
and so on.
The multiplicity controlled efficacy analyses will be tested sequentially in the following 
order:
1.
Primary 1:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on the PP population in HCV GT 1, 
2, 4, 5 and 6-infected subjects:  If this endpoint is statistically significant, then 
proceed to the following efficacy endpoint.  If this endpoint is not statistically 
significant then stop the testing procedure and declare that no endpoints in the 
study met statistical significance.  
2.
Primary 2:  Efficacy of the SVR12 rate of 8-week treatment duration compared to 
the historical 12 week treatment duration based on ITT population in HCV GT 1, 2, 
4, 5 or 6-infected subjects:  If this endpoint is statistically significant, then declare 
the SVR12 endpoint is statistically significant on both PP and ITT population in 
HCV GT 1, 2, 4, 5 or 6-infected subjects.  If not, then announce that SVR12
endpoint is statistically significant based on only the PP population in HCV GT 1, 
2, 4, 5 or 6-infected subjects and stop testing.
3.
Key Secondary 1:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on the PP population 
in HCV GT 1, 2, 3, 4, 5 and 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both PP 
and ITT population in HCV GT 1, 2, 4, 5 or 6-infected subjects and on the PP 
population in HCV GT 1 - 6-infected subjects.  If not, then announce that SVR12


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endpoint is statistically significant based on only the preceding populations and 
stop testing.  
4.
Key Secondary 2:  Efficacy of the SVR12 rate of 8-week treatment duration 
compared to the historical 12 week treatment duration based on ITT population in 
HCV GT 1, 2, 3, 4, 5 or 6-infected subjects:  If this endpoint is statistically 
significant, then declare the SVR12 endpoint is statistically significant on both PP 
and ITT population in HCV GT 1, 2, 4, 5 or 6-infected subjects and on both the PP 
and ITT population in HCV GT 1 - 6-infected subjects.  If not, then announce that 
SVR12 endpoint is statistically significant based on only the preceding populations 
and stop testing.
10.3
Primary Efficacy Analysis
The two primary efficacy analyses included in the fixed-sequence testing procedure as 
described in Section 10.2 are:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT 1, 2, 4, 5 or 6-infected subjects 
based on the PP population in the 8-week treatment duration achieving SVR12 is 
greater than 94%.
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT 1, 2, 4, 5 or 6-infected subjects 
based on the ITT population in the 8-week treatment duration achieving SVR12 is 
greater than 93%.
The two primary efficacy analyses will be tested using the hierarchical order outlined 
above to control the Type I error rate.  Only if success has been demonstrated for the first 
primary efficacy analysis of SVR12 based on the PP population in HCV GT 1, 2, 4, 5 or 


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6-infected subjects, will the testing proceed to the second primary efficacy analysis of 
SVR12 based on the ITT population in HCV GT 1, 2, 4, 5 or 6-infected subjects. 
For the first primary efficacy analysis, the PP population (defined in Section 5.1.2) will be 
used.  The PP analysis is used to reduce the risk of bias toward no treatment difference 
that can occur due to dropouts or other measurement problems, since the subjects 
excluded in the PP population experience SVR failure for reasons that do not help in 
discriminating between treatment durations.  
For both primary efficacy analyses, the percentage of subjects achieving SVR12 and a 
two-sided 95% confidence interval will be calculated using the normal approximation to 
the binomial distribution, unless the number of subjects who failed to achieve SVR12 is 
less than 5, then the Wilson's score method1 will be used for the confidence interval 
instead. 
10.4
Secondary Efficacy Analyses
10.4.1
Key Secondary Efficacy Analyses
The two key secondary efficacy analyses included in the fixed-sequence as described in 
Section 10.2 are listed below:
1.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT 1, 2, 3, 4, 5, and 6-infected 
subjects based on the PP population in the 8-week treatment duration achieving 
SVR12 is greater than 94%;
2.
Efficacy of the 8-week treatment duration compared to the historical 12-week 
treatment duration will be demonstrated if the lower bound of the two-sided 95% 
confidence interval for the percentage of HCV GT 1, 2, 3, 4, 5, and 6-infected 
subjects based on the ITT population in the 8-week treatment duration achieving 
SVR12 is greater than 93%.


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Only if success was demonstrated for both primary efficacy analyses will testing proceed 
to the two key secondary efficacy analyses in the order listed above.  If success has been 
demonstrated for the first key secondary efficacy analysis of SVR12 based on the PP 
population in HCV GT 1 - 6-infected subjects, then testing will proceed to the second key 
secondary efficacy analysis of SVR12 based on the ITT population in HCV GT 1 -
6-infected subjects.
10.4.2
Other Secondary Efficacy Analyses
The other secondary efficacy analyses, which are not included in the fixed sequence, are 
listed below:
●
The percentage of HCV GT3-infected subjects in the PP population who 
achieve SVR12; 
●
The percentage of HCV GT3-infected subjects in the ITT population who 
achieve SVR12;
●
The percentage of subjects in the ITT population with on-treatment virologic 
failure (defined as On-treatment virologic failure), and
●
The percentage of subjects in the ITT population with post-treatment relapse 
(defined as Relapse12; subjects with reinfection will be summarized 
separately).
For the analyses of SVR12 among HCV GT3-infected subjects, the number and percentage 
of subjects achieving SVR12 will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of on-treatment virologic failure and post-treatment relapse, the number 
and percentage of subjects in the ITT population will be summarized along with a 
two-sided 95% confidence interval using Wilson's score method.  


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10.5
Sensitivity Analyses
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated, if applicable, as a sensitivity analysis for the primary and key secondary 
efficacy analyses of SVR12 based on the PP and ITT populations.
The percentage of subjects in the mITT-GT and mITT-GT-VF populations achieving 
SVR12, as applicable, will be summarized as well as the corresponding two-sided 95% 
confidence interval using Wilson score's method and the normal approximation to 
binomial distribution. 
Listings of subjects excluded from the mITT-GT, mITT-GT-VF, and PP populations will 
be provided, as applicable.
10.5.1
Imputation Approaches
In addition to imputing SVR12 as described in Section 6.3, SVR12 will be presented in the 
ITT population using the following other methods to impute missing HCV RNA values:
●
imputing any missing HCV RNA values in the SVR12 window by carrying 
forward the last non-missing (post-baseline) HCV RNA value prior to the 
SVR12 window.
●
impute as described in Section 6.3 but treat SVR12 non-responders who were 
categorized as "prematurely discontinued study drug with no on-treatment 
virologic failure" or "missing follow-up data in the SVR12 window" as 
successes.
For each of these, the percentage of subjects with SVR12 will be presented along with 
two-sided 95% Normal and Wilson score confidence intervals.
10.6
Efficacy Subgroup Analysis
The subgroup analyses will be performed based on the ITT and mITT-GT-VF 
populations.  The number and percentage of subjects with SVR12 will be presented for the 
following subgroups:


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●
HCV genotype and subtype (as defined in Section 10.8);
●
Sex (male or female);
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Race (White, Black/African-American, Asian, or other) and (black or non-
black);
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
●
Geographic region (North America, Europe, or ROW);
●
Baseline BMI (< 30, or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 800,000 or ≥ 800,00 IU/mL; < 1,000,000 or 
≥1,000,000 IU/mL);
●
Baseline Child-Pugh score (5, 6, or > 6)
●
Baseline platelet count (< 100 or ≥ 100 × 109/L; < 150 or ≥ 150 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline FibroTest (< 0.75 or ≥ 0.75);
●
Baseline APRI (≤ 1, > 1 to ≤ 2, or > 2); 
●
Baseline FIB-4 (< 1.45, ≥ 1.45 to ≤ 3.25, or > 3.25); 
●
Baseline AST/ALT ratio (≤ 1 or >1); 
●
Baseline total bilirubin (< 34.2 or ≥ 34.2 umol/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, or ≥ 90 mL/min);
●
Baseline eGFR (< 60, ≥ 60 to < 90, or ≥ 90 mL/min/1.73 m2);
●
Subject on stable opiate substitution (yes/no);
●
History of diabetes (yes/no);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no).
The 2-sided 95% confidence interval using Wilson's score method will be produced if 
there are at least 10 subjects in the subgroup.
In addition, stepwise logistic regression will be performed on SVR12 with all subgroup 
variables used as predictors of response based on the mITT-GT-VF population.  Some 


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variables will be treated as continuous to decrease the chance of separation or quasi-
separation and some variables may be eliminated if missing for many subjects.
10.7
Additional Efficacy Analyses
The following additional efficacy analyses will be performed in the ITT population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR4 (HCV RNA < LLOQ 4 weeks 
after the last actual dose of study drug);
●
The percentage of subjects who achieve SVR24 (HCV RNA < LLOQ 24 weeks 
after the last actual dose of study drug);
●
The percentage of subjects who experience post-treatment relapse after 
achieving SVR12 (Relapse24).
In the above analyses for SVR, virologic failure, and relapse, the percentage of subjects 
with a two-sided 95% Wilson score interval will be summarized.  Imputations for missing 
data will be performed as described in Section 7.0 for analysis of SVR, where a missing 
response will be imputed as a failure after performing the described imputation.  All other 
endpoints will be presented using data as observed.
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject number and the SVR visit window corresponding to the first 
occurrence of relapse.  A similar listing will be prepared for subjects who prematurely 
discontinued treatment and relapsed after having HCV RNA < LLOQ at their Final 
Treatment Visit.
A listing of subjects in the ITT population excluded from the relapse denominator 
(e.g., study drug duration < 52 days for subjects assigned to 8 weeks of treatment) will be 
provided, as applicable.


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The number and percentage of subjects who do not achieve SVR12 will be summarized by 
reason for non-response (as defined in Section 10.1).  A listing of subject numbers and 
reason for non-response will be prepared.  A similar summary and listing will be prepared 
for subjects who do not achieve SVR24.
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and 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 where both SVR12 and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is 
the proportion of subjects who achieve SVR12 and SVR24 out of all subjects who achieved 
SVR12.  The NPV of SVR12 on SVR24 is the proportion of subjects who neither achieve 
SVR12 nor SVR24 out of all subjects who did not achieve SVR12.  Similarly, the 
concordance between SVR4 and SVR12 will be summarized. 
10.8
Resistance Analyses
For all subjects, full length NS3/4A or NS5A from baseline samples will be sequenced by 
next generation sequencing (NGS).  For subjects who experience virologic failure (on-
treatment virologic failure or post-treatment relapse as defined in Section 10.1), full 
length NS3/4A and NS5A genes from the first sample after virologic failure with HCV 
RNA ≥ 1000 IU/mL will be sequenced by NGS.  An appropriate subtype specific 
prototypic reference sequence will be used for comparison with sequences from samples.  
Subjects who experience virologic failure (VF) will be referred to as subjects in the 
primary virologic failure (PVF) population, and a listing by subject that includes HCV 
genotype/subtype, IL28B genotype, reason for SVR12 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 HCV 
genotype/subtype and reason for SVR12 non-response in the subject identifier for each 
subject.  A separate listing will summarize all subjects in the PVF population for whom 
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Subjects treated with study drug who do not achieve SVR12 due to reasons other than 
virologic failure (prematurely discontinued study drug with no on-treatment virologic 
failure, HCV reinfection, missing SVR12 data, or other reasons as described in 
Section 10.1, Reasons for SVR12 Non-Response), but have a time point with HCV RNA 
≥1000 IU/mL after treatment discontinuation will have the sample at that time point 
sequenced.  These subjects will be referred to as the non-PVF population.  A listing of all 
subjects in the non-PVF population with post-baseline sequencing available will be 
created that is similar to the listing of subjects in the PVF population with post-baseline 
sequencing available.
Included time points for analyses on samples from subjects who do not achieve SVR12 are 
1) the sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that resistance-associated 
substitutions were detected by NGS at the time of HCV virologic failure/treatment 
discontinuation.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions are listed in Table 6.  Appropriate subtype-specific prototypic reference 
sequence will be used for comparison with sequences from samples.
Table 6.
Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 
122, 132 (GT1a only), 155, 156, 158, 
168, 170, 175 (GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 
(GT3 only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 
58, 62, 92, 93
24, 28, 30, 31, 58, 92, 93 (all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93


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The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched substitution:  substitution present in both the baseline and a post-
baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample [(post-
baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution:  A post-baseline substitution or an enriched 
substitution.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
amino acid positions for each DAA target (NS3/4A and NS5A) (ITT).
●
A listing of all baseline polymorphisms (15% detection threshold) at non-
signature amino acid positions for each DAA target (NS3/4A and NS5A) for 
subjects in the PVF population.
●
A by subject listing of baseline polymorphisms (15% detection threshold) at 
signature amino acid positions in subjects with polymorphisms across both 
NS3 and NS5A, or those with multiple baseline polymorphisms within any 
one target (NS3/4A or NS5A).


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●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15% (ITT).  
This table includes prevalence of each baseline polymorphism, and a summary 
of number of subjects with polymorphisms in NS3 only, in NS5A only, any in 
NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total 
(include all subtypes) (ITT).
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by genotype, and total 
(include all genotypes) (ITT).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed for the mITT-GT-VF population as follows:  for each polymorphism, the SVR12
rate will be calculated for subjects with and without the polymorphism and the 2 rates will 
be compared.  Analysis will be grouped by HCV subtype and DAA target (NS3/4A or 
NS5A).
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
●
Polymorphism at each non-signature amino acid position (vs. no 
polymorphism at that position) at a detection threshold of 15%.
Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 


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amino acid positions at 15% detection threshold, the SVR12 rate will be calculated for the 
mITT-GT-VF population, and the rates with or without polymorphisms will be compared 
using Fisher's exact test.  Analysis will be separated by HCV subtype.  The following 
tables will be provided:
●
Comparison of SVR12 rates by subtype, and total (include all subtypes)
●
Comparison of SVR12 rates by genotype, and total (include all genotypes)
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
●
Listings by subject and time point of all post-baseline substitutions at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3 and NS5A).
●
The persistence of post-baseline variants at signature resistance-associated 
amino acid positions for each target (NS3 and NS5A) from subjects will be 
assessed at Post-Treatment Week 24.  Listings by subject and time point of all 
treatment-emergent variants will be provided for each DAA target (NS3 and 
NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LIPA assay 
results from the Central laboratory will be used to categorize the subject.  This 


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information will be presented in summaries of efficacy subgroup analyses and resistance 
analyses.
A summary of HCV subtype as provided by the central laboratory (Sanger sequencing or 
Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) versus phylogenetic analysis 
also will be provided.
10.9
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  
TSQM, SF-36v22 and FSS.  Missing data for each measurement will be handled as 
described in Section 6.3.
The TSQM is a 14-item instrument and includes assessments of satisfaction with a 
medication's effectiveness (Effectiveness, three items), lack of side effects (Side Effects; 
five items), convenience (three items) and the subject's global satisfaction (Global 
Satisfaction; three items).  No imputation will be applied to each measurement for missing 
items.  TSQM scores range from 0 – 100 with higher scores indicating better satisfaction. 
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 
(Mental Component Summary; SF-36-MCS) and physical (Physical Component 
Summary; SF-36-PCS) health status.  Imputation will be applied to each domain as 
described in Section 6.3.  The score for each of the 8 domains ranges from 0 to 100 and 
will be normalized according to the user manual.  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 any item with multiple responses will be set to "missing."  Subject's 
responses to the SF-36v2 will be summarized for the SF-36-PCS and SF-36-MCS 
measures and eight individual domain measures.
The FSS measures the impact of fatigue over the past week on specific types of 
functioning.  The survey consists of 9 questions using a 7-point Likert scale.  A total score 


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is calculated as the average of the individual item responses (adding up all the answers 
and dividing by nine).  Higher FSS scores indicate a higher degree of impact of fatigue.  
Imputation will be applied to the total score as described in Section 6.3.
Summary statistics (n and mean) at each visit and for the change from baseline (n, mean, 
SD, minimum and maximum) to each applicable post-baseline timepoint will be provided 
for SF-36v2 (SF-36-PCS and SF-36-MCS and eight individual domains) scores and for 
the FSS total score.  In addition, summary statistics (n, mean, SD, median, minimum and 
maximum) for the TSQM subscales (global satisfaction, convenience, effectiveness, side 
effects) at Weeks 2, 4, and 8 will be provided.  
The following analyses of PROs also will be performed:
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 3 points in the 
SF-36-MCS and SF-36-PCS;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 5 points in the 
SF-36-MCS and SF-36-PCS;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 5 points in the 
SF-36 domain scores;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 0.7 in the FSS 
total score;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable timepoint of greater than or equal to 1 in the FSS 
total score.
If a subject starts another treatment for HCV, then all PRO values for this subject 
measured on or after the start date of the new HCV treatment will be excluded from 
analyses.


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11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized using the safety population.
11.2
Analysis of Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The actual version of the MedDRA coding dictionary will be 
noted in the clinical study report.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are 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 AE, 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).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term (PT).  The SOCs will 
be presented in alphabetical order, and the PTs will be presented in alphabetical order 
within each SOC. 
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE;


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Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
●
Treatment-emergent AEs of grade 3 or higher;
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (GLE/PIB);
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB);
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Event by SOC and PT
Subjects reporting more than one AE for a given preferred term will be counted only once 
for that term (most severe/highest grade incident for the severity tables and most related 
incident for the relationship tables).  Subjects reporting more than one AE within an SOC 
will be counted only once for that SOC.  Subjects reporting more than one AE will be 
counted only once in the overall total.
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (GLE/PIB);


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●
Grade 3 or higher treatment-emergent AEs;
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB);
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death.
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be created.
Adverse Event by PT
The number and percentage of subjects experiencing treatment-emergent AEs will be 
tabulated according to PT and sorted by overall frequency.  Similar summaries will be 
provided for Grade 3 or higher treatment-emergent AEs, DAA-related treatment-emergent 
AEs, DAA-related Grade 3 or higher treatment-emergent AEs, and DAA-related 
treatment-emergent serious AEs. 
Adverse Events by Maximum Severity Grade Level
Treatment-emergent AEs and DAA-related treatment emergent AEs will be summarized 
by maximum severity grade level of each PT.  Each AE will be assigned a grade level 
(Grade 1, 2, 3, 4, or 5) by the investigator.  If a subject has an AE with unknown severity, 
then the subject will be counted in the severity grade level category of "unknown," even if 
the subject has another occurrence of the same event with a severity present.  The only 
exception is if the subject has another occurrence of the same AE with the highest grade 
level (Grade 5).  In this case, the subject will be counted under the "Grade 5" category.


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Adverse Event by Maximum Relationship
Treatment-emergent AEs also will be summarized by maximum relationship of each PT 
to study drug (DAAs), 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 the "Reasonable Possibility" category.
Adverse Events of Special Interest
For the hepatic decompensation/hepatic failure AE of special interest defined below, the 
number and percentage of subjects experiencing at least one treatment-emergent AE in the 
search will be presented overall and by SOC and PT.  In addition, a listing of treatment-
emergent AEs for subjects meeting the search criterion will be provided.  For the 
hepatocellular carcinoma AE of special interest, a listing of all AEs meeting the search 
criterion will be provided.
●
Hepatic decompensation and hepatic failure 
○
Treatment-emergent events only
○
Product MedDRA Query (PMQ) of "Hepatic decompensation and hepatic 
failure"
●
Hepatocellular carcinoma 
○
All post-baseline cases, treatment-emergent and non-treatment emergent
○
Search based on specific MedDRA preferred terms of hepatocellular 
carcinoma, hepatic neoplasm, hepatic cancer, hepatic cancer metastatic, 
and hepatic cancer recurrent.
11.2.3
Listing of Adverse Event
The following listings of AEs will be prepared:


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All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
●
Treatment-emergent serious AEs,
●
Treatment-emergent AEs leading to death,
●
Treatment-emergent AEs leading to discontinuation of study drug,
●
Treatment-emergent AEs leading to study drug interruption.
11.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional lab testing due to 
an SAE, will be used in all analyses.  The protocol-defined hematology and clinical 
chemistry laboratory tests will be summarized.
Some of the laboratory variables are calculated by the laboratory vendor including 
indirect bilirubin, creatinine clearance, and eGFR by MDRD.  The central lab calculates 
eGFR by MDRD using the following equation, where serum creatinine is measured in 
mg/dL and age is measured in years:
GFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1.154 × (Age)–0.203 × 1.212 (if 
Black) × 0.742 (if Female).
The central lab calculates the estimated creatinine clearance (CrCl) based on the following 
Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum 
creatinine (mg/dL) × 72].
11.3.1
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 


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the time of first dose if time is available.  The same baseline value will be used for change 
to Treatment Period visits and change to PT Period visits.
Mean changes from baseline to each post-baseline visit, including applicable post 
treatment visits, will be summarized for the overall safety population.  Each protocol-
specified laboratory parameter will be summarized with the sample size, baseline mean, 
visit mean, change from baseline mean, standard deviation, minimum, median, and 
maximum. 
Changes in the laboratory parameters listed in Section 11.3.1 will be tabulated using shift 
tables.  Laboratory data values will be categorized as low, normal, or high based on the 
normal ranges of the laboratory used for each sample.  A shift table from baseline to 
minimum value and maximum value during the Treatment Period will be created.  In this 
shift table, the number and percentage of subjects with baseline values within or above the 
normal range (baseline high or normal) and a minimum value below the normal range 
(post-baseline low) and the number and percentage of subjects with baseline values within 
or below the normal range (baseline low or normal) and a maximum value above the 
normal range (post-baseline high) will be summarized.
Child-Pugh scores will be categorized as 5, 6, > 6, or missing at baseline and each 
protocol-specified post-baseline visit, including applicable post-treatment visits.  Shift 
tables from baseline to each post-baseline visit will be created.  The shift tables will cross-
tabulate the frequency of subjects with baseline values in each category versus the post-
baseline categories.  For each baseline category and across the baseline categories, the 
percentage of subjects in each post-baseline category (excluding the post-baseline 
category of missing) will be calculated. 
The laboratory parameters defined in Table 7 will be assigned a toxicity grade of 1, 2, 3, 
or 4.  The number and percentage of subjects with a maximum toxicity grade of 1, 2, 3 or 
4 will be summarized.  The post-baseline value must be in a toxicity grade that is more 
extreme than the toxicity grade corresponding to the baseline value in order to be counted.  
The summary will also include the number and percentage of subjects with a maximum of 


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at least Grade 3 for all laboratory parameters in Table 7.  A listing of all relevant 
laboratory parameters will be provided for each subject who had an increase to Grade 2 or 
higher for all laboratory variables in Table 7.
Table 7.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
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
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Absolute 
Neutrophil Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L < 75.0 – 50.0 × 109/L < 50.0 – 25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Assessment of Hepatic Laboratory Values
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized:
●
Post-nadir (preceding value is lower than the subsequent value) ALT 
> 5 × ULN (regardless of grade change);
●
Total bilirubin ≥ 2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered);
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin ≤ 2 × ULN.


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Four listings (one for each bullet above) of all liver function tests including ALT, AST, 
total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.  
Hepatic Laboratory Abnormalities of Interest
Among the events assessed under "Assessment of Hepatic Laboratory Values," the 
following criteria are of interest:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post nadir ALT > 3 × ULN and a concurrent total bilirubin > 2 × ULN with a 
direct bilirubin:total bilirubin ratio > 0.4. 
To support the assessment of hepatic laboratory abnormalities of interest, the following 
potential events will be summarized:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN and direct/total 
bilirubin ratio > 0.4.
Two listings (one for each bullet) of all liver function tests including ALT, AST, total, 
indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline phosphatase 
values will be provided for each subject who met the criterion defined above.
For the assessments of hepatic laboratory values and hepatic laboratory abnormalities of 
potential interest, the maximum ratio relative to the ULN will be used to determine if 
subjects meet any of the criteria listed above.  The ALT and total bilirubin values do not 
need to be concurrent in order to meet the defined criteria in statistical summaries.  For 
ALT, the post-baseline value must represent an increase from the first nadir (including 
baseline) to be counted.  First nadir is defined as the last value prior to the first increase.  
For total bilirubin, a subject will be counted if the post-baseline laboratory value meets 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), except where noted 


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above.  A confirmed post-nadir increase in ALT is defined as two consecutive values of 
ALT > 5 × ULN after nadir, either both during treatment or at the final treatment 
measurement and the next consecutive post-treatment measurement.  A single post-nadir 
ALT value of greater than 5 × ULN followed by lost to follow-up (no additional ALT 
values) also will be considered as confirmed (i.e., will not require confirmation).  The 
ratio of direct to total bilirubin will be calculated using the same date/time sample 
corresponding to the total bilirubin elevation.
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 (PCS) vital sign findings are presented in 
Table 8.
Table 8.
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
Body Temperature
> 38.3°C AND An increase of 
≥1.1°C from baseline


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11.4.2
Statistical Methods
The baseline value for vital signs 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 change to TP visits and 
change to PT Period visits.
Mean changes from baseline to each post-baseline visit, including applicable PT visits, 
will be summarized.  Each vital sign parameter will be summarized with the baseline 
mean, visit mean, change from baseline mean, standard deviation, minimum, median, and 
maximum.  
The number and percentage of subjects with on-treatment values meeting the specified 
criteria for PCS vital sign values (Table 8) will be summarized.  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 vital sign values for the subjects meeting PCS 
criteria during treatment.
12.0
Summary of Changes
12.1
Summary of Changes from SAP Version 1.0
●
Updates were made to the study objectives, sample size, and efficacy analysis 
sections to reflect the changes in protocol Amendment 3 regarding the 
inclusion of GT3 subjects.
●
The list of variables to be used in the summary of demographic and baseline 
characteristics as well as the subgroup analysis were slightly modified to be 
consistent with protocol Amendment 3 (e.g., adding in genotype 3 and 
subtypes, and geographic region).
●
The language in the section on the analysis of hepatic laboratory abnormalities 
of interest was edited to be consistent with analysis plans across the GLE/PIB 
Phase 3b program.


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13.0
References
1.
Julious SA.  Two-sided confidence intervals for the single proportion:  comparison 
of seven methods by Robert G. Newcombe, Statistics in Medicine 
1998;17:857-872.  Stat Med.  2005;24(21):3383-4.
2.
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's manual for the SF-36v2 health 
survey.  2nd ed.  Lincoln, RI:  QualityMetric Incorporated; 2007.