Clinical trial NCT02966795
Conditions: Hepatitis C Virus (HCV)
Keywords: glecaprevir pibrentasvir compensated cirrhosis non-cirrhotic interferon (IFN) pegylated interferon (pegIFN) ribavirin (RBV) sofosbuvir (SOF) Sustained Virologic Response 12 weeks post dosing (SVR12) Chronic Genotype 5 or 6 Infection
Sponsor: AbbVie
Start date: 2017-01-25; Completion date: 2018-08-29
Enrollment: 84 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of glecaprevir/pibrentasvir for an 8- or 12-week treatment duration in participants with chronic hepatitis C virus (HCV) genotype (GT) 5 or 6 infection, with or without compensated cirrhosis respectively.

Detailed description:

Arms: arm 1: Non-cirrhotic participants with hepatitis C virus genotype 5 or 6 received oral glecaprevir/pibrentasir (300 mg/120 mg) once daily with food for 8 weeks, according to label. arm 2: Participants with hepatitis C virus genotype 5 or 6 and compensated cirrhosis received oral glecaprevir/pibrentasir (300 mg/120 mg) once daily with food for 12 weeks, according to label.
Interventions: intervention 1: Glecaprevir/Pibrentasvir
Intervention descriptions: intervention 1: Fixed-dose combination tablets taken orally once a day.

Protocol documents:
Prot_000.pdf: 
Glecaprevir/Pibrentasvir
M16-126 Protocol Amendment 1
EudraCT 2016-003192-22
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1.0
Title Page
Clinical Study Protocol M16-126
A Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir
(PIB) in Adults with Chronic Hepatitis C Virus (HCV) 
Genotype 5 or 6 Infection
Incorporating Amendment 1
AbbVie Investigational
  Product:
Glecaprevir/Pibrentasvir
Date:
28 July 2017
Development Phase:
3b
Study Design:
This is an open-label, multicenter study
EudraCT Number:
2016-003192-22
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc. (AbbVie)*
Sponsor/Emergency 
  Contact:
* 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.
NCT02966795


Glecaprevir/Pibrentasvir
M16-126 Protocol Amendment 1
EudraCT 2016-003192-22
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
15 September 2016
The purpose of this amendment is to:
●
Update Section 3.0, Introduction, GLE and PIB
Rationale:  Updated per the AbbVie Glecaprevir/Pibrentasvir Fixed-Dose 
Combination Investigator's Brochure Edition 2.  06 September 2016; including 
Addendum 1 Edition 2 November 2016.
●
Update Section 5.2.3.3, Prohibited Therapy, Table 1, Prohibited Medications 
and Supplements
Rationale:  To allow the investigator to reintroduce the medications 
prohibited by the protocol 14 or more days following the last dose of study 
drug instead of 30 days or more, based on the half-lives of G/P
●
Update Section 5.3.1.1, Study Procedures, Hepatocellular Carcinoma 
Screening:  Liver Ultrasound, Appendix C, Study Activities – Treatment 
Period, and Appendix D, Study Activities – Post Treatment (PT) Period
Rationale:   To remove Alpha Fetoprotein from the protocol, because the 
protocol-required HCC screening incorporates the more sensitive and specific 
imaging exams (ultrasound, MRI, PET scan) and determination of Alpha 
Fetoprotein levels is not necessary.  The HCC Screening Liver Ultrasound at 
Post-Treatment Week 24 was added to ascertain the subject did not develop 
HCC during the course of the trial.
●
Update Section 5.3.2.1, Collection of Samples for Analysis
Rationale:  To correct the blood volume drawn for Pharmacokinetic Samples 
●
Update Section 7.0, Protocol Deviations, alternative contact
Rationale:  To reflect current study personnel.
●
Updated Section 8.1.2.1 Primary Efficacy Endpoints


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Rationale:  Regulatory authority feedback requested that for high SVR12 rates 
less than 100% the Wilson score test be used for calculating the 95% 
confidence interval in the primary efficacy analysis, rather than using the 
normal approximation to the binomial distribution.  To comply with this 
feedback, the Wilson score method will be used to calculate the confidence 
intervals for the primary efficacy endpoints if the number of SVR12 non-
responders is less than 5, otherwise normal approximation to the binomial 
distribution will be used.
●
Appendix B, List of Protocol Signatories 
Rationale:  To reflect current study personnel.
●
Correct minor typographical and grammatical errors throughout the protocol
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


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M16-126 Protocol Amendment 1
EudraCT 2016-003192-22
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-126
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir
Pibrentasvir
Date of Protocol Synopsis:  28 July 2017
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Adults with Chronic Hepatitis C Virus (HCV) Genotype 5 or 6 Infection
Objectives:
!
The primary objectives of this study are to assess the efficacy (by evaluating the percentage of 
subjects achieving SVR12) and safety of glecaprevir/pibrentasvir in adults with chronic 
hepatitis C virus (HCV) genotype (GT) 5 or 6 infection with or without compensated cirrhosis.  
The efficacy of glecaprevir/pibrentasvir will be assessed by genotypes across treatment 
durations (or cirrhosis status) and the safety of glecaprevir/pibrentasvir will be assessed by 
treatment duration (or cirrhosis status) across genotypes.
!
The secondary objectives are to assess efficacy of glecaprevir/pibrentasvir by hepatitis C virus 
(HCV) genotype (GT) 5 or 6 infection across treatment duration (or cirrhosis status) by 
evaluating the percentages of subjects with HCV on-treatment virologic failure and HCV 
virologic relapse across treatment durations (or cirrhosis status).
Additional objectives are to assess pharmacokinetics and emergence and persistence of viral variants in 
these treatment regimens.
Investigators:  Multicenter
Study Sites:  Approximately 26
Study Population:  Chronic HCV GT5 or 6-infected male and female adults aged 18 years or older, 
without cirrhosis or with compensated cirrhosis, who are either HCV treatment-naïve (i.e., has never 
received a single dose of any approved or investigational anti-HCV medication) or treatment 
experienced (i.e., has failed prior interferon [IFN] or pegylated interferon [pegIFN] with or without 
ribavirin [RBV], or sofosbuvir [SOF] plus RBV with or without pegIFN therapy).
Number of Subjects to be Enrolled:  Approximately 80 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
glecaprevir/pibrentasvir for an 8- or 12-week treatment duration in adults with chronic HCV GT5 or 6 
infection, with or without compensated cirrhosis, who are either HCV treatment-naïve or treatment-
experienced with IFN or pegIFN with or without RBV (defined as P/R treatment-experienced) or SOF 
plus RBV with or without pegIFN (defined as SOF plus RBV treatment-experienced).  Approximately 
80 subjects meeting the eligibility criteria will be enrolled globally.  Approximately 30 GT5-infected 
subjects and approximately 50 GT6-infected subjects will be enrolled in the study.  The study enrollment 
will be monitored to meet the following enrollment criteria: 1) a minimum of 15 GT5 and 30 GT6 
subjects and 2) up to approximately 16 subjects with compensated cirrhosis (regardless of GT).
Approximately 80 eligible subjects will be enrolled into one of the following treatment arms:


Glecaprevir/Pibrentasvir
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Methodology (Continued):
!
Arm A:  HCV GT 5 or 6 non-cirrhotic subjects will be treated with GLE/PIB 300 mg/120 mg 
once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 5 or 6 subjects with compensated cirrhosis will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of two periods:
Treatment Period:  Eligible subjects will be enrolled to receive glecaprevir/pibrentasvir 300 mg/120 mg 
once daily (QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, and 8 for all 
subjects and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment 
of adverse events, vital signs, adherence, concomitant medications, HCV RNA, HCV resistance, 
glecaprevir and pibrentasvir pharmacokinetic assays, and clinical laboratory tests, will be conducted at 
each visit.
Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment Period will be 
followed for 24 weeks to monitor HCV RNA levels to evaluate efficacy and the emergence and 
persistence of resistant viral variants.
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 viral variants 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 GT5 or 6 infection.
3.
Subject has a positive anti-HCV Ab and plasma HCV RNA ≥ 1000 IU/mL at Screening Visit.
4.
Subject must be HCV treatment-naïve (i.e., has never received a single dose of any approved or 
investigational anti-HCV medication) or treatment-experienced (i.e., has failed prior interferon 
[IFN] or pegylated interferon [pegIFN] with or without ribavirin [RBV], or sofosbuvir [SOF] plus 
RBV with or without pegIFN therapy).  Prior HCV treatment with any other approved or 
investigational medications is not allowed.  Previous HCV treatment must have been completed 
≥2 months prior to screening.
5.
Subject must be documented as having no cirrhosis or compensated cirrhosis (as described in 
Section 5.3.1.1) non-cirrhotic or cirrhotic.
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.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol in the opinion of the investigator. 
3.
Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti-human 
immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed during screening indicating co-infection with more than one HCV 
genotype.
5.
History of severe, life-threatening or other significant sensitivity to any excipients of the study drug.


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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.
Duration of Treatment:  Subjects without cirrhosis will receive glecaprevir/pibrentasvir for 8 weeks, 
while subjects with compensated cirrhosis will receive glecaprevir/pibrentasvir for 12 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, and vital signs.
Patient Reported Outcomes (PROs):
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 Work Productivity and Activity Impairment Questionnaire:  
Hepatitis C (WPAI:  Hepatitis C) will assess work and activity impairment due to HCV.
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, 
the variants at baseline 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 variants 
relative to baselines in available samples.
Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug) within each genotype (GT5 and GT6 subjects) 
separately across treatment arms.  The primary endpoint will be analyzed based on intention to treat 
(ITT) population.  The number and percentage of subjects achieving SVR12 will be summarized with a 
two-sided 95% confidence interval based on the normal approximation of the binomial distribution 
unless the rate for SVR12 is 100%, where the Wilson's score method will be used to calculate the 
confidence interval.
The secondary efficacy endpoints within each genotype (GT5 and GT6 subjects) separately, across 
treatment arms are:
!
The percentage of subjects with on-treatment HCV virologic failure.
!
The percentage of subjects with post-treatment HCV virologic relapse.
For on-treatment virologic failure and post-treatment relapse, the number and percentage of subjects will 
be summarized along with a two-sided 95% confidence interval using Wilson's score method.  Analyses 
of additional efficacy endpoints and efficacy subgroup analyses will be performed.


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Statistical Methods (Continued):
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures will be 
summarized.
Safety:
Safety summaries will be provided by the treatment arm (i.e., cirrhosis status/study drug duration) and 
overall.  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) 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 grade and relationship to study drug.  Change from baseline in laboratory 
tests and vital signs measurements to each time point of collection will be summarized, and values that 
are potentially clinically significant, according to predefined criteria, will be summarized by treatment 
arm (i.e., cirrhosis status/study drug duration) and overall.  Changes from baseline to post-baseline in the 
CTCAE grading of laboratory values will also be summarized.
Pharmacokinetic:
Plasma concentrations of glecaprevir and pibrentasvir will be tabulated for each subject and treatment 
arm.  Summary statistics will be computed for each treatment arm.  Population pharmacokinetic analyses 
will be performed using the actual sampling time relative to dosing.  Pharmacokinetic models will be 
built using a non-linear mixed-effect modeling approach.
Resistance:
For all subjects receiving study drug, the variants at signature resistance-associated amino acid positions 
at baseline 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 
variants in available post-baseline samples identified by NGS and comparison to the baseline sequences, 
2) the amino acid variants 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 resistance by NGS.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
ABT-267
Ombitasvir
ABT-450
Paritaprevir
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
APRI
Aminotransferase/platelet ratio index
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC24
AUC for the 24-hour dosing interval
β
Apparent terminal phase elimination rate constant
BID
Twice Daily
BMI
Body mass index
BUN
Blood urea nitrogen
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
CPK
Creatine phosphokinase
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed tomography
Ctrough
Pre-dose trough plasma concentration
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
EC50
Half maximal effective concentration
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture


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EDTA
Edetic acid (ethylenediaminetetraacetic acid)
EOT
End of treatment
EU
European Union
GCP
Good Clinical Practice
GCSF
granulocyte colony stimulating factor
GGT
Gamma-glutamyl transferase
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
Hemoglobin A1c
Glycated hemoglobin
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
IL28B
Interleukin 28B
IMP
Investigational Medical Product
INR
International normalized ratio
IP-10
Interferon gamma-induced protein 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention To Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging


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NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS
Non-structural 
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
PK
Pharmacokinetic
POR
Proof of receipt
P/R
pegIFN/RBV
PRO
Patient reported outcome
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase PCR
SAD
Single Ascending Dose
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
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
t1/2
Terminal phase elimination half-life


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Tmax
Time to maximum observed plasma concentration (Cmax)
TN
Treatment-naïve
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
WOCBP
Women of child bearing potential
Definition of Terms
Study Drug
glecaprevir/pibrentasvir
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................................................................................................. 4
1.3
List of Abbreviations and Definition of Terms........................................ 8
2.0
Table of Contents ................................................................ 12
3.0
Introduction......................................................................... 17
3.1
Differences Statement .......................................................................... 23
3.2
Benefits and Risks................................................................................ 23
4.0
Study Objective ................................................................... 24
4.1
Primary Objectives............................................................................... 24
4.2
Secondary Objectives ........................................................................... 24
5.0
Investigational Plan.............................................................24
5.1
Overall Study Design and Plan:  Description ........................................ 24
5.1.1
Screening ............................................................................................. 26
5.1.1.1
Rescreening.......................................................................................... 26
5.1.2
Treatment Period.................................................................................. 27
5.1.3
Post-Treatment Period.......................................................................... 28
5.2
Selection of Study Population............................................................... 28
5.2.1
Inclusion Criteria.................................................................................. 28
5.2.2
Exclusion Criteria................................................................................. 30
5.2.3
Prior and Concomitant Therapy............................................................ 33
5.2.3.1
Prior HCV Therapy .............................................................................. 33
5.2.3.2
Concomitant Therapy........................................................................... 35
5.2.3.3
Prohibited Therapy............................................................................... 35
5.2.4
Contraception Recommendations and Pregnancy Testing ..................... 36
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 38
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 38
5.3.1.1
Study Procedures.................................................................................. 38
5.3.1.2
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples................................................................................. 49


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5.3.1.3
Meals and Dietary Requirements.......................................................... 50
5.3.2
Drug Concentration Measurements....................................................... 50
5.3.2.1
Collection of Samples for Analysis....................................................... 50
5.3.2.2
Handling/Processing of Samples........................................................... 50
5.3.2.3
Disposition of Samples......................................................................... 51
5.3.2.4
Measurement Methods ......................................................................... 51
5.3.3
Efficacy Variables................................................................................ 51
5.3.3.1
Primary Variable .................................................................................. 51
5.3.3.2
Secondary Variables............................................................................. 51
5.3.3.3
HCV Resistance Variables.................................................................... 52
5.3.4
Safety Variables ................................................................................... 52
5.3.5
Pharmacokinetic Variables ................................................................... 52
5.3.6
Pharmacogenetic Exploratory Research Variables ................................ 52
5.4
Removal of Subjects from Therapy or Assessment ............................... 53
5.4.1
Discontinuation of Individual Subjects ................................................. 53
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 54
5.4.2
Discontinuation of Entire Study............................................................ 55
5.5
Treatments ........................................................................................... 55
5.5.1
Treatments Administered...................................................................... 55
5.5.2
Identity of Investigational Products ...................................................... 56
5.5.2.1
Packaging and Labeling........................................................................ 56
5.5.2.2
Storage and Disposition of Study Drug................................................. 56
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 57
5.5.4
Selection and Timing of Dose for Each Subject.................................... 57
5.5.5
Blinding ............................................................................................... 57
5.5.6
Treatment Compliance ......................................................................... 57
5.5.7
Drug Accountability ............................................................................. 58
5.6
Discussion and Justification of Study Design........................................ 59
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 59
5.6.2
Appropriateness of Measurements........................................................ 60
5.6.3
Suitability of Subject Population .......................................................... 60
5.6.4
Selection of Doses in the Study ............................................................ 61
5.6.4.1
Rationale for Dose Selections............................................................... 61


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5.6.4.1.1
GLE and PIB Dose and Treatment Duration......................................... 62
5.6.4.2
Risk of Development of Resistance Mutations During 
Combination DAA Trials ..................................................................... 63
6.0
Complaints........................................................................... 64
6.1
Medical Complaints ............................................................................. 64
6.1.1
Definitions ........................................................................................... 65
6.1.1.1
Adverse Event...................................................................................... 65
6.1.1.2
Serious Adverse Events........................................................................ 65
6.1.2
Adverse Event Severity ........................................................................ 67
6.1.3
Relationship to Study Drug................................................................... 68
6.1.4
Adverse Event Collection Period.......................................................... 68
6.1.5
Adverse Event Reporting...................................................................... 69
6.1.6
Pregnancy............................................................................................. 71
6.1.7
Toxicity Management........................................................................... 71
6.1.7.1
Management of Increases in ALT......................................................... 72
6.2
Product Complaint................................................................................ 72
6.2.1
Definition............................................................................................. 72
6.2.2
Reporting ............................................................................................. 73
7.0
Protocol Deviations ............................................................. 73
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 74
8.1
Statistical and Analytical Plans............................................................. 74
8.1.1
Demographics and Baseline Characteristics.......................................... 75
8.1.2
Efficacy................................................................................................ 76
8.1.2.1
Primary Efficacy Endpoints.................................................................. 76
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 77
8.1.2.3
Sensitivity Analysis.............................................................................. 77
8.1.2.4
Subgroup Analysis ............................................................................... 78
8.1.2.5
Additional Efficacy Endpoints.............................................................. 79
8.1.3
Patient Reported Outcomes .................................................................. 79
8.1.4
Resistance Analyses ............................................................................. 80
8.1.5
Safety................................................................................................... 83
8.1.5.1
Adverse Events..................................................................................... 83


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8.1.5.2
Clinical Laboratory Data ...................................................................... 83
8.1.5.3
Vital Signs Data ................................................................................... 84
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................. 84
8.2
Determination of Sample Size .............................................................. 86
8.3
Randomization Methods....................................................................... 86
9.0
Ethics.................................................................................... 87
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 87
9.2
Ethical Conduct of the Study................................................................ 87
9.3
Subject Information and Consent.......................................................... 88
10.0
Source Documents and Case Report Form 
Completion ..........................................................................89
10.1
Source Documents................................................................................ 89
10.2
Case Report Forms............................................................................... 89
11.0
Data Quality Assurance ...................................................... 90
12.0
Use of Information ..............................................................90
13.0
Completion of the Study ..................................................... 91
14.0
Investigator's Agreement....................................................92
15.0
Reference List......................................................................93
List of Tables
Table 1.
Prohibited Medications and Supplements ............................................. 36
Table 2.
Clinical Laboratory Tests ..................................................................... 41
Table 3.
Child-Pugh Classification of Severity of Cirrhosis................................ 44
Table 4.
Identity of Investigational Products ...................................................... 56
List of Figures
Figure 1.
Study Design (Treatment Period).......................................................... 25
Figure 2.
Adverse Event Collection..................................................................... 69


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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.......................................... 95
Appendix B.
List of Protocol Signatories .................................................................. 97
Appendix C.
Study Activities – Treatment Period ..................................................... 98
Appendix D.
Study Activities – Post-Treatment (PT) Period ....................................101
Appendix E.
Protocol Amendment:  List of Changes ...............................................103


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3.0
Introduction
Hepatitis C viral (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, and GT6 is 
primarily found in south-east Asia.5  Depending on various risk factors, between 10% and 
40% of all patients with chronic HCV infection will develop cirrhosis.6
Death 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
Prior to the approval of sofosbuvir (SOF) in 2014, the recommended treatment for GT5 
and GT6 HCV infection was pegINF/RBV for 48 weeks.  The inclusion of SOF to 
pegIFN/RBV shortened the treatment to 12 weeks, and this was supported by a Phase 3 
open-label study where a total of 7 treatment-naive GT5 (n = 1) and  GT6 (n = 6) subjects 
were treated with pegINF/RBV plus SOF regimen for 12 weeks where all subjects 
achieved SVR12 (100%).9
AbbVie is currently developing two "next generation" DAA drugs, glecaprevir (GLE), an 
HCV non-structural (NS) protein 3/4A protease inhibitor (PI) and pibrentasvir (PIB), an 
NS5A inhibitor, for use in combination for the treatment of chronic HCV infection.  The 
objectives of this study are to evaluate the efficacy and safety of GLE/PIB used together 
for the treatment of those with chronic HCV GT5 or 6 infection with or without 
compensated cirrhosis.


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Glecaprevir (GLE)
GLE is an NS3/4A PI with potent and pangenotypic activity.  Its EC50 values against 
HCV replicon stable cell lines with GT1a, 1b, 2a, 3a, 4a and 6a NS3 are 0.85, 0.94, 2.7, 
1.6, 2.8 and 0.86 nM, respectively.  GLE EC50 data for a stable replicon cell line 
containing NS3 from GT5a is not available, but in a transient transfection assay using a 
replicon containing NS3 from GT5a, GLE demonstrated an EC50 of ~0.15 nM, which was 
similar to the GLE EC50 values for GT1a and GT1b replicons in the same assay.  GLE 
demonstrates a high genetic barrier to resistance and maintains activity against common 
variants that emerge following exposure to first generation PIs.
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.10
Pibrentasvir (PIB)
PIB is an NS5A inhibitor with potent and pangenotypic activity.  The in vitro antiviral 
activity of PIB against HCV GT1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a is similar, with EC50
values of 1.8, 4.3, 2.3, 1.9, 2.1, 1.9, 1.4 and 2.8 pM, respectively, in stable replicon cell 
lines.  It demonstrates a high genetic barrier to resistance and maintains activity against 
common resistance-associated variants in NS5A in all GTs.  PIB is greater than 100-fold 
more active than the first generation NS5A inhibitors (ombitasvir, daclatasvir, and 
ledipasvir) against key resistance-associated variants.
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.10
GLE and PIB
In general, GLE and PIB combination has been well tolerated when administered to over 
800 healthy volunteers and 2,376 subjects were randomized or enrolled in the 
registrational studies or supportive Phase 2 studies to receive GLE 300 mg QD and PIB 
120 mg QD.  Of these, 2,369 subjects received at least 1 dose of study drug.  The efficacy 
rates were high (> 95%) among treatment-naive or pegIFN + RBV-experienced non-


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cirrhotic HCV-infected GT-1 – 6 subjects treated with 8 weeks of GLE/PIB in Phase 2 
studies.  Among cirrhotic GT1 treatment-naïve or pegIFN + RBV-experienced treated 
with GLE/PIB for 12 weeks, efficacy was high (> 95%).  However, longer than 12 weeks 
treatment may be beneficial to improve efficacy among non-cirrhotic GT3 pegIFN + 
RBV-experienced as efficacy rate was < 95%.  Most frequently reported AEs in Phase 2 
studies were mild to moderate and clinically manageable.  Overall, GLE and PIB regimen 
has demonstrated a favorable safety profile in Phase 1 and 2 studies.
Additive or synergistic in vitro anti-HCV activity has been demonstrated with the 
combination of GLE and PIB. 
EC50s of PIB for GTs 1 – 6 are similar; EC50s of GLE for GTs 1 – 6 are similar.  GLE and 
PIB exposure are similar and increased, respectively, when administered together.  
Therefore, GLE and PIB are expected to demonstrate efficacy in subjects infected with 
these less prevalent genotypes (GT5 and 6).
When GLE was given in combination with PIB in healthy volunteers, results showed that 
GLE exposures were not significantly changed when co-administered with PIB (≤ 31% 
difference); however, the exposure of PIB increased in a GLE-dose-dependent manner 
(from 1.5-fold at 100 mg GLE up to 3- to 4-fold at 400 mg GLE).
Results of clinical DDI studies conducted to date have shown that as perpetrators of DDIs, 
GLE/PIB combination had no clinically meaningful impact on drugs that are substrates of 
CYP or UGT enzymes.  The GLE/PIB combination increased exposure of substrates for 
P-gp, BCRP, OATP1B1, and OATP1B3 transporters.  Except for some OATP inhibitors 
(e.g., high dose cyclosporine), ritonavir-boosted protease inhibitors and P-gp inducers, 
GLE and PIB exposures were minimally affected by co administrations of other drugs.
Phase 2 Studies (Studies M14-867 and M14-868) assessed efficacy, safety, and 
pharmacokinetics of the combination of GLE and PIB in HCV GT1 (Study M14-867 
Part 1) or GT2- or 3-infected (Study M14-868 Part 1) in treatment-naïve (TN) and PR-
experienced non-cirrhotic subjects, respectively, GT4 – 6 (Study M14-867 Part 2) or 


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GT2- or 3-infected (Study M14-868 Parts 1 and 2) treatment-naïve and PR-experienced 
subjects with and without cirrhosis.
In Part 1 of Study M14-867, 100% (40/40) of GT1-infected subjects without cirrhosis 
treated with GLE 200 mg QD + PIB 120 mg QD for 12 weeks and 97.4% (38/39) of 
subjects treated with GLE 200 mg QD + PIB 40 mg QD for 12 weeks achieved SVR12.  
One subject in the GLE 200 mg QD + PIB 120 mg QD for 12 weeks group experienced 
relapse at Post-Treatment Week 4.  In Part 2 of Study M14-867, 97% (33/34) of GT1-
infected subjects without cirrhosis treated with GLE 300 mg QD + PIB 120 mg QD for 
8 weeks achieved SVR12 (one subject discontinued due to metastatic cancer with HCV 
RNA undetectable at last visit).
In Part 1 of Study M14-868, a total of 195 subjects were enrolled and evenly distributed 
within the GT2 and GT3-infected groups.  Two subjects discontinued due to Treatment-
Emergent Adverse Events (Subjects 5904 and 9309 in Arm F), one subject discontinued 
due to virologic failure (Subject 9106 in Arm F), two subjects were lost to follow-up 
(Subjects 2005 in Arm F and Subject 2403 in Arm G), and one subject withdrew consent 
(Subject 4613 in Arm A).  Two of these subjects (Subjects 5904 and 9309; both Arm F) 
achieved SVR12.
The SVR12 rates for each of the treatment regimens were 96% (24/25) (including a subject 
who was lost to follow-up) of subjects treated with GLE 300 mg QD + PIB 120 mg QD 
for 12 weeks, 100% (24/24) of subjects treated with GLE 200 mg QD + PIB 120 mg QD 
for 12 weeks and 100% (25/25) of subjects treated with GLE 200 mg QD + PIB 120 mg 
QD + RBV for 12 weeks, and 98.1% (53/54) of subjects treated with GLE 300 mg QD + 
PIB 120 mg QD for 8 weeks.
In Part 1 of Study M14-868, 30 subjects with HCV GT3 infection non cirrhotic, treatment 
naïve and PR-experienced were treated with GLE 300 mg and PIB 120 mg without 
ribavirin for 12 weeks and 93.3% (28/30 subjects) achieved SVR12.  One subject in this 
arm experienced relapse at Post-Treatment Week 4 and one subject had missing SVR12
data.


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In Part 2 of Study M14-867, 100% of subjects infected with HCV GT4, GT5 or GT6 non-
cirrhotic, treatment-naïve and PR-experienced receiving treatment with GLE 300 mg QD 
+ PIB 120 mg QD for 12 weeks achieved SVR12 (34/34).  GT1-infected treatment-naïve 
and PR-experienced subjects with compensated cirrhosis were also evaluated with the 
same.  Among the GT1 cirrhotic subjects, 96% (26/27) have achieved SVR12, with 
one subject experiencing relapse at Post-Treatment Week 4.
In Study M14-868 Part 2, among 29 treatment-naïve non-cirrhotic subjects with GT3 
infection treated for 8 weeks with GLE 300 mg QD + PIB 120 mg QD, no subject 
experienced on-treatment virologic failure or post-treatment relapse.  One of the 
29 subjects had missing SVR12 data.  Among 24 treatment-naïve cirrhotic subjects with 
GT3 infection treated for 12 weeks with GLE 300 mg QD + PIB 120 mg QD, no subject 
experienced on-treatment virologic failure or post-treatment relapse. 
To date, safety data across all arms in Part 1 of Studies M14-867 and M14-868 
encompassing 276 subjects treated with GLE at doses 200 and 300 mg and PIB at doses 
40 and 120 mg (with and without RBV in Study M14-868) for 12 weeks show that the 
most frequently reported adverse events were fatigue, nausea, and headache (occurring in 
> 5% of subjects).  Most of them were Grade 1 in severity.  There were no increases in the 
frequency or severity of any adverse event associated between the different regimens of 
GLE 200 mg plus 40 mg or 120 mg PIB, and GLE 300 mg plus 120 mg PIB.
Of the 276 subjects, there have been 4 (1.5%) treatment-emergent SAEs reported in 
Studies M14-867 and M14-868 combined (all assessed as not related to GLE or PIB):  
metastatic prostate cancer, pneumonia, atrial fibrillation, and B-cell lymphoma and 
one SAE that was not treatment-emergent (spontaneous abortion – also assessed as not 
related).  Two subjects (0.7%; 2/276) had treatment-emergent adverse events leading to 
treatment discontinuation.  Both were GT3-infected subjects in the GLE/PIB 
[200 mg/120 mg] QD + RBV for 12 weeks group of Study M14-868.  One subject with 
history of irritable bowel disease discontinued for Grade 2 AE of abdominal pain assessed 
as having a reasonable possibility of relatedness to both the DAAs and RBV.  Baseline 
ALT elevations for this subject normalized during treatment and there were no on-


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treatment ALT elevations above baseline; subject had total bilirubin elevations that were 
primarily indirect.  The abdominal pain for this subject resolved after discontinuation 
from study drug.  The other subject discontinued for the aforementioned Grade 4 SAE of 
B-cell lymphoma for the purposes of initiating chemotherapy.
In both Studies M14-867 and M14-868, in all subjects with baseline alanine 
aminotransferase (ALT) elevations, the ALT levels showed a trend toward normal or 
became normal with DAA treatment.  There have been no on-treatment ALT elevations 
above baseline.  The ALT normalization pattern was similar across all arms (i.e., all GLE 
and PIB dose levels) in both studies.  Other laboratory abnormalities were infrequent and 
primarily associated with the well-described hemolytic effect of RBV, manifesting as 
Grade 1 anemia in a total of 4 subjects, all occurring in Study M14 868 RBV-containing 
arms.  Observed total bilirubin elevations were Grade 1 or 2 with predominantly indirect 
fraction, were mostly isolated occurrences, and normalized or stabilized with continued 
DAA therapy.  Total bilirubin elevations were primarily observed in the RBV-containing 
arms.
The safety of the combination regimen of GLE and PIB in subjects with compensated 
cirrhosis is investigated in Study M14-867 Part 2 (GLE/PIB [200 mg/120 mg] QD for 
12 weeks) and Study M14-868 Part 2 (GLE/PIB [300 mg/120 mg] QD for 12 weeks with 
and without ribavirin or for 16 weeks without ribavirin.  Based on 82 subjects with 
compensated cirrhosis enrolled in these arms who have received 4 weeks or more of 
treatment, the GLE and PIB regimen has demonstrated a favorable safety profile in this 
patient population.  The majority of adverse events have been Grade 1 or 2 and there have 
been no treatment discontinuations.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data for GLE, PIB, and the combination of GLE and PIB can 
be found in the GLE and PIB Fixed-Dose Combination Investigator's Brochure.10


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3.1
Differences Statement
The current Study, M16-126, is a Phase 3b study in which the efficacy and safety of co-
formulated GLE/PIB will be evaluated in treatment-naïve or treatment-experienced 
(i.e., has failed prior IFN or pegIFN with RBV, or SOF plus RBV with or without pegIFN 
therapy), chronic HCV GT5 or 6 infected adults without cirrhosis or with compensated 
cirrhosis for 8 or 12 weeks, respectively.  The ongoing Studies M14-868 (Part 4) and 
M13-583 are assessing the efficacy, safety, and pharmacokinetics of GLE/PIB for 8 or 
12 weeks in mono-infected HCV GT4 – 6 subjects without cirrhosis.  The ongoing 
Phase 3 Study M14-172 is assessing the efficacy, safety, and pharmacokinetics of 
GLE/PIB in mono-infected HCV GT1, 2, 4 – 6 subjects with compensated cirrhosis for 
12 weeks of treatment.
The current study, Study M16-126, evaluates GT5 and GT6 subjects in a wider 
geographic region compared with prior studies.  Importantly, this study will generate 
additional efficacy and safety data following 8 weeks of treatment with GLE/PIB.
3.2
Benefits and Risks
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment, and the convenience of a once daily regimen.
Adverse events that are known, and those not previously described, may occur with 
GLE/PIB as detailed in the informed consent of 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 PIB/GLE are detailed 
in Section 3.0 and in the Investigator's Brochure.10
Risks associated with PIB/GLE, including the risks of toxicity, virologic failure, and 
development of resistant mutations (Section 5.3.4), appear to be limited and manageable 


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based upon the available data.  Given the potential for SVR in this population of HCV 
GT5 or 6 infected subjects, the risk-benefit assessment is favorable.
4.0
Study Objective
4.1
Primary Objectives
The primary objectives of this study are to assess the efficacy (by evaluating the 
percentage of subjects achieving SVR12) and safety of glecaprevir/pibrentasvir in adults 
with chronic hepatitis C virus (HCV) genotype (GT) 5 or 6 infection with or without 
compensated cirrhosis.  The efficacy of glecaprevir/pibrentasvir will be assessed by 
genotypes across treatment durations (or cirrhosis status) and the safety of 
glecaprevir/pibrentasvir will be assessed by treatment duration (or cirrhosis status) across 
genotypes.
4.2
Secondary Objectives
The secondary objectives are to assess efficacy of glecaprevir/pibrentasvir by hepatitis C 
virus (HCV) genotype (GT) 5 or 6 infection across treatment duration (or cirrhosis status) 
by evaluating the following:
●
The percentages of subjects with HCV on-treatment virologic failure;
●
The percentages of subjects with HCV virologic relapse across treatment 
durations (or cirrhosis status).
Additional objectives are to assess pharmacokinetics and emergence and persistence of 
viral variants in these treatment regimens.
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 
GLE/PIB in HCV treatment-naïve or treatment-experienced (i.e., has failed prior IFN or 
pegIFN with or without RBV, or SOF plus RBV with or without pegIFN therapy), chronic 


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HCV GT5 or 6 infected subjects, without cirrhosis (F0-F3) for an 8-week treatment 
duration or with compensated cirrhosis (F4) for a 12-week treatment duration.
This study will consist of 2 periods as follows:
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB for an 
8 or 12 week treatment duration based on cirrhotic status.
Post-Treatment Period:  Subjects who complete or prematurely discontinue the 
Treatment Period will be followed for 24 weeks after their last dose of study 
drug to evaluate efficacy and to monitor HCV RNA and the emergence and 
persistence of viral variants.
A study schematic is shown in Figure 1.
Figure 1.
Study Design (Treatment Period)
*
Approximately 30 GT5-infected subjects and approximately 50 GT6-infected subjects will be enrolled in the 
study.  The study enrollment will be monitored to meet the following enrollment criteria:  1) a minimum of 
15 GT5 and 30 GT6 subjects and 2) up to approximately 16 subjects with compensated cirrhosis (regardless 
of GT).
Approximately 80 eligible subjects will be enrolled into one of the following treatment 
arms:
●
Arm A:  HCV GT 5 or 6 non-cirrhotic subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
●
Arm B:  HCV GT 5 or 6 subjects with compensated cirrhosis will be treated 
with GLE/PIB 300 mg/120 mg once daily (QD) for 12 weeks.


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The study was designed to enroll approximately 80 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
5.1.1
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 35 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);
●
A positive HIV test;
●
HCV genotype does not meet Inclusion Criterion 4, Section 5.2.1, or meets 
Exclusion Criteria 4 and 5, Section 5.2.2;
●
A positive serum pregnancy test (if female).
Otherwise subjects may be retested or rescreened only once.
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 any panel that is 
repeated.  If any of the retest result(s) are exclusionary, the subject may not be rescreened.


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Subjects that are rescreened outside of the initial 35 day screening period must be 
rescreened for all laboratory and eligibility criteria, not just those that were exclusionary.
Subjects who rescreen or subjects not meeting the study eligibility criteria must be 
identified by site personnel as a screen failure in the IRT.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT.  Subjects will be 
administered study drug 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 
include chemistry, hematology, and urinalysis as specified in Table 2.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3.1 and Section 5.3.1.1 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 study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out 
of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
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.


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5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug 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 variants.
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 C 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 C.
5.2
Selection of Study Population
The study population consists of male and female adults aged 18 years or older with 
chronic HCV GT5 and GT6 infection, without cirrhosis or with compensated cirrhosis, 
who are treatment naïve (i.e., subject has never received a single dose of any approved or 
investigational anti-HCV medication) or treatment experienced (i.e., subject has failed 
prior IFN or pegIFN with or without RBV therapy, or SOF plus RBV with or without 
pegIFN).  Subjects who 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, OR permanently surgically 
sterile OR for women of childbearing potential 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 the last dose of study drug.
For male subjects, no contraception is required.
3.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.


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Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in Section 5.2.4) at Screening do not require pregnancy 
testing.
4.
Screening laboratory result indicating HCV GT5 or 6 infection.
5.
Subject has positive anti-HCV Ab and plasma HCV RNA ≥ 1000 IU/mL at 
Screening Visit.
6.
Chronic HCV infection defined as one of the following:
●
Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before 
Screening, or
●
A liver biopsy consistent with chronic HCV infection, or
●
Abnormal alanine aminotransferase (ALT) levels for at least 6 months before 
Screening.
7.
Subject must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication) or treatment-experienced 
(i.e., has failed prior interferon [IFN] or pegylated interferon [pegIFN] with or 
without ribavirin [RBV], or sofosbuvir [SOF] plus RBV with or without pegIFN 
therapy).  Prior HCV treatment with any other approved or investigational 
medications is not allowed.  Previous HCV treatment must have been completed 
≥2 months prior to screening.
8.
Subjects who are on stable opioid replacement must be on a therapy with 
methadone or buprenorphine with or without naloxone for at least 6 months prior to 
screening.
9.
Subject must be documented as having no cirrhosis or compensated cirrhosis (as 
described in Section 5.3.1.1).
10.
Cirrhotic Subjects Only:  Compensated cirrhosis defined as Child-Pugh score of 
≤6 at Screening and no current or past evidence of Child-Pugh B or C 
Classification or clinical history of liver decompensation including ascites noted on 
physical exam, hepatic encephalopathy or esophageal variceal bleeding.


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11.
Cirrhotic Subjects Only:  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.
12.
Subjects 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.
13.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
Rationale for Inclusion Criteria
1, 4 – 7, 8 – 11
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
12, 13
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:
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.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 


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investigator (see Section 5.6.3 for information about subjects using opioid 
replacement therapy).
3.
Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti-
human immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed during screening indicating co-infection with more than 
one HCV genotype.
5.
Requirement for and inability or unwillingness to safely discontinue the 
medications or supplements listed in Table 1 at least 2 weeks or 10 half-lives 
(whichever is longer) prior to the first dose of any study drug.
6.
Requirement for chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
7.
Clinically significant abnormalities, other than HCV infection, based upon the 
results of a medical history, physical examination, vital signs, laboratory profile, 
and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable 
candidate for this study in the opinion of the investigator, including, but not limited 
to:
●
Uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) 
level > 8.5% at the Screening Visit.
●
Active or suspected malignancy or history of malignancy (other than basal cell 
skin cancer or cervical carcinoma in situ) in the past 5 years.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, 
psychiatric, or other medical disease or disorder, which is unrelated to the 
existing HCV infection.
8.
Any cause of liver disease other than chronic HCV infection, including but not 
limited to the following:
●
Hemochromatosis.
●
Alpha-1 antitrypsin deficiency.


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●
Wilson's disease.
●
Autoimmune hepatitis.
●
Alcoholic liver disease.
●
Steatohepatitis on liver biopsy considered to be the primary cause of the liver 
disease rather than concomitant/incidental with HCV infection.
9.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
ALT > 10 × ULN
●
AST > 10 × ULN
●
Calculated creatinine clearance (using Cockcroft-Gault method) of 
< 50 mL/min
●
Direct bilirubin > ULN
●
Albumin < 3.0 mg/dL for subjects with cirrhosis; < LLN for subjects without 
cirrhosis
●
International normalized ratio (INR) > 1.5 × ULN, unless subject has known 
hemophilia or is on a stable anticoagulant regimen affecting INR
●
Hemoglobin < 10 g/dL for women; < 11 g/dL for men
●
Platelets < 60,000 cells per mm3 for subjects with cirrhosis; < 90,000 cells per 
mm3 for subjects without cirrhosis
10.
History of solid organ transplantation.
11.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks (whichever is longer) prior to 
study drug administration.
12.
Receipt of any other investigational or commercially available direct acting anti-
HCV agents other than sofosbuvir (e.g., telaprevir, boceprevir, simeprevir, 
asunaprevir, paritaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
or dasabuvir).
13.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive GLE/PIB.


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14.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
15.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 6, 9, 10, 13 – 15
In order to ensure safety of the subjects throughout the study
2, 5, 11, 12
In order to avoid bias for the evaluation of efficacy and safety, 
including concomitant use of other medications
3, 4, 7 – 8
To exclude subjects with HIV and liver diseases other than 
chronic HCV GT5 and GT6 infection
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 study drug is stopped, must be 
recorded in the electronic case report form (eCRF) along with the reason for use, date(s) 
of administration including start and end dates, and dosage information including dose, 
route, and frequency.  The investigator should review all concomitant medications for any 
potential interactions.
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drug.  Only medications associated with HCV or taken for 
a serious adverse event (SAE) will be recorded thereafter.
The AbbVie 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) or treatment-experienced (i.e., has 


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failed prior interferon [IFN] or pegylated interferon [pegIFN] with or without ribavirin 
[RBV], or sofosbuvir [SOF] plus RBV with or without pegIFN therapy).  Prior HCV 
treatment with any other approved or investigational medications is not allowed.
Subjects will be categorized as:
●
HCV Treatment-naïve:  subject has never received any treatment for HCV 
infection.
●
Subjects with an allowed prior HCV treatment will be categorized as:
○
Non-responder:  HCV RNA detected at the end of a prior treatment 
course (except for breakthrough, which is captured separately).  These 
subjects are further categorized as:
●
Null responder:  failed to achieve a 1 log10 IU/mL reduction in HCV 
RNA by Week 4 or a 2 log10 IU/mL reduction in HCV RNA by 
Week 12 during a prior treatment course;
●
Partial responder:  achieved at least a 2 log10 IU/mL reduction in HCV 
RNA by Week 12 during a prior treatment course but failed to achieve 
HCV RNA undetectable (or unquantifiable) at the end of treatment;
●
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder.
○
Breakthrough:  confirmed ≥ 1 log10 IU/mL increase from nadir or 
achieved HCV RNA undetectable (or unquantifiable) during a prior 
treatment course but HCV RNA was quantifiable during or at the end of 
treatment.
○
Relapse:  achieved HCV RNA undetectable (or unquantifiable) at the end 
of a prior treatment course but HCV RNA was detectable following 
cessation of therapy.
○
Other:  subject received a prior treatment course and reason for not 
achieving SVR is other than above.
○
Unknown:  subject received a prior treatment course and reason for not 
achieving SVR is unknown.


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Subjects must have discontinued prior HCV treatment ≥ 2 months prior to the Screening 
Visit in order to be eligible for the study.  For subjects who had multiple HCV treatment 
courses, the categorization of previous response category will be based on the last prior 
treatment.
5.2.3.2
Concomitant Therapy
Subjects should be on a stable dose of concomitant medications for at least 2 weeks prior 
to initiation of study drug.  The investigator should confirm that a concomitant 
medication/supplement can be safely administered with study drug.  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 drug, if applicable.
5.2.3.3
Prohibited Therapy
Subjects must be able and willing to safely discontinue any prohibited medications or 
supplements listed in Table 1 at least 2 weeks or 10 half-lives (whichever is longer) prior 
to the first dose of any study drug and not use these during the entire Treatment Period 
and for 14 days following discontinuation of study drug.


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Table 1.
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*
Ethinyl estradiol
Astemizole, cisapride, terfenadine
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) must not be taken with the 
study drug.  Subjects receiving these statins must discontinue the prohibited statin at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of study drug and, based on  investigator's judgment, (a) switch to 
pravastatin or rosuvastatin or (b) interrupt statin therapy throughout the treatment period and until 14 days after the 
last dose of study drug.  If treating with pravastatin or rosuvastatin, it is recommended to reduce the pravastatin 
dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug.
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.
The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 
not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
5.2.4
Contraception Recommendations and Pregnancy Testing
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 surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy).


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For women of childbearing potential (WOCBP):
●
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) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation.
○
Vasectomized partner(s), provided the vasectomized partner has received 
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).
○
Progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action, initiated at least 1 month prior 
to Study Day 1.
○
Male or female condom with or without spermicide.  Condoms without 
spermicide are acceptable only in countries where spermicide is not 
available.
○
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, symptom-thermal, post-ovulation 
methods] and withdrawal are not acceptable).
For male study subjects, no contraception is required.


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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.
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 updated 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.  Waist circumference will be measured at 
Screening; however, if it is not measured at Screening, it can be measured on Day 1.


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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 
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 2
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 


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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.
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 will 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 Meyrin
Geneva Switzerland
(For sites in Europe, Russia and South Africa)
Covance (Asia) Pte Ltd
1 International Business Park
#01-01 The Synergy
Singapore 609917
(For sites in Asia Pacific)


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Table 2.
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
Total bilirubina,b
Direct and indirect bilirubin
Alanine transaminase 
(SGPT/ALT)
Aspartate transaminase 
(SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Cholesterol
Total protein
Glucose
Triglycerides
Low Density Lipoproteins 
(LDL)c,d
High Density Lipoprotein (HDL)d
Albumina
Chloride
Bicarbonate
Magnesium
Total insulin
Gamma-glutamyl transferase 
(GGT)
Creatinine clearance (Cockcroft-
Gault calculation)
HBsAge
Anti-HCV Abe
HIV Abe
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG)
for femalesf
HCV RNA
Hepatitis B Panelg
Hemoglobin A1Ce
IL28Bd
HCV genotype and subtypee
Pharmacogenetic sample 
(optional)
Alpha2-macroglobulinb
Haptoglobinb
Apolipoprotein A1b
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Also a component of Child-Pugh Assessment.
b.
Component of FibroTest and collected only if needed during the Screening Period.
c.
Directly measured.
d.
Performed only at Baseline.
e.
Performed only at Screening.
f.
Pregnancy testing is not required for females of non-childbearing potential.
g.
Performed at Day 1 for all subjects and also performed for management of transaminase elevation 
(Section 6.1.7.1).
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
A serum pregnancy test will be performed for all female subjects of childbearing potential 
at Screening.  Additional urine pregnancy tests will be performed every 4 weeks, starting 
at Day 1 (prior to enrollment) during the treatment period, including at the last Treatment 
Period visit and until 30 days of last study drug dose, as indicated in Appendix C and 
Appendix D.  Determination of postmenopausal status will be made during the Screening 
period, based on the subject's history.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in Section 5.2.4) 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 (hepatitis B surface antigen), 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 
necessary.  The HIV results will not be reported by the central laboratory to the clinical 
database.


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Liver Diagnostic Testing
Subjects will be considered to be non-cirrhotic or cirrhotic based on the definitions below:
Non-Cirrhotic
●
A liver biopsy within 24 months prior to or during Screening demonstrating 
the absence of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, 
Scheuer, or Laennec fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; or
●
A FibroScan® score of < 12.5 kPa within ≤ 6 months of Screening or during 
Screening period (FibroScan® must be approved by the local regulatory agency 
to qualify for entrance criteria); or
●
A Screening FibroTest score of ≤ 0.48 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) < 1.
Cirrhotic
●
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3, Ishak 
score of > 4 or on a liver biopsy conducted during Screening; or
●
A FibroScan® score of ≥ 12.5 kPa within ≤ 6 months of Screening or during 
Screening period (FibroScan® must be approved by the local regulatory agency 
to qualify for entrance criteria); or
●
A Screening FibroTest result that is ≥ 0.75 and an APRI > 2.
In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
Fibrotest/APRI using the above criteria (indeterminate FibroTest [0.48 < result < 0.75], or 
conflicting FibroTest and APRI results [e.g., FibroTest ≤ 0.48, but APRI ≥ 1]), a liver 
biopsy or FibroScan® is required.  Liver biopsy results will supersede Fibrotest/APRI or 
FibroScan® results and be considered definitive.  At Screening, it is recommended that 
subjects should otherwise meet all of the inclusion criteria and none of the exclusion 
criteria before undergoing a liver biopsy.


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Child-Pugh Score and Category
Subjects with compensated cirrhosis 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 3.  Child-Pugh score will be determined at the 
visits indicated in Appendix C and Appendix D.  
Table 3.
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)
*
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.
**
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
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Study 
Day 1 prior to dosing to confirm the subject has not progressed to hepatic decompensation 
since Screening for all subjects who have compensated cirrhosis.  Grading system 
guidelines for ascites are listed above in Table 3.


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Hepatocellular Carcinoma (HCC) Screening:  Liver Ultrasound 
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Visit and at Post-Treatment Week 24, as indicated in Appendix C and 
Appendix D, for subjects with compensated cirrhosis only.  In-between those visits, HCC 
screening should be performed according to standard of care.
At the Screening Visit and at Post-Treatment Week 24, subjects with compensated 
cirrhosis will be required to undergo a liver ultrasound to screen for HCC, unless the 
subject has a historical liver ultrasound, CT scan or MRI performed for HCC screening 
within 3 months prior to those visits, in which case the result of the historical ultrasound, 
CT scan 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., CT scan or MRI) 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.
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 


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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.
Work Productivity and Activity Impairment (WPAI)-HCV Specific Instrument –
Version 2
The WPAI-Hepatitis C questionnaire is an instrument to measure impairments in both 
paid work and unpaid work from HCV-infected people.  It measures absenteeism, 
presenteeism, overall work productivity loss, as well as impairments in unpaid activity 
because of hepatitis C.  The WPAI-Hepatitis C consists of 6 questions:  1 = currently 
employed; 2 = hours missed due to hepatitis C; 3 = hours missed other reasons; 
4 = hours actually worked; 5 = degree hepatitis C affected productivity while working 
(using a 0 to 10 visual analog scale [VAS]); 6 = degree hepatitis C affected 
productivity in regular unpaid activities (VAS).  The WPAI-Hepatitis C should require 
approximately 5 minutes to complete.
PRO instruments should be consistently presented so that subjects complete the 
questionnaires in the following order:  the SF-36v2 and WPAI-Hepatitis C.  PRO 
instruments should be completed prior to drug administration on Day 1 and prior to any 
discussion of adverse events or any review of laboratory findings, including HCV RNA 
levels.
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.


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Subject numbers will be unique 5-digit numbers and will begin with 10001 with the 
first three digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  Subjects will be enrolled on Study Day 1 as described in Section 5.5.4.
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 Subgenotype
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.
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.


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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 Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Appendix C and 
Appendix D.  Archive plasma 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 of each study drug taken prior to 
the scheduled pharmacokinetic sample collection during the Treatment Period.
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:


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●
The study coordinator should make sure the subject is given the dosing card at 
the visits listed in Appendix C.
●
The Investigator or designee will contact the subject approximately 2 days 
before the scheduled visit date to review the importance of proper study drug 
administration relative to the pharmacokinetic blood collection and 
documentation of dosing times on the dosing card.  The date and time of the 
contact will be entered into the subject's source documents.
●
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
Subjects will have the option to provide samples for optional pharmacogenetic 
exploratory research.  Subjects may still participate in the main study even if they decide 
not to participate in this optional exploratory research.
Optional whole blood samples for DNA and RNA isolation will be collected on Day 1, 
EOT Week 8 or 12, 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:  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 
plasma 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 assay method 
by the Drug Analysis 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 Variable
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).
5.3.3.2
Secondary Variables
The secondary efficacy variables are:
●
The percentage of subjects with HCV on-treatment virologic failure.
●
The percentage of subjects with HCV virologic relapse.


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5.3.3.3
HCV Resistance Variables
For all subjects receiving study drug, the variants at signature resistance-associated amino 
acid positions at baseline 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 variants in available post-baseline samples identified by 
NGS and comparison to the baseline sequence, 2) the amino acid variants 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 resistance 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
Individual plasma concentrations of GLE and PIB will be tabulated and summarized.  
Values for the pharmacokinetic parameters of GLE and PIB, including apparent clearance 
(CL/F) and apparent volume of distribution (V/F) will be estimated using population 
pharmacokinetic modeling procedures.  Additional parameters may be calculated if useful 
in the interpretation of the data.
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 


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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 
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-


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Treatment Period where the subject will be monitored for 24 weeks for HCV RNA and 
the emergence and persistence of resistant viral variants.
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 HCV virologic failure for the 
purposes of subject management:
●
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.
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study drug treatment until the virologic failure criteria has been 
confirmed.  Subjects meeting the virologic failure criteria 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 variants until 24 weeks post-treatment.


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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Glecaprevir/pibrentasvir (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).


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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 4.
Table 4.
Identity of Investigational Products
Investigational 
Product
Manufacturer
Mode of 
Administration
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 Drug
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).


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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 the treatment assignment.  Enrolled subjects will 
be assigned to either Arm A (8 weeks of treatment) or Arm B (12 weeks of treatment) 
based on cirrhotic status.  The study drug kit numbers will be assigned according to 
schedules computer-generated before the start of the study by the AbbVie Statistics 
Department.
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.
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
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 


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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 assessment of treatment 
compliance.  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.
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 
throughout the Treatment Period.  The monitor will review study drug accountability on 
an ongoing basis.  Final accountability will be verified by the monitor at the end of study 
drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug bottle of 
GLE/PIB the IRT system must be contacted and informed of the misplaced or damaged 


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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.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The current study (Study M16-126) is a Phase 3b study designed to evaluate the efficacy 
(percent of patients achieving SVR12) and safety of combination regimen of GLE 300 mg 
and PIB 120 mg QD in treatment-naïve and -experienced subjects infected with chronic 
HCV GT5 and GT6 infection without cirrhosis or with compensated cirrhosis for 8 weeks 
or 12 weeks, respectively. 
Treatment durations were selected based on available data (all SVR4 and available SVR12
rates) from 8-week or 12-week treatment groups receiving GLE/PIB combinations in 
Studies M14-867 and M14-868 in HCV GT1, GT2, GT3, GT4, GT5, and GT6-infected 
non-cirrhotic patients with or without previous treatment experience.


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The 8-week treatment duration has been evaluated in 34 GT1, 54 GT2, and 29 GT3 
treatment-naïve and -experienced subjects without cirrhosis in Part 2 of Studies M14-867 
and M14-868, respectively, and demonstrated robust SVR12 rates without virologic 
failures, to date.  SVR12 rates were 97% (33/34), 98% (53/54), and 97% (28/29%) for 
GT1, GT2, and GT3, respectively.  In addition, the GLE/PIB 300 mg/120 mg combination 
regimen demonstrated 100% SVR12 in a total of 34 GT4, GT5, and GT6-infected non-
cirrhotic subjects when taken for a 12-week duration.  Based on the efficacy data 
presented above, the 8-week treatment duration is anticipated to achieve high SVR rates 
in GT5 – 6-infected treatment-naïve and -experienced subjects without cirrhosis.13,14
The 12-week duration of the GLE/PIB combination regimen in adults with chronic HCV 
genotype (GT) 1, 2, 4, 5, or 6 infection with compensated cirrhosis is being evaluated in 
an ongoing Phase 3 (Study M14-172) study.  The number of GT5 (n = 3) and GT6 (n = 7) 
subjects enrolled were small.
With an expected SVR rate approaching 100%, as observed in the Phase 2 Studies, the 
benefit of a non-inferiority design with an active-comparator is limited.  This design is 
therefore believed to be an appropriate approach for demonstrating efficacy in these GTs 
of lower prevalence.
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
This study plans to enroll HCV GT5, or 6-infected subjects, with or without compensated 
cirrhosis who are HCV treatment-naïve or treatment-experienced in order to assess the 
safety, pharmacokinetics and antiviral activity of GLE/PIB.  Subjects who are treatment-
naïve as well as those who have failed prior IFN or pegIFN (with or without RBV), or 
SOF plus RBV (with or without pegIFN) therapy for their HCV infection are included in 
the study in order to evaluate the efficacy of GLE/PIB regimen in this diverse cohort of 


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HCV GT5 and GT6-infected subjects.  There is no expectation of cross-resistance 
between IFN, pegIFN, RBV, or SOF with either GLE or PIB because of the differences in 
their mechanisms of action.  Subjects who have failed treatment with a PI or NS5A 
inhibitor alone or in combination with interferon (with or without RBV) will not be 
permitted to enroll, because the results from ongoing Phase 2 study evaluating the 
regimen in DAA experienced patients (Study M15-410) are not available.
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 
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.
In order to be enrolled in the study, subjects who are on stable opiate replacement must be 
on a therapy with methadone or buprenorphine with or without naloxone for at least 
6 months prior to screening.  This is based on the results from Study M13-602 that 
evaluated the pharmacokinetic, pharmacodynamic, safety, and tolerability effects of the 
co-administration of methadone or buprenorphine/naloxone and GLE/PIB in adult 
subjects on stable opioid therapy, which showed acceptable safety and no relevant 
pharmacokinetic or pharmacodynamic interactions.
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.


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5.6.4.1.1
GLE and PIB Dose and Treatment Duration
Based on the results from the Phase 2b studies, Studies M14-867 and M14-868, the 
300 mg dose of the GLE and 120 mg dose of PIB in combination has been selected for 
Phase 3 studies in HCV GT1 to 6 treatment-naïve and -experienced, cirrhotic and non-
cirrhotic populations.  This dose has been demonstrated efficacious for the proposed 
Phase 3 study populations with12-week planned study duration and would reduce chances 
of virologic failures across genotypes and difficult-to-treat patient populations to 
maximize the chance for SVR.  Importantly, one thousand and six HCV-infected subjects 
have been dosed with the combination of GLE and PIB in ongoing Phase 2b and Phase 3 
studies to date.  This combination has been well-tolerated and safe across all studies 
including cirrhotic and prior treatment experienced subjects (Data on file).  The most 
frequently reported adverse events were fatigue, nausea and headache and were mostly 
Grade 1 or 2 in severity.  In all subjects with baseline ALT elevations, ALT levels 
normalized or trended toward normal with DAA treatment, and there have been no on-
treatment ALT elevations above baseline grade.
Results from GLE 300 mg QD + PIB 120 mg QD for 8-week treatment duration in HCV 
GT1 (n = 34) Study M14-867 Part 2) and HCV GT2 (n = 54) (Study M14-868 Part 2) 
showed 97.1% and 98.1% SVR12 respectively.  In Study M14-867 Part 2, GLE 300 mg 
QD + PIB 120 mg QD for 12 weeks was evaluated in 34 DAA-naïve HCV GT4 (n = 22), 
GT5 (n = 1), and GT6 (n = 11)-infected non-cirrhotic subjects.  All 34 subjects achieved 
SVR12.  Based on exposure-response analyses, simulations were conducted to predict 
SVR rates for GLE and PIB administered 8 weeks in HCV GT4-infected subjects and 
showed > 95% SVR in this population.  GLE 300 mg QD + PIB 120 mg QD for 8 weeks 
will be used in this study for HCV genotype 5 and 6 non-cirrhotic subjects.
Efficacy results from Part 2 of Study M14-868 in GT3 treatment-naïve cirrhotic patients 
showed 100% SVR12 for GLE 300 mg + PIB 120 mg QD administered for 12 weeks.  
Based on simulations conducted to predict SVR rates of 300 mg/120 mg GLE/PIB for 12 
and 16 weeks in HCV GT1 subjects with cirrhosis, this GLE/PIB dose could provide 
improved SVR rates compared to lower doses and a duration of 12 weeks could achieve 


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an SVR rate close to 100% in cirrhotic subjects with HCV GT1 infection.  Longer 
duration (e.g., 16 weeks) of 300 mg/120 mg GLE/PIB QD treatment is not expected to 
provide a significant improvement in the SVR rate (in GT1).  Similar to GT1, the 
predicted SVR rates for GT2 subjects with cirrhosis following 300 mg/120 mg GLE/PIB 
QD treatment for 12 weeks is 98%.  This dose is also anticipated to yield high SVR rate 
following 12-week treatment duration in GT4 to GT6 infected cirrhotic population.
In summary, based on clinical trial data and exposure-response analyses, it is expected 
that GLE 300 mg + PIB 120 mg QD will achieve high SVR rate in both non-cirrhosis 
(administered for 8 weeks) and compensated cirrhosis subjects (administered for 
12 weeks).
5.6.4.2
Risk of Development of Resistance Mutations During 
Combination DAA Trials
In subjects treated with a DAA, variants with amino acid substitution(s) in the targeted 
protein conferring resistance to the DAA can be selected.  For example, in AbbVie HCV 
Phase 3 studies in which patients with GT1 infection were treated with the NS3/4A 
protease inhibitor paritaprevir and NS5A inhibitor ombitasvir, variants that conferred 
resistance to paritaprevir or ombitasvir were detected in patients experiencing virologic 
failure.  While resistance data from patients treated with the combination of PIB and GLE 
are limited, it is expected that PIB, an NS5A inhibitor, will be able to suppress the 
appearance of virus containing resistance-associated variants in NS3 that confer resistance 
to GLE, because there should not be any cross-resistance in variants 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 variants 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 
variants that conferred only modest levels of resistance to PIB.  It remains to be seen 
whether the development of resistance in subjects treated with PIB resembles that seen in 
vitro.  Based on accumulated clinical and in vitro data to date, the risk of development of 


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resistant variants during GLE and PIB combination trials is reduced when compared to 
treatment with first generation protease and NS5A inhibitors.  For example, the 
combination of PIB and GLE achieved high SVR rates with few virologic failures in 
DAA-naïve patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection in the Phase 2 
SURVEYOR-I and -II studies.  These results support the prediction that the risk of 
development of resistance-associated variants 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 
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.


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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 the study will not be considered 
an adverse event if the surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been pre planned prior to study entry.  However, if the pre-
existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
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.


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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).
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.


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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" 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).
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 immediately 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.


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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
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, 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.


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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 
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


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For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
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:
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 
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 


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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. However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to 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 
the investigator.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4" 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.


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Specific toxicity management guidelines apply to the instances of increases in ALT 
(Section 6.1.7.1).
6.1.7.1
Management of Increases in ALT
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 additional testing as appropriate (e.g., hepatitis B panel).
●
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.
Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director.
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.


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For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
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.
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 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 


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Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitors:
Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to Statistical 
Methods and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued treatment.  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.
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.


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Safety, and demographic 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.
Sensitivity analyses of the primary efficacy endpoint, when applicable, will be performed 
on the intention-to-treat population modified to exclude subjects not of GT5, 6 according 
to phylogenetic analyses (mITT-GT), and on the mITT-GT population further 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).  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.
8.1.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all treated subjects by 
HCV GT (GT5 and 6 separately, across arms), by Arm (A and B), and overall.  
Demographics include age, weight, height, BMI, gender, race, and ethnicity.  Baseline 
characteristics include HCV genotype subtype, IL28B genotype, prior HCV treatment 
history, baseline HCV RNA level, fibrosis stage (F0 – F1, F2, F3, F4 [if applicable]), 
tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) 
status, former injection drug user, (yes, within last 12 months; yes, more than 12 months 
ago; or no) use of stable opiate substitution, history of diabetes, baseline metabolic 
syndrome, history of bleeding disorders, history of depression or bipolar disorder, history 
of cardiovascular disease, geographic region, and all other subgroup variables defined in 
Section 8.1.2.4.


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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 BMI), 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.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Efficacy analyses will be performed within each genotype (GT5 and GT6 subjects) across 
treatment arms (representing the recommended per cirrhosis status) and in the combined 
treatment arms.
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 will be reported as C/C, C/T, or T/T by the central laboratory.
8.1.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint is the percentage of subjects in who achieve SVR12 (HCV 
RNA < LLOQ 12 weeks after the last actual dose of study drug) within each genotype 
(GT5 and GT6 subjects) across the treatment arms.  The primary endpoint will be 
analyzed based on ITT population.  The number and percentage of subjects achieving 
SVR12 will be summarized along with a two-sided 95% confidence interval using the 


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normal approximation to the binomial distribution, unless the number of SVR12 non-
responders is less than 5, where the Wilson's score method will be used for the confidence 
interval instead.
A summary of reason for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints within each genotype (GT5 and GT6 subjects) 
separately, across treatment arms are:
●
The percentage of subjects with HCV on-treatment virologic failure;
●
The percentage of subjects with post-treatment HCV virologic relapse.  
Subjects with reinfection based on HCV NGS will be summarized separately 
from relapse.
The secondary endpoints of HCV on-treatment virologic failure and post-treatment HCV 
virologic relapse will be analyzed within each genotype (GT5 and GT6 subjects) 
separately, across the treatment arms.
For the analysis of post-treatment HCV virologic relapse, completion of treatment is 
defined as any subject with study drug duration of 52 days and 77 days or greater for 
subjects allocated to treatment durations of 8 weeks and 12 weeks, respectively.
For on-treatment virologic failure and post-treatment relapse, the number and percentage 
of subjects will be summarized along with a two-sided 95% confidence interval using 
Wilson's score method.
8.1.2.3
Sensitivity Analysis
As sensitivity analyses, the number and percentage of subjects in the mITT-GT and 
mITT-GT-VF populations achieving SVR12, as applicable, will be summarized along with 


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a two-sided 95% confidence interval using the normal approximation and a two-sided 
95% confidence interval using the Wilson's score method.
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated as a sensitivity analysis for the primary endpoint of SVR12 based on ITT 
population.
8.1.2.4
Subgroup Analysis
The subgroup analyses will be performed within each genotype separately.  The summary 
statistics of subjects with SVR12 will be provided for the following subgroups:
●
Prior HCV treatment history (naïve or experienced);
●
For treatment-experienced subjects, type of previous treatment (IFN- or SOF-
based);
●
IL28B genotype (CC or non-CC);
●
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);
●
BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 6,000,000 or ≥ 6,000,000 IU/mL);
●
Baseline fibrosis stage (F0-F1, F2, F3, or F4);
●
Baseline cirrhosis Status (Yes/No)
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min)
●
Baseline eGFR (< 90 or  ≥ 90 mL/min/1.73 m2)
●
History of diabetes (yes/no);
●
Baseline metabolic syndrome;
●
Subject on stable opiate substitution (yes/no);


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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 by genotype:
●
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 four weeks after the last actual 
dose of study drug (SVR4);
●
The percentage of subjects who achieve SVR24 twenty-four weeks after the last 
actual dose of study drug (SVR24);
●
The percentage of subjects who 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 
interval.
A descriptive summary of SVR12 endpoints will be provided for GT5 and GT6 subjects 
separately and combined for all non-cirrhotic subjects who received 8 weeks of treatment 
and cirrhotic subjects who received 12 weeks of treatment in any of the following studies:  
Studies M14-868 Part 4, M14-172, or M16-126, using meta analytic methods.
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 Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  For WPAI Hepatitis 
C scores, no imputation will be performed for missing items.


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The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (MCS) and Physical Component Summary (PCS) scores; 
WPAI activity impairment due to hepatitis C, overall work impairment, absenteeism, and 
presenteeism scores will be summarized descriptively at each visit and for change from 
baseline to each visit.  For each of these scores, mean change from Baseline to Final 
Treatment Visit and from Baseline to Post-Treatment Week 12 will be summarized using 
an analysis of covariance (ANCOVA) model with baseline score as a covariate.
The following analyses of patient reported outcomes (PROs) also will be performed:
●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable timepoint of greater than or 
equal to 3 points in the SF-36 MCS and PCS;
●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable timepoint of greater than or 
equal to 5 points in the SF-36 MCS and PCS;
●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable timepoint of greater than or 
equal to 5 points in the SF-36 domain scores;
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 (on-treatment virologic failure 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.


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Signature resistance-associated amino acid positions are 36, 43, 54, 55, 56, 80, 155, 156, 
and 168 in NS3; and 24, 28, 29, 30, 31, 32, 58, 92, and 93 in NS5A.
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant by NGS in a baseline sample (≥ 2% or ≥ 15% 
prevalence within a subject's viral population depending on variant frequency 
threshold utilized) that was not present in the appropriate prototypic reference 
amino acid sequence for a given DAA target (NS3/4A or NS5A).
●
Variant at signature amino acid position:  variant (relative to reference) present 
in a baseline or a post-baseline sample at a signature amino acid position.
●
Post-baseline variant:  an amino acid variant 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 variant:  variant 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 variant by NGS:  A post-baseline variant or an enriched 
variant.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
A listing of all baseline variants (2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A).
●
A listing of all baseline variants (15% detection threshold) at non-signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A) for subjects who experience virologic failure.
●
The number and percentage of subjects with baseline variants at signature 
amino acid positions at detection thresholds of 2% and 15%.


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Analysis 2:  The impact of baseline variants on treatment outcome will be assessed as 
follows:  for each variant, the SVR12 rate will be calculated for subjects with and without 
the variant 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 variants on treatment 
outcome:
●
For each signature amino acid position, presence of any variant at that position 
(vs no variant at that position), using detection thresholds of both 2% and 15%.
●
Each individual variant at each signature amino acid position (vs not that 
variant) using detection thresholds of 2% and 15%.
●
Variants at each non-signature amino acid position at a detection threshold of 
15%.
Analysis 3:  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 variants 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 variant at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A 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 


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results from the Central laboratory will be used to categorize the subject.  This 
information will be presented in summaries of efficacy subgroup analyses.
8.1.5
Safety
Safety summaries will be provided by the treatment arm (i.e., cirrhosis status/study drug 
duration) and overall.  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 
each 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.
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.  Changes from baseline to post-baseline in the CTCAE grading of 
laboratory values will also be summarized.


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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.
In addition, the number and percentage of subjects with post-baseline values meeting pre-
specified criteria for Potentially Clinically Significant laboratory values or toxicity grades 
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.  The number and percentage of subjects with post-baseline values meeting 
pre-defined criteria for PCS (Potentially Clinically Significant) vital signs values during 
treatment will be summarized.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE and PIB and possible metabolites and pharmacokinetic 
parameter values for GLE and PIB will be tabulated for each subject and group.  
Summary statistics will be computed for each time and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version 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 


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


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TVCLi = Theta(1) + Theta(2) (Comedication [1,2,…]) + Theta(3) (WTi-median value) + 
Theta(4) (AGEi – median value).
Where TVCLi = Typical value of clearance for an individual1, 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 anticipated that approximately a total of 80 HCV infected patients, (~30 GT5-infected 
subjects and ~50 GT6-infected subjects) will be enrolled in the study.  A minimum of 
15 GT5 and 30 GT6 subjects will be enrolled and up to approximately 16 subjects with 
compensated cirrhosis (regardless of GT) will be enrolled.  No formal hypothesis is being 
tested.  If the observed SVR12 rate in this study is 97% among 30 GT5 subjects and 
50 GT6 subjects, then the half-width of 2-sided 95% normal approximation intervals are 
0.061 and 0.047 for the GT5 and GT6 subjects, respectively.  
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be allocated to a treatment arm 
according to their cirrhosis status (presence/absence).


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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.
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 for optional pharmacogenetic exploratory research.  The 
nature of the testing should be explained and the subject given an opportunity to ask 
questions.  The informed consent must be signed before the samples are collected and any 
testing is performed.  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 on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 


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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 pharmacogenetic 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 
pharmacogenetic exploratory research may be used in scientific publications or presented 
at medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.


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


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for GLE/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 Multicenter, Open-Label Study to Evaluate the Efficacy and 
Safety of Glecaprevir (GLE)/Pibrentasvir (PIB) in Adults with 
Chronic Hepatitis C Virus (HCV) Genotype 5 or 6 Infection
Protocol Date:
28 July 2017
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.
Lawitz E, Mangia A, Wyles D, et al.  Sofosburvir for previously untreated chronic 
hepatitis C infection.  N Engl J Med.  2013;368(20):1878-87.  
10.
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's 
Brochure Edition 2.  06 September 2016; including Addendum 1 Edition 2.  
November 2016.


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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 Infections (CROI); 
March 03-06, 2014; Boston, Massachusetts.  Poster 636.Sulkowski MS.  HCV 
therapy in HIV-infected patients.  Liver Int.  2013;33 (Suppl 1):63-7.
12.
Gottwein JM, Scheel TK, Jensen TB, et al.  Differential efficacy of protease 
inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant 
viruses.  Gastroenterology.  2011;141(3):1067-79.
13.
Poordad F, Felizarta F, Wang S, et al.  High SVR rates with the combination of 
ABT-493 + ABT-530 for 8 weeks in non-cirrhotic patients with HCV genotype 1 
or 2 infection.  Poster presented at:  European Association for the Study of the 
Liver (EASL); April 13-17, 2016; Barcelona, Spain.
14.
Muir A, Strasser S, Wang S, et al.  High SRV rates with ABT-493 + ABT-530 co-
administered for 8 weeks in non-cirrhotic patients with HCV genotype 3 infection.  
Poster presented at:  51st Annual Meeting of the European Association for the 
Study of the Liver (EASL); April 13-17, 2016; Barcelona, Spain.


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


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Bioanalysis
Statistics
Clinical


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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Informed Consentc
X
Dispense/Review Study Drug Dosing Card
X (Dispense only)
X
X
X
X
X (Review only)
Medical Historyd
X
X
Physical Exam 
X
X
X
Vital Signs, Weight, Waist Circumference,e Heighte
X
X
X
X
X
X
X
ECG
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])f
X (s)
X (u)
X (u)
X (u)
X (u)
HBsAg, Anti-HCV Ab, Anti-HIV Ab
X
Hepatitis B Panel
X
Hemoglobin A1C (HgbA1c)g
X
HCV Genotype and Subgenotype
X
FibroTest and APRI or FibroScan® or Liver Biopsyh
X
IL28B Samplei
X
Pharmacogenetic DNA and RNA Sample (optional)
X
X
Total Insulin
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
Adverse Event Assessmentj
X
X
X
X
X
X
X


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Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Study Drug Dispensed
X
X
Xk
HCV RNA Samples
X
X
X
X
X
X
X
Study Drug Accountability and Review of Study Drug 
Adherencek
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
Pharmacokinetic Samplesl
X
X
X
X
X
X
Child-Pugh Scorem
X
X
Clinical Assessment of Hepatic Decompensationm
X
HCC Screening Liver ultrasoundm
X
Patient Reported Outcomes Instruments (PROs)n
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Weeks 8 or 12 depending on allocated arm.
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.
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 
consent, if applicable.
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
e.
Height will be measured at the Screening Visit only.  Waist circumference will be measured at the Screening Visit, but if it is not measured at Screening, it may be measured 
on Day 1.
f.
Pregnancy testing is not required for women not of childbearing potential as defined in Section 5.2.4.


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g.
For those with history of Diabetes Mellitus.
h.
For subjects who have not had a qualifying liver biopsy within the previous 24 months or a qualifying FibroScan within the previous 6 months.
i.
If the IL28B sample is not collected at Study Day 1, it may be collected at any other visit during the study.
j.
See specific information regarding adverse event collection in Section 6.1.1.1.
k
Dispensation at Week 8 and Study Drug Accountability at Week 12 are only applicable to Arm B.  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, 12 (if applicable) or Premature D/C.
l.
PK samples will be collected at each scheduled study visit.  Detail regarding timing of samples is provided in Section 5.3.2.1.
m.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver Ultrasound are only performed for subjects in Arm B (compensated cirrhotic) as described in 
Section 5.3.1.1.
n.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.


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Appendix D.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
Xb
Total Insulin
X
Pregnancy Test (urine)c
X (u)
X (u)b
Concomitant Medication Assessment
X
Xd
Xd
Child-Pugh Scoree
X
X
Adverse Event Assessment
Xf
Xg
Xg
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Archive Plasma Sample
X
X
X
Pharmacogenetic DNA and RNA Sample (optional) 
X
Patient Reported Outcomes Instruments (PROs)h
X
HCC Screening Liver Ultrasound
Xi
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.
b.
Hematology/Chemistry/Urinalysis/Coagulation Panel and Pregnancy Test are not required at PT Wk 24, but only at PT D/C if subject discontinued prior to PT Wk 4.
c.
Urine pregnancy testing is not required in the PT period for women that are not of childbearing potential.
d.
Only medications associate with HCV treatment or taken for a serious adverse event (SAE) will be collected after 30 days post-dosing.
e.
Only for subjects in Arm B (compensated cirrhosis).
f.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.
g.
Only SAEs will be collected thereafter as described in Section 6.1.4.


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h.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
i.
HCC Screening Liver Ultrasound performed only for subjects in Arm B (compensated cirrhotic) as described in Section 5.3.1.1.
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 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
sAFP
Alpha fetoprotein
Section 3.0  Introduction
Subsection GLE and PIB
First paragraph, first and second sentence previously read:
In general, GLE and PIB combination has been well tolerated when administered to over 
800 healthy volunteers and 500 HCV-infected subjects.  The efficacy rates were high 
(> 95%) among treatment-naives or pegIFN + RBV-experienced noncirrhotic HCV-
infected GT-1 – 6 subjects treated with 8 weeks of GLE/PIB in Phase 2 studies
Has been changed to read:
In general, GLE and PIB combination has been well tolerated when administered to over 
800 healthy volunteers and 2,376 subjects were randomized or enrolled in the 
registrational studies or supportive Phase 2 studies to receive GLE 300 mg QD and PIB 
120 mg QD.  Of these, 2,369 subjects received at least 1 dose of study drug.  The efficacy 
rates were high (> 95%) among treatment-naive or pegIFN + RBV-experienced non-
cirrhotic HCV-infected GT-1 – 6 subjects treated with 8 weeks of GLE/PIB in Phase 2 
studies.
Section 3.0  Introduction
Subsection GLE and PIB
Eighth, ninth and tenth paragraph previously read:
In Part 1 of Study M14-868, no subject has experienced on treatment virologic failure or 
post-treatment relapse among the 74 subjects with HCV GT2 infection.  Excluding 


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one subject who was lost to follow-up, all 73 subjects with HCV GT2 infection achieved 
SVR12.  The SVR12 rates for each of the treatment regimens were 96% (24/25) (including 
a subject who was lost to follow-up) of subjects treated with GLE 300 mg QD + PIB 
120 mg QD for 12 weeks, 100% (24/24) of subjects treated with GLE 200 mg QD + PIB 
120 mg QD for 12 weeks and 100% (25/25) of subjects treated with GLE 200 mg QD + 
PIB 120 mg QD + RBV for 12 weeks.
In Part 1of Study M14-868, 121 subjects with HCV GT3 infection were treated with GLE 
300 mg and PIB 120 mg without ribavirin for 12 weeks and 93.3% (28/30 subjects) 
achieved SVR12.  One subject in this arm experienced relapse at Post-Treatment Week 4 
and one subject had missing SVR12 data.
In Part 2 of Study M14-867, 100% of subjects infected with HCV GT4, GT5 or GT6 
receiving treatment with GLE 300 mg QD + PIB 120 mg QD for 12 weeks achieved 
SVR12 (34/34).  GT1-infected treatment-naïve and PR-experienced subjects with 
compensated cirrhosis were also evaluated with the same.  Among the GT1 cirrhotic 
subjects, 96% (26/27) have achieved SVR12, with one subject experiencing relapse at 
Post-Treatment Week 4.
Has been changed to read:
In Part 1 of Study M14-868, a total of 195 subjects were enrolled and evenly distributed 
within the GT2 and GT3-infected groups.  Two subjects discontinued due to Treatment-
Emergent Adverse Events (Subjects 5904 and 9309 in Arm F), one subject discontinued 
due to virologic failure (Subject 9106 in Arm F), two subjects were lost to follow-up 
(Subjects 2005 in Arm F and Subject 2403 in Arm G), and one subject withdrew consent 
(Subject 4613 in Arm A).  Two of these subjects (Subjects 5904 and 9309; both Arm F) 
achieved SVR12.
The SVR12 rates for each of the treatment regimens were 96% (24/25) (including a subject 
who was lost to follow-up) of subjects treated with GLE 300 mg QD + PIB 120 mg QD 
for 12 weeks, 100% (24/24) of subjects treated with GLE 200 mg QD + PIB 120 mg QD 


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for 12 weeks and 100% (25/25) of subjects treated with GLE 200 mg QD + PIB 120 mg 
QD + RBV for 12 weeks, and 98.1% (53/54) of subjects treated with GLE 300 mg QD +
PIB 120 mg QD for 8 weeks.
In Part 1 of Study M14-868, 30 subjects with HCV GT3 infection non cirrhotic, treatment 
naïve and PR-experienced were treated with GLE 300 mg and PIB 120 mg without 
ribavirin for 12 weeks and 93.3% (28/30 subjects) achieved SVR12.  One subject in this 
arm experienced relapse at Post-Treatment Week 4 and one subject had missing SVR12
data.
In Part 2 of Study M14-867, 100% of subjects infected with HCV GT4, GT5 or GT6 non-
cirrhotic, treatment-naïve and PR-experienced receiving treatment with GLE 300 mg QD 
+ PIB 120 mg QD for 12 weeks achieved SVR12 (34/34).  GT1-infected treatment-naïve 
and PR-experienced subjects with compensated cirrhosis were also evaluated with the 
same.  Among the GT1 cirrhotic subjects, 96% (26/27) have achieved SVR12, with 
one subject experiencing relapse at Post-Treatment Week 4.
Section 3.0  Introduction
Subsection GLE and PIB
Twelfth paragraph, first and second sentence previously read:
To date, safety data across all arms in Part 1 of Studies M14-867 and M14-868 
encompassing 274 subjects treated with GLE at doses 200 and 300 mg and PIB at doses 
40 and 120 mg (with and without RBV in Study M14-868) for 12 weeks show that the 
most frequently reported adverse events were fatigue, nausea, and headache (occurring in 
> 5% of subjects).  Most of them were Grade 1 or 2 in severity.  
Has been changed to read:
To date, safety data across all arms in Part 1 of Studies M14-867 and M14-868 
encompassing 276 subjects treated with GLE at doses 200 and 300 mg and PIB at doses 
40 and 120 mg (with and without RBV in Study M14-868) for 12 weeks show that the 


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most frequently reported adverse events were fatigue, nausea, and headache (occurring in 
> 5% of subjects).  Most of them were Grade 1 in severity.  
Section 3.0  Introduction
Subsection GLE and PIB
Thirteenth paragraph, first and second sentence previously read:
Of the 274 subjects, there have been 4 (1.5%) treatment-emergent SAEs reported in 
Studies M14-867 and M14-868 combined (all assessed as not related to GLE or PIB): 
metastatic prostate cancer, pneumonia, atrial fibrillation, and B-cell lymphoma and one 
SAE that was not treatment-emergent (spontaneous abortion – also assessed as not 
related).  Two subjects (0.7%; 2/274) had treatment-emergent adverse events leading to
treatment discontinuation.  
Has been changed to read:
Of the 276 subjects, there have been 4 (1.5%) treatment-emergent SAEs reported in 
Studies M14-867 and M14-868 combined (all assessed as not related to GLE or PIB):  
metastatic prostate cancer, pneumonia, atrial fibrillation, and B-cell lymphoma and 
one SAE that was not treatment-emergent (spontaneous abortion – also assessed as not 
related).  Two subjects (0.7%; 2/276) had treatment-emergent adverse events leading to 
treatment discontinuation.  
Section 5.2.3.2  Concomitant Therapy
Last paragraph previously read:
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, 30 days following discontinuation 
of study drug, if applicable.
Has been changed to read:
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 


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medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drug, if applicable.
Section 5.2.3.3  Prohibited Therapy
Previously read:
Subjects must be able and willing to safely discontinue any prohibited medications or 
supplements listed in Table 1 at least 2 weeks or 10 half-lives (whichever is longer) prior 
to the first dose of any study drug and not use these during the entire Treatment Period 
and for 30 days following discontinuation of study drug.
Table 1.
Prohibited Medications and Supplements
Medication or Supplement Name
Any herbal supplements (including milk thistle), red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drug.  Subjects receiving these statins should either switch to pravastatin or rosuvastatin prior to the 
first dose of study drug or may interrupt statin therapy throughout the treatment period and until 30 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 reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking 
with the study drug.
Use of ethinyl estradiol containing oral contraceptives with the GLE and PIB combination 
was associated with ALT increases in some healthy female subjects.  Hormonal 
contraceptives (including oral, topical [including vaginal rings], injectable, or implantable 
varieties) and hormonal replacement therapy containing ethinyl estradiol may not be used 
from 2 weeks prior to the first dose of GLE/PIB until 30 days after the end of GLE/PIB 
dosing.  Progestin-only contraceptives and hormonal replacement therapy, such as those 
containing norethindrone, desogestrel, or levonorgestrel, without ethinyl estradiol, may be 
used with GLE/PIB.  Post-menopausal hormone replacement therapy, such as with 
esterified or conjugated estrogens, i.e., not containing ethinyl estradiol, may be used with 
GLE/PIB at the discretion of the Investigator.


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The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 
not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
Has been changed to read:
Subjects must be able and willing to safely discontinue any prohibited medications or 
supplements listed in Table 1 at least 2 weeks or 10 half-lives (whichever is longer) prior 
to the first dose of any study drug and not use these during the entire Treatment Period 
and for 14 days following discontinuation of study drug.
Table 1.
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*
Ethinyl estradiol
Astemizole, cisapride, terfenadine
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) must not be taken with the 
study drug.  Subjects receiving these statins must discontinue the prohibited statin at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of study drug and, based on  investigator's judgment, (a) switch to 
pravastatin or rosuvastatin or (b) interrupt statin therapy throughout the treatment period and until 14 days after the 
last dose of study drug.  If treating with pravastatin or rosuvastatin, it is recommended to reduce the pravastatin 
dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug.
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.
The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 


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not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
Table 2.  Clinical Laboratory Tests
Column "Clinical Chemistry," test "Albumina" previously read:
Albumina
Has been changed to read:
Albumina
Table 2.  Clinical Laboratory Tests
Column "Other Tests"
Delete:  
Alpha Fetoprotein (sAFP)h
Table 2.  Clinical Laboratory Tests
Delete:  table note "h."
Performed only for subjects in Arm B as described in Section 5.3.1.1.
Section 5.3.1.1  Study Procedures
Subsection Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha 
Fetoprotein
Subsection title and text previously read:
Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
Subjects with compensated cirrhosis who do not have a historical qualifying liver 
ultrasound, CT, or MRI will have an ultrasound performed during Screening.  A positive 
ultrasound result suspicious for HCC will be confirmed with CT scan or MRI during 
Screening.  Suspicious ultrasound lesions confirmed by CT or MRI are exclusionary.  
Subjects with compensated cirrhosis will have alpha fetoprotein assayed at the visits 
indicated in Appendix C and Appendix D.  


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Has been changed to read:
Hepatocellular Carcinoma (HCC) Screening:  Liver Ultrasound 
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Visit and at Post-Treatment Week 24, as indicated in Appendix C and 
Appendix D, for subjects with compensated cirrhosis only.  In-between those visits, HCC 
screening should be performed according to standard of care.
At the Screening Visit and at Post-Treatment Week 24, subjects with compensated 
cirrhosis will be required to undergo a liver ultrasound to screen for HCC, unless the 
subject has a historical liver ultrasound, CT scan or MRI performed for HCC screening 
within 3 months prior to those visits, in which case the result of the historical ultrasound, 
CT scan 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., CT scan or MRI) at a study visit should be discussed 
with the study designated physician.
Section 5.3.2.1  Collection of Samples for Analysis
Bullet, first sentence previously read:
At all Treatment-Period visits:  a single sample (4 mL) will be collected without regard to 
the time of dosing.  
Has been changed to read:
At all Treatment-Period visits:  a single sample (3 mL) will be collected without regard to 
the time of dosing.  
Section 5.6.4.1.1  GLE and PIB Dose and Treatment Duration
Delete:  last paragraph
The maximum dose of GLE/PIB will not exceed 300 mg/120 mg per day for up to 
12 weeks.


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Section 7.0  Protocol Deviations
Contact information previously read:
Primary Contact:
Alternate Contact:
Has been changed to read:
Primary Contact:
Alternate Contact:
Section 8.1.2.1  Primary Efficacy Endpoints
First paragraph, last sentence previously read:
The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the rate for SVR12 is 100%, where the Wilson's score method will be 
used for the confidence interval instead.


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Has been changed to read:
The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the number of SVR12 non-responders is less than 5, where the 
Wilson's score method will be used for the confidence interval instead.
Section 15.0  Reference List
Reference 10 previously read:
AbbVie.  ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure Edition 1.  
23 September 2015.
Has been changed to read:
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's Brochure 
Edition 2.  06 September 2016; including Addendum 1 Edition 2.  November 2016.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Bioanalysis
Statistics
Clinical
Clinical Drug Supply 
Management


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Has been changed to read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Bioanalysis
Statistics
Clinical


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Appendix C.  Study Activities – Treatment Period
Header row previously read:
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8*
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Has been changed to read:
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Appendix C.  Study Activities – Treatment Period
Activity "Vital Signs, Weight, Waist Circumferencee, Heighte" and "HCC Screening Liver ultrasound and Alpha 
Fetoproteinm" previously read:
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8*
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Vital Signs, Weight, Waist Circumferencee, Heighte
X
X
X
X
X
X
X
HCC Screening Liver ultrasound and Alpha Fetoproteinm
X


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Has been changed to read:
Activity
Screening
Day 1a
Wk 1
Wk 2
Wk 4
Wk 8
Wk 8 EOT or Wk 12 
EOT* or Premature 
D/C from Treatmentb
Vital Signs, Weight, Waist Circumference,e Heighte
X
X
X
X
X
X
X
HCC Screening Liver ultrasoundm
X


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Appendix C.  Study Activities – Treatment Period
Table note "m." previously read:
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, Liver Ultrasound, 
and Alpha Fetoprotein are only performed for subjects in Arm B (compensated cirrhotic) 
as described in Section 5.3.1.1.
Has been changed to read:
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver 
Ultrasound are only performed for subjects in Arm B (compensated cirrhotic) as described 
in Section 5.3.1.1.


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Appendix D.  Study Activities – Post-Treatment (PT) Period
Delete:  Activity "Alpha Fetoproteine"
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Alpha Fetoproteine
X
Appendix D.  Study Activities – Post-Treatment (PT) Period
Add:  Activity "HCC Screening Liver Ultrasound"
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
HCC Screening Liver Ultrasound
Xi


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Appendix D.  Study Activities – Post-Treatment (PT) Period
Add:  table note "i."
HCC Screening Liver Ultrasound performed only for subjects in Arm B (compensated 
cirrhotic) as described in Section 5.3.1.1.



SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-126 – Statistical Analysis Plan
Version 1.0 – 15 May 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-126
A Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir 
(PIB) in Adults with Chronic Hepatitis C Virus (HCV) 
Genotype 5 or 6 Infection
Date:  15 May 2018
Version 1.0
NCT02966795


Glecaprevir/Pibrentasvir
M16-126 – Statistical Analysis Plan
Version 1.0 – 15 May 2018
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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
4.4
Planned Analyses ................................................................................... 7
5.0
Analysis Populations .............................................................8
5.1
Definitions for Analysis Populations ...................................................... 8
5.1.1
Intention-to-Treat (ITT) Population ........................................................ 8
5.1.2
Modified Intention-to-Treat (mITT) Populations .................................... 8
5.1.3
Safety Population ................................................................................... 8
6.0
Analysis Conventions ............................................................9
6.1
Definition of Baseline, Final Treatment, and Final Post-Treatment 
Assessments ........................................................................................... 9
6.1.1
Baseline.................................................................................................. 9
6.1.2
Study Days............................................................................................. 9
6.2
Definition of Analysis Windows........................................................... 10
6.3
Missing Data Imputation ...................................................................... 13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications.........................................14
7.1
Demographic and Baseline Characteristics ........................................... 14
7.2
Medical History.................................................................................... 20
7.3
Prior, Concomitant and Post-Treatment Medications ............................ 21
8.0
Subject Disposition..............................................................21
8.1
Disposition of Safety Population .......................................................... 21
9.0
Study Drug Exposure and Compliance..............................22
9.1
Exposure .............................................................................................. 22
9.2
Compliance .......................................................................................... 23
10.0
Efficacy Analysis .................................................................23


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10.1
General Considerations......................................................................... 23
10.2
Handling of Multiplicity....................................................................... 28
10.3
Primary Efficacy Analysis.................................................................... 28
10.4
Secondary Efficacy Analyses ............................................................... 29
10.5
Sensitivity Analyses for SVR ............................................................... 29
10.6
Efficacy Subgroup Analysis ................................................................. 29
10.7
Additional Efficacy Analyses ............................................................... 30
10.8
Resistance Analyses ............................................................................. 32
10.9
Patient Reported Outcomes .................................................................. 36
11.0
Safety Analysis.....................................................................39
11.1
General Considerations......................................................................... 39
11.2
Analysis of Adverse Events.................................................................. 39
11.2.1
Treatment-Emergent Adverse Events.................................................... 40
11.2.2
Tabulations of Treatment-Emergent Adverse Events ............................ 40
11.2.3
Adverse Events of Special Interest........................................................ 42
11.2.4
Listing of Adverse Events..................................................................... 43
11.3
Analysis of Laboratory Data................................................................. 43
11.3.1
Variables and Criteria Defining Abnormality........................................ 44
11.3.2
Statistical Methods ............................................................................... 45
11.4
Analysis of Vital Signs and Weight ...................................................... 48
11.4.1
Variables and Criteria Defining Abnormality........................................ 48
11.4.2
Statistical Methods ............................................................................... 49
12.0
Summary of Changes .......................................................... 49
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP Version 1.0 ............................................................................ 49
13.0
References............................................................................51
List of Tables
Table 1.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Safety Laboratory, Vital Sign Measurements, and PRO 
Instruments (Treatment Period) ............................................................ 11


Glecaprevir/Pibrentasvir
M16-126 – Statistical Analysis Plan
Version 1.0 – 15 May 2018
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Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 12
Table 3.
Analysis Time Windows for Safety Laboratory, Vital Sign 
Measurements, and PRO Instruments (Post-Treatment Period)............. 12
Table 4.
Baseline Fibrosis Stage......................................................................... 18
Table 5.
Child-Pugh Classification of Severity of Cirrhosis................................ 18
Table 6.
Clinical Identification of Metabolic Syndrome ..................................... 19
Table 7.
Medical History eCRF.......................................................................... 20
Table 8.
Signature Amino Acid Positions and Key Subsets of Amino Acid 
Positions............................................................................................... 33
Table 9.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 45
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Values............ 49
List of Figures
Figure 1.
Study Schematic..................................................................................... 6


Glecaprevir/Pibrentasvir
M16-126 – Statistical Analysis Plan
Version 1.0 – 15 May 2018
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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Statistics and Statistical Programming Departments for glecaprevir
(GLE)/pibrentasvir (PIB) study Protocol M16-126.  Study M16-126 evaluates the efficacy 
and safety of GLE/PIB in HCV treatment-naïve or treatment-experienced (i.e., has failed 
prior interferon [IFN] or pegylated-IFN [pegIFN] with or without ribavirin [RBV], or 
sofosbuvir [SOF] plus RBV with or without pegIFN therapy), chronic hepatitis C virus 
(HCV) genotype (GT) 5 or 6-infected subjects, without cirrhosis for an 8-week treatment 
duration or with compensated cirrhosis for a 12-week treatment duration.
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M16-126 incorporating Amendment 1 dated 
28 July 2017, and describes analysis conventions to guide the statistical programming.  
Unless noted otherwise, all analyses will be performed using SAS® Version 9.4 (SAS 
Institute Inc., Carry, NC 27513) or later under the Unix operating system.
The SAP will not be updated in the case of future administrative or minor amendments to 
the protocol unless the changes have any impact on the analysis of study data.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the efficacy (by evaluating the 
percentage of subjects achieving a 12-week sustained virologic response, SVR12) and 
safety of GLE/PIB in adults with chronic HCV GT5 or 6 infection with or without 
compensated cirrhosis.
The secondary objectives are to assess the efficacy of GLE/PIB in adults with HCV GT 5 
or 6 infection with or without compensated cirrhosis by evaluating the percentages of 
subjects with on-treatment virologic failure and post-treatment relapse.


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4.2
Design Diagram
Study M16-126 is a Phase 3b, open-label, nonrandomized, multicenter study to evaluate 
the efficacy and safety of GLE/PIB in adults with chronic HCV GT5 or 6 infection, 
without cirrhosis or with compensated cirrhosis, who are either treatment-naïve or 
treatment-experienced with IFN or pegIFN with or without RBV or treatment-experienced 
with SOF plus RBV with or without pegIFN. 
The study will enroll approximately 80 eligible subjects.  A minimum of 15 GT5 and 
30 GT6 subjects and up to approximately 16 subjects with compensated cirrhosis 
(regardless of GT) will be enrolled.  Each subject will be assigned to one of two treatment 
arms based on their cirrhosis status.  Non-cirrhotic subjects (Arm A) will be treated with 
GLE/PIB 300 mg/120 mg once daily for 8 weeks, while subjects with compensated 
cirrhosis (Arm B) will be treated with GLE/PIB 300 mg/120 mg once daily for 12 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, 
and 8 for all subjects and an additional Week 12 visit for subjects in Arm B.  Subjects 
who complete or prematurely discontinue study drug will be followed for 24 weeks.  
During the Post-Treatment Period, all subjects will have visits at Post-Treatment Weeks 4, 
12, and 24.
Figure 1.
Study Schematic
4.3
Sample Size
In Phase 2 and 3 studies, Study M14-868 and Study M14-172, GT 5 and 6 subjects were 
enrolled to demonstrate the pangenotypic efficacy of GLE/PIB across GT1-6 for the label 


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approved treatment duration.  The current study, Study M16-126, serves to generate 
additional efficacy and safety data from GT 5 and 6 subjects in a wider geographic region.  
Therefore, no formal hypothesis will be tested in this study.  The sample size of this study 
is determined based on operational considerations of enrolling subjects with less common 
HCV genotypes.
If the observed SVR12 rate in this study is 97% among the expected 30 GT5 and 50 GT6 
subjects, then the expected 95% confidence intervals (CIs) for the SVR12 rate using the 
Wilson's score method1 are (84.2%, 99.3%) and (88.2%, 99.1%), respectively, based on 
the Wilson's score CIs calculated for 1000 simulated samples of 30 GT5 and 50 GT6 
subjects with an SVR12 rate of 97% using SAS®.  The Wilson's score method is expected 
to be used instead of the normal approximation method because the number of SVR12
non-responders is expected to be less than 5 (see Section 10.3).
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.  
The primary analysis will occur after all subjects have completed the Post-Treatment 
Week 12 Visit or prematurely discontinued from the study.  For the primary analysis, data 
will be locked after performing appropriate data cleaning.  Results from the primary 
analysis (e.g., SVR12 data) will be described in the primary clinical study report (CSR).
The end-of-study analysis will be conducted when all subjects enrolled in the study have 
completed the Post-Treatment Week 24 Visit or prematurely discontinued from the study.  
Data collected after the primary analysis will be added to a new version of the database 
which will be cleaned and locked at the end of the study and included in the final CSR 
(results related to SVR12 will not be updated).
There is no intention of stopping the study early based on efficacy findings from the 
primary analysis.  The intention is to follow all subjects who receive study drug for 
24 weeks following treatment.


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5.0
Analysis Populations
5.1
Definitions for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
ITT population.  Demographic, baseline characteristics, exposure, compliance, 
concomitant medication and medical history analyses will be performed on the ITT 
population overall and according to the treatment arm assignment, i.e., subject grouping 
will be based on the arm to which the subject was assigned.  Demographic and baseline 
characteristics will also be summarized by GT.  Efficacy analyses will be performed by 
GT (GT5 and GT6) and for the overall ITT population.
5.1.2
Modified Intention-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 as described in Section 10.5, when applicable, will be 
performed on the ITT population modified to exclude subjects who do not have HCV 
GT5 or 6 infection or with multiple/mixed genotypes (final HCV genotype as determined 
in Section 10.8) (mITT-GT), and on the mITT-GT population further modified to exclude 
subjects who do not achieve SVR12 for reasons other than virologic failure (mITT-GT-
VF). 
5.1.3
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population.  Safety analyses will be performed on the overall safety population, 
combining Arms A and B.


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6.0
Analysis Conventions
6.1
Definition of Baseline, Final Treatment, and Final Post-
Treatment Assessments
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 collected 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 both 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 (Days Relative to the First Dose of Study Drug)
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 


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first study drug dose day.  There is no Study Day 0.  Study Day 1 is the day of the 
first dose of study drug.
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 and resistance, the time windows specified in Table 1
and Table 2 describe how these data are assigned to protocol-specified time points during 
the Treatment and Post-Treatment Periods, respectively.  All time points and 
corresponding time windows are defined based on the date/time of blood sample 
collection.
For safety laboratory data, patient reported outcome (PRO) data and vital sign data, 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 (except 
for when used in analyses of SVR) to the nominal time will be used.  If there are 


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two observations equally distant to the nominal time, the latest one will be used in 
analyses.  For analyses of SVR (e.g., SVR12), the last value in the window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used to calculate descriptive 
statistics and in analyses of the mean change from baseline.  For summaries of shifts from 
baseline and potentially clinically 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, 
Safety Laboratory, Vital Sign Measurements, and PRO 
Instruments (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 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.
For Arm B only.
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.  Study Drug End Day 0 is defined as the day of the last dose of study drug.
Note:
For all windows, data must be on or before Study Drug End Day 2.  The result closest to the scheduled time 
point will be used.  PRO instruments are collected at Day 1 Visit and End of Treatment Visit (Week 8 for 
Arm A and Week 12 for Arm B, or Premature Discontinuation Visit).


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Table 2.
Analysis Time Windows for HCV RNA and Resistance 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 to 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.  For all 
windows, data must occur after Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the 
last dose of study drug.
Table 3.
Analysis Time Windows for Safety Laboratory, Vital Sign 
Measurements, and PRO Instruments (Post-Treatment Period)
Scheduled Timea
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 Visitb
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
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.  Study Drug End Day 0 is defined as the day of 
the last dose of study drug.
Note:
The result closest to the scheduled time point will be used.  For all windows, data must occur after Study Drug 
End Day 2.  Vital signs are collected at every Post-Treatment visit; hematology, chemistry, urinalysis, and 
coagulation panels are collected at Post-Treatment Week 4 Visit or at Post-Treatment Discontinuation Visit if 
subject discontinues prior to Post-Treatment Week 4.  PRO instruments are collected at Post-Treatment 
Week 12 Visit. 


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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 PROs will be as follows.  If a respondent answers at 
least 50% of the items in a multi-item scale of the Short Form 36 Version 2 (SF-36v2) 
Health Status Survey, 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 


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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.  
Missing data handling conventions for scores related to the Work Productivity and 
Activity Impairment Questionnaire (WPAI) – Hepatitis C are specified in Section 10.9.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
The ITT population will be used to summarize demographics and baseline characteristics, 
medical history and previous, concomitant, and post-treatment medications; data will be 
summarized across all subjects and by assigned treatment arm.  Demographics and 
baseline characteristics will also be summarized by GT.
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects in each category.  Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean, 
standard deviation, median, 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, waist circumference, and 
body mass index (BMI).  Categorical demographic variables include sex, race, Asian race 
(Asian or non-Asian), types of Asian race (as captured in the eCRF form 'Demographics':  
Japanese, Chinese, Korean, Taiwanese, and Other, which can include Vietnamese, 
Burmese, Cambodian, etc.), 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, Asia, or rest of world [ROW]).  
When defining geographic region, sites in the United States and Canada will be grouped 
under North America; sites in Belgium and France will be grouped under Europe; sites in 


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Singapore and Vietnam will be grouped under Asia; sites in Australia, New Zealand and 
South Africa will be grouped as ROW.
Continuous baseline characteristics include baseline log10 HCV RNA level, homeostasis 
model of assessment – insulin resistance (HOMA-IR), creatinine clearance (Cockcroft-
Gault calculation), eGFR (using the modification of diet in renal disease [MDRD] 
formula), platelet count, albumin, GGT, LDL, HDL, APRI, FIB-4, AST, ALT, total, 
direct, and indirect bilirubin.
Categorical baseline characteristics include:
●
HCV GT (5, or 6) and available subtype (as determined by the central 
laboratory);
●
Cirrhosis status (cirrhotic or non-cirrhotic);
●
Prior HCV treatment history (naïve or experienced);
●
For treatment-experienced subjects, type of previous regimen (IFN- or SOF-
based);
●
For treatment-experienced subjects, type of non-response to previous treatment 
(on-treatment non-responder, breakthrough, post-treatment relapse, or 
unknown/other);
●
IL28B genotype (CC, CT, or TT; CC or non-CC); 
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL, < 2,000,000 or 
≥ 2,000,000 IU/mL);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L); 
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 90, ≥ 90 mL/min/1.73 m2);
●
History of diabetes (yes/no);
●
History of bleeding disorders (yes/no);
●
History of depression or bipolar disorder (yes/no);


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●
History of cardiovascular disease (yes/no);
●
Baseline metabolic syndrome (yes/no);
●
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Use of stable opiate substitution (yes/no);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no);
●
Tobacco use (current, former, never, or unknown);
●
Alcohol use (current, former, never, or unknown).
In addition, for cirrhotic subjects, the following will be summarized: 
●
Baseline Child-Pugh score (5, 6, or > 6).
Summaries of baseline resistance are described in Section 10.8.
For treatment-experienced subjects, any regimen that contains SOF with or without IFN 
or RBV is SOF-based.  Otherwise, any regimen that contains IFN with or without RBV is 
IFN-based.
Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.
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.  IL28B rs12979860 will be resulted as C/C, C/T, or 
T/T by the central laboratory.
HOMA-IR is defined as fasting glucose (mmol/L) × fasting insulin (μIU/mL) ÷ 22.5.  
Subjects who do not have concurrent fasting glucose and fasting insulin values at baseline 
will be excluded from the summary of baseline HOMA-IR.
Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores, 
FibroScan scores, or FibroTest scores.  Only one score will be used to categorize each 


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subject even if a subject has more than one score recorded.  If a biopsy score is present, 
then it will be used to categorize the subject, regardless of the FibroScan/FibroTest score.  
Similarly, if a FibroScan score is present along with a FibroTest score, then the FibroScan 
score will be used to categorize the subject.  If biopsy and FibroScan scores are not 
present and more than one FibroTest result is available, then the baseline FibroTest result 
(i.e., last non-missing FibroTest result on or before Day 1) will be used to categorize the 
subject.  Subjects will be categorized as F0-F1, F2, F3, or F4 according to Table 4.
Presence or absence of cirrhosis will be determined as collected in EDC ("What is the 
subject's cirrhosis status?" – "cirrhotic" or "non-cirrhotic").
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 points 
assigned for each of the five observed findings as defined in Table 5.
Baseline APRI and FIB-4 are defined as 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 
values of AST, ALT, and platelet count at baseline, or subjects who are missing age will 
be excluded from the summary of FIB-4.
AST Level (U/L)
APRI =
AST (Upper Limit of Normal) (U/L)
× 100
Platelet Count (109/L)
FIB-4
=
Age (years) × AST Level (U/L)
(Platelet Count (109/L)×√ALT (U/L)


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Table 4.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, Batts 
Ludwig, Knodell, IASL, 
Scheuer, or Laennec Score
Liver Biopsy 
Ishak Score
FibroScan 
(kPa)
FibroTest*
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥ 8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 12.5
0.59 to 0.74
F4
4
≥ 5
≥ 12.5
≥ 0.75
*
APRI will not be used to derive Baseline Fibrosis Stage.  However, per inclusion/exclusion criteria, subjects need 
to have concordant FibroTest and APRI scores in order to determine eligibility.
Table 5.
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 to 
medication)
*
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.
The central laboratory calculates the estimated creatinine clearance (CrCl) based on the 
following Cockcroft-Gault formula:


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CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum creatinine 
(mg/dL) × 72].
The central laboratory calculates the eGFR by MDRD based on the following formula:
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1.154 × (Age)–0.203 × (0.742 if female) 
× (1.212 if Black or African American).
Subjects will be classified as having metabolic syndrome if at least 3 of the 
5 characteristics in Table 6 are present.
Table 6.
Clinical Identification of Metabolic Syndrome
Risk Factor
Defining Level in 
Conventional Units
Defining Level in SI Units
Abdominal obesity, given as waist 
circumference
Men
> 40 in
> 102 cm
Women
> 35 in
> 88 cm
Triglycerides
≥ 150 mg/dL
≥ 1.695 mmol/L
HDL cholesterol
Men
< 40 mg/dL
< 1.03452 mmol/L
Women
< 50 mg/dL
< 1.29315 mmol/L
Blood pressure (BP)
Systolic BP ≥ 130 or Diastolic BP 
≥ 85 mmHg
Systolic BP ≥ 130 or 
Diastolic BP ≥ 85 mmHg
Fasting glucose
≥ 100 mg/dL
≥ 5.5507 mmol/L
Reference:  Grundy 2004.2
Histories of diabetes, bleeding disorders, depression or bipolar disorder, and 
cardiovascular disease will be based on the Medical History (MH) eCRF, as defined in 
Table 7.


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Table 7.
Medical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Diabetes
Metabolic
Diabetes mellitus
Bleeding disorders
Blood
Clotting/bleeding problems
Factor deficiency
Hemophilia
Von Willebrand disease
Depression or bipolar 
disorder
Neurologic and Psychiatric System
Bipolar disorder
Depression
Cardiovascular disease
Cardiovascular
Angina
Cardiac arrhythmia
Cardiovascular disease
Congenital heart disease
Congestive heart failure
Coronary artery disease
Hypertension
Myocardial infarction
Myocarditis
Peripheral vascular disease-arterial
Peripheral vascular disease-venous
Valvular heart disease
Vasculitis
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.


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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.  A concomitant medication is defined as any medication that started prior to 
the date of the first dose of study drug and continued to be taken on or after the first dose 
of study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug.  A post-treatment medication for 
the treatment of HCV is defined as any medication taken on or after the last dose of study 
drug and entered as "Post-treatment HCV medications" on the eCRF.
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.  The prior HCV medications taken by 
treatment experienced subjects and collected on the "Last Prior HCV Therapy" and 
"Second to Last Prior HCV Therapy" eCRFs will be summarized separately from other 
prior medications, and will not be included in the summaries of all prior and concomitant 
medications.
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 by 
investigator for each treatment arm and overall.
●
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;


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●
Subjects who prematurely discontinued from the study;
●
Subjects ongoing in the Post-Treatment Period (if applicable at the time of 
analysis).
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF) for each treatment arm and 
overall.  Similar summaries will be provided for discontinuations from the study.
The number and percentage of subjects with reported study drug interruptions will be 
summarized by treatment arm and overall.  Reasons for study drug interruptions will be 
presented in the CSR listings.
9.0
Study Drug Exposure and Compliance
Exposure and compliance will be summarized on the ITT population by treatment arm 
and overall.
9.1
Exposure
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 duration of exposure during the Treatment Period.
Study drug duration will also be summarized with frequencies and percentages using the 
following categories:
●
1 to 15 days
●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days


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●
> 90 days
In addition, the number and percentage of subjects with study drug duration of ≥ 52 days 
for Arm A and ≥ 77 days for Arm B will be summarized.
9.2
Compliance
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of tablets dispensed and returned for each kit is recorded.  The compliance for the 
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.  If a subject is not able to 
return any of the dispensed kit, that subject's compliance will be regarded as missing.
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 for each treatment arm and overall.  A 
listing of compliance for each subject will be provided.  The percentage of compliant 
subjects will be summarized for each treatment arm and overall, based on data as 
observed.  Subjects with missing values for compliance will not be included in the 
denominator.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
All efficacy analyses will be performed on the ITT population, unless otherwise specified.  
To support the primary analysis, sensitivity analyses will be conducted for it using the 
mITT-GT and mITT-GT-VF populations.


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Missing data will be imputed for analyses of the HCV RNA endpoints of SVR and 
virologic failure as described in Section 6.3 and for analyses of PROs as described in 
Section 6.3 and Section 10.9.
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 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.
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.
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).


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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; if a subject meets 
both definitions of Breakthrough and EOT failure, he or she will be categorized as 
Breakthrough only.
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 window) for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment, excluding 
reinfection as described below.
Relapse24 = confirmed HCV RNA ≥ LLOQ within the SVR24 window for a subject who 
achieved SVR12 and has HCV RNA data available in the SVR24 window, excluding 
reinfection.
Relapseoverall = confirmed HCV RNA ≥ LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the Post-Treatment Period for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment, 
excluding reinfection.


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Virologic failure for SVR12 = On-treatment virologic failure or Relapse12.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as any 
subject with study drug duration of 52 days or greater for Arm A, and 77 days or greater 
for Arm B.  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 NS3/4A 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 NS3/4A or NS5A, and/or NS5B 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 
subgenotype switch is confirmed by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
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);


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2.
HCV reinfection (see definition described earlier);
3.
Relapse12;
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 in Arm A, and < 77 days for subjects in 
Arm B] and did not meet the On-treatment virologic failure or HCV reinfection
definitions);
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);
2.
HCV reinfection;
3.
Relapse12;
4.
Relapse24;
5.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects in Arm A, and < 77 days for subjects in 
Arm B] and did not meet the On-treatment virologic failure, HCV reinfection, 
Relapse12, or Relapse24 definitions);


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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 and SVR24 nonresponse defined above, subjects are only to be 
counted in one category in the order shown above.  Specifically, subjects who were SVR12
or SVR24 nonresponders meeting the definition of HCV reinfection will be counted in the 
reinfection category regardless of whether they meet the definition of prematurely 
discontinued study drug, Relapse12 or Relapse24.
10.2
Handling of Multiplicity
No multiplicity adjustment is needed for this study because there is no hypothesis testing 
for the primary and secondary efficacy endpoints.
10.3
Primary Efficacy Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug) in the ITT population.  The number and percentage of subjects 
achieving SVR12 will be summarized by GT (GT5 and GT6) across treatment arms.  The 
number and percentage of subjects achieving SVR12 will be calculated along with a 
two-sided 95% CI using the normal approximation to the binomial distribution, unless the 
number of SVR12 non-responders is less than 5, where the Wilson's score method1 will be 
used to calculate the CI instead.
A summary of reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.  A listing of subjects who do not achieve SVR12 by 
reason for non-response will also be provided.


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10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment virologic failure;
●
The percentage of subjects with Relapse12.
The number and percentage of subjects with on-treatment virologic failure and Relapse12
in the ITT population will be summarized along with two-sided 95% Wilson score CIs by 
GT (GT5 and GT6) across treatment arms.
10.5
Sensitivity Analyses for SVR
As sensitivity analyses, the number and percentage of subjects in the mITT-GT and 
mITT-GT-VF populations achieving SVR12 will be summarized by GT (GT5 and GT6) 
across treatment arms, along with two-sided 95% CIs using the normal approximation to 
the binomial distribution and the Wilson's score method.
A different CI will be calculated for the primary endpoint of SVR12 based on the ITT 
population as a sensitivity analysis.  If the number of SVR12 non-responders is ≥ 5, then 
the two-sided 95% CI using Wilson's score method will be calculated.  If the number of 
SVR12 non-responders is < 5, the two-sided 95% CI using the normal approximation to 
the binomial distribution will be calculated.
Listings of subjects excluded from the mITT-GT and mITT-GT-VF populations will be 
provided, as applicable.
10.6
Efficacy Subgroup Analysis
The percentage of subjects with SVR12 in the ITT population will be presented along with 
two-sided 95% Wilson score CIs by GT (GT5 and GT6) across treatment arms, and 
overall, for the following subgroups:
●
Prior HCV treatment history (naïve or experienced);


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●
For treatment-experienced subjects, type of previous regimen (IFN- or SOF-
based);
●
IL28B genotype (CC or non-CC);
●
Sex (male or female);
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Race (White, Black/African-American, Asian, or other) and (Asian or non-
Asian);
●
Baseline BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL, < 2,000,000 or 
≥ 2,000,000 IU/mL);
●
Baseline fibrosis stage (F0 – F1, F2, F3, or F4);
●
Baseline cirrhosis status (yes/no);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 90 or ≥ 90 mL/min/1.73 m2);
●
History of diabetes (yes/no);
●
Baseline metabolic syndrome (yes/no);
●
Use of stable opiate substitution (yes/no);
●
Former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no)
The 2-sided 95% Wilson score confidence interval will be produced if there are at least 
10 subjects in the subgroup.
10.7
Additional Efficacy Analyses
As additional analyses, the analyses of SVR12 (as described in Section 10.3) and on-
treatment virologic failure and Relapse12 (as described in Section 10.4) in the ITT 
population and the sensitivity analyses of SVR12 in the mITT-GT and mITT-GT-VF 
populations (as described in Section 10.5) will be performed for the overall population 


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across treatment arms and genotypes.  For the SVR12 endpoints, two-sided 95% CIs using 
both the normal approximation to the binomial distribution and the Wilson's score method 
will be calculated.  For the other endpoints, only the two-sided 95% CI using Wilson's 
score method will be calculated.
The following additional efficacy endpoints will be summarized and analyzed for the ITT 
population, by GT (GT5 and GT6) across treatment arms and overall:
●
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 with SVR4;
●
The percentage of subjects with SVR24;
●
The percentage of subjects who relapsed after achieving SVR12 (Relapse24).
●
The percentage of subjects with virologic failure through Post-Treatment 
Week 12 (i.e., the SVR12 non-responders due to on-treatment virologic 
failure or Relapse12)
For each of the above endpoints, a two-sided 95% CI using Wilson's score method will be 
calculated along with the number and percentage of subjects.  Imputations for missing 
data will be performed as described in Section 6.3 for all the additional endpoints listed 
above except the first one.
For the overall ITT population and by GT, a summary of the subjects who completed 
treatment and relapsed (defined as Relapseoverall) will be prepared displaying the number 
and percentage of subjects relapsing overall and by the SVR visit window where the 
first relapse occurred (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 summary will be prepared for subjects who 
prematurely discontinued treatment and relapsed after having HCV RNA < LLOQ at their 
Final Treatment Visit.  


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The number and percentage of subjects who do not achieve SVR24 will be summarized by 
reason for non-response (as defined in Section 10.1) for the overall ITT population and by 
GT.  For the overall ITT population, the number and percentage of subjects who do not 
achieve SVR12 will also be summarized by reason for non-response.  Listings of the 
subject numbers of those who do not achieve SVR12 and SVR24 and the reasons for non-
response will also be prepared.
The concordance between SVR12 and SVR24 will be assessed for the overall population 
(across genotype and treatment arm) 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 SVR24 out of all subjects who achieved SVR12.  The NPV of SVR12 on 
SVR24 is the proportion of subjects who do not achieve SVR24 out of all subjects who did 
not achieve SVR12.  Similarly, the concordance between SVR4 and SVR12 will be 
summarized for the overall population.
10.8
Resistance Analyses
For all subjects, full length NS3/4A and NS5A will be sequenced from baseline samples 
by next generation sequencing (NGS).  For all subjects who experience virologic failure 
(on-treatment virologic failure or Relapseoverall 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.  For all other subjects who do not achieve 
SVR12 or SVR24 (prematurely discontinued study drug with no on-treatment virologic 
failure, HCV reinfection, missing SVR12 or SVR24 data or other reasons as described in 
Section 10.1, Reasons for SVR12 Non-Response and Reasons for SVR24 Non-
Response) but have a post-treatment time point with HCV RNA ≥1000 IU/mL, full 
length NS3/4A and NS5A genes from the first post-treatment sample with HCV RNA 
≥1000 IU/mL will also be sequenced by NGS.


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For all subjects who do not achieve SVR12 or SVR24, a listing by subject that includes 
HCV genotype/subtype, reason for SVR12 or SVR24 non-response, and baseline resistance 
data availability besides key baseline characteristics will be produced.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions for the respective inhibitor class are shown in Table 8.  Appropriate subtype-
specific prototypic reference sequences will be used for comparison with sequences from 
samples.
Table 8.
Signature Amino Acid Positions and Key Subsets of Amino Acid 
Positions
Target/Genotype
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
NS3
5, 6
36, 43, 54, 55, 56, 80, 155, 156, 168
155, 156, 168
NS5A
5, 6
24, 28, 29, 30, 31, 32, 58, 92, 93
24, 28, 30, 31, 58, 92, 93
Included time points for analyses on available samples from subjects who do not achieve 
SVR12 are:  1) the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level of ≥ 1000 IU/mL, and 2) 24 weeks post-DAA 
treatment, provided that resistance-associated variants were detected by NGS at the time 
of HCV virologic failure/ treatment discontinuation.
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 or NS5A).
●
Variant at signature amino acid position: variant (relative to reference) present 
in a baseline or a 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 variant:  a variant 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 variant.
Analysis 1
The following analyses will be performed for all subjects, separated by HCV 
genotype/subtype (including total):
●
A listing of all subjects with baseline polymorphisms (2% detection threshold) 
at signature amino acid positions for each DAA target (NS3and NS5A) in the 
ITT population. HCV genotype/subtype and treatment outcome (SVR12 or 
reason for SVR12 non-response) will be displayed for each subject.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15% for 
subjects in the ITT population. This table includes prevalence of each baseline 
polymorphism, and a summary of the number of subjects with polymorphisms 
in NS3 only, NS5A only, any in NS3 or NS5A, and in both NS3 and NS5A.
●
Total number and percentage of subjects in the ITT population with baseline 
polymorphisms at a key subset of amino acid positions in NS3 only, in NS5A 
only, in NS3 + NS5A, any in NS3, any in NS5A, and any in NS3 or NS5A at 
15% detection threshold.
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 two rates will be 


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compared using Fisher's exact test.  Analysis will be grouped by HCV genotype/subtype 
(including total) and DAA target (NS3 or NS5A).  The analysis will include the number 
of subjects within each genotype/subtype (including total) with polymorphisms in NS3 
only, in NS5A only, any in NS3 or NS5A, and in both NS3 + 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%.
Analysis 3
In subjects with or without baseline polymorphisms in NS3 only, in NS5A only, in 
NS3 + NS5A, any in NS3, any in NS5A, and any in NS3 or NS5 at the key subset of 
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 genotype/subtype (including 
total).
Analysis 4
The following listings will be produced for subjects who do not achieve SVR12 or SVR24
and have post-baseline sequence available.  HCV genotype/subtype and reason for SVR12
or SVR24 non-response will be displayed for each subject.
●
Listings by subject and time point of all treatment-emergent substitutions
relative to the baseline amino acid sequences will be provided for each DAA 
target (NS3 and NS5A). 
●
Listings by subject and time point of all variants at signature amino acid 
positions in a post-baseline time point relative to the appropriate prototypic 


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reference amino acid sequence will be provided for each DAA target (NS3 and 
NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequence from baseline samples for all 
subjects in order to accurately determine their genotype/subtype.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A, and/or NS5A sequences performed by AbbVie.  If the 
phylogenetic analysis is available, then it will be used to determine the subject's HCV 
genotype and subtype.  If it is not available, then the Sanger sequencing assay result will 
be used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis results nor the Sanger sequencing assay results are 
available, then the Inno-LIPA assay results will be used to categorize the subject.
This subtype information will be presented in summaries of efficacy subgroup analyses.  
The baseline characteristic summary will use the results from the central laboratory 
(Sanger sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]).
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 PROs:  Short Form 36 - Version 2 
(SF-36v2), Work Productivity and Activity Impairment-Hepatitis C (WPAI-HCV) 
Specific Instrument Version 2.
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 


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(Mental Component Summary; MCS) and physical (Physical Component Summary; 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.3  The standardization of the normalized scores will provide the norm-
based scores with a mean of 50 and a standard deviation of 10.  The two summary scores 
are based on the norm-based scores.  Per the SF-36v2 instrument manual, the score for 
any item with multiple responses will be set to "missing."  Subjects' responses to the 
SF-36v2 will be summarized for the PCS and MCS measures and 8 individual domain 
measures.
The WPAI Hepatitis C consists of 6 questions:  Q1 = currently employed; Q2 = hours
missed due to HCV-related health problems; Q3 = hours missed other reasons; Q4 = hours 
actually worked; Q5 = degree hepatitis C affected productivity while working (using a 
0 to 10 VAS); Q6 = degree hepatitis C affected productivity in regular unpaid activities 
(VAS).
The four main impairment scores (S1 – S4) are expressed as percent impairment based on 
the above questions: 
S1.  Absenteeism (percent work time missed due to hepatitis C):
S2.  Presenteeism (percent impairment while working due to hepatitis C):
S3.  Percent overall work impairment due to hepatitis C:
!∀
#
∃%
&
∋
(
4
2
2
100
Q
Q
Q
!∀
#
∃%
&
( 10
5
100
Q


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S4.  Percent activity impairment due to hepatitis C:
The following missing data handling conventions are applied:
●
Define Employment as a binary YES or NO variable where YES corresponds 
to "Employed" and NO corresponds to "Not Employed."
○
A subject will be considered "employed" at a given visit if Q1 = YES or 
Q2 > 0 or Q4 > 0.
○
A subject will be considered "unemployed" at a given visit if Q1 = NO and 
no positive hours recorded under Q2 and Q4 (i.e., if Q1 = NO AND Q2 ≤ 0 
AND Q4 ≤ 0, then UNEMPLOYED).
○
Employment status for a subject will be considered "missing" at a given 
visit if Q1 = missing and no positive hours recorded under Q2 and Q4.
●
If a subject is "unemployed" or employment status is "missing," then S1, S2, 
and S3 will be set to "missing."
●
If Q2 = 0 and Q4 = 0 or missing then Q2/(Q2 + Q4) = missing (i.e., S1 = 
missing).
●
If Q2 = 0 and Q4 = 0, then set S3 to missing.
●
If Q2 is missing or Q4 is missing, then set S1 and S3 to missing.
●
If Q4 = missing, then DO NOT set Q5 = missing.
●
If Q5 is missing, then apply the following rules:
○
If Q2 > 0, Q4 = 0, and Q5 = missing, then S3 = 100%.
○
If Q2 = 0, Q4 > 0, and Q5 = missing, then S3 is missing.
○
If Q2 > 0, Q4 > 0, and Q5 = missing, then S3 is missing.
!
∀
#
∃
%
&
(
)
∗
+
,
−
.
∋
/
∋
∋
(
10
5
4
2
2
1
4
2
2
100
Q
Q
Q
Q
Q
Q
Q
!∀
#
∃%
&
( 10
6
100
Q


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Summary statistics for each protocol-specified visit (number of non-missing observations 
and mean) and for change from baseline to each protocol-specified visit (number of non-
missing observations, mean, standard deviation, minimum and maximum) will be 
provided for (1) the SF-36v2 PCS score, MCS score, and 8 individual domain scores, and 
(2) the WPAI-HCV activity impairment, overall work impairment, absenteeism, and 
presenteeism scores.
The following analyses of PROs also will be performed:
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable time point of greater than or equal to 2.5 points in 
the SF-36 MCS and PCS;
●
Number and percentage of subjects who have experienced an increase from 
baseline at each applicable time point of greater than or equal to 5 points in the 
SF-36 domain scores;
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.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized using the safety population.  Data will be summarized for 
the overall population across genotype and across treatment arm.
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.


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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
For all the summaries in this section, the number and percentage of subjects with 
treatment-emergent AEs will be tabulated.
Adverse Event Overview
An overview of AEs will be presented that consists of the number and percentage of 
subjects experiencing at least one event for each of the following treatment-emergent AE 
categories:
●
Any treatment-emergent AE;
●
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;


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●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects with treatment-emergent AEs will also be 
tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT) for 
the summaries listed below.  The SOCs will be presented in alphabetical order, and the 
PTs will be presented in alphabetical order within each SOC.
●
Treatment-emergent AEs;
●
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 leading to death.
Subjects reporting more than one AE for a given PT 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.
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.


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A listing of treatment-emergent AEs grouped by SOC and PT with subject numbers will 
be created for each treatment arm.
Adverse Events by Preferred Term
The following summaries of treatment-emergent AEs tabulated according to PT and 
sorted by the overall frequency across the two treatment arms will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB).
Subjects reporting more than one AE for a given PT 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 will be counted only 
once in the overall total.
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 tabulated by SOC.  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.
11.2.3
Adverse Events of Special Interest
Adverse events of special interest include the following:


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Hepatic decompensation/hepatic failure events, identified using the AbbVie 
Product MedDRA Query (PMQ) for Hepatic Decompensation and Hepatic 
Failure;
●
Hepatocellular carcinoma events, identified using the PTs of hepatocellular 
carcinoma, hepatic neoplasm, hepatic cancer, hepatic cancer metastatic, and 
hepatic cancer recurrent.
For the hepatic decompensation/ hepatic failure AE of special interest, the number and 
percentage of subjects experiencing at least one treatment-emergent AE in the search will 
be presented by SOC and PT and across all SOCs/PTs.  In addition, a by-subject listing of 
treatment-emergent AEs meeting the search criterion will be provided.
For the hepatocellular carcinoma AE of special interest, a by-subject listing of all post-
baseline (i.e., including both treatment-emergent and non-treatment emergent) AEs 
meeting the search criterion will be provided.
11.2.4
Listing of Adverse Events
The following listings of AEs will be prepared:
●
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 discontinuation of study drug,
●
Treatment-emergent AEs leading to study drug interruption.
●
AEs (treatment-emergent or all, as applicable) in each of the AEs of special 
interest categories.
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to a serious AE, will be used in all analyses.


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11.3.1
Variables and Criteria Defining Abnormality
Hematology variables to be summarized include:  hematocrit, hemoglobin, red blood cell 
(RBC) count, white blood cell (WBC) count, neutrophils, bands, lymphocytes, 
monocytes, basophils, eosinophils, platelet count, reticulocyte count, prothrombin time 
(PT), international normalized ratio (INR), and activated partial thromboplastin time 
(aPTT).
Chemistry variables to be summarized include:  blood urea nitrogen (BUN), creatinine, 
total bilirubin, direct and indirect bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, sodium, potassium, calcium, inorganic 
phosphorus, cholesterol, total protein, glucose, triglycerides, albumin, chloride, 
bicarbonate, magnesium, total insulin, gamma-glutamyl transferase (GGT), creatinine 
clearance (calculated using Cockcroft-Gault formula), and eGFR (calculated using 
MDRD equation). 
Urinalysis variables to be summarized include:  specific gravity and pH.
The definitions of toxicity grades for laboratory parameters are presented in Table 9.


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Table 9.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST 
> 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
GGT
> 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
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/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
--
Glucose 
(increased)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 – 27.8 mmol/L
> 27.8 mmol/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Cholesterol
> ULN – 7.75 mmol/L
> 7.75 –
10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
11.3.2
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 
the time of first dose if time is available.  The same baseline value will be used for 
changes to Treatment Period visits and changes to Post-Treatment Period visits.
Visit Values
For each laboratory parameter listed in Section 11.3.1, values at each visit (baseline and 
post-baseline, including applicable post-treatment visits) will be summarized with the 


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sample size, mean, standard deviation, minimum, median, and maximum.  Figures 
presenting mean values over time will be produced.
Change from Baseline
For each laboratory parameter listed in Section 11.3.1, changes from baseline to each 
post-baseline visit, including applicable post-treatment visits, will be summarized with the 
sample size, baseline mean; visit mean; and change from baseline mean, standard 
deviation, minimum, median, and maximum.  
Shift Tables
Individual 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 normal ranges of the laboratory used for each sample.  Shift tables from baseline 
to minimum value and maximum value during the Treatment Period will be created.  For 
each parameter, the shift tables will cross tabulate the frequency of subjects with baseline 
values below/within the normal range to maximum above the normal range and with 
baseline values within/above the normal range to minimum below the normal range.
Maximum Toxicity Grade
The laboratory parameters listed in Table 9 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 
during the Treatment Period will be tabulated.  To be counted, the post-baseline value 
must have a toxicity grade that is more extreme than the toxicity grade corresponding to 
the baseline value.  For each laboratory parameter in Table 9, the summary will also 
include the number and percentage of subjects with a maximum of at least Grade 3.  A 
listing of all relevant laboratory parameters will be provided for each subject who had an 
increase to Grade 2 or higher for any laboratory variable in Table 9.


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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.
Four listings (one for each bullet above) of all hepatic laboratory values 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/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.


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Two listings (one for each bullet) of all hepatic laboratory values 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 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 (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 10.


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Table 10.
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
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 changes to Treatment 
Period visits and changes to Post-Treatment Period visits.
For each vital sign parameter listed in Section 11.4.1, values at each visit (baseline and 
post-baseline, including applicable post-treatment visits) will be summarized with the 
sample size, 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 10) 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 Between the Latest Version of the 
Protocol and SAP Version 1.0
1.
New expected confidence intervals are calculated in Section 4.3 Sample Size
because the rule of choosing between the normal approximation method and 


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Wilson's score method for the primary endpoint has been updated in the protocol 
(also see Section 10.3)
2.
All safety analyses have been changed to be performed only for the overall 
population because integrated safety analyses on Phase 3 studies showed no 
difference in safety profiles between subjects with compensated cirrhosis and 
without cirrhosis.
3.
The race category of Black/non-Black has been changed to Asian/non-Asian in 
Section 7.1 and Section 10.6 because the Asian population is of interest to this 
study while very few Black subjects are expected to enroll.  Also, different Asian 
types will be summarized among the baseline characteristics (Section 7.1).
4.
The category of baseline HCV RNA level has been changed from 6,000,000 IU/mL 
to 2,000,000 IU/mL because it is a better cutoff based on previous studies.
5.
Efficacy endpoints will also be summarized for the overall population 
(Section 10.6, Section 10.7 and Section 10.9) in order to provide results across all 
subjects in the study.
6.
The integrated efficacy analysis combining GT5 and GT6 subjects from 
Studies M14-868 Part 4, M14-172 and M16-126 using meta-analytic methods has 
been removed because there is no plan for a label update with such data.
7.
The resistance analyses (Section 10.8) have been updated to reflect current HCV 
project standards.
8.
Text in PRO analyses of mean change from baseline has been updated for better 
clarity (Section 10.9).
9.
Missing data handling conventions for scores related to the Work Productivity and 
Activity Impairment Questionnaire (WPAI) – Hepatitis C are specified in 
Section 10.9.
10.
Methods for the assessment of hepatic laboratory values and hepatic laboratory 
abnormalities of interest have been added to Section 11.3.2 to reflect current HCV 
project standards.


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11.
The summaries of changes from baseline for vital signs have been replaced with 
summaries of visit values to reflect current HCV project standards (Section 11.4.2).
13.0
References
1.
Newcombe RG.  Two-sided confidence intervals for the single proportion:  
comparison of seven methods.  Stat Med.  1998;17(8):857-72.
2.
Grundy SM, Brewer HB Jr, Cleeman JI, et al.  Definition of metabolic syndrome:  
report of the National Heart, Lung, and Blood Institute/American Heart 
Association conference on scientific issues related to definition.  Circulation.  
2004;109(3):433-8.
3.
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.