Conditions: Hepatitis C Virus (HCV)
Keywords: Chronic Hepatitis C Virus Chronic Kidney Disease Glecaprevir Pibrentasvir Hepatitis C Virus Genotype Compensated cirrhosis Non-cirrhotic Interferon (IFN) Treatment naïve Sofosbuvir (SOF) Pegylated interferon (pegIFN) Ribavirin (RBV)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
This was a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) in participants with chronic hepatitis C virus (HCV) genotype (GT) 1 - 6 infection without liver cirrhosis or with compensated liver cirrhosis and with chronic renal impairment in participants who were either HCV treatment-naïve (TN) or prior treatment-experienced (TE) with interferon (IFN) or pegylated interferon (PegIFN) with or without ribavirin (RBV), or sofosbuvir (SOF) plus RBV with or without pegIFN.

Detailed description:
The study included a 42-day screening period, a treatment period of either 8, 12, or 16 weeks, and a 24-week post-treatment period. The duration of treatment was determined by product labeling. Participants received glecaprevir/pibrentasvir (GLE/PIB) 300 mg/120 mg once daily. Participants who completed or prematurely discontinued the treatment period were followed for 24 weeks after their last dose of study drug to monitor safety, hepatitis C virus ribonucleic acid (HCV RNA), and the emergence and persistence of viral substitutions.

Arms:
arm 1: HCV genotype 1,2,4-6 non-cirrhotic, treatment-naive or treatment-experienced; genotype 3 non-cirrhotic, treatment-naïve participants treated with glecaprevir/pibrentasvir (GLE/PIB): three 100 mg/40 mg co-formulated tablets once daily with food for 8 weeks arm 2: HCV genotype 1,2,4-6 compensated cirrhosis, treatment-naive or treatment-experienced; genotype 3 compensated cirrhosis, treatment- naïve participants treated with glecaprevir/pibrentasvir (GLE/PIB): three 100 mg/40 mg co-formulated tablets once daily with food for 12 weeks arm 3: HCV genotype 3 non-cirrhotic or with compensated cirrhosis, treatment-experienced participants treated with glecaprevir/pibrentasvir (GLE/PIB): three 100 mg/40 mg co-formulated tablets once daily with food for 16 weeks

Interventions: intervention 1: Glecaprevir/pibrentasvir
Intervention descriptions: intervention 1: Film-coated tablet

Protocol document:
Prot_000.pdf: 
Glecaprevir/Pibrentasvir
M16-127 Protocol Amendment 3
EudraCT 2016-004182-60
1
1.0
Title Page
Clinical Study Protocol M16-127
A Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Glecaprevir/Pibrentasvir in 
Renally-Impaired Adults with Chronic Hepatitis C 
Virus Genotype 1 – 6 Infection (EXPEDITION-5)
Incorporating Administrative Change 1 and 2 and 
Amendments 1 and 2 and 3
AbbVie Investigational
  Product:
glecaprevir/pibrentasvir
Date:
30 January 2018
Development Phase:
3b
Study Design:
This is an open-label study
EudraCT Number:
2016-004182-60
Investigators
Multicenter.  Investigator information on file at AbbVie.
Sponsor:
*AbbVie
* 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.
/$5


Glecaprevir/Pibrentasvir
M16-127 Protocol Amendment 3
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
20 December 2016
Amendment 1
20 January 2017
Amendment 2
27 July 2017
The purpose of this amendment is to:
D
Update to Renal Biomarker Sample and Archive Plasma Sample in 
Section 5.3.1.1 Study Procedures.
Rationale:  To clarify that serum samples for tumor necrosis factor-alpha 
(TNF-) will not be collected and analyzed.  Instead, the Archive Plasma 
samples collected throughout the study will analyze tumor necrosis factor-
alpha (TNF-).
D
Update Table 9, Signature Amino Acid Positions and the Key Subset of 
Amino Acid Positions, in Section 8.1.4, Resistance Analyses.
Rationale: To reflect the correct analyses of the signature amino acid position 
of GT3. 
D
Update Appendix D, Study Activities – Post-Treatment (PT) Period.
Rationale:  To further clarify that Hematology/Chemistry/Coagulation will 
only be performed if the subject discontinues prior to PT Wk 4 unless the 
patient is cirrhotic, in which labs will be collected to test INR, total bilirubin 
and albumin in the Post-Treatment Period.
D
Update pharmacokinetics-related text in Synopsis.
Rationale:  Removed from synopsis the text that was referring to the potential
population pharmacokinetic analysis that may be performed.  Details on this 
potential analysis are provided in Section 8.1.6.
D
Administrative and terminology changes and typographical and grammatical 
errors were corrected throughout the protocol.


Glecaprevir/Pibrentasvir
M16-127 Protocol Amendment 3
EudraCT 2016-004182-60
3
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


Glecaprevir/Pibrentasvir
M16-127 Protocol Amendment 3
EudraCT 2016-004182-60
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-127
Name of Study Drug:  
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  30 January 2018
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of 
Glecaprevir/Pibrentasvir in Renally-Impaired Adults with Chronic Hepatitis C Virus Genotype 1 – 6 
Infection (EXPEDITION-5)
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 (GLE/PIB) in adults with 
chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection with or without compensated 
cirrhosis and with chronic renal impairment in both HCV treatment-naïve and treatment-
experienced subjects.  The efficacy of GLE/PIB will be assessed based on the overall 
population (i.e., across treatment durations, genotypes, and cirrhosis status) and the safety of 
GLE/PIB will be assessed by treatment duration and cirrhosis status across genotypes. 
!
Secondary objectives are to assess the percentage of subjects with HCV on-treatment virologic 
failure and the percentage of subjects with HCV virologic relapse across treatment durations, 
genotypes, and cirrhosis status.
Investigators:  Multicenter trial
Study Sites:  Approximately 40 sites globally
Study Population:  Chronic HCV GT1 – 6-infected adults aged 18 years or older with chronic renal 
impairment.  Subjects with renal impairment will include Chronic Kidney Disease (CKD) Stage 3b 
(eGFR 30 to < 45 mL/min/1.73 m2), Stage 4 (eGFR 15 to < 30 mL/min/1.73 m2) and Stage 5 
(eGFR < 15 mL/min/1.73 m2 or dialysis-dependent) subjects.
Number of Subjects to be Enrolled:  Approximately 120 subjects
Methodology:  
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy and safety of 
GLE/PIB for 8, 12, or 16 weeks in chronic HCV GT1 – 6 infected subjects with chronic renal 
impairment, with or without compensated cirrhosis, who are either HCV treatment-naïve (TN) or prior 
treatment-experienced (TE) with interferon (IFN) or pegylated IFN (pegIFN) with or without ribavirin 
(RBV), or sofosbuvir (SOF) plus RBV with or without pegIFN.
This study will enroll approximately 120 eligible subjects at approximately 40 sites.  Subjects with renal 
impairment will include CKD Stage 3b (eGFR 30 to < 45 mL/min/1.73 m2), Stage 4 (eGFR 15 to 
< 30 mL/min/1.73 m2) and Stage 5 (eGFR < 15 mL/min/1.73 m2 or dialysis-dependent) subjects.  The 
study enrollment will be monitored to meet the following non-mutually exclusive enrollment criteria:  
(1) up to approximately 40 subjects with Stage 3b CKD, (2) up to approximately 75 HCV GT1-infected 
subjects, (3) up to approximately 30 subjects with compensated cirrhosis.


Glecaprevir/Pibrentasvir
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EudraCT 2016-004182-60
5
Methodology (Continued):  
Subjects will be enrolled to one of the following treatment arms:
!
Arm A:  HCV GT1, 2, 4 – 6 subjects without cirrhosis who are TN or TE and HCV 
GT 3 subjects without cirrhosis who are TN will be treated for 8 weeks. 
!
Arm B:  HCV GT1, 2, 4 – 6 subjects with cirrhosis who are TN or TE and HCV GT 3 subjects 
with cirrhosis who are TN will be treated for 12 weeks.  
!
Arm C:  All HCV GT3 subjects who are TE will be treated for 16 weeks.
Note:  Subjects with mixed HCV genotype infection should receive whichever duration is longer based 
on their genotypes, cirrhosis status and treatment experience.  For subjects with an indeterminate 
genotype, treatment duration will default to the respective GT3 duration based upon treatment-
experience and cirrhosis status.
The study will consist of a Screening Period, Treatment period and Post Treatment period:
Treatment Period:
Enrolled subjects will receive GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks (Arm A), 12 weeks 
(Arm B), or 16 weeks (Arm C).  Scheduled visits in the Treatment Period consist of Day 1 and Weeks 4 
and 8 for all subjects, an additional Week 12 visit for subjects in Arms B and C, and an additional 
Week 16 visit for subjects in Arm C.  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 
in the Post-Treatment Period.
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 following 
completion or premature discontinuation of the Treatment Period.  Study procedures to monitor safety, 
clinical laboratory tests, HCV RNA, and to evaluate the efficacy and the emergence and persistence of 
resistant virus will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female at least 18 years of age at time of Screening.
2.
Positive for anti-HCV antibody (Ab) at Screening and HCV RNA M 1,000 IU/mL at Screening.
3.
Subject has an Estimated Glomerular Filtration Rate (eGFR) < 45mL/min/1.73 m2 as estimated by 
the MDRD method at screening according to 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 is dialysis-dependent.  Subjects requiring dialysis should have been receiving dialysis 
for at least 1 month prior to enrollment, and may be on hemodialysis or peritoneal dialysis.
4.
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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
5.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements.
Main Exclusion:  
1.
Female 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.
Current HBV or HIV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative HBsAg and Anti-
HBs), or;
!
A positive anti-human immunodeficiency virus antibody (HIV Ab).
3.
Clinical history of acute renal failure in the 3 months prior to screening.
4.
Clinically significant abnormalities or co-morbidities, or recent (within 6 months prior to study drug 
administration) alcohol or drug abuse that make the subject an unsuitable candidate for this study in 
the opinion of the investigator.
5.
Receipt of any investigational or commercially available direct acting anti-HCV agents other than 
sofosbuvir (e.g., telaprevir, boceprevir, simeprevir, paritaprevir, grazoprevir, daclatasvir, ledipasvir, 
ombitasvir, elbasvir, velpatasvir or dasabuvir).
Investigational Products:
glecaprevir/pibrentasvir (GLE/PIB) 100 mg/40 mg Film-coated tablet
Doses:
glecaprevir/pibrentasvir (GLE/PIB) 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  
!
Subjects will receive GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks (Arm A), 
12 weeks (Arm B) or 16 weeks (Arm C).
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.


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Criteria for Evaluation (Continued):
Patient Reported Outcomes (PROs):
The Kidney Disease Quality of Life (KDQOL-36™) will be used to assess the impact of kidney disease 
on a patient's quality of life.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the 
appropriate prototypic reference sequence; and 2) for subjects who do not achieve SVR12, post-baseline 
substitutions relative to baseline.
Pharmacokinetic:
Individual plasma concentrations of glecaprevir and pibrentasvir, and their possible metabolites will be 
tabulated and summarized.  
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) based on overall population (i.e., across treatment 
durations, genotypes, and cirrhosis status).  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 number of SVR12 non-responders is less than 5, where the Wilson's score method 
will be used to calculate the confidence interval.  No hypothesis will be tested.
The secondary efficacy endpoints are:
!
The percentage of subjects with on-treatment HCV virologic failure across treatment arms
!
The percentage of subjects with post-treatment HCV virologic relapse across treatment arms
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.
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures will be 
summarized.


Glecaprevir/Pibrentasvir
M16-127 Protocol Amendment 3
EudraCT 2016-004182-60
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Statistical Methods (Continued):
Resistance:
For all subjects receiving study drugs and with available samples, baseline polymorphisms at signature 
resistance-associated amino acid positions identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drugs who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA M 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the baseline 
sequence, 2) the amino acid substitutions in available post-baseline samples at signature resistance-
associated positions identified by NGS and comparison to the appropriate prototypic reference sequence, 
and 3) the persistence of viral substitutions by NGS.
Pharmacokinetic:
Individual plasma concentrations of glecaprevir, pibrentasvir, and their possible metabolites will be 
tabulated and summarized. 
Safety:
Safety summaries will be provided by the treatment duration and cirrhosis status 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 through 30 days post study drug dosing) will be 
tabulated by MedDRA System Organ Class (SOC) and preferred term.  The tabulation of the number of 
subjects with treatment-emergent adverse events also will be provided by 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 vital sign values that are potentially clinically significant, according 
to predefined criteria, will be summarized by treatment duration and cirrhosis status across genotypes 
and overall.  Changes from baseline to post-baseline in the CTCAE grading of laboratory values will 
also be summarized.


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9
1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
APRI
Aminotransferase/platelet ratio index
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC24
AUC for the 24-hour dosing interval
U
Apparent terminal phase elimination rate constant
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence Interval
CL/F
Apparent oral plasma 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
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


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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
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention-To-Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
KDQOL-36
Kidney Disease Quality of Life (KDQOL)-36
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
mITT-VF
Intention-To-Treat population excluding subjects who did not achieve SVR12
for non-virologic reasons
MRI
Magnetic resonance imaging
NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS
Non-structural 
NS3A
Nonstructural viral protein 3A
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


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PK
Pharmacokinetic
POR
Proof of receipt
PRO
Patient reported outcome
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
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
Tmax
Time to maximum observed plasma concentration (Cmax)
TE
Treatment-experienced
TN
Treatment-naïve
ULN
Upper limit of normal
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


Glecaprevir/Pibrentasvir
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12
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........................................ 9
2.0
Table of Contents ................................................................ 12
3.0
Introduction......................................................................... 17
3.1
Differences Statement .......................................................................... 27
3.2
Benefits and Risks................................................................................ 28
4.0
Study Objective ................................................................... 30
4.1
Primary Objective ................................................................................ 30
4.2
Secondary Objectives ........................................................................... 30
5.0
Investigational Plan.............................................................30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.1.1
Screening Period .................................................................................. 33
5.1.1.1
Rescreening.......................................................................................... 34
5.1.2
Treatment Period (TP).......................................................................... 35
5.1.3
Post-Treatment (PT) Period.................................................................. 35
5.2
Selection of Study Population............................................................... 36
5.2.1
Inclusion Criteria.................................................................................. 36
5.2.2
Exclusion Criteria................................................................................. 38
5.2.3
Prior and Concomitant Therapy............................................................ 40
5.2.3.1
Prior HCV Therapy .............................................................................. 40
5.2.3.2
Concomitant Therapy........................................................................... 41
5.2.3.3
Prohibited Therapy............................................................................... 42
5.2.4
Contraception Recommendations ......................................................... 43
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 44
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 44
5.3.1.1
Study Procedures.................................................................................. 44
5.3.1.2
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples................................................................................. 56


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5.3.1.3
Meals and Dietary Requirements.......................................................... 57
5.3.2
Drug Concentration Measurements....................................................... 57
5.3.2.1
Collection of Samples for Analysis....................................................... 57
5.3.2.2
Handling/Processing of Samples........................................................... 57
5.3.2.3
Disposition of Samples......................................................................... 58
5.3.2.4
Measurement Methods ......................................................................... 58
5.3.3
Efficacy Variables................................................................................ 58
5.3.3.1
Primary Variable .................................................................................. 58
5.3.3.2
Secondary Variables............................................................................. 58
5.3.3.3
HCV Resistance Variables.................................................................... 59
5.3.4
Safety Variables ................................................................................... 59
5.3.5
Pharmacokinetic Variables ................................................................... 59
5.3.6
Pharmacogenetic Exploratory Research Variables ................................ 59
5.4
Removal of Subjects from Therapy or Assessment ............................... 60
5.4.1
Discontinuation of Individual Subjects ................................................. 60
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 61
5.4.2
Discontinuation of Entire Study............................................................ 61
5.5
Treatments ........................................................................................... 62
5.5.1
Treatments Administered...................................................................... 62
5.5.2
Identity of Investigational Products ...................................................... 62
5.5.2.1
Packaging and Labeling........................................................................ 63
5.5.2.2
Storage and Disposition of Study Drug................................................. 63
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 63
5.5.4
Selection and Timing of Dose for Each Subject.................................... 64
5.5.5
Blinding ............................................................................................... 64
5.5.6
Treatment Compliance ......................................................................... 64
5.5.7
Drug Accountability ............................................................................. 65
5.6
Discussion and Justification of Study Design........................................ 66
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 66
5.6.2
Appropriateness of Measurements........................................................ 66
5.6.3
Suitability of Subject Population .......................................................... 66
5.6.4
Selection of Doses in the Study ............................................................ 67
5.6.4.1
Rationale for Dose Selections............................................................... 67


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5.6.4.2
GLE and PIB Dose and Treatment Duration......................................... 67
6.0
Complaints........................................................................... 68
6.1
Medical Complaints ............................................................................. 68
6.1.1
Definitions ........................................................................................... 68
6.1.1.1
Adverse Event...................................................................................... 68
6.1.1.2
Serious Adverse Events........................................................................ 69
6.1.2
Adverse Event Severity ........................................................................ 70
6.1.3
Relationship to Study Drug................................................................... 71
6.1.4
Adverse Event Collection Period.......................................................... 72
6.1.5
Adverse Event Reporting...................................................................... 73
6.1.6
Pregnancy............................................................................................. 75
6.1.7
Toxicity Management........................................................................... 75
6.1.7.1
Management of Transaminase Elevation............................................... 76
6.2
Product Complaint................................................................................ 76
6.2.1
Definition............................................................................................. 76
6.2.2
Reporting ............................................................................................. 77
7.0
Protocol Deviations ............................................................. 77
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 78
8.1
Statistical and Analytical Plans............................................................. 78
8.1.1
Demographics and Baseline Characteristics.......................................... 79
8.1.2
Efficacy................................................................................................ 80
8.1.2.1
Primary Efficacy Endpoints.................................................................. 80
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 81
8.1.2.3
Sensitivity Analysis.............................................................................. 81
8.1.2.4
Subgroup Analysis ............................................................................... 82
8.1.2.5
Additional Efficacy Endpoints.............................................................. 82
8.1.3
Patient Reported Outcomes .................................................................. 83
8.1.4
Resistance Analyses ............................................................................. 84
8.1.5
Safety................................................................................................... 88
8.1.5.1
Adverse Events..................................................................................... 88
8.1.5.2
Clinical Laboratory Data ...................................................................... 88
8.1.5.3
Vital Signs Data ................................................................................... 89


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8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................. 89
8.2
Determination of Sample Size .............................................................. 90
8.3
Randomization Methods....................................................................... 90
9.0
Ethics.................................................................................... 90
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 90
9.2
Ethical Conduct of the Study................................................................ 91
9.3
Subject Information and Consent.......................................................... 91
10.0
Source Documents and Case Report Form 
Completion ..........................................................................92
10.1
Source Documents................................................................................ 92
10.2
Case Report Forms............................................................................... 93
11.0
Data Quality Assurance ...................................................... 94
12.0
Use of Information .............................................................. 94
13.0
Completion of the Study ..................................................... 95
14.0
Investigator's Agreement.................................................... 96
15.0
Reference List......................................................................97
List of Tables
Table 1.
Overview of Clinical Studies by Subject Population ............................. 20
Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 
– 6 (ITT Population, Phase 2 and 3 Analysis Set) ................................. 22
Table 3.
Adverse Events Reported for M 5.0% of Subjects (Phase 2 and 3 
Analysis Set)........................................................................................ 25
Table 4.
Definition of Chronic Kidney Disease Stages ....................................... 33
Table 5.
Prohibited Medications and Supplements ............................................. 42
Table 6.
Clinical Laboratory Tests ..................................................................... 48
Table 7.
Child-Pugh Classification of Severity of Cirrhosis................................ 51
Table 8.
Identity of Investigational Products ...................................................... 62
Table 9.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ...................................................................................... 85


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List of Figures
Figure 1.
Study Schematic................................................................................... 32
Figure 2.
Adverse Event Collection..................................................................... 73
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.......................................... 99
Appendix B.
List of Protocol Signatories .................................................................101
Appendix C.
Study Activities – Treatment Period ....................................................102
Appendix D.
Study Activities – Post-Treatment (PT) Period ....................................105
Appendix E.
Protocol Amendment:  List of Changes ...............................................107


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with over 
170 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype 1 (GT1) being the most prevalent worldwide.2  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%).3-5  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, and GT7 has recently been described in Central 
Africa.6
Depending on various risk factors, between 10% and 40% of patients with chronic HCV 
infection will develop cirrhosis.7  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.7  Patients 
diagnosed with HCC have a 33% probability of death during the first year.7  Successful 
treatment of HCV has been shown to significantly reduce the risk of disease progression 
and related mortality as well as the development of HCC.8,9
Infection with HCV is common among patients with end stage renal disease (ESRD) 
undergoing dialysis in the US, EU and Japan with a prevalence of 3% to 23%, depending 
on the country.10  Among patients with ESRD, the presence of HCV correlates with 
higher rates of mortality than in the HCV-negative population.11  Therefore, patients with 
renal disease are an important special population for study when evaluating new HCV 
treatments.
While a significant proportion of the HCV-infected population has renal impairment, 
safety and efficacy data of direct-acting antiviral agents (DAAs) in patients with severe 
renal impairment (i.e., creatinine clearance < 30 mL/min) is limited.  Currently approved 
regimens to treat patients with severe renal impairment include 
ombitasvir/paritaprevir/ritonavir with dasabuvir with or without ribavirin (RBV) for HCV 
GT1 infection, ombitasvir/paritaprevir/ritonavir with RBV for HCV GT4 infection, and 


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elbasvir/grazoprevir with or without RBV to treat HCV GT1 and GT4 infection.12-14  The 
development of a safe and effective, RBV-free, pangenotypic regimen to treat HCV 
infected patients with severe chronic kidney disease remains an important unmet medical 
need.
AbbVie is currently developing two "next generation" DAAs, glecaprevir (GLE, formerly 
known as ABT-493), an HCV NS3/4A protease inhibitor and pibrentasvir (PIB, formerly 
known as ABT-530), an NS5A inhibitor, for use in combination for the treatment of 
chronic HCV infection.  GLE and PIB each have potent in vitro antiviral activity against 
genotypes 1 through 615 and a high genetic barrier to resistance, with no or little loss of 
potency against common resistant-associated substitutions.  Additive or synergistic 
in vitro anti-HCV activity has been demonstrated with the combination of GLE and PIB.  
GLE 100 mg and PIB 40 mg are co-formulated into a fixed-dose combination tablet 
(hereafter referred to as GLE/PIB), which provides patients with a convenient once-daily 
(QD), fixed-dose combination treatment regimen of three tablets QD to maximize 
treatment compliance.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data can be found in the Investigator's Brochure.16
Glecaprevir/Pibrentasvir (GLE/PIB)
Overview of GLE/PIB Registrational Program and Supportive Studies
The GLE/PIB registrational program included a broad subject population including 
subjects with compensated liver disease and subjects with severe renal insufficiency   
across all genotypes using a single GLE/PIB dose of 300 mg/120 mg QD.  Supportive 
Phase 2 studies used the Phase 2 formulation of separate GLE and PIB tablets, with each 
tablet containing 100 mg and 40 mg, respectively.  Treatment arms from these supportive 
Phase 2 studies using the regimen selected for registrational studies (GLE 300 mg plus 
PIB 120 mg) were pooled with arms from the registrational studies for analyses of 
efficacy and safety.  Treatment-naïve (TN) and TE subjects to any combination of 
pegylated IFN (pegIFN), RBV, sofosbuvir (SOF), NS5A inhibitors, or PIs were allowed 


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in the program.  In addition, the program included subjects with human 
immunodeficiency virus (HIV) coinfection (Study M13-590), subjects with chronic 
kidney disease [CKD] Stages 4 – 5, including those on hemodialysis (Study M15-462), 
subjects with compensated cirrhosis (Studies M14-172, M15-462, and M14-868 Part 3), 
and subjects with or without cirrhosis who failed a previous regimen containing an NS5A 
inhibitor and/or an NS3/4A PI (Study M15-410).
A total of 2,376 subjects were randomized or enrolled in the registrational studies or 
supportive Phase 2 studies to receive GLE 300 mg QD and PIB 120 mg QD.  Of these, 
2,369 subjects received at least 1 dose of study drug (Table 1).


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Table 1.
Overview of Clinical Studies by Subject Population
Genotype
Clinical Study 
Summary of Study Design 
TN and TE Subjects Without Cirrhosis
GT1
M13-590
GLE/PIB 300 mg/120 mg QD for 8 (n = 351) or 12 weeks (n = 352)
M14-867
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 34)
GT2
M15-464
GLE/PIB 300 mg/120 mg QD (n = 202) or placebo (n = 100) for 
12 weeks
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 199) or 12 weeks 
(n = 25)
GT3
M13-594
GLE/PIB 300 mg/120 mg QD for 8 (n = 157) or 12 weeks (n = 233) 
or SOF 400 mg + DCV 60 mg QD for 12 weeks (n = 115) (all 
subjects in study were TN)
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 29; TN only), 
12 weeks (n = 76), or 16 weeks (n = 22; TE only)
GT4, 5, 6
M13-583
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 121)
M14-867
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 32)
M14-868
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 58)
TN and TE Subjects with Cirrhosis
GT1, 2, 4, 5, 6
M14-172
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 146)
GT3
M14-868
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 64; TN only) or 
16 weeks (n = 51; TE only)
Subjects with CKD Stages 4 – 5 With or Without Cirrhosis
GT1 – 6
M15-462
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 104)
NS5A Inhibitor and/or PI-Experienced Subjects With or Without Cirrhosis
GT1, 4
M15-410
GLE/PIB 300 mg/120 mg QD for 12 (n = 66) or 16 weeks (n = 47)
CKD = chronic kidney disease; DCV = daclatasvir; GLE = glecaprevir; GT = genotype; NS5A = nonstructural viral 
protein 5A; PI = protease inhibitor; PIB = pibrentasvir; QD = once daily; SOF = sofosbuvir; TE = treatment-
experienced; TN = treatment-naïve
Efficacy
In TN or IFN, pegIFN, RBV, and/or SOF treatment-experienced (TE-PRS) subjects, the 
pooled overall SVR12 rates with GLE/PIB were > 97% across GT1, 2, 4, 5 and 6 
regardless of treatment experience, treatment duration, including any degree of renal 
impairment, presence of cirrhosis, or HIV-1 coinfection (Table 2).  


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Among subjects with GT3 infection, the pooled SVR12 rates across durations were 95.2% 
among all subjects, 96.6% among cirrhotic subjects, and 100% among subjects with CKD 
Stages 4 – 5.  The SVR12 rates among subjects previously treated with a PI and/or NS5A 
inhibitor were M 89.0% for GT1 and GT4.


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Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 –
6 (ITT Population, Phase 2 and 3 Analysis Set)
Genotype
TN
n/N (%)
95% CIa
TE-PRS
n/N (%)
95% CIa
TN + TE-PRS
TE-NS5A 
and/or PIs
n/N (%)
95% CIa
Overall
n/N (%)
95% CIa
Alla
Cirrhotic
n/N (%)
95% CIb
CKD 4 – 5
n/N (%)
95% CIb
Phase 2 
and 3 
Analysis 
Set
1604/1640 
(97.8)
97.1, 98.5
602/616 
(97.7)
96.6, 98.9
2206/2256 
(97.8)
97.2, 98.4
274/281 
(97.5)
95.7, 99.3
102/104 
(98.1)
95.4, 100.0
101/113 
(89.4)
83.7, 95.1
2307/2369 
(97.4)
96.7, 98.0
GT1
555/561 
(98.9)
98.1, 99.8
326/328 
(99.4)
98.5, 100.0
881/889 
(99.1)
98.5, 99.7
98/101 
(97.0)
93.7, 100.0
53/55
(96.4)
91.4, 100.0
97/109 
(89.0)
83.1, 94.9
978/998c
(98.0)
97.1, 98.8
GT2
365/369 
(98.9)
97.9, 100.0
95/97 
(97.9)
95.1, 100.0
460/466 
(98.7)
97.7, 99.7
35/35 
(100)
100.0, 
100.0
16/16 
(100)
100.0, 100.0
N/A
460/466 
(98.7)
97.7, 99.7
GT3
499/521 
(95.8)
94.0, 97.5
113/122
(92.6)
88.0, 97.3
612/643 
(95.2)
93.5, 96.8
112/116 
(96.6)
93.2, 99.9
11/11 
(100)
100.0, 100.0
N/A
612/643 
(95.2)
93.5, 96.8
GT4
119/122 
(97.5)
94.8, 100.0
55/56 
(98.2)
94.7, 100.0
174/178 
(97.8)
95.6, 99.9
20/20 
(100) 
100.0, 
100.0
20/20 
(100) 
100.0, 100.0
4/4 
(100) 
100.0, 
100.0
178/182 
(97.8)
95.7, 99.9
GT5
26/26 
(100)
100.0, 
100.0
6/6 
(100)
100.0, 
100.0
32/32 
(100)
100.0, 
100.0
2/2 
(100) 
100.0, 
100.0
1/1 
(100) 
100.0, 100.0
N/A
32/32 
(100) 
100.0, 100.0
GT6
40/41 
(97.6)
92.8, 100.0
7/7 
(100)
100.0, 
100.0
47/48 
(97.9)
93.8, 100.0
7/7 
(100)
100.0, 
100.0
1/1 
(100)
100.0, 100.0
N/A
47/48 
(97.9)
93.8, 100.0
CI = confidence interval; CKD = chronic kidney disease; GT = genotype; HCV = hepatitis C virus; ITT = intention-to-
treat; N/A = not applicable; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; PRS = regimens containing 
interferon, pegylated interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic response 12 weeks 
postdosing; TE = treatment-experienced; TN = treatment-naïve; TE-NS5A and/or PI = TE with NS5A inhibitor and/or 
PI
a.
CI was calculated using a stratum-weighted proportion and variance.
b.
CI was calculated using the normal approximation to the binomial distribution.
c.
Eleven subjects were classified by the central laboratory and treated as GT2 but included here as GT1 due to being 
identified as such by phylogenetic analysis; all 11 subjects achieved SVR12.  
Cross reference:  Summary of Clinical Efficacy R&D/16/0146:  Table 1.2__2.2


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Impact of Baseline Polymorphisms on Treatment Outcome
The association between baseline polymorphisms and treatment outcome in subjects who 
received GLE 300 mg QD with PIB 120 mg QD in the registrational or supportive 
Phase 2 studies was evaluated by conducting an integrated analysis of baseline sequence 
data.  Next-generation sequencing (NGS) was conducted on all baseline samples at 15% 
detection threshold at key amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 
31, 58, 92, and 93 in NS5A. 
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% 
(1/34) of subjects with HCV genotype 1, 2, 3, 4, 5 and 6 infection, respectively.  Baseline 
polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% 
(136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV 
genotype 1, 2, 3, 4, 5, and 6 infection, respectively.
The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1-, 2-, 4-, 5-, or 6-infected subjects.
Within GT3-infected subjects, baseline polymorphisms in NS3 and the NS5A 
polymorphisms at positions 24, 28, 31, 58, 92, or 93 did not have an impact on treatment 
outcome. 
Amino Acid Substitutions in Subjects Experiencing Virologic Failure
Among TN and TE-PRS subjects with or without cirrhosis treated for 8, 12, or 16 weeks, 
23 subjects experienced virologic failure (2 with GT1, 2 with GT2, and 19 with GT3).  
One GT3-infected subject experiencing virologic failure was determined to have been 
reinfected with GT3a virus distinct from the one present at baseline.  Therefore, baseline 
polymorphisms and treatment-emergent substitutions were analyzed for 22 subjects 
experiencing virologic failure. 
Among the 2 GT1-infected subjects, 1 had treatment-emergent substitutions A156V in 


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NS3 and Q30R/L31M/H58D in NS5A, and 1 had treatment-emergent Q30R/H58D (while 
Y93N was present at baseline and post-treatment) in NS5A.
Among the 2 GT2-infected subjects, no treatment-emergent substitutions were observed 
in NS3 or NS5A; the prevalent M31 polymorphism in NS5A was present at baseline and 
post-treatment in both subjects.
Among the 18 GT3-infected subjects, the majority of subjects had treatment-emergent 
variants at the time of failure in NS3 (61.1%, 11/18) and NS5A (88.9%, 16/18).  
Treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, and Q168L/R were 
observed in 11 subjects, and A166S or Q168R was present at both baseline and 
post-treatment in 5 subjects.  Treatment-emergent NS5A substitutions M28G, A30G/K, 
L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n = 9) or 
Y93H (n = 5) at both baseline and post-treatment.
Integrated Safety Results
A summary of treatment-emergent adverse events (AEs) from pooled analyses of the 
registrational studies and supportive Phase 2 studies are presented in Table 3.  The 
severity of the underlying renal disease and its associated comorbidities in patients with 
CKD Stages 4 and 5, the frequency and severity of the AEs in subjects enrolled 
Study M15-462 were expected to be higher than in subjects enrolled in the other 
registrational studies.  Therefore, the summary of adverse events reported in Table 3 does 
not include the results of Study M15-462 which is listed separately.
As shown in Table 3, the AEs occurring with a frequency M 5% are headache, fatigue, 
nausea and diarrhea.  The majority of subjects experienced an AE, which were mostly 
considered to be mild in severity by the investigator (Grade 1).  Rates of AEs that were 
serious, led to premature study drug discontinuation or had a severity Grade M 3 were low.  
Including data from Study M15-462, there were 7 deaths, none of which were related to 
study drug, and the majority occurred several months after the last dose of study drug. 


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Table 3.
Adverse Events Reported for H 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related Adverse 
Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade M 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Termd
Headache
410 (18.1)
298 (13.2)
Fatigue
330 (14.6)
259 (11.4)
Nausea
208 (9.2)
172 (7.6)
Diarrhea
146 (6.4)
86 (3.8)
AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse 
event
a.
Excludes Study M15-462.
b.
DAAs = GLE, PIB, or GLE/PIB.
c.
Includes nontreatment-emergent deaths.  One additional death occurred in Study M15-462.
d.
DAA-related AEs reported for M 5.0% of subjects in the Phase 2 and 3 Analysis Set. 
Cross reference:  Summary of Clinical Safety R&D/16/0147:  Table 2.2__2.2, Table 2.2__3.2
Adverse events in subjects without cirrhosis (n = 1,977) were similar in type, frequency, 
and severity compared with subjects with cirrhosis (n = 288).  The safety profile in 
subjects with HCV/HIV-1 coinfection (n = 33) was similar to that in HCV monoinfected 
subjects.  Overall, the safety profile of GLE/PIB in the elderly population (M 65 years old, 
n = 328) was comparable to the safety profile in the non-elderly population (n = 2,041).
In Study M15-462, GLE/PIB was generally well-tolerated in subjects with CKD Stage 4 
and 5 as evidenced by a treatment discontinuation rate of 1.9% (2/104) due to AEs that 
were considered DAA-related.  No subject experienced a serious AE that was assessed as 
DAA-related.  The safety profile in subjects in Study M15-462 was consistent with 


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underlying ESRD and its associated comorbidities.  Pruritus was the most common AE 
among subjects (20.2%) in this study followed by fatigue (14.4%) and nausea (11.5%).  
Pruritus was not an unexpected finding, as it is commonly observed in patients with 
severe renal impairment.  Laboratory abnormalities were infrequent with no subject 
experiencing a Grade 3 or higher elevation in ALT or AST and 1 subject experiencing a 
Grade 3 elevation in total bilirubin.  
The frequency and severity of hepatic-related AEs as well as liver chemistry 
abnormalities evaluating potential hepatotoxicity were low across the Phase 2 and 3 
studies.  Liver-related safety results indicated that:
D
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin M 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
o
ALT abnormalities in 3 of these 4 subjects were not clinically significant 
o
One subject experienced concurrent ALT > 3 × ULN (increased from nadir 
grade) and total bilirubin M 2 × ULN in the context of multiple gallstones 
and was not consistent to have drug-induced liver injury
D
Based on exposure-response analyses, no exposure-dependent ALT increases 
were observed in subjects with ALT abnormalities 
D
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression
D
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.  
A total of 6 (0.3%) subjects experienced a de novo event of HCC.  In all 
6 subjects, the events were considered related to subject's medical history of 
underlying liver disease and not to GLE/PIB.  


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In summary, GLE/PIB demonstrated a favorable safety profile similar across durations of 
8, 12, and 16 weeks.  The regimen was well tolerated across a broad and diverse 
population of subjects, including subjects with cirrhosis, HIV coinfection, and CKD 
Stage 4 or 5.   
Common study drug-related AEs occurring in M 5% of subjects were headache, fatigue, 
nausea and were mostly Grade 1 (mild) in severity.  Serious AEs and AEs leading to 
premature study drug discontinuation were rare.  There were no hematological or blood 
chemistry findings of concern or considered likely related to treatment.  Unlike other 
protease inhibitors, no liver-related toxicities and no cases consistent with drug-induced 
liver injury were identified.
The objectives of this study are to evaluate the efficacy and safety of GLE/PIB in CKD 
Stage 3b, 4 and 5 subjects with HCV GT1 – 6 infection with or without compensated 
cirrhosis.
3.1
Differences Statement
The Phase 3 registration Study M15-462 evaluated GLE/PIB for a duration of 12 weeks, 
regardless of cirrhosis status or prior treatment experience, in HCV GT1 – 6-infected 
subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 
29 mL/min/1.73 m2) or ESRD (estimated GFR < 15 mL/min/1.73 m2 or requiring 
dialysis).  The patient population in Study M16-127 will be expanded compared to 
Study M15-462 to include subjects with less severe chronic renal disease by including up 
to 40 subjects with CKD Stage 3b (eGFR 30 to < 45 mL/min/1.73 m2) and will also 
include HCV GT3-infected subjects with prior treatment experience.  Compared to 
Study M15-462 which evaluated a single treatment duration of 12 weeks, the present 
study will evaluate treatment durations 8, 12 and 16 weeks based on HCV genotype, 
cirrhosis status and prior treatment experience.


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3.2
Benefits and Risks
This Phase 3b study is a three arm study in which eligible HCV GT1 – 6 infected subjects 
will receive GLE/PIB for 8, 12 or 16 weeks based on their genotype, cirrhosis status and 
prior treatment experience.  The combination of GLE/PIB has been evaluated in 
six Phase 3 registration studies and three Phase 2b supportive studies.  The results of these 
studies suggest that the likelihood of successfully demonstrating a high SVR12 rate in 
HCV GT1 – 6 subjects with renal impairment is high.
The Phase 3 Study M15-462 evaluated a 12 week duration of GLE/PIB in 104 CKD 
Stage 4 and 5 subjects, including 85 subjects on hemodialysis, with HCV GT1 –
6 infection with and without cirrhosis.  The SVR12 rate of 98% (102/104) was observed 
based on the ITT population; no subject experienced virologic failure.  In addition, the 
regimen was generally well-tolerated in subjects with renal impairment as evidenced by a 
low treatment-discontinuation rate due to AEs, no drug-related serious AEs, AEs that 
were mostly mild to moderate in severity and infrequent laboratory abnormalities.  These 
results support the recommendation that adults with chronic HCV infection and severe 
renal impairment and ESRD follow the duration recommendations for subjects with 
normal renal function.  
At present, no DAA regimen is approved for use in patients with HCV GT 2, 3, 5 and 
6 infection with severe renal impairment (CrCl < 30 mL/min).  In addition, approved 
DAA regimens for use in patients with HCV GT1 and 4 often include the use of RBV 
which is associated with toxicity in this patient population.  Therefore, identification of a 
safe, efficacious, RBV-sparing regimen is a benefit for the CKD Stage 4 and 5 population.  
Moreover, an 8 week treatment duration in HCV GT1 – 6 treatment-naïve patients 
without cirrhosis is a benefit compared to currently available regimens which are typically 
12 weeks or more in duration.  Other potential benefits of treatment with GLE/PIB 
include a higher genetic barrier to development of drug resistance compared to 
first generation protease and NS5A inhibitors and the development of resistance was 
infrequently observed as high rates of SVR12 were demonstrated across the Phase 2 and 
3 studies.


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In the Phase 2 and 3 studies, no significant toxicity or trends in liver chemistry 
abnormalities were observed and rates of study drug-related-SAEs and AEs leading to 
study drug discontinuation were low.  Cases of potentially clinically significant ALT and 
total bilirubin elevations were rare in the Phase 2 and 3 analysis set with ALT elevations 
> 5 × upper limit of normal (ULN) occurring in < 0.1% (2/2,265) subjects and total 
bilirubin elevations > 3 × ULN occurring in 0.4% (8/2,265) subjects; no cases consistent 
with drug induced liver injury (DILI) were reported.  No subject discontinued study drug 
due to ALT or bilirubin elevations.
Additional risks associated with GLE/PIB include the development of 
resistance-associated substitutions.  In subjects treated with a DAA, amino acid 
substitution(s) in the targeted protein conferring resistance to the DAA can be selected.  It 
is expected that PIB, an NS5A inhibitor, will be able to suppress the appearance of virus 
containing resistance-associated substitutions in NS3 that confer resistance to GLE, 
because there should not be any cross-resistance in substitutions resistant to DAAs 
targeting different proteins.  The converse is expected to be true as well – GLE should be 
able to suppress the appearance of virus containing NS5A substitutions conferring 
resistance to PIB.  In addition, in vitro resistant colony selection studies in HCV replicon 
cells containing GT1 – 6 NS5A demonstrated that PIB had a high genetic barrier to 
resistance – very few colonies were selected, and most of those that were selected 
contained NS5A substitutions that conferred only modest levels of resistance to PIB.  
Based on accumulated clinical and in vitro data to date, the risk of development of 
resistance-associated substitutions during GLE and PIB combination trials is reduced 
when compared to treatment with first generation protease and NS5A inhibitors.  The 
combination of PIB and GLE achieved high SVR rates with few virologic failures in the 
Phase 2 and 3 studies.  These results support the prediction that the risk of development of 
resistance-associated substitutions with GLE and PIB combination treatment is low.
Risks associated with GLE/PIB, including the risks of AEs, hepatic laboratory
abnormalities, virologic failure and development of resistance-associated substitutions, 
appear limited and manageable based on the results from the Phase 2 and 3 studies.  Given 


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the potential for achieving high rates of cure in renally-impaired HCV GT1 – 6 subjects, 
the risk-benefit balance is favorable.
4.0
Study Objective
4.1
Primary Objective
The primary objectives of this study are to assess the efficacy (by evaluating the 
percentage of subjects achieving SVR12) and safety of GLE/PIB in adults with chronic 
hepatitis C virus (HCV) genotype (GT) 1 – 6 infection with or without compensated 
cirrhosis and with chronic renal impairment in both HCV treatment-naïve and treatment-
experienced subjects.  The efficacy of GLE/PIB will be assessed based on the overall 
population (i.e., across treatment durations, genotypes, and cirrhosis status) and the safety 
of GLE/PIB will be assessed by treatment duration and cirrhosis status across genotypes.
4.2
Secondary Objectives
The secondary objectives are to assess efficacy of GLE/PIB based on overall population 
(i.e., across treatment durations, genotypes, and cirrhosis status) by evaluating the 
following:
D
The percentage of subjects with HCV on-treatment virologic failure;
D
The percentage of subjects with HCV virologic relapse.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy 
and safety of GLE/PIB for 8, 12, or 16 weeks in HCV GT1 – 6-infected subjects with 
chronic renal impairment, with or without compensated cirrhosis, who are either HCV 
treatment-naïve or prior treatment-experienced with interferon [IFN] or pegylated IFN 
[pegIFN] with or without RBV, or sofosbuvir [SOF] plus RBV with or without pegIFN.


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This study will consist of a Screening Period, a Treatment Period and a Post-Treatment 
Period.
Screening Period:  Subjects have up to 42 days following the Screening Visit to confirm 
eligibility and enroll into the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg 
QD for 8 weeks (Arm A), 12 weeks (Arm B), or 16 weeks (Arm C). 
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 
substitutions.
A study schematic is shown below in Figure 1.


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Figure 1.
Study Schematic


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The study enrollment will be monitored to meet the following non-mutually exclusive 
enrollment criteria:  (1) up to approximately 40 subjects with Stage 3b CKD, (2) up to 
approximately 75 HCV GT1-infected subjects, (3) up to approximately 30 subjects with 
compensated cirrhosis. 
The study population will include subjects with HCV GT1 – 6; subjects with mixed HCV 
genotype infection should receive whichever duration is longer based on their genotypes, 
cirrhosis status and treatment experience.  For subjects with an indeterminate genotype, 
treatment duration will default to the respective GT3 duration based upon treatment-
experience and cirrhosis status.
Subjects with renal impairment will be categorized during screening as having CKD 
Stage 3b, Stage 4 or Stage 5; CKD categorization for each subject at screening will be 
used throughout the study.  These categories are defined according to eGFR in Table 4
below:
Table 4.
Definition of Chronic Kidney Disease Stages
CKD Stage
eGFR (mL/min/1.73 m2)*
3b
30 to < 45
4
15 to < 30
5
< 15 or requiring dialysis
*
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1 154 × Age–0 203 × (0.742 if female) × (1.21 if black).
The study was designed to enroll approximately 120 eligible 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 Period
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 


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the subject meets all of the eligibility criteria specified in Section 5.2.1 and Section 5.2.2
during the period from the Screening Visit through Study Day 1 prior to dosing, and will 
record the results of this assessment and the details of the informed consent process in the 
subject's medical records.  Eligible subjects have up to 42 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
D
A positive hepatitis B surface antigen (HBsAg); or
D
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative 
HBsAg and Anti-HBs); or
D
A confirmed positive human immunodeficiency virus (HIV) antibody test; or
D
A confirmed positive pregnancy test (if female).
Subjects who meet all eligibility criteria with the exception of laboratory parameters may 
retest once within the 42-day screening period without prior AbbVie approval.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary albumin 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.
Subjects who fail to enroll within 42 days of Screening, regardless of the reason for 
falling outside of the 42-day screening window, may be allowed to rescreen only once 
without approval of the AbbVie Scientific Director.  These subjects must be rescreened 
for all laboratory and eligibility criteria, not just those that were exclusionary.
For subjects who rescreen or subjects that do not meet the study eligibility criteria 
including upon retest/rescreen, the site personnel must contact the IRT and identify the 
subject as a screen failure.


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Subjects who rescreen and meet all eligibility criteria to enroll to the study will retain the 
same subject number, assigned at the Screening Visit, throughout the study.
5.1.2
Treatment Period (TP)
After meeting the eligibility criteria, subjects will be enrolled via IRT system.  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 and hematology as specified in Table 6.  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 criterion will be evaluated and applied by the investigator as 
detailed in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.4.1.
5.1.3
Post-Treatment (PT) Period
All subjects who received at least one dose of study drug and either complete treatment or 
prematurely discontinue study drug will be monitored in the Post-Treatment Period for 
safety, clinical laboratory tests, HCV RNA, and the emergence and persistence of resistant 
viral substitutions for an additional 24 weeks following the last dose of study drug. 


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The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.  Study visits during the Post-Treatment Period are detailed in Appendix D.
Subjects who prematurely discontinue the Post-Treatment Period should return to the site 
for a Post-Treatment discontinuation visit as outlined in Appendix D.  
5.2
Selection of Study Population
The study population is selected to address the significant unmet medical need for a safe 
and efficacious, RBV-sparing, pangenotypic DAA regimen to treat HCV in subjects with 
chronic renal impairment.  The study population consists of HCV TN (i.e., patient has not 
received a single dose of any approved or investigational regimen for treatment of HCV) 
or TE (i.e., IFN or pegIFN with or without RBV, or SOF plus RBV with or without 
pegIFN) HCV GT1 – 6-infected adult male and female subjects with or without 
compensated cirrhosis, who have CKD Stage 3b, Stage 4 or Stage 5. 
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 defined as:
D
Age > 55 years with no menses for 12 or more months without an 
alternative medical cause; or
D
Age ] 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L; or
D
Permanently surgical sterile (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
OR


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D
A Woman of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at Study Day 1 
through at least 30 days after the last dose of study drug.
3.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine or serum pregnancy test at Study Day 1.
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.
Estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73 m2 as estimated 
by the MDRD method at screening according to 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 are dialysis-dependent.  Subjects requiring dialysis 
should have been receiving dialysis for at least 1 month prior to enrollment, and 
may be on hemodialysis or peritoneal dialysis.
5.
Subject has positive anti-HCV antibody (Ab) at Screening and plasma HCV RNA 
M 1000 IU/mL at Screening.
6.
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.
7.
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.
8.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.


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Rationale for Inclusion Criteria
1, 4 – 6
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
7, 8
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.
Current HBV or HIV infection on screening tests, defined as:
D
A positive HBsAg, or;
D
HBV DNA > LLOQ in subjects with isolated positive HBcAb (i.e., negative 
HBsAg and Anti-HBs), or;
D
A positive anti-human immunodeficiency virus antibody (HIV Ab).
3.
Requirement for and inability to safely discontinue the medications or supplements 
listed in Table 5 at least 14 days or 10 half-lives (whichever is longer) prior to the 
first dose of any study drug.  
4.
Any current or historical clinical evidence of decompensated cirrhosis, including 
any current or past evidence of Child-Pugh B or C classification, hepatic 
encephalopathy or variceal bleeding; radiographic evidence of small ascites; or 
prior or current empiric use of lactulose/rifaximin for neurologic indications.  
Prophylactic use of beta blockers is not exclusionary.


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5.
Clinically significant abnormalities or co-morbidities, or recent (within 6 months 
prior to study drug administration) alcohol or drug abuse that make the subject an 
unsuitable candidate for this study in the opinion of the investigator.
6.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
D
Albumin < 2.8 mg/dL
D
Hemoglobin < 9 g/dL
D
Platelets < 50,000 cells per mm3
7.
History of solid organ transplantation, unless the implanted organ has since been 
removed, or is non-functional, and subject is no longer on immunosuppressive 
medication.  If the organ is non-functional, the subject must be clinically stable off 
of immunosuppressive medication for a minimum of 6 months prior to screening.
8.
Clinical history of acute renal failure in the 3 months prior to screening.
9.
Receipt of any investigational or commercially available direct acting anti-HCV 
agents other than sofosbuvir (e.g., telaprevir, boceprevir, simeprevir, paritaprevir, 
grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir or dasabuvir). 
10.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drugs.
11.
Subjects who cannot participate in the study per local law.
12.
History of any suspected or confirmed hepatocellular carcinoma.
Rationale for Exclusion Criteria
1, 4 – 8, 10 – 12
In order to ensure safety of the subjects throughout the study
3, 9
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
2, 5
To exclude subjects with HIV and liver diseases other than 
chronic HCV infection


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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 drugs are stopped, must 
be recorded in the electronic case report form (eCRF) along with the reason for use, 
date(s) of administration including start and end dates, and dosage information including 
dose, route and frequency.  The investigator should review all concomitant medications 
for any potential interactions.
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in EDC.
The AbbVie Scientific Director should be contacted if there are any questions regarding 
concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
Subject must be HCV treatment-naïve (i.e., patient has not received a single dose of any 
approved or investigational anti-HCV regimen) or treatment-experienced (i.e., has failed 
prior IFN or pegIFN with or without RBV, or SOF plus RBV with or without pegIFN 
therapy).  Previous HCV treatment must have been completed M 2 months prior to 
screening.  
Subjects will be categorized as:
D
HCV treatment-naïve:  subject has never received any treatment for HCV 
infection.
D
Subjects with an allowed prior treatment will be categorized as:


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^
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:
D
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;
D
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 at the end of treatment;
D
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder.
^
Breakthrough:  confirmed M 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 (or quantifiable) 
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.
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
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions.  The investigator should refer to product labeling 
as needed to determine if, due to renal impairment, some medications may be 
contraindicated or require dose adjustment.


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Management of hematopoietic growth factor therapy, if initiated by the investigator 
during the study, is the responsibility of the investigator; growth factors will not be 
provided by AbbVie, and AbbVie will not reimburse for the expense of growth factors or 
their use.  Investigators should refer to the current package inserts of the growth factors 
for additional information regarding their use.
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements, and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses 14 days following discontinuation 
of study drugs as applicable.
5.2.3.3
Prohibited Therapy
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 5 at least 14 days or 10 half-lives (whichever is longer) prior to the 
first dose of GLE/PIB and not use these during the entire Treatment Period and for 
14 days following discontinuation of study drugs.  
Table 5.
Prohibited Medications and Supplements
Medication or Supplement Name
red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) must not be taken with the 
study drugs.  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 based on investigator's judgment, and either a) switch to 
pravastatin or rosuvastatin or b) interrupt statin therapy throughout the treatment period beginning at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of study drugs and until 14 days after the last dose of 
study drug.  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.
Contraceptives and/or hormonal replacement therapies containing only progestins (such as
those containing norethindrone, desogestrel, or levonorgestrel) or those containing 


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progestins with non-ethinyl estradiol estrogens (e.g., esterified or conjugated) may be used
with GLE/PIB at the discretion of the Investigator.
GLE/PIB is not recommended for use in patients requiring stable cyclosporine doses 
> 100 mg per day.  GLE/PIB may be initiated in subjects receiving cyclosporine ] 100 mg 
per day.15
5.2.4
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Woman of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.
D
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
D
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.
D
Bilateral tubal occlusion/ligation.
D
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
D
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
D
Intrauterine device (IUD).
D
Intrauterine hormone-releasing system (IUS).
D
Male or female condom with or without spermicide.
D
Cap, diaphragm or sponge with spermicide.
D
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).


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D
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
For male study subjects no contraception is required.
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C and Appendix D.
5.3.1.1
Study Procedures
Informed Consent 
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco, alcohol, and drug use, will be 
taken at Screening.  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.


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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.  
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 or upon subject discontinuation.  Blood 
pressure and pulse rate will 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 Screening visit as 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:
D
Normal ECG
D
Abnormal ECG – not clinically significant
D
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.


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Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 6
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 drug intake (with the exception of the Screening Visit, which may be 
non-fasting).  Subjects whose visits occur prior to the morning dose of study drug should 
be instructed to fast after midnight until the blood sample is collected in the morning and 
thereafter take their study medications with food.  Subjects whose visits occur following 
the morning dose of study drug should be instructed to fast after breakfast until the study 
visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug, which should be taken with food.  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.  
All labs collected during the study will be shipped to the central laboratory with the 
exception of the Day 1 serum pregnancy test in anuric women of child bearing potential 
which will be sent to a local lab.  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


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Table 6.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Additional Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Reticulocyte count
Prothrombin Time/international 
normalized ratio (INR)
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin 
Direct and indirect bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin 
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)
Anti-HCV Aba
HIV Aba
FSH (all females)
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG)b
HCV RNA
HCV genotype and subtypea
HBsAgc
Anti-HBc IgMc
Anti-HBc Totalc
Anti-HBsc
HBV DNAd
Alpha2-macroglobuline
Haptoglobine
Apolipoprotein A1e
Anti-HAV IgMf
Anti-HAV IgGf
Anti-HEV IgGf
Anti-HEV IgMf
HEV RNAf
a.
Performed only at Screening.
b.
Required only for females of childbearing potential.
c.
Performed at Screening for all subjects and also performed for management of transaminase elevations 
(Section 6.1.7.1).
d.
Performed at Screening for subjects who have occult HBV infection (positive Anti-HBc Total with negative 
HBsAg and Anti-HBs) and also performed for management of transaminase elevation (Section 6.1.7.1).
e.
Component of FibroTest and collected only if needed during the Screening Period.
f.
Performed for management of transaminase elevation (Section 6.1.7.1).
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
D
The investigator will repeat the test to verify the out-of-range value.
D
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.


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D
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.  Subjects who are anuric (unable to void) will have serum pregnancy tests 
performed instead of urine pregnancy tests.  Determination of postmenopausal status will 
be made during the Screening period, based on the subject's history.
D
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in the inclusion criteria) at Screening do not 
require pregnancy testing.
Concomitant Medication Assessment
Please refer to Section 5.2.3.2.
Hepatitis B and HIV Screen
HBsAg (hepatitis B surface antigen) will be performed at Screening, and as needed, for 
management of transaminase elevations.  Anti-HBc IgM, Anti-HBc Total and Anti-HBs 
will be performed at Screening and, as needed, for management of transaminase 
elevations.  HBV DNA will be performed at Screening for subjects who have occult HBV 
infection (positive Anti-HBc Total with negative HBsAg and Anti-HBs) and also 
performed for management of transaminase elevations.


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Liver Diagnostic Testing
Subjects will be considered to be non-cirrhotic or cirrhotic based on the definitions below:
Non-Cirrhotic
D
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
D
A FibroScan® score of < 12.5 kPa within ] 6 months of Screening or during 
Screening period; or
D
A Screening FibroTest score of ] 0.48 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) < 1.
Cirrhotic
D
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
D
A FibroScan® score of M 12.5 kPa at any time prior to screening or during 
Screening period; or
D
A Screening FibroTest result that is M 0.75 and an APRI > 2.
In the absence of a qualifying liver biopsy, subjects with an indeterminate FibroTest result 
(0.48 < result < 0.75), or conflicting FibroTest and APRI results (e.g., FibroTest ] 0.48, 
but APRI M 1) should be evaluated based on the investigator's clinical judgment to 
determine the presence or absence of cirrhosis. 
If more than one method is used to determine the presence or absence of cirrhosis, the 
results of a liver biopsy will take precedence over FibroScan and FibroTest/APRI and the 
results of FibroScan will take precedence over FibroTest/APRI.


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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).  Child-Pugh score will be determined only for subjects with 
compensated cirrhosis at the visits indicated in Appendix C and Appendix D.
Table 7.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, `mol/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)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points
*
None; 
Slight ascites = Ascites detectable only by ultrasound examination; 
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen; 
Severe ascites = Large or gross ascites with marked abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram; 
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves; 
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves; 
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves; 
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic 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 7.


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Hepatocellular Carcinoma Screening 
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Study Visit and at the last Post-treatment Study Visit, as indicated in 
Appendix C and Appendix D, for subjects with compensated cirrhosis only.  Between 
those visits, HCC screening should be performed according to standard of care.
At the Screening Study Visit and at the last Post-treatment Study Visit, subjects with 
compensated cirrhosis will be required to have a liver ultrasound performed on them to 
screen for HCC, unless the subject has a historical liver ultrasound, CT or MRI performed 
for HCC screening within 3 months prior to those visits, in which case the result of the 
historical US, CT or MRI will be used as the result for the Study Visit assessment.  A 
positive ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  
Alternate methods of screening for HCC (i.e., MRI or CT) at a study visit should be 
discussed with the study designated physician.
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments (where allowed per local 
regulatory guidelines) on the study days specified in Appendix C and Appendix D.  
Subjects should be instructed to follow the instructions provided with the 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 the instruments may have site personnel read 
the questionnaires to them.  Site personnel should encourage completion of the instrument 
at all specified visits and should ensure that a response is entered for all items. 
PRO instruments should be completed prior to drug administration on Day 1 and on 
subsequent visits, the PRO instrument should be administered prior to any discussion of 
adverse events or any review of laboratory findings, including HCV RNA levels.


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Kidney Disease Quality of Life (KDQOL36™)
The KDQOL-36 is a disease specific Quality of Life instrument to be used in patients with 
chronic kidney disease.  The KDQOL-36 consists of 4 subscales aimed at quantifying 
both general health and disease specific attributes.  The subscales include:  the Short 
Form-12 (a general health subscale SF-12), burden of kidney disease, 
symptoms/problems, and effects of kidney disease.
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.
Screening numbers will be unique 6 digit numbers and will begin with 100001 with the 
first three digits representing the investigative site, and the last three digits representing 
the subjects at that site.  Enrolled subjects will keep their screening number as their 
subject number.  Subjects will be enrolled on Study Day 1 as described in Section 5.5.3.
Study Drug Compliance for Kits
Individual bottles of GLE/PIB will be provided for subject dosing to the site.  Each 
subject will have compliance documented by the site in the subject's source notes for 
GLE/PIB.  At each Study Drug Accountability Visit in Appendix C, the overall number of 
tablets of GLE/PIB remaining in each bottle will be recorded and entered in the IRT 
system along with the date of reconciliation. 
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subgenotype 
Plasma samples for HCV genotype and subgenotype determination will be collected at 
Screening.  Genotype and subgenotype will be assessed using the Versant® HCV 
Genotype Inno LiPA Assay, version 2.0 or higher (LiPA; Siemens Healthcare 


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Diagnostics, Tarrytown, NY).  If the LiPA assay is unable to genotype a sample, its 
genotype and subtype will be determined by a Sanger sequencing assay of 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.
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.
Renal Biomarker Samples 
Urine samples for urine total protein/creatinine ratio, urine albumin/creatinine ratio and 
for urine neutrophil gelatinase-associated lipocalin (NGAL) will be collected at the study 
visits indicated in Appendix C and Appendix D.  Urine samples will be collected only 
from subjects that are not on dialysis.
Serum samples for C-reactive protein (CRP) will be collected at the study visits indicated 
in Appendix C and Appendix D.
The archive plasma samples will be used for tumor necrosis factor-alpha (TNF-a) 
collected at the study visits indicated in Appendix C and Appendix D in addition to 
possible analyses as indicated in the Archive Plasma Sample.


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Specific instructions for preparation and storage of urine samples will be provided by the 
central laboratory, AbbVie, or its designee.
Archive Urine Sample
Archive urine samples will be collected at the study visits indicated in Appendix C and 
Appendix D.  Archive urine samples will be collected only from subjects that are not on 
dialysis.  Archive urine samples are being collected for possible additional analyses, 
including but not limited to, safety/efficacy assessments, renal biomarkers, 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.
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, renal biomarker for tumor necrosis factor-alpha 
(TNF-a), study drug or metabolite measurements, viral load, safety/efficacy assessments, 
HCV gene sequencing, HCV resistance testing, and other possible predictors of response, 
as determined by 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.


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The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes and the 
eCRF.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
D
The Investigator or designee should make sure the subject is given the dosing 
card at Day 1 and at every study visit until the subject completes study drug 
treatment.
D
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.
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, 12, or 16, and PT Week 12 from each subject who consents to provide 
samples for exploratory research.
AbbVie (or people or companies working with AbbVie) will store the optional 
pharmacogenetic exploratory research samples in a secure storage space with adequate 


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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
All study drugs should be 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, PIB, and their possible metabolites, 
will be collected by venipuncture at each study visit as indicated below and in 
Appendix C. 
At all Treatment Period visits, except for Day 1, a single blood sample for 
pharmacokinetic analysis 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 the plasma samples for the pharmacokinetic assays of GLE, PIB, and their 
possible metabolites will be provided by the central laboratory, AbbVie, 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 their 
possible metabolites, 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 AbbVie or the reference 
laboratories following separately provided instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of GLE and PIB will be determined using validated assay methods 
in the Drug Analysis Department at AbbVie.  Plasma concentrations of possible 
metabolites of any analytes listed above may be determined using either validated or non-
validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA in IU/mL at various time points 
from Day 1 through 24 weeks after completion of treatment or discontinuation of study.
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:
D
The percentage of subjects with HCV on-treatment virologic failure.
D
The percentage of subjects with post-treatment HCV relapse.
Additional objectives are to assess the pharmacokinetics of GLE/PIB, and the emergence 
and persistence of viral substitutions in the study population.


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5.3.3.3
HCV Resistance Variables
For all subjects receiving GLE/PIB and with available samples, baseline polymorphisms 
at signature resistance associated amino acid positions identified by next generation 
sequencing (NGS) and comparison to the appropriate prototypic reference sequence will 
be analyzed.
The following resistance information will be analyzed for subjects receiving GLE/PIB 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
M 1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the baseline sequences, 2) the amino acid 
substitutions in available post-baseline samples at signature resistance-associated 
positions identified by NGS and comparison to the appropriate prototypic reference 
sequence, and 3) the persistence of viral substitutions by NGS.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, ECG, and laboratory tests assessments.
5.3.5
Pharmacokinetic Variables
Individual plasma concentrations of GLE and PIB will be tabulated and summarized.
5.3.6
Pharmacogenetic Exploratory Research Variables
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 


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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-Treatment Period where the subject will be monitored for 24 weeks for HCV RNA, 
the emergence and persistence of resistant viral substitutions.
If a subject is discontinued from study drug or the Post-Treatment Period with an ongoing 
adverse event or an unresolved laboratory result that is significantly outside of the 
reference range, the investigator will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of DAAs may 
be continued at the Principal Investigator's discretion after discussion with the subject, if 


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the benefit of continuing DAAs is felt to outweigh the potential risk.  Specific instructions 
regarding subject pregnancy can be found in Section 6.1.6.  Subjects 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:
D
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurements of > 1 log10 IU/mL above nadir) at any time point during 
treatment; or
D
Confirmed HCV RNA M 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements M 100 IU/mL) after HCV RNA < LLOQ during treatment.
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic failure criteria has been 
confirmed.  Subjects meeting 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 substitutions until 24 weeks post-treatment.
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.


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5.5
Treatments
5.5.1
Treatments Administered
Each dose of study drug, GLE/PIB, will be dispensed in the form of co-formulated tablets 
at the visits listed in Appendix C.  Subjects will be instructed to take study drugs 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 GLE/PIB 100 mg/40 mg tablets.  GLE/PIB will 
be taken orally at GLE/PIB 300 mg/120 mg (three × GLE/PIB 100 mg/40 mg tablets) QD 
and with food.
Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  The site will also contact the IRT 
system to provide study drug return information for each kit at the visits specified in 
Appendix C.  At the end of the Treatment Period or at the Premature D/C Visit from the 
Treatment Period, the site will contact the IRT system to provide the discontinuation visit 
date information and study drug return information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the virologic stopping 
criterion defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drugs to be used in this study is presented in Table 8.
Table 8.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
glecaprevir/pibrentasvir
AbbVie
Oral
Film-coated tablet
100 mg/40 mg


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5.5.2.1
Packaging and Labeling
Study drugs 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
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.
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), Arm B (12 weeks of treatment) or 
Arm C (16 weeks of treatment) based on genotype, cirrhosis status and prior treatment 
experience.  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.


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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 three tablets of GLE/PIB will be dosed together QD (three tablets once daily) with 
food.  
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing adherence with the treatment regimen with regard to virologic response and 
potential development of resistance.
At each study visit during the Treatment Period denoted in Appendix C, subjects will be 
instructed to bring all bottles of study drug (full, partial or empty) for assessment of 
treatment compliance.  At post-baseline dispensing 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 the source and IRT.  Treatment compliance will be based on the number of 
tablets dispensed, as recorded in IRT, and the number of remaining tablets.  If poor 
compliance is noted, the subject should be counseled and this should be documented in 
the subject's source.


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


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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is an open-label study to evaluate the safety and efficacy of GLE/PIB administered 
for 8, 12 or 16 weeks in renally impaired subjects (CKD Stages 3b to 5) with HCV GT1 –
6, with or without compensated cirrhosis.  The combination regimen of GLE/PIB was 
evaluated in non-renally impaired HCV GT1 – 6 infected subjects with and without 
compensated cirrhosis in the registrational studies and in CKD Stage 4 and 5 subjects with 
and without cirrhosis in the EXPEDITION-4 study (discussed in detail in Section 3.0).  
Based upon the results of these studies, AbbVie plans to evaluate the same combination 
regimen of GLE/PIB used in the registrational studies in an expanded population of 
renally-impaired subjects for durations consistent with the proposed label-
recommendation.  The selection of a three arm study design is appropriate in order to 
ensure that subjects receive the appropriate treatment duration based on their genotype, 
cirrhosis status and prior treatment experience.  
In view of the expected high SVR rate in this study and the established safety profile of 
GLE/PIB in patients with renal impairment, a control arm would be of limited value for 
efficacy comparison.  In this context, an open-label, three-arm study is appropriate to 
adequately describe the efficacy and safety of this regimen when administered for the 
proposed label recommended durations.  
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.  Clonal and population 
sequencing methods are experimental.
5.6.3
Suitability of Subject Population
This study is planned to enroll treatment-naïve or previous treatment-experienced (IFN or 
pegIFN with or without RBV, pegIFN/RBV plus SOF, or SOF plus RBV) chronic HCV 
GT1 – 6-infected subjects, with or without compensated cirrhosis, with CKD Stages 3b to 


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5.  With the exception of CKD Stage 3b subjects and the more inclusive eligibility criteria 
implemented in this study (e.g., GT3 treatment-experienced subjects, removal of specific 
laboratory, BMI and medical history exclusion criteria), the population enrolled in this 
study will be comparable to the population enrolled in the EXPEDITION-4 study.  In 
addition, with the exception of renal impairment, the study population is comparable to 
that enrolled in the broader registrational Phase 2 and 3 studies in non-CKD subjects.  
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The dose of GLE/PIB 300 mg/120 mg to be used in this study is the proposed label-
recommended dose.  These doses have been administered to over 2,300 subjects in the 
registrational program, and have shown high SVR12 rates with a favorable safety profile.
5.6.4.2
GLE and PIB Dose and Treatment Duration
The Phase 3 study EXPEDITION-4 evaluated a 12 week duration of GLE/PIB in 
104 CKD Stage 4 and 5 subjects, including 85 subjects on hemodialysis, with HCV 
GT1 – 6 infection with and without cirrhosis.  The SVR12 rate of 98% (102/104) and no 
virologic failure was observed in this study support the use of GLE/PIB in renally-
impaired subjects.  In the registrional program, the efficacy in CKD patients was 
comparable to that observed for non-CKD subjects, suggesting that treatment 
recommendations for CKD patients should follow those for patients without renal 
impairment.  Therefore, the current study will evaluate the proposed GLE/PIB label 
recommended treatment durations.  
As described in Section 3.0, the high SVR12 rates observed in non-CKD patients with and 
without cirrhosis support the proposed recommended treatment durations of 8, 12, and 
16 weeks based on genotype, cirrhosis status and prior treatment experience.


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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 6.1.5.  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.
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), 


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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 usually not considered to 
be AEs or serious adverse events (SAEs).  However, laboratory abnormalities or changes 
in vital signs that result in study drug discontinuation or interruption, necessitate 
therapeutic medical intervention, meet protocol specific criteria (see Section 6.1.7
regarding toxicity management) and/or are deemed clinically significant by the 
investigator, should be recorded as AEs or SAEs as defined in Section 6.1.1.1 and 
Section 6.1.1.2.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.


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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
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).


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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 
CTCAE 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.
6.1.3
Relationship to Study Drug
Assessment of relatedness will be made with respect to the DAAs (GLE/PIB).  The 
investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:


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Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient
evidence (information) to suggest a causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
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 and serious 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.


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For safety concerns, contact the Antiviral Safety Team at:
For any subject safety concerns, please contact the physician listed below:
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:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.


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6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 
investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).  If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment.  
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, 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.
Specific toxicity management guidelines apply to the instances of: increases in ALT 
(Section 6.1.7.1).


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6.1.7.1
Management of Transaminase Elevation
If a subject experiences a post-baseline increase in ALT to > 5 × ULN and also > 2 × the 
baseline value, the subject should have a confirmatory ALT measurement performed.  If 
the ALT is confirmed to be > 5 × ULN and also > 2 × the baseline value, the 
recommendations below should be followed:
D
Complete hepatic questionnaire.
D
Evaluate for an alternate etiology for ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain HBsAg, Anti-HBc IgM, Anti-HBc Total, Anti-HBs, HBV DNA, 
Anti-HAV IgM, Anti-HAV IgG, Anti-HEV IGM, Anti-HEV IgG, and HEV 
RNA and other additional tests, as appropriate.
D
Manage the subject as medically appropriate.
D
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
D
Discontinue study drugs if any of the following is observed at any time:
^
ALT level is M 20 × ULN in the absence of an alternate etiology.
^
Increasing direct bilirubin or INR or onset of other symptoms/signs of liver 
failure.
^
At the discretion of the investigator.
Alternate management of ALT increases requires approval of the AbbVie TA MD.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 


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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 protocol waivers, or intentional/prospective deviations from the 
protocol unless when necessary to eliminate an immediate hazard to study subjects.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB), and the following AbbVie personnel:


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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study and whether any 
instances of protocol non-compliance should be reported to regulatory authorities as a 
serious breach of GCP and the protocol.
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 study.  The data for the primary analysis will be locked after 
data cleaning.  Data after PT Week 12 will be added to a new version of the database 
which will be cleaned and locked at the end of the study.
SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All confidence intervals will be two-sided with an alpha level of 0.05.
Descriptive statistics will be provided, such as the number of observations (N), mean, and 
standard deviation (SD) for continuous variables and counts and percentages for discrete 
variables.
Safety and demographic analyses will be performed on all subjects who receive at least 
one dose of study drug.


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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 who did not achieve 
SVR12 for reasons other than virologic failure (mITT-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 subjects in the ITT 
population by arm (A, B and C) and overall.  Demographics include age, weight, height, 
BMI, gender, race, and ethnicity.  Baseline characteristics will be summarized as 
continuous variables (where appropriate) and as categorical variables, including all 
subgroup variables defined in Section 8.1.2.4, and including HCV genotype and subtype,  
prior HCV treatment history, baseline HCV RNA level, fibrosis stage (F0 – F1, F2, F3, or 
F4), dialysis (yes or no), CKD stage (Stage 3b, Stage 4, Stage 5), cirrhosis (yes/no), 
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, history of depression or 
bipolar disorder, and geographic region.
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).


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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.  
The efficacy analyses will be performed based on overall population, i.e., across treatment
durations, genotypes, and cirrhosis status. 
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 that are HCV RNA detected or HCV RNA not detected.  HCV RNA M LLOQ 
are all quantifiable values.
8.1.2.1
Primary Efficacy Endpoints
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) based on overall 
population across treatment durations, genotypes, and cirrhosis status.  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 to calculate the confidence interval instead.
A summary of reason for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.


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8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
D
The percentage of subjects with HCV on-treatment virologic failure (defined 
as confirmed increase of > 1 log10 IU/mL above nadir during treatment, 
confirmed HCV RNA M 100 IU/mL after HCV RNA < LLOQ during 
treatment, or HCV RNA M LLOQ at the end of treatment with at least 6 weeks 
of treatment), and 
D
The percentage of subjects with post-treatment HCV virologic relapse (defined 
as confirmed HCV RNA M LLOQ between end of treatment and 12 weeks 
after the last dose of study drug among subjects who completed treatment as 
planned with HCV RNA < LLOQ at the end of treatment; excluding subjects 
who have been shown to be reinfected)
For the analysis of post-treatment HCV virologic relapse, completion of treatment is 
defined as any subject with study drug duration of 52 days, 77 days, and 103 days or 
greater for subjects allocated to treatment durations of 8 weeks, 12, and 16 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% CI using Wilson's score 
method.
8.1.2.3
Sensitivity Analysis
As sensitivity analyses, the number and percentage of subjects in the mITT-VF population 
achieving SVR12, as applicable, will be summarized along with a two-sided 95% 
confidence interval using the normal approximation and a two-sided 95% CI 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.


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8.1.2.4
Subgroup Analysis
The percentage of subjects with SVR12 will be calculated, as will the corresponding 
two sided 95% Wilson score intervals, for the following subgroups:
D
HCV genotype and available subtype;
D
Prior HCV treatment history (treatment-naïve or treatment-experienced);
D
For treatment-experienced subjects, type of previous regimen (IFN- or 
SOF-based);
D
Age (< 65 or M 65 years) and (< 75 or M 75 years);
D
Race (White, Black/African-American, Asian, or other) and (black or non-
black);
D
Baseline HCV RNA level (< 1,000,000 or M 1,000,000 IU/mL and 
(< 6,000,000 or M 6,000,000 IU/mL);
D
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
D
Baseline cirrhosis Status (Yes/No)
D
Baseline platelet count (< 90 or M 90 × 109/L);
D
Baseline albumin (< 35 or M 35 g/L);
D
History of diabetes (yes/no);
D
Subject on stable opiate substitution;
D
Hemodialysis;
D
Peritoneal dialysis;
D
Chronic kidney disease stage;
Further details about subgroup analyses will be described in the statistical analysis plan.  
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized based on overall 
population:
D
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);


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D
The percentage of subjects who achieve SVR4 (SVR 4 weeks after the last 
actual dose of study drug);
D
The percentage of subjects who achieve SVR24 (SVR 24 weeks after the last 
actual dose of study drug);
D
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.
8.1.3
Patient Reported Outcomes
Subjects will complete the self-administered PRO instrument (where allowed per local 
regulatory guidelines) on the study days specified in Appendix C and Appendix D. 
Subjects should be instructed to follow the instructions provided with the 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 the instrument may have site personnel read 
the questionnaire to them.  Site personnel will encourage completion of the instrument at 
all specified visits and will ensure that a response is entered for all items.
The mean change from baseline to each applicable post-baseline timepoint in KDQOL-36
(SF-12, burden of kidney disease, symptoms and problems and effects of kidney disease 
on daily life) will be summarized descriptively at each visit and for change from baseline 
to each post baseline visit.
Additional analyses of PROs will be performed as useful and appropriate.
The PRO instrument should be completed prior any study procedures at each visit and 
prior to any discussion of adverse events or any review of laboratory findings, including 
HCV RNA levels.


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8.1.4
Resistance Analyses
For all subjects, full length NS3/4A and NS5A from baseline samples will be sequenced 
by NGS.  For subjects who do not achieve SVR12, full length NS3/4A and NS5A from the 
first sample after failure/discontinuation with HCV RNA M 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 M 1000 IU/mL after treatment discontinuation, will have the sample 
at that time point sequenced.
Only samples with an HCV RNA level of M 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level M 1000 IU/mL will be used.  Included time 
points for analyses on samples from subjects who do not achieve SVR12 are 1) the sample 
closest in time after failure/discontinuation with an HCV RNA level of M 1000 IU/mL,
and 2) 24 weeks post-DAA treatment, provided that resistance-associated substitutions 
were detected by NGS at the time of HCV virologic failure/treatment discontinuation.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions are listed in Table 9.  Appropriate subtype specific prototypic reference 
sequence will be used for comparison with sequences from samples.


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Table 9.
Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino 
Acid Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 132 
(GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 (GT3-only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 
93 (all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
The following definitions will be used in the HCV resistance analyses:
D
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (M 2% 
or M 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
D
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in post-baseline sample at a signature amino acid position.
D
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 M 2% of the sequences from the post-baseline sample.
D
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post-baseline % – baseline %) M 20]
D
Treatment-emergent substitution:  A post-baseline substitution or an enriched 
polymorphism.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:


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D
A listing of all baseline polymorphisms (2% detection threshold) at signature 
amino acid positions for each DAA target (NS3/4A and NS5A).
D
A listing of all baseline polymorphisms (15% detection threshold) at non-
signature amino acid positions for each DAA target (NS3/4A and NS5A) for 
subjects who experience virologic failure.
D
A by subject listing of baseline polymorphisms (15% detection threshold) at 
signature amino acid positions in subjects with polymorphisms across both 
NS3 and NS5A, or those with multiple baseline polymorphisms within any 
one target (NS3/4A or NS5A).
D
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
D
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total  
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared.  Analysis 
will be grouped by HCV subtype and DAA target (NS3/4A or NS5A). 
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
D
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%.
D
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
D
Polymorphisms at each non-signature amino acid position at a detection 
threshold of 15%.


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Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 
amino acid positions at 15% detection threshold, the SVR12 rate will be calculated, and 
the rates with or without polymorphisms will be compared using Fisher's exact test.  
Analysis will be separated by HCV subtype.  The following tables will be provided:
D
Comparison of SVR12 rates by subtype, and total (include all subtypes)
D
Comparison of SVR12 rates by genotype, and total (include all subtypes)
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
D
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
D
Listings by subject and time point of all post-baseline substitution at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
The persistence of post-baseline substitutions at signature amino acid positions for each 
target will be assessed by NGS at Post-Treatment Week 24.  A listing by subject and time 
point of all post-baseline substitutions relative to the baseline amino acid sequence will be 
provided for each DAA target.
If resistance-associated substitutions are not detected in a given target for a subject at the 
time of failure/discontinuation, then that target may not be sequenced in subsequent 
samples from that subject.
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 


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region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LiPA assay 
results from the Central laboratory will be used to categorize the subject.  This 
information will be presented in summaries of efficacy subgroup analyses.
8.1.5
Safety
Safety summaries will be provided by treatment duration and cirrhosis status across 
genotypes 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 (PT).  The tabulation of the number of subjects 
with treatment-emergent adverse events by severity grade and relationship to study drug 
(DAAs) also will 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 available measurement prior to the initial dose of study drug.  Mean 
changes from baseline to each post-baseline visit, including Final Treatment Visit, will be 


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summarized descriptively.  Changes from baseline to post-baseline in the CTCAE grading 
of laboratory values will also be summarized.
8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each post-baseline visit, including Final Treatment Visit, will be 
summarized descriptively.  The number and percentage of subjects with post-baseline 
values meeting pre-defined criteria for Potentially Clinically Significant (PCS) vital signs 
values will be summarized.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE, PIB, and their possible metabolites 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 may be performed using the actual sampling time 
relative to dosing.  Population pharmacokinetic models will be built using a non-linear 
mixed-effect modeling approach (NONMEM) with the NONMEM software (Version VI, 
or higher version).  The structure of the starting pharmacokinetic model will be based on 
the pharmacokinetic analysis of data from previous studies.  Apparent oral clearance 
(CL/F) and apparent volume of distribution (V/F) of the PK analytes will be the 
pharmacokinetic parameters of major interest in the NONMEM analyses.  If necessary, 
other parameters, including the parameters describing absorption characteristics, may be 
fixed if useful in the analysis.  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.


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Relationship between exposure (noncompartmental or population pharmacokinetic model 
based values of concentrations over time, AUC, Ctrough or some other appropriate measure 
of exposure) and clinical observations (antiviral activity or virologic end points, such as 
SVR12 response) will be explored, if appropriate.  Exposure-response relationships for 
primary and secondary efficacy variables and/or some safety measures of interest may 
also be explored.  Exposure response relationships will be explored using a logistic 
regression analysis and/or a semi-mechanistic viral dynamic model.  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 120 HCV GT1 – 6 infected subjects with chronic renal 
impairment, with or without compensated cirrhosis, who are either HCV TN or TE with 
IFN or pegIFN with or without RBV, or SOF plus RBV with or without pegIFN will be 
enrolled in the study.  No formal hypothesis is being tested.  If the observed SVR12 rate in 
this study is 97% among 120 HCV GT1 – 6 renally impaired subjects, then the half-width 
of 2-sided 95% normal approximation interval is 0.031.
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be enrolled into the study.
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 


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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 and approval by 
Regulatory Authority (ies), if required by local regulations, prior to implementation of any 
changes made to the study design.  The investigator will be required to submit, maintain 
and archive study essential documents according to ICH GCP and all other applicable 
regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
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 


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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.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a pharmacogenetic informed consent, approved by an IRB/IEC, after the nature of 
the testing has been explained and the subject has had an opportunity to ask questions.  
The pharmacogenetic informed consent must be signed before the pharmacogenetic 
testing is performed.  If the subject does not consent to the pharmacogenetic testing, it will 
not impact the subject's 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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 


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for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.


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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
To ensure data integrity and subject safety, a study monitor will continuously, throughout 
the study, verify that all subjects sign the informed consent prior to any study specific 
procedures being conducted, that the protocol procedures are being followed 
appropriately, and that the information provided in the eCRF is complete, accurate, and 
supported by information in source documents.
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 exploratory 
pharmacogenetic research may be provided to investigators and 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 submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for 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/Pibrentasvir in Renally-Impaired Adults with 
Chronic Hepatitis C Virus Genotype 1 – 6 Infection 
(EXPEDITION-5) 
Protocol Date:
30 January 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
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.
3.
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.
4.
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.
5.
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.
6.
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.
7.
European Association for Study of Liver.  EASL Clinical Practice Guidelines:  
Management of hepatitis C virus infection.  J Hepatol.  2014;60(2):392-420.
8.
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.
9.
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.
10.
Kidney International Volume 65, Issue 6, June 2004, Pages 2335-42.


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11.
Perico N, Cattaneo D, Bikbov B, et al.  Hepatitis C infection and chronic renal 
diseases.  Clin J Am Soc Nephrol.  2009;4(1):207-20.
12.
Viekira Pak [package insert].  North Chicago, IL; AbbVie Inc., 2014.
13.
Technivie [package insert].  North Chicago, IL; AbbVie Inc., 2015.
14.
Zepatier [package insert].  Whitehouse Station, NJ; Merck & Co. Inc., 2016.
15.
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.
16.
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's 
Brochure Edition 2.  06 September 2016.


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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
Therapeutic Area
Therapeutic Area
Bioanalysis
Statistics
Clinical Program Development


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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 4
Wk 8b
Wk 12b
EOT*/Premature 
D/Cb
Informed Consentc
X
Medical Historyd
X
X
Physical Exam
X
X
X
Vital Signs, Weight, Heighte
X
X
X
X
X
X
ECG
X
Hematology/Chemistryf/Coagulation Panel
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])g
X (s)
X (u, s)
X (u, s)
X (u, s)
X (u, s)
X (u, s)
Hepatitis B, Hepatitis C, and HIV Testing
X
HCV Genotype and Subgenotype
X
Liver Biopsy or FibroTest/APRI, or 
FibroScan®h
X
FSH (all females)
X
Pharmacogenetic DNA/RNA Sample 
(optional)c
X
X
Child-Pugh Score (cirrhotic subjects only)
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
Clinical Assessment of Hepatic 
Decompensation (cirrhotic subjects only)
X
HCC Screening (cirrhotic subjects only)i
X
Adverse Event Assessmentj
X
X
X
X
X
X


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Activity
Screening
Day 1a
Wk 4
Wk 8b
Wk 12b
EOT*/Premature 
D/Cb
PRO Instrumentsk
X
X
X
X
Study Drugs Dispensed
X
X
Xl
Xl
Study Drug Accountability and Review of 
Study Drug Adherence
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
Pharmacokinetic Samplesm
X
X
X
X
Archive Urine Sample – only for non-
dialysis subjects 
X
X
Urine and Serum Samples for Renal 
Biomarkers – urine sample only for non-
dialysis subjects
X
X
X
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Week 8 (Arm A), Week 12 (Arm B), or Week 16 (Arm C) in accordance with Section 5.1 and activities should be conducted that are located in the 
EOT column.
a.
All procedures to be performed prior to first dose.
b.
The Week 8 study visits apply to all subjects whose treatment duration is 12 weeks (Arm B) and 16 weeks (Arm C) in accordance with Section 5.1.  The Week 12 study visits 
apply to all subjects whose treatment duration is 16 weeks (Arm C) in accordance with Section 5.1.  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.  Subjects need to sign the IRB/IEC 
approved optional pharmacogenetic consent at any time during the study but prior to the collection of any pharmacogenotic samples, 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.  


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f.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour fast prior to drug intake (with the exception of the Screening Visit, which may be 
non-fasting).
g.
Pregnancy testing is not required for females of non-childbearing potential as defined in Inclusion Criterion 2.  Female subjects who are anuric (unable to void) will have 
serum pregnancy tests performed instead of urine pregnancy tests.  Female subjects that can provide a urine sample will have a urine pregnancy test.
h.
For subjects who have not had a qualifying liver biopsy (within the previous 24 months for non-cirrhotics or at any time prior to Screening for cirrhotics) or a qualifying 
FibroScan® (within the previous 6 months for non cirrhotics or at any time prior to Screening for cirrhotics).
i.
Required only for subjects with cirrhosis. An HCC Screening assessment is required per protocol only in the Screening Study Visit and at the Post-Treatment Period Week 24 
Visit, or upon discontinuation.  From Day 1 to EOT or premature D/C Study Visit, HCC screening should be performed as part of the Standard of Care for the subject.  Please 
refer to Section 5.3.1.1, item "Hepatocellular Carcinoma Screening" for details on this study procedure.
j.
See specific information regarding adverse event collection in Section 6.1.4.
k.
PRO should be administered before any study procedures at Day 1.  For all other visits, PRO should be administered prior to any discussion of adverse events or any review 
of laboratory findings, including HCV RNA levels.
l.
The Week 8 dispensation is only required for subjects whose treatment is 12 weeks (Arm B) or 16 weeks (Arm C) and the Week 12 dispensation is only required for subjects 
whose treatment is 16 weeks (Arm C) in accordance with Section 5.1.
m.
Details regarding timing of PK samples are provided in Section 5.3.2.1.


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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/Coagulation Panelg
X
Xb
Pregnancy Testc
X, (u, s)
X (u, s)c
PRO Instrumentsd
X
X
Concomitant Medication Assessmente
X
X
X
Adverse Event Assessmentf
X
X
X
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Archive Plasma Sample
X
X
X
Pharmacogenetic DNA/RNA Sample (optional)
X
Child-Pugh Score (cirrhotic subjects only)g
X
X
Archive Urine Sample – only for non-dialysis subjects
X
X
HCC Screening (cirrhotic subjects only)h
X
Urine and Serum Samples for Renal Biomarkers – urine sample 
only for non-dialysis subjects
X
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit procedures.
b.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are only required at PT D/C if subject discontinued prior to PT Wk 4 and not required at PT Wk 24. 
c.
Women of childbearing potential do not require pregnancy testing beyond PT Wk 4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior 
to PT Wk 4.  Female subjects who are anuric (unable to void) will have serum pregnancy tests performed instead of urine pregnancy tests.


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d.
PROs should be administered before any study procedures, prior to any discussion of adverse events or any review of laboratory findings, including HCV RNA levels at any
visit.
e.
Only medications taken for SAEs and treatment of HCV will be collected after 30 days post-dosing.
f.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  All spontaneously reported SAEs will be collected thereafter.  See specific information regarding 
adverse event collection in Section 6.1.4.
g.
The Child-Pugh assessment at the PT Wk 12 and 24 visits requires that an abbreviated physical examination and lab draws are conducted.  No other analytes will be resulted 
as part of the labs drawn at these time points.  Please refer to Section 5.3.1.1 Study Procedures, 'Child-Pugh Score and Category.'
h.
Required only for subjects with cirrhosis.  Please report to Section 5.3.1.1, item "Hepatocellular Carcinoma Screening" for details on this study procedure.


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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:"
"Emergency Contact:" previously read:
Has been changed to read:
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Pharmacokinetic:"
Delete:  last sentence
Values for the pharmacokinetic parameters including apparent clearance (CL/F) and 
apparent volume of distribution (V/F) will be estimated using population pharmacokinetic 
modeling procedures.


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Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Pharmacokinetic:"
Delete:  last paragraph
Pharmacokinetic data from this study may be combined with data from other studies for 
the population pharmacokinetic analyses.  Actual sampling times relative to dosing will be 
used for the analyses.  Pharmacokinetic models will be built using a non-linear mixed-
effect modeling approach with the NONMEM software.  The structure of the starting 
pharmacokinetic model will be based on the pharmacokinetic analysis of data from 
previous studies in HCV-infected subjects and healthy subjects.  Apparent clearance 
(CL/F) and apparent volume of distribution (V/F) of glecaprevir, pibrentasvir, and their 
possible metabolites will be the pharmacokinetic parameters of major interest in the 
NONMEM analyses.  Relationship between exposure and clinical observations (antiviral 
activity) will be explored.
Section 5.3.1.1  Study Procedures
Subsection Renal Biomarker Samples
Second paragraph previously read:
Serum samples for tumor necrosis factor-alpha (TNF-a) and C-reactive protein (CRP) will 
be collected at the study visits indicated in Appendix C and Appendix D.
Has been changed to read:
Serum samples for C-reactive protein (CRP) will be collected at the study visits indicated 
in Appendix C and Appendix D.
The archive plasma samples will be used for tumor necrosis factor-alpha (TNF-a) 
collected at the study visits indicated in Appendix C and Appendix D in addition to 
possible analyses as indicated in the Archive Plasma Sample.


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Section 5.3.1.1  Study Procedures
Subsection Archive Plasma Sample
First paragraph, last sentence previously read:
Archive plasma samples are being collected for possible additional analyses, including but 
not limited to study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, HCV resistance testing, and other possible predictors 
of response, as determined by AbbVie.
Has been changed to read:
Archive plasma samples are being collected for possible additional analyses, including but 
not limited to, renal biomarker for tumor necrosis factor-alpha (TNF-a), study drug or 
metabolite measurements, viral load, safety/efficacy assessments, HCV gene sequencing, 
HCV resistance testing, and other possible predictors of response, as determined by 
AbbVie.
Section 6.1.5  Adverse Event Reporting
"Primary Therapeutic Area Medical Director:" previously read:


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Has been changed to read:
Table 9.  Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Previously read:
Target
Signature Amino Acid Positions
Key Subset of Amino 
Acid Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 132 
(GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
Has been changed to read:
Target
Signature Amino Acid Positions
Key Subset of Amino 
Acid Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 132 
(GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 (GT3-only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 
93 (all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Bioanalysis
Statistics
Clinical
Has been changed to read:
Functional Area
Pharmacokinetics
Therapeutic Area
Therapeutic Area
Bioanalysis
Statistics
Clinical Program Development


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Appendix D.  Study Activities – Post-Treatment (PT) Period
Previously read:
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Pregnancy Test
X, (u, s)
X (u, s)b
PRO Instrumentsc
X
X
Concomitant Medication Assessmentd
X
X
X
Adverse Event Assessmente
X
X
X
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Archive Plasma Sample
X
X
X
Pharmacogenetic DNA/RNA Sample (optional)
X
Child-Pugh Score (cirrhotic subjects only)f
X
X
Archive Urine Sample – only for non-dialysis subjects
X
X
HCC Screening (cirrhotic subjects only)g
X
Urine and Serum Samples for Renal Biomarkers – urine sample 
only for non-dialysis subjects
X
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit procedures.
b.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are only required at PT D/C if subject discontinued prior to PT Wk 4.  Women of childbearing potential do not 
require pregnancy testing beyond PT Wk 4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to PT Wk 4.  Pregnancy testing in PT 
Period is not required for females of non-childbearing potential as defined in Inclusion Criterion 2.  Female subjects who are anuric (unable to void) will have serum 
pregnancy tests performed instead of urine pregnancy tests.


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c.
PROs should be administered before any study procedures, prior to any discussion of adverse events or any review of laboratory findings, including HCV RNA levels at any 
visit.
d.
Only medications taken for SAEs and treatment of HCV will be collected after 30 days post-dosing.
e.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  All spontaneously reported SAEs will be collected thereafter.  See specific information regarding 
adverse event collection in Section 6.1.4.
f.
An abbreviated physical examination will need to be conducted for assessment of ascites and hepatic encephalopathy.
g.
Required only for subjects with cirrhosis.  Please report to Section 5.3.1.1, item "Hepatocellular Carcinoma Screening" for details on this study procedure.


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Has been changed to read:
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panelg
X
Xb
Pregnancy Testc
X, (u, s)
X (u, s)c
PRO Instrumentsd
X
X
Concomitant Medication Assessmente
X
X
X
Adverse Event Assessmentf
X
X
X
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Archive Plasma Sample
X
X
X
Pharmacogenetic DNA/RNA Sample (optional)
X
Child-Pugh Score (cirrhotic subjects only)g
X
X
Archive Urine Sample – only for non-dialysis subjects
X
X
HCC Screening (cirrhotic subjects only)h
X
Urine and Serum Samples for Renal Biomarkers – urine sample 
only for non-dialysis subjects
X
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit procedures.
b.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are only required at PT D/C if subject discontinued prior to PT Wk 4 and not required at PT Wk 24. 
c.
Women of childbearing potential do not require pregnancy testing beyond PT Wk 4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior 
to PT Wk 4.  Female subjects who are anuric (unable to void) will have serum pregnancy tests performed instead of urine pregnancy tests.


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d.
PROs should be administered before any study procedures, prior to any discussion of adverse events or any review of laboratory findings, including HCV RNA levels at any 
visit.
e.
Only medications taken for SAEs and treatment of HCV will be collected after 30 days post-dosing.
f.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  All spontaneously reported SAEs will be collected thereafter.  See specific information regarding 
adverse event collection in Section 6.1.4.
g.
The Child-Pugh assessment at the PT Wk 12 and 24 visits requires that an abbreviated physical examination and lab draws are conducted.  No other analytes will be resulted 
as part of the labs drawn at these time points.  Please refer to Section 5.3.1.1 Study Procedures, 'Child-Pugh Score and Category.'
h.
Required only for subjects with cirrhosis.  Please report to Section 5.3.1.1, item "Hepatocellular Carcinoma Screening" for details on this study procedure.



SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-127
A Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Glecaprevir/Pibrentasvir in 
Renally-Impaired Adults with Chronic Hepatitis C 
Virus Genotype 1 – 6 Infection (EXPEDITION-5)
Date: 06 Feb 2018
Version 1.0
NCT03069365 


Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 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............................................................................................ 7
4.4
Planned Analyses ................................................................................... 8
5.0
Analysis Populations .............................................................8
5.1
Definitions of Analysis Populations........................................................ 8
5.1.1
Intention-to-Treat (ITT) Population ........................................................ 8
5.1.2
Modified Intention-to-Treat (mITT) Populations .................................... 9
5.1.3
Safety Population ................................................................................... 9
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........................................................................................... 10
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 ............................................................... 28
10.5
Sensitivity Analyses for SVR ............................................................... 29
10.5.1
Imputation Approaches......................................................................... 29
10.6
Efficacy Subgroup Analysis ................................................................. 29
10.7
Additional Efficacy Analyses ............................................................... 30
10.8
Resistance Analyses ............................................................................. 31
10.8.1
Presence of Baseline Polymorphisms for Subgroup Analyses of 
SVR12................................................................................................... 36
10.9
Patient Reported Outcomes .................................................................. 37
11.0
Safety Analysis.....................................................................38
11.1
General Considerations......................................................................... 38
11.2
Analysis of Adverse Events.................................................................. 38
11.2.1
Treatment-Emergent Adverse Events.................................................... 38
11.2.2
Tabulations of Treatment-Emergent Adverse Events ............................ 38
11.2.3
Adverse Events of Special Interest........................................................ 41
11.2.4
Listings of Adverse Events................................................................... 42
11.3
Analysis of Laboratory Data................................................................. 42
11.3.1
Variables and Criteria Defining Abnormality........................................ 42
11.3.2
Statistical Methods ............................................................................... 44
11.4
Analysis of Vital Signs and Weight ...................................................... 48
11.4.1
Variables and Criteria Defining Abnormality........................................ 48
11.4.2
Statistical Methods ............................................................................... 48
11.5
Analysis of Child-Pugh Score............................................................... 49
12.0
Summary of Changes .......................................................... 49
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ............................................................................................... 49
13.0
References............................................................................49


Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
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List of Tables
Table 1.
Analysis Time Windows for HCV RNA and Resistance 
Endpoints, Safety Laboratory and Vital Sign Measurements, Child 
Pugh Scores and PRO Instruments (Treatment Period) ......................... 11
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 12
Table 3.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements, Child Pugh Scores and PRO Instruments 
(Post-Treatment Period) ....................................................................... 12
Table 4.
Definition of Chronic Kidney Disease Stages ....................................... 16
Table 5.
Baseline Fibrosis Stage......................................................................... 17
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 19
Table 7.
Medical/Surgical History eCRF............................................................ 20
Table 8.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ...................................................................................... 32
Table 9.
Amino Acid Positions for Subgroup Analysis....................................... 36
Table 10.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 44
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values............ 48
List of Figures
Figure 1.
Study Schematic..................................................................................... 7


Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 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 Study M16-127.  
Study M16-127 evaluates the efficacy and safety of GLE/PIB in adults with chronic 
hepatitis C virus (HCV) genotype (GT) 1 – 6 infection with compensated cirrhosis or 
without cirrhosis and with chronic renal impairment in both HCV treatment-naïve (TN) 
and interferon/pegylated interferon (IFN), ribavirin (RBV) and/or SOF treatment-
experienced (TE) subjects.
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M16-127 incorporating Administrative Change 1 and 
2 and Amendment 1 and 2 and 3 dated 30 January 2018, and describes analysis 
conventions to guide the statistical programming.  Analyses will be performed using 
SAS® Version 9.4 (SAS Institute, Inc., Cary, NC) or later under the UNIX operating 
system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the efficacy (by evaluating the 
percentage of subjects achieving SVR12) and safety of GLE/PIB in adults with chronic 
hepatitis C virus (HCV) genotype (GT) 1 – 6 infection with compensated cirrhosis or 
without cirrhosis and with chronic renal impairment in both HCV TN and TE subjects.  
The efficacy of GLE/PIB will be assessed based on the overall population (i.e., across 
treatment durations, genotypes, and cirrhosis status), and the safety of GLE/PIB will be 
assessed by treatment duration and cirrhosis status across genotypes.
The secondary objectives are to assess the efficacy of GLE/PIB based on the overall 
population (i.e., across treatment durations, genotypes, and cirrhosis status) by evaluating 
the following:


Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 2018
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G
The percentage of subjects with HCV on-treatment virologic failure;
G
The percentage of subjects with HCV virologic relapse.
4.2
Design Diagram
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy 
and safety of GLE/PIB for 8, 12, or 16 weeks in HCV GT1 – 6-infected subjects with 
chronic renal impairment, with compensated cirrhosis or without cirrhosis, who are either 
HCV TN or prior TE with interferon [IFN] or pegylated IFN [pegIFN] with or without 
RBV, or sofosbuvir [SOF] plus RBV with or without pegIFN.  This study will consist of a 
Screening Period, a Treatment Period, and a Post-Treatment Period.  A study schematic is 
shown below in Figure 1.
The study is designed to enroll approximately 120 eligible subjects.  The study enrollment 
will be monitored to meet the following non-mutually exclusive enrollment criteria:  
(1) up to approximately 40 subjects with Stage 3b CKD, (2) up to approximately 
75 HCV GT1-infected subjects, (3) up to approximately 30 subjects with compensated 
cirrhosis.
Subjects will be enrolled into one of the following treatment arms:
G
Arm A:  HCV GT1, 2, 4 – 6 subjects without cirrhosis who are TN or TE and 
HCV GT 3 subjects without cirrhosis who are TN will be treated for 8 weeks.
G
Arm B:  HCV GT1, 2, 4 – 6 subjects with compensated cirrhosis who are TN 
or TE and HCV GT 3 subjects with compensated cirrhosis who are TN will be 
treated for 12 weeks.  
G
Arm C:  All HCV GT3 subjects who are TE will be treated for 16 weeks.
Subjects with mixed HCV genotype infection should receive whichever duration is longer 
based on their genotypes, cirrhosis status, and treatment experience.  For subjects with an 
indeterminate genotype, treatment duration will default to the respective GT3 duration 
based upon treatment-experience and cirrhosis status.


Glecaprevir/Pibrentasvir
M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 2018
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Figure 1.
Study Schematic
4.3
Sample Size
It is anticipated that approximately 120 HCV GT1 – 6 infected subjects with chronic renal 
impairment, with compensated cirrhosis or without cirrhosis, who are either HCV TN or 
TE with IFN or pegIFN with or without RBV, or SOF plus RBV with or without pegIFN 
will be enrolled in the study.  No formal hypothesis is being tested.  If the observed SVR12
rate in this study is 97% among 120 HCV GT1 – 6 renally impaired subjects, then the 
half-width of the 2-sided 95% confidence interval (CI) using the normal approximation to 
the binomial distribution is 0.031 (nQuery Advisor, Version 8.0, Statistical Solutions, 
Ltd., Boston, MA).


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M16-127 – Statistical Analysis Plan
Version 1.0 – 06 Feb 2018
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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.
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.  Results from the final analysis 
will be described in the clinical study report (CSR).
There is no intention of stopping the study early based on efficacy findings the primary 
analysis.  The intention is to follow all subjects who receive study drug for 24 weeks 
following treatment.
5.0
Analysis Populations
5.1
Definitions of Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
All subjects who receive at least one dose of study drug will be included in the ITT 
population.  Demographic, baseline characteristic, exposure, concomitant medication and 
medical history analyses will be performed on the ITT population overall and according to 
the treatment assignment, i.e., subject grouping will be based on the arm to which the 
subject was assigned.  Efficacy analyses will be performed on the overall ITT population, 
combining Arms A, B and C which are the recommended duration per labelling.  


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5.1.2
Modified Intention-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 as described in Section 10.5 will be performed on the ITT 
population modified to exclude subjects who did not achieve SVR12 for reasons other than 
virologic failure (mITT-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 analysis will be performed on the overall ITT population, combining 
Arms A, B and C.
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 available must be before the time of first dose to be 
considered baseline, and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 
time or if time is not available, then the average of these measurements will be considered 
as the baseline value.  The same baseline value will be used for analyses of the Treatment 
and Post-Treatment Periods.


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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 
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, the time windows specified in Table 1 and Table 2
describe how efficacy data are assigned to protocol-specified time points during the 
Treatment and Post-Treatment Periods, respectively.  All time points and corresponding 
time windows are defined based on the date/time of blood sample collection.


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For safety laboratory data, PRO data, Child Pugh score 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 
in analyses of SVR) to the nominal time will be used.  If there are two observations 
equally distant to the nominal time, the latest one will be used in analyses.  For analyses 
of SVR (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 and Resistance Endpoints, 
Safety Laboratory and Vital Sign Measurements, Child Pugh 
Scores and PRO Instruments (Treatment Period)
Scheduled Visit
Nominal Day
(Study Day)
Time Window
(Study Day Range)
Day 1/Baselinea
1
O 1a
Week 4
28
2 to 42
Week 8
56
43 to 70
Week 12b,c
84
71 to 98
Week 16c
112
99 to 126
Final Treatment Visitd
2 to O 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 12-week and 16-week treatment duration only.
c.
For 16-week treatment duration only.
d.
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, Week 4, Week 12 (Arm C only) and End of 
Treatment Visit, which can be at Week 8, 12 or 16 depending on treatment assignment, 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 for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  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 and Vital Sign 
Measurements, Child Pugh Scores and PRO Instruments
(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
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 visit 
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 and coagulation 
panels are collected at PTW4 or PT D/C (if subject discontinued prior to PTW4).  PRO instruments and Child 
Pugh Scores are collected at PTW12 and PTW24 (or PT D/C).


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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
If a respondent answers at least 50% of the items in a multi-item scale of the Kidney 
Disease Quality of Life (KDQOL-36), 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.  


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If a subject starts another treatment for HCV, then all PRO assessment values for this 
subject measured on or after the start date of the new HCV treatment will be excluded 
from analyses.  
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
The ITT population will be used to summarize demographics, baseline characteristics, 
medical history and previous, concomitant, and post-treatment medications; data will be 
summarized across all subjects and by assigned treatment arm. 
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 and baseline characteristics include age, weight, height, body 
mass index (BMI), baseline log10 HCV RNA level, creatinine clearance (Cockcroft-Gault 
calculation), eGFR (using the modification of diet in renal disease [MDRD] formula), 
platelet count, albumin, GGT, APRI, FIB-4, AST, ALT, and total, direct and indirect 
bilirubin.
Categorical demographic and baseline characteristics include:
G
Age (< 65 or R 65 years) and (< 75 or R 75 years);
G
Sex (male or female);
G
Race and black race:  black or non-black;
G
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
G
Geographic region (North America, Europe, or rest of world);


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G
Country;
G
Baseline BMI (< 30 or R 30 kg/m2);
G
HCV genotype and subtype (using central laboratory results and final 
genotype/subtype results, see Section 10.8);
G
Prior HCV treatment history (naïve or experienced);
G
For treatment-experienced subjects, type of previous regimen (IFN- or SOF-
based);
G
Baseline cirrhosis status (yes/no);
G
For cirrhotic subjects, Baseline Child-Pugh score (5, 6, or > 6);
G
Chronic Kidney Disease stage at screening (Stage 3b, Stage 4, Stage 5 without 
dialysis, or Stage 5 requiring dialysis);
G
For treatment-experienced subjects, type of non-response to previous treatment 
(on-treatment non-responder, breakthrough, post-treatment relapse, or 
unknown/other);
G
Baseline HCV RNA level (< 1,000,000; R 1,000,000 to < 2,000,000; or 
R 2,000,000 IU/mL);
G
Baseline platelet count (< 90 or R 90 × 109/L);
G
Baseline albumin (< 35 or R 35 g/L);
G
Baseline eGFR (< 15, R 15 to < 30, R 30 to < 45, or R 45 mL/min/1.73 m2);
G
Baseline creatinine clearance (< 15, or R 15 mL/min);
G
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
G
Concomitant use of Proton Pump Inhibitors (PPIs);
G
Concomitant use of Statins (yes/no);
G
Dialysis at screening (yes/no);
G
For dialysis subjects, type of dialysis (hemodialysis, peritoneal dialysis, or 
other);
G
Tobacco use (user, ex-user, or non-user);
G
Alcohol use (drinker, ex-drinker, or non-drinker);
G
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);


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G
Use of stable opiate substitution (yes/no);
G
History of diabetes (yes/no);
G
History of depression or bipolar disorder (yes/no);
G
History of bleeding disorders (yes/no);
G
History of cardiovascular disease (yes/no);
G
History of hypertension (yes/no);
Summaries of baseline resistance are described in Section 10.8.
For TE 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.  Any concomitant medication coded to the WHO Drug 
Dictionary ATC code of C10AA or C10BX will be counted as a statin.  
CKD categorization at screening is defined according to eGFR and requirement of 
dialysis in Table 4 below:
Table 4.
Definition of Chronic Kidney Disease Stages
CKD Stage
eGFR (mL/min/1.73 m2)*
3b
30 to < 45
4
15 to < 30
5
< 15 or requiring dialysis
*
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1 154 × Age–0 203 × (0.742 if female) × (1.21 if black).
Dialysis at screening is defined as any dialysis that started prior to the Day 1 visit based 
on the eCRF "Dialysis Treatment Prior to and Initiated During Study."  For subjects 
requiring dialysis, hemodialysis is defined as intermittent hemodiafiltration, intermittent 
hemodialysis, intermittent hemofiltration, continuous RRT, or sustained low efficiency 
(daily) dialysis; peritoneal dialysis is defined as automated peritoneal dialysis or 
continuous ambulatory peritoneal dialysis.


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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 
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 5.
Table 5.
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
O 0.48
F2 
2
3
R 8.8 to < 9.6
0.49 to 0.58
F3
3
4
R 9.6 to < 12.5
0.59 to 0.74
F4
4
R 5
R 12.5
R 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.
The central laboratory calculates the estimated creatinine clearance (CrCl) based on the 
following Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum creatinine 
(mg/dL) × 72].
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 African American).


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Baseline APRI and FIB-4 are calculated by the equations below.  Subjects who do not 
have concurrent AST and platelet values at baseline will be excluded from the summary 
of baseline APRI.  Age is defined in years at baseline.  Subjects who do not have 
concurrent values of AST, ALT and platelet count at baseline or subjects who are missing 
age will be excluded from the summary of FIB-4.
APRI =
AST Level (U/L)
AST (Upper Limit of Normal)(U/L)
Platelet Count (10!/L)
× 100
FIB-4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10!/L) × )ALT (U/L)
Presence or absence of cirrhosis will be determined as collected in IRT/EDC ("subject's 
cirrhosis status?" – "Compensated 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 6.


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Table 6.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, Ymol/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)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points
*
None; 
Slight ascites = Ascites detectable only by ultrasound examination; 
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen; 
Severe ascites = Large or gross ascites with marked abdominal distension.
**
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.
Histories of diabetes, bleeding disorders, depression or bipolar disorder, hypertension, and 
cardiovascular disease will be based on the Medical/Surgical History eCRF, as defined in 
Table 7.


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Table 7.
Medical/Surgical History eCRF
Medical/Surgical 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
Hypertension
Cardiovascular
Hypertension
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 (GLE/PIB).  A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study drug and continued to be taken on or 
after the first dose of study drug or any medication that started on or after the date of the 
first dose of study drug, but not after the date of the last dose of study drug.  A post-
treatment medication for the treatment of HCV is defined as any medication taken on or 
after the last dose of study drug and entered as "Post-treatment HCV medications" on the 
eCRF.
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 summary of all prior and concomitant 
medication.
8.0
Subject Disposition
The number and percentage of subjects who screen failed for any reason will be 
summarized for subjects who screen failed and by each screen fail reason.
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.
G
Enrolled subjects;
G
Subjects who took at least one dose of study drug;
G
Subjects who completed study drug;
G
Subjects who prematurely discontinued study drug;


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G
Subjects who completed the study;
G
Subjects who prematurely discontinued from the study;
G
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.  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
The duration of exposure to study drug will be summarized for each treatment arm and 
overall in the safety population.  Duration of exposure is defined for each subject as the 
last study drug dose date minus the first study drug dose date plus 1 day.
During each treatment period, descriptive statistics (mean, standard deviation, median, 
minimum, and maximum) will be presented for exposure.  Study drug duration will also 
be summarized with frequencies and percentages using the following categories:
G
1 to 15 days
G
16 to 30 days
G
31 to 45 days
G
46 to 60 days
G
61 to 75 days


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G
76 to 90 days
G
91 to 105 days 
G
> 105 days 
In addition, the number and percentage of subjects with study drug duration of R 52 days 
for Arm A, R 77 days for Arm B and R 103 days for Arm C will be summarized.
9.2
Compliance
For each kit, the total number of tablets dispensed and returned is recorded.  The 
compliance for study drug (glecaprevir/pibrentasvir) during the Treatment Period will be 
calculated as the percentage of tablets taken relative to the total tablets expected to be 
taken.  The total number of tablets expected to be taken will be equal to the total number 
of tablets that should have been taken per the protocol for the duration that the subject was 
in the Treatment Period (date of last dose of study drug – date of first dose of study drug 
+ 1).  Study drug interruptions recorded on the eCRF will not be subtracted from the 
duration.
A subject is considered to be compliant if the percentage is between 80% and 120%.  
Compliance will be calculated for each subject and summarized with the mean, median, 
standard deviation, minimum, and maximum by treatment arm.  A listing of compliance 
for each subject will be provided.  The percentage of compliant subjects will be 
summarized for each treatment arm based on data as observed.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
All efficacy analyses will be performed on the ITT population, unless otherwise specified. 
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.


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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 R 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 R 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 R LLOQ.
Breakthrough = confirmed HCV RNA R 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 (R 100 IU/mL or 
> 1 log10 above nadir) followed by lost to follow-up also will be considered a 
breakthrough (i.e., will not require confirmation).
EOT failure = HCV RNA R 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 R 36 days.


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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 
active study drug) without any confirmed quantifiable (R 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 
active study drug) without any confirmed quantifiable (R 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 
active study drug) without any confirmed quantifiable (R LLOQ) post-treatment value 
before or during that SVR window.
Relapse12 = confirmed HCV RNA R LLOQ between end of treatment and 12 weeks after 
last actual dose of active 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 R 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 R LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment, excluding 
reinfection.
Virologic failure for SVR12 = On-treatment virologic failure or Relapse12


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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 a 
study drug duration of 52 days or greater for Arm A, 77 days or greater for Arm B, and 
103 days or greater for Arm C.  If the last available post-treatment value is R LLOQ, then 
the subject will be considered a relapse (i.e., will not require confirmation).
HCV reinfection is defined as confirmed HCV RNA R LLOQ after the end of active 
treatment in a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with 
the post treatment detection of a different HCV genotype, subtype, or clade compared 
with baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B 
gene sequences.  Reinfection in the case of the same HCV subtype is defined as a clade 
switch, as indicated by the lack of clustering between the baseline and post-treatment 
sequences by phylogenetic analysis.  If phylogenetic analysis is not possible due to 
technical difficulties, HCV reinfection may be determined with a confirmed HCV 
genotype or subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and no genotype, subtype, or clade switch compared with baseline as 
determined by phylogenetic analysis of the NS3 or NS5A gene sequences.  If 
phylogenetic analysis is not possible due to technical difficulties, the subject will be 
defined as having a post-treatment relapse unless an HCV genotype or subtype switch is 
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);
2.
HCV reinfection (see definition described earlier);
3.
Relapse12;


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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 Arm A, < 77 days for Arm B, and < 103 days 
for Arm C] and did not meet the On-treatment virologic failure or 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 Arm A, < 77 days for Arm B, and < 103 days 
for Arm C] and did not meet the On-treatment virologic failure, HCV 
reinfection, Relapse12, or Relapse24 definitions);
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
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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 1 category.  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
There will be no hypothesis testing for the primary and secondary efficacy endpoints.  
Therefore, there will be no adjustment for multiple comparisons.
10.3
Primary Efficacy Analysis
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) based on the overall ITT 
population across treatment durations, genotypes, and cirrhosis status.  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 the reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.
10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
G
The percentage of subjects with HCV on-treatment virologic failure, and 
G
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For on-treatment virologic failure and post-treatment relapse, the number and percentage 
of subjects will be calculated along with a two-sided 95% CI using Wilson's score method 
for the overall ITT population. 
10.5
Sensitivity Analyses for SVR
As sensitivity analyses, the number and percentage of subjects in the mITT-VF population 
achieving SVR12, as applicable, will be summarized along with a two-sided 95% CI using 
the normal approximation and a two-sided 95% CI using the Wilson's score method.
The two-sided 95% CI using Wilson's score method will also be calculated as a sensitivity 
analysis for the primary endpoint of SVR12 based on the ITT population.
A listing of subjects excluded from mITT-VF population will be provided. 
10.5.1
Imputation Approaches
No imputation methods will be employed other than those described in Section 6.3. 
10.6
Efficacy Subgroup Analysis
The percentage of subjects with SVR12 in the ITT population will be calculated with the 
corresponding two sided 95% Wilson score intervals, for the following subgroups:
G
HCV genotype and available subtype (based on final HCV genotype and 
subtype determination);
G
Prior HCV treatment history (TN or TE);
G
For TE subjects, type of previous regimen (IFN- or SOF-based);
G
Age (< 65 or R 65 years) and (< 75 or R 75 years);
G
Sex (male or female);
G
Race (White, Black/African-American, Asian, or other) and black race:  black 
or non-black;
G
Baseline BMI (< 30, or R 30 kg/m2); 


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G
Baseline HCV RNA level (< 1,000,000; R 1,000,000 to < 2,000,000; or 
R 2,000,000 IU/mL);
G
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
G
Baseline cirrhosis Status (yes/no)
G
Baseline platelet count (< 90 or R 90 × 109/L);
G
Baseline albumin (< 35 or R 35 g/L);
G
History of diabetes (yes/no);
G
Subject on stable opiate substitution (yes/no);
G
For dialysis subjects, dialysis type (hemodialysis, peritoneal dialysis, or other);
G
Chronic kidney disease stage at screening (Stage 3b, 4, 5 without dialysis, or 
5 requiring dialysis);
G
Baseline polymorphisms in NS3 and/or NS5A.
The presence of baseline polymorphisms in the above listed subgroup analyses is defined 
in Section 10.8.1. 
10.7
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized for the ITT population:
G
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
G
The percentage of subjects with SVR4;
G
The percentage of subjects with SVR24;
G
The percentage of subjects who relapsed after achieving SVR12 (Relapse24).
G
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)
The number and percentage of subjects meeting each additional efficacy endpoint will be 
calculated along with a two-sided 95% CI using the Wilson's score method.  Imputations 
for missing data will be performed as described in Section 6.3 for analysis of SVR, 


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virologic failure, and relapse.  The first bulleted endpoint above will be presented using 
data as observed.
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject number and the SVR visit window corresponding to the first HCV 
RNA value of those indicating the 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.  A listing of subjects in the ITT 
population excluded from the relapse denominator (e.g., study drug duration < 52 days for 
subjects assigned to 8 weeks of treatment) will be provided, as applicable.
A listing of subject numbers and reasons for non-response to SVR12 will be prepared.  A 
similar summary and listing will be prepared for subjects who do not achieve SVR24 (as 
defined in Section 10.1).
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and the positive predictive value (PPV) and negative predictive value 
(NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is a percentage 
defined as the number of subjects achieving both SVR12 and SVR24 and the number of 
subjects where both SVR12 and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is 
the proportion of subjects who achieve 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.
10.8
Resistance Analyses 
For all subjects, full length NS3/4A and NS5A from baseline samples will be sequenced 
by next generation sequencing (NGS).  For subjects who experience virologic failure (on-
treatment virologic failure or post-treatment relapse as defined in Section 10.1), full 
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R 1000 IU/mL will be sequenced by NGS.  Subjects treated with study drug who do not 
achieve SVR12 due to reasons other than virologic failure (i.e., prematurely discontinued 
study drug with no on-treatment virologic failure, HCV reinfection, missing SVR12 data 
or other reasons as described in Section 10.1, Reasons for SVR12 Non-Response), but 
have a time point with HCV RNA R 1000 IU/mL after treatment discontinuation, will 
have the sample at that time point sequenced.  
Only samples with an HCV RNA level of R 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level R 1000 IU/mL will be used. 
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions for the respective inhibitor class are listed in Table 8.  Appropriate subtype-
specific prototypic reference sequence will be used for comparison with sequences from 
samples.
Table 8.
Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino 
Acid Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 
(GT3-only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 
92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
Included time points for analyses on samples from subjects who do not achieve SVR12 are 
1) the sample closest in time after failure/discontinuation with an HCV RNA level of 
R 1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that resistance-associated 


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variants were detected by NGS at the time of HCV virologic failure/treatment 
discontinuation.
The following definitions will be used in the resistance analyses:
G
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (R 2% 
or R 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
G
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in post-baseline sample at a signature amino acid position.
G
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 R 2% of the sequences from the post-baseline sample.
G
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post-baseline % – baseline %) R 20]
G
Treatment-emergent substitution:  A post-baseline substitution or an enriched 
polymorphism.
Analysis 1:  The following analyses will be provided for all subjects, separated by Arm, 
HCV subtype, and treatment experience (treatment-naïve or treatment-experienced, and 
overall):
G
A listing of all subjects with baseline polymorphisms (2% detection threshold) 
at signature amino acid positions for each DAA target (NS3/4A and NS5A).
G
A listing of all subjects with baseline polymorphisms (15% detection 
threshold) at non-signature amino acid positions for each DAA target (NS3/4A 
and NS5A) for subjects who experience virologic failure.


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G
A by-subject listing of baseline polymorphisms (15% detection threshold) at 
signature amino acid positions in subjects with polymorphisms across both 
NS3 and NS5A, or those with multiple baseline polymorphisms within any 
one target (NS3/4A or NS5A).
G
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
G
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total  
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared.  Analysis 
will be grouped by Arm, HCV subtype, treatment experience (treatment-naïve or 
treatment-experienced, and overall), and DAA target (NS3/4A or NS5A). 
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
G
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%.
G
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
G
Polymorphisms at each non-signature amino acid position at a detection 
threshold of 15%.
Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 
amino acid positions at 15% detection threshold, the SVR12 rate will be calculated, and 
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Analysis will be separated by Arm, HCV subtype, treatment experience (treatment-naïve 
or treatment-experienced, and overall).  The following tables will be provided:
G
Comparison of SVR12 rates by subtype, and total (include all subtypes)
G
Comparison of SVR12 rates by genotype, and total (include all subtypes)
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 or SVR24, and who have post-baseline resistance data available:
G
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
G
Listings by subject and time point of all post-baseline substitution at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
G
The persistence of post-baseline substitutions at signature amino acid positions 
for each target will be assessed by NGS at Post-Treatment Week 24.  A listing 
by subject and time point of all post-baseline substitutions relative to the 
baseline amino acid sequence will be provided for each DAA target.  If 
resistance-associated substitutions are not detected in a given target for a 
subject at the time of failure/discontinuation, then that target may not be 
sequenced in subsequent samples from that subject.
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LiPA assay 
results from the Central laboratory will be used to categorize the subject.  This 
information will be presented in summaries of efficacy subgroup analyses. 


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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 genotype 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.  Listing of HCV genotype and subtype will 
be provided separately for central laboratory results and phylogenetic analysis results.
10.8.1
Presence of Baseline Polymorphisms for Subgroup 
Analyses of SVR12
For the efficacy subgroup analyses defined in Section 10.6, any NS3/4A variant and any 
NS5A variant are defined as follows using the subset of signature amino acid positions of 
interest for HCV (Table 9), where baseline variants based on R 15% NGS detection 
threshold are considered.  
For example, all HCV genotype 2 subjects with any baseline variant at amino acid 
positions 155, 156, or 168 will be counted as having any NS3/4A variant at baseline; any 
HCV genotype 2 subjects with any baseline variant at amino acid positions 24, 28, 30, 92, 
or 93 will be counted as having any NS5A variant at baseline.
Table 9.
Amino Acid Positions for Subgroup Analysis
Target
Genotype
Subgroup Amino Acid Positions
(All Variants at These 
Positions are to Be Included)
NS3/4A
1, 2, 3, 4, 5, 6
155, 156, 168
NS5A
1a
28, 30, 31, 93, H58D, E62A
1b
31, 93
2
24, 28, 30, 92, 93
3
24, 28, 30, 31, 58, 93
4
24, 28, 30, 31, 93
5
24, 28, 30, 31, 58, 92, 93
6
24, 28, 30, 31, 58, 92, 93


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The number and percentage of subjects in the ITT and mITT-VF populations will be 
summarized for the presence of baseline resistance- associated variants of: 
1.
Any NS3/4A variant at baseline (yes/no);
2.
Any NS5A variant at baseline (yes/no);
3.
Any NS3/4A variant at baseline or any NS5A variant at baseline (yes/no); 
4.
Both NS3/4A and NS4A variant at baseline (i.e., any NS3/4A variant at baseline 
and any NS5A variant at baseline) (yes/no);
5.
Presence or absence of any variant 
5a. Any NS3/4A variant at baseline only (i.e., without baseline NS5A variants);
5b. Any NS5A variant at baseline only (i.e., without baseline NS3/4A variants); 
5c. Both NS3/4A and NS5A variant at baseline; 
5d. None (i.e., no baseline variant in either NS3/4A or in NS5A at baseline).
10.9
Patient Reported Outcomes
The Kidney Disease Quality of Life (KDQOL36™) instruments will be used to collect 
patient reported outcomes (PROs).  The KDQOL-36 is a disease specific Quality of Life 
instrument to be used in patients with chronic kidney disease.  The KDQOL-36 consists 
of 4 subscales aimed at quantifying both general health and disease specific attributes.  
The subscales include:  the Short Form-12 (a general health subscale SF-12), burden of 
kidney disease, symptoms/problems, and effects of kidney disease.  The results of the 
SF-12 instrument are summarized into the Physical Component Summary (PCS) score 
and the Mental Component Summary (MCS) score.  The raw scores are transformed 
linearly to a range of 0 to 100, with higher scores indicating better health-related Quality 
of Life.2-4
Summary statistics for each protocol-specified visit (number of non-missing observations, 
mean) and for change from baseline to each protocol-specified, post-baseline visit 


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(number of non-missing observations, mean, standard deviation, minimum, maximum) 
will be provided for the KDQOL-36 subscale scores (SF-12 summarized by PCS and 
MCS, burden of kidney disease, symptoms/problems, and effects of kidney disease). 
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 analyses will be performed using the safety population.  Data will be summarized 
overall (across all arms).
11.2
Analysis of Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The actual version of the MedDRA coding dictionary will be 
noted in the clinical study report.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with an onset date that is after the 
first dose of study drug and no more than 30 days after the last dose of study drug.  Events 
where the onset date is the same as the study drug start date are assumed to be treatment-
emergent.  If an incomplete onset date was collected for an AE, the event will be assumed 
to be treatment-emergent, unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term (PT).  The SOCs will 


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be presented in alphabetical order, and the preferred terms will be presented in 
alphabetical order within each SOC.
Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most severe/highest grade incident for the severity tables and most related incident 
for the relationship tables).  Subjects reporting more than one AE within a SOC will be 
counted only once for that SOC.  Subjects reporting more than one AE will be counted 
only once in the overall total.
Adverse Event Overview
An overview of AEs will be presented, consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
G
Any treatment-emergent AE;
G
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (glecaprevir/pibrentasvir);
G
Treatment-emergent AEs of grade 3 or higher;
G
Treatment-emergent AEs of grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (glecaprevir/pibrentasvir);
G
Serious treatment-emergent AEs;
G
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
G
Treatment-emergent AEs leading to discontinuation of study drug;
G
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
G
Serious treatment-emergent AEs leading to discontinuation of study drug;
G
Treatment-emergent AEs leading to interruption of study drug;
G
Treatment-emergent AEs leading to death;
G
Deaths.


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Adverse Events by SOC and PT
The following summaries of AEs by SOC and PT will be generated by treatment arm and 
overall:
G
Treatment-emergent AEs;
G
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (glecaprevir/pibrentasvir);
G
Treatment-emergent AEs of grade 3 or higher;
G
Treatment-emergent adverse events of grade 3 or higher with a "reasonable 
possibility" of being related to DAA (glecaprevir/pibrentasvir);
G
Serious treatment-emergent AEs;
G
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
G
Treatment-emergent AEs leading to discontinuation of study drug;
G
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
G
Serious treatment-emergent AEs leading to discontinuation of study drug;
G
Treatment-emergent AEs leading to interruption of study drug;
G
Treatment-emergent AEs leading to death.
A listing of treatment-emergent AEs grouped by SOC and preferred term with subject 
numbers will be created.
Adverse Events by PT
The number and percentage of subjects experiencing treatment-emergent AEs will be 
tabulated according to PT and sorted by overall frequency in the safety population.  
Similar summaries will be provided for grade 3 or higher treatment emergent AEs, DAA-
related treatment-emergent AEs, DAA-related grade 3 or higher treatment-emergent AEs, 
and DAA-related treatment-emergent serious AEs. 


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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 preferred term.  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.
Adverse Events by Maximum Relationship
Treatment-emergent AEs also will be summarized by maximum relationship of each 
preferred term to study drug (DAAs), as assessed by the investigator.  If a subject has an 
AE with unknown relationship, then the subject will be counted in the relationship 
category of "unknown," even if the subject has another occurrence of the same event with 
a relationship present.  The only exception is if the subject has another occurrence of the 
same AE with a relationship assessment of "Reasonable Possibility."  In this case, the 
subject will be counted under the "Reasonable Possibility" category.
11.2.3
Adverse Events of Special Interest
Adverse events of special interest include the following:
G
Hepatic decompensation/hepatic failure events, identified using the AbbVie 
Product MedDRA Query (PMQ) for Hepatic Decompensation and Hepatic 
Failure.
G
Hepatocellular carcinoma events, identified using the preferred terms 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 


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be presented by SOC and preferred term and across all SOCs/preferred terms.  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
Listings of Adverse Events
The following listings of AEs will be prepared:
G
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
G
Treatment-emergent serious AEs,
G
Treatment-emergent AEs leading to death,
G
Treatment-emergent AEs leading to discontinuation of study drug,
G
Treatment-emergent AEs leading to study drug interruption,
G
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.
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).


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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, total protein, glucose, albumin, chloride, bicarbonate, magnesium, gamma-
glutamyl transferase (GGT), creatinine clearance (calculated using Cockcroft-Gault), and 
eGFR by MDRD.
The definitions of toxicity grades for laboratory parameters are presented in Table 10.


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Table 10.
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
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Absolute Neutrophil 
Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN –
75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 –
25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Creatinine clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Lymphocyte
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Glucose (high)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 –
27.8 mmol/L
> 27.8 mmol/L
Glucose (low)
< 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
aPTT
> ULN – 1.5 × ULN
>1.5 – 2.5 × ULN
> 2.5 × ULN
--
Sodium (low)
< LLN – 130 mmol/L
--
< 130 – 120 mmol/L
< 120 mmol/L
Sodium (high)
> ULN –
150 mmol/L
> 150 – 155 mmol/L
> 155 – 160 mmol/L
> 160 mmol/L
Potassium (low)
< LLN – 130 mmol/L
--
< 130 – 120 mmol/L
< 120 mmol/L
Potassium (high) 
> ULN – 5.5 mmol/L
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L
> 7.0 mmol/L
Magnesium (low)
< LLN – 0.5 mmol/L
< 0.5 – 0.4 mmol/L
< 0.4 – 0.3 mmol/L
< 0.3 mmol/L
Magnesium (high)
> ULN –
1.23 mmol/L
--
> 1.23 –
3.30 mmol/L
> 3.30 mmol/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 


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the time of first dose if time is available.  The same baseline value will be used for 
changes at Treatment Period visits and changes at Post-Treatment Period visits.
Changes from baseline to each post-baseline visit, including applicable post-treatment 
visits, will be summarized.  Each protocol-specified laboratory parameter will be 
summarized with the sample size, baseline mean; visit mean; and change from baseline 
mean, standard deviation, minimum, median, and maximum.
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 
baselineto 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.
The laboratory parameters listed in Table 10 will be assigned a toxicity grade of 1, 2, 3, or 
4.  The number and percentage of subjects with a maximum toxicity grade of 1, 2, 3 or 4 
will be 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 10, 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 10. 
For CKD 3B and 4 subjects at screening, laboratory calculated eGFR by MDRD at 
Screening, EOT, and Post Treatment Week 4 will be summarized by mean, sd, minimum, 
maximum, median and interquartile range as well as by a box-plot. 
CKD categorization at EOT is defined according to eGFR and requirement of dialysis in 
Table 4.  For CKD 3B and 4 subjects at screening, number and percentage of subjects 


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changing in CKD stage (improvement, no change, or decline) between screening and EOT 
will also be summarized and graphed by treatment arm.  For CKD 3B and 4 subjects at 
screening, a listing will be provided for subjects with CKD stage worsening based on any 
eGFR criteria or initiated dialysis treatment during the treatment and post treatment 
period.  A separate listing will also be provided for subjects not on dialysis prior to 
screening while started dialysis post screening. 
Assessment of Hepatic Laboratory Values
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized:
G
Post-nadir (preceding value is lower than the subsequent value) ALT 
> 5 × ULN (regardless of grade change);
G
Total bilirubin R 2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered);
G
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN;
G
Post-nadir ALT > 3 × ULN and total bilirubin O 2 × ULN.
Four listings (one for each bullet above) of all liver function tests including ALT, AST, 
total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.  
Hepatic Laboratory Abnormalities of Interest 
Among the events assessed under "Assessment of Hepatic Laboratory Values," the 
following criteria are of interest:
G
Confirmed post-nadir ALT > 5 × ULN;
G
Post-nadir ALT > 3 × ULN and a concurrent total bilirubin > 2 × ULN with a 
direct bilirubin:total bilirubin ratio > 0.4. 


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


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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 11.
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic Blood Pressure
O 90 mmHg AND A decrease of 
R 20 mmHg from baseline
R 180 mmHg AND An increase of 
R 20 mmHg from baseline
Diastolic Blood Pressure
O 50 mmHg AND A decrease of 
R 15 mmHg from baseline
R 105 mmHg AND An increase of 
R 15 mmHg from baseline
Pulse Rate
O 50 bpm AND A decrease of 
R 15 bpm from baseline
R 120 bpm AND An increase of 
R 15 bpm from baseline
Weight
A decrease of R 15% from 
baseline
An increase of R 15% from 
baseline
Body Temperature
> 38.3°C AND An increase of 
R 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 at Treatment 
Period visits and changes at Post-Treatment Period visits.
Changes from baseline to each post-baseline visit, including applicable post-treatment 
visits, will be summarized.  Each vital sign parameter will be summarized with the 
baseline mean; visit mean; and change from baseline mean, standard deviation, minimum, 
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The number and percentage of subjects with on-treatment values meeting the specified 
criteria for PCS vital sign values (Table 11) 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.
11.5
Analysis of Child-Pugh Score
For subjects with compensated cirrhosis, Child-Pugh scores will be categorized as 5, 6, 
> 6, or missing at baseline and each protocol-specified post-baseline visit, including 
applicable post-treatment visits.  Shift tables from baseline to each post-baseline visit will 
be created for the cirrhotic subjects in the safety population.  The shift tables will cross-
tabulate the frequency of subjects with baseline values in each category versus the post-
baseline categories.  For each baseline category and across the baseline categories, the 
percentage of subjects in each post-baseline category (excluding the post-baseline 
category of missing) will be calculated. 
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP
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.
Hays RD, Kallich JD, Mapes DL, et al.  Development of the kidney disease quality 
of life (KDQOL) instrument.  Qual Life Res.  1994;3(5):329-38.
3.
Hays RD, Kallich JD, Mapes DL, et al.  Kidney disease quality of life short form 
(KDQOL-SFTM), version 1.3:  a manual for use and scoring.  Washington, DC:  
RAND; 1997.


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4.
Ware JE, Kosinski M, Keller SD.  SF-12:  How to score the SF-12 physical and 
mental health summary scales.  Boston, MA:  The Health Institute, New England 
Medical Center, Second Edition, 1995.