Clinical trial NCT03219216
Conditions: Hepatitis C Virus (HCV)
Keywords: Chronic Hepatitis C Virus (HCV) Genotype 1 - 6 Metavir System Fibrosis Score Glecaprevir Pibrentasvir Treatment naïve Cirrhosis Compensated cirrhosis
Sponsor: AbbVie
Start date: 2018-06-06; Completion date: 2019-03-11
Enrollment: 100 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Phase 3, open-label, multicenter study to evaluate the efficacy and safety of glecaprevir (GLE)/pibrentasvir (PIB) for an 8 or 12-week treatment duration in adults in Brazil with chronic hepatitis C virus (HCV) genotype (GT) 1 to GT6 infection, without cirrhosis or with compensated cirrhosis, who were HCV treatment-naïve.

Detailed description:
This was a Phase 3, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB for an 8- or 12-week treatment duration in adults in Brazil with chronic HCV GT1 to GT6 infection, without cirrhosis or with compensated cirrhosis with a METAVIR System Fibrosis Score of F2 to F3 (without cirrhosis) or F4 (with compensated cirrhosis) or equivalent, who were HCV treatment-naïve.

Arms: arm 1: Arm A: Hepatitis C virus (HCV) genotype (GT) 1 to GT6 participants without cirrhosis (fibrosis stage F2 to F3) received glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (QD) for 8 weeks. arm 2: Arm B: HCV GT1 to GT6 participants with compensated cirrhosis (F4) received GLE/PIB 300 mg/120 mg QD for 12 weeks.
Interventions: intervention 1: Glecaprevir/Pibrentasvir
Intervention descriptions: intervention 1: Film-coated tablet

Protocol documents:
Prot_000.pdf: 
Glecaprevir/Pibrentasvir
M16-156 Clinical Study Report
R&D/19/0075
1
16.0
Appendices
16.1
Study Information
16.1__1
Protocol and Protocol Amendments
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 2
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
17 February 2017
Amendment 1
08 November 2017
The purpose of this amendment is to:
●
Update Section 1.0, Title Page and Section 6.1.5, Adverse Event Reporting
Rationale:  Updated contact information to reflect changes on study team.
●
Update Section 1.2, Synopsis
Rationale:  Updated the synopsis to be consistent with the text in the protocol.
●
Update Section 4.1, Primary Objectives and Section 8.1.6, Safety 
Rationale:  Updates were made to safety endpoints to combine results across 
durations as these durations are the approved durations for 
glecaprevir/pibrentasvir.
●
Update Section 5.1, Overall Study Design and Plan:  Description 
Rationale:  Updated the enrollment criteria for GT3 subjects.
●
Update Section 5.2.1, Inclusion Criteria, Inclusion Criterion 7 
Rationale:  Clarified the criterion by specifying the METAVIR equivalent 
fibrosis stage and the Child-Pugh score for F4 subjects.
●
Update Section 5.2.2, Exclusion Criteria, Exclusion Criterion 8 
Rationale:  Clarified the exclusion criterion by removing language that 
applied to subjects with CKD Stage 4 or 5 as this was a typographical error. 
●
Update Section 5.2.2, Exclusion Criteria, Exclusion Criterion 10 
Rationale:  Updated the list to reflect the recent approval of 
glecaprevir/pibrentasvir in Brazil and also to correct the generic name of 
paritaprevir to veruprevir, the denomination approved in Brazil. 
●
Update Section 5.2.3.4, Prohibited Therapy and Section 5.6.4.1.1, GLE and 
PIB Dose and Treatment Duration 
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 2
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Rationale:  Updated the investigational product ABT-493/ABT-530 with 
generic names.
●
Update Section 5.3.1.1, Study Procedures, Hepatitis B, Hepatitis C Virus and 
HIV Screen 
Rationale:  Updated to allow HBV DNA testing at Screening, as needed, to 
exclude occult HCV infection.
●
Update Section 5.3.1.1, Study Procedures, Liver Diagnostic Testing  
Rationale:  Updated to include Child-Pugh classification score for subjects 
with compensated cirrhosis.
●
Update Section 5.3.1.1, Study Procedures, Child-Pugh Score and Category
Rationale:  Clarified the language to state that all subjects with cirrhosis will 
undergo Child-Pugh score assessment at Screening.
●
Update Section 5.3.1.1, Study Procedures, Flow Cytometry, HIV RNA and 
HIV Resistance Testing Samples 
Rationale:  Removed language regarding HIV treatment failure after the use 
of highly active antiretroviral therapy (HAART), as it was a typographical 
error.  HIV treatment failure is defined in Section 5.4.1.2.
●
Update Section 6.1.6, Pregnancy 
Rationale:  Updated the pregnancy language according to align with current 
company standards for Pregnancy follow-up. 
●
Update Section 8.1.4, HCV Resistance Analyses 
Rationale:  Updated the section to include additional analyses being 
performed. 
●
Update Appendix B, List of Protocol Signatories
Rationale:  Updated to reflect changes in signatories.
●
Update Appendix C, Study Activities.
Rationale:  Updated the tables and footnotes to be consistent with the changes 
made in the body of the protocol text.
●
Minor clerical updates/typographical correction made throughout the protocol.
Rationale:  Revised text to correct typographical errors, improve consistency 
and readability throughout the protocol.
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M16-156 Protocol Amendment 2
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An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix F.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 2
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-156
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  02 August 2018
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults in Brazil with Chronic Hepatitis C Virus (HCV) 
Genotype 1 – 6 Infection
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following therapy) and safety of 
GLE/PIB combination in treatment-naïve adults in Brazil with chronic hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis.  The efficacy and 
safety endpoints will be analyzed on the overall population (i.e., across treatment durations and 
genotypes).
!
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by evaluating the 
percentages of subjects with HCV on-treatment virologic failure (OTVF) and HCV virologic 
relapse across treatment durations and genotypes.
Investigators:  Multicenter, single country (Brazil)
Study Sites:  Approximately 14
Study Population:  Chronic HCV GT 1 – 6-infected male and female adults with Metavir equivalent 
fibrosis stage of F2 – F4, at least 18 years of age, without cirrhosis or with compensated cirrhosis, who 
are HCV treatment-naïve (i.e., has never received a single dose of any approved or investigational anti-
HCV medication).
Number of Subjects to be Enrolled: Approximately 100 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB 
combination for an 8 or 12-week treatment duration in adults in Brazil with chronic HCV GT1 – 6 
infection, without cirrhosis (F2 – F3) or with compensated cirrhosis (F4), who are HCV treatment-naïve.  
Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The study enrollment will be 
monitored to meet the following enrollment criteria:  1) a minimum of 35 GT1 and approximately 
25 GT3 subjects and 2) approximately 80 F2 – F3 and a maximum of approximately 20 F4 subjects.
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Methodology (Continued):  
Approximately 100 eligible subjects will be enrolled into one of the following treatment arms:
!
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 and F3) subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of a Screening Period, Treatment Period and Post Treatment Period:
Screening Period:  Subjects will have up to 35 days following the Screening Visit to confirm eligibility 
and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg once daily 
(QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on their cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 4 and 8 for all subjects 
and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment of 
adverse events, vital signs, study medication adherence, concomitant medications, HCV RNA, HCV 
resistance, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks to monitor safety, HCV RNA levels and the emergence and persistence of 
resistance-associated substitutions.
During the Post-Treatment Period, all subjects will have visits at PT Weeks 4 and 12, following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant viral variants will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject has positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
2.
Subject must be documented as without cirrhosis (METAVIR equivalent fibrosis stage of F2 – F3), 
or with compensated cirrhosis (METAVIR equivalent fibrosis stage of F4 with a Child-Pugh score 
≤6).  See Section 5.3.1.1 for Liver Diagnostic Testing and Child-Pugh score and Category.
3.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a positive test result for 
anti-Human Immunodeficiency Virus antibody at Screening and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study), or 
On a stable, qualifying HIV ART regimen for at least 8 weeks prior to Baseline.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at Screening (by the 
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 12 months 
prior to Screening (by an approved plasma HIVRNA quantitative assay including but not limited to:  
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
4.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month prior to 
enrollment, and may be on hemodialysis or peritoneal dialysis.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 2
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
5.
Subjects With Compensated Cirrhosis 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.
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Current HBV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., with negative HBsAg and 
Anti-HBs)
3.
History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug.
4.
Any current or past clinical evidence of Child-Pugh B or C classification (score of > 6) or any current 
or past clinical history of liver decompensation including ascites on physical exam, hepatic 
encephalopathy or variceal bleeding.  Prophylactic use of beta blockers is not exclusionary (see 
Section 5.3.1.1).
5.
Laboratory parameters exclusions:
!
ALT > 10 × ULN; AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL 
!
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
!
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with compensated cirrhosis) 
6.
Receipt of any investigational or commercially available anti-HCV agents including, but not limited 
to:  interferon, pegylated interferon, ribavirin, sofosbuvir, telaprevir, boceprevir, simeprevir, 
asunaprevir, veruprevir, glecaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
voxilaprevir, velpatasvir, pibrentasvir, or dasabuvir.
Investigational Products:
Glecaprevir/Pibrentasvir 100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food.
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects without cirrhosis will receive GLE/PIB for 8 weeks, while subjects 
with compensated cirrhosis will receive GLE/PIB for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
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Criteria for Evaluation (Continued):
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Patient Reported Outcomes (PROs):
The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the functional health 
and well-being of subjects.  The Treatment Satisfaction Questionnaire (TSQM) will be used to assess 
treatment satisfaction with the GLE/PIB combined regime.  EuroQol-5 Dimensions-3 Level (EQ-5D-3L) 
is a health state utility instrument that evaluates preference for health status (utility); subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS).
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline substitutions 
relative to the corresponding baseline sequence in available samples.
Pharmacokinetic:  
Individual plasma concentrations of GLE, PIB, 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) across all genotypes (GT1 – 6 subjects) and treatment 
groups.  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, in which case the Wilson's score method will be used to calculate the 
confidence interval.
The secondary efficacy endpoints are:
!
The percentage of subjects with OTVF.
!
The percentage of subjects with post-treatment HCV virologic relapse.
Subgroup analysis based on the treatment arm (i.e., without cirrhosis/with compensated cirrhosis) will be 
performed.  For the secondary efficacy endpoints and subgroup analysis, the two-sided 95% confidence 
interval will be calculated using Wilson's score method.  
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures for 
SF-36 and EQ-5D-3L will be summarized.  Summary measures at each applicable visit will be 
summarized for the TSQM.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 2
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Statistical Methods (Continued):
Safety:  
Safety summaries will be provided 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.  
Resistance:
For all subjects receiving study drug, baseline polymorphisms at signature resistance-associated amino 
acid positions identified by next generation sequencing (NGS) and comparison to the appropriate 
prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the 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.
Pharmacokinetic:
Individual plasma concentrations of GLE, PIB, and their possible metabolites will be tabulated and 
summarized.
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADC
AIDS-Defining Conditions
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Anti-HBc
Anti-Hepatitis B core antibody
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
ART
Antiretroviral therapy
AUC
Area under the plasma concentration-time curve
BMI
Body mass index
BUN
Blood urea nitrogen
CKD
Chronic kidney disease
CL/F
Apparent oral plasma clearance
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed tomography
Ctrough
Pre-dose trough plasma concentration
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EQ-5D-3L
EuroQol-5 Dimensions-3 Level
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HAART
Highly active antiretroviral therapy
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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
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
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
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS5A
Nonstructural viral protein 5A
OTVF
On-treatment virologic failure
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
PK
Pharmacokinetic
POR
Proof of receipt
P/R
pegIFN/RBV
PRO
Patient reported outcome
PT
Post-Treatment
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QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SF-36v2
Short Form 36 – Version 2 Health Survey
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
TE
Treatment Experienced
TN
Treatment-naïve
TSQM
Treatment Satisfaction Questionnaire-Medicine
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
WOCBP
Women of child bearing potential
Definition of Terms
Study Drug
glecaprevir/pibrentasvir
Study Day 1
First day of study drug dosing 
Treatment Period
Day 1 through last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 12 or 
Post-Treatment Discontinuation
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 10
2.0
Table of Contents ................................................................ 13
3.0
Introduction......................................................................... 18
3.1
Differences Statement .......................................................................... 28
3.2
Benefits and Risks................................................................................ 29
4.0
Study Objective ................................................................... 29
4.1
Primary Objectives............................................................................... 29
4.2
Secondary Objectives ........................................................................... 30
5.0
Investigational Plan............................................................. 30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.1.1
Screening Period .................................................................................. 31
5.1.1.1
Rescreening.......................................................................................... 32
5.1.2
Treatment Period.................................................................................. 33
5.1.3
Post-Treatment Period.......................................................................... 34
5.2
Selection of Study Population............................................................... 34
5.2.1
Inclusion Criteria.................................................................................. 34
5.2.2
Exclusion Criteria................................................................................. 37
5.2.3
Prior and Concomitant Therapy............................................................ 39
5.2.3.1
Prior HCV Therapy .............................................................................. 40
5.2.3.2
Prior and Concomitant HIV Therapy .................................................... 40
5.2.3.3
Concomitant Therapy........................................................................... 40
5.2.3.4
Prohibited Therapy............................................................................... 41
5.2.4
Contraception Recommendations ......................................................... 42
5.3
Efficacy, Pharmacokinetic, and Safety Assessments/Variables ............. 43
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 43
5.3.1.1
Study Procedures.................................................................................. 43
5.3.1.2
Meals and Dietary Requirements.......................................................... 55
5.3.2
Drug Concentration Measurements....................................................... 55
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5.3.2.1
Collection of Samples for Analysis....................................................... 55
5.3.2.2
Handling/Processing of Samples........................................................... 55
5.3.2.3
Disposition of Samples......................................................................... 55
5.3.2.4
Measurement Methods ......................................................................... 56
5.3.3
Efficacy Variables................................................................................ 56
5.3.3.1
Primary Variable .................................................................................. 56
5.3.3.2
Secondary Variables............................................................................. 56
5.3.3.3
HCV Resistance Variables.................................................................... 56
5.3.4
Safety Variables ................................................................................... 57
5.3.5
Pharmacokinetic Variables ................................................................... 57
5.4
Removal of Subjects from Therapy or Assessment ............................... 57
5.4.1
Discontinuation of Individual Subjects ................................................. 57
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 58
5.4.1.2
Failure to Maintain HIV Virologic Suppression.................................... 59
5.4.2
Discontinuation of Entire Study............................................................ 60
5.5
Treatments ........................................................................................... 60
5.5.1
Treatments Administered...................................................................... 60
5.5.2
Identity of Investigational Products ...................................................... 61
5.5.2.1
Packaging and Labeling........................................................................ 61
5.5.2.2
Storage and Disposition of Study Drug................................................. 61
5.5.3
Method of Assigning Subjects to Treatment Groups............................. 62
5.5.4
Selection and Timing of Dose for Each Subject .................................... 62
5.5.5
Blinding ............................................................................................... 62
5.5.6
Treatment Compliance ......................................................................... 63
5.5.7
Drug Accountability ............................................................................. 63
5.6
Discussion and Justification of Study Design........................................ 64
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 64
5.6.2
Appropriateness of Measurements........................................................ 65
5.6.3
Suitability of Subject Population .......................................................... 65
5.6.4
Selection of Doses in the Study ............................................................ 65
5.6.4.1
Rationale for Dose Selections............................................................... 65
5.6.4.1.1
GLE and PIB Dose and Treatment Duration......................................... 66
6.0
Complaints........................................................................... 67
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6.1
Medical Complaints ............................................................................. 67
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...................................................................... 72
6.1.6
Pregnancy............................................................................................. 74
6.1.7
Toxicity Management........................................................................... 75
6.1.7.1
Management of Increases in ALT......................................................... 75
6.1.8
Collection of Data Regarding Known AIDS-Defining Conditions ........ 76
6.2
Product Complaint................................................................................ 76
6.2.1
Definition............................................................................................. 76
6.2.2
Reporting ............................................................................................. 76
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................................................................................................ 79
8.1.2.1
Primary Efficacy Endpoints.................................................................. 80
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 80
8.1.2.3
Sensitivity Analysis.............................................................................. 81
8.1.2.4
Subgroup Analysis ............................................................................... 81
8.1.2.5
Additional Efficacy Endpoints.............................................................. 82
8.1.3
Patient Reported Outcomes .................................................................. 82
8.1.4
HCV Resistance Analyses .................................................................... 83
8.1.5
HIV Resistance Analyses ..................................................................... 86
8.1.6
Safety................................................................................................... 87
8.1.6.1
Adverse Events..................................................................................... 87
8.1.6.2
Clinical Laboratory Data ...................................................................... 87
8.1.6.3
Vital Signs Data ................................................................................... 87
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8.1.6.4
HCV/HIV Co-Infection ........................................................................ 88
8.1.7
Pharmacokinetic and Exposure-Response Analyses.............................. 88
8.2
Determination of Sample Size .............................................................. 89
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 ..........................................................................91
10.1
Source Documents................................................................................ 91
10.2
Case Report Forms............................................................................... 92
11.0
Data Quality Assurance ...................................................... 93
12.0
Use of Information .............................................................. 93
13.0
Completion of the Study ..................................................... 93
14.0
Investigator's Agreement....................................................95
15.0
Reference List...................................................................... 96
List of Tables
Table 1.
Overview of Clinical Studies by Subject Population ............................. 21
Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype –
GT1 – 6 (ITT Population, Phase 2 and 3 Analysis Set) ......................... 23
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)........................................................................................ 26
Table 4.
Prohibited Medications and Supplements ............................................. 41
Table 5.
Clinical Laboratory Tests ..................................................................... 46
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 49
Table 7.
Identity of Investigational Products ...................................................... 61
Table 8.
Recommended GLE/PIB Duration for TN Patients............................... 66
Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)................................... 67
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List of Figures
Figure 1.
Study Design........................................................................................ 31
Figure 2.
Adverse Event Collection..................................................................... 72
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.......................................... 98
Appendix B.
List of Protocol Signatories .................................................................100
Appendix C.
Study Activities – Treatment Period ....................................................101
Appendix D.
Study Activities – Post-Treatment (PT) Period ....................................104
Appendix E.
List of AIDS-Defining Conditions.......................................................106
Appendix F.
Protocol Amendment:  List of Changes ...............................................108
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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 
184 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype 1 (GT1) being the most prevalent worldwide.  HCV genotypes 2 (GT2) and 3 
(GT3) infections are more common in Latin America (5% to 30%), Europe (20% to 40%) 
and Asia (30% to 45%).2-4  HCV GT4 is commonly found in parts of Africa and the 
Middle East, particularly in Egypt, GT5 is primarily found in South Africa, and GT6 is 
primarily found in south-east Asia, and GT7 has recently been described in Central 
Africa.5  Genotype 1 (GT1) is the most frequent in all regions in Brazil (65%), followed 
by genotype 3 (30%) and GT2 (5%).  Genotypes 4 to 6 are rarely reported (0.3%) in 
Brazil.6
Depending on various risk factors, between 10% and 40% of all patients with chronic 
HCV infection will develop cirrhosis.  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.  Patients 
diagnosed with hepatocellular carcinoma 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 hepatocellular 
carcinoma.8,9
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF plus simeprevir [SMV], SOF plus daclatasvir 
[DCV], ombitasvir [OBV]/veruprevir/ritonavir [r] ± dasabuvir [DSV], elbasvir 
[EBR]/grazoprevir [GZR], and SOF/velpatasvir [VEL]).10,11  In Brazil, the National HCV 
Program provides specific regimens to a subset of subjects with confirmed HCV and 
specific GT infection.  The mono HCV infected subjects must have confirmed Metavir F3 
and F4 fibrosis stage, and the HCV/HIV co-infected should be treated regardless of liver 
fibrosis staging.  A treatment guideline recommends SOF + DCV or SOF + SMV for 
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GT1; SOF + RBV for GT2; SOF + pegIFN or SOF + DCV for GT3; and SOF + pegIFN + 
RBV or SOF + DCV for GT4.  Duration of treatment is based on history of monoinfection 
with HCV, or co-infection with HIV, GT subtype and fibrosis staging.  These regimens 
are available across the country and prescribed free of charge within the country's 
universal health care system.  
However, these approved and recommended regimens are not equally potent across all 
HCV genotypes and subpopulations.  Additional limitations of several current regimens 
include the requirement of ribavirin (RBV) for certain populations, significant drug to 
drug interactions, limited options for subjects with renal insufficiency, reduced efficacy in 
patients with baseline amino acid polymorphisms associated with reduced susceptibility to 
the HCV nonstructural 5A (NS5A) inhibitors or NS3/4A protease inhibitors (PI), and 
limited options for patients who have failed regimens containing an NS5A inhibitor 
and/or PI.  Efficacy in GT3-infected patients, particularly those who are treatment-
experienced (TE) and/or cirrhotic, is also substantially lower than what is observed for 
other genotypes.12
AbbVie has developed two "next generation" DAAs, glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5A inhibitor, for use in combination for the treatment of HCV.  GLE and PIB each 
has potent in vitro antiviral activity against genotypes 1 through 613 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.14
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GLE/PIB
Overview of GLE/PIB Registrational Program and Supportive Phase 2 Studies
The GLE/PIB registrational program included a broad subject population including 
subjects with compensated liver disease and subjects with severe renal insufficiency 
across GT1 – 6 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, SOF, NS5A inhibitors, or PIs were allowed 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 treatment-naïve (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 compensated cirrhosis, or HIV 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 ≥ 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 in NS3 and NS5A 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, data was analyzed at the 15% detection threshold, and baseline 
polymorphisms at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 
92, and 93 in NS5A were examined for impact on SVR12. 
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 did not have an impact on 
treatment outcome.  The NS5A polymorphisms at positions 24, 28, 31, 58, 92, or 93 
(including Y93H) did not have an impact on treatment outcome, whereas the A30K 
polymorphism was associated with a slightly decreased SVR12 rate.  Given the low 
prevalence of A30K (6.3%; 39/615) and that the majority of subjects with A30K achieved 
SVR12, its impact on overall SVR is expected to be minimal.
Amino Acid Substitutions in Subjects Experiencing Virologic Failure
Among TN and TE-PRS subjects without cirrhosis or with compensated cirrhosis treated 
for 8, 12, or 16 weeks, 23 subjects experienced virologic failure (2 with GT1, 2 with GT2, 
and 19 with GT3).  A GT3-infected subject experiencing virologic failure was determined 
to have been reinfected with GT3a virus distinct from the one present at baseline.  
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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 
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 
substitutions 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.  Given 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.
As shown in Table 3, AEs occurring with a  frequency > 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 ≥ 3 were low.  Including 
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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. 
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related Adverse 
Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade ≥ 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Term
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.
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 compensated 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 
(≥ 65 years old, n = 328) was comparable to the safety profile in the non-elderly 
population (n = 2,041).
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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 (n = 104) in Study M15-462 was consistent 
with underlying severe renal impairment 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.15  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.  No safety signal or toxicity related to 
GLE/PIB specific to subjects with CKD Stage 4 and 5 has been identified.
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 (excluding Study M15-462).  Liver-related safety results indicated that:
●
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
○
ALT abnormalities in 3 of these 4 subjects were not clinically significant
○
One subject experienced concurrent ALT > 3 × ULN (increased from nadir 
grade) and total bilirubin ≥ 2 × ULN in the context of multiple gallstones 
that was not consistent with drug-induced liver injury
●
Based on exposure-response analyses, no GLE/PIB exposure-dependent ALT 
increases were observed in subjects with ALT abnormalities
●
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression
●
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.
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●
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.  
●
There were no cases consistent with drug-induced liver injury.
In summary, GLE/PIB demonstrated a favorable safety profile that was 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 compensated cirrhosis, HIV co-
infection, and CKD Stage 4 or 5.
Common GLE/PIB-related AEs (ADRs) occurring in ≥ 5% of subjects were headache, 
fatigue, nausea.  Adverse drug reactions 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 
to be related to treatment.  Unlike other protease inhibitors, no liver-related toxicities and 
no cases consistent with drug-induced liver injury were identified.  
3.1
Differences Statement
The GLE/PIB fixed dose combination for 8 and 12 weeks was explored in treatment-naïve 
and -experienced HCV GT1 – 6 infected subjects, without cirrhosis or with compensated 
cirrhosis including subjects with HIV/HCV co-infection and subjects with CKD Stage 4 
or 5 in several Phase 3 studies conducted in a randomized, controlled, double-blind or 
open-label fashion. 
This is the first Phase 3b study designed to evaluate HCV GT1 – 6 treatment-naïve 
subjects without cirrhosis (Metavir F2 – F3) and with compensated cirrhosis (Metavir F4) 
treated with GLE/PIB for 8 or 12 weeks, respectively, in Brazil.  This country did not 
participate in the Global GLE/PIB program.
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3.2
Benefits and Risks
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation DAA protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment for NS5A inhibitor and PI naive, and the convenience of a once 
daily regimen.  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 
show high SVR12 rates among subjects with HCV GT 1 – 6 infection who receive 
treatment with GLE/PIB.
Adverse events that are known, and those not previously identified, may occur with 
GLE/PIB as detailed in the informed consent of this study.  In addition, subjects may 
experience inconvenience or discomfort related to the study visits or study procedures.  
Additional safety data for each DAA alone and the combination of PIB/GLE are detailed 
in Section 3.0 and in the Investigator's Brochure.14
Risks associated with GLE/PIB, including the risks of adverse reactions, virologic failure, 
and development of resistance-associated substitutions (Section 5.3.4), appear to be 
limited and manageable based upon the available data.  Given the potential for high 
SVR12 rates in populations of HCV-infected subjects, including HIV/HCV co-infected, 
and with CKD 4 – 5, the risk-benefit profile for GLE/PIB is favorable.
4.0
Study Objective
4.1
Primary Objectives
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following 
therapy) and safety of GLE/PIB combination in treatment-naïve adults in Brazil with 
chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection without cirrhosis or with 
compensated cirrhosis.  The efficacy and safety endpoints will be analyzed on the overall 
population (i.e., across treatment durations and genotypes).
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4.2
Secondary Objectives
The secondary objectives are to assess efficacy of GLE/PIB based on overall population 
(i.e., across treatment durations and genotypes) by evaluating the following:
●
The percentages of subjects with HCV on-treatment virologic failure (OTVF);
●
The percentages 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, multicenter study to evaluate the efficacy and safety of 
GLE/PIB for an 8- or 12-week treatment duration in adults in Brazil with chronic HCV 
GT1 – 6 infection, without cirrhosis or with compensated cirrhosis with a METAVIR 
System Fibrosis Score of F2, F3 or F4 (F2-F4) or equivalent,16 who are HCV treatment-
naïve.  Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The 
study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of 35 GT1 and approximately 25 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
This study will consist of a Screening Period, a Treatment Period and a Post-Treatment 
Period.
Screening Period:  Subjects will have up to 35 days following the Screening Visit to 
confirm eligibility and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg 
once daily (QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on 
cirrhosis status.
Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment 
Period will be followed for 12 weeks to monitor HCV RNA levels to evaluate efficacy 
and the emergence and persistence of resistance-associated substitutions.
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A study schematic is shown below in Figure 1. 
Figure 1.
Study Design
*
The study enrollment will be monitored to meet the following  enrollment criteria:  1) a minimum of 
approximately 35 GT1 and 25 GT3 subjects and 2) approximately 80 F2 – F3 and a maximum of 
approximately 20 F4 subjects.
Approximately 100 eligible subjects will be enrolled into one of the following treatment 
arms:
●
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 – F3) subjects will be treated 
with GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks. 
●
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be 
treated with GLE/PIB 300 mg/120 mg once daily (QD) for 12 weeks.
The study was designed to enroll approximately 100 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening may 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 
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 
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record the results of this assessment and the details of the informed consent process in the 
subject's medical records.  Eligible subjects have up to 35 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
A positive Hepatitis B surface antigen (HBsAg);
●
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative 
HBsAg and Anti-HBs); or
●
If Woman of Childbearing Potential (WOCBP), a positive serum pregnancy 
test;
●
Development of decompensated liver disease during the screening period, as 
defined by the Exclusion Criterion 6.
Otherwise subjects may be retested or rescreened only once unless approved by the 
Primary Therapeutic Area Medical Director.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on any panel that is 
repeated.  If any of the retest result(s) are exclusionary, the subject may not be rescreened 
again.
Subjects that exceed the initial 35 day screening period should be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary during the 
first screening attempt (with the exception of HIV, HBV, HCV genotype and subtype, 
follicle stimulating hormone (FSH), which do not need to be repeated).  The FibroScan 
and liver biopsy do not need to be repeated for rescreened subjects provided that the date 
of the liver biopsy is within 24 months of the rescreening date and the FibroScan is within 
6 months of the rescreening date (Section 5.1.1).
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Subjects who rescreen or subjects not meeting the study eligibility criteria must be 
identified by site personnel as a screen failure in both IRT and EDC systems.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT on Study Day 1.  
Subjects will be administered study drug at the site on Study Day 1, and provided 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 5.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3 and Section 5.3.1.1.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out 
of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
HCV virologic failure criteria will be evaluated and applied by the investigator as detailed 
in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.4.1.  Subjects who prematurely discontinue 
from study treatment will continue to be followed in the Post-Treatment Period (see 
Section 5.1.3).
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5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug will be monitored in the 
Post-Treatment Period for 12 weeks following the last dose of study drug for safety, HCV 
RNA, and the emergence and persistence of HCV resistance-associated substitutions.
The Post-Treatment Period will begin the day following the last dose of study drug.  
Study visits during the Post-Treatment period are detailed in Appendix D and 
Section 5.3.1.1.
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a Post-Treatment discontinuation visit as outlined in Appendix D.
5.2
Selection of Study Population
The study population consists of male and female adults aged 18 years or older with 
chronic HCV GT1 – 6 infection with METAVIR equivalent fibrosis stage of F2 – F4 
(without cirrhosis or with compensated cirrhosis) who are HCV treatment naïve 
(i.e., subject has never received a single dose of any approved or investigational anti-HCV 
medication).  Subjects with HIV/HCV co-infection and subjects at all CKD stages (CKD 
Stages 1 – 5) are allowed to participate.17  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
1.
Male or female, at least 18 years of age at time of Screening.
2.
If female, subject must be either 
Postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L; or
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●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
OR
●
A WOCBP practicing at least one protocol specified method of birth control 
(Section 5.2.4), starting at Study Day 1 (or earlier) 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 pregnancy test at Study Day 1.
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy testing.
4.
Screening laboratory result indicating HCV GT1-, 2-, 3-, 4-, 5- and/or 6-infection.  
Mixed and indeterminate genotypes are acceptable.
5.
Subject has positive plasma HCV antibody and HCV RNA viral load 
≥1000 IU/mL at Screening Visit.
6.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a 
positive test result for anti-Human Immunodeficiency Virus antibody at Screening 
and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to 
initiate ART treatment while participating in this study), or on a stable, qualifying 
HIVART regimen for at least 8 weeks prior to Baseline.  (Substituting TDF for 
TAF as part of the combination regimen is allowed at any time.)
The HIVART regimen must include at least one of the following ARV agents:
●
Raltegravir (RAL)
●
Dolutegravir (DTG)
●
Rilpivirine (RPV)
●
Elvitegravir/cobicistat (EVG/COBI)
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In addition to the above medications, HIV Ab positive subjects (both without 
cirrhosis or with compensated cirrhosis) may take a nucleoside/nucleotide reverse 
transcriptase inhibitor (N(t)RTI) backbone containing any of the following:
●
Tenofovir disoproxil fumarate (TDF)
●
Tenofovir alafenamide (TAF)
●
Abacavir (ABC)
●
Emtricitabine (FTC)
●
Lamivudine (3TC)
Subjects receiving any other HIV ART in addition to those noted above are not 
eligible for enrollment in the study.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at 
Screening (by the COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and 
at least once during the 12 months prior to Screening (by an approved plasma 
HIVRNA quantitative assay including but not limited to:  COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
7.
Subject must be documented as without cirrhosis (METAVIR equivalent fibrosis 
stage of F2 – 3), or with compensated cirrhosis (METAVIR equivalent fibrosis 
stage of F4 with a Child-Pugh score of ≤ 6).  See Section 5.3.1.1 for Liver 
Diagnostic Testing and Child-Pugh Score and Category.
8.
Subjects with compensated cirrhosis 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.
9.
Subject must voluntarily sign and date an informed consent form, approved by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the 
initiation of any Screening or study specific procedures.
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10.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
11.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month 
prior to enrollment, and may be on hemodialysis or peritoneal dialysis.
Rationale for Inclusion Criteria
1, 4 – 11
In order to select the appropriate subject population with 
appropriate disease characteristics for evaluation
2, 3
The impact of GLE and PIB on human pregnancies has not been 
established.  However, assessment of the completed nonclinical 
reproductive toxicology studies indicates that there is no 
drug-related effect on teratogenicity/fetotoxicity.  In addition, the 
compounds are non-genotoxic
10
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
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 infection on screening tests, defined as:
●
A positive HBsAg, or;
●
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., with 
negative HBsAg and Anti-HBs)
3.
Requirement for and inability or unwillingness to safely discontinue the 
medications or supplements listed in Table 4 at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of any study drug.
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4.
Requirement for chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
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.
Any current or past clinical evidence of Child-Pugh B or C classification (score of 
> 6) or any current or past clinical history of liver decompensation including ascites 
on physical exam, hepatic encephalopathy or variceal bleeding.  Prophylactic use 
of beta blockers is not exclusionary (see Section 5.3.1.1).
7.
Laboratory parameters exclusions:
●
ALT > 10 × ULN; AST > 10 × ULN
●
Total Bilirubin > 3.0 mg/dL 
●
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
●
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with 
compensated cirrhosis)
8.
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.  
9.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks (whichever is longer) prior to 
study drug administration.
10.
Receipt of any investigational or commercially available anti-HCV agents, 
including, but not limited to:  interferon, pegylated interferon ribavirin, sofosbuvir, 
telaprevir, boceprevir, simeprevir, asunaprevir, veruprevir, glecaprevir, 
grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, voxilaprevir, velpatasvir, 
pibrentasvir, or dasabuvir.
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11.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
12.
Treatment for an AIDS-Defining Conditions (ADC) (Appendix E) within 6 months 
of Screening.
13.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 3, 4, 6 – 13
In order to ensure safety of the subjects throughout the study
2, 5
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
the consent through the Treatment Period and 30 days after study drug is stopped, must be 
recorded in the electronic case report form (eCRF) along with the reason for use, date(s) 
of administration including start and end dates, and dosage information including dose, 
route, and frequency.  The investigator should review all concomitant medications for any 
potential drug-drug 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 Primary Therapeutic Area Medical Director should be contacted if 
there are any questions regarding concomitant or prior therapies.
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5.2.3.1
Prior HCV Therapy
Subjects must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication). 
5.2.3.2
Prior and Concomitant HIV Therapy
Subject on an HIV ART regimen must include ARV agents as defined in Inclusion 
Criterion 6 (Section 5.2.1).
Subjects will maintain the same dose and dosing interval of their HIV ART regimen upon 
initiating the study drugs regimen.
Subjects must remain on the same HIV ART regimen for the entire Treatment Period.  
Any change to an allowed HIV ART regimen during the Treatment Period must be 
discussed with the AbbVie TA MD prior to the change, unless the change is being made 
to address an immediate safety concern. 
Subjects receiving any other HIV ART in addition to those listed in Inclusion Criterion 6 
(Section 5.2.1) would not be eligible for enrollment in the study.
5.2.3.3
Concomitant Therapy
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions.  
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drugs, if applicable.
Flu shots and other vaccinations are allowed during Screening through the Post-Treatment 
Period for all subjects.  Flu shots and vaccinations may affect plasma HIV RNA levels.
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5.2.3.4
Prohibited Therapy
Medications or supplements prohibited to be administered with GLE/PIB 
(glecapravir/pibrentasvir) are listed in Table 4.  Since GLE/PIB has received marketing 
authorization in Brazil, any medications in the local label that are contraindicated to be 
administered with GLE/PIB are also considered to be prohibited medications.  Subjects 
must be able to safely discontinue any prohibited medications or supplements at least 
14 days or 10 half-lives (whichever is longer) prior to the first dose of any study drug and 
not use these during the entire Treatment Period and for 14 days following 
discontinuation of study drugs.
Table 4.
Prohibited Medications and Supplements
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, efavirenz, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with
the study drug.  After signing the informed consent form, subjects receiving these statins should either (a) switch to 
pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug 
or (b) interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives (whichever 
is longer) prior to the first dose of study drug until 14 days after the last dose of study drug, based on investigator's 
judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to either 1) reduce or limit 
the pravastatin or rosuvastatin dose in accordance with the GLE/PIB (glecapravir/pibrentasvir) product label (if 
approved in the country); or 2) reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD 
when taking with the study drug if GLE/PIB is not yet approved in the country.
Contraceptives and/or hormonal replacement therapies containing only 
progestins/progestogens (such as those containing norethindrone, desogestrel, or 
levonorgestrel) or those containing progestins/progestogens with non-ethinyl estradiol 
estrogens (e.g., esterified or conjugated) may be used with GLE/PIB at the discretion of 
the Investigator.
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The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 
not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
For HCV/HIV coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 2 weeks prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 30 days following discontinuation of study drugs.  
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:
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
●
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.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.
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●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptom-thermal, post-ovulation methods] and 
withdrawal are not acceptable).
For male study subjects, no contraception is required.
5.3
Efficacy, Pharmacokinetic, 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 (Treatment Period) and Appendix D
(Post-Treatment Period).
5.3.1.1
Study Procedures
Informed Consent
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco, alcohol and drug use, will be 
taken from each subject at Screening Visit.  The subject's medical history will be updated 
at the Study Day 1 Visit.  This updated medical history will serve as the baseline for 
clinical assessment.
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Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Height will be measured only at Screening.  
Vital Signs and Weight
Body temperature, blood pressure, pulse, and body weight will be measured at each study 
visit as specified in Appendix C and Appendix D.  Blood pressure and pulse rate should 
be measured after the subject has been sitting for at least 3 minutes.  The subject should 
wear lightweight clothing and no shoes during weighing.  The vital signs performed on 
Day 1 of the Treatment Period will serve as the baseline for clinical assessment.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at the visits indicated in Appendix C.  The ECG 
should be performed prior to blood collection.
The ECG will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
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Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 5
at the visits indicated in Appendix C and Appendix D.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast prior to study drug intake (with the exception of the Screening Visit, which may be 
non-fasting).  Subjects whose visits occur prior to the morning dose of study drug should 
be instructed to fast after midnight until the blood sample is collected in the morning and 
thereafter take their study medications with food.  Subjects whose visits occur following 
the morning dose of study drug should be instructed to fast after breakfast until the study 
visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug.  Blood samples should still be drawn if the subject did not fast 
for at least 8 hours.  Fasting or non-fasting status will be recorded in the source 
documents and on the laboratory requisition.  The baseline laboratory test results for 
clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
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 address:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
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Table 5.
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)
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine transaminase (ALT)
Aspartate transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)
Anti-HCV Aba
HCV RNA
HCV genotype and subtypea
HIV Aba
HIV RNAb
Hepatitis B Panel (Anti-HBc
Total, Anti-HBs and HBsAg)c
Anti-HBc IgMc
Anti-HBc Totalc
Anti-HBsc
Anti-HAV
IgMd
Anti_HAV Totald
Anti-HEV IgGd
Anti-HEV IgMd
HEV RNAd
HBV DNAe
Follicle Stimulating Hormone 
(FSH)f
Urine and Serum
Human Chorionic 
Gonadotropin (hCG) for 
femalesg
Alpha2-macroglobulinh
Haptoglobinh
Apolipoprotein A1h
CD4, CD4%b
CD8, CD8%b
CD4:CD8b
a.
Performed only at Screening.
b.
Only for known HCV/HIV co-infected subjects.
c.
Performed at Screening for all subjects and also performed for management of transaminase elevations 
(Section 6.1.7.1). 
d.
Performed for management of transaminase elevation (Section 6.1.7.1).
e.
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).
f.
Only performed if requested during screening for post-menopausal women < 55 to verify FSH level if site does not 
have a previous result available.
g.
Required only for females of child bearing potential.
h.
Component of FibroTest and collected only if required for FibroTest calculation during the Screening Period.
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For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug or requires a subject to receive treatment will be recorded 
as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.1.7.
Pregnancy Testing
●
WOCBP must have a negative serum pregnancy test result at Screening, and a 
negative urine pregnancy test at Study Day 1.  
●
Monthly pregnancy testing should be performed during treatment, including at 
the last dose and until 30 days of last study drug dose, as indicated in 
Appendix C and Appendix D.  
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result. 
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in inclusion criterion #2) at Screening do not 
require pregnancy testing.
Concomitant Medication Assessment
Please refer to Section 5.2.3.2.
Hepatitis B, Hepatitis C Virus and HIV Screen
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab testing will be performed 
at Screening.  HBV DNA testing may be performed to exclude occult HBV infection.  
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The investigator must discuss any local reporting requirements to local health agencies 
with the subject.  The site will report these results per local regulations, if necessary.  The 
HIV results will not be reported by the central laboratory to the clinical database.
Liver Diagnostic Testing
Subjects will be considered to be without cirrhosis or with cirrhosis based on the 
definitions below:
Without Cirrhosis (F2 and F3)
●
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 2 – 3, Ishak fibrosis score of 3 or 4; or
●
A FibroScan® score of 8.8 to < 12.5 kPa within ≤ 6 months of Screening or 
during Screening period (FibroScan® must be approved by the local regulatory 
agency to qualify for entrance criteria); or
●
A Screening FibroTest score of 0.49 to 0.72 (inclusive).18
With Cirrhosis (F4)
●
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3, Ishak 
score of > 4 or on a liver biopsy conducted during Screening; or
●
A FibroScan® score of ≥ 12.5 kPa within ≤ 6 months of Screening or during 
Screening period (FibroScan® must be approved by the local regulatory agency 
to qualify for entrance criteria); or
●
A Screening FibroTest result that is ≥ 0.73.
The result of the liver biopsy supersedes the results of FibroScan and FibroTest and result 
of FibroScan supersedes the results of FibroTest.  At Screening, it is recommended that 
subjects should otherwise meet all other inclusion criteria and none of the exclusion 
criteria before undergoing a liver biopsy.
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Subjects with cirrhosis will be defined as having compensated cirrhosis if the Child-Pugh 
Score at screening is ≤ 6.
Child-Pugh Score and Category
All subjects with cirrhosis will have Child-Pugh scores assessed at screening.  The 
Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters and 
2 clinical assessments) as shown in Table 6.  Child-Pugh score will be determined at the 
visits indicated in Appendix C and Appendix D.
Table 6.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites**
None
Slight
Moderate to severe
Hepatic encephalopathy*
None
Grade 1 or 2 (or suppressed 
with medication)
Grade 3 or 4 (or 
refractory)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points.
*
None:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
** None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites, as defined in Exclusion 
Criterion #6, 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 
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compensated cirrhosis.  Subjects who present symptoms and signs of hepatic 
decompensation, including assessment at Day 1 prior to receiving study drug, will neither 
be dosed nor enrolled into the trial.
Hepatocellular Carcinoma Screening:  Liver Ultrasound
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Visit and at the last Post-Treatment Study Visit, as indicated in Appendix C
and Appendix D, for subjects with compensated cirrhosis only.  In-between those visits, 
HCC screening should be performed according to standard of care.
At the Screening Visit and at the last Post-Treatment Study Visit, subjects with 
compensated cirrhosis will be required to undergo a liver ultrasound to screen for HCC, 
unless the subject has a historical liver ultrasound, CT scan or MRI performed for HCC 
screening within 3 months prior to those visits, in which case the result of the historical 
ultrasound, CT scan or MRI will be used as the result for the Study Visit assessment.  A 
positive ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  
Alternate methods of screening for HCC (i.e., CT scan or MRI) at a study visit should be 
discussed with the study designated physician.
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments on the study visits 
specified in Appendix C and Appendix D.  Subjects should be instructed to follow the 
instructions provided with each instrument and to provide the best possible response to 
each item.  Site personnel shall not provide interpretation or assistance to subjects other 
than encouragement to complete the tasks.  Subjects who are functionally unable to read 
any of the instruments may have site personnel read the questionnaires to them.  Site 
personnel should encourage completion of each instrument at all specified visits and 
should ensure that a response is entered for all items.
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Short Form 36 – Version 2 Health Survey (SF-36v2)
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use broad variety of health conditions and is the standard in literature for HCV.  
The SF-36v2 instrument comprises 36 total items (questions) targeting a subject's 
functional health and well-being in 8 domains (physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional and mental health).  
Domain scores are also aggregated into a Physical Component Summary score and a 
Mental Component Summary score.  Higher SF-36v2 scores indicate a better state of 
health.  The SF-36v2 should require approximately 10 minutes to complete.
Treatment Satisfaction Questionnaire-Medicine (TSQM)
The TSQM is a 14-item instrument and includes assessments of satisfaction with a 
medication's effectiveness (Effectiveness, three items), lack of side effects (Side Effects; 
five items), convenience (three items) and the subject's global satisfaction (Global 
Satisfaction; three items). 
The subject should complete the questionnaire before site personnel perform any clinic 
assessments and before any interaction with the site personnel has occurred to avoid 
biasing the subject's response.  TSQM scores range from 0 – 100 with higher scores 
indicating better satisfaction.  The TSQM should require approximately 5 minutes to 
complete.
EuroQol-5 Dimensions-3 Level (EQ-5D-3L)
The EQ-5D-3L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 
3 levels of severity.  Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies.  Subjects also rate their 
perception of their overall health on a separate visual analogue scale (VAS).  The 
EQ-5D-3L should require approximately 5 minutes to complete.
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PRO instruments should be consistently presented so that subjects complete the 
questionnaires in the following order:  the SF-36v2, TSQM, and EQ-5D-3L.  PRO 
instruments should be completed prior to drug administration on Day 1 and prior to any 
discussion of adverse events or any review of laboratory findings, including HCV RNA 
levels, at all study specified visits listed in Appendix C and Appendix D.  The TSQM is 
the only PRO assessment that will not be performed at Day 1.
Enrollment and Assignment of Subject Numbers
All Screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet all the Inclusion Criteria and none of the Exclusion Criteria at Screening will 
proceed to enrollment via the IRT system on Study Day 1.
Subject numbers will be unique 4 digit numbers and will begin with 1001 with the 
first two digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  Subjects will be enrolled on Study Day 1 as described in Section 5.5.4.
Study Drug Compliance for Kits
Individual bottles of GLE/PIB will be provided for subject dosing to the site.  Each 
subject will have compliance documented by the site in the subject's source notes for 
GLE/PIB.  At each Study Drug Accountability Visit in Appendix C, the overall number of 
tablets of GLE/PIB remaining in each bottle will be recorded and entered in the IRT 
system along with the date of reconciliation.
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subgenotype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
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sample, its genotype and subtype will be evaluated by a Sanger sequencing assay of a 
region of the NS5B gene by the central laboratory.
HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
Appendix D.  Plasma HCV RNA levels will be determined for each sample collected by 
the central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV 
Quantitative Test, v2.0.  The lower limit of detection (LLOD) and lower limit of 
quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
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.
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 study drug taken prior to the 
scheduled pharmacokinetic sample collection visits during the Treatment Period as 
detailed in Appendix C.
The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes and the 
eCRF.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
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●
The Investigator or designee should make sure the subject is given the dosing 
card at the visits listed in Appendix C.
●
The Investigator or designee will contact the subject approximately 2 days 
before the scheduled visit date to review the importance of proper study drug 
administration relative to the pharmacokinetic blood collection and 
documentation of dosing times on the dosing card.  The date and time of the 
contact will be entered into the subject's source documents.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.
Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
For subjects with HCV/HIV coinfection, samples for plasma HIV RNA levels and flow 
cytometry (including but not limited to CD4+ T-cell and CD8+ T-cell counts [absolute 
and percent]) will be obtained at the times specified in Appendix C and Appendix D.  
Plasma HIV-1 RNA will be measured by the central laboratory using the Roche COBAS 
AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 HIV-1 Assay.  Results below the 
LLOD are reported as:  "Not Detected."
If a HIV RNA level result of subject on stable HIV ART is ≥ 200 copies/mL, the subject's 
HIV RNA is to be repeated as noted in Section 5.4.1.2.  At the time the repeat plasma 
HIV RNA is drawn, a sample should be obtained for HIV genotypic resistance testing.  If 
the subject's repeat HIV RNA is ≥ 500 copies/mL, the sample obtained for HIV genotypic 
resistance testing will be analyzed.
HIV protease (PR), reverse transcriptase (RT) and integrase (IN) sequences, as applicable, 
will be analyzed by Monogram Biosciences using the GenoSure® Prime drug resistance 
assay.
If the subject's repeat HIV RNA is < 200 copies/mL, then the subject will resume routine 
plasma HIV RNA assessments as shown in Appendix C and Appendix D, and described 
in Section 5.4.1.2.
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Specific instructions for preparation and storage of flow cytometry, plasma HIV RNA, 
and HIV resistance samples will be provided by the central laboratory, AbbVie, or its 
designee.
5.3.1.2
Meals and Dietary Requirements
Study drug (GLE/PIB) tablets should be dosed together and taken with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of GLE, PIB, and their possible metabolites will 
be collected by venipuncture at each study visit indicated below and in Appendix C.
●
At all Treatment-Period visits, except 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 plasma samples for the pharmacokinetic assays of GLE, PIB, and their possible 
metabolites will be provided by the central laboratory, AbbVie, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of GLE, PIB, and their 
possible metabolites will be packed in dry ice sufficient to last during transport, and 
transferred from the study site to the central laboratory.
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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 any possible GLE 
and PIB metabolites may also be determined using either validated or non-validated 
methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 12 weeks after completion or discontinuation of study drug.
5.3.3.1
Primary Variable
The primary efficacy variable is the percentage of subjects who achieve SVR12 (HCV 
RNA < LLOQ 12 weeks after the last actual dose of study drug).
5.3.3.2
Secondary Variables
The secondary efficacy variables are:
●
The percentage of subjects with HCV OTVF.
●
The percentage of subjects with HCV virologic relapse.
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.
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The following resistance information will be analyzed for subjects receiving study drug 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples at 
signature resistance-associated positions 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 resistance-associated 
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, PIB, and their potential metabolites, if 
measured, will be tabulated and summarized.  
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If, during the course of study drug administration, the subject prematurely discontinues, 
the procedures outlined for the applicable Premature D/C Visit should be completed as 
defined in Appendix C and Appendix D.  Ideally this should occur on the day of study 
drug discontinuation, but no later than 2 days after their final dose of study drug and prior 
to the initiation of any other anti-HCV therapy.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
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investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  The last dose of any study drug and reason for discontinuation will be recorded 
in the EDC (electronic data capture) system.  The subject should then begin the Post-
Treatment Period where the subject will be monitored for 12 weeks for HCV RNA and 
the emergence and persistence of resistant viral substitutions.
If a subject is discontinued from study drug or in the Post-Treatment Period with an 
ongoing adverse event or an unresolved laboratory result that is significantly outside of 
the reference range, the investigator will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of study drug 
may be continued at the Principal Investigator's discretion after discussion with the 
subject, if the benefit of continuing study drug is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  If a 
subject is discontinued, subject will be monitored for SVR in the Post-Treatment Period 
as described in Section 5.1.3.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of HCV virologic failure for the 
purposes of subject management:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment.
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
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When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study drug treatment until the virologic failure criteria has been 
confirmed.  Subjects meeting the virologic failure criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistance-associated viral substitutions until 12 weeks post-treatment.  
Alternative management will only be considered with the approval of TA MD.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV RNA will be assessed at each scheduled study visit during the Treatment and Post 
Treatment Period, as detailed in Appendix C and Appendix D.
The criteria for failure to maintain HIV virologic suppression among subjects on stable 
ARTs is as follows:
●
HIV RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 2 weeks 
apart, in a subject compliant with their HIV ARV therapy
Subjects should remain on HCV study drug treatment and his/her current ART regimen 
while the failure to maintain HIV virologic suppression is being confirmed.  A 
confirmatory HIV RNA and HIV genotypic resistance blood draw can be done as an 
unscheduled visit.  However, if this blood draw falls on the date of a scheduled study visit 
(Appendix C and Appendix D), only a single HIV RNA and HIV genotypic resistance 
blood draw needs to be performed at this visit.
At the time a confirmatory HIV RNA is drawn, a sample for HIV genotypic resistance 
testing should also be obtained; this sample will be analyzed if the subject's repeat plasma 
HIV RNA is ≥ 500 copies/mL.  Subjects should remain on HCV study drug treatment and 
his/her current ART regimen while the failure to maintain HIV virologic suppression is
being confirmed.  A confirmatory HIV RNA and HIV genotypic resistance blood draw 
can be done as an unscheduled visit.  However, if this blood draw falls on the date of a 
scheduled study visit (Appendix C and Appendix D), only a single HIV RNA and HIV 
genotypic resistance blood draw needs to be performed at this visit.
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During the Treatment Period, subjects with confirmed failure to maintain HIV RNA 
suppression should continue HCV study drug treatment unless there is a requirement for 
prohibited concomitant medications (Section 5.2.3.2) to construct a new HIV ART 
regimen. 
Clinical management of failure to maintain HIV virologic suppression during the study 
(Treatment and Post-Treatment Period) will be handled by the Investigator according to 
current HIV treatment guidelines and local standard of care.  Subject's change of HIV 
ART regimen must be discussed with the AbbVie TA MD prior to the change being 
made, unless the change is being made to address an immediate safety concern.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of GLE/PIB will be dispensed in the form of film-coated co-formulated tablets 
at the visits listed in Appendix C.  Subjects will be instructed to take study drug at the 
same time every day with food.  Please refer to Section 5.3.1.1 and Section 5.3.2.1 for 
more details.
GLE/PIB will be provided by AbbVie as 100 mg/40 mg film-coated tablets.  GLE/PIB 
will be taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) 
QD and with food.
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Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  The site will also contact the IRT 
system to provide study drug return information for each kit at the visits specified in 
Appendix C.  At the end of the Treatment Period or at the Premature D/C Visit from the 
Treatment Period, the site will contact the IRT system to provide the discontinuation visit 
date information and study drug return information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the HCV virologic 
failure criteria defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drug to be used in this study is presented in Table 7.
Table 7.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode of Administration
Dosage Form
Strength
Glecaprevir/Pibrentasvir
AbbVie
Oral
Film-coated 
tablet
100 mg/
40 mg
5.5.2.1
Packaging and Labeling
Study drug will be supplied in bottles.  Each bottle will be labeled as required per country 
requirements.  Labels must remain affixed to the bottles.  All blank spaces should be 
completed by site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions
Glecaprevir/Pibrentasvir bottles
15° to 25°C (59° to 77°F)
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
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maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie (or designee).
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive the treatment assignment.  Enrolled subjects will 
be assigned to either Arm A (8 weeks of treatment) or Arm B (12 weeks of treatment) 
based on cirrhosis status.  The study drug kit numbers will be assigned according to 
schedules computer-generated before the start of the study by the AbbVie Statistics 
Department.
Contact information and user guidelines for IRT use will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.
All tablets of GLE/PIB will be dosed together (three tablets once daily).  All subjects 
should take all doses of study medications with food.
5.5.5
Blinding
This is an open-label study.
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5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing compliance with the treatment regimen with regard to HCV virologic response 
and potential development of resistance due to poor compliance.
At each study visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial, or empty) for assessment of treatment 
compliance.  At Study Drug Accountability visits denoted in Appendix C, study site 
personnel will assess subject compliance by inspecting the contents of the bottles and 
record the status of each one, as well as the exact number of remaining tablets of 
GLE/PIB in IRT.  Treatment compliance will be based on the number of tablets 
dispensed, as recorded in IRT, and the number of remaining tablets.  If poor compliance is 
noted, the subject should be counseled and this should be documented in the subject's 
source.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include lot number, kit number, number of tablets dispensed, subject number, initials 
of person who dispensed study drug, and date dispensed for each subject.  An overall 
accountability of the study drug will be performed and verified by the AbbVie monitor 
throughout the Treatment Period.  The monitor will review study drug accountability on 
an ongoing basis.  Final accountability will be verified by the monitor at the end of study 
drug treatment at the site.
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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.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The GLE/PIB combination regimen for 8- and 12-weeks in HCV treatment-naïve subjects 
without cirrhosis and with compensated cirrhosis respectively, was evaluated in HCV 
GT1 – 6 infected subjects in the Phase 3 studies discussed in detail in Section 3.0.  A high 
(> 97%) efficacy and positive safety profile was demonstrated in these studies.  AbbVie 
plans to evaluate the same combination regimen at the proposed label durations in a 
similar HCV GT1 – 6 infected population in Brazil.  The study is designed to include 
subpopulations of HCV-infected patients (e.g., GT1 and GT3; severe renal disorder and 
HIV/HCV co-infected population) that represents the unmet clinical treatment need in 
Brazil.  The selection of a two arm study design is appropriate so that treatment naïve 
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GT1 – 6 Brazilian subjects receive the proposed label treatment duration based on their 
cirrhosis status. 
In view of the expected high SVR rate in this study and the established safety profile of 
GLE/PIB in patients with advanced fibrosis, a control arm would be of limited value for 
efficacy comparison.  In this context, an open-label study is appropriate to adequately 
describe the efficacy and safety of this regimen administered for the proposed global label 
recommended durations for treatment naïve subjects.
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.  Next generation sequencing 
(NGS) methods are experimental.
5.6.3
Suitability of Subject Population
This study is intended to enroll HCV treatment-naïve adults in Brazil with chronic HCV 
genotype 1 – 6 without cirrhosis and with compensated cirrhosis with METAVIR 
equivalent fibrosis stage F2-F4.  Patients with HCV/HIV co-infection and CKD
Stages 1 – 5 may participate in the study.  The study population includes subpopulations 
of HCV-infected patients (e.g., GT1 and GT3; severe CKD and HIV/HCV co-infected 
populations) with high unmet clinical treatment need currently in Brazil.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The dose GLE/PIB 300 mg/120 mg QD 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.
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5.6.4.1.1
GLE and PIB Dose and Treatment Duration
GLE/PIB is proposed to be indicated for the treatment of chronic HCV infection in adults.  
In DAA-treatment naïve adults, the recommended oral dose of GLE/PIB is 
three 100 mg/40 mg tablets QD with food (total daily dose of 300 mg/120 mg) for 
8 weeks in subjects without cirrhosis and for 12 weeks in subjects with compensated 
cirrhosis based on the ITT SVR12 rates in the registrational studies.  Only HCV treatment 
naïve subjects will be enrolled in this study.  The efficacy in subjects with CKD4 – 5 did 
not differ from those without CKD.  Similar efficacy result was observed on HCV/HIV 
co-infected subjects and HCV monoinfected subjects.  The recommended durations for all 
HCV treatment naive patients of all HCV genotypes are summarized in Table 8, and 
SVR12 is summarized by GT in Table 9.  These are recommendations for all HCV-
infected patients, including those co-infected with HIV and patients with any degree of 
renal impairment.
A favorable safety profile has been observed in HCV-infected subjects without cirrhosis 
or with compensated cirrhosis who received the GLE + PIB 300 mg + 120 mg dose 
combination.  No dose response relationship was observed for adverse events, or for 
treatment-emergent post-nadir alanine aminotransferase elevations.
The maximum dose of GLE/PIB will not exceed 300 mg/120 mg per day for 12 weeks.
Table 8.
Recommended GLE/PIB Duration for TN Patients
Patient Population
Recommended Treatment Duration
No Cirrhosis
Cirrhosis
Genotype 1 – 6
8 weeks
12 weeks
GLE = glecaprevir; PIB = pibrentasvir; TN = treatment-naïve
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Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)
SVR12%
GT1
GT2
GT3
GT4 – 6
GT1 – 6
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
All
TNa + TE-P/R, SOF/R or PIb
99.0
97.2
98.0
100
95.2
96.6
93.1
100
97.4
97.6
97.5
cirr = cirrhosis; GT = genotype; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; P/R = regimens 
containing interferon, pegylated interferon, and/or ribavirin; SOF/R = regimens containing sofosbuvir and ribavirin; 
SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naive
a.
Recommended treatment duration for subjects without cirrhosis is 8 weeks and with cirrhosis is 12 weeks.
b.
Recommended treatment duration for GT1, 2, 4 – 6 subjects without cirrhosis is 8 weeks and with cirrhosis is 
12 weeks.  Recommended treatment duration for GT3 subjects is 16 weeks.
Cross reference:  AbbVie.  R&D16/0146.  Summary of Clinical Efficacy for Glecaprevir/Pibrentasvir in HCV.  2016.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.1.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
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considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (see Section 6.1.7 regarding toxicity management) and/or if the 
investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an adverse event if the surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe 
form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to 
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).
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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4). 
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity. 
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
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Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL*
Grade 3
Severe or medically significant but not 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
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is sufficient evidence (information) 
to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
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If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
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Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie 
within 1 working day after the site becomes aware of the pregnancy.  If a pregnancy 
occurs in a study subject or in the partner of a study subject, information regarding the 
pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written 
informed consent from the partner must be obtained prior to collection of any such 
information.  AbbVie will provide a separate consent form for this purpose.  Information 
regarding pregnancy in a subject or a subject's partners will be collected for pregnancies 
occurring from the date of the first dose through 30 days following the last dose of study 
drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital 
anomaly is considered a SAE and must be reported to AbbVie within 24 hours after the 
site becomes aware of the event.
Please refer to Section 5.4.1 for management of study drug in case of pregnancy.
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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).
6.1.7.1
Management of Increases in ALT
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also > 2 × 
baseline value, the subject should have a confirmatory ALT measurement performed.  If, 
the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Complete the hepatic questionnaire.
●
Evaluate for an alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain Anti-HAV IgM, Anti-HAV Total, Anti-HBc IgM, Anti-HBc Total, 
Anti-HBs, HBV DNA, HBsAg, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, as appropriate.
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drug if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
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○
Increasing direct bilirubin or INR or onset of symptoms/signs of liver 
failure.
○
At the discretion of the investigator.
Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director.
6.1.8
Collection of Data Regarding Known AIDS-Defining 
Conditions
HIV infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  A list of these known AIDS-Defining Conditions (ADC) is 
presented in Appendix E.  The events listed in Appendix E will be summarized as 
HIV-related events, not as adverse events.  These ADCs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
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Email:
Email:
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.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
An interim data lock may occur in the study if interim study results are needed for 
regulatory interaction purposes.  No changes to the study design or treatment of subjects 
would result from this interim analysis; therefore, no adjustment for multiplicity is 
needed.
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.
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).
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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 and SVR12) based on defined visit windows.  A backward 
imputation method will be used to impute missing responses for SVR analyses.
8.1.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all treated subjects by 
Arm (A and B), and overall.  Demographics include age, weight, height, body mass index 
(BMI), gender, race, and ethnicity.  Baseline characteristics include HCV genotype 
subtype, CKD stage, baseline HCV RNA level, fibrosis stage (F2, F3, F4), tobacco (user, 
ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) status, injection 
drug user (yes, within last 12 months; yes, more than 12 months ago; or no), use of stable 
opiate substitution, history of diabetes, baseline metabolic syndrome, history of bleeding 
disorders, history of depression or bipolar disorder, history of cardiovascular disease, and 
HIV coinfection status.
All the demographics and baseline characteristics will be summarized as continuous or 
categorical variables where appropriate.  Summary statistics (N, mean, median, SD, and 
range) will be generated for continuous variables (e.g., age and BMI), and the number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).
Treatment compliance to study drug will be calculated based on the percentage of tablets 
taken relative to the total tablets expected to be taken.  A subject is considered to be 
compliant if the percentage is between 80% and 120%.  Compliance will be calculated for 
each subject and summarized with the mean, median, standard deviation, minimum, and 
maximum.  The percentage of compliant subjects will be summarized.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
The efficacy analyses will be performed across all treatment durations and genotypes.
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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 notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, regardless of whether the HCV RNA is detectable or not.  HCV RNA 
≥LLOQ are all quantifiable values.
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) across all genotypes 
(GT1 – 6 subjects) will be analyzed on combined treatment groups.  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 using the normal approximation to the binomial distribution, unless the number of 
SVR12 non-responders is less than 5, in which case the Wilson's score method will be used 
for the confidence interval instead.
A summary of reason for SVR12 non-response (e.g., OTVF, relapse, other) will be 
provided.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The percentage of subjects with HCV OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA 
≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment with at least 6 weeks of treatment), and 
●
The percentage of subjects with post-treatment HCV virologic relapse (defined 
as confirmed HCV RNA ≥ 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)
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For the analysis of post-treatment HCV virologic relapse, completion of treatment is 
defined as any subject with study drug duration of 52 days or greater and 77 days or 
greater for subjects allocated to treatment durations of 8 weeks and 12 weeks, 
respectively.
For OTVF 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 to the binomial distribution and a 
two-sided 95% confidence interval using the Wilson's score method.
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated as a sensitivity analysis for the primary endpoint of SVR12 based on ITT 
population.
8.1.2.4
Subgroup Analysis
The subgroup analyses will be performed based on the combined treatment groups.  The 
percentage of subjects with SVR12 will be calculated, as will the corresponding two sided 
95% Wilson score intervals, for the following subgroups:
●
HCV genotype and available subtype
●
Sex
●
Age 
●
Race 
●
Baseline HCV RNA level 
●
Baseline fibrosis stage 
●
Baseline cirrhosis status 
●
Baseline platelet count 
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●
Baseline albumin 
●
Chronic Kidney Disease Stage 
●
HIV co-infection 
●
HIV ART regimen (for HIV coinfected)
●
Baseline CD4+ count (for HIV coinfected)
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized by genotype:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR 4 weeks after the last actual dose 
of study drug (SVR4);
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
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that domain will be considered missing.  The Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  For TSQM, if a 
respondent answers at least 2 items in the 3 item scales of Side Effects or Effectiveness, 
the missing items will be imputed with the average score of the answered items in the 
same scale.  For EQ-5D-3L, health state index and VAS scores no imputation will be 
performed for missing items.
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The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
(SF-36-PCS) scores; EQ5D-3L health state index and VAS score will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
For each of these scores, mean change from Baseline to Final Treatment Visit and from 
Baseline to Post-Treatment Week 12 will be summarized using an analysis of covariance 
(ANCOVA) model with baseline score as a covariate.
The following analyses of patient reported outcomes (PROs) also will be performed:
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
3 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 domain scores;
TSQM Effectiveness, Side Effects, Convenience, and Global Satisfaction scores will be 
summarized descriptively at each applicable visit.
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
HCV Resistance Analyses
For all subjects with an available sample, full length NS3/4A and NS5A genes from 
baseline samples will be sequenced by NGS.  For subjects who experience virologic 
failure (OTVF or post-treatment relapse), full length NS3/4A and NS5A genes from the 
first available sample after virologic failure with HCV RNA ≥ 1000 IU/mL will be 
sequenced by NGS.  An appropriate subtype specific prototypic reference sequence will 
be used for comparison with sequences from samples.  Subjects treated with study drug 
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who do not achieve SVR12 due to reasons other than virologic failure but have a time 
point with HCV RNA ≥1000 IU/mL after treatment discontinuation, will have the sample 
at that time point sequenced.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥ 1000 IU/mL will be used.  
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions for the respective inhibitor class are identified.  An appropriate subtype-specific 
prototypic reference sequence will be used for comparison with sequences from each 
sample.
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in a post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample [(post-
baseline % – baseline %) ≥ 20].
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●
Treatment-emergent substitution by NGS:  A post-baseline substitution or an 
enriched polymorphism detected by NGS.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
By-subject listings of all baseline polymorphisms at signature amino acid 
positions for each DAA target (NS3/4A and NS5A) at detection thresholds of 
2% and 15%.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total 
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared.  Analysis 
will be grouped by HCV subtype and DAA target (NS3/4A or NS5A).
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
Analysis 3:  In subjects with or without 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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the rates with or without polymorphisms will be compared using Fisher's exact test.  
Analysis will be separated by HCV subtype.
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequence will be provided for each DAA target (NS3/4A 
and NS5A). 
●
Listings by subject and time point of all post-baseline substitutions at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LIPA assay 
results from the Central laboratory will be used to categorize the subject.  This final HCV 
genotype subtype will be used in efficacy subgroup analyses.
8.1.5
HIV Resistance Analyses
In a subject being evaluated for failure to maintain HIV virologic suppression, if the 
confirmatory plasma HIV RNA level is ≥ 500 copies/mL, the subject's HIV PR, RT, 
and/or IN sequences, as applicable, will be analyzed by Monogram Biosciences using the 
GenoSure® Prime drug resistance assays.  The number of subjects who demonstrate HIV 
genotypic resistance and the genotypic resistance mutations detected in the samples 
obtained from these subjects will be tabulated and summarized.  Resistance will be 
defined as described by the IAS-USA Panel.19
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8.1.6
Safety
Safety summaries will be provided overall (i.e., across study drug durations).  All subjects 
who receive at least one dose of study drug will be included in the safety analyses.
8.1.6.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term.  The tabulation of the number of subjects with 
treatment-emergent adverse events by severity grade (Grades 1 – 5) and relationship to 
each study drug will also be provided.  Subjects reporting more than one adverse event for 
a given MedDRA preferred term will be counted only once for that term using the most 
severe grade for the severity grade table and the most related for the relationship to study 
drug tables.  Subjects reporting more than one type of event within a SOC will be counted 
only once for that SOC.
Additional analyses will be described in the statistical analysis plan.
8.1.6.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last non-missing measurement prior to the initial dose of study drug.  Mean changes from 
baseline to each post-baseline visit, including Final Treatment Visit, will be summarized 
descriptively.  Changes from baseline to maximum post-baseline CTCAE grade of 
laboratory values will also be summarized.
8.1.6.3
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 
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values meeting pre-defined criteria for Potentially Clinically Significant (PCS) vital signs 
values will be summarized.
8.1.6.4
HCV/HIV Co-Infection
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV co-infection overall:
●
The percentage of subjects with plasma HIV RNA suppression at the end of 
treatment and at Post-Treatment Week 12 using the FDA Snapshot Algorithm;
●
The number and percentage of subjects with plasma HIV RNA < 20 copies/mL 
at each applicable time point;
●
Change from baseline in CD4+ T-cell count (absolute and percent) to each 
applicable post-baseline time point;
●
Change from baseline in lymphocytes (count and percentage) and CD8+ T-cell 
counts (absolute and percent) to each applicable post-baseline time point;
●
The listing of subjects with a plasma HIV RNA value ≥ 200 copies/mL at any 
baseline or post-baseline visit during the study.
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall.
8.1.7
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE, PIB, and their possible metabolites, if measured, 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:
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Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) of the 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.
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) may 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 utilize 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 a total of approximately 100 HCV infected treatment naïve GT1 – 6 
subjects will be enrolled in this study.  No formal hypothesis is being tested.  If the 
observed SVR12 rate in this study is 97% among 100 HCV GT1 – 6 treatment naive 
subjects, then the half-width of 2-sided 95% normal approximation interval is 3.3%.
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8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be allocated to a treatment arm 
according to their cirrhosis status (presence/absence).
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific, and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information, and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain, and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date (SAE CRF) may serve 
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as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
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
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator 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.
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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 (GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults 
in Brazil with Chronic Hepatitis C Virus (HCV) Genotype 1 – 6 
Infection
Protocol Date: 
02 August 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al.  A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
Bruggmann P, Berg T, Øvrehus AL, et al.  Historical epidemiology of hepatitis C 
virus (HCV) in selected countries.  J Viral Hepat.  2014;21 Suppl 1:5-33.
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.
EPCLUSA® (sofosbuvir and velpatasvir) [US Prescribing Information].  Foster 
City, CA; Gilead Sciences, Inc., 2016.
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11.
American Association for the Study of Liver Diseases.  Hepatitis C guidance:  
AASLD-IDSA recommendations for testing, managing, and treating hepatitis C.  
Available at:  http://www.hcvguidelines.org.  Updated:  24 February 2016.  
Changes made:  10 March 2016.
12.
Protocol clinic e diretrizes terapeuticas para hepatitis C e coinfections.  MoH.  
2015.
13.
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.
14.
AbbVie.  ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure 
Edition 2.  06 September 2016.
15.
AbbVie.  R&D/16/0159.  A single-arm, open-label, study to evaluate the efficacy 
and safety of ABT-493/ABT-530 in renally-impaired adults with chronic 
hepatitis C virus genotype 1 – 6 infection (EXPEDITION-4) (Study M15-462).  
2016.
16.
Theise ND.  Liver biopsy assessment in chronic viral hepatitis: a personal, practical 
approach.  Mod Pathol.  2007;20 Suppl 1:S3-14.
17.
Kidney Disease:  Improving Global Outcomes (KDIGO) CKD-MBD Update Work 
Group.  KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, 
Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and 
Bone Disorder (CKD-MBD).  Kidney Int.  2017;7 (Suppl):1-59.
18.
Available From:  http://www.biopredictive.com/intl/physician/fibrotest-for-
hcv/view?set_language=en.
19.
Johnson VA, Calvez V, Gunthard HF, et al.  Update of the drug resistance 
mutations in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):6-14.
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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Bioanalysis
Clinical
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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Informed Consentc
X
Dispense/Review Study Drug Dosing Card
X (Dispense only)
X
X
X (Review only)
Medical Historyd
X
X
Physical Exame
X
X
X
Vital Signs, Weight, Heightf
X
X
X
X
X
ECG
X
Hematology/Chemistryg/Coagulation Panel
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u)
X (u)
X (u)
X (u)
Anti-HCV Ab, Anti-HIV Ab
X
Hepatitis B Panel 
X
HCV Genotype and Subgenotype
X
FibroTest or FibroScan® or Liver Biopsyi
X
Concomitant Medication Assessment
X
X
X
X
X
Adverse Event Assessmentk
X
X
X
X
X
Study Drug Dispensed
X
X
Xk
HCV RNA Samples
X
X
X
X
X
Study Drug Accountability and Review of Study Drug 
Adherence
X
X
Xl
HCV Resistance Sample 
X
X
X
X
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Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Pharmacokinetic Samplesm
X
X
X
Child-Pugh Score (cirrhotic subjects only)n
X
X
Clinical Assessment of Hepatic Decompensation (cirrhotic 
subjects only)n
X
HCC Screening Liver ultrasound (cirrhotic subjects only)n
X
Patient Reported Outcomes Instruments (PROs)o
X
X
Flow cytometry samplep
X
X
X
HIV RNAp
X
X
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Week 8 or 12 in accordance with treatment duration as described in Section 5.1. 
a.
All procedures to be performed prior to first dose. 
b.
Subjects who prematurely discontinue during 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).
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
e.
A symptom-directed physical examination may be performed at any other visit, when necessary.  Any significant physical examination findings after the first dose will be 
recorded as adverse events.
f.
Height will be measured at the Screening Visit only.
g.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour fast prior to study drug intake (with the exception of the Screening Visit, which 
may be non-fasting).
h.
Pregnancy testing is not required for women not of childbearing potential as defined in Section 5.2.4.
i.
For subjects who have not had a qualifying liver biopsy within the previous 24 months for subjects without cirrhosis or at any time for subjects with compensated cirrhosis) or 
a qualifying FibroScan® within the previous 6 months for subjects without cirrhosis or at any time prior to Screening for subjects with compensated cirrhosis).
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j.
Subjects with a historical negative Liver Ultrasound, CT or MRI (within 3 months prior to screening) are not required to have a screening Liver Ultrasound performed.  If 
additional Liver Ultrasound testing is required it should be completed as an unscheduled visit.  A positive ultrasound result suspicious of HCC will be confirmed with CT scan 
or MRI.  A liver ultrasound should be performed at the end of treatment visit if it has been 6 months or more since the historical evaluation.
k.
See specific information regarding adverse event collection in Section 6.1.1.1.
l.
Dispensation at Week 8 and Study Drug Accountability at Week 12 are only applicable to Arm B.  Subjects should bring all study drug to every visit for the site to review 
adherence.  However, the site will record the number of tablets returned only at the Study Drug Accountability Visits at Weeks 4, 8, 12 (if applicable) or Premature D/C.
m.
PK samples will be collected at each scheduled study visit.  Detail regarding timing of samples is provided in Section 5.3.2.1.
n.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver Ultrasound are only performed for subjects in Arm B as described in Section 5.3.1.1.
o.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.  TSQM will be the only PRO not administered at Day 1.
p.
For HCV/HIV co-infected subjects.
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Appendix D.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 4
PT Wk 12
PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Xc
Pregnancy Test (urine)d 
X (u)
X (u)c
Concomitant Medication Assessmente
X
Xe
Xe
Child-Pugh Score (cirrhotic subjects only)
X
X
Adverse Event Assessmentf
Xf
Xg
Xg
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Patient Reported Outcomes Instruments (PROs)h
X
X
Flow cytometry sampleh
X
X
HIV RNAi
X
X
HCC Screening:  Liver Ultrasoundj
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.
Chemistry/Coagulation panel will only be collected at PT Wk 12 for subjects in Arm B (compensated cirrhosis). 
c.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are not required at PT Wk 12, but only at PT D/C if subject discontinues prior to PT Wk 4.
d.
Women of childbearing potential do not require pregnancy testing beyond PTW4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to 
PTW4.  Pregnancy testing in PT Period is not required for females of non-childbearing potential as defined in Section 5.2.4.
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.  
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g.
Only SAEs will be collected thereafter as described in Section 6.1.4.
h.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
i.
For HCV/HIV co-infected subjects.
j.
HCC Screening Liver Ultrasound performed only subjects in Arm B as described in Section 5.3.1.1. 
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.
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Appendix E.
List of AIDS-Defining Conditions
Collection of data regarding known AIDS-Defining Conditions is covered in 
Section 6.1.8.
AIDS-Defining Conditions:
●
Bacterial infections, multiple or recurrent*
●
Candidiasis of bronchi, trachea, or lungs
●
Candidiasis of esophagus†
●
Cervical cancer, invasive§
●
Coccidioidomycosis, disseminated or extrapulmonary
●
Cryptococcosis, extrapulmonary
●
Cryptosporidiosis, chronic intestinal (> 1 month's duration)
●
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 
> 1 month
●
Cytomegalovirus retinitis (with loss of vision)†
●
Encephalopathy, HIV related
●
Herpes simplex:  chronic ulcers (> 1 month's duration) or bronchitis, 
pneumonitis, or esophagitis (onset at age > 1 month)
●
Histoplasmosis, disseminated or extrapulmonary
●
Isosporiasis, chronic intestinal (> 1 month's duration)
●
Kaposi sarcoma†
●
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia 
complex*,†
●
Lymphoma, Burkitt (or equivalent term)
●
Lymphoma, immunoblastic (or equivalent term)
●
Lymphoma, primary, of brain
●
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary†
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●
Mycobacterium tuberculosis of any site, pulmonary,†,§ disseminated,† or 
extrapulmonary†
●
Mycobacterium, other species or unidentified species, disseminated† or 
extrapulmonary†
●
Pneumocystis jirovecii pneumonia†
●
Pneumonia, recurrent†,§
●
Progressive multifocal leukoencephalopathy
●
Salmonella septicemia, recurrent
●
Toxoplasmosis of brain, onset at age > 1 month†
●
Wasting syndrome attributed to HIV
*
Only among children aged < 13 years.  (CDC.  1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age.  MMWR 1994;43[No. RR-12].)
†
Condition that might be diagnosed presumptively.
§
Only among adults and adolescents aged > 13 years.  (CDC.  1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults.  MMWR 1992;41[No. RR-17].)
Cross reference:  Morbidity and Mortality Weekly Report (MMWR).  AIDS Defining Conditions.  2008.  Available 
from:  https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2 htm.
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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M16-156
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  08 November 2017
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults in Brazil with Chronic Hepatitis C Virus (HCV) 
Genotype 1 – 6 Infection
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following therapy) and safety of 
GLE/PIB combination in treatment-naïve adults in Brazil with chronic hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis.  The efficacy 
endpoints will be analyzed based on combined treatment duration and genotypes and safety 
analysis will be done by individual treatment groups.
!
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by evaluating the 
percentages of subjects with HCV on-treatment virologic failure (OTVF) and HCV virologic 
relapse across treatment durations and genotypes.
Investigators:  Multicenter, single country (Brazil)
Study Sites:  Approximately 14
Study Population:  Chronic HCV GT 1 – 6-infected male and female adults with Metavir equivalent 
fibrosis stage of F2 – F4, at least 18 years of age, without cirrhosis or with compensated cirrhosis, who 
are HCV treatment-naïve (i.e., has never received a single dose of any approved or investigational anti-
HCV medication).
Number of Subjects to be Enrolled: Approximately 100 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB 
combination for an 8 or 12-week treatment duration in adults in Brazil with chronic HCV GT1 – 6 
infection, without cirrhosis (F2 – F3) or with compensated cirrhosis (F4), who are HCV treatment-naïve.  
Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The study enrollment will be 
monitored to meet the following enrollment criteria:  1) a minimum of 35 GT1 and 35 GT3 subjects and 
2) approximately 80 F2 – F3 and a maximum of approximately 20 F4 subjects.
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Methodology (Continued):  
Approximately 100 eligible subjects will be enrolled into one of the following treatment arms:
!
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 and F3) subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of a Screening Period, Treatment Period and Post Treatment Period:
Screening Period:  Subjects will have up to 35 days following the Screening Visit to confirm eligibility 
and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg once daily 
(QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on their cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 4 and 8 for all subjects 
and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment of 
adverse events, vital signs, study medication adherence, concomitant medications, HCV RNA, HCV 
resistance, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks to monitor safety, HCV RNA levels and the emergence and persistence of 
resistance-associated substitutions.
During the Post-Treatment Period, all subjects will have visits at PT Weeks 4 and 12, following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant viral variants will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject has positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
2.
Subject must be documented as without cirrhosis with METAVIR equivalent fibrosis stage of F2 –
F3 or with compensated cirrhosis (F4) based on results of a liver biopsy, or FibroScan, or FibroTest 
score (as described in Section 5.3.1.1).
3.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a positive test result for 
anti-Human Immunodeficiency Virus antibody at Screening and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study), or 
On a stable, qualifying HIV ART regimen for at least 8 weeks prior to Baseline.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at Screening (by the 
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 12 months 
prior to Screening (by an approved plasma HIVRNA quantitative assay including but not limited to:  
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
4.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month prior to 
enrollment, and may be on hemodialysis or peritoneal dialysis.
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
5.
Subjects With Compensated Cirrhosis 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.
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Current HBV 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)
3.
History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug.
4.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical history, 
including on Day 1 prior to dose, of liver decompensation including hepatic encephalopathy or 
variceal bleeding, radiographic evidence of small ascites, or empiric use of lactulose/rifaximin.  
Prophylactic use of beta blockers is not exclusionary (see Section 5.3.1.1).
5.
Laboratory parameters exclusions:
!
ALT > 10 × ULN; AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL 
!
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
!
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with compensated cirrhosis) 
6.
Receipt of any investigational or commercially available anti-HCV agents examples include, but are 
not limited to:  interferon, pegylated interferon, ribavirin, sofosbuvir, telaprevir, boceprevir, 
simeprevir, asunaprevir, paritaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
voxilaprevir, velpatasvir or dasabuvir.
Investigational Products:
Glecaprevir/Pibrentasvir 100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food.
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects without cirrhosis will receive GLE/PIB for 8 weeks, while subjects 
with compensated cirrhosis will receive GLE/PIB for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
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Criteria for Evaluation (Continued):
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Patient Reported Outcomes (PROs):
The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the functional health 
and well-being of subjects.  The Treatment Satisfaction Questionnaire (TSQM) will be used to assess 
treatment satisfaction with the GLE/PIB combined regime.  EuroQol-5 Dimensions-3 Level (EQ-5D-3L) 
is a health state utility instrument that evaluates preference for health status (utility); subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS).
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline substitutions 
relative to the corresponding baseline sequence in available samples.
Pharmacokinetic:  
Individual plasma concentrations of GLE, PIB, 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) across all genotypes (GT1 – 6 subjects) and treatment 
groups.  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, in which case the Wilson's score method will be used to calculate the 
confidence interval.
The secondary efficacy endpoints are:
!
The percentage of subjects with OTVF.
!
The percentage of subjects with post-treatment HCV virologic relapse.
Subgroup analysis based on the treatment arm (i.e., without cirrhosis/with compensated cirrhosis) will be 
performed.  For the secondary efficacy endpoints and subgroup analysis, the two-sided 95% confidence 
interval will be calculated using Wilson's score method.  
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures for 
SF-36 and EQ-5D-3L will be summarized.  Summary measures at each applicable visit will be 
summarized for the TSQM.
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Statistical Methods (Continued):
Safety:  
Safety summaries will be provided by the treatment arm (i.e., cirrhosis status/study drug duration) and 
overall.  All subjects who receive at least one dose of study drug will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug 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.  
Resistance:
For all subjects receiving study drug, baseline polymorphisms at signature resistance-associated amino 
acid positions identified by next generation sequencing (NGS) and comparison to the appropriate 
prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the 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.
Pharmacokinetic:
Individual plasma concentrations of GLE, PIB, and their possible metabolites will be tabulated and 
summarized.  Pharmacokinetic data from this study may be combined with data from other studies for the 
population pharmacokinetic analyses using a non-linear mixed-effect modeling approach with the 
NONMEM software.  Relationships between exposure and clinical observations (antiviral activity) may 
be explored.
Has been changed to read:
AbbVie Inc.
Protocol Number:  M16-156
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  02 August 2018
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults in Brazil with Chronic Hepatitis C Virus (HCV) 
Genotype 1 – 6 Infection
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Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following therapy) and safety of 
GLE/PIB combination in treatment-naïve adults in Brazil with chronic hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis.  The efficacy and 
safety endpoints will be analyzed on the overall population (i.e., across treatment durations and 
genotypes).
!
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by evaluating the 
percentages of subjects with HCV on-treatment virologic failure (OTVF) and HCV virologic 
relapse across treatment durations and genotypes.
Investigators:  Multicenter, single country (Brazil)
Study Sites:  Approximately 14
Study Population:  Chronic HCV GT 1 – 6-infected male and female adults with Metavir equivalent 
fibrosis stage of F2 – F4, at least 18 years of age, without cirrhosis or with compensated cirrhosis, who 
are HCV treatment-naïve (i.e., has never received a single dose of any approved or investigational anti-
HCV medication).
Number of Subjects to be Enrolled: Approximately 100 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB 
combination for an 8 or 12-week treatment duration in adults in Brazil with chronic HCV GT1 – 6 
infection, without cirrhosis (F2 – F3) or with compensated cirrhosis (F4), who are HCV treatment-naïve.  
Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The study enrollment will be 
monitored to meet the following enrollment criteria:  1) a minimum of 35 GT1 and approximately 
25 GT3 subjects and 2) approximately 80 F2 – F3 and a maximum of approximately 20 F4 subjects.
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Methodology (Continued):  
Approximately 100 eligible subjects will be enrolled into one of the following treatment arms:
!
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 and F3) subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of a Screening Period, Treatment Period and Post Treatment Period:
Screening Period:  Subjects will have up to 35 days following the Screening Visit to confirm eligibility 
and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg once daily 
(QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on their cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 4 and 8 for all subjects 
and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment of 
adverse events, vital signs, study medication adherence, concomitant medications, HCV RNA, HCV 
resistance, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks to monitor safety, HCV RNA levels and the emergence and persistence of 
resistance-associated substitutions.
During the Post-Treatment Period, all subjects will have visits at PT Weeks 4 and 12, following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant viral variants will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject has positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
2.
Subject must be documented as without cirrhosis (METAVIR equivalent fibrosis stage of F2 – F3), 
or with compensated cirrhosis (METAVIR equivalent fibrosis stage of F4 with a Child-Pugh score 
≤6).  See Section 5.3.1.1 for Liver Diagnostic Testing and Child-Pugh score and Category.
3.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a positive test result for 
anti-Human Immunodeficiency Virus antibody at Screening and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study), or 
On a stable, qualifying HIV ART regimen for at least 8 weeks prior to Baseline.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at Screening (by the 
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 12 months 
prior to Screening (by an approved plasma HIVRNA quantitative assay including but not limited to:  
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
4.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month prior to 
enrollment, and may be on hemodialysis or peritoneal dialysis.
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
5.
Subjects With Compensated Cirrhosis 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.
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Current HBV infection on screening tests, defined as:
!
A positive HBsAg, or;
!
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., with negative HBsAg and 
Anti-HBs)
3.
History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug.
4.
Any current or past clinical evidence of Child-Pugh B or C classification (score of > 6) or any current 
or past clinical history of liver decompensation including ascites on physical exam, hepatic 
encephalopathy or variceal bleeding.  Prophylactic use of beta blockers is not exclusionary (see 
Section 5.3.1.1).
5.
Laboratory parameters exclusions:
!
ALT > 10 × ULN; AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL 
!
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
!
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with compensated cirrhosis) 
6.
Receipt of any investigational or commercially available anti-HCV agents including, but not limited 
to:  interferon, pegylated interferon, ribavirin, sofosbuvir, telaprevir, boceprevir, simeprevir, 
asunaprevir, veruprevir, glecaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
voxilaprevir, velpatasvir, pibrentasvir, or dasabuvir.
Investigational Products:
Glecaprevir/Pibrentasvir 100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food.
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects without cirrhosis will receive GLE/PIB for 8 weeks, while subjects 
with compensated cirrhosis will receive GLE/PIB for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
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Criteria for Evaluation (Continued):
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Patient Reported Outcomes (PROs):
The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the functional health 
and well-being of subjects.  The Treatment Satisfaction Questionnaire (TSQM) will be used to assess 
treatment satisfaction with the GLE/PIB combined regime.  EuroQol-5 Dimensions-3 Level (EQ-5D-3L) 
is a health state utility instrument that evaluates preference for health status (utility); subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS).
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline substitutions 
relative to the corresponding baseline sequence in available samples.
Pharmacokinetic:  
Individual plasma concentrations of GLE, PIB, 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) across all genotypes (GT1 – 6 subjects) and treatment 
groups.  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, in which case the Wilson's score method will be used to calculate the 
confidence interval.
The secondary efficacy endpoints are:
!
The percentage of subjects with OTVF.
!
The percentage of subjects with post-treatment HCV virologic relapse.
Subgroup analysis based on the treatment arm (i.e., without cirrhosis/with compensated cirrhosis) will be 
performed.  For the secondary efficacy endpoints and subgroup analysis, the two-sided 95% confidence 
interval will be calculated using Wilson's score method.  
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures for 
SF-36 and EQ-5D-3L will be summarized.  Summary measures at each applicable visit will be 
summarized for the TSQM.
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Statistical Methods (Continued):
Safety:  
Safety summaries will be provided 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.  
Resistance:
For all subjects receiving study drug, baseline polymorphisms at signature resistance-associated amino 
acid positions identified by next generation sequencing (NGS) and comparison to the appropriate 
prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the 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.
Pharmacokinetic:
Individual plasma concentrations of GLE, PIB, and their possible metabolites will be tabulated and 
summarized.
Section 3.0  Introduction
First paragraph, last sentence previously read:
Genotypes 4 to 6 are rarely reported (0.3%) in the country.6
Has been changed to read:
Genotypes 4 to 6 are rarely reported (0.3%) in Brazil.6
Section 3.0  Introduction
Third paragraph, first sentence previously read:
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF plus simeprevir [SMV], SOF plus daclatasvir 
[DCV], ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] ± dasabuvir [DSV], elbasvir 
[EBR]/grazoprevir [GZR], and SOF/velpatasvir [VEL]).10,11
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Has been changed to read:
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF plus simeprevir [SMV], SOF plus daclatasvir 
[DCV], ombitasvir [OBV]/veruprevir/ritonavir [r] ± dasabuvir [DSV], elbasvir 
[EBR]/grazoprevir [GZR], and SOF/velpatasvir [VEL]).10,11
Section 3.0  Introduction
Fourth paragraph, second sentence previously read:
Additional limitations of several current regimens include the requirement of ribavirin 
(RBV) for certain populations, significant drug to drug interactions, limited options for 
subjects with renal insufficiency, reduced efficacy in patients with baseline amino acid 
polymorphisms associated with reduced susceptibility to the HCV nonstructural 5A 
(NS5A) inhibitors (NS5AI) or NS3/4A protease inhibitors (PI), and limited options for 
patients who have failed regimens containing an NS5AI and/or PI.
Has been changed to read:
Additional limitations of several current regimens include the requirement of ribavirin 
(RBV) for certain populations, significant drug to drug interactions, limited options for 
subjects with renal insufficiency, reduced efficacy in patients with baseline amino acid 
polymorphisms associated with reduced susceptibility to the HCV nonstructural 5A 
(NS5A) inhibitors or NS3/4A protease inhibitors (PI), and limited options for patients 
who have failed regimens containing an NS5A inhibitor and/or PI.
Section 3.0  Introduction
Fifth paragraph, first sentence previously read:
AbbVie has developed two "next generation" DAAs, glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5AI, for use in combination for the treatment of HCV.  GLE and PIB each has 
potent in vitro antiviral activity against genotypes 1 through 613 and a high genetic barrier 
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to resistance, with no or little loss of potency against common resistant-associated 
substitutions.  
Has been changed to read:
AbbVie has developed two "next generation" DAAs, glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5A inhibitor, for use in combination for the treatment of HCV.  GLE and PIB each 
has potent in vitro antiviral activity against genotypes 1 through 613 and a high genetic 
barrier to resistance, with no or little loss of potency against common resistant-associated 
substitutions.  
Section 3.2  Benefits and Risks
First paragraph, first sentence previously read:
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation DAA protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment for NS5AI and PI naive, and the convenience of a once daily 
regimen.  
Has been changed to read:
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation DAA protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment for NS5A inhibitor and PI naive, and the convenience of a once 
daily regimen.  
Section 4.1  Primary Objectives
Last sentence previously read:
The efficacy endpoints will be analyzed based on combined treatment duration and 
genotypes and safety analysis will be done by individual treatment groups.
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Has been changed to read:
The efficacy and safety endpoints will be analyzed on the overall population (i.e., across 
treatment durations and genotypes).
Section 5.1  Overall Study Design and Plan:  Description
First paragraph, last sentence previously read:
The study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
Has been changed to read:
The study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of 35 GT1 and approximately 25 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
Figure 1.  Study Design
Table note "*" previously read:
The study enrollment will be monitored to meet the following  enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 –
F3 and a maximum of approximately 20 F4 subjects.
Has been changed to read:
The study enrollment will be monitored to meet the following  enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 25 GT3 subjects and 2) approximately 80 F2 –
F3 and a maximum of approximately 20 F4 subjects.
Section 5.2  Selection of Study Population
Second sentence previously read:
Subjects with HIV/HCV co-infection and subjects at all CKD stages (CKD Stages 1 – 5) 
are allowed to participate.
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Has been changed to read:
Subjects with HIV/HCV co-infection and subjects at all CKD stages (CKD Stages 1 – 5) 
are allowed to participate.17
Section 5.2.1  Inclusion Criteria
Criterion 2, last bullet previously read:
A 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.
Has been changed to read:
A WOCBP practicing at least one protocol specified method of birth control 
(Section 5.2.4), starting at Study Day 1 (or earlier) through at least 30 days after the last 
dose of study drug.
Section 5.2.1  Inclusion Criteria
Criterion 3, last paragraph previously read:
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.
Has been changed to read:
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined above) at Screening do not require pregnancy testing.
Section 5.2.1  Inclusion Criteria
Criterion 7 previously read:
Subject must be documented as without cirrhosis with METAVIR equivalent fibrosis 
stage of F2 – 3 or with compensated cirrhosis (F4) based on results of a liver biopsy, or 
FibroScan, or FibroTest score (as described in Section 5.3.1.1).
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Has been changed to read:
Subject must be documented as without cirrhosis (METAVIR equivalent fibrosis stage of 
F2 – 3), or with compensated cirrhosis (METAVIR equivalent fibrosis stage of F4 with a 
Child-Pugh score of ≤ 6).  See Section 5.3.1.1 for Liver Diagnostic Testing and Child-
Pugh Score and Category.
Section 5.2.2  Exclusion Criteria
Criterion 2, last bullet previously read:
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative HBsAg and 
Anti-HBs)
Has been changed to read:
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., with negative 
HBsAg and Anti-HBs)
Section 5.2.2  Exclusion Criteria
Criterion 6, first sentence previously read:
Any current or past clinical evidence of Child-Pugh B or C classification (score of > 6) or 
clinical history of liver decompensation including ascites on physical exam, including 
hepatic encephalopathy or variceal bleeding.
Has been changed to read:
Any current or past clinical evidence of Child-Pugh B or C classification (score of > 6) or 
any current or past clinical history of liver decompensation including ascites on physical 
exam, hepatic encephalopathy or variceal bleeding.  
Section 5.2.2  Exclusion Criteria
Criterion 8
Delete:  last sentence
This only applies to subjects with CKD Stage 4 or 5.
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Section 5.2.2  Exclusion Criteria
Criterion 10 previously read:
Receipt of any investigational or commercially available anti-HCV agents examples 
include, but are not limited to:  interferon, pegylated interferon ribavirin, sofosbuvir, 
telaprevir, boceprevir, simeprevir, asunaprevir, paritaprevir, grazoprevir, daclatasvir, 
ledipasvir, ombitasvir, elbasvir, voxilaprevir, velpatasvir or dasabuvir.
Has been changed to read:
Receipt of any investigational or commercially available anti-HCV agents, including, but 
not limited to:  interferon, pegylated interferon ribavirin, sofosbuvir, telaprevir, 
boceprevir, simeprevir, asunaprevir, veruprevir, glecaprevir, grazoprevir, daclatasvir,
ledipasvir, ombitasvir, elbasvir, voxilaprevir, velpatasvir, pibrentasvir, or dasabuvir.
Section 5.2.3.4  Prohibited Therapy
First paragraph, second sentence previously read:
For subjects in the study in countries where GLE/PIB has received marketing 
authorization, any medications in the local label that are contraindicated to be 
administered with GLE/PIB are also considered to be prohibited medications.
Has been changed to read:
Since GLE/PIB has received marketing authorization in Brazil, any medications in the 
local label that are contraindicated to be administered with GLE/PIB are also considered 
to be prohibited medications.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Last bullet previously read:
Samples will be sent to the following addresses:
Has been changed to read:
Samples will be sent to the following address:
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Section 5.3.1.1  Study Procedures
Subsection Pregnancy Testing
Last bullet previously read:
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in the inclusion criteria) at Screening do not require pregnancy testing.
Has been changed to read:
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in inclusion criterion #2) at Screening do not require pregnancy testing.
Section 5.3.1.1  Study Procedures
Subsection Hepatitis B, Hepatitis C Virus and HIV Screen
First sentence previously read:
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.
Has been changed to read:
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab testing will be performed 
at Screening.  HBV DNA testing may be performed to exclude occult HBV infection.
Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
First paragraph previously read:
Subjects will be considered to be without cirrhosis or with compensated cirrhosis based 
on the definitions below:
Has been changed to read:
Subjects will be considered to be without cirrhosis or with cirrhosis based on the 
definitions below:
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Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
Heading "With Compensated Cirrhosis (F4)"
Heading previously read:
With Compensated Cirrhosis (F4)
Has been changed to read:
With Cirrhosis (F4)
Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
Subheading "With Compensated Cirrhosis (F4)"
Add:  new last paragraph
Subjects with cirrhosis will be defined as having compensated cirrhosis if the Child-Pugh 
Score at screening is ≤6.
Section 5.3.1.1  Study Procedures
Subsection Child-Pugh Score and Category
First sentence previously read:
Subjects with compensated cirrhosis will have Child-Pugh scores assessed, except those 
who are on ongoing use of anticoagulants.  
Has been changed to read:
All subjects with cirrhosis will have Child-Pugh scores assessed at screening.  
Table 6.  Child-Pugh Classification of Severity of Cirrhosis
Table note "*" previously read:
Grade 0:  normal consciousness, personality, neurological examination,
electroencephalogram.
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Has been changed to read:
None:  normal consciousness, personality, neurological examination, 
electroencephalogram.
Section 5.3.1.1  Study Procedures
Subsection Clinical Assessment of Hepatic Decompensation
Previously read:
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 6.  Subjects who present symptoms and 
signs of hepatic decompensation including assessment at Day 1 prior to receiving study 
drug, will not be enrolled into the trial.
Has been changed to read:
A clinical assessment of hepatic encephalopathy and ascites, as defined in Exclusion 
Criterion #6, 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.  Subjects who present symptoms and signs of hepatic 
decompensation, including assessment at Day 1 prior to receiving study drug, will neither 
be dosed nor enrolled into the trial.
Section 5.3.1.1  Study Procedures
Subsection Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
Delete:  last sentence
HIV treatment failure is defined as detectable HIV RNA after 6 months of highly active 
antiretroviral therapy (HAART) or HIV RNA detectable after a period of undetectable 
measurement following use of HAART.
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Section 5.3.2.4  Measurement Methods
First sentence previously read:
Plasma concentrations of GLE and PIB will be determined using a validated assay 
methods in the Drug Analysis Department at AbbVie.
Has been changed to read:
Plasma concentrations of GLE and PIB will be determined using validated assay methods 
in the Drug Analysis Department at AbbVie.
Section 5.3.3.1  Primary Variable
Previously read:
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).
Has been changed to read:
The primary efficacy variable is the percentage of subjects who achieve SVR12 (HCV 
RNA < LLOQ 12 weeks after the last actual dose of study drug).
Section 5.3.3.3  HCV Resistance Variables
Last paragraph previously read:
The following resistance information will be analyzed for subjects receiving study drug 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the 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 resistance-associated substitutions by NGS.
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occurs in a study subject or in the partner of a study subject, information regarding the 
pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written 
informed consent from the partner must be obtained prior to collection of any such 
information.  AbbVie will provide a separate consent form for this purpose.  Information 
regarding pregnancy in a subject or a subject's partners will be collected for pregnancies 
occurring from the date of the first dose through 30 days following the last dose of study 
drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital 
anomaly is considered a SAE and must be reported to AbbVie within 24 hours after the 
site becomes aware of the event.
Please refer to Section 5.4.1 for management of study drug in case of pregnancy.
Section 8.1  Statistical and Analytical Plans
First paragraph, last sentence previously read:
No changes to the study design or treatment of subjects would result from this interim 
analysis, so adjustment for multiplicity is needed.
Has been changed to read:
No changes to the study design or treatment of subjects would result from this interim 
analysis; therefore, no adjustment for multiplicity is needed.
Section 8.1.1  Demographics and Baseline Characteristics
First paragraph, last sentence previously read:
Baseline characteristics include HCV genotype subtype, CKD stage, baseline HCV RNA 
level, fibrosis stage (F2, F3, F4), tobacco (user, ex user, or non-user) and alcohol use 
(drinker, ex-drinker, or non-drinker) status, injection drug user (yes, within last 12 
months; yes, more than 12 months ago; or no), use of stable opiate substitution, history of 
diabetes, baseline metabolic syndrome, history of bleeding disorders, history of 
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depression or bipolar disorder, history of cardiovascular disease, geographic region, and 
HIV coinfection status.
Has been changed to read:
Baseline characteristics include HCV genotype subtype, CKD stage, baseline HCV RNA 
level, fibrosis stage (F2, F3, F4), tobacco (user, ex-user, or non-user) and alcohol use 
(drinker, ex-drinker, or non-drinker) status, injection drug user (yes, within last 
12 months; yes, more than 12 months ago; or no), use of stable opiate substitution, history 
of diabetes, baseline metabolic syndrome, history of bleeding disorders, history of 
depression or bipolar disorder, history of cardiovascular disease, and HIV coinfection 
status.
Section 8.1.2.1  Primary Efficacy Endpoints
First paragraph, first sentence previously read:
The primary efficacy endpoint is the percentage of subjects who achieve SVR12 (HCV 
RNA < LLOQ 12 weeks after the last actual dose of study drug) within all genotypes 
(GT1 – 6 subjects) will be analyzed on combined treatment groups.  
Has been changed to read:
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) across all genotypes 
(GT1 – 6 subjects) will be analyzed on combined treatment groups.  
Section 8.1.2.2  Secondary Efficacy Endpoints
Second paragraph previously read:
For the analysis of post-treatment HCV virologic relapse, completion of treatment is 
defined as any subject with study drug duration of 52 days and 77 days or greater for 
subjects allocated to treatment durations of 8 weeks and 12 weeks, respectively.
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Has been changed to read:
For the analysis of post-treatment HCV virologic relapse, completion of treatment is
defined as any subject with study drug duration of 52 days or greater and 77 days or 
greater for subjects allocated to treatment durations of 8 weeks and 12 weeks, 
respectively.
Section 8.1.2.5  Additional Efficacy Endpoints
Last bullet previously read:
The percentage of subjects who achieve SVR4 4 weeks after the last actual dose of study 
drug (SVR4);
Has been changed to read:
The percentage of subjects who achieve SVR 4 weeks after the last actual dose of study 
drug (SVR4);
Section 8.1.4  HCV Resistance Analyses
First paragraph, first sentence previously read:
For all subjects with an available sample, full length NS3/4A or NS5A from baseline 
samples will be sequenced by NGS.  
Has been changed to read:
For all subjects with an available sample, full length NS3/4A and NS5A genes from 
baseline samples will be sequenced by NGS. 
Section 8.1.4  HCV Resistance Analyses
Add:  new third paragraph
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions for the respective inhibitor class are identified.  An appropriate subtype-specific 
prototypic reference sequence will be used for comparison with sequences from each 
sample.
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Section 8.1.4  HCV Resistance Analyses
Fourth paragraph and bullet list previously read:
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A).
●
A listing of all baseline polymorphisms (15% detection threshold) at 
non-signature resistance-associated amino acid positions for each DAA target 
(NS3/4A and NS5A) for subjects who experience virologic failure.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
Has been changed to read:
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
By-subject listings of all baseline polymorphisms at signature amino acid 
positions for each DAA target (NS3/4A and NS5A) at detection thresholds of 
2% and 15%.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total 
(include all subtypes).
Section 8.1.4  HCV Resistance Analyses
Sixth paragraph
Delete:  last bullet
Polymorphisms at each non-signature amino acid position at a detection threshold of 15%.
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M16-156 Protocol Amendment 2
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Section 8.1.4  HCV Resistance Analyses
Add:  new seventh paragraph
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.
Section 8.1.4  HCV Resistance Analyses
Seventh paragraph previously read:
Analysis 3:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
Has been changed to read:
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
Section 8.1.5  HIV Resistance Analyses
First sentence previously read:
If a subject develops a confirmed, plasma HIV RNA level ≥ 500 copies/mL after starting 
the study, the subject's HIV PR, RT, and/or IN sequences, as applicable, will be analyzed 
by Monogram Biosciences using the GenoSure® Prime drug resistance assays.  
Has been changed to read:
In a subject being evaluated for failure to maintain HIV virologic suppression, if the 
confirmatory plasma HIV RNA level is ≥ 500 copies/mL, the subject's HIV PR, RT, 
and/or IN sequences, as applicable, will be analyzed by Monogram Biosciences using the 
GenoSure® Prime drug resistance assays.  
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Section 8.1.6  Safety
First sentence previously read:
Safety summaries will be provided by the treatment arm (i.e., study drug duration 
assigned by cirrhosis status) and overall.  
Has been changed to read:
Safety summaries will be provided overall (i.e., across study drug durations).  
Section 8.1.6.4  HCV/HIV Co-Infection
First paragraph previously read:
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV co-infection overall and in each treatment arm:
Has been changed to read:
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV co-infection overall:
Section 8.1.6.4  HCV/HIV Co-Infection
Last paragraph previously read:
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall and within each treatment arm.
Has been changed to read:
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
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as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall.
Section 15.0  Reference List
Add:  new Reference 17
Kidney Disease:  Improving Global Outcomes (KDIGO) CKD-MBD Update Work 
Group.  KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, 
Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-
MBD).  Kidney Int.  2017;7 (Suppl):1-59.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Bioanalysis
Clinical
Has been changed to read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Bioanalysis
Clinical
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Appendix C.  Study Activities – Treatment Period
Activity "Child-Pugh Score (subjects with compensated cirrhosis only)n," "Clinical 
Assessment of Hepatic Decompensation (subjects with compensated cirrhosis 
only)n," and "HCC Screening Liver ultrasound (subjects with compensated cirrhosis 
only)n," previously read:
Child-Pugh Score (subjects with compensated cirrhosis only)n
Clinical Assessment of Hepatic Decompensation (subjects with compensated cirrhosis 
only)n
HCC Screening Liver ultrasound (subjects with compensated cirrhosis only)n
Has been changed to read:
Child-Pugh Score (cirrhotic subjects only)n
Clinical Assessment of Hepatic Decompensation (cirrhotic subjects only)n
HCC Screening Liver ultrasound (cirrhotic subjects only)n
Appendix C.  Study Activities – Treatment Period
Table note "n." previously read:
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver 
Ultrasound are only performed for subjects in Arm B (compensated cirrhotic) as described 
in Section 5.3.1.1.
Has been changed to read:
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver 
Ultrasound are only performed for subjects in Arm B as described in Section 5.3.1.1.
Appendix D.  Study Activities – Post-Treatment (PT) Period
Activity "Child-Pugh Score (subjects with compensated cirrhosis only)" previously 
read:
Child-Pugh Score (subjects with compensated cirrhosis only)
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Has been changed to read:
Child-Pugh Score (cirrhotic subjects only)
Appendix D.  Study Activities – Post-Treatment (PT) Period
Table note "j." previously read:
HCC Screening Liver Ultrasound performed only subjects in Arm B (compensated 
cirrhosis) as described in Section 5.3.1.1.
Has been changed to read:
HCC Screening Liver Ultrasound performed only subjects in Arm B as described in 
Section 5.3.1.1.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 1
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
17 February 2017
The purpose of this amendment is to:
●
Update Section 1.0, Title Page
Rationale:  A 24-hour emergency number was added in the event emergency 
calls need to be re-directed to a designated back-up AbbVie Therapeutic Area 
Medical Director (TA MD).  Language was updated, per the latest protocol 
template.
●
Update Synopsis, Study Sites to 14
Rationale:  Increased the number of sites per recommendation from 
Regulatory Authority. 
●
Update Section 1.3, List of Abbreviations and Definition of Terms, 
Section 5.2.2, Exclusion Criteria, Section 6.1.8, Collection of Data Regarding 
Known AIDS-Defining Conditions, and Appendix E, List of AIDS-Defining 
Conditions
Rationale:  Updated the abbreviation for AIDS-Defining Conditions 
throughout the protocol and the list of AIDS-Defining Conditions.
●
Update Section 5.2.1, Inclusion Criteria, Section 5.3.1.1, Study Procedures, 
and Appendix C, Study Activities – Treatment Period
Rationale:  To remove the serum pregnancy test at Study Day 1 so that only a 
urine pregnancy test is required.
●
Update Section 5.2.2, Exclusion Criteria, and Appendix C, Study Activities –
Treatment Period
Rationale:  Exclusion Criterion 6 was updated to remove the calculation of 
Child-Pugh Score at Day 1 since only assessment of liver decompensation will 
be done prior to dose.
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●
Update Section 5.2.3.4, Prohibited Therapy, Table 4, Prohibited Medications 
and Supplements
Rationale:  To allow the investigator to reintroduce the medications 
prohibited by the protocol 14 or more days following the last dose of study 
drug instead of 30 days or more based on the half-lives of glecaprevir and 
pibrentasvir.  Guidance for investigators for prohibited medications or 
supplements administered with ABT-493/ABT-530 was also provided.  
One additional prohibited medication was added to Table 4.  Updated the 
table's footnote text to specify the discontinuation period for HMG-CoA 
reductase inhibitors prior to the first dose of study drug.  Added progestogen 
in the section to be consistent with the language in the AbbVie protocol 
template.
●
Update Section 5.3.1.1, Study Procedures, Hepatocellular Carcinoma 
Screening:  Liver Ultrasound, Appendix C, Study Activities – Treatment 
Period, and Appendix D, Study Activities – Post-Treatment (PT) Period
Rationale:  The HCC Screening Liver Ultrasound at the last Post-Treatment 
Study Visit was added to ascertain the subject did not develop HCC during the 
course of the trial. 
●
Update Section 1.2, Synopsis, Section 5.3.1.1, Study Procedures, Patient 
Reported Outcomes (PRO) Instruments (Questionnaires), Appendix C, Study 
Activities – Treatment Period
Rationale:  Removed the administration of the Treatment Satisfaction 
Questionnaire from the Day 1 study visit.
●
Update Section 6.1.7.1, Management of Increases in ALT
Rationale:  Updated the section by deleting anti-hepatitis A virus 
immunoglobulin test and replacing it with anti-hepatitis A virus total test as a 
result of an error in the original list of tests.
●
Update Section 7.0, Protocol Deviations
Rationale:  Updated contact information
●
Update Section 8.1.1, Demographics and Baseline Characteristics
Rationale:  To remove one of the baseline characteristics from the summary of 
subjects as it was not applicable for this study. 
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M16-156 Protocol Amendment 1
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●
Update Synopsis and Section 8.1.2.1, Primary Efficacy Endpoints
Rationale:  For high SVR12 rates, that are nonetheless less than 100%, the 
normal approximation to binomial distribution does not provide good 
coverage.  Thus, the Wilson score test will be used for calculating the 
95% confidence interval in the primary efficacy analysis, rather than using the 
normal approximation to the binomial distribution, if the number of SVR12
non-responders is less than 5; otherwise, the normal approximation to the 
binomial distribution will be used.
●
Update Synopsis and Section 8.1.3, Patient Reported Outcomes
Rationale:  To remove mean change from baseline calculation for TSQM 
Effectiveness, Side Effects, Convenience, and Global Satisfaction scores.  The 
Treatment Satisfaction Questionnaire (TSQM) is to measure the satisfaction of 
a treatment.  At Day 1 prior to dosing, the subject has not received any study 
medication.
●
Update Synopsis and Section 8.1.2.5, Additional Efficacy Endpoints
Rationale:  To remove the endpoint of the percentage of subjects with relapse 
after SVR12 as this information will not be collected. 
●
Update Section 6.2.2, Reporting, Section 9.1, Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB), Section 10.1, Source Documents, 
and Section 13.0, Completion of the Study.
Rationale:  Language was updated, per the latest AbbVie protocol template.
●
Update Appendix B, List of Protocol Signatories
Rationale:  Updated to reflect changes in signatories.
●
Update Appendix D, Study Activities – Post-Treatment (PT) Period
Rationale:  Updated collection of chemistry/coagulation panel during PT 
WK12 visit for subjects with compensated cirrhosis.
●
Minor clerical updates/typographical correction made throughout the protocol.
Rationale:  Revised text to correct typographical errors, improve consistency 
and readability throughout the protocol.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix F.
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M16-156 Protocol Amendment 1
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-156
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  08 November 2017
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults in Brazil with Chronic Hepatitis C Virus (HCV) 
Genotype 1 – 6 Infection
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following therapy) and safety of 
GLE/PIB combination in treatment-naïve adults in Brazil with chronic hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis.  The efficacy 
endpoints will be analyzed based on combined treatment duration and genotypes and safety 
analysis will be done by individual treatment groups.
!
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by evaluating the 
percentages of subjects with HCV on-treatment virologic failure (OTVF) and HCV virologic 
relapse across treatment durations and genotypes.
Investigators:  Multicenter, single country (Brazil)
Study Sites:  Approximately 14
Study Population:  Chronic HCV GT 1 – 6-infected male and female adults with Metavir equivalent 
fibrosis stage of F2 – F4, at least 18 years of age, without cirrhosis or with compensated cirrhosis, who 
are HCV treatment-naïve (i.e., has never received a single dose of any approved or investigational anti-
HCV medication).
Number of Subjects to be Enrolled: Approximately 100 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB 
combination for an 8 or 12-week treatment duration in adults in Brazil with chronic HCV GT1 – 6 
infection, without cirrhosis (F2 – F3) or with compensated cirrhosis (F4), who are HCV treatment-naïve.  
Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The study enrollment will be 
monitored to meet the following enrollment criteria:  1) a minimum of 35 GT1 and 35 GT3 subjects and 
2) approximately 80 F2 – F3 and a maximum of approximately 20 F4 subjects.
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M16-156 Protocol Amendment 1
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Methodology (Continued):  
Approximately 100 eligible subjects will be enrolled into one of the following treatment arms:
!
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 and F3) subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of a Screening Period, Treatment Period and Post Treatment Period:
Screening Period:  Subjects will have up to 35 days following the Screening Visit to confirm eligibility 
and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg once daily 
(QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on their cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 4 and 8 for all subjects 
and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment of 
adverse events, vital signs, study medication adherence, concomitant medications, HCV RNA, HCV 
resistance, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks to monitor safety, HCV RNA levels and the emergence and persistence of 
resistance-associated substitutions.
During the Post-Treatment Period, all subjects will have visits at PT Weeks 4 and 12, following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant viral variants will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject has positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
2.
Subject must be documented as without cirrhosis with METAVIR equivalent fibrosis stage of F2 –
F3 or with compensated cirrhosis (F4) based on results of a liver biopsy, or FibroScan, or FibroTest 
score (as described in Section 5.3.1.1).
3.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a positive test result for 
anti-Human Immunodeficiency Virus antibody at Screening and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study), or 
On a stable, qualifying HIV ART regimen for at least 8 weeks prior to Baseline.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at Screening (by the 
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 12 months 
prior to Screening (by an approved plasma HIVRNA quantitative assay including but not limited to:  
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
4.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month prior to 
enrollment, and may be on hemodialysis or peritoneal dialysis.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 1
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
5.
Subjects With Compensated Cirrhosis 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.
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Current HBV 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)
3.
History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug.
4.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical history, 
including on Day 1 prior to dose, of liver decompensation including hepatic encephalopathy or 
variceal bleeding, radiographic evidence of small ascites, or empiric use of lactulose/rifaximin.  
Prophylactic use of beta blockers is not exclusionary (see Section 5.3.1.1).
5.
Laboratory parameters exclusions:
!
ALT > 10 × ULN; AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL 
!
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
!
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with compensated cirrhosis) 
6.
Receipt of any investigational or commercially available anti-HCV agents examples include, but are 
not limited to:  interferon, pegylated interferon, ribavirin, sofosbuvir, telaprevir, boceprevir, 
simeprevir, asunaprevir, paritaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
voxilaprevir, velpatasvir or dasabuvir.
Investigational Products:
Glecaprevir/Pibrentasvir 100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food.
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects without cirrhosis will receive GLE/PIB for 8 weeks, while subjects 
with compensated cirrhosis will receive GLE/PIB for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
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Criteria for Evaluation (Continued):
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Patient Reported Outcomes (PROs):
The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the functional health 
and well-being of subjects.  The Treatment Satisfaction Questionnaire (TSQM) will be used to assess 
treatment satisfaction with the GLE/PIB combined regime.  EuroQol-5 Dimensions-3 Level (EQ-5D-3L) 
is a health state utility instrument that evaluates preference for health status (utility); subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS).
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline substitutions 
relative to the corresponding baseline sequence in available samples.
Pharmacokinetic:  
Individual plasma concentrations of GLE, PIB, 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) across all genotypes (GT1 – 6 subjects) and treatment 
groups.  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, in which case the Wilson's score method will be used to calculate the 
confidence interval.
The secondary efficacy endpoints are:
!
The percentage of subjects with OTVF.
!
The percentage of subjects with post-treatment HCV virologic relapse.
Subgroup analysis based on the treatment arm (i.e., without cirrhosis/with compensated cirrhosis) will be 
performed.  For the secondary efficacy endpoints and subgroup analysis, the two-sided 95% confidence 
interval will be calculated using Wilson's score method.  
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures for 
SF-36 and EQ-5D-3L will be summarized.  Summary measures at each applicable visit will be 
summarized for the TSQM.
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Glecaprevir/Pibrentasvir
M16-156 Protocol Amendment 1
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Statistical Methods (Continued):
Safety:  
Safety summaries will be provided by the treatment arm (i.e., cirrhosis status/study drug duration) and 
overall.  All subjects who receive at least one dose of study drug will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug 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.  
Resistance:
For all subjects receiving study drug, baseline polymorphisms at signature resistance-associated amino 
acid positions identified by next generation sequencing (NGS) and comparison to the appropriate 
prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the 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.
Pharmacokinetic:
Individual plasma concentrations of GLE, PIB, and their possible metabolites will be tabulated and 
summarized.  Pharmacokinetic data from this study may be combined with data from other studies for the 
population pharmacokinetic analyses using a non-linear mixed-effect modeling approach with the 
NONMEM software.  Relationships between exposure and clinical observations (antiviral activity) may 
be explored.
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADC
AIDS-Defining Conditions
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Anti-HBc
Anti-Hepatitis B core antibody
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
ART
Antiretroviral therapy
AUC
Area under the plasma concentration-time curve
BMI
Body mass index
BUN
Blood urea nitrogen
CKD
Chronic kidney disease
CL/F
Apparent oral plasma clearance
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed tomography
Ctrough
Pre-dose trough plasma concentration
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EQ-5D-3L
EuroQol-5 Dimensions-3 Level
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HAART
Highly active antiretroviral therapy
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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
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
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
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS5A
Nonstructural viral protein 5A
OTVF
On-treatment virologic failure
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
PK
Pharmacokinetic
POR
Proof of receipt
P/R
pegIFN/RBV
PRO
Patient reported outcome
PT
Post-Treatment
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QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SF-36v2
Short Form 36 – Version 2 Health Survey
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
TE
Treatment Experienced
TN
Treatment-naïve
TSQM
Treatment Satisfaction Questionnaire-Medicine
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
WOCBP
Women of child bearing potential
Definition of Terms
Study Drug
glecaprevir/pibrentasvir
Study Day 1
First day of study drug dosing 
Treatment Period
Day 1 through last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 12 or 
Post-Treatment Discontinuation
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 10
2.0
Table of Contents ................................................................ 13
3.0
Introduction......................................................................... 18
3.1
Differences Statement .......................................................................... 28
3.2
Benefits and Risks................................................................................ 29
4.0
Study Objective ................................................................... 29
4.1
Primary Objectives............................................................................... 29
4.2
Secondary Objectives ........................................................................... 30
5.0
Investigational Plan............................................................. 30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.1.1
Screening Period .................................................................................. 32
5.1.1.1
Rescreening.......................................................................................... 32
5.1.2
Treatment Period.................................................................................. 33
5.1.3
Post-Treatment Period.......................................................................... 34
5.2
Selection of Study Population............................................................... 34
5.2.1
Inclusion Criteria.................................................................................. 34
5.2.2
Exclusion Criteria................................................................................. 37
5.2.3
Prior and Concomitant Therapy............................................................ 39
5.2.3.1
Prior HCV Therapy .............................................................................. 40
5.2.3.2
Prior and Concomitant HIV Therapy .................................................... 40
5.2.3.3
Concomitant Therapy........................................................................... 40
5.2.3.4
Prohibited Therapy............................................................................... 41
5.2.4
Contraception Recommendations ......................................................... 43
5.3
Efficacy, Pharmacokinetic, 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
Meals and Dietary Requirements.......................................................... 56
5.3.2
Drug Concentration Measurements....................................................... 56
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5.3.2.1
Collection of Samples for Analysis....................................................... 56
5.3.2.2
Handling/Processing of Samples........................................................... 56
5.3.2.3
Disposition of Samples......................................................................... 56
5.3.2.4
Measurement Methods ......................................................................... 57
5.3.3
Efficacy Variables................................................................................ 57
5.3.3.1
Primary Variable .................................................................................. 57
5.3.3.2
Secondary Variables............................................................................. 57
5.3.3.3
HCV Resistance Variables.................................................................... 57
5.3.4
Safety Variables ................................................................................... 58
5.3.5
Pharmacokinetic Variables ................................................................... 58
5.4
Removal of Subjects from Therapy or Assessment ............................... 58
5.4.1
Discontinuation of Individual Subjects ................................................. 58
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 59
5.4.1.2
Failure to Maintain HIV Virologic Suppression.................................... 60
5.4.2
Discontinuation of Entire Study............................................................ 61
5.5
Treatments ........................................................................................... 61
5.5.1
Treatments Administered...................................................................... 61
5.5.2
Identity of Investigational Products ...................................................... 62
5.5.2.1
Packaging and Labeling........................................................................ 62
5.5.2.2
Storage and Disposition of Study Drug................................................. 62
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 63
5.5.4
Selection and Timing of Dose for Each Subject.................................... 63
5.5.5
Blinding ............................................................................................... 63
5.5.6
Treatment Compliance ......................................................................... 64
5.5.7
Drug Accountability ............................................................................. 64
5.6
Discussion and Justification of Study Design........................................ 65
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 65
5.6.2
Appropriateness of Measurements........................................................ 66
5.6.3
Suitability of Subject Population .......................................................... 66
5.6.4
Selection of Doses in the Study ............................................................ 66
5.6.4.1
Rationale for Dose Selections............................................................... 66
5.6.4.1.1
GLE and PIB Dose and Treatment Duration......................................... 67
6.0
Complaints........................................................................... 68
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6.1
Medical Complaints ............................................................................. 68
6.1.1
Definitions ........................................................................................... 69
6.1.1.1
Adverse Event...................................................................................... 69
6.1.1.2
Serious Adverse Events........................................................................ 70
6.1.2
Adverse Event Severity ........................................................................ 71
6.1.3
Relationship to Study Drug................................................................... 72
6.1.4
Adverse Event Collection Period.......................................................... 73
6.1.5
Adverse Event Reporting...................................................................... 73
6.1.6
Pregnancy............................................................................................. 75
6.1.7
Toxicity Management........................................................................... 75
6.1.7.1
Management of Increases in ALT......................................................... 76
6.1.8
Collection of Data Regarding Known AIDS-Defining Conditions ........ 77
6.2
Product Complaint................................................................................ 77
6.2.1
Definition............................................................................................. 77
6.2.2
Reporting ............................................................................................. 77
7.0
Protocol Deviations ............................................................. 78
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 79
8.1
Statistical and Analytical Plans............................................................. 79
8.1.1
Demographics and Baseline Characteristics.......................................... 80
8.1.2
Efficacy................................................................................................ 80
8.1.2.1
Primary Efficacy Endpoints.................................................................. 81
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 81
8.1.2.3
Sensitivity Analysis.............................................................................. 82
8.1.2.4
Subgroup Analysis ............................................................................... 82
8.1.2.5
Additional Efficacy Endpoints.............................................................. 83
8.1.3
Patient Reported Outcomes .................................................................. 83
8.1.4
HCV Resistance Analyses .................................................................... 84
8.1.5
HIV Resistance Analyses ..................................................................... 87
8.1.6
Safety................................................................................................... 87
8.1.6.1
Adverse Events..................................................................................... 88
8.1.6.2
Clinical Laboratory Data ...................................................................... 88
8.1.6.3
Vital Signs Data ................................................................................... 88
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8.1.6.4
HCV/HIV Co-Infection ........................................................................ 89
8.1.7
Pharmacokinetic and Exposure-Response Analyses.............................. 89
8.2
Determination of Sample Size .............................................................. 90
8.3
Randomization Methods....................................................................... 90
9.0
Ethics.................................................................................... 91
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 91
9.2
Ethical Conduct of the Study................................................................ 91
9.3
Subject Information and Consent.......................................................... 92
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 ..................................................... 94
14.0
Investigator's Agreement.................................................... 96
15.0
Reference List......................................................................97
List of Tables
Table 1.
Overview of Clinical Studies by Subject Population ............................. 21
Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 
– 6 (ITT Population, Phase 2 and 3 Analysis Set) ................................. 23
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)........................................................................................ 26
Table 4.
Prohibited Medications and Supplements ............................................. 42
Table 5.
Clinical Laboratory Tests ..................................................................... 47
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 50
Table 7.
Identity of Investigational Products ...................................................... 62
Table 8.
Recommended GLE/PIB Duration for TN Patients............................... 67
Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)................................... 68
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List of Figures
Figure 1.
Study Design........................................................................................ 31
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.
List of AIDS-Defining Conditions.......................................................107
Appendix F.
Protocol Amendment:  List of Changes ...............................................109
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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 
184 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype 1 (GT1) being the most prevalent worldwide.  HCV genotypes 2 (GT2) and 3 
(GT3) infections are more common in Latin America (5% to 30%), Europe (20% to 40%)
and Asia (30% to 45%).2-4  HCV GT4 is commonly found in parts of Africa and the 
Middle East, particularly in Egypt, GT5 is primarily found in South Africa, and GT6 is 
primarily found in south-east Asia, and GT7 has recently been described in Central 
Africa.5  Genotype 1 (GT1) is the most frequent in all regions in Brazil (65%), followed 
by genotype 3 (30%) and GT2 (5%).  Genotypes 4 to 6 are rarely reported (0.3%) in the 
country.6
Depending on various risk factors, between 10% and 40% of all patients with chronic 
HCV infection will develop cirrhosis.  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.  Patients 
diagnosed with hepatocellular carcinoma 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 hepatocellular 
carcinoma.8,9
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF plus simeprevir [SMV], SOF plus daclatasvir 
[DCV], ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] ± dasabuvir [DSV], elbasvir 
[EBR]/grazoprevir [GZR], and SOF/velpatasvir [VEL]).10,11  In Brazil, the National HCV 
Program provides specific regimens to a subset of subjects with confirmed HCV and 
specific GT infection.  The mono HCV infected subjects must have confirmed Metavir F3 
and F4 fibrosis stage, and the HCV/HIV co-infected should be treated regardless of liver 
fibrosis staging.  A treatment guideline recommends SOF + DCV or SOF + SMV for 
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GT1; SOF + RBV for GT2; SOF + pegIFN or SOF + DCV for GT3; and SOF + pegIFN + 
RBV or SOF + DCV for GT4.  Duration of treatment is based on history of monoinfection 
with HCV, or co-infection with HIV, GT subtype and fibrosis staging.  These regimens 
are available across the country and prescribed free of charge within the country's 
universal health care system.  
However, these approved and recommended regimens are not equally potent across all 
HCV genotypes and subpopulations.  Additional limitations of several current regimens 
include the requirement of ribavirin (RBV) for certain populations, significant drug to 
drug interactions, limited options for subjects with renal insufficiency, reduced efficacy in 
patients with baseline amino acid polymorphisms associated with reduced susceptibility to 
the HCV nonstructural 5A (NS5A) inhibitors (NS5AI) or NS3/4A protease inhibitors (PI), 
and limited options for patients who have failed regimens containing an NS5AI and/or PI.  
Efficacy in GT3-infected patients, particularly those who are treatment-experienced (TE) 
and/or cirrhotic, is also substantially lower than what is observed for other genotypes.12
AbbVie has developed two "next generation" DAAs, glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5AI, for use in combination for the treatment of HCV.  GLE and PIB each has 
potent in vitro antiviral activity against genotypes 1 through 613 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.14
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GLE/PIB
Overview of GLE/PIB Registrational Program and Supportive Phase 2 Studies
The GLE/PIB registrational program included a broad subject population including 
subjects with compensated liver disease and subjects with severe renal insufficiency 
across GT1 – 6 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, SOF, NS5A inhibitors, or PIs were allowed 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 treatment-naïve (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 compensated cirrhosis, or HIV 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 ≥ 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 in NS3 and NS5A 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, data was analyzed at the 15% detection threshold, and baseline 
polymorphisms at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 
92, and 93 in NS5A were examined for impact on SVR12. 
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 did not have an impact on 
treatment outcome.  The NS5A polymorphisms at positions 24, 28, 31, 58, 92, or 93 
(including Y93H) did not have an impact on treatment outcome, whereas the A30K 
polymorphism was associated with a slightly decreased SVR12 rate.  Given the low 
prevalence of A30K (6.3%; 39/615) and that the majority of subjects with A30K achieved 
SVR12, its impact on overall SVR is expected to be minimal.
Amino Acid Substitutions in Subjects Experiencing Virologic Failure
Among TN and TE-PRS subjects without cirrhosis or with compensated cirrhosis treated 
for 8, 12, or 16 weeks, 23 subjects experienced virologic failure (2 with GT1, 2 with GT2, 
and 19 with GT3).  A GT3-infected subject experiencing virologic failure was determined 
to have been reinfected with GT3a virus distinct from the one present at baseline.  
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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 
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 
substitutions 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.  Given 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.
As shown in Table 3, AEs occurring with a  frequency > 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 ≥ 3 were low.  Including 
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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. 
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related Adverse 
Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade ≥ 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Term
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.
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 compensated 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 
(≥ 65 years old, n = 328) was comparable to the safety profile in the non-elderly 
population (n = 2,041).
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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 (n = 104) in Study M15-462 was consistent 
with underlying severe renal impairment 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.15  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.  No safety signal or toxicity related to 
GLE/PIB specific to subjects with CKD Stage 4 and 5 has been identified.
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 (excluding Study M15-462).  Liver-related safety results indicated that:
●
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
○
ALT abnormalities in 3 of these 4 subjects were not clinically significant
○
One subject experienced concurrent ALT > 3 × ULN (increased from nadir 
grade) and total bilirubin ≥ 2 × ULN in the context of multiple gallstones 
that was not consistent with drug-induced liver injury
●
Based on exposure-response analyses, no GLE/PIB exposure-dependent ALT 
increases were observed in subjects with ALT abnormalities
●
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression
●
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.
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●
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.  
●
There were no cases consistent with drug-induced liver injury.
In summary, GLE/PIB demonstrated a favorable safety profile that was 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 compensated cirrhosis, HIV co-
infection, and CKD Stage 4 or 5.
Common GLE/PIB-related AEs (ADRs) occurring in ≥ 5% of subjects were headache, 
fatigue, nausea.  Adverse drug reactions 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 
to be related to treatment.  Unlike other protease inhibitors, no liver-related toxicities and 
no cases consistent with drug-induced liver injury were identified.  
3.1
Differences Statement
The GLE/PIB fixed dose combination for 8 and 12 weeks was explored in treatment-naïve 
and -experienced HCV GT1 – 6 infected subjects, without cirrhosis or with compensated 
cirrhosis including subjects with HIV/HCV co-infection and subjects with CKD Stage 4 
or 5 in several Phase 3 studies conducted in a randomized, controlled, double-blind or 
open-label fashion. 
This is the first Phase 3b study designed to evaluate HCV GT1 – 6 treatment-naïve 
subjects without cirrhosis (Metavir F2 – F3) and with compensated cirrhosis (Metavir F4) 
treated with GLE/PIB for 8 or 12 weeks, respectively, in Brazil.  This country did not 
participate in the Global GLE/PIB program.
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3.2
Benefits and Risks
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation DAA protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment for NS5AI and PI naive, and the convenience of a once daily 
regimen.  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 show high 
SVR12 rates among subjects with HCV GT 1 – 6 infection who receive treatment with 
GLE/PIB.
Adverse events that are known, and those not previously identified, may occur with 
GLE/PIB as detailed in the informed consent of this study.  In addition, subjects may 
experience inconvenience or discomfort related to the study visits or study procedures.  
Additional safety data for each DAA alone and the combination of PIB/GLE are detailed 
in Section 3.0 and in the Investigator's Brochure.14
Risks associated with GLE/PIB, including the risks of adverse reactions, virologic failure, 
and development of resistance-associated substitutions (Section 5.3.4), appear to be 
limited and manageable based upon the available data.  Given the potential for high 
SVR12 rates in populations of HCV-infected subjects, including HIV/HCV co-infected, 
and with CKD 4 – 5, the risk-benefit profile for GLE/PIB is favorable.
4.0
Study Objective
4.1
Primary Objectives
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following 
therapy) and safety of GLE/PIB combination in treatment-naïve adults in Brazil with 
chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection without cirrhosis or with 
compensated cirrhosis.  The efficacy endpoints will be analyzed based on combined 
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treatment duration and genotypes and safety analysis will be done by individual treatment 
groups.
4.2
Secondary Objectives
The secondary objectives are to assess efficacy of GLE/PIB based on overall population 
(i.e., across treatment durations and genotypes) by evaluating the following:
●
The percentages of subjects with HCV on-treatment virologic failure (OTVF);
●
The percentages 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, multicenter study to evaluate the efficacy and safety of 
GLE/PIB for an 8- or 12-week treatment duration in adults in Brazil with chronic HCV 
GT1 – 6 infection, without cirrhosis or with compensated cirrhosis with a METAVIR 
System Fibrosis Score of F2, F3 or F4 (F2-F4) or equivalent,16 who are HCV treatment-
naïve.  Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The 
study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
This study will consist of a Screening Period, a Treatment Period and a Post-Treatment 
Period.
Screening Period:  Subjects will have up to 35 days following the Screening Visit to 
confirm eligibility and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg 
once daily (QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on 
cirrhosis status.
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Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment 
Period will be followed for 12 weeks to monitor HCV RNA levels to evaluate efficacy 
and the emergence and persistence of resistance-associated substitutions.
A study schematic is shown below in Figure 1. 
Figure 1.
Study Design
*
The study enrollment will be monitored to meet the following  enrollment criteria:  1) a minimum of 
approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 – F3 and a maximum of 
approximately 20 F4 subjects.
Approximately 100 eligible subjects will be enrolled into one of the following treatment 
arms:
●
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 – F3) subjects will be treated 
with GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks. 
●
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be 
treated with GLE/PIB 300 mg/120 mg once daily (QD) for 12 weeks.
The study was designed to enroll approximately 100 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening may not be enrolled.
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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 
the subject meets all of the eligibility criteria specified in Section 5.2.1 and Section 5.2.2
during the period from the Screening Visit through Study Day 1 prior to dosing, and will 
record the results of this assessment and the details of the informed consent process in the 
subject's medical records.  Eligible subjects have up to 35 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
A positive Hepatitis B surface antigen (HBsAg);
●
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative 
HBsAg and Anti-HBs); or
●
If Woman of Childbearing Potential (WOCBP), a positive serum pregnancy 
test;
●
Development of decompensated liver disease during the screening period, as 
defined by the Exclusion Criterion 6.
Otherwise subjects may be retested or rescreened only once unless approved by the 
Primary Therapeutic Area Medical Director.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on any panel that is 
repeated.  If any of the retest result(s) are exclusionary, the subject may not be rescreened 
again.
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Subjects that exceed the initial 35 day screening period should be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary during the 
first screening attempt (with the exception of HIV, HBV, HCV genotype and subtype, 
follicle stimulating hormone (FSH), which do not need to be repeated).  The FibroScan 
and liver biopsy do not need to be repeated for rescreened subjects provided that the date 
of the liver biopsy is within 24 months of the rescreening date and the FibroScan is within 
6 months of the rescreening date (Section 5.1.1).
Subjects who rescreen or subjects not meeting the study eligibility criteria must be 
identified by site personnel as a screen failure in both IRT and EDC systems.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT on Study Day 1.  
Subjects will be administered study drug at the site on Study Day 1, and provided 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 5.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3 and Section 5.3.1.1.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out 
of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
HCV virologic failure criteria will be evaluated and applied by the investigator as detailed 
in Section 5.4.1.1.
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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.  Subjects who prematurely discontinue 
from study treatment will continue to be followed in the Post-Treatment Period (see 
Section 5.1.3).
5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug will be monitored in the 
Post-Treatment Period for 12 weeks following the last dose of study drug for safety, HCV 
RNA, and the emergence and persistence of HCV resistance-associated substitutions.
The Post-Treatment Period will begin the day following the last dose of study drug.  
Study visits during the Post-Treatment period are detailed in Appendix D and 
Section 5.3.1.1.
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a Post-Treatment discontinuation visit as outlined in Appendix D.
5.2
Selection of Study Population
The study population consists of male and female adults aged 18 years or older with 
chronic HCV GT1 – 6 infection with METAVIR equivalent fibrosis stage of F2 – F4 
(without cirrhosis or with compensated cirrhosis) who are HCV treatment naïve 
(i.e., subject has never received a single dose of any approved or investigational anti-HCV 
medication).  Subjects with HIV/HCV co-infection and subjects at all CKD stages (CKD 
Stages 1 – 5) are allowed to participate.  Subjects who meet all 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 
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Postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L; or
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
OR
●
A 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 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.
Screening laboratory result indicating HCV GT1-, 2-, 3-, 4-, 5- and/or 6-infection.  
Mixed and indeterminate genotypes are acceptable.
5.
Subject has positive plasma HCV antibody and HCV RNA viral load 
≥1000 IU/mL at Screening Visit.
6.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a 
positive test result for anti-Human Immunodeficiency Virus antibody at Screening 
and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to 
initiate ART treatment while participating in this study), or on a stable, qualifying 
HIVART regimen for at least 8 weeks prior to Baseline.  (Substituting TDF for 
TAF as part of the combination regimen is allowed at any time.)
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The HIVART regimen must include at least one of the following ARV agents:
●
Raltegravir (RAL)
●
Dolutegravir (DTG)
●
Rilpivirine (RPV)
●
Elvitegravir/cobicistat (EVG/COBI)
In addition to the above medications, HIV Ab positive subjects (both without 
cirrhosis or with compensated cirrhosis) may take a nucleoside/nucleotide reverse 
transcriptase inhibitor (N(t)RTI) backbone containing any of the following:
●
Tenofovir disoproxil fumarate (TDF)
●
Tenofovir alafenamide (TAF)
●
Abacavir (ABC)
●
Emtricitabine (FTC)
●
Lamivudine (3TC)
Subjects receiving any other HIV ART in addition to those noted above are not 
eligible for enrollment in the study.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at 
Screening (by the COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and 
at least once during the 12 months prior to Screening (by an approved plasma 
HIVRNA quantitative assay including but not limited to:  COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
7.
Subject must be documented as without cirrhosis with METAVIR equivalent 
fibrosis stage of F2 – 3 or with compensated cirrhosis (F4) based on results of a 
liver biopsy, or FibroScan, or FibroTest score (as described in Section 5.3.1.1).
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8.
Subjects with compensated cirrhosis 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.
9.
Subject must voluntarily sign and date an informed consent form, approved by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the 
initiation of any Screening or study specific procedures.
10.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
11.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month 
prior to enrollment, and may be on hemodialysis or peritoneal dialysis.
Rationale for Inclusion Criteria
1, 4 – 11
In order to select the appropriate subject population with 
appropriate disease characteristics for evaluation
2, 3
The impact of GLE and PIB on human pregnancies has not been 
established.  However, assessment of the completed nonclinical 
reproductive toxicology studies indicates that there is no 
drug-related effect on teratogenicity/fetotoxicity.  In addition, the 
compounds are non-genotoxic
10
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
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.
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2.
Current HBV 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)
3.
Requirement for and inability or unwillingness to safely discontinue the 
medications or supplements listed in Table 4 at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of any study drug.
4.
Requirement for chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
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.
Any current or past clinical evidence of Child-Pugh B or C classification (score of 
> 6) or clinical history of liver decompensation including ascites on physical exam, 
including hepatic encephalopathy or variceal bleeding.  Prophylactic use of beta 
blockers is not exclusionary (see Section 5.3.1.1).
7.
Laboratory parameters exclusions:
●
ALT > 10 × ULN; AST > 10 × ULN
●
Total Bilirubin > 3.0 mg/dL 
●
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
●
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with 
compensated cirrhosis)
8.
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.  
This only applies to subjects with CKD Stage 4 or 5.
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9.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks (whichever is longer) prior to 
study drug administration.
10.
Receipt of any investigational or commercially available anti-HCV agents 
examples include, but are not limited to:  interferon, pegylated interferon ribavirin, 
sofosbuvir, telaprevir, boceprevir, simeprevir, asunaprevir, paritaprevir, 
grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, voxilaprevir, velpatasvir 
or dasabuvir.
11.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
12.
Treatment for an AIDS-Defining Conditions (ADC) (Appendix E) within 6 months 
of Screening.
13.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 3, 4, 6 – 13
In order to ensure safety of the subjects throughout the study
2, 5
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
the consent through the Treatment Period and 30 days after study drug is stopped, must be 
recorded in the electronic case report form (eCRF) along with the reason for use, date(s) 
of administration including start and end dates, and dosage information including dose, 
route, and frequency.  The investigator should review all concomitant medications for any 
potential drug-drug interactions.
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During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the Post-
Treatment Period, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in EDC.  The AbbVie Primary Therapeutic Area Medical Director should be contacted if 
there are any questions regarding concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
Subjects must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication). 
5.2.3.2
Prior and Concomitant HIV Therapy
Subject on an HIV ART regimen must include ARV agents as defined in Inclusion 
Criterion 6 (Section 5.2.1).
Subjects will maintain the same dose and dosing interval of their HIV ART regimen upon 
initiating the study drugs regimen.
Subjects must remain on the same HIV ART regimen for the entire Treatment Period.  
Any change to an allowed HIV ART regimen during the Treatment Period must be 
discussed with the AbbVie TA MD prior to the change, unless the change is being made 
to address an immediate safety concern. 
Subjects receiving any other HIV ART in addition to those listed in Inclusion Criterion 6 
(Section 5.2.1) would not be eligible for enrollment in the study.
5.2.3.3
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.  
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During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drugs, if applicable.
Flu shots and other vaccinations are allowed during Screening through the Post-Treatment 
Period for all subjects.  Flu shots and vaccinations may affect plasma HIV RNA levels.
5.2.3.4
Prohibited Therapy
Medications or supplements prohibited to be administered with ABT-493/ABT-530 are 
listed in Table 4.  For subjects in the study in countries where ABT-493/ABT-530 
(glecapravir/pibrentasvir) has received marketing authorization, any medications in the 
local label that are contraindicated to be administered with ABT-493/ABT-530 
(glecapravir/pibrentasvir) are also considered to be prohibited medications.  Subjects must 
be able to safely discontinue any prohibited medications or supplements at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of any study drug and not use 
these during the entire Treatment Period and for 14 days following discontinuation of 
study drugs.
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Table 4.
Prohibited Medications and Supplements
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, efavirenz, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drug.  After signing the informed consent form, subjects receiving these statins should either (a) switch to 
pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug 
or (b) interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives (whichever 
is longer) prior to the first dose of study drug until 14 days after the last dose of study drug, based on investigator's 
judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to either 1) reduce or limit 
the pravastatin or rosuvastatin dose in accordance with the ABT-493/ABT-530 product label (if approved in the 
country); or 2) reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the 
study drug if ABT-493/ABT-530 is not yet approved in the country.
Contraceptives and/or hormonal replacement therapies containing only 
progestins/progestogens (such as those containing norethindrone, desogestrel, or 
levonorgestrel) or those containing progestins/progestogens with non-ethinyl estradiol 
estrogens (e.g., esterified or conjugated) may be used with GLE/PIB at the discretion of 
the Investigator.
The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 
not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
For HCV/HIV coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 2 weeks prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 30 days following discontinuation of study drugs.  
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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:
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
●
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.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.
●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptom-thermal, post-ovulation methods] and 
withdrawal are not acceptable).
For male study subjects, no contraception is required.
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5.3
Efficacy, Pharmacokinetic, 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 (Treatment Period) and Appendix D
(Post-Treatment Period).
5.3.1.1
Study Procedures
Informed Consent
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco, alcohol and drug use, will be 
taken from each subject at Screening Visit.  The subject's medical history will be updated 
at the Study Day 1 Visit.  This updated medical history will serve as the baseline for 
clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Height will be measured only at Screening.  
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Vital Signs and Weight
Body temperature, blood pressure, pulse, and body weight will be measured at each study 
visit as specified in Appendix C and Appendix D.  Blood pressure and pulse rate should 
be measured after the subject has been sitting for at least 3 minutes.  The subject should 
wear lightweight clothing and no shoes during weighing.  The vital signs performed on 
Day 1 of the Treatment Period will serve as the baseline for clinical assessment.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at the visits indicated in Appendix C.  The ECG 
should be performed prior to blood collection.
The ECG will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 5
at the visits indicated in Appendix C and Appendix D.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast prior to study drug intake (with the exception of the Screening Visit, which may be 
non-fasting).  Subjects whose visits occur prior to the morning dose of study drug should 
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be instructed to fast after midnight until the blood sample is collected in the morning and 
thereafter take their study medications with food.  Subjects whose visits occur following 
the morning dose of study drug should be instructed to fast after breakfast until the study 
visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug.  Blood samples should still be drawn if the subject did not fast 
for at least 8 hours.  Fasting or non-fasting status will be recorded in the source 
documents and on the laboratory requisition.  The baseline laboratory test results for 
clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Samples will be sent to the following addresses:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
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Table 5.
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)
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine transaminase (ALT)
Aspartate transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)
Anti-HCV Aba
HCV RNA
HCV genotype and subtypea
HIV Aba
HIV RNAb
Hepatitis B Panel (Anti-HBc
Total, Anti-HBs and HBsAg)c
Anti-HBc IgMc
Anti-HBc Totalc
Anti-HBsc
Anti-HAV
IgMd
Anti_HAV Totald
Anti-HEV IgGd
Anti-HEV IgMd
HEV RNAd
HBV DNAe
Follicle Stimulating Hormone 
(FSH)f
Urine and Serum
Human Chorionic 
Gonadotropin (hCG) for 
femalesg
Alpha2-macroglobulinh
Haptoglobinh
Apolipoprotein A1h
CD4, CD4%b
CD8, CD8%b
CD4:CD8b
a.
Performed only at Screening.
b.
Only for known HCV/HIV co-infected subjects.
c.
Performed at Screening for all subjects and also performed for management of transaminase elevations 
(Section 6.1.7.1). 
d.
Performed for management of transaminase elevation (Section 6.1.7.1).
e.
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).
f.
Only performed if requested during screening for post-menopausal women < 55 to verify FSH level if site does not 
have a previous result available.
g.
Required only for females of child bearing potential.
h.
Component of FibroTest and collected only if required for FibroTest calculation during the Screening Period.
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For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug or requires a subject to receive treatment will be recorded 
as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.1.7.
Pregnancy Testing
●
WOCBP must have a negative serum pregnancy test result at Screening, and a 
negative urine pregnancy test at Study Day 1.  
●
Monthly pregnancy testing should be performed during treatment, including at 
the last dose and until 30 days of last study drug dose, as indicated in 
Appendix C and Appendix D.  
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result. 
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in the inclusion criteria) at Screening do not 
require pregnancy testing.
Concomitant Medication Assessment
Please refer to Section 5.2.3.2.
Hepatitis B, Hepatitis C Virus and HIV Screen
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.  The investigator must discuss any local reporting requirements to local health 
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agencies with the subject.  The site will report these results per local regulations, if 
necessary.  The HIV results will not be reported by the central laboratory to the clinical 
database.
Liver Diagnostic Testing
Subjects will be considered to be without cirrhosis or with compensated cirrhosis based 
on the definitions below:
Without Cirrhosis (F2 and F3)
●
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 2 – 3, Ishak fibrosis score of 3 or 4; or
●
A FibroScan® score of 8.8 to < 12.5 kPa within ≤ 6 months of Screening or 
during Screening period (FibroScan® must be approved by the local regulatory 
agency to qualify for entrance criteria); or
●
A Screening FibroTest score of 0.49 to 0.72 (inclusive).17
With Compensated Cirrhosis (F4)
●
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3, Ishak 
score of > 4 or on a liver biopsy conducted during Screening; or
●
A FibroScan® score of ≥ 12.5 kPa within ≤ 6 months of Screening or during 
Screening period (FibroScan® must be approved by the local regulatory agency 
to qualify for entrance criteria); or
●
A Screening FibroTest result that is ≥ 0.73.
The result of the liver biopsy supersedes the results of FibroScan and FibroTest and result 
of FibroScan supersedes the results of FibroTest.  At Screening, it is recommended that 
subjects should otherwise meet all other inclusion criteria and none of the exclusion 
criteria before undergoing a liver biopsy.
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Child-Pugh Score and Category
Subjects with compensated cirrhosis will have Child-Pugh scores assessed, except those 
who are on ongoing use of anticoagulants.  The Child-Pugh score uses five clinical 
measures of liver disease (3 laboratory parameters and 2 clinical assessments) as shown in 
Table 6.  Child-Pugh score will be determined at the visits indicated in Appendix C and 
Appendix D.
Table 6.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites**
None
Slight
Moderate to severe
Hepatic encephalopathy*
None
Grade 1 or 2 (or suppressed 
with medication)
Grade 3 or 4 (or 
refractory)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points.
*
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
** None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Study 
Day 1 prior to dosing to confirm the subject has not progressed to hepatic decompensation 
since Screening for all subjects who have compensated cirrhosis.  Grading system 
guidelines for ascites are listed above in Table 6.  Subjects who present symptoms and 
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signs of hepatic decompensation including assessment at Day 1 prior to receiving study 
drug, will not be enrolled into the trial.
Hepatocellular Carcinoma Screening:  Liver Ultrasound
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Visit and at the last Post-Treatment Study Visit, as indicated in Appendix C
and Appendix D, for subjects with compensated cirrhosis only.  In-between those visits, 
HCC screening should be performed according to standard of care.
At the Screening Visit and at the last Post-Treatment Study Visit, subjects with 
compensated cirrhosis will be required to undergo a liver ultrasound to screen for HCC, 
unless the subject has a historical liver ultrasound, CT scan or MRI performed for HCC 
screening within 3 months prior to those visits, in which case the result of the historical 
ultrasound, CT scan or MRI will be used as the result for the Study Visit assessment.  A 
positive ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  
Alternate methods of screening for HCC (i.e., CT scan or MRI) at a study visit should be 
discussed with the study designated physician.
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments on the study visits 
specified in Appendix C and Appendix D.  Subjects should be instructed to follow the 
instructions provided with each instrument and to provide the best possible response to 
each item.  Site personnel shall not provide interpretation or assistance to subjects other 
than encouragement to complete the tasks.  Subjects who are functionally unable to read 
any of the instruments may have site personnel read the questionnaires to them.  Site 
personnel should encourage completion of each instrument at all specified visits and 
should ensure that a response is entered for all items.
Short Form 36 – Version 2 Health Survey (SF-36v2)
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use broad variety of health conditions and is the standard in literature for HCV.  
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The SF-36v2 instrument comprises 36 total items (questions) targeting a subject's 
functional health and well-being in 8 domains (physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional and mental health).  
Domain scores are also aggregated into a Physical Component Summary score and a 
Mental Component Summary score.  Higher SF-36v2 scores indicate a better state of 
health.  The SF-36v2 should require approximately 10 minutes to complete.
Treatment Satisfaction Questionnaire-Medicine (TSQM)
The TSQM is a 14-item instrument and includes assessments of satisfaction with a 
medication's effectiveness (Effectiveness, three items), lack of side effects (Side Effects; 
five items), convenience (three items) and the subject's global satisfaction (Global 
Satisfaction; three items). 
The subject should complete the questionnaire before site personnel perform any clinic 
assessments and before any interaction with the site personnel has occurred to avoid 
biasing the subject's response.  TSQM scores range from 0 – 100 with higher scores 
indicating better satisfaction.  The TSQM should require approximately 5 minutes to 
complete.
EuroQol-5 Dimensions-3 Level (EQ-5D-3L)
The EQ-5D-3L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 
3 levels of severity.  Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies.  Subjects also rate their 
perception of their overall health on a separate visual analogue scale (VAS).  The 
EQ-5D-3L should require approximately 5 minutes to complete.
PRO instruments should be consistently presented so that subjects complete the 
questionnaires in the following order:  the SF-36v2, TSQM, and EQ-5D-3L.  PRO 
instruments should be completed prior to drug administration on Day 1 and prior to any 
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discussion of adverse events or any review of laboratory findings, including HCV RNA 
levels, at all study specified visits listed in Appendix C and Appendix D.  The TSQM is 
the only PRO assessment that will not be performed at Day 1.
Enrollment and Assignment of Subject Numbers
All Screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet all the Inclusion Criteria and none of the Exclusion Criteria at Screening will 
proceed to enrollment via the IRT system on Study Day 1.
Subject numbers will be unique 4 digit numbers and will begin with 1001 with the 
first two digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  Subjects will be enrolled on Study Day 1 as described in Section 5.5.4.
Study Drug Compliance for Kits
Individual bottles of GLE/PIB will be provided for subject dosing to the site.  Each 
subject will have compliance documented by the site in the subject's source notes for 
GLE/PIB.  At each Study Drug Accountability Visit in Appendix C, the overall number of 
tablets of GLE/PIB remaining in each bottle will be recorded and entered in the IRT 
system along with the date of reconciliation.
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subgenotype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
sample, its genotype and subtype will be evaluated by a Sanger sequencing assay of a 
region of the NS5B gene by the central laboratory.
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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
Appendix D.  Plasma HCV RNA levels will be determined for each sample collected by 
the central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV 
Quantitative Test, v2.0.  The lower limit of detection (LLOD) and lower limit of 
quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Day 1 
and at the study visits indicated in Appendix C and Appendix D.  Specific instructions for 
preparation and storage of HCV RNA and HCV resistance samples will be provided by 
the central laboratory, AbbVie, or its designee.
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 study drug taken prior to the 
scheduled pharmacokinetic sample collection visits during the Treatment Period as 
detailed in Appendix C.
The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes and the 
eCRF.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
●
The Investigator or designee should make sure the subject is given the dosing 
card at the visits listed in Appendix C.
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●
The Investigator or designee will contact the subject approximately 2 days 
before the scheduled visit date to review the importance of proper study drug 
administration relative to the pharmacokinetic blood collection and 
documentation of dosing times on the dosing card.  The date and time of the 
contact will be entered into the subject's source documents.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.
Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
For subjects with HCV/HIV coinfection, samples for plasma HIV RNA levels and flow 
cytometry (including but not limited to CD4+ T-cell and CD8+ T-cell counts [absolute 
and percent]) will be obtained at the times specified in Appendix C and Appendix D.  
Plasma HIV-1 RNA will be measured by the central laboratory using the Roche COBAS 
AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 HIV-1 Assay.  Results below the 
LLOD are reported as:  "Not Detected."  HIV treatment failure is defined as detectable 
HIV RNA after 6 months of highly active antiretroviral therapy (HAART) or HIV RNA 
detectable after a period of undetectable measurement following use of HAART.
If a HIV RNA level result of subject on stable HIV ART is ≥ 200 copies/mL, the subject's 
HIV RNA is to be repeated as noted in Section 5.4.1.2.  At the time the repeat plasma 
HIV RNA is drawn, a sample should be obtained for HIV genotypic resistance testing.  If 
the subject's repeat HIV RNA is ≥ 500 copies/mL, the sample obtained for HIV genotypic 
resistance testing will be analyzed.
HIV protease (PR), reverse transcriptase (RT) and integrase (IN) sequences, as applicable, 
will be analyzed by Monogram Biosciences using the GenoSure® Prime drug resistance 
assay.
If the subject's repeat HIV RNA is < 200 copies/mL, then the subject will resume routine 
plasma HIV RNA assessments as shown in Appendix C and Appendix D, and described 
in Section 5.4.1.2.
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Specific instructions for preparation and storage of flow cytometry, plasma HIV RNA, 
and HIV resistance samples will be provided by the central laboratory, AbbVie, or its 
designee.
5.3.1.2
Meals and Dietary Requirements
Study drug (GLE/PIB) tablets should be dosed together and taken with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of GLE, PIB, and their possible metabolites will 
be collected by venipuncture at each study visit indicated below and in Appendix C.
●
At all Treatment-Period visits, except 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 plasma samples for the pharmacokinetic assays of GLE, PIB, and their possible 
metabolites will be provided by the central laboratory, AbbVie, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of GLE, PIB, and their 
possible metabolites will be packed in dry ice sufficient to last during transport, and 
transferred from the study site to the central laboratory.
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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 a validated assay 
methods in the Drug Analysis Department at AbbVie.  Plasma concentrations of any 
possible GLE and PIB metabolites may also be determined using either validated or 
non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 12 weeks after completion or discontinuation of study drug.
5.3.3.1
Primary Variable
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).
5.3.3.2
Secondary Variables
The secondary efficacy variables are:
●
The percentage of subjects with HCV OTVF.
●
The percentage of subjects with HCV virologic relapse.
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.
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The following resistance information will be analyzed for subjects receiving study drug 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the 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 resistance-associated 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, PIB, and their potential metabolites, if 
measured, will be tabulated and summarized.  
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 
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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 12 weeks for HCV RNA and 
the emergence and persistence of resistant viral substitutions.
If a subject is discontinued from study drug or in the Post-Treatment Period with an 
ongoing adverse event or an unresolved laboratory result that is significantly outside of 
the reference range, the investigator will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of study drug 
may be continued at the Principal Investigator's discretion after discussion with the 
subject, if the benefit of continuing study drug is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  If a 
subject is discontinued, subject will be monitored for SVR in the Post-Treatment Period 
as described in Section 5.1.3.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of HCV virologic failure for the 
purposes of subject management:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment.
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study drug treatment until the virologic failure criteria has been 
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confirmed.  Subjects meeting the virologic failure criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistance-associated viral substitutions until 12 weeks post-treatment.  
Alternative management will only be considered with the approval of TA MD.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV RNA will be assessed at each scheduled study visit during the Treatment and Post 
Treatment Period, as detailed in Appendix C and Appendix D.
The criteria for failure to maintain HIV virologic suppression among subjects on stable 
ARTs is as follows:
●
HIV RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 2 weeks 
apart, in a subject compliant with their HIV ARV therapy
Subjects should remain on HCV study drug treatment and his/her current ART regimen 
while the failure to maintain HIV virologic suppression is being confirmed.  A 
confirmatory HIV RNA and HIV genotypic resistance blood draw can be done as an 
unscheduled visit.  However, if this blood draw falls on the date of a scheduled study visit 
(Appendix C and Appendix D), only a single HIV RNA and HIV genotypic resistance 
blood draw needs to be performed at this visit.
At the time a confirmatory HIV RNA is drawn, a sample for HIV genotypic resistance 
testing should also be obtained; this sample will be analyzed if the subject's repeat plasma 
HIV RNA is ≥ 500 copies/mL.  Subjects should remain on HCV study drug treatment and 
his/her current ART regimen while the failure to maintain HIV virologic suppression is 
being confirmed.  A confirmatory HIV RNA and HIV genotypic resistance blood draw 
can be done as an unscheduled visit.  However, if this blood draw falls on the date of a 
scheduled study visit (Appendix C and Appendix D), only a single HIV RNA and HIV 
genotypic resistance blood draw needs to be performed at this visit.
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During the Treatment Period, subjects with confirmed failure to maintain HIV RNA 
suppression should continue HCV study drug treatment unless there is a requirement for 
prohibited concomitant medications (Section 5.2.3.2) to construct a new HIV ART 
regimen. 
Clinical management of failure to maintain HIV virologic suppression during the study 
(Treatment and Post-Treatment Period) will be handled by the Investigator according to 
current HIV treatment guidelines and local standard of care.  Subject's change of HIV 
ART regimen must be discussed with the AbbVie TA MD prior to the change being 
made, unless the change is being made to address an immediate safety concern.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of GLE/PIB will be dispensed in the form of film-coated co-formulated tablets 
at the visits listed in Appendix C.  Subjects will be instructed to take study drug at the 
same time every day with food.  Please refer to Section 5.3.1.1 and Section 5.3.2.1 for 
more details.
GLE/PIB will be provided by AbbVie as 100 mg/40 mg film-coated tablets.  GLE/PIB 
will be taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) 
QD and with food.
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Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  The site will also contact the IRT 
system to provide study drug return information for each kit at the visits specified in 
Appendix C.  At the end of the Treatment Period or at the Premature D/C Visit from the 
Treatment Period, the site will contact the IRT system to provide the discontinuation visit 
date information and study drug return information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the HCV virologic 
failure criteria defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drug to be used in this study is presented in Table 7.
Table 7.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode of Administration
Dosage Form
Strength
Glecaprevir/Pibrentasvir
AbbVie
Oral
Film-coated 
tablet
100 mg/
40 mg
5.5.2.1
Packaging and Labeling
Study drug will be supplied in bottles.  Each bottle will be labeled as required per country 
requirements.  Labels must remain affixed to the bottles.  All blank spaces should be 
completed by site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions
Glecaprevir/Pibrentasvir bottles
15° to 25°C (59° to 77°F)
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
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maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie (or designee).
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive the treatment assignment.  Enrolled subjects will 
be assigned to either Arm A (8 weeks of treatment) or Arm B (12 weeks of treatment) 
based on cirrhosis status.  The study drug kit numbers will be assigned according to 
schedules computer-generated before the start of the study by the AbbVie Statistics 
Department.
Contact information and user guidelines for IRT use will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.
All tablets of GLE/PIB will be dosed together (three tablets once daily).  All subjects 
should take all doses of study medications with food.
5.5.5
Blinding
This is an open-label study.
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5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing compliance with the treatment regimen with regard to HCV virologic response 
and potential development of resistance due to poor compliance.
At each study visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial, or empty) for assessment of treatment 
compliance.  At Study Drug Accountability visits denoted in Appendix C, study site 
personnel will assess subject compliance by inspecting the contents of the bottles and 
record the status of each one, as well as the exact number of remaining tablets of 
GLE/PIB in IRT.  Treatment compliance will be based on the number of tablets 
dispensed, as recorded in IRT, and the number of remaining tablets.  If poor compliance is 
noted, the subject should be counseled and this should be documented in the subject's 
source.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include lot number, kit number, number of tablets dispensed, subject number, initials 
of person who dispensed study drug, and date dispensed for each subject.  An overall 
accountability of the study drug will be performed and verified by the AbbVie monitor 
throughout the Treatment Period.  The monitor will review study drug accountability on 
an ongoing basis.  Final accountability will be verified by the monitor at the end of study 
drug treatment at the site.
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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.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The GLE/PIB combination regimen for 8- and 12-weeks in HCV treatment-naïve subjects 
without cirrhosis and with compensated cirrhosis respectively, was evaluated in HCV 
GT1 – 6 infected subjects in the Phase 3 studies discussed in detail in Section 3.0.  A high 
(> 97%) efficacy and positive safety profile was demonstrated in these studies.  AbbVie 
plans to evaluate the same combination regimen at the proposed label durations in a 
similar HCV GT1 – 6 infected population in Brazil.  The study is designed to include 
subpopulations of HCV-infected patients (e.g., GT1 and GT3; severe renal disorder and 
HIV/HCV co-infected population) that represents the unmet clinical treatment need in 
Brazil.  The selection of a two arm study design is appropriate so that treatment naïve 
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GT1 – 6 Brazilian subjects receive the proposed label treatment duration based on their 
cirrhosis status. 
In view of the expected high SVR rate in this study and the established safety profile of 
GLE/PIB in patients with advanced fibrosis, a control arm would be of limited value for 
efficacy comparison.  In this context, an open-label study is appropriate to adequately 
describe the efficacy and safety of this regimen administered for the proposed global label 
recommended durations for treatment naïve subjects.
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.  Next generation sequencing 
(NGS) methods are experimental.
5.6.3
Suitability of Subject Population
This study is intended to enroll HCV treatment-naïve adults in Brazil with chronic HCV 
genotype 1 – 6 without cirrhosis and with compensated cirrhosis with METAVIR 
equivalent fibrosis stage F2-F4.  Patients with HCV/HIV co-infection and CKD
Stages 1 – 5 may participate in the study.  The study population includes subpopulations 
of HCV-infected patients (e.g., GT1 and GT3; severe CKD and HIV/HCV co-infected 
populations) with high unmet clinical treatment need currently in Brazil.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The dose GLE/PIB 300 mg/120 mg QD 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.
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5.6.4.1.1
GLE and PIB Dose and Treatment Duration
GLE/PIB is proposed to be indicated for the treatment of chronic HCV infection in adults.  
In DAA-treatment naïve adults, the recommended oral dose of GLE/PIB is 
three 100 mg/40 mg tablets QD with food (total daily dose of 300 mg/120 mg) for 
8 weeks in subjects without cirrhosis and for 12 weeks in subjects with compensated 
cirrhosis based on the ITT SVR12 rates in the registrational studies.  Only HCV treatment 
naïve subjects will be enrolled in this study.  The efficacy in subjects with CKD4 – 5 did 
not differ from those without CKD.  Similar efficacy result was observed on HCV/HIV 
co-infected subjects and HCV monoinfected subjects.  The recommended durations for all 
HCV treatment naive patients of all HCV genotypes are summarized in Table 8, and 
SVR12 is summarized by GT in Table 9.  These are recommendations for all HCV-
infected patients, including those co-infected with HIV and patients with any degree of 
renal impairment.
A favorable safety profile has been observed in HCV-infected subjects without cirrhosis 
or with compensated cirrhosis who received the GLE + PIB 300 mg + 120 mg dose 
combination.  No dose response relationship was observed for adverse events, or for 
treatment-emergent post-nadir alanine aminotransferase elevations.
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for 
12 weeks.
Table 8.
Recommended GLE/PIB Duration for TN Patients
Patient Population
Recommended Treatment Duration
No Cirrhosis
Cirrhosis
Genotype 1 – 6
8 weeks
12 weeks
GLE = glecaprevir; PIB = pibrentasvir; TN = treatment-naïve
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Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)
SVR12%
GT1
GT2
GT3
GT4 – 6
GT1 – 6
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
All
TNa + TE-P/R, SOF/R or PIb
99.0
97.2
98.0
100
95.2
96.6
93.1
100
97.4
97.6
97.5
cirr = cirrhosis; GT = genotype; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; P/R = regimens 
containing interferon, pegylated interferon, and/or ribavirin; SOF/R = regimens containing sofosbuvir and ribavirin; 
SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naive
a.
Recommended treatment duration for subjects without cirrhosis is 8 weeks and with cirrhosis is 12 weeks.
b.
Recommended treatment duration for GT1, 2, 4 – 6 subjects without cirrhosis is 8 weeks and with cirrhosis is 
12 weeks.  Recommended treatment duration for GT3 subjects is 16 weeks.
Cross reference:  AbbVie.  R&D16/0146.  Summary of Clinical Efficacy for Glecaprevir/Pibrentasvir in HCV.  2016.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.1.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
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considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (see Section 6.1.7 regarding toxicity management) and/or if the 
investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an adverse event if the surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe 
form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to 
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).
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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4). 
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity. 
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
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Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL*
Grade 3
Severe or medically significant but not 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
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is sufficient evidence (information) 
to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
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If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
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In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 
investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).  If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  All adverse events and 
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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).
6.1.7.1
Management of Increases in ALT
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also > 2 × 
baseline value, the subject should have a confirmatory ALT measurement performed.  If, 
the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Complete the hepatic questionnaire.
●
Evaluate for an alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain Anti-HAV IgM, Anti-HAV Total, Anti-HBc IgM, Anti-HBc Total, 
Anti-HBs, HBV DNA, HBsAG, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, as appropriate.
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drug if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of liver 
failure.
○
At the discretion of the investigator.
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Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director.
6.1.8
Collection of Data Regarding Known AIDS-Defining 
Conditions
HIV infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  A list of these known AIDS-Defining Conditions (ADC) is 
presented in Appendix E.  The events listed in Appendix E will be summarized as 
HIV-related events, not as adverse events.  These ADCs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day 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 
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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.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
An interim data lock may occur in the study if interim study results are needed for 
regulatory interaction purposes.  No changes to the study design or treatment of subjects 
would result from this interim analysis, so adjustment for multiplicity is needed.
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.
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 and SVR12) based on defined visit windows.  A backward 
imputation method will be used to impute missing responses for SVR analyses.
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8.1.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all treated subjects by 
Arm (A and B), and overall.  Demographics include age, weight, height, body mass index 
(BMI), gender, race, and ethnicity.  Baseline characteristics include HCV genotype 
subtype, CKD stage, baseline HCV RNA level, fibrosis stage (F2, F3, F4), tobacco (user, 
ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) status, injection 
drug user (yes, within last 12 months; yes, more than 12 months ago; or no), use of stable 
opiate substitution, history of diabetes, baseline metabolic syndrome, history of bleeding 
disorders, history of depression or bipolar disorder, history of cardiovascular disease, 
geographic region, and HIV coinfection status.
All the demographics and baseline characteristics will be summarized as continuous or 
categorical variables where appropriate.  Summary statistics (N, mean, median, SD, and 
range) will be generated for continuous variables (e.g., age and BMI), and the number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).
Treatment compliance to study drug will be calculated based on the percentage of tablets 
taken relative to the total tablets expected to be taken.  A subject is considered to be 
compliant if the percentage is between 80% and 120%.  Compliance will be calculated for 
each subject and summarized with the mean, median, standard deviation, minimum, and 
maximum.  The percentage of compliant subjects will be summarized.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
The efficacy analyses will be performed across all treatment durations and genotypes.
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 
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< 15 IU/mL, regardless of whether the HCV RNA is detectable or not.  HCV RNA 
≥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) within all genotypes 
(GT1 – 6 subjects) will be analyzed on combined treatment groups.  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 using the normal approximation to the binomial distribution, unless the number of 
SVR12 non-responders is less than 5, in which case the Wilson's score method will be used 
for the confidence interval instead.
A summary of reason for SVR12 non-response (e.g., OTVF, relapse, other) will be 
provided.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The percentage of subjects with HCV OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA 
≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment with at least 6 weeks of treatment), and 
●
The percentage of subjects with post-treatment HCV virologic relapse (defined 
as confirmed HCV RNA ≥ 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 and 77 days or greater for 
subjects allocated to treatment durations of 8 weeks and 12 weeks, respectively.
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For OTVF 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 to the binomial distribution and a 
two-sided 95% confidence interval using the Wilson's score method.
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated as a sensitivity analysis for the primary endpoint of SVR12 based on ITT 
population.
8.1.2.4
Subgroup Analysis
The subgroup analyses will be performed based on the combined treatment groups.  The 
percentage of subjects with SVR12 will be calculated, as will the corresponding two sided 
95% Wilson score intervals, for the following subgroups:
●
HCV genotype and available subtype
●
Sex
●
Age 
●
Race 
●
Baseline HCV RNA level 
●
Baseline fibrosis stage 
●
Baseline cirrhosis status 
●
Baseline platelet count 
●
Baseline albumin 
●
Chronic Kidney Disease Stage 
●
HIV co-infection 
●
HIV ART regimen (for HIV coinfected)
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●
Baseline CD4+ count (for HIV coinfected)
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized by genotype:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR4 4 weeks after the last actual 
dose of study drug (SVR4);
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
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that domain will be considered missing.  The Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  For TSQM, if a 
respondent answers at least 2 items in the 3 item scales of Side Effects or Effectiveness, 
the missing items will be imputed with the average score of the answered items in the 
same scale.  For EQ-5D-3L, health state index and VAS scores no imputation will be 
performed for missing items.
The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
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(SF-36-PCS) scores; EQ5D-3L health state index and VAS score will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
For each of these scores, mean change from Baseline to Final Treatment Visit and from 
Baseline to Post-Treatment Week 12 will be summarized using an analysis of covariance 
(ANCOVA) model with baseline score as a covariate.
The following analyses of patient reported outcomes (PROs) also will be performed:
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
3 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 domain scores;
TSQM Effectiveness, Side Effects, Convenience, and Global Satisfaction scores will be 
summarized descriptively at each applicable visit.
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
HCV Resistance Analyses
For all subjects with an available sample, full length NS3/4A or NS5A from baseline 
samples will be sequenced by NGS.  For subjects who experience virologic failure (OTVF 
or post-treatment relapse), full length NS3/4A and NS5A genes from the first available 
sample after virologic failure with HCV RNA ≥ 1000 IU/mL will be sequenced by NGS.  
An appropriate subtype specific prototypic reference sequence will be used for 
comparison with sequences from samples.  Subjects treated with study drug who do not 
achieve SVR12 due to reasons other than virologic failure but have a time point with 
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HCV RNA ≥1000 IU/mL after treatment discontinuation, will have the sample at that 
time point sequenced.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥ 1000 IU/mL will be used.  
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in a post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample [(post-
baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution by NGS:  A post-baseline substitution or an 
enriched polymorphism detected by NGS.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
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●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A).
●
A listing of all baseline polymorphisms (15% detection threshold) at 
non-signature resistance-associated amino acid positions for each DAA target 
(NS3/4A and NS5A) for subjects who experience virologic failure.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
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:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
●
Polymorphisms at each non-signature amino acid position at a detection 
threshold of 15%.
Analysis 3:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A). 
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●
Listings by subject and time point of all post-baseline substitutions at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LIPA assay 
results from the Central laboratory will be used to categorize the subject.  This final HCV 
genotype subtype will be used in efficacy subgroup analyses.
8.1.5
HIV Resistance Analyses
If a subject develops a confirmed, plasma HIV RNA level ≥ 500 copies/mL after starting 
the study, the subject's HIV PR, RT, and/or IN sequences, as applicable, will be analyzed 
by Monogram Biosciences using the GenoSure® Prime drug resistance assays.  The 
number of subjects who demonstrate HIV genotypic resistance and the genotypic 
resistance mutations detected in the samples obtained from these subjects will be 
tabulated and summarized.  Resistance will be defined as described by the IAS-USA 
Panel.18
8.1.6
Safety
Safety summaries will be provided by the treatment arm (i.e., study drug duration 
assigned by cirrhosis status) and overall.  All subjects who receive at least one dose of 
study drug will be included in the safety analyses.
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8.1.6.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term.  The tabulation of the number of subjects with 
treatment-emergent adverse events by severity grade (Grades 1 – 5) and relationship to 
each study drug will also be provided.  Subjects reporting more than one adverse event for 
a given MedDRA preferred term will be counted only once for that term using the most 
severe grade for the severity grade table and the most related for the relationship to study 
drug tables.  Subjects reporting more than one type of event within a SOC will be counted 
only once for that SOC.
Additional analyses will be described in the statistical analysis plan.
8.1.6.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last non-missing measurement prior to the initial dose of study drug.  Mean changes from 
baseline to each post-baseline visit, including Final Treatment Visit, will be summarized 
descriptively.  Changes from baseline to maximum post-baseline CTCAE grade of 
laboratory values will also be summarized.
8.1.6.3
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.
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8.1.6.4
HCV/HIV Co-Infection
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV co-infection overall and in each treatment arm:
●
The percentage of subjects with plasma HIV RNA suppression at the end of 
treatment and at Post-Treatment Week 12 using the FDA Snapshot Algorithm;
●
The number and percentage of subjects with plasma HIV RNA < 20 copies/mL 
at each applicable time point;
●
Change from baseline in CD4+ T-cell count (absolute and percent) to each 
applicable post-baseline time point;
●
Change from baseline in lymphocytes (count and percentage) and CD8+ T-cell 
counts (absolute and percent) to each applicable post-baseline time point;
●
The listing of subjects with a plasma HIV RNA value ≥ 200 copies/mL at any 
baseline or post-baseline visit during the study.
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall and within each treatment arm.
8.1.7
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE, PIB, and their possible metabolites, if measured, will be 
tabulated for each subject and group.  Summary statistics will be computed for each time 
and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
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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.
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) may 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 utilize 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 a total of approximately 100 HCV infected treatment naïve GT1 – 6 
subjects will be enrolled in this study.  No formal hypothesis is being tested.  If the 
observed SVR12 rate in this study is 97% among 100 HCV GT1 – 6 treatment naive 
subjects, then the half-width of 2-sided 95% normal approximation interval is 3.3%.
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be allocated to a treatment arm 
according to their cirrhosis status (presence/absence).
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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific, and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information, and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain, and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
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9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
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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.
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 
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investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator 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 
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investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for GLE/PIB Fixed-Dose 
Combination.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety 
of Glecaprevir (GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults 
in Brazil with Chronic Hepatitis C Virus (HCV) Genotype 1 – 6 
Infection
Protocol Date: 
08 November 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al.  A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
Bruggmann P, Berg T, Øvrehus AL, et al.  Historical epidemiology of hepatitis C 
virus (HCV) in selected countries.  J Viral Hepat.  2014;21 Suppl 1:5-33.
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.
EPCLUSA® (sofosbuvir and velpatasvir) [US Prescribing Information].  Foster 
City, CA; Gilead Sciences, Inc., 2016.
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11.
American Association for the Study of Liver Diseases.  Hepatitis C guidance:  
AASLD-IDSA recommendations for testing, managing, and treating hepatitis C.  
Available at:  http://www.hcvguidelines.org.  Updated:  24 February 2016.  
Changes made:  10 March 2016.
12.
Protocol clinic e diretrizes terapeuticas para hepatitis C e coinfections.  MoH.  
2015.
13.
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.
14.
AbbVie.  ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure 
Edition 2.  06 September 2016.
15.
AbbVie.  R&D/16/0159.  A single-arm, open-label, study to evaluate the efficacy 
and safety of ABT-493/ABT-530 in renally-impaired adults with chronic 
hepatitis C virus genotype 1 – 6 infection (EXPEDITION-4) (Study M15-462).  
2016.
16.
Theise ND.  Liver biopsy assessment in chronic viral hepatitis: a personal, practical 
approach.  Mod Pathol.  2007;20 Suppl 1:S3-14.
17.
Available From:  http://www.biopredictive.com/intl/physician/fibrotest-for-
hcv/view?set_language=en.
18.
Johnson VA, Calvez V, Gunthard HF, et al.  Update of the drug resistance 
mutations in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):6-14.
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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Bioanalysis
Clinical
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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Informed Consentc
X
Dispense/Review Study Drug Dosing Card
X (Dispense only)
X
X
X (Review only)
Medical Historyd
X
X
Physical Exame
X
X
X
Vital Signs, Weight, Heightf
X
X
X
X
X
ECG
X
Hematology/Chemistryg/Coagulation Panel
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u)
X (u)
X (u)
X (u)
Anti-HCV Ab, Anti-HIV Ab
X
Hepatitis B Panel 
X
HCV Genotype and Subgenotype
X
FibroTest or FibroScan® or Liver Biopsyi
X
Concomitant Medication Assessment
X
X
X
X
X
Adverse Event Assessmentk
X
X
X
X
X
Study Drug Dispensed
X
X
Xk
HCV RNA Samples
X
X
X
X
X
Study Drug Accountability and Review of Study Drug 
Adherence
X
X
Xl
HCV Resistance Sample 
X
X
X
X
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Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Pharmacokinetic Samplesm
X
X
X
Child-Pugh Score (subjects with compensated cirrhosis 
only)n
X
X
Clinical Assessment of Hepatic Decompensation (subjects 
with compensated cirrhosis only)n
X
HCC Screening Liver ultrasound (subjects with 
compensated cirrhosis only)n
X
Patient Reported Outcomes Instruments (PROs)o
X
X
Flow cytometry samplep
X
X
X
HIV RNAp
X
X
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Week 8 or 12 in accordance with treatment duration as described in Section 5.1. 
a.
All procedures to be performed prior to first dose. 
b.
Subjects who prematurely discontinue during 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).
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
e.
A symptom-directed physical examination may be performed at any other visit, when necessary.  Any significant physical examination findings after the first dose will be 
recorded as adverse events.
f.
Height will be measured at the Screening Visit only.
g.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour fast prior to study drug intake (with the exception of the Screening Visit, which 
may be non-fasting).
h.
Pregnancy testing is not required for women not of childbearing potential as defined in Section 5.2.4.
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i.
For subjects who have not had a qualifying liver biopsy within the previous 24 months for subjects without cirrhosis or at any time for subjects with compensated cirrhosis) or 
a qualifying FibroScan® within the previous 6 months for subjects without cirrhosis or at any time prior to Screening for subjects with compensated cirrhosis).
j.
Subjects with a historical negative Liver Ultrasound, CT or MRI (within 3 months prior to screening) are not required to have a screening Liver Ultrasound performed.  If 
additional Liver Ultrasound testing is required it should be completed as an unscheduled visit.  A positive ultrasound result suspicious of HCC will be confirmed with CT scan 
or MRI.  A liver ultrasound should be performed at the end of treatment visit if it has been 6 months or more since the historical evaluation.
k.
See specific information regarding adverse event collection in Section 6.1.1.1.
l.
Dispensation at Week 8 and Study Drug Accountability at Week 12 are only applicable to Arm B.  Subjects should bring all study drug to every visit for the site to review 
adherence.  However, the site will record the number of tablets returned only at the Study Drug Accountability Visits at Weeks 4, 8, 12 (if applicable) or Premature D/C.
m.
PK samples will be collected at each scheduled study visit.  Detail regarding timing of samples is provided in Section 5.3.2.1.
n.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver Ultrasound are only performed for subjects in Arm B (compensated cirrhotic) as described in 
Section 5.3.1.1.
o.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.  TSQM will be the only PRO not administered at Day 1.
p.
For HCV/HIV co-infected subjects.
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Appendix D.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 4
PT Wk 12
PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Xc
Pregnancy Test (urine)d 
X (u)
X (u)c
Concomitant Medication Assessmente
X
Xe
Xe
Child-Pugh Score (subjects with compensated 
cirrhosis only)
X
X
Adverse Event Assessmentf
Xf
Xg
Xg
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Patient Reported Outcomes Instruments (PROs)h
X
X
Flow cytometry sampleh
X
X
HIV RNAi
X
X
HCC Screening:  Liver Ultrasoundj
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.
Chemistry/Coagulation panel will only be collected at PT Wk 12 for subjects in Arm B (compensated cirrhosis). 
c.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are not required at PT Wk 12, but only at PT D/C if subject discontinues prior to PT Wk 4.
d.
Women of childbearing potential do not require pregnancy testing beyond PTW4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to 
PTW4.  Pregnancy testing in PT Period is not required for females of non-childbearing potential as defined in Section 5.2.4.
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.  
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g.
Only SAEs will be collected thereafter as described in Section 6.1.4.
h.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
i.
For HCV/HIV co-infected subjects.
j.
HCC Screening Liver Ultrasound performed only subjects in Arm B (compensated cirrhosis) as described in Section 5.3.1.1. 
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.
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Appendix E.
List of AIDS-Defining Conditions
Collection of data regarding known AIDS-Defining Conditions is covered in 
Section 6.1.8.
AIDS-Defining Conditions:
●
Bacterial infections, multiple or recurrent*
●
Candidiasis of bronchi, trachea, or lungs
●
Candidiasis of esophagus†
●
Cervical cancer, invasive§
●
Coccidioidomycosis, disseminated or extrapulmonary
●
Cryptococcosis, extrapulmonary
●
Cryptosporidiosis, chronic intestinal (> 1 month's duration)
●
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 
> 1 month
●
Cytomegalovirus retinitis (with loss of vision)†
●
Encephalopathy, HIV related
●
Herpes simplex:  chronic ulcers (> 1 month's duration) or bronchitis, 
pneumonitis, or esophagitis (onset at age > 1 month)
●
Histoplasmosis, disseminated or extrapulmonary
●
Isosporiasis, chronic intestinal (> 1 month's duration)
●
Kaposi sarcoma†
●
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia 
complex*,†
●
Lymphoma, Burkitt (or equivalent term)
●
Lymphoma, immunoblastic (or equivalent term)
●
Lymphoma, primary, of brain
●
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary†
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●
Mycobacterium tuberculosis of any site, pulmonary,†,§ disseminated,† or 
extrapulmonary†
●
Mycobacterium, other species or unidentified species, disseminated† or 
extrapulmonary†
●
Pneumocystis jirovecii pneumonia†
●
Pneumonia, recurrent†,§
●
Progressive multifocal leukoencephalopathy
●
Salmonella septicemia, recurrent
●
Toxoplasmosis of brain, onset at age > 1 month†
●
Wasting syndrome attributed to HIV
*
Only among children aged < 13 years.  (CDC.  1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age.  MMWR 1994;43[No. RR-12].)
†
Condition that might be diagnosed presumptively.
§
Only among adults and adolescents aged > 13 years.  (CDC.  1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults.  MMWR 1992;41[No. RR-17].)
Cross reference:  Morbidity and Mortality Weekly Report (MMWR).  AIDS Defining Conditions.  2008.  Available 
from:  https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2 htm.
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Appendix F.
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:"
Add:
Emergency 24 hour Number:  +1 973-784-6402
Section 1.1  Synopsis
Subsection Objective:
Second bullet previously read:
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by 
evaluating the percentages of subjects with HCV on-treatment virologic failure and HCV 
virologic relapse across treatment durations and genotypes.
Has been changed to read:
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by 
evaluating the percentages of subjects with HCV on-treatment virologic failure (OTVF) 
and HCV virologic relapse across treatment durations and genotypes.
Section 1.1  Synopsis
Subsection Study Sites:
Previously read:
Approximately 12
Has been changed to read:
Approximately 14
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Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
First paragraph, third, fourth and fifth sentence previously read:
The number and percentage of subjects achieving SVR12 will be summarized with a 
two-sided 95% confidence interval.  If the SVR12 is less than 100%, then the normal 
approximation for the binomial distribution will be used as a confidence interval.  If the 
SVR12 rate is 100%, the Wilson's score method will be used to calculate the confidence 
interval.
Has been changed to read:
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, in which case the 
Wilson's score method will be used to calculate the confidence interval.
Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
First bullet previously read:
The percentage of subjects with on-treatment HCV virologic failure
Has been changed to read:
The percentage of subjects with OTVF.
Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "PROs:"
Previously read:
Change from baseline to each applicable visit in the patient reported outcome summary 
measures will be summarized.
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Has been changed to read:
Change from baseline to each applicable visit in the patient reported outcome summary 
measures for SF-36 and EQ-5D-3L will be summarized.  Summary measures at each 
applicable visit will be summarized for the TSQM.
Section 1.3  List of Abbreviations and Definition of Terms
Add:
ADC
AIDS-Defining Conditions
OTVF
On-treatment virologic failure
Section 4.2  Secondary Objectives
First bullet previously read:
The percentages of subjects with HCV on-treatment virologic failure;
Has been changed to read:
The percentages of subjects with HCV on-treatment virologic failure (OTVF);
Section 5.2.1  Inclusion Criteria
Criterion 3, first paragraph previously read:
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.
Has been changed to read:
Females of childbearing potential must have a negative serum pregnancy test result at 
Screening, and a negative urine pregnancy test at Study Day 1.
Section 5.2.2  Exclusion Criteria
Criterion 6, first sentence previously read:
Any current or past clinical evidence of Child-Pugh B or C classification or clinical 
history, including on Day 1 prior to dose, of liver decompensation including hepatic 
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encephalopathy or variceal bleeding, radiographic evidence of small ascites, or empiric 
use of lactulose/rifaximin.
Has been changed to read:
Any current or past clinical evidence of Child-Pugh B or C classification (score of > 6) or 
clinical history of liver decompensation including ascites on physical exam, including 
hepatic encephalopathy or variceal bleeding.
Section 5.2.2  Exclusion Criteria
Criterion 12 previously read:
Treatment for an AIDS-associated opportunistic infection (OI) (Appendix E) within 
6 months of Screening.
Has been changed to read:
Treatment for an AIDS-Defining Conditions (ADC) (Appendix E) within 6 months of 
Screening.
Section 5.2.3.4  Prohibited Therapy
First paragraph previously read:
Subjects must be able and willing to safely discontinue any prohibited medications or 
supplements listed in Table 4 at least 14 days or 10 half-lives (whichever is longer) prior 
to the first dose of GLE/PIB and not use these during the entire Treatment Period and for 
14 days following discontinuation of study drug.  For medications contraindicated with 
ABT-493/ABT-530 (glecapravir/pibrentasvir), refer to the recommended prescribing 
information section of the approval local product label where the regimen has received 
marketing authorization.  If locally approved labels are not available, refer to Table 4.
Has been changed to read: 
Medications or supplements prohibited to be administered with ABT-493/ABT-530 are 
listed in Table 4.  For subjects in the study in countries where ABT-493/ABT-530 
(glecapravir/pibrentasvir) has received marketing authorization, any medications in the 
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local label that are contraindicated to be administered with ABT-493/ABT-530 
(glecapravir/pibrentasvir) are also considered to be prohibited medications.  Subjects must 
be able to safely discontinue any prohibited medications or supplements at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of any study drug and not use 
these during the entire Treatment Period and for 14 days following discontinuation of 
study drugs.
Table 4.  Prohibited Medications and Supplements
Second row
Add:
efavirenz,
Table 4.  Prohibited Medications and Supplements
Table note "*" previously read:
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) 
should not be taken with study drugs.  Subjects receiving these statins should either 
switch to pravastatin or rosuvastatin prior to the first dose of study drugs or may interrupt 
statin therapy throughout the treatment period and until 14 days after the last dose of study 
drug, based on investigator's judgment.  If switching to or continuing pravastatin or 
rosuvastatin, it is recommended to reduce the pravastatin dose by 50% or limit the 
rosuvastatin dose to 10 mg QD when taking with the study drugs.
Has been changed to read:
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) 
should not be taken with the study drug.  After signing the informed consent form, 
subjects receiving these statins should either (a) switch to pravastatin or rosuvastatin at 
least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug or 
(b) interrupt statin therapy throughout the treatment period beginning at least 14 days or 
10 half-lives (whichever is longer) prior to the first dose of study drug until 14 days after 
the last dose of study drug, based on investigator's judgment.  If switching to or 
continuing pravastatin or rosuvastatin, it is recommended to either 1) reduce or limit the 
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pravastatin or rosuvastatin dose in accordance with the ABT-493/ABT-530 product label 
(if approved in the country); or 2) reduce the pravastatin dose by 50% or limit the 
rosuvastatin dose to 10 mg QD when taking with the study drug if ABT-493/ABT-530 is 
not yet approved in the country.
Section 5.2.3.4  Prohibited Therapy
Second paragraph previously read:
Use of ethinyl estradiol containing oral contraceptives with GLE/PIB was associated with 
ALT increases in some healthy female subjects.  Hormonal contraceptives (including oral, 
topical [including vaginal rings], injectable, or implantable varieties) containing ethinyl 
estradiol may not be used from 14 days prior to the first dose of GLE/PIB until 14 days 
after the end of GLE/PIB dosing.  Progestin-only contraceptives such as those containing 
norethindrone, desogestrel, or levonorgestrel, without ethinyl estradiol, may be used with 
GLE/PIB.  Post-menopausal hormone replacement therapy, i.e., estradiol, esterified or 
conjugated estrogens, as long as they do not contain ethinyl estradiol, may be used with 
GLE/PIB at the discretion of the Investigator.
Has been changed to read:
Contraceptives and/or hormonal replacement therapies containing only 
progestins/progestogens (such as those containing norethindrone, desogestrel, or 
levonorgestrel) or those containing progestins/progestogens with non-ethinyl estradiol 
estrogens (e.g., esterified or conjugated) may be used with GLE/PIB at the discretion of 
the Investigator.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Fourth paragraph, address previously read:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
(For sites in North America)
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Has been changed to read:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Testing
First bullet previously read:
WOCBP must have a negative serum pregnancy test result at Screening, and a negative 
serum or urine pregnancy test at Study Day 1.
Has been changed to read:
WOCBP must have a negative serum pregnancy test result at Screening, and a negative 
urine pregnancy test at Study Day 1.
Section 5.3.1.1  Study Procedures
Subsection Hepatocellular Carcinoma Screening:  Liver Ultrasound
Previously read:
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver will be performed as indicated in Appendix C for subjects with compensated 
cirrhosis only.  Subjects with compensated cirrhosis who do not have a historical
qualifying liver ultrasound, CT, or MRI within the past 3 months will have an ultrasound 
performed during Screening.  A positive ultrasound result suspicious for HCC will be 
confirmed with CT scan or MRI during Screening.  Suspicious ultrasound lesions 
confirmed by CT or MRI are exclusionary.
Has been changed to read:
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Visit and at the last Post-Treatment Study Visit, as indicated in Appendix C
and Appendix D, for subjects with compensated cirrhosis only.  In-between those visits, 
HCC screening should be performed according to standard of care.
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At the Screening Visit and at the last Post-Treatment Study Visit, subjects with 
compensated cirrhosis will be required to undergo a liver ultrasound to screen for HCC, 
unless the subject has a historical liver ultrasound, CT scan or MRI performed for HCC 
screening within 3 months prior to those visits, in which case the result of the historical 
ultrasound, CT scan or MRI will be used as the result for the Study Visit assessment.  A 
positive ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  
Alternate methods of screening for HCC (i.e., CT scan or MRI) at a study visit should be 
discussed with the study designated physician.
Section 5.3.1.1  Study Procedures
Subsection Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Heading "EuroQol-5 Dimensions-3 Level (EQ-5D-3L)"
Last paragraph
Add:  new last sentence
The TSQM is the only PRO assessment that will not be performed at Day 1.
Section 5.3.3  Efficacy Variables
Previously read:
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 24 weeks after completion or discontinuation of the study.
Has been changed to read:
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 12 weeks after completion or discontinuation of study drug.
Section 5.3.3.2  Secondary Variables
First bullet previously read:
The percentage of subjects with HCV on-treatment virologic failure.
Has been changed to read:
The percentage of subjects with HCV OTVF.
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Section 6.0  Complaints
Last paragraph, last sentence previously read:
For product complaints, please refer to Section 6.1.8.
Has been changed to read:
For product complaints, please refer to Section 6.2.
Section 6.1.7.1  Management of Increases in ALT
First paragraph, second bullet previously read:
Evaluate for an alternate etiology of ALT elevation; document in the source, update the 
medical history and concomitant medications eCRF (if applicable), and obtain Anti-HAV 
IgM, Anti-HAV IgG, Anti-HBc IgM, Anti-HBc Total, Anti-HBs, HBV DNA, HBsAG, 
Anti-HEV IgM, Anti-HEV IgG and HEV RNA, and other additional tests, as appropriate.
Has been changed to read:
Evaluate for an alternate etiology of ALT elevation; document in the source, update the 
medical history and concomitant medications eCRF (if applicable), and obtain Anti-HAV 
IgM, Anti-HAV Total, Anti-HBc IgM, Anti-HBc Total, Anti-HBs, HBV DNA, HBsAG, 
Anti-HEV IgM, Anti-HEV IgG and HEV RNA, and other additional tests, as appropriate.
Section 6.1.8  Collection of Data Regarding Known AIDS-Associated Opportunistic 
Infections
Section title and text previously read:
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections
HIV infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  A list of these known AIDS-associated opportunistic infections 
(OI) is presented in Appendix E.  The events listed in Appendix E will be summarized as 
HIV-related events, not as adverse events.  These OIs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
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Has been changed to read:
Baseline characteristics include HCV genotype subtype, CKD stage, baseline HCV RNA 
level, fibrosis stage (F2, F3, F4), tobacco (user, ex-user, or non-user) and alcohol use 
(drinker, ex-drinker, or non-drinker) status, injection drug user (yes, within last 
12 months; yes, more than 12 months ago; or no), use of stable opiate substitution, history 
of diabetes, baseline metabolic syndrome, history of bleeding disorders, history of 
depression or bipolar disorder, history of cardiovascular disease, geographic region, and 
HIV coinfection status.
Section 8.1.2.1  Primary Efficacy Endpoints
Third, fourth and fifth sentence previously read:
The number and percentage of subjects achieving SVR12 will be summarized with a 
two-sided 95% confidence interval.  If the SVR12 is less than 100%, then the normal 
approximation of the binomial distribution will be used as a confidence interval.  If the 
SVR12 rate is 100%, the Wilson's score method will be used to calculate the confidence 
interval.
Has been changed to read:
The number and percentage of subjects achieving SVR12 will be summarized 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, in which case the 
Wilson's score method will be used for the confidence interval instead.
A summary of reason for SVR12 non-response (e.g., OTVF, relapse, other) will be 
provided.
Section 8.1.2.2  Secondary Efficacy Endpoints
First bullet previously read:
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 
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≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA ≥ LLOQ at the 
end of treatment with at least 6 weeks of treatment), and
Has been changed to read:
The percentage of subjects with HCV OTVF (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA ≥ 100 IU/mL after 
HCV RNA < LLOQ during treatment, or HCV RNA ≥ LLOQ at the end of treatment with 
at least 6 weeks of treatment), and
Section 8.1.2.2  Secondary Efficacy Endpoints
Last paragraph previously read:
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.
Has been changed to read:
For OTVF 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.
Section 8.1.2.5  Additional Efficacy Endpoints
Delete:  last bullet
The percentage of subjects who relapse after achieving SVR12.
Section 8.1.3  Patient Reported Outcomes
Second paragraph previously read:
The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
(SF-36-PCS) scores; EQ5D-3L health state index and VAS score; TSQM Effectiveness, 
Side Effects, Convenience, and Global Satisfaction scores will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
For each of these scores, mean change from Baseline to Final Treatment Visit and from 
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Baseline to Post-Treatment Week 12 will be summarized using an analysis of covariance 
(ANCOVA) model with baseline score as a covariate.
Has been changed to read:
The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
(SF-36-PCS) scores; EQ5D-3L health state index and VAS score will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
For each of these scores, mean change from Baseline to Final Treatment Visit and from 
Baseline to Post-Treatment Week 12 will be summarized using an analysis of covariance 
(ANCOVA) model with baseline score as a covariate.
Section 8.1.3  Patient Reported Outcomes
Add:  new sixth paragraph
TSQM Effectiveness, Side Effects, Convenience, and Global Satisfaction scores will be 
summarized descriptively at each applicable visit.
Section 8.1.4  HCV Resistance Analyses
Second sentence previously read:
For subjects who experience virologic failure (on-treatment virologic failure or post-
treatment relapse), full length NS3/4A and NS5A genes from the first available sample 
after virologic failure with HCV RNA ≥ 1000 IU/mL will be sequenced by NGS.
Has been changed to read:
For subjects who experience virologic failure (OTVF or post-treatment relapse), full 
length NS3/4A and NS5A genes from the first available sample after virologic failure 
with HCV RNA ≥ 1000 IU/mL will be sequenced by NGS.
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Section 9.1  Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB)
Second paragraph, last sentence previously read:
The investigator will be required to submit, maintain, and archive study essential 
documents according to ICH GCP.
Has been changed to read:
The investigator will be required to submit, maintain, and archive study essential 
documents according to ICH GCP and all other applicable regulatory requirements.
Section 10.1 Source Documents
First paragraph
Add:  new fourth and fifth sentence
The Investigator Awareness Date (SAE CRF) may serve as the source for this data point.  
This adverse event data point required for eCRF completion can be entered directly in the 
eCRF.
Section 13.0  Completion of the Study
Second paragraph, first sentence previously read:
The investigator must retain any records related to the study according to local 
requirements.
Has been changed to read:
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.
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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Clinical
Clinical Drug Supply Management
Has been changed to read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Bioanalysis
Clinical
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Appendix C.  Study Activities – Treatment Period
Activity "Pregnancy Test (serum [s] urine [u])h," "Child-Pugh Score (subjects with compensated cirrhosis only)," "Clinical 
Assessment of Hepatic Decompensation (subjects with compensated cirrhosis only)" and "HCC Screening Liver ultrasound 
(subjects with compensated cirrhosis only)" previously read:
Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u, s)
X (u)
X (u)
X (u)
Child-Pugh Score (subjects with compensated cirrhosis 
only) 
X
X
X
Clinical Assessment of Hepatic Decompensation (subjects 
with compensated cirrhosis only)
X
HCC Screening Liver ultrasound (subjects with 
compensated cirrhosis only) 
X
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Has been changed to read:
Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u)
X (u)
X (u)
X (u)
Child-Pugh Score (subjects with compensated cirrhosis 
only)n
X
X
Clinical Assessment of Hepatic Decompensation (subjects 
with compensated cirrhosis only)n
X
HCC Screening Liver ultrasound (subjects with 
compensated cirrhosis only)n
X
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Appendix C.  Study Activities – Treatment Period
Add:  new table note "n."
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation, and Liver 
Ultrasound are only performed for subjects in Arm B (compensated cirrhotic) as described 
in Section 5.3.1.1.
Appendix C.  Study Activities – Treatment Period
Tablenote "o."
Add:  new last sentence
TSQM will be the only PRO not administered at Day 1.
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Appendix D.  Study Activities – Post-Treatment (PT) Period
Previously read:
Activity
PT Wk 4
PT Wk 12
PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Pregnancy Test (urine)c 
X (u)
X (u)b
Concomitant Medication Assessmentd
X
Xd
Xd
Child-Pugh Score (subjects with compensated 
cirrhosis only)
X
X
Adverse Event Assessmente
Xe
Xf
Xf
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Patient Reported Outcomes Instruments (PROs)g
X
X
Flow cytometry sampleh
X
X
HIV RNAh
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 not required at PT Wk 12, but only at PT D/C if subject discontinues prior to PT Wk 4.
c.
Women of childbearing potential do not require pregnancy testing beyond PTW4. Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to 
PTW4.  Pregnancy testing in PT Period is not required for females of non-childbearing potential as defined in Section 5.2.4.
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.
Only SAEs will be collected thereafter as described in Section 6.1.4.
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g.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
h.
For HCV/HIV co-infected subjects.
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.
Has been changed to read:
Activity
PT Wk 4
PT Wk 12
PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Xc
Pregnancy Test (urine)d 
X (u)
X (u)c
Concomitant Medication Assessmente
X
Xe
Xe
Child-Pugh Score (subjects with compensated 
cirrhosis only)
X
X
Adverse Event Assessmentf
Xf
Xg
Xg
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Patient Reported Outcomes Instruments (PROs)h
X
X
Flow cytometry sampleh
X
X
HIV RNAi
X
X
HCC Screening:  Liver Ultrasoundj
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.
Chemistry/Coagulation panel will only be collected at PT Wk 12 for subjects in Arm B (compensated cirrhosis). 
c.
Hematology/Chemistry/Coagulation Panel and Pregnancy Test are not required at PT Wk 12, but only at PT D/C if subject discontinues prior to PT Wk 4.
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d.
Women of childbearing potential do not require pregnancy testing beyond PTW4.  Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to 
PTW4.  Pregnancy testing in PT Period is not required for females of non-childbearing potential as defined in Section 5.2.4.
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.
Only SAEs will be collected thereafter as described in Section 6.1.4.
h.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
i.
For HCV/HIV co-infected subjects.
j.
HCC Screening Liver Ultrasound performed only subjects in Arm B (compensated cirrhosis) as described in Section 5.3.1.1. 
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.
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Appendix E.  List of AIDS-Associated Opportunistic Infections
Appendix title and text previously read:
Appendix E.
List of AIDS-Associated Opportunistic Infections 
Collection of data regarding known AIDS-associated opportunistic infections is covered 
in Section 6.1.8.
AIDS-Defining Conditions:
●
Aspergillosis
●
Bartonellosis
●
Candidiasis (*Bronchi; *Esophagus; *Lungs; Oropharyngeal [Thrush]; 
*Trachea; Vulvovaginal [Persistent, Frequent, or Poorly Responsive to 
Therapy])
●
*Coccidioidomycosis
●
*Cryptococcosis
●
*Cryptosporidiosis
●
Cytomegalovirus (*Retinitis; *Cytomegalovirus Disease [other than liver, 
spleen or nodes])
●
Enteric infections, Recurrent (Bacterial)
●
Herpes Simplex Virus (*Bronchitis; *Esophagitis; *Pneumonitis; *Chronic 
Ulcer(s) [> 1 month in duration])
●
*Histoplasmosis
●
Human Herpesvirus-8 Disease (Kaposi Sarcoma, Primary Effusion 
Lymphoma, Multicentric Castleman's Disease)
●
Human Papilloma Virus Infections
●
*Isosporiasis (Cystoisosporiasis)
●
Microsporidiosis
●
*Mycobacterium avium – Complex Disease (Disseminated)
●
*Mycobacterium tuberculosis – Infection and Disease
●
*Pneumonia
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●
*Pneumonia, recurrent bacterial (and/or other respiratory infections including 
sinusitis, bronchitis, otitis)
●
*Progressive multifocal leukoencephalopathy (JC Virus Infection)
●
Syphilis
●
*Toxoplasma Gondii Encephalitis
●
Varicella Zoster Virus Diseases
*
AIDS-defining event as described by CDC Surveillance Case Definition of 1993.
Cross reference:  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV Infected Adults and 
Adolescents.  Available from:  http://aidsinfo nih.gov/guidelines.
Has been changed to read:
Appendix E.
List of AIDS-Defining Conditions
Collection of data regarding known AIDS-Defining Conditions is covered in 
Section 6.1.8.
AIDS-Defining Conditions:
●
Bacterial infections, multiple or recurrent*
●
Candidiasis of bronchi, trachea, or lungs
●
Candidiasis of esophagus†
●
Cervical cancer, invasive§
●
Coccidioidomycosis, disseminated or extrapulmonary
●
Cryptococcosis, extrapulmonary
●
Cryptosporidiosis, chronic intestinal (> 1 month's duration)
●
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 
> 1 month
●
Cytomegalovirus retinitis (with loss of vision)†
●
Encephalopathy, HIV related
●
Herpes simplex:  chronic ulcers (> 1 month's duration) or bronchitis, 
pneumonitis, or esophagitis (onset at age > 1 month)
●
Histoplasmosis, disseminated or extrapulmonary
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●
Isosporiasis, chronic intestinal (> 1 month's duration)
●
Kaposi sarcoma†
●
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia 
complex*,†
●
Lymphoma, Burkitt (or equivalent term)
●
Lymphoma, immunoblastic (or equivalent term)
●
Lymphoma, primary, of brain
●
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary†
●
Mycobacterium tuberculosis of any site, pulmonary,†,§ disseminated,† or 
extrapulmonary†
●
Mycobacterium, other species or unidentified species, disseminated† or 
extrapulmonary†
●
Pneumocystis jirovecii pneumonia†
●
Pneumonia, recurrent†,§
●
Progressive multifocal leukoencephalopathy
●
Salmonella septicemia, recurrent
●
Toxoplasmosis of brain, onset at age > 1 month†
●
Wasting syndrome attributed to HIV
*
Only among children aged < 13 years.  (CDC.  1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age.  MMWR 1994;43[No. RR-12].)
†
Condition that might be diagnosed presumptively.
§
Only among adults and adolescents aged > 13 years.  (CDC.  1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults.  MMWR 1992;41[No. RR-17].)
Cross reference:  Morbidity and Mortality Weekly Report (MMWR).  AIDS Defining Conditions.  2008.  Available 
from:  https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2 htm.
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1.1
Synopsis
AbbVie Inc.
Protocol Number:  M16-156
Name of Study Drug:  Glecaprevir, Pibrentasvir
Phase of Development:  3b
Name of Active Ingredient:  Glecaprevir, 
Pibrentasvir
Date of Protocol Synopsis:  16 February 2017
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults in Brazil with Chronic Hepatitis C Virus (HCV) 
Genotype 1 – 6 Infection
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following therapy) and safety of 
GLE/PIB combination in treatment-naïve adults in Brazil with chronic hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis.  The efficacy 
endpoints will be analyzed based on combined treatment duration and genotypes and safety 
analysis will be done by individual treatment groups.
!
The secondary objectives are to assess efficacy of GLE/PIB by hepatitis C virus (HCV) 
genotype (GT) 1 – 6 infection without cirrhosis or with compensated cirrhosis by evaluating the 
percentages of subjects with HCV on-treatment virologic failure and HCV virologic relapse 
across treatment durations and genotypes.
Investigators:  Multicenter, single country (Brazil)
Study Sites:  Approximately 12
Study Population:  Chronic HCV GT 1 – 6-infected male and female adults with Metavir equivalent 
fibrosis stage of F2 – F4, at least 18 years of age, without cirrhosis or with compensated cirrhosis, who 
are HCV treatment-naïve (i.e., has never received a single dose of any approved or investigational anti-
HCV medication).
Number of Subjects to be Enrolled: Approximately 100 subjects
Methodology:
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of GLE/PIB 
combination for an 8 or 12-week treatment duration in adults in Brazil with chronic HCV GT1 – 6 
infection, without cirrhosis (F2 – F3) or with compensated cirrhosis (F4), who are HCV treatment-naïve.  
Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The study enrollment will be 
monitored to meet the following enrollment criteria:  1) a minimum of 35 GT1 and 35 GT3 subjects and 
2) approximately 80 F2 – F3 and a maximum of approximately 20 F4 subjects.
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M16-156 Protocol
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Methodology (Continued):  
Approximately 100 eligible subjects will be enrolled into one of the following treatment arms:
!
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 and F3) subjects will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 8 weeks.
!
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be treated with GLE/PIB 
300 mg/120 mg once daily (QD) for 12 weeks.
The study will consist of a Screening Period, Treatment Period and Post Treatment Period:
Screening Period:  Subjects will have up to 35 days following the Screening Visit to confirm eligibility 
and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg once daily 
(QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on their cirrhosis status.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 4 and 8 for all subjects 
and an additional Week 12 visit for subjects in Arm B.  Study procedures, including assessment of 
adverse events, vital signs, study medication adherence, concomitant medications, HCV RNA, HCV 
resistance, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks to monitor safety, HCV RNA levels and the emergence and persistence of 
resistance-associated substitutions.
During the Post-Treatment Period, all subjects will have visits at PT Weeks 4 and 12, following 
completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the emergence 
and persistence of resistant viral variants will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject has positive plasma HCV antibody and HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
2.
Subject must be documented as without cirrhosis with METAVIR equivalent fibrosis stage of F2 –
F3 or with compensated cirrhosis (F4) based on results of a liver biopsy, or FibroScan, or FibroTest 
score (as described in Section 5.3.1.1).
4.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a positive test result for 
anti-Human Immunodeficiency Virus antibody at Screening and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study), or 
On a stable, qualifying HIV ART regimen for at least 8 weeks prior to Baseline.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at Screening (by the 
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 12 months 
prior to Screening (by an approved plasma HIVRNA quantitative assay including but not limited to:  
COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
5.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month prior to 
enrollment, and may be on hemodialysis or peritoneal dialysis.
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
6.
Subjects With Compensated Cirrhosis 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.
Main Exclusion:
1.
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Current HBV 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)
3.
History of severe, life-threatening, or other significant sensitivity to any excipients of the study drug.
4.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical history, 
including on Day 1 prior to dose, of liver decompensation including hepatic encephalopathy or 
variceal bleeding, radiographic evidence of small ascites, or empiric use of lactulose/rifaximin.  
Prophylactic use of beta blockers is not exclusionary (see Section 5.3.1.1).
5.
Laboratory parameters exclusions:
!
ALT > 10 × ULN; AST > 10 × ULN
!
Total Bilirubin > 3.0 mg/dL 
!
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
!
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with compensated cirrhosis) 
6.
Receipt of any investigational or commercially available anti-HCV agents examples include, but are 
not limited to:  interferon, pegylated interferon, ribavirin, sofosbuvir, telaprevir, boceprevir, 
simeprevir, asunaprevir, paritaprevir, grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, 
voxilaprevir, velpatasvir or dasabuvir.
Investigational Products:
Glecaprevir/Pibrentasvir 100 mg/40 mg Film-coated tablet
Doses:
Glecaprevir/Pibrentasvir 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food.
Reference Therapy:
N/A
Doses:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects without cirrhosis will receive GLE/PIB for 8 weeks, while subjects 
with compensated cirrhosis will receive GLE/PIB for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
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Criteria for Evaluation (Continued):
Safety:  
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Patient Reported Outcomes (PROs):
The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the functional health 
and well-being of subjects.  The Treatment Satisfaction Questionnaire (TSQM) will be used to assess 
treatment satisfaction with the GLE/PIB combined regime.  EuroQol-5 Dimensions-3 Level (EQ-5D-3L) 
is a health state utility instrument that evaluates preference for health status (utility); subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS).
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
baseline polymorphisms at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequences; and 2) for subjects who do not achieve SVR12, post-baseline substitutions 
relative to the corresponding baseline sequence in available samples.
Pharmacokinetic:  
Individual plasma concentrations of GLE, PIB, 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) across all genotypes (GT1 – 6 subjects) and treatment 
groups.  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.  If the SVR12 is less than 100%, then the normal approximation for the binomial distribution will 
be used as a confidence interval.  If the SVR12 rate is 100%, the Wilson's score method will be used to 
calculate the confidence interval.
The secondary efficacy endpoints are:
!
The percentage of subjects with on-treatment HCV virologic failure.
!
The percentage of subjects with post-treatment HCV virologic relapse.
Subgroup analysis based on the treatment arm (i.e., without cirrhosis/with compensated cirrhosis) will be 
performed.  For the secondary efficacy endpoints and subgroup analysis, the two-sided 95% confidence 
interval will be calculated using Wilson's score method.  
PROs:
Change from baseline to each applicable visit in the patient reported outcome summary measures will be 
summarized.
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Statistical Methods (Continued):
Safety:  
Safety summaries will be provided by the treatment arm (i.e., cirrhosis status/study drug duration) and 
overall.  All subjects who receive at least one dose of study drug will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins or 
worsens in severity after initiation of study drug 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.  
Resistance:
For all subjects receiving study drug, baseline polymorphisms at signature resistance-associated amino 
acid positions identified by next generation sequencing (NGS) and comparison to the appropriate 
prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the 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.
Pharmacokinetic:
Individual plasma concentrations of GLE, PIB, and their possible metabolites will be tabulated and 
summarized.  Pharmacokinetic data from this study may be combined with data from other studies for the 
population pharmacokinetic analyses using a non-linear mixed-effect modeling approach with the 
NONMEM software.  Relationships between exposure and clinical observations (antiviral activity) may 
be explored.
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1.2
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Anti-HBc
Anti-Hepatitis B core antibody
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
ART
Antiretroviral therapy
AUC
Area under the plasma concentration-time curve
BMI
Body mass index
BUN
Blood urea nitrogen
CKD
Chronic kidney disease
CL/F
Apparent oral plasma clearance
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed tomography
Ctrough
Pre-dose trough plasma concentration
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EQ-5D-3L
EuroQol-5 Dimensions-3 Level
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HAART
Highly active antiretroviral therapy
HBV
Hepatitis B Virus
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HCC
Hepatocellular carcinoma
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
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
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NGS
Next generation sequence
NONMEM
Non-linear mixed-effect modeling
NS5A
Nonstructural viral protein 5A
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
PK
Pharmacokinetic
POR
Proof of receipt
P/R
pegIFN/RBV
PRO
Patient reported outcome
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
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RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SF-36v2
Short Form 36 – Version 2 Health Survey
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
TE
Treatment Experienced
TN
Treatment-naïve
TSQM
Treatment Satisfaction Questionnaire-Medicine
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
WOCBP
Women of child bearing potential
Definition of Terms
Study Drug
glecaprevir/pibrentasvir
Study Day 1
First day of study drug dosing 
Treatment Period
Day 1 through last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 12 or 
Post-Treatment Discontinuation
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Synopsis................................................................................................. 2
1.2
List of Abbreviations and Definition of Terms........................................ 7
2.0
Table of Contents ................................................................ 10
3.0
Introduction......................................................................... 15
3.1
Differences Statement .......................................................................... 25
3.2
Benefits and Risks................................................................................ 26
4.0
Study Objective ................................................................... 26
4.1
Primary Objectives............................................................................... 26
4.2
Secondary Objectives ........................................................................... 27
5.0
Investigational Plan............................................................. 27
5.1
Overall Study Design and Plan:  Description ........................................ 27
5.1.1
Screening Period .................................................................................. 29
5.1.1.1
Rescreening.......................................................................................... 29
5.1.2
Treatment Period.................................................................................. 30
5.1.3
Post-Treatment Period.......................................................................... 31
5.2
Selection of Study Population............................................................... 31
5.2.1
Inclusion Criteria.................................................................................. 31
5.2.2
Exclusion Criteria................................................................................. 34
5.2.3
Prior and Concomitant Therapy............................................................ 36
5.2.3.1
Prior HCV Therapy .............................................................................. 37
5.2.3.2
Prior and Concomitant HIV Therapy .................................................... 37
5.2.3.3
Concomitant Therapy........................................................................... 38
5.2.3.4
Prohibited Therapy............................................................................... 38
5.2.4
Contraception Recommendations ......................................................... 39
5.3
Efficacy, Pharmacokinetic, and Safety Assessments/Variables ............. 40
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 40
5.3.1.1
Study Procedures.................................................................................. 41
5.3.1.2
Meals and Dietary Requirements.......................................................... 53
5.3.2
Drug Concentration Measurements....................................................... 53
5.3.2.1
Collection of Samples for Analysis....................................................... 53
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5.3.2.2
Handling/Processing of Samples........................................................... 53
5.3.2.3
Disposition of Samples......................................................................... 53
5.3.2.4
Measurement Methods ......................................................................... 54
5.3.3
Efficacy Variables................................................................................ 54
5.3.3.1
Primary Variable .................................................................................. 54
5.3.3.2
Secondary Variables............................................................................. 54
5.3.3.3
HCV Resistance Variables.................................................................... 54
5.3.4
Safety Variables ................................................................................... 55
5.3.5
Pharmacokinetic Variables ................................................................... 55
5.4
Removal of Subjects from Therapy or Assessment ............................... 55
5.4.1
Discontinuation of Individual Subjects ................................................. 55
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 56
5.4.1.2
Failure to Maintain HIV Virologic Suppression.................................... 57
5.4.2
Discontinuation of Entire Study............................................................ 58
5.5
Treatments ........................................................................................... 58
5.5.1
Treatments Administered...................................................................... 58
5.5.2
Identity of Investigational Products ...................................................... 59
5.5.2.1
Packaging and Labeling........................................................................ 59
5.5.2.2
Storage and Disposition of Study Drug................................................. 59
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 60
5.5.4
Selection and Timing of Dose for Each Subject .................................... 60
5.5.5
Blinding ............................................................................................... 60
5.5.6
Treatment Compliance ......................................................................... 61
5.5.7
Drug Accountability ............................................................................. 61
5.6
Discussion and Justification of Study Design........................................ 62
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 62
5.6.2
Appropriateness of Measurements........................................................ 63
5.6.3
Suitability of Subject Population .......................................................... 63
5.6.4
Selection of Doses in the Study ............................................................ 63
5.6.4.1
Rationale for Dose Selections............................................................... 63
5.6.4.1.1
GLE and PIB Dose and Treatment Duration......................................... 64
6.0
Complaints........................................................................... 65
6.1
Medical Complaints ............................................................................. 65
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6.1.1
Definitions ........................................................................................... 66
6.1.1.1
Adverse Event...................................................................................... 66
6.1.1.2
Serious Adverse Events........................................................................ 67
6.1.2
Adverse Event Severity ........................................................................ 68
6.1.3
Relationship to Study Drug................................................................... 69
6.1.4
Adverse Event Collection Period.......................................................... 70
6.1.5
Adverse Event Reporting...................................................................... 70
6.1.6
Pregnancy............................................................................................. 72
6.1.7
Toxicity Management........................................................................... 72
6.1.7.1
Management of Increases in ALT......................................................... 73
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections ....................................................................... 74
6.2
Product Complaint................................................................................ 74
6.2.1
Definition............................................................................................. 74
6.2.2
Reporting ............................................................................................. 74
7.0
Protocol Deviations ............................................................. 75
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 76
8.1
Statistical and Analytical Plans............................................................. 76
8.1.1
Demographics and Baseline Characteristics.......................................... 77
8.1.2
Efficacy................................................................................................ 77
8.1.2.1
Primary Efficacy Endpoints.................................................................. 78
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 78
8.1.2.3
Sensitivity Analysis.............................................................................. 79
8.1.2.4
Subgroup Analysis ............................................................................... 79
8.1.2.5
Additional Efficacy Endpoints.............................................................. 80
8.1.3
Patient Reported Outcomes .................................................................. 80
8.1.4
HCV Resistance Analyses .................................................................... 81
8.1.5
HIV Resistance Analyses ..................................................................... 84
8.1.6
Safety................................................................................................... 84
8.1.6.1
Adverse Events..................................................................................... 84
8.1.6.2
Clinical Laboratory Data ...................................................................... 85
8.1.6.3
Vital Signs Data ................................................................................... 85
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8.1.6.4
HCV/HIV Co-Infection ........................................................................ 85
8.1.7
Pharmacokinetic and Exposure-Response Analyses.............................. 86
8.2
Determination of Sample Size .............................................................. 87
8.3
Randomization Methods....................................................................... 87
9.0
Ethics.................................................................................... 87
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 87
9.2
Ethical Conduct of the Study................................................................ 88
9.3
Subject Information and Consent.......................................................... 88
10.0
Source Documents and Case Report Form 
Completion ..........................................................................89
10.1
Source Documents................................................................................ 89
10.2
Case Report Forms............................................................................... 89
11.0
Data Quality Assurance ...................................................... 90
12.0
Use of Information .............................................................. 90
13.0
Completion of the Study ..................................................... 91
14.0
Investigator's Agreement....................................................92
15.0
Reference List...................................................................... 93
List of Tables
Table 1.
Overview of Clinical Studies by Subject Population ............................. 18
Table 2.
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 
– 6 (ITT Population, Phase 2 and 3 Analysis Set) ................................. 20
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)........................................................................................ 23
Table 4.
Prohibited Medications and Supplements ............................................. 38
Table 5.
Clinical Laboratory Tests ..................................................................... 44
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 47
Table 7.
Identity of Investigational Products ...................................................... 59
Table 8.
Recommended GLE/PIB Duration for TN Patients............................... 64
Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)................................... 65
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List of Figures
Figure 1.
Study Design........................................................................................ 28
Figure 2.
Adverse Event Collection..................................................................... 70
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.......................................... 95
Appendix B.
List of Protocol Signatories .................................................................. 97
Appendix C.
Study Activities – Treatment Period ..................................................... 98
Appendix D.
Study Activities – Post-Treatment (PT) Period ....................................101
Appendix E.
List of AIDS-Associated Opportunistic Infections ...............................103
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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 
184 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype 1 (GT1) being the most prevalent worldwide.  HCV genotypes 2 (GT2) and 3 
(GT3) infections are more common in Latin America (5% to 30%), Europe (20% to 40%) 
and Asia (30% to 45%).2-4  HCV GT4 is commonly found in parts of Africa and the 
Middle East, particularly in Egypt, GT5 is primarily found in South Africa, and GT6 is 
primarily found in south-east Asia, and GT7 has recently been described in Central 
Africa.5  Genotype 1 (GT1) is the most frequent in all regions in Brazil (65%), followed 
by genotype 3 (30%) and GT2 (5%).  Genotypes 4 to 6 are rarely reported (0.3%) in the 
country.6
Depending on various risk factors, between 10% and 40% of all patients with chronic 
HCV infection will develop cirrhosis.  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.  Patients 
diagnosed with hepatocellular carcinoma 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 hepatocellular 
carcinoma.8,9
At the time of initiation of this study, therapy for HCV had improved considerably with 
the approval of several interferon (IFN)-free direct-acting antiviral agent (DAA) regimens 
(ledipasvir [LDV]/sofosbuvir [SOF], SOF plus simeprevir [SMV], SOF plus daclatasvir 
[DCV], ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] ± dasabuvir [DSV], elbasvir 
[EBR]/grazoprevir [GZR], and SOF/velpatasvir [VEL]).10,11  In Brazil, the National HCV 
Program provides specific regimens to a subset of subjects with confirmed HCV and 
specific GT infection.  The mono HCV infected subjects must have confirmed Metavir F3 
and F4 fibrosis stage, and the HCV/HIV co-infected should be treated regardless of liver 
fibrosis staging.  A treatment guideline recommends SOF + DCV or SOF + SMV for 
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GT1; SOF + RBV for GT2; SOF + pegIFN or SOF + DCV for GT3; and SOF + pegIFN + 
RBV or SOF + DCV for GT4.  Duration of treatment is based on history of monoinfection 
with HCV, or co-infection with HIV, GT subtype and fibrosis staging.  These regimens 
are available across the country and prescribed free of charge within the country's 
universal health care system.  
However, these approved and recommended regimens are not equally potent across all 
HCV genotypes and subpopulations.  Additional limitations of several current regimens 
include the requirement of ribavirin (RBV) for certain populations, significant drug to 
drug interactions, limited options for subjects with renal insufficiency, reduced efficacy in 
patients with baseline amino acid polymorphisms associated with reduced susceptibility to 
the HCV nonstructural 5A (NS5A) inhibitors (NS5AI) or NS3/4A protease inhibitors (PI), 
and limited options for patients who have failed regimens containing an NS5AI and/or PI.  
Efficacy in GT3-infected patients, particularly those who are treatment-experienced (TE) 
and/or cirrhotic, is also substantially lower than what is observed for other genotypes.12
AbbVie has developed two "next generation" DAAs, glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5AI, for use in combination for the treatment of HCV.  GLE and PIB each has 
potent in vitro antiviral activity against genotypes 1 through 613 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.14
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GLE/PIB
Overview of GLE/PIB Registrational Program and Supportive Phase 2 Studies
The GLE/PIB registrational program included a broad subject population including 
subjects with compensated liver disease and subjects with severe renal insufficiency 
across GT1 – 6 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, SOF, NS5A inhibitors, or PIs were allowed 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 treatment-naïve (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 compensated cirrhosis, or HIV 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 ≥ 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 in NS3 and NS5A 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, data was analyzed at the 15% detection threshold, and baseline 
polymorphisms at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 
92, and 93 in NS5A were examined for impact on SVR12. 
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 did not have an impact on 
treatment outcome.  The NS5A polymorphisms at positions 24, 28, 31, 58, 92, or 93 
(including Y93H) did not have an impact on treatment outcome, whereas the A30K 
polymorphism was associated with a slightly decreased SVR12 rate.  Given the low 
prevalence of A30K (6.3%; 39/615) and that the majority of subjects with A30K achieved 
SVR12, its impact on overall SVR is expected to be minimal.
Amino Acid Substitutions in Subjects Experiencing Virologic Failure
Among TN and TE-PRS subjects without cirrhosis or with compensated cirrhosis treated 
for 8, 12, or 16 weeks, 23 subjects experienced virologic failure (2 with GT1, 2 with GT2, 
and 19 with GT3).  A GT3-infected subject experiencing virologic failure was determined 
to have been reinfected with GT3a virus distinct from the one present at baseline.  
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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 
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 
substitutions 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.  Given 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.
As shown in Table 3, AEs occurring with a  frequency > 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 ≥ 3 were low.  Including 
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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. 
Table 3.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related Adverse 
Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade ≥ 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Term
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.
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 compensated 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 
(≥ 65 years old, n = 328) was comparable to the safety profile in the non-elderly 
population (n = 2,041).
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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 (n = 104) in Study M15-462 was consistent 
with underlying severe renal impairment 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.15  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.  No safety signal or toxicity related to 
GLE/PIB specific to subjects with CKD Stage 4 and 5 has been identified.
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 (excluding Study M15-462).  Liver-related safety results indicated that:
●
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
○
ALT abnormalities in 3 of these 4 subjects were not clinically significant
○
One subject experienced concurrent ALT > 3 × ULN (increased from nadir 
grade) and total bilirubin ≥ 2 × ULN in the context of multiple gallstones 
that was not consistent with drug-induced liver injury
●
Based on exposure-response analyses, no GLE/PIB exposure-dependent ALT 
increases were observed in subjects with ALT abnormalities
●
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression
●
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.
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●
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.  
●
There were no cases consistent with drug-induced liver injury.
In summary, GLE/PIB demonstrated a favorable safety profile that was 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 compensated cirrhosis, HIV co-
infection, and CKD Stage 4 or 5.
Common GLE/PIB-related AEs (ADRs) occurring in ≥ 5% of subjects were headache, 
fatigue, nausea.  Adverse drug reactions 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 
to be related to treatment.  Unlike other protease inhibitors, no liver-related toxicities and 
no cases consistent with drug-induced liver injury were identified.  
3.1
Differences Statement
The GLE/PIB fixed dose combination for 8 and 12 weeks was explored in treatment-naïve 
and -experienced HCV GT1 – 6 infected subjects, without cirrhosis or with compensated 
cirrhosis including subjects with HIV/HCV co-infection and subjects with CKD Stage 4 
or 5 in several Phase 3 studies conducted in a randomized, controlled, double-blind or 
open-label fashion. 
This is the first Phase 3b study designed to evaluate HCV GT1 – 6 treatment-naïve 
subjects without cirrhosis (Metavir F2 – F3) and with compensated cirrhosis (Metavir F4) 
treated with GLE/PIB for 8 or 12 weeks, respectively, in Brazil.  This country did not 
participate in the Global GLE/PIB program.
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3.2
Benefits and Risks
Benefits of treatment with GLE/PIB include:  potent and pangenotypic antiviral activity 
in vitro, higher genetic barrier to development of drug resistance across genotypes 
compared to first generation DAA protease and NS5A inhibitors, no need for RBV, 8 or 
12 weeks of treatment for NS5AI and PI naive, and the convenience of a once daily 
regimen.  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 show high 
SVR12 rates among subjects with HCV GT 1 – 6 infection who receive treatment with 
GLE/PIB.
Adverse events that are known, and those not previously identified, may occur with 
GLE/PIB as detailed in the informed consent of this study.  In addition, subjects may 
experience inconvenience or discomfort related to the study visits or study procedures.  
Additional safety data for each DAA alone and the combination of PIB/GLE are detailed 
in Section 3.0 and in the Investigator's Brochure.14
Risks associated with GLE/PIB, including the risks of adverse reactions, virologic failure, 
and development of resistance-associated substitutions (Section 5.3.4), appear to be 
limited and manageable based upon the available data.  Given the potential for high 
SVR12 rates in populations of HCV-infected subjects, including HIV/HCV co-infected, 
and with CKD 4 – 5, the risk-benefit profile for GLE/PIB is favorable.
4.0
Study Objective
4.1
Primary Objectives
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks following 
therapy) and safety of GLE/PIB combination in treatment-naïve adults in Brazil with 
chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection without cirrhosis or with
compensated cirrhosis.  The efficacy endpoints will be analyzed based on combined 
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treatment duration and genotypes and safety analysis will be done by individual treatment 
groups.
4.2
Secondary Objectives
The secondary objectives are to assess efficacy of GLE/PIB based on overall population 
(i.e., across treatment durations and genotypes) by evaluating the following:
●
The percentages of subjects with HCV on-treatment virologic failure;
●
The percentages 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, multicenter study to evaluate the efficacy and safety of 
GLE/PIB for an 8- or 12-week treatment duration in adults in Brazil with chronic HCV 
GT1 – 6 infection, without cirrhosis or with compensated cirrhosis with a METAVIR 
System Fibrosis Score of F2, F3 or F4 (F2-F4) or equivalent,16 who are HCV treatment-
naïve.  Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The 
study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
This study will consist of a Screening Period, a Treatment Period and a Post-Treatment 
Period.
Screening Period:  Subjects will have up to 35 days following the Screening Visit to 
confirm eligibility and enroll in the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg 
once daily (QD) for an 8 (Arm A) or 12 (Arm B) week treatment duration based on 
cirrhosis status.
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Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment 
Period will be followed for 12 weeks to monitor HCV RNA levels to evaluate efficacy 
and the emergence and persistence of resistance-associated substitutions.
A study schematic is shown below in Figure 1. 
Figure 1.
Study Design
*
The study enrollment will be monitored to meet the following  enrollment criteria:  1) a minimum of 
approximately 35 GT1 and 35 GT3 subjects and 2) approximately 80 F2 – F3 and a maximum of 
approximately 20 F4 subjects.
Approximately 100 eligible subjects will be enrolled into one of the following treatment 
arms:
●
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 – F3) subjects will be treated 
with GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks. 
●
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be 
treated with GLE/PIB 300 mg/120 mg once daily (QD) for 12 weeks.
The study was designed to enroll approximately 100 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening may not be enrolled.
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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 
the subject meets all of the eligibility criteria specified in Section 5.2.1 and Section 5.2.2
during the period from the Screening Visit through Study Day 1 prior to dosing, and will 
record the results of this assessment and the details of the informed consent process in the 
subject's medical records.  Eligible subjects have up to 35 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
A positive Hepatitis B surface antigen (HBsAg);
●
HBV DNA > LLOQ in subjects with isolated positive anti-HBc (i.e., negative 
HBsAg and Anti-HBs); or
●
If Woman of Childbearing Potential (WOCBP), a positive serum pregnancy 
test;
●
Development of decompensated liver disease during the screening period, as 
defined by the Exclusion Criterion 6.
Otherwise subjects may be retested or rescreened only once unless approved by the 
Primary Therapeutic Area Medical Director.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on any panel that is 
repeated.  If any of the retest result(s) are exclusionary, the subject may not be rescreened 
again.
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Subjects that exceed the initial 35 day screening period should be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary during the 
first screening attempt (with the exception of HIV, HBV, HCV genotype and subtype, 
follicle stimulating hormone (FSH), which do not need to be repeated).  The FibroScan 
and liver biopsy do not need to be repeated for rescreened subjects provided that the date 
of the liver biopsy is within 24 months of the rescreening date and the FibroScan is within 
6 months of the rescreening date (Section 5.1.1).
Subjects who rescreen or subjects not meeting the study eligibility criteria must be 
identified by site personnel as a screen failure in both IRT and EDC systems.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT on Study Day 1.  
Subjects will be administered study drug at the site on Study Day 1, and provided 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 5.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3 and Section 5.3.1.1.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out 
of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
HCV virologic failure criteria will be evaluated and applied by the investigator as detailed 
in Section 5.4.1.1.
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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.  Subjects who prematurely discontinue 
from study treatment will continue to be followed in the Post-Treatment Period (see 
Section 5.1.3).
5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug will be monitored in the 
Post-Treatment Period for 12 weeks following the last dose of study drug for safety, HCV 
RNA, and the emergence and persistence of HCV resistance-associated substitutions.
The Post-Treatment Period will begin the day following the last dose of study drug.  
Study visits during the Post-Treatment period are detailed in Appendix D and 
Section 5.3.1.1.
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a Post-Treatment discontinuation visit as outlined in Appendix D.
5.2
Selection of Study Population
The study population consists of male and female adults aged 18 years or older with 
chronic HCV GT1 – 6 infection with METAVIR equivalent fibrosis stage of F2 – F4 
(without cirrhosis or with compensated cirrhosis) who are HCV treatment naïve 
(i.e., subject has never received a single dose of any approved or investigational anti-HCV 
medication).  Subjects with HIV/HCV co-infection and subjects at all CKD stages (CKD 
Stages 1 – 5) are allowed to participate.  Subjects who meet all 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 
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Postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L; or
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
OR
●
A 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.
Screening laboratory result indicating HCV GT1-, 2-, 3-, 4-, 5- and/or 6-infection.  
Mixed and indeterminate genotypes are acceptable.
5.
Subject has positive plasma HCV antibody and HCV RNA viral load 
≥1000 IU/mL at Screening Visit.
6.
Subjects who are known to be HCV/HIV co-infected may enroll if they have a 
positive test result for anti-Human Immunodeficiency Virus antibody at Screening 
and are:
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to 
initiate ART treatment while participating in this study), or on a stable, qualifying 
HIVART regimen for at least 8 weeks prior to Baseline.  (Substituting TDF for 
TAF as part of the combination regimen is allowed at any time.)
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The HIVART regimen must include at least one of the following ARV agents:
●
Raltegravir (RAL)
●
Dolutegravir (DTG)
●
Rilpivirine (RPV)
●
Elvitegravir/cobicistat (EVG/COBI)
In addition to the above medications, HIV Ab positive subjects (both without 
cirrhosis or with compensated cirrhosis) may take a nucleoside/nucleotide reverse 
transcriptase inhibitor (N(t)RTI) backbone containing any of the following:
●
Tenofovir disoproxil fumarate (TDF)
●
Tenofovir alafenamide (TAF)
●
Abacavir (ABC)
●
Emtricitabine (FTC)
●
Lamivudine (3TC)
Subjects receiving any other HIV ART in addition to those noted above are not 
eligible for enrollment in the study.
Subjects on stable HIV ART must have Plasma HIVRNA below 50 copies/mL at 
Screening (by the COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and 
at least once during the 12 months prior to Screening (by an approved plasma 
HIVRNA quantitative assay including but not limited to:  COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
7.
Subject must be documented as without cirrhosis with METAVIR equivalent 
fibrosis stage of F2 – 3 or with compensated cirrhosis (F4) based on results of a 
liver biopsy, or FibroScan, or FibroTest score (as described in Section 5.3.1.1).
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8.
Subjects with compensated cirrhosis 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.
9.
Subject must voluntarily sign and date an informed consent form, approved by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the 
initiation of any Screening or study specific procedures.
10.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
11.
Subjects requiring dialysis should have been receiving dialysis for at least 1 month 
prior to enrollment, and may be on hemodialysis or peritoneal dialysis.
Rationale for Inclusion Criteria
1, 4 – 11
In order to select the appropriate subject population with 
appropriate disease characteristics for evaluation
2, 3
The impact of GLE and PIB on human pregnancies has not been 
established.  However, assessment of the completed nonclinical 
reproductive toxicology studies indicates that there is no 
drug-related effect on teratogenicity/fetotoxicity.  In addition, the 
compounds are non-genotoxic
10
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
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.
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2.
Current HBV 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)
3.
Requirement for and inability or unwillingness to safely discontinue the 
medications or supplements listed in Table 4 at least 14 days or 10 half-lives
(whichever is longer) prior to the first dose of any study drug.
4.
Requirement for chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
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.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical 
history, including on Day 1 prior to dose, of liver decompensation including 
hepatic encephalopathy or variceal bleeding, radiographic evidence of small 
ascites, or empiric use of lactulose/rifaximin.  Prophylactic use of beta blockers is 
not exclusionary (see Section 5.3.1.1).
7.
Laboratory parameters exclusions:
●
ALT > 10 × ULN; AST > 10 × ULN
●
Total Bilirubin > 3.0 mg/dL 
●
Albumin < LLN (without cirrhosis); < 2.8 mg/dL (with compensated cirrhosis) 
●
Platelets < 90,000 103/μL (without cirrhosis); < 60,000 103/μL (with 
compensated cirrhosis)
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8.
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.  
This only applies to subjects with CKD Stage 4 or 5.
9.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks (whichever is longer) prior to 
study drug administration.
10.
Receipt of any investigational or commercially available anti-HCV agents 
examples include, but are not limited to:  interferon, pegylated interferon ribavirin, 
sofosbuvir, telaprevir, boceprevir, simeprevir, asunaprevir, paritaprevir, 
grazoprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir, voxilaprevir, velpatasvir 
or dasabuvir.
11.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
12.
Treatment for an AIDS-associated opportunistic infection (OI) (Appendix E) 
within 6 months of Screening.
13.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 3, 4, 6 – 13
In order to ensure safety of the subjects throughout the study
2, 5
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
the consent through the Treatment Period and 30 days after study drug is stopped, must be 
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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 drug-drug 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 Primary Therapeutic Area Medical Director should be contacted if 
there are any questions regarding concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
Subjects must be HCV treatment-naïve (i.e., has never received a single dose of any 
approved or investigational anti-HCV medication). 
5.2.3.2
Prior and Concomitant HIV Therapy
Subject on an HIV ART regimen must include ARV agents as defined in Inclusion 
Criterion 6 (Section 5.2.1).
Subjects will maintain the same dose and dosing interval of their HIV ART regimen upon 
initiating the study drugs regimen.
Subjects must remain on the same HIV ART regimen for the entire Treatment Period.  
Any change to an allowed HIV ART regimen during the Treatment Period must be 
discussed with the AbbVie TA MD prior to the change, unless the change is being made 
to address an immediate safety concern. 
Subjects receiving any other HIV ART in addition to those listed in Inclusion Criterion 6 
(Section 5.2.1) would not be eligible for enrollment in the study.
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5.2.3.3
Concomitant Therapy
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions.  
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drugs, if applicable.
Flu shots and other vaccinations are allowed during Screening through the Post-Treatment 
Period for all subjects.  Flu shots and vaccinations may affect plasma HIV RNA levels.
5.2.3.4
Prohibited Therapy
Subjects must be able and willing to safely discontinue any prohibited medications or 
supplements listed in Table 4 at least 14 days or 10 half-lives (whichever is longer) prior 
to the first dose of GLE/PIB and not use these during the entire Treatment Period and for 
14 days following discontinuation of study drug.
Table 4.
Prohibited Medications and Supplements
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
study drugs.  Subjects receiving these statins should either switch to pravastatin or rosuvastatin prior to the 
first dose of study drugs or may interrupt statin therapy throughout the treatment period and until 14 days after the 
last dose of study drug, based on investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, 
it is recommended to reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking 
with the study drugs.
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Use of ethinyl estradiol containing oral contraceptives with GLE/PIB was associated with 
ALT increases in some healthy female subjects.  Hormonal contraceptives (including oral, 
topical [including vaginal rings], injectable, or implantable varieties) containing ethinyl 
estradiol may not be used from 14 days prior to the first dose of GLE/PIB until 14 days 
after the end of GLE/PIB dosing.  Progestin-only contraceptives such as those containing 
norethindrone, desogestrel, or levonorgestrel, without ethinyl estradiol, may be used with 
GLE/PIB.  Post-menopausal hormone replacement therapy, i.e., estradiol, esterified or 
conjugated estrogens, as long as they do not contain ethinyl estradiol, may be used with 
GLE/PIB at the discretion of the Investigator.
The chronic use of systemic immunosuppressants is prohibited from 2 weeks prior to the 
first dose of study drug and until 30 days after the last dose of study drug including, but 
not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
For HCV/HIV coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 2 weeks prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 30 days following discontinuation of study drugs.  
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:
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
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●
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.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.
●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptom-thermal, post-ovulation methods] and 
withdrawal are not acceptable).
For male study subjects, no contraception is required.
5.3
Efficacy, Pharmacokinetic, 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 (Treatment Period) and Appendix D
(Post-Treatment Period).
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5.3.1.1
Study Procedures
Informed Consent
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco, alcohol and drug use, will be 
taken from each subject at Screening Visit.  The subject's medical history will be updated 
at the Study Day 1 Visit.  This updated medical history will serve as the baseline for 
clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Height will be measured only at Screening.  
Vital Signs and Weight
Body temperature, blood pressure, pulse, and body weight will be measured at each study 
visit as specified in Appendix C and Appendix D.  Blood pressure and pulse rate should 
be measured after the subject has been sitting for at least 3 minutes.  The subject should 
wear lightweight clothing and no shoes during weighing.  The vital signs performed on 
Day 1 of the Treatment Period will serve as the baseline for clinical assessment.
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12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at the visits indicated in Appendix C.  The ECG 
should be performed prior to blood collection.
The ECG will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 5
at the visits indicated in Appendix C and Appendix D.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast prior to study drug intake (with the exception of the Screening Visit, which may be 
non-fasting).  Subjects whose visits occur prior to the morning dose of study drug should 
be instructed to fast after midnight until the blood sample is collected in the morning and 
thereafter take their study medications with food.  Subjects whose visits occur following 
the morning dose of study drug should be instructed to fast after breakfast until the study 
visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug.  Blood samples should still be drawn if the subject did not fast 
for at least 8 hours.  Fasting or non-fasting status will be recorded in the source 
documents and on the laboratory requisition.  The baseline laboratory test results for 
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clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Samples will be sent to the following addresses:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
(For sites in North America)
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Table 5.
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)
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine transaminase (ALT)
Aspartate transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)
Anti-HCV Aba
HCV RNA
HCV genotype and subtypea
HIV Aba
HIV RNAb
Hepatitis B Panel (Anti-HBc
Total, Anti-HBs and HBsAg)c
Anti-HBc IgMc
Anti-HBc Totalc
Anti-HBsc
Anti-HAV
IgMd
Anti_HAV Totald
Anti-HEV IgGd
Anti-HEV IgMd
HEV RNAd
HBV DNAe
Follicle Stimulating Hormone 
(FSH)f
Urine and Serum
Human Chorionic 
Gonadotropin (hCG) for 
femalesg
Alpha2-macroglobulinh
Haptoglobinh
Apolipoprotein A1h
CD4, CD4%b
CD8, CD8%b
CD4:CD8b
a.
Performed only at Screening.
b.
Only for known HCV/HIV co-infected subjects.
c.
Performed at Screening for all subjects and also performed for management of transaminase elevations 
(Section 6.1.7.1). 
d.
Performed for management of transaminase elevation (Section 6.1.7.1).
e.
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).
f.
Only performed if requested during screening for post-menopausal women < 55 to verify FSH level if site does not 
have a previous result available.
g.
Required only for females of child bearing potential.
h.
Component of FibroTest and collected only if required for FibroTest calculation during the Screening Period.
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For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug or requires a subject to receive treatment will be recorded 
as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.1.7.
Pregnancy Testing
●
WOCBP must have a negative serum pregnancy test result at Screening, and a 
negative serum or urine pregnancy test at Study Day 1.  
●
Monthly pregnancy testing should be performed during treatment, including at 
the last dose and until 30 days of last study drug dose, as indicated in 
Appendix C and Appendix D.  
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result. 
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in the inclusion criteria) at Screening do not 
require pregnancy testing.
Concomitant Medication Assessment
Please refer to Section 5.2.3.2.
Hepatitis B, Hepatitis C Virus and HIV Screen
HBsAg, anti-HBc and anti-HBs, anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.  The investigator must discuss any local reporting requirements to local health 
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agencies with the subject.  The site will report these results per local regulations, if 
necessary.  The HIV results will not be reported by the central laboratory to the clinical 
database.
Liver Diagnostic Testing
Subjects will be considered to be without cirrhosis or with compensated cirrhosis based 
on the definitions below:
Without Cirrhosis (F2 and F3)
●
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 2 – 3, Ishak fibrosis score of 3 or 4; or
●
A FibroScan® score of 8.8 to < 12.5 kPa within ≤ 6 months of Screening or 
during Screening period (FibroScan® must be approved by the local regulatory 
agency to qualify for entrance criteria); or
●
A Screening FibroTest score of 0.49 to 0.72 (inclusive).17
With Compensated Cirrhosis (F4)
●
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3, Ishak 
score of > 4 or on a liver biopsy conducted during Screening; or
●
A FibroScan® score of ≥ 12.5 kPa within ≤ 6 months of Screening or during 
Screening period (FibroScan® must be approved by the local regulatory agency 
to qualify for entrance criteria); or
●
A Screening FibroTest result that is ≥ 0.73.
The result of the liver biopsy supersedes the results of FibroScan and FibroTest and result 
of FibroScan supersedes the results of FibroTest.  At Screening, it is recommended that 
subjects should otherwise meet all other inclusion criteria and none of the exclusion 
criteria before undergoing a liver biopsy.
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Child-Pugh Score and Category
Subjects with compensated cirrhosis will have Child-Pugh scores assessed, except those 
who are on ongoing use of anticoagulants.  The Child-Pugh score uses five clinical 
measures of liver disease (3 laboratory parameters and 2 clinical assessments) as shown in 
Table 6.  Child-Pugh score will be determined at the visits indicated in Appendix C and 
Appendix D.
Table 6.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites**
None
Slight
Moderate to severe
Hepatic encephalopathy*
None
Grade 1 or 2 (or suppressed 
with medication)
Grade 3 or 4 (or 
refractory)
Child-Pugh category A:  5 – 6 points; Child-Pugh category B:  7 – 9 points; Child-Pugh category C:  10 – 15 points.
*
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
** None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Study 
Day 1 prior to dosing to confirm the subject has not progressed to hepatic decompensation 
since Screening for all subjects who have compensated cirrhosis.  Grading system 
guidelines for ascites are listed above in Table 6.  Subjects who present symptoms and 
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signs of hepatic decompensation including assessment at Day 1 prior to receiving study 
drug, will not be enrolled into the trial.
Hepatocellular Carcinoma Screening:  Liver Ultrasound
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver will be performed as indicated in Appendix C for subjects with compensated 
cirrhosis only.  Subjects with compensated cirrhosis who do not have a historical 
qualifying liver ultrasound, CT, or MRI within the past 3 months will have an ultrasound 
performed during Screening.  A positive ultrasound result suspicious for HCC will be 
confirmed with CT scan or MRI during Screening.  Suspicious ultrasound lesions 
confirmed by CT or MRI are exclusionary.
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments on the study visits 
specified in Appendix C and Appendix D.  Subjects should be instructed to follow the 
instructions provided with each instrument and to provide the best possible response to 
each item.  Site personnel shall not provide interpretation or assistance to subjects other 
than encouragement to complete the tasks.  Subjects who are functionally unable to read 
any of the instruments may have site personnel read the questionnaires to them.  Site 
personnel should encourage completion of each instrument at all specified visits and 
should ensure that a response is entered for all items.
Short Form 36 – Version 2 Health Survey (SF-36v2)
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use broad variety of health conditions and is the standard in literature for HCV.  
The SF-36v2 instrument comprises 36 total items (questions) targeting a subject's 
functional health and well-being in 8 domains (physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional and mental health).  
Domain scores are also aggregated into a Physical Component Summary score and a 
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Mental Component Summary score.  Higher SF-36v2 scores indicate a better state of 
health.  The SF-36v2 should require approximately 10 minutes to complete.
Treatment Satisfaction Questionnaire-Medicine (TSQM)
The TSQM is a 14-item instrument and includes assessments of satisfaction with a 
medication's effectiveness (Effectiveness, three items), lack of side effects (Side Effects; 
five items), convenience (three items) and the subject's global satisfaction (Global 
Satisfaction; three items). 
The subject should complete the questionnaire before site personnel perform any clinic 
assessments and before any interaction with the site personnel has occurred to avoid 
biasing the subject's response.  TSQM scores range from 0 – 100 with higher scores 
indicating better satisfaction.  The TSQM should require approximately 5 minutes to 
complete.
EuroQol-5 Dimensions-3 Level (EQ-5D-3L)
The EQ-5D-3L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 
3 levels of severity.  Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies.  Subjects also rate their 
perception of their overall health on a separate visual analogue scale (VAS).  The 
EQ-5D-3L should require approximately 5 minutes to complete.
PRO instruments should be consistently presented so that subjects complete the 
questionnaires in the following order:  the SF-36v2, TSQM, and EQ-5D-3L.  PRO 
instruments should be completed prior to drug administration on Day 1 and prior to any 
discussion of adverse events or any review of laboratory findings, including HCV RNA 
levels, at all study specified visits listed in Appendix C and Appendix D.
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Enrollment and Assignment of Subject Numbers
All Screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet all the Inclusion Criteria and none of the Exclusion Criteria at Screening will 
proceed to enrollment via the IRT system on Study Day 1.
Subject numbers will be unique 4 digit numbers and will begin with 1001 with the 
first two digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  Subjects will be enrolled on Study Day 1 as described in Section 5.5.4.
Study Drug Compliance for Kits
Individual bottles of GLE/PIB will be provided for subject dosing to the site.  Each 
subject will have compliance documented by the site in the subject's source notes for 
GLE/PIB.  At each Study Drug Accountability Visit in Appendix C, the overall number of 
tablets of GLE/PIB remaining in each bottle will be recorded and entered in the IRT 
system along with the date of reconciliation.
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subgenotype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
sample, its genotype and subtype will be evaluated by a Sanger sequencing assay of a 
region of the NS5B gene by the central laboratory.
HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
Appendix D.  Plasma HCV RNA levels will be determined for each sample collected by 
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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.
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 study drug taken prior to the 
scheduled pharmacokinetic sample collection visits during the Treatment Period as 
detailed in Appendix C.
The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes and the 
eCRF.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
●
The Investigator or designee should make sure the subject is given the dosing 
card at the visits listed in Appendix C.
●
The Investigator or designee will contact the subject approximately 2 days 
before the scheduled visit date to review the importance of proper study drug 
administration relative to the pharmacokinetic blood collection and 
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documentation of dosing times on the dosing card.  The date and time of the 
contact will be entered into the subject's source documents.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.
Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
For subjects with HCV/HIV coinfection, samples for plasma HIV RNA levels and flow 
cytometry (including but not limited to CD4+ T-cell and CD8+ T-cell counts [absolute 
and percent]) will be obtained at the times specified in Appendix C and Appendix D.  
Plasma HIV-1 RNA will be measured by the central laboratory using the Roche COBAS 
AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 HIV-1 Assay.  Results below the 
LLOD are reported as:  "Not Detected."  HIV treatment failure is defined as detectable 
HIV RNA after 6 months of highly active antiretroviral therapy (HAART) or HIV RNA 
detectable after a period of undetectable measurement following use of HAART.
If a HIV RNA level result of subject on stable HIV ART is ≥ 200 copies/mL, the subject's 
HIV RNA is to be repeated as noted in Section 5.4.1.2.  At the time the repeat plasma 
HIV RNA is drawn, a sample should be obtained for HIV genotypic resistance testing.  If 
the subject's repeat HIV RNA is ≥ 500 copies/mL, the sample obtained for HIV genotypic 
resistance testing will be analyzed.
HIV protease (PR), reverse transcriptase (RT) and integrase (IN) sequences, as applicable, 
will be analyzed by Monogram Biosciences using the GenoSure® Prime drug resistance 
assay.
If the subject's repeat HIV RNA is < 200 copies/mL, then the subject will resume routine 
plasma HIV RNA assessments as shown in Appendix C and Appendix D, and described 
in Section 5.4.1.2.
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Specific instructions for preparation and storage of flow cytometry, plasma HIV RNA, 
and HIV resistance samples will be provided by the central laboratory, AbbVie, or its 
designee.
5.3.1.2
Meals and Dietary Requirements
Study drug (GLE/PIB) tablets should be dosed together and taken with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of GLE, PIB, and their possible metabolites will 
be collected by venipuncture at each study visit indicated below and in Appendix C.
●
At all Treatment-Period visits, except 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 plasma samples for the pharmacokinetic assays of GLE, PIB, and their possible 
metabolites will be provided by the central laboratory, AbbVie, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of GLE, PIB, and their 
possible metabolites will be packed in dry ice sufficient to last during transport, and 
transferred from the study site to the central laboratory.
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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 a validated assay 
methods in the Drug Analysis Department at AbbVie.  Plasma concentrations of any 
possible GLE and PIB metabolites may also be determined using either validated or 
non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 24 weeks after completion or discontinuation of the 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:
●
The percentage of subjects with HCV on-treatment virologic failure.
●
The percentage of subjects with HCV virologic relapse.
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.
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The following resistance information will be analyzed for subjects receiving study drug 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the 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 resistance-associated 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, PIB, and their potential metabolites, if 
measured, will be tabulated and summarized.  
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 
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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 12 weeks for HCV RNA and 
the emergence and persistence of resistant viral substitutions.
If a subject is discontinued from study drug or in the Post-Treatment Period with an 
ongoing adverse event or an unresolved laboratory result that is significantly outside of 
the reference range, the investigator will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of study drug 
may be continued at the Principal Investigator's discretion after discussion with the 
subject, if the benefit of continuing study drug is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  If a 
subject is discontinued, subject will be monitored for SVR in the Post-Treatment Period 
as described in Section 5.1.3.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of HCV virologic failure for the 
purposes of subject management:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment.
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study drug treatment until the virologic failure criteria has been 
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confirmed.  Subjects meeting the virologic failure criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistance-associated viral substitutions until 12 weeks post-treatment.  
Alternative management will only be considered with the approval of TA MD.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV RNA will be assessed at each scheduled study visit during the Treatment and Post 
Treatment Period, as detailed in Appendix C and Appendix D.
The criteria for failure to maintain HIV virologic suppression among subjects on stable 
ARTs is as follows:
●
HIV RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 2 weeks 
apart, in a subject compliant with their HIV ARV therapy
Subjects should remain on HCV study drug treatment and his/her current ART regimen 
while the failure to maintain HIV virologic suppression is being confirmed.  A 
confirmatory HIV RNA and HIV genotypic resistance blood draw can be done as an 
unscheduled visit.  However, if this blood draw falls on the date of a scheduled study visit 
(Appendix C and Appendix D), only a single HIV RNA and HIV genotypic resistance 
blood draw needs to be performed at this visit.
At the time a confirmatory HIV RNA is drawn, a sample for HIV genotypic resistance 
testing should also be obtained; this sample will be analyzed if the subject's repeat plasma 
HIV RNA is ≥ 500 copies/mL.  Subjects should remain on HCV study drug treatment and 
his/her current ART regimen while the failure to maintain HIV virologic suppression is 
being confirmed.  A confirmatory HIV RNA and HIV genotypic resistance blood draw 
can be done as an unscheduled visit.  However, if this blood draw falls on the date of a 
scheduled study visit (Appendix C and Appendix D), only a single HIV RNA and HIV 
genotypic resistance blood draw needs to be performed at this visit.
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During the Treatment Period, subjects with confirmed failure to maintain HIV RNA 
suppression should continue HCV study drug treatment unless there is a requirement for 
prohibited concomitant medications (Section 5.2.3.2) to construct a new HIV ART 
regimen. 
Clinical management of failure to maintain HIV virologic suppression during the study 
(Treatment and Post-Treatment Period) will be handled by the Investigator according to 
current HIV treatment guidelines and local standard of care. Subject's change of HIV 
ART regimen must be discussed with the AbbVie TA MD prior to the change being 
made, unless the change is being made to address an immediate safety concern.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of GLE/PIB will be dispensed in the form of film-coated co-formulated tablets 
at the visits listed in Appendix C.  Subjects will be instructed to take study drug at the 
same time every day with food.  Please refer to Section 5.3.1.1 and Section 5.3.2.1 for 
more details.
GLE/PIB will be provided by AbbVie as 100 mg/40 mg film-coated tablets.  GLE/PIB 
will be taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) 
QD and with food.
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Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  The site will also contact the IRT 
system to provide study drug return information for each kit at the visits specified in 
Appendix C.  At the end of the Treatment Period or at the Premature D/C Visit from the 
Treatment Period, the site will contact the IRT system to provide the discontinuation visit 
date information and study drug return information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the HCV virologic 
failure criteria defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drug to be used in this study is presented in Table 7.
Table 7.
Identity of Investigational Products
Investigational Product
Manufacturer
Mode of Administration
Dosage Form
Strength
Glecaprevir/Pibrentasvir
AbbVie
Oral
Film-coated 
tablet
100 mg/
40 mg
5.5.2.1
Packaging and Labeling
Study drug will be supplied in bottles.  Each bottle will be labeled as required per country 
requirements.  Labels must remain affixed to the bottles.  All blank spaces should be 
completed by site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions
Glecaprevir/Pibrentasvir bottles
15° to 25°C (59° to 77°F)
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
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maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie (or designee).
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive the treatment assignment.  Enrolled subjects will 
be assigned to either Arm A (8 weeks of treatment) or Arm B (12 weeks of treatment) 
based on cirrhosis status.  The study drug kit numbers will be assigned according to 
schedules computer-generated before the start of the study by the AbbVie Statistics 
Department.
Contact information and user guidelines for IRT use will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.
All tablets of GLE/PIB will be dosed together (three tablets once daily).  All subjects 
should take all doses of study medications with food.
5.5.5
Blinding
This is an open-label study.
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5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing compliance with the treatment regimen with regard to HCV virologic response 
and potential development of resistance due to poor compliance.
At each study visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial, or empty) for assessment of treatment 
compliance.  At Study Drug Accountability visits denoted in Appendix C, study site 
personnel will assess subject compliance by inspecting the contents of the bottles and 
record the status of each one, as well as the exact number of remaining tablets of 
GLE/PIB in IRT.  Treatment compliance will be based on the number of tablets 
dispensed, as recorded in IRT, and the number of remaining tablets.  If poor compliance is 
noted, the subject should be counseled and this should be documented in the subject's 
source.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include lot number, kit number, number of tablets dispensed, subject number, initials 
of person who dispensed study drug, and date dispensed for each subject.  An overall 
accountability of the study drug will be performed and verified by the AbbVie monitor 
throughout the Treatment Period.  The monitor will review study drug accountability on 
an ongoing basis.  Final accountability will be verified by the monitor at the end of study 
drug treatment at the site.
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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.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The GLE/PIB combination regimen for 8- and 12-weeks in HCV treatment-naïve subjects 
without cirrhosis and with compensated cirrhosis respectively, was evaluated in HCV 
GT1 – 6 infected subjects in the Phase 3 studies discussed in detail in Section 3.0.  A high 
(> 97%) efficacy and positive safety profile was demonstrated in these studies.  AbbVie 
plans to evaluate the same combination regimen at the proposed label durations in a 
similar HCV GT1 – 6 infected population in Brazil.  The study is designed to include 
subpopulations of HCV-infected patients (e.g., GT1 and GT3; severe renal disorder and 
HIV/HCV co-infected population) that represents the unmet clinical treatment need in 
Brazil.  The selection of a two arm study design is appropriate so that treatment naïve 
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GT1 – 6 Brazilian subjects receive the proposed label treatment duration based on their 
cirrhosis status. 
In view of the expected high SVR rate in this study and the established safety profile of 
GLE/PIB in patients with advanced fibrosis, a control arm would be of limited value for 
efficacy comparison.  In this context, an open-label study is appropriate to adequately 
describe the efficacy and safety of this regimen administered for the proposed global label 
recommended durations for treatment naïve subjects.
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.  Next generation sequencing 
(NGS) methods are experimental.
5.6.3
Suitability of Subject Population
This study is intended to enroll HCV treatment-naïve adults in Brazil with chronic HCV 
genotype 1 – 6 without cirrhosis and with compensated cirrhosis with METAVIR 
equivalent fibrosis stage F2-F4.  Patients with HCV/HIV co-infection and CKD
Stages 1 – 5 may participate in the study.  The study population includes subpopulations 
of HCV-infected patients (e.g., GT1 and GT3; severe CKD and HIV/HCV co-infected 
populations) with high unmet clinical treatment need currently in Brazil.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The dose GLE/PIB 300 mg/120 mg QD 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.
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5.6.4.1.1
GLE and PIB Dose and Treatment Duration
GLE/PIB is proposed to be indicated for the treatment of chronic HCV infection in adults.  
In DAA-treatment naïve adults, the recommended oral dose of GLE/PIB is 
three 100 mg/40 mg tablets QD with food (total daily dose of 300 mg/120 mg) for 
8 weeks in subjects without cirrhosis and for 12 weeks in subjects with compensated 
cirrhosis based on the ITT SVR12 rates in the registrational studies.  Only HCV treatment 
naïve subjects will be enrolled in this study.  The efficacy in subjects with CKD4 – 5 did 
not differ from those without CKD.  Similar efficacy result was observed on HCV/HIV 
co-infected subjects and HCV monoinfected subjects.  The recommended durations for all 
HCV treatment naive patients of all HCV genotypes are summarized in Table 8, and 
SVR12 is summarized by GT in Table 9.  These are recommendations for all HCV-
infected patients, including those co-infected with HIV and patients with any degree of 
renal impairment.
A favorable safety profile has been observed in HCV-infected subjects without cirrhosis 
or with compensated cirrhosis who received the GLE + PIB 300 mg + 120 mg dose 
combination.  No dose response relationship was observed for adverse events, or for 
treatment-emergent post-nadir alanine aminotransferase elevations.
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for 
12 weeks.
Table 8.
Recommended GLE/PIB Duration for TN Patients
Patient Population
Recommended Treatment Duration
No Cirrhosis
Cirrhosis
Genotype 1 – 6
8 weeks
12 weeks
GLE = glecaprevir; PIB = pibrentasvir; TN = treatment-naïve
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Table 9.
Summary of SVR12 Rates for TN and TE-PR, SOF/R or PI by 
Subject Population (Phase 2 and 3 Analysis Set)
SVR12%
GT1
GT2
GT3
GT4 – 6
GT1 – 6
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
No 
Cirr
Cirr
All
TNa + TE-P/R, SOF/R or PIb
99.0
97.2
98.0
100
95.2
96.6
93.1
100
97.4
97.6
97.5
cirr = cirrhosis; GT = genotype; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; P/R = regimens 
containing interferon, pegylated interferon, and/or ribavirin; SOF/R = regimens containing sofosbuvir and ribavirin; 
SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naive
a.
Recommended treatment duration for subjects without cirrhosis is 8 weeks and with cirrhosis is 12 weeks.
b.
Recommended treatment duration for GT1, 2, 4 – 6 subjects without cirrhosis is 8 weeks and with cirrhosis is 
12 weeks.  Recommended treatment duration for GT3 subjects is 16 weeks.
Cross reference:  AbbVie.  R&D16/0146.  Summary of Clinical Efficacy for Glecaprevir/Pibrentasvir in HCV.  2016.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.1.  For product complaints, please refer to Section 6.1.8.
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 
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considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (see Section 6.1.7 regarding toxicity management) and/or if the 
investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an adverse event if the surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe 
form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to 
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).
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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4). 
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity. 
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
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Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL*
Grade 3
Severe or medically significant but not 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
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is sufficient evidence (information) 
to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential 
alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
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If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
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In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 
investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).  If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  All adverse events and 
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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).
6.1.7.1
Management of Increases in ALT
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also > 2 × 
baseline value, the subject should have a confirmatory ALT measurement performed.  If, 
the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Complete the hepatic questionnaire.
●
Evaluate for an alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain Anti-HAV IgM, Anti-HAV IgG, Anti-HBc IgM, Anti-HBc Total, 
Anti-HBs, HBV DNA, HBsAG, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, as appropriate.
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drug if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of liver 
failure.
○
At the discretion of the investigator.
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Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director.
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections
HIV infected subjects participating in clinical trials may develop infections typically
associated with AIDS.  A list of these known AIDS-associated opportunistic infections 
(OI) is presented in Appendix E.  The events listed in Appendix E will be summarized as 
HIV-related events, not as adverse events.  These OIs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
An interim data lock may occur in the study if interim study results are needed for 
regulatory interaction purposes.  No changes to the study design or treatment of subjects 
would result from this interim analyses, so adjustment for multiplicity is needed.
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.
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 and SVR12) based on defined visit windows.  A backward 
imputation method will be used to impute missing responses for SVR analyses.
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8.1.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all treated subjects by 
Arm (A and B), and overall.  Demographics include age, weight, height, body mass index 
(BMI), gender, race, and ethnicity.  Baseline characteristics include HCV genotype 
subtype, prior HCV treatment history, CKD stage, baseline HCV RNA level, fibrosis 
stage (F2, F3, F4), tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-
drinker, or non-drinker) status, injection drug user (yes, within last 12 months; yes, more 
than 12 months ago; or no), use of stable opiate substitution, history of diabetes, baseline 
metabolic syndrome, history of bleeding disorders, history of depression or bipolar 
disorder, history of cardiovascular disease, geographic region, and HIV coinfection status.
All the demographics and baseline characteristics will be summarized as continuous or 
categorical variables where appropriate.  Summary statistics (N, mean, median, SD, and 
range) will be generated for continuous variables (e.g., age and BMI), and the number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).
Treatment compliance to study drug will be calculated based on the percentage of tablets 
taken relative to the total tablets expected to be taken.  A subject is considered to be 
compliant if the percentage is between 80% and 120%.  Compliance will be calculated for 
each subject and summarized with the mean, median, standard deviation, minimum, and 
maximum.  The percentage of compliant subjects will be summarized.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
The efficacy analyses will be performed across all treatment durations and genotypes.
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 
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< 15 IU/mL, regardless of whether the HCV RNA is detectable or not.  HCV RNA 
≥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) within all genotypes 
(GT1 – 6 subjects) will be analyzed on combined treatment groups.  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.  If the SVR12 is less than 100%, then the normal approximation of the binomial 
distribution will be used as a confidence interval.  If the SVR12 rate is 100%, the Wilson's 
score method will be used to calculate the confidence interval.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
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 ≥ 100 IU/mL after HCV RNA < LLOQ during 
treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks 
of treatment), and 
●
The percentage of subjects with post-treatment HCV virologic relapse (defined 
as confirmed HCV RNA ≥ 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 and 77 days or greater for 
subjects allocated to treatment durations of 8 weeks and 12 weeks, respectively.
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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 to the binomial distribution and a 
two-sided 95% confidence interval using the Wilson's score method.
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated as a sensitivity analysis for the primary endpoint of SVR12 based on ITT 
population.
8.1.2.4
Subgroup Analysis
The subgroup analyses will be performed based on the combined treatment groups.  The 
percentage of subjects with SVR12 will be calculated, as will the corresponding two sided 
95% Wilson score intervals, for the following subgroups:
●
HCV genotype and available subtype
●
Sex
●
Age 
●
Race 
●
Baseline HCV RNA level 
●
Baseline fibrosis stage 
●
Baseline cirrhosis status 
●
Baseline platelet count 
●
Baseline albumin 
●
Chronic Kidney Disease Stage 
●
HIV co-infection 
●
HIV ART regimen (for HIV coinfected)
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●
Baseline CD4+ count (for HIV coinfected)
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized by genotype:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR4 4 weeks after the last actual 
dose of study drug (SVR4);
●
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
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that domain will be considered missing.  The Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  For TSQM, if a 
respondent answers at least 2 items in the 3 item scales of Side Effects or Effectiveness, 
the missing items will be imputed with the average score of the answered items in the 
same scale.  For EQ-5D-3L, health state index and VAS scores no imputation will be 
performed for missing items.
The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
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(SF-36-PCS) scores; EQ5D-3L health state index and VAS score; TSQM Effectiveness, 
Side Effects, Convenience, and Global Satisfaction scores will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
For each of these scores, mean change from Baseline to Final Treatment Visit and from 
Baseline to Post-Treatment Week 12 will be summarized using an analysis of covariance 
(ANCOVA) model with baseline score as a covariate.
The following analyses of patient reported outcomes (PROs) also will be performed:
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
3 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 MCS and PCS;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
5 points in the SF-36 domain scores;
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
HCV Resistance Analyses
For all subjects with an available sample, full length NS3/4A or NS5A from baseline 
samples will be sequenced by NGS.  For subjects who experience virologic failure (on-
treatment virologic failure or post-treatment relapse), full length NS3/4A and NS5A genes 
from the first available sample after virologic failure with HCV RNA ≥ 1000 IU/mL will 
be sequenced by NGS.  An appropriate subtype specific prototypic reference sequence 
will be used for comparison with sequences from samples.  Subjects treated with study 
drug who do not achieve SVR12 due to reasons other than virologic failure but have a time 
point with HCV RNA ≥1000 IU/mL after treatment discontinuation, will have the sample 
at that time point sequenced.
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Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥ 1000 IU/mL will be used.  
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Polymorphism/substitution at a signature amino acid position:  polymorphism 
(relative to reference) present in a baseline sample or substitution (relative to 
baseline) present in a post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample [(post-
baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution by NGS:  A post-baseline substitution or an 
enriched polymorphism detected by NGS.
Analysis 1:  The following analyses will be provided for all subjects, separated by HCV 
subtype:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A).
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●
A listing of all baseline polymorphisms (15% detection threshold) at 
non-signature resistance-associated amino acid positions for each DAA target 
(NS3/4A and NS5A) for subjects who experience virologic failure.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
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:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
●
Polymorphisms at each non-signature amino acid position at a detection 
threshold of 15%.
Analysis 3:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A). 
●
Listings by subject and time point of all post-baseline substitutions at signature 
amino acid position relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
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HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LIPA assay 
results from the Central laboratory will be used to categorize the subject.  This final HCV 
genotype subtype will be used in efficacy subgroup analyses.
8.1.5
HIV Resistance Analyses
If a subject develops a confirmed, plasma HIV RNA level ≥ 500 copies/mL after starting 
the study, the subject's HIV PR, RT, and/or IN sequences, as applicable, will be analyzed 
by Monogram Biosciences using the GenoSure® Prime drug resistance assays.  The 
number of subjects who demonstrate HIV genotypic resistance and the genotypic 
resistance mutations detected in the samples obtained from these subjects will be 
tabulated and summarized.  Resistance will be defined as described by the IAS-USA 
Panel.18
8.1.6
Safety
Safety summaries will be provided by the treatment arm (i.e., study drug duration 
assigned by cirrhosis status) and overall.  All subjects who receive at least one dose of 
study drug will be included in the safety analyses.
8.1.6.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term.  The tabulation of the number of subjects with 
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treatment-emergent adverse events by severity grade (Grades 1 – 5) and relationship to 
each study drug will also be provided.  Subjects reporting more than one adverse event for 
a given MedDRA preferred term will be counted only once for that term using the most 
severe grade for the severity grade table and the most related for the relationship to study 
drug tables.  Subjects reporting more than one type of event within a SOC will be counted 
only once for that SOC.
Additional analyses will be described in the statistical analysis plan.
8.1.6.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last non-missing measurement prior to the initial dose of study drug.  Mean changes from 
baseline to each post-baseline visit, including Final Treatment Visit, will be summarized 
descriptively.  Changes from baseline to maximum post-baseline CTCAE grade of 
laboratory values will also be summarized.
8.1.6.3
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.
8.1.6.4
HCV/HIV Co-Infection
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV co-infection overall and in each treatment arm:
●
The percentage of subjects with plasma HIV RNA suppression at the end of 
treatment and at Post-Treatment Week 12 using the FDA Snapshot Algorithm;
●
The number and percentage of subjects with plasma HIV RNA < 20 copies/mL 
at each applicable time point;
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●
Change from baseline in CD4+ T-cell count (absolute and percent) to each 
applicable post-baseline time point;
●
Change from baseline in lymphocytes (count and percentage) and CD8+ T-cell 
counts (absolute and percent) to each applicable post-baseline time point;
●
The listing of subjects with a plasma HIV RNA value ≥ 200 copies/mL at any 
baseline or post-baseline visit during the study.
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall and within each treatment arm.
8.1.7
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE, PIB, and their possible metabolites, if measured, will be 
tabulated for each subject and group.  Summary statistics will be computed for each time 
and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) of the 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) may 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 utilize 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 a total of approximately 100 HCV infected treatment naïve GT1 – 6 
subjects will be enrolled in this study.  No formal hypothesis is being tested.  If the 
observed SVR12 rate in this study is 97% among 100 HCV GT1 – 6 treatment naive 
subjects, then the half-width of 2-sided 95% normal approximation interval is 3.3%.
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be allocated to a treatment arm 
according to their cirrhosis status (presence/absence).
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 prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain, and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
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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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
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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.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
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other than for regulatory purposes.  Aggregate data from optional exploratory 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.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for GLE/PIB Fixed-Dose 
Combination.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter, Open-Label Study to Evaluate the Efficacy and Safety 
of Glecaprevir (GLE)/Pibrentasvir (PIB) in Treatment-Naïve Adults 
in Brazil with Chronic Hepatitis C Virus (HCV) Genotype 1 – 6 
Infection
Protocol Date: 
16 February 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al.  A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
Bruggmann P, Berg T, Øvrehus AL, et al.  Historical epidemiology of hepatitis C 
virus (HCV) in selected countries.  J Viral Hepat.  2014;21 Suppl 1:5-33.
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.
EPCLUSA® (sofosbuvir and velpatasvir) [US Prescribing Information].  Foster 
City, CA; Gilead Sciences, Inc., 2016.
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11.
American Association for the Study of Liver Diseases.  Hepatitis C guidance:  
AASLD-IDSA recommendations for testing, managing, and treating hepatitis C.  
Available at:  http://www.hcvguidelines.org.  Updated:  24 February 2016.  
Changes made:  10 March 2016.
12.
Protocol clinic e diretrizes terapeuticas para hepatitis C e coinfections.  MoH.  
2015.
13.
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.
14.
AbbVie.  ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure 
Edition 2.  06 September 2016.
15.
AbbVie.  R&D/16/0159.  A single-arm, open-label, study to evaluate the efficacy 
and safety of ABT-493/ABT-530 in renally-impaired adults with chronic 
hepatitis C virus genotype 1 – 6 infection (EXPEDITION-4) (Study M15-462).  
2016.
16.
Theise ND.  Liver biopsy assessment in chronic viral hepatitis: a personal, practical 
approach.  Mod Pathol.  2007;20 Suppl 1:S3-14.
17.
Available From:  http://www.biopredictive.com/intl/physician/fibrotest-for-
hcv/view?set_language=en.
18.
Johnson VA, Calvez V, Gunthard HF, et al.  Update of the drug resistance 
mutations in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):6-14.
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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Clinical
Statistics
Clinical
Clinical Drug Supply 
Management
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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Informed Consentc
X
Dispense/Review Study Drug Dosing Card
X (Dispense only)
X
X
X (Review only)
Medical Historyd
X
X
Physical Exame
X
X
X
Vital Signs, Weight, Heightf
X
X
X
X
X
ECG
X
Hematology/Chemistryg/Coagulation Panel
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u, s)
X (u)
X (u)
X (u)
Anti-HCV Ab, Anti-HIV Ab
X
Hepatitis B Panel 
X
HCV Genotype and Subgenotype
X
FibroTest or FibroScan® or Liver Biopsyi
X
Concomitant Medication Assessment
X
X
X
X
X
Adverse Event Assessmentk
X
X
X
X
X
Study Drug Dispensed
X
X
Xk
HCV RNA Samples
X
X
X
X
X
Study Drug Accountability and Review of Study Drug 
Adherence
X
X
Xl
HCV Resistance Sample 
X
X
X
X
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Activity
Screening
Day 1a
Wk 4
Wk 8 
(Arm B 
Only)
EOT (Arm A and 
Arm B) or Premature 
D/C from Treatmentb
Pharmacokinetic Samplesm
X
X
X
Child-Pugh Score (subjects with compensated cirrhosis 
only) 
X
X
X
Clinical Assessment of Hepatic Decompensation (subjects 
with compensated cirrhosis only)
X
HCC Screening Liver ultrasound (subjects with 
compensated cirrhosis only) 
X
Patient Reported Outcomes Instruments (PROs)n
X
X
Flow cytometry sampleo
X
X
X
HIV RNAo
X
X
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Week 8 or 12 in accordance with treatment duration as described in Section 5.1. 
a.
All procedures to be performed prior to first dose. 
b.
Subjects who prematurely discontinue during 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).
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
e.
A symptom-directed physical examination may be performed at any other visit, when necessary.  Any significant physical examination findings after the first dose will be 
recorded as adverse events.
f.
Height will be measured at the Screening Visit only.
g.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour fast prior to study drug intake (with the exception of the Screening Visit, which 
may be non-fasting).
h.
Pregnancy testing is not required for women not of childbearing potential as defined in Section 5.2.4.
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i.
For subjects who have not had a qualifying liver biopsy within the previous 24 months for subjects without cirrhosis or at any time for subjects with compensated cirrhosis) or 
a qualifying FibroScan® within the previous 6 months for subjects without cirrhosis or at any time prior to Screening for subjects with compensated cirrhosis).
j.
Subjects with a historical negative Liver Ultrasound, CT or MRI (within 3 months prior to screening) are not required to have a screening Liver Ultrasound performed.  If 
additional Liver Ultrasound testing is required it should be completed as an unscheduled visit.  A positive ultrasound result suspicious of HCC will be confirmed with CT scan 
or MRI.  A liver ultrasound should be performed at the end of treatment visit if it has been 6 months or more since the historical evaluation.
k.
See specific information regarding adverse event collection in Section 6.1.1.1.
l.
Dispensation at Week 8 and Study Drug Accountability at Week 12 are only applicable to Arm B.  Subjects should bring all study drug to every visit for the site to review 
adherence.  However, the site will record the number of tablets returned only at the Study Drug Accountability Visits at Weeks 4, 8, 12 (if applicable) or Premature D/C.
m.
PK samples will be collected at each scheduled study visit.  Detail regarding timing of samples is provided in Section 5.3.2.1.
n.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
o.
For HCV/HIV co-infected subjects.
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Appendix D.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 4
PT Wk 12
PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Coagulation Panel
X
Xb
Pregnancy Test (urine)c 
X (u)
X (u)b
Concomitant Medication Assessmentd
X
Xd
Xd
Child-Pugh Score (subjects with compensated 
cirrhosis only)
X
X
Adverse Event Assessmente
Xe
Xf
Xf
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Patient Reported Outcomes Instruments (PROs)g
X
X
Flow cytometry sampleh
X
X
HIV RNAh
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 not required at PT Wk 12, but only at PT D/C if subject discontinues prior to PT Wk 4.
c.
Women of childbearing potential do not require pregnancy testing beyond PTW4. Pregnancy testing will be performed at PT D/C visit only if the subject discontinues prior to 
PTW4.  Pregnancy testing in PT Period is not required for females of non-childbearing potential as defined in Section 5.2.4.
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.  
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f.
Only SAEs will be collected thereafter as described in Section 6.1.4.
g.
PROs should be administered before any study procedures in the order listed in Section 5.3.1.1.
h.
For HCV/HIV co-infected subjects.
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.
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Appendix E.
List of AIDS-Associated Opportunistic Infections
Collection of data regarding known AIDS-associated opportunistic infections is covered 
in Section 6.1.8.
●
Aspergillosis
●
Bartonellosis
●
Candidiasis (*Bronchi; *Esophagus; *Lungs; Oropharyngeal [Thrush]; 
*Trachea; Vulvovaginal [Persistent, Frequent, or Poorly Responsive to 
Therapy])
●
*Coccidioidomycosis
●
*Cryptococcosis
●
*Cryptosporidiosis
●
Cytomegalovirus (*Retinitis; *Cytomegalovirus Disease [other than liver, 
spleen or nodes])
●
Enteric infections, Recurrent (Bacterial)
●
Herpes Simplex Virus (*Bronchitis; *Esophagitis; *Pneumonitis; *Chronic 
Ulcer(s) [> 1 month in duration])
●
*Histoplasmosis
●
Human Herpesvirus-8 Disease (Kaposi Sarcoma, Primary Effusion 
Lymphoma, Multicentric Castleman's Disease)
●
Human Papilloma Virus Infections
●
*Isosporiasis (Cystoisosporiasis)
●
Microsporidiosis
●
*Mycobacterium avium – Complex Disease (Disseminated)
●
*Mycobacterium tuberculosis – Infection and Disease
●
*Pneumonia
●
*Pneumonia, recurrent bacterial (and/or other respiratory infections including 
sinusitis, bronchitis, otitis)
●
*Progressive multifocal leukoencephalopathy (JC Virus Infection)
●
Syphilis
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●
*Toxoplasma Gondii Encephalitis
●
Varicella Zoster Virus Diseases
*
AIDS-defining event as described by CDC Surveillance Case Definition of 1993.
Cross reference:  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV Infected Adults and 
Adolescents.  Available from:  http://aidsinfo nih.gov/guidelines.
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SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-156 Clinical Study Report
R&D/19/0075
1
16.1__9
Documentation of Statistical Methods
16.1__9.1
Statistical Analysis Plan
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Glecaprevir/Pibrentasvir
M16-156 – Statistical Analysis Plan
Version 1.0 – 29 Jan 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M16-156
A Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir
(PIB) in Treatment-Naïve Adults in Brazil with 
Chronic Hepatitis C Virus (HCV) Genotype 1 – 6 
Infection
Date:  29 Jan 2019
Version 1.0
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................5
4.1
Objectives ..................................................................................................5
4.2
Design Diagram .........................................................................................6
4.3
Sample Size................................................................................................6
4.4
Planned Analyses .......................................................................................7
5.0
Analysis Populations ...............................................................7
5.1
Definitions of Analysis Populations ..........................................................7
5.1.1
Intention-to-Treat (ITT) Population...........................................................7
5.1.2
Modified Intention-to-Treat (mITT) Populations ......................................8
5.1.3
Safety Population.......................................................................................8
6.0
Analysis Conventions ..............................................................8
6.1
Definition of Baseline, Final Treatment, and Final Post-Treatment 
Assessments ...............................................................................................8
6.1.1
Baseline......................................................................................................8
6.1.2
Study Days.................................................................................................9
6.2
Definition of Analysis Windows ...............................................................9
6.3
Missing Data Imputation..........................................................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications...........................................13
7.1
Demographic and Baseline Characteristics .............................................13
7.2
Medical History .......................................................................................19
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 ..........................................................................27
10.3
Primary Efficacy Analysis .......................................................................27
10.4
Secondary Efficacy Analyses...................................................................27
10.5
Sensitivity Analyses for SVR ..................................................................28
10.5.1
Imputation Approaches............................................................................28
10.6
Efficacy Subgroup Analysis ....................................................................29
10.7
Additional Efficacy Analyses ..................................................................30
10.8
HCV Resistance Analyses .......................................................................31
10.9
Patient Reported Outcomes......................................................................35
11.0
Safety Analysis.......................................................................36
11.1
General Considerations............................................................................36
11.2
Analysis of Adverse Events.....................................................................36
11.2.1
Treatment-Emergent Adverse Events ......................................................36
11.2.2
Tabulations of Treatment-Emergent Adverse Events..............................37
11.2.3
Adverse Events of Special Interest ..........................................................39
11.2.4
Listings of Adverse Events ......................................................................40
11.3
Analysis of Laboratory Data....................................................................40
11.3.1
Variables and Criteria Defining Abnormality..........................................40
11.3.2
Statistical Methods...................................................................................43
11.4
Analysis of Vital Signs and Weight.........................................................45
11.4.1
Variables and Criteria Defining Abnormality..........................................45
11.4.2
Statistical Methods...................................................................................46
11.5
Analysis of Child-Pugh Score..................................................................46
12.0
Summary of Changes ............................................................47
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ...................................................................................................47
13.0
References...............................................................................47
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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)...........................10
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)...........................................................................11
Table 3.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements, Child Pugh Scores and PRO Instruments 
(Post-Treatment Period)...........................................................................11
Table 4.
Definition of Chronic Kidney Disease Stages .........................................15
Table 5.
Dialysis Related Preferred Terms and Lowest Level Terms ...................16
Table 6.
Baseline Fibrosis Stage............................................................................17
Table 7.
Child-Pugh Classification of Severity of Cirrhosis .................................18
Table 8.
Medical/Surgical History eCRF...............................................................19
Table 9.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ..........................................................................................32
Table 10.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................42
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values.............46
List of Figures
Figure 1.
Study Design..............................................................................................6
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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 M16-156.  
Study M16-156 evaluates the efficacy and safety of GLE/PIB in treatment-naïve adults in 
Brazil with chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection without 
cirrhosis (fibrosis stage of F2 – F3) for an 8-week treatment duration or with compensated 
cirrhosis (fibrosis stage F4) for a 12-week treatment duration. 
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M16-156 incorporating Amendment 1 and 2 dated 
02 August 2018, and describes analysis conventions to guide the statistical programming.  
Analyses will be performed using SAS® Version 9.4 (SAS Institute, Inc., Cary, NC 
27513) 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 (HCV RNA < LLOQ 12 weeks following 
therapy) and safety of GLE/PIB combination in treatment-naïve adults in Brazil with 
chronic hepatitis C virus (HCV) genotype (GT) 1 – 6 infection without cirrhosis or with 
compensated cirrhosis.  The efficacy and safety endpoints will be analyzed on the overall 
population (i.e., across treatment durations and genotypes).
The secondary objectives are to assess efficacy of GLE/PIB based on overall population 
(i.e., across treatment durations and genotypes) by evaluating the following:
●
The percentages of subjects with HCV on-treatment virologic failure (OTVF);
●
The percentages of subjects with HCV virologic relapse. 
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4.2
Design Diagram
This is a Phase 3b, open-label, multicenter study to evaluate the efficacy and safety of 
GLE/PIB for an 8- or 12-week treatment duration in adults in Brazil with chronic HCV 
GT1 – 6 infection, without cirrhosis or with compensated cirrhosis with a METAVIR 
System Fibrosis Score of F2, F3 or F4 (F2 - F4) or equivalent, who are HCV treatment-
naïve.  Approximately 100 subjects meeting the eligibility criteria will be enrolled.  The 
study enrollment will be monitored to meet the following enrollment criteria:  1) a 
minimum of approximately 35 GT1 and 25 GT3 subjects and 2) approximately 80 F2 – 3 
and a maximum of approximately 20 F4 subjects.
Subjects will be enrolled into one of the following treatment arms:
●
Arm A:  HCV GT 1 – 6 without cirrhosis (F2 – F3) subjects will be treated 
with GLE/PIB 300 mg/120 mg once daily (QD) for 8 weeks. 
●
Arm B:  HCV GT 1 – 6 subjects with compensated cirrhosis (F4) will be 
treated with GLE/PIB 300 mg/120 mg once daily (QD) for 12 weeks.
A study schematic is shown below in Figure 1.
Figure 1.
Study Design
4.3
Sample Size
It is anticipated that a total of approximately 100 HCV infected treatment naïve 
GT1 – 6 subjects will be enrolled in this study.  No formal hypothesis is being tested.  If 
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the observed SVR12 rate in this study is 97% among 100 HCV GT1 – 6 treatment naive 
subjects, then the half-width of 2-sided 95% normal approximation to the binomial 
distribution confidence interval will be 3.3% (EAST 6.4).
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.  
An interim data lock may occur in the study if interim study results are needed for 
regulatory interaction purposes.  No changes to the study design or treatment of subjects 
would result from this interim analysis; therefore, no adjustment for multiplicity is 
needed.
The end-of-study analysis will be conducted when all subjects enrolled in the study have 
completed the Post-Treatment Week 12 Visit or prematurely discontinued from the study.  
Data will be locked after performing appropriate data cleaning.  Results from this analysis 
(e.g., SVR12 data) will be described in the final clinical study report (CSR).
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 Arm A and Arm B which administer the recommended duration of GLE/PIB 
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 population, combining 
Arms A and B.
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 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.  If multiple 
measurements that are prior to dosing are recorded on the same date, 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.
Safety assessments that are related to a serious adverse event that occurred on the 
first dose day are excluded when applying this algorithm.
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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 are 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
≤ 1a
Week 4
28
2 to 42
Week 8
56
43 to 70
Week 12b
84
71 to 98
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 12-week treatment duration only.
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day 2. Study Drug End Day 0 is defined as the day of the last dose of study drug.
Note:
For all windows, data must be on or before Study Drug End Day 2.  The result closest to the scheduled time 
point will be used.  PRO instruments are collected at Day 1 and End of Treatment Visit, which can be at 
Week 8, or 12 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
SVR4b
28
3 to 56
SVR12b
84
57 to 126
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 and SVR12.  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 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 (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 SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
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for that domain will be considered missing.  The Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  For TSQM, if a 
respondent answers at least 2 items in the 3 item scales of Side Effects or Effectiveness, 
the missing items will be imputed with the average score of the answered items in the 
same scale.  For EQ-5D-3L, health state index and VAS scores no imputation will be 
performed for missing items.
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:
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Sex (male or female);
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●
Race (White, Black/African-American, Asian, American Indian or Alaska 
Native, or Native Hawaiian or Other Pacific Islander) and black race (black or 
non-black);
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
●
Baseline BMI (< 30 or ≥ 30 kg/m2);
●
HCV genotype and subtype (using central laboratory results and final
genotype/subtype results, see Section 10.8);
●
Cirrhosis status (yes/no);
●
Chronic Kidney Disease stage (Stage 1, 2, 3, 4, or 5);
●
Baseline HCV RNA level (< 1,000,000; ≥ 1,000,000 to < 2,000,000; or 
≥2,000,000 IU/mL);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline eGFR (< 15, ≥ 15 to < 30, ≥ 30 to < 45, ≥ 45 to < 60,or 
≥60 mL/min/1.73 m2);
●
Baseline creatinine clearance (< 15, ≥ 15 to < 30, ≥ 30 to < 45, ≥ 45 to < 60, or 
≥ 60 mL/min);
●
Baseline fibrosis stage (equivalent to Metavir F0 - F1, F2, F3, or F4);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no);
●
Tobacco use (current, former, never, or unknown);
●
Alcohol use (current, former, never, or unknown);
●
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Use of stable opiate substitution (yes/no);
●
History of diabetes (yes/no);
●
History of depression or bipolar disorder (yes/no);
●
History of bleeding disorders (yes/no);
●
History of cardiovascular disease (yes/no);
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In addition, for cirrhotic subjects, the following will be summarized:
●
Baseline Child-Pugh score (5, 6, or > 6).
Summaries of baseline resistance are described in Section 10.8.
Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.
Baseline CKD categorization is defined according to eGFR as shown in Table 4 below:
Table 4.
Definition of Chronic Kidney Disease Stages
CKD Stage
eGFR (mL/min/1.73 m2)*
1
≥90
2
60 to < 90
3
30 to < 60
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).
Subjects will be determined to be requiring dialysis based on the Medical History (MH) 
eCRF.  Requiring dialysis is defined as having medical history coded with any of the 
Preferred Terms or Lowest Level Terms specified Table 5.
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Table 5.
Dialysis Related Preferred Terms and Lowest Level Terms
Category
Preferred Term
Lowest Level Term
Dialysis
Artificial kidney device user
Haemodialysis fistula thrombosis
Dialysis
Dialysis access malfunction
Dialysis device insertion
Dialysis induced hypertension
Haemodialysis
Hypotension during dialysis
Haemofiltration
Thrombosis prophylaxis in hemodialysis
Peritoneal dialysis
Dialysis device complication
Renal replacement therapy
Dialysis dementia
Bloody peritoneal effluent
Dialysis efficacy test
Dialysis amyloidosis
Dependence on renal dialysis
Dialysis disequilibrium syndrome
Artificial kidney clotting during dialysis
Dialysis membrane reaction
Blood leak in dialyser
Dialysis related complication
Extensive interdialytic weight gain
Haemodialysis complication
Haemodialysis-induced symptom
Inadequate haemodialysis
Intradialytic parenteral nutrition
Peritoneal cloudy effluent
Peritoneal dialysis complication
Peritoneal effluent abnormal
Peritoneal effluent erythrocyte count 
increased
Peritoneal effluent leukocyte count 
increased
Ultrafiltration failure
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 
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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 6.
Table 6.
Baseline Fibrosis Stage
Baseline 
Fibrosis Stage, 
Metavir 
Equivalents
Liver Biopsy 
Metavir, Batts 
Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest*
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥ 8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 12.5
0.59 to 0.72
F4
4
≥ 5
≥ 12.5
≥ 0.73
*
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.
Presence or absence of cirrhosis will be determined as collected in EDC which includes 
the instructions, "Please indicate the subject's Metavir system fibrosis score" – "F2 - F3"
is considered as non-cirrhotic and "F4" is considered cirrhotic."
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).
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 
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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 ሺU/Lሻ
AST ሺUpper Limit of NormalሻሺU/Lሻ
Platelet Count ሺ10ଽ/Lሻ
ൈ100
FIB-4 ൌ
Age ሺyearsሻൈ AST Level ሺU/Lሻ
Platelet Count ሺ10ଽ/LሻൈඥALT ሺU/Lሻ
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 7.
Table 7.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2 (or 
suppressed with 
medication)
Grade 3 or 4 (or 
refractory 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.
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7.2
Medical History
Medical history 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.
Medical history data will be summarized and presented by primary MedDRA System 
Organ Class (SOC) and Preferred Term (PT).  The SOCs will be presented in alphabetical 
order, and the preferred terms will be presented in alphabetical order within each SOC.
The number and percentage of subjects with a particular preferred term will be 
summarized.  Subjects reporting more than one preferred term within a SOC will be 
counted only once for that SOC.
Histories of diabetes, bleeding disorders, depression or bipolar disorder, and 
cardiovascular disease will be defined by a subject having medical history coded to at 
least one preferred term within any of the high level terms specified for the category in 
Table 8.
Table 8.
Medical/Surgical History eCRF
Medical History eCRF
Category
MedDRA High Level Term Name
Diabetes
Diabetic complications cardiovascular
Diabetic complications dermal
Diabetic complications gastrointestinal
Diabetic complications NEC
Diabetic complications neurological
Diabetic complications ophthalmic
Diabetic complications renal
Diabetes mellitus (incl subtypes)
Hyperglycaemic conditions NEC
Bleeding disorders
Coagulation factor deficiencies
Coagulopathies
Platelet disorders NEC
Thrombocytopenias
Coagulation disorders congenital
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Table 8.
Medical/Surgical History eCRF (Continued)
Medical History eCRF
Category
MedDRA High Level Term Name
Depression or bipolar disorder
Depressive disorders
Bipolar disorders
Mood alterations with manic symptoms
Cardiovascular disease
Coronary artery disorders NEC
Ischaemic coronary artery disorders
Cardiac conduction disorders
Rate and rhythm disorders NEC
Supraventricular arrhythmias
Ventricular arrhythmias and cardiac arrest
Congenital cardiac malpositions and transpositions
Congenital cardiac structural defects NEC
Congenital cardiovascular disorders NEC
Cardiac disorders congenital NEC
Cardiac hypoplasias congenital
Cardiac malpositions congenital
Cardiac septal defects congenital
Cardiac valve disorders congenital
Cardiovascular disorders congenital NEC
Great vessel disorders congenital
Multiple cardiac abnormalities congenital
Persistent foetal circulation disorders
Heart failure signs and symptoms
Heart failures NEC
Left ventricular failures
Right ventricular failures
Accelerated and malignant hypertension
Renal hypertensions
Vascular hypertensive disorders NEC
Coronary necrosis and vascular insufficiency
Infectious myocarditis
Noninfectious myocarditis
Peripheral vasoconstriction, necrosis and vascular insufficiency
Aortic valvular disorders
Cardiac valve disorders NEC
Mitral valvular disorders
Pulmonary valvular disorders
Tricuspid valvular disorders
Aortic inflammatory disorders
Arterial inflammations
Vasculitides NEC
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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 either as (1) 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 (2) 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.  
8.0
Subject Disposition
The number and percentage of subjects who screen failed for any reason, and for each 
screen failure reason, will be summarized for all subjects who screen failed.
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized by 
investigator for each treatment arm and overall.
●
Enrolled subjects;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
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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:
●
1 to 15 days
●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days
●
> 90 days 
In addition, the number and percentage of subjects with study drug duration of ≥ 52 days 
for Arm A and ≥ 77 days for Arm B will be summarized.
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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.
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. A subject is considered to be compliant if the 
percentage is between 80% and 120%. 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. 
Sensitivity analyses will be conducted for it using the mITT-VF populations.
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR and for analyses of PROs as described in Section 6.3 and Section 10.9.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
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HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-treatment virologic failure = Breakthrough or EOT failure; if a subject meets both 
definitions of Breakthrough and EOT failure, he or she will be categorized as 
Breakthrough only. 
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SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
active study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value 
before or during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
active study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value 
before or during that SVR window.
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of active study drug (up to and including the SVR12 window) for a subject 
with HCV RNA < LLOQ at Final Treatment Visit who completed treatment (as defined 
below), excluding HCV reinfection as described below.
Relapseoverall = confirmed HCV RNA ≥ LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the Post-Treatment Period for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment (as 
defined below), excluding HCV reinfection.
Virologic failure rate for SVR12 = any subject who experiences On-treatment virologic 
failure or Relapse12 out of all ITT subjects.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.
Completion of treatment: For the analysis of relapse, completion of treatment is defined 
as study drug duration of 52 days or greater for Arm A and 77 days or greater for Arm B.  
If the last available post-treatment value is ≥ LLOQ, then the subject will be considered a 
relapse (i.e., will not require confirmation). 
HCV reinfection: HCV reinfection is defined as confirmed HCV RNA ≥ 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, 
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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 and 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;
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 and < 77 days for Arm B] 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]);
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6.
Other (defined as any SVR12 non-responder not meeting the definitions of 
[1] – [5]).
For the reasons for SVR12 nonresponse defined above, subjects are only to be counted in 
1 category. Specifically, subjects who were SVR12 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 or relapse12.
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 endpoints.
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.  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. A listing of subjects who do not achieve SVR12 by 
reason for non-response will also be provided.
10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
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 ≥ 100 IU/mL after HCV RNA < LLOQ during 
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treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks 
of treatment), and 
●
The percentage of subjects with Relapse12 (defined as confirmed HCV 
RNA ≥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 or greater and 77 days or 
greater for subjects allocated to treatment durations of 8 weeks and 12 weeks, 
respectively.
For on-treatment virologic failure and post-treatment relapse, the number and percentage 
of subjects will be summarized along with a two-sided 95% CI using Wilson's score 
method. 
10.5
Sensitivity Analyses for SVR
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. 
As sensitivity analyses, the number and percentage of subjects in the mITT-VF population 
achieving SVR12 will be summarized by genotype and overall, along with a two-sided 
95% confidence interval using the normal approximation to the binomial distribution and 
a two-sided 95% confidence interval using the Wilson's score method. Listings of 
subjects excluded from mITT-VF population will be provided, as applicable. 
10.5.1
Imputation Approaches
No imputation methods will be employed other than those described in Section 6.3. 
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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:
●
HCV genotype and available subtype (based on final HCV genotype and 
subtype determination);
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Sex (male or female);
●
Race (White, Black/African-American, Asian, or other) and black race (black 
or non-black);
●
Baseline BMI (< 30, or ≥ 30 kg/m2); 
●
Baseline HCV RNA level (< 1,000,000 ≥ 1,000,000 to < 2,000,000; or 
≥2,000,000 IU/mL);
●
Baseline fibrosis stage (equivalent to Metavir F2, F3, or F4);
●
Cirrhosis Status (yes/no)
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 15, ≥ 15 to < 30, ≥ 30 to < 60, ≥ 60 to < 90, or 
≥ 90 mL/min);
●
Baseline eGFR (< 15, ≥ 15 to < 30, ≥ 30 to < 60, ≥ 60 to < 90, or 
≥90 mL/min/1.73 m2);
●
History of diabetes (yes/no);
●
Subject on stable opiate substitution (yes/no);
●
Former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no)
The 2-sided 95% Wilson score confidence interval will be produced if there are at least 
10 subjects in the subgroup.
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10.7
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized for the ITT population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects with SVR4;
The percentage of subjects with virologic failure through Post-Treatment Week 12. 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, 
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 Relapse12) 
will be prepared displaying the number of subjects relapsing overall and by SVR visit 
window (within the SVR4, SVR12 windows or after SVR12 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, study drug duration < 77 days for subjects assigned to 12 weeks of 
treatment, or no post treatment HCV RNA) will be provided, as applicable.
A listing of subject numbers and reasons for non-response to SVR12 will be prepared.
The concordance between SVR4 and SVR12 will be assessed for the overall population 
(across treatment arms) by the agreement between SVR4 and SVR12 and the positive 
predictive value (PPV) and negative predictive value (NPV) of SVR4 on SVR12.  The 
agreement between SVR4 and SVR12 is a percentage defined as the number of subjects 
achieving both SVR4 and SVR12 and the number of subjects where both SVR4 and SVR12
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are not achieved.  The PPV of SVR4 on SVR12 is the proportion of subjects who achieve 
SVR12 out of all subjects who achieved SVR4.  The NPV of SVR4 on SVR12 is the 
proportion of subjects who do not achieve SVR12 out of all subjects who did not achieve 
SVR4.
10.8
HCV 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 
length NS3/4A and NS5A from the first sample after virologic failure with HCV RNA 
≥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 ≥ 1000 IU/mL after treatment discontinuation, will 
have the sample at that time point sequenced.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification. Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥ 1000 IU/mL will be used. 
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 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
Included time points for analyses on samples from subjects who do not achieve SVR12 are 
1) the sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1000 IU/mL, and 2) 12 weeks post-DAA treatment, provided that resistance-associated 
variants were detected by NGS at the time of HCV virologic failure/treatment 
discontinuation.
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3/4A or NS5A).
●
Substitution at signature amino acid position: substitution (relative to
reference) present at a detection threshold of ≥ 2% or ≥ 15% (depending on 
frequency threshold utilized) within a subject's viral population in a baseline or 
a post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
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●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample [(post 
baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution:  A post-baseline substitution or an enriched 
polymorphism.
Analysis 1:  The following analyses will be provided for all subjects by HCV subtype,:
●
By-subject listings of all baseline polymorphisms at signature amino acid 
positions for each DAA target (NS3/4A and NS5A) at detection thresholds of 
2% and 15%.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total 
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared.  Analysis 
will be grouped by HCV subtype, and DAA target (NS3/4A or NS5A). 
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
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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.
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12, and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
●
Listings by subject and time point of substitutions at signature amino acid 
positions (relative to reference sequence) will be provided for each DAA target 
(NS3/4A and NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from all subjects in order to accurately determine genotype/subtype.  If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the Central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available.  Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay results is available, then the Inno-LiPA assay 
results from the Central laboratory will be used to categorize the subject.  This 
information will be presented in summaries of efficacy subgroup analyses. 
The baseline characteristic summary will use the results from the central laboratory 
(Sanger sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]). A 
summary of HCV genotype subtype as provided by the central laboratory (Sanger 
sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) versus 
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phylogenetic analysis also will be provided. Listing of HCV genotype and subtype will 
be provided separately for central laboratory results and phylogenetic analysis results.
10.9
Patient Reported Outcomes
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use in a broad variety of health conditions and is the standard in literature for 
HCV.  The SF-36v2 instrument comprises 36 total items (questions) targeting a subject's 
functional health and well-being in 8 domains (physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional and mental health).  
Domain scores are also aggregated into a Physical Component Summary score and a 
Mental Component Summary score.  Higher SF-36v2 scores indicate a better state of 
health.  
The TSQM is a 14-item instrument and includes assessments of satisfaction with a 
medication's effectiveness (Effectiveness, three items), lack of side effects (Side Effects; 
five items), convenience (three items) and the subject's global satisfaction (Global 
Satisfaction; three items). TSQM scores range from 0 – 100 with higher scores indicating 
better satisfaction.
The EQ-5D-3L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 
3 levels of severity.  Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies.  Subjects also rate their 
perception of their overall health on a separate visual analogue scale (VAS).  
The mean change from baseline to each applicable post-baseline timepoint in the SF-36v2 
Mental Component Summary (SF-36-MCS) and Physical Component Summary 
(SF-36-PCS) scores; EQ5D-3L health state index and VAS score will be summarized 
descriptively at each applicable visit and for change from baseline to each applicable visit.  
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The following analyses of patient reported outcomes (PROs) also will be performed:
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable timepoint of greater than or equal to 
1/2 standard deviation (SD) at baseline points in the SF-36 MCS, PCS and 
SF-36 domain scores2,3
TSQM Effectiveness, Side Effects, Convenience, and Global Satisfaction scores will be 
summarized descriptively at each applicable visit.
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 both 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).
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11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term (PT).  The SOCs will 
be presented in alphabetical order, and the 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.
If a subject has an AE with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same AE with a relationship assessment of "Reasonable Possibility."  In 
this case, the subject will be counted under the "Reasonable Possibility" category.
Adverse Event Overview
An overview of AEs will be presented, consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs of grade 3 or higher;
●
Treatment-emergent AEs of grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (glecaprevir/pibrentasvir);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
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●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Events by SOC and PT
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent AEs;
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Treatment-emergent AEs leading to death.
A listing of treatment-emergent AEs grouped by SOC and preferred term with subject 
numbers will be created.
Adverse Events by Preferred Term
The following summaries of treatment-emergent AEs tabulated according to PT and 
sorted by the overall frequency across the two treatment arms will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
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●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB).
Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most severe/highest grade incident for the severity tables and most related incident 
for the relationship tables).  Subjects reporting more than one AE will be counted only 
once in the overall total.
Adverse Events by Maximum Severity Grade Level
Treatment-emergent AEs and DAA-related treatment-emergent AEs will be summarized 
by maximum severity grade level of each 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.
11.2.3
Adverse Events of Special Interest
Adverse events of special interest include the following:
●
Hepatic decompensation/hepatic failure events, identified using the AbbVie 
Product MedDRA Query (PMQ) for Hepatic Decompensation and Hepatic 
Failure.
●
Hepatocellular carcinoma events, identified using the 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:
●
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
●
Treatment-emergent serious AEs,
●
Treatment-emergent AEs leading to discontinuation of study drug,
●
Treatment-emergent AEs leading to study drug interruption,
●
AEs (treatment-emergent or all, as applicable) in each of the AEs of special 
interest categories.
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to a serious AE, will be used in all analyses.
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, prothrombin time (PT), international 
normalized ratio (INR), and activated partial thromboplastin time (aPTT).
Chemistry variables to be summarized include:  blood urea nitrogen (BUN), creatinine, 
total bilirubin, direct and indirect bilirubin, alanine aminotransferase (ALT), aspartate 
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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
Cholesterol
> ULN – 7.75 mmol/L
> 7.75 – 10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
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
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11.3.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 
the time of first dose if time is available.  The same baseline value will be used for 
changes 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 11 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 11, 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 11. 
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Assessment of Hepatic Laboratory Values
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized:
●
Post-nadir (preceding value is lower than the subsequent value) ALT 
> 5 × ULN (regardless of grade change);
●
Total bilirubin ≥ 2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered);
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin ≤ 2 × ULN.
Four listings (one for each bullet above) of all liver function tests including ALT, AST, 
total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.  
Hepatic Laboratory Abnormalities of Interest 
Among the events assessed under "Assessment of Hepatic Laboratory Values," the 
following criteria are of interest:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and a concurrent total bilirubin > 2 × ULN with a 
direct bilirubin:total bilirubin ratio > 0.4. 
To support the assessment of hepatic laboratory abnormalities of interest, the following 
potential events will be summarized:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN and direct/total 
bilirubin ratio > 0.4.
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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.
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.
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Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic Blood Pressure
≤ 90 mmHg AND A decrease of 
≥20 mmHg from baseline
≥ 180 mmHg AND An increase of 
≥ 20 mmHg from baseline
Diastolic Blood Pressure
≤ 50 mmHg AND A decrease of 
≥15 mmHg from baseline
≥ 105 mmHg AND An increase of 
≥ 15 mmHg from baseline
Pulse Rate
≤ 50 bpm AND A decrease of ≥ 
15 bpm from baseline
≥ 120 bpm AND An increase of 
≥15 bpm from baseline
Weight
A decrease of ≥ 15% from baseline
An increase of ≥ 15% from baseline
Body Temperature
> 38.3°C AND An increase of 
≥1.1°C from baseline
11.4.2
Statistical Methods
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for changes 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, 
median, and maximum.
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 
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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
●
Remove demographic and baseline characteristic analyses, subgroup analysis 
related to HCV/HIV Co-infection subjects because no HCV/HIV Co-infection 
subjects enrolled
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.
Wyrwich KW. Minimal important difference thresholds and the standard error of 
measurement: is there a connection?. J Biopharm Sta.  2004;14(1):97-110.
3.
Rejas J, Pardo A, Ruiz MA.  Standard error of measurement as a valid alternative 
to minimally important difference for evaluating the magnitude of changes in 
patient-reported outcomes measures. J Clin Epidemiol.  2008;61(4):350-6.
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16.1__9.2
PMQ Preferred Terms
CMQ NAME
PREFERRED 
TERM
MEDDRA 
VERSION
CMQ 
VERSION
PREFERRED 
TERM CODE
CMQ 
CODE
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Acute hepatic 
failure
21.1
21.1.3
10000804
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Acute on 
chronic liver 
failure
21.1
21.1.3
10077305
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Ascites
21.1
21.1.3
10003445
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Bacterascites
21.1
21.1.3
10068547
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Coma hepatic
21.1
21.1.3
10010075
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Gastric varices 
haemorrhage
21.1
21.1.3
10057572
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Hepatic 
encephalopathy
21.1
21.1.3
10019660
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Hepatic failure
21.1
21.1.3
10019663
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Hepatic 
hydrothorax
21.1
21.1.3
10067365
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Hepatorenal 
failure
21.1
21.1.3
10019845
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Hepatorenal 
syndrome
21.1
21.1.3
10019846
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Intestinal 
varices 
haemorrhage
21.1
21.1.3
10078058
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Liver 
transplant
21.1
21.1.3
10024714
80000172
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CMQ NAME
PREFERRED 
TERM
MEDDRA 
VERSION
CMQ 
VERSION
PREFERRED 
TERM CODE
CMQ 
CODE
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Minimal 
hepatic 
encephalopathy
21.1
21.1.3
10076204
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Oesophageal 
varices 
haemorrhage
21.1
21.1.3
10030210
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Paracentesis
21.1
21.1.3
10061905
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Peritonitis 
bacterial
21.1
21.1.3
10062070
80000172
Hepatic Decompensation and Hepatic 
Failure (Anti-Hepatitis C Virus 
Product Specific)
Subacute 
hepatic failure
21.1
21.1.3
10056956
80000172
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