Clinical trial NCT03212521
Conditions: Hepatitis C Virus (HCV)
Keywords: chronic hepatitis C virus (HCV) Hepatitis HCV genotype aspartate aminotransferase platelet Aspartate aminotransferase to Platelet Ratio Index (APRI) glecaprevir pibrentasvir Sustained Virologic Response 12 weeks post dosing (SVR12)
Sponsor: AbbVie
Start date: 2017-08-07; Completion date: 2018-08-13
Enrollment: 230 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A study to evaluate the efficacy and safety of glecaprevir(GLE)/pibrentasvir(PIB) in treatment-naïve participants with chronic hepatitis C virus (HCV) genotypes 1-6 infection and with an aspartate aminotransferase to platelet ratio index (APRI) of less than or equal to 1.

Detailed description:

Arms: arm 1: Participants received oral glecaprevir/pibrentasvir (300 mg/120 mg) once daily with food for 8 weeks.
Interventions: intervention 1: Glecaprevir/Pibrentasvir
Intervention descriptions: intervention 1: Glecaprevir/pibrentasvir 100 mg/40 mg co-formulated tablets taken orally as 3 tablets once a day.

Protocol documents:
Prot_000.pdf: 
NCT03212521


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
10
3
STUDY OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES
11
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
EXPLORATORY ENDPOINTS
12
3.5
SAFETY ENDPOINTS
12
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
18
5.4
PRIOR AND CONCOMITANT THERAPY
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
19
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
20
5.7
STUDY DRUG
21
5.8
RANDOMIZATION/DRUG ASSIGNMENT
21
5.9
PROTOCOL DEVIATIONS
22
6
SAFETY CONSIDERATIONS
22
6.1
COMPLAINTS AND ADVERSE EVENTS
22
6.2
TOXICITY MANAGEMENT
25
6.3
PRODUCT COMPLAINT
25


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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
26
7.1
STATISTICAL AND ANALYTICAL PLANS
26
7.2
DEFINITION FOR ANALYSIS POPULATIONS
26
7.3
STATISTICAL ANALYSES
26
8
ETHICS
28
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
28
8.2
ETHICAL CONDUCT OF THE STUDY
28
8.3
SUBJECT CONFIDENTIALITY
28
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
29
10 DATA QUALITY ASSURANCE
29
11 COMPLETION OF THE STUDY
29
12 REFERENCES
29
LIST OF TABLES
TABLE 1.
IDENTITY OF STUDY DRUG
21
LIST OF FIGURES
FIGURE 1.
STUDY DESIGN SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
31
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
34
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
35
APPENDIX D.
ACTIVITY SCHEDULE
36


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APPENDIX E.
PROTOCOL AMENDMENT SUMMARY OF CHANGES
39








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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Hepatitis C viral infection is a global health problem, with over 184 million individuals infected 
worldwide.1  Successful treatment of HCV has been shown to significantly reduce the risk of disease 
progression and related mortality.2,3  The advent of DAAs has dramatically changed the HCV treatment 
outcomes, with SVR rates over 90% with shorter treatment durations and improved tolerability 
compared to peginterferon based regimens.  However with the first generation DAAs,4 there is still a 
need for a comprehensive patient assessment, including determination of fibrosis status, genotype and 
subtype, and baseline characteristics (such as quantitative viral load) in order to determine the best 
treatment strategy (regimen, duration, addition of RBV).  The next generation DAAs are typically 
pangenotypic but the optimal treatment duration still depends on fewer key baseline characteristics 
such as cirrhosis status and GT.2  Fibrosis status is usually assessed by liver biopsy (an invasive method) 
or a noninvasive method such as transient elastography which is currently not available worldwide.5  
Due to prior limitations on treatment availability, patients with advanced liver disease were prioritized 
to receive treatment with DAAs.5  As these patient populations have consistently achieved SVR, the 
focus is shifting to patients with milder forms of liver disease (i.e., non-cirrhotic) for whom HCV 
treatment is also cost effective (as these patients have a low risk of developing cirrhosis after achieving 
SVR).3,5-7  In addition, some models have shown that scaling up therapy for the patient population with 
mild liver disease is a key strategy towards HCV eradication by impacting disease prevalence and 
transmission.5
AbbVie's next generation DAAs include GLE, an HCV NS3/4A PI, and PIB, an HCV NS5A inhibitor.  Each 
DAA has potent antiviral activity against the major HCV GTs in vitro with no or little loss of potency 
against common single-position NS3 and NS5A resistance-associated substitutions.  
Glecaprevir/pibrentasvir fixed-dose combination tablets have been developed for the treatment of 
chronic HCV infection.8,9
The GLE/PIB registrational program assessed a broad population including subjects with compensated 
liver disease and subjects with severe renal insufficiency across all GTs 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 and treatment experienced subjects to any combination of pegylated interferon, RBV, 
sofosbuvir, NS5A inhibitors, or PIs were allowed in the program.  In addition, the program included 
subjects with HIV co-infection (Study M13-590), subjects with chronic kidney disease 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).


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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.8-13
In treatment naïve subjects with compensated cirrhosis GLE/PIB achieved SVR12 rates over 98%, 
including in subjects with GT3, with 12 weeks of therapy as in SURVEYOR II Part 3 (Study M14-868 –
GT3).10
Based on the efficacy data presented above, the 8-week treatment duration is anticipated to achieve 
high SVR12 rates in GT1 – 6-infected treatment-naïve subjects without cirrhosis.10,12
In Phase 3 trial, ENDURANCE-1 (M13-590), that has explored chronic HCV GT1 treatment naïve adult 
subjects without cirrhosis, the administration GLE/PIB for 8 weeks has shown SVR12 rates of 99.1% 
(348/351 including 1 subject with missing data).  This was non-inferior to the 12 week arm data.11  In the 
combined analysis from Phase 2, SURVEYOR II-Part 4 study that has explored chronic GT2, 4, 5 and 6 
treatment-naïve adult subjects without cirrhosis, the administration GLE/PIB for 8 weeks has shown 
SVR12 rates of 96.5% (196/203, including 3 subjects with missing data).12  These results were similar to 
12 weeks of GLE/PIB in this population.  For chronic HCV GT3 treatment-naïve adult subjects without-
cirrhosis, the SVR12 rate for 8 weeks of therapy was 94.9% (149/157 including 2 subjects with missing 
data), also non-inferior to 12 weeks of therapy as demonstrated in ENDURANCE-3 (Study M13-594).13
While a pangenotypic regimen that has high efficacy across all treatment-naïve non-cirrhotic patients 
with 8 week treatment duration is very attractive for treatment simplification and scaling up 
therapy6,7,14, the need for a comprehensive patient evaluation with more complex diagnostic tests such 
as liver biopsy and transient elastography to identify cirrhosis can still be a barrier to access to 
treatment.5  Some guidelines recommend that serum biomarkers can be used in the absence of 
transient elastography.4,5,7,14  The World Health Organization (WHO) guidelines state that non-invasive 
monitoring is considered to be preferable to invasive testing.  The WHO considers that APRI, Fibrosis-4 
score (FIB-4) and transient elastography are the most useful tests for assessing the stage of liver 
disease.5  Several serum biomarkers have been evaluated to identify patients with cirrhosis or advanced 
fibrosis.  Among these, the APRI has been extensively studied and a meta-analysis including more than 
16,000 patients has shown mean accuracy of 0.84 to identify non-cirrhotic patients with a cut off ≤ 1.6  
The negative predictive value, i.e., the probability of identifying non-cirrhotic patients when in a 
population with an estimated cirrhosis prevalence of around 18% for APRI ≤ 1 using sensitivity and 
specificity reported in this meta-analysis was calculated to be around 94%.  In addition, APRI is a widely 
available low cost test that is very easy to perform and is validated to diagnose fibrosis and cirrhosis.5,6  
The APRI cut off ≤ 1 is recommended in guidelines to rule out cirrhosis.6,7,14  Being able to easily identify 
patients that are eligible for 8 week treatment could simplify treatment algorithms and reserve liver 
biopsy and transient elastography for those patients who really need a more advanced evaluation. 
This study is being conducted to further assess the safety and efficacy of 8 weeks of GLE/PIB 
combination regimen (300 mg GLE/120 mg PIB, QD) in treatment-naïve adults with chronic HCV GT1 –
GT6 infection and APRI ≤ 1.


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Clinical Hypothesis
The clinical hypothesis of this study is that 8 weeks of therapy with GLE/PIB in treatment-naïve GT1 –
GT6 subjects that have APRI ≤1 will achieve high efficacy rates as observed in treatment-naïve, 
non-cirrhotic subjects evaluated in Phase 2 – 3 clinical trials for 8 weeks.
2.2 Benefits and Risks to Subjects
Chronic HCV infection is a major global health problem impacting quality of life, morbidity, as well as 
mortality.  Evidence suggests that effective treatment of HCV can cure the infection as well as improve 
liver function.1-3
The GLE/PIB regimen is an oral, RBV-free pangenotypic regimen that provides high SVR12 rates ≥ 95% in 
subjects with compensated liver disease infected with HCV GT1 – GT6, with the majority of subjects 
treated for 8 – 12 weeks.  Low relapse rates < 3% were observed in GT1 – GT6 treatment-naïve subjects 
without cirrhosis following 8 weeks of treatment, demonstrating no benefit of an additional 4 weeks of 
treatment.  Among these subjects, an 8-week regimen of GLE/PIB achieved SVR rates similar to 
12 weeks of treatment and to the only currently approved pangenotypic HCV regimen.  However, 
GLE/PIB achieved similar efficacy with a significant reduction of the duration of treatment, which may 
improve subjects' adherence, access to treatment, and convenience, and also reduce the burden 
associated with additional medical visits and procedures.
Based on safety data from the registrational and supportive clinical trials where 2369 HCV-infected 
subjects were treated, the fixed-dose combination of GLE/PIB demonstrated a favorable safety profile.  
The most frequent GLE/PIB related adverse events (AEs) include headache, fatigue and nausea, and 
were mostly Grade 1 (mild) in severity.  Grade 3 or higher AEs and serious adverse events (SAEs) were 
uncommon, occurring in 3.8% and 3.1%, of subjects, respectively.  Similarly, the overall rate of study 
drug discontinuations due to AEs was low (0.5%).8,9  Safety in subjects with cirrhosis was shown to be 
similar to subjects without cirrhosis.8,9
Potential risks that may occur with GLE/PIB therapy include hepatotoxicity, development of viral 
resistance, and the development of toxicities from drug-drug interactions (DDIs).  The potential risks for 
GLE/PIB can be monitored, mitigated and managed in clinical practice.
No trends in liver chemistry abnormalities have been observed in Phase 2 and Phase 3 studies, including 
in subjects with compensated cirrhosis.  ALT elevation from nadir to > 5 × ULN occurred in 3/2367 (0.1%) 
of subjects; none of these subjects prematurely discontinued study drug due to the elevation in ALT.  
Similarly, Grade 3 increases in bilirubin were rare (0.4%), predominantly indirect, and without bilirubin-
related AEs.  There were no cases identified consistent with drug-induced liver injury.
While there is a risk for the development of amino acid substitutions conferring resistance to GLE and/or 
PIB in subjects who fail the therapy, it may be possible to successfully retreat these subjects.
The risk of toxicities from DDIs are addressed and mitigated by the product information, which ensures 
awareness of these risks by both subjects and healthcare providers.  Appropriate recommendations for 
dose adjustments of certain medications or avoidance of coadministration with other specific 
medications are provided in the product information.


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Pharmacological class risks include Hepatitis B Virus (HBV) reactivation with DAA treatment.  As the risk 
of HBV reactivation in subjects treated with GLE/PIB has not been studied, HBV co-infected subjects will 
be excluded from the study.
Aminotransferase/platelet ratio index score ≤ 1 has a high negative predictive value in the general 
chronic hepatitis C population.  Additional eligibility criteria of normal platelets and normal albumin as 
well as the absence of previous diagnosis of cirrhosis have been added to mitigate the risk of including 
cirrhotic subjects.  Also according to WHO analysis, the potential increase in treatment availability 
resulting from increased access to low-cost, non-invasive monitoring and reduced risk of adverse events 
from liver biopsy was felt to outweigh the potential harms of false-negative case identification by APRI.5
Given the potential for achieving high rates of SVR in naïve non-cirrhotic subjects with HCV GT1 – GT6 
infection and the favorable safety profile of GLE/PIB, the overall benefit-risk balance of the GLE/PIB 
regimen is, therefore, positive and supports the use in subjects with chronic HCV with compensated liver 
disease, including subjects with renal impairment and HIV-1 co-infection. 
For further details, please see findings from completed studies, including safety data in the GLE/PIB 
Investigator Brochure and addendum.8,9
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The primary objective of this study is: 
•
To demonstrate the efficacy (by achieving high SVR12 rate) and safety of 8 weeks of treatment 
with the GLE/PIB combination regimen in treatment-naïve adults with HCV GT1 – GT6 infection 
with APRI ≤ 1.  The primary efficacy objective will be assessed based on mITT population across 
GTs HCV GT1 – GT6.
The secondary objectives of this study are:
•
To demonstrate the efficacy (by achieving high SVR12 rate) of 8 weeks of treatment with the 
GLE/PIB combination regimen in treatment naïve adults with HCV GT1 – GT6 infection with APRI 
≤ 1 based on ITT population.  
•
Assess the percentage of subjects with HCV on-treatment virologic failures across GTs in adults 
with HCV GT1 – GT6 infection with APRI ≤ 1 based on ITT population.
•
Assess the percentage of subjects with HCV virologic relapse across GTs in adults with HCV GT1 –
GT6 infection with APRI ≤ 1 based on ITT population.


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3.2 Primary Endpoint
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 genotypes in adults with HCV GT1 – GT6 based 
on mITT population. 
3.3 Secondary Endpoints
Secondary endpoints are:
•
Percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose 
of study drug) across GTs in adults with HCV GT1 – GT6 based on ITT population
•
Percentage of subjects with on-treatment virologic failure based on ITT population
•
Percentage of subjects with post-treatment relapse based on ITT population
3.4 Exploratory Endpoints
•
SVR12 in subjects with APRI ≤ 0.7 and APRI ≤ 0.5 based on ITT population
•
Percentage of subjects with virologic failure with Fibrotest > 0.75 based on ITT population
•
Percentage of subjects with SVR12 by key groups (HCV genotype and subtype; age) based on ITT 
population
•
Adherence to treatment based on ITT population
3.5 Safety Endpoints
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, 
electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry including hepatic 
function parameters) as a measure of safety and tolerability for the entire study duration.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
This is a Phase 3b, multicenter, non-randomized, open label study to evaluate the efficacy and safety of 
GLE/PIB in HCV treatment-naïve adult subjects with chronic HCV GT1 – 6 and APRI ≤ 1 for 8 weeks.
The study is designed to enroll approximately 230 subjects (maximum of 20% [46] enrollment of 
GT3-infected subject) at approximately 43 sites worldwide. 


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This study will consist of a Screening Period, a Treatment Period, and a Post-Treatment Period.
Screening Period:  Subjects have up to 35 days following the Screening Visit to confirm eligibility and 
enroll into the study.
Treatment Period:  Eligible subjects will be enrolled to receive GLE/PIB 300 mg/120 mg QD for 8 weeks.
Post-Treatment (PT) Period:  Subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 12 weeks (Wks) after their last dose of study drug to evaluate efficacy and to 
monitor HCV RNA, and the emergence and persistence of viral substitutions.
Figure 1.
Study Design Schematic
4.2
Discussion of Study Design
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard parameters used for assessing disease activity in subjects with 
HCV.  All clinical and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
This subject population will include treatment-naïve subjects only.  While data from registrational and 
Phase 2 supportive trials shows that high SVR12 rates can be achieved with 8 weeks of GLE/PIB, slightly 
lower rates were achieved in treatment-experienced subjects across all GTs.  To reduce the risk of Post-
Treatment relapse, treatment-experienced subjects will be excluded from this study.
Aminotransferase/platelet ratio index ≤ 1 has been shown to have high sensibility and therefore high 
predictive negative value in ruling out cirrhosis.  It is very likely that the population that will be included 
in this study using this biomarker will be non-cirrhotic.  However, in order to decrease the risk of 


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enrolling truly cirrhotic subjects, subjects with clinical signs of cirrhosis, history of decompensation, or 
with lab abnormalities compatible with cirrhosis (low platelets and/or low albumin) will be excluded 
from this study.
Hepatitis C virus-infected subjects with chronic HCV infection have moderate stable elevations of AST 
and ALT levels and are considered representative of the population who will receive anti-HCV therapy.  
This study will include stable subjects with HIV/HCV co-infection, as this sub-population is shown to have 
similar results as mono-infected treatment-naïve non cirrhotic subjects with 8 weeks treatment duration 
in Study M14-730.  As HBV co-infected subjects may have some alteration in APRI scores (due to 
inflammation) and it is difficult to interpret the APRI score in HBV/HCV co-infected population, subjects 
co-infected with HBV will be excluded from the population.  
The age range selected for this study, 18 years of age or older, is also intended to be representative of 
the target population.  Similarly, a substantial portion of the HCV-infected population have a relatively 
high body mass index, and given the acceptable safety and pharmacokinetic profiles of GLE/PIB in 
previous studies, this protocol will enroll subjects without a body mass index restriction.
Glecaprevir/pibrentasvir has shown similar efficacy and safety in subjects at all stages of renal 
impairment, including subjects with chronic kidney disease Stage 4 or 5 and in dialysis.  However, as 
subjects with creatinine clearance < 30 mL/minute can show falsely low APRI levels which may increase 
the risk of enrolling a truly cirrhotic subject.  Therefore, subjects with creatinine clearance 
< 30 mL/minute will be excluded from this study.
Selection of Dose in the Study
The dose of GLE/PIB (300 mg/120 mg by mouth 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.  The maximum dose of 
GLE/PIB will not exceed 300 mg/120 mg per day for up to 8 weeks.
Selection of Treatment Duration
Treatment duration was selected based on available data (SVR12 rates) from 12-week and 8-week 
treatment groups receiving GLE/PIB combinations (Studies M13-590, M15-464, M13-594, M13-583, and 
M14-868) in HCV GT1 – GT6-infected non-cirrhotic subjects as well as exposure-response modeling and 
simulations.  With robust antiviral activity demonstrated in in vitro and in vivo studies, the 8-week 
GLE/PIB 300 mg/120 mg combination is predicted to be optimal across HCV non-cirrhotic, treatment-
naïve GT1 – GT6-infected subjects.  
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the statements below will result in exclusion from study participation.








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If female, subject must be either post-menopausal, permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) or a woman of childbearing potential (WOCBP) 
and must practice at least one of the following methods of birth control, throughout the study including 
30 days after the last study drug dose is given.
!
Contraceptives and/or hormonal replacement therapies containing only progestins (such as 
those containing norethindrone, desogestrel, or levonorgestrel) or those containing progestins 
with non-ethinyl estradiol estrogens (e.g., esterified or conjugated) associated with inhibition of 
ovulation initiated at least 1 month prior to study Baseline Day 1.
!
Bilateral tubal occlusion/ligation.
!
Intrauterine device (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
Vasectomized sexual partner(s) (the vasectomized partner(s) provided the vasectomized partner 
has received medical assessment of the surgical success and is the sole sexual partner of the 
trial participant).
•
Male or female condom with or without spermicide.
•
Cap, diaphragm or sponge with spermicide.
•
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier method).
!
True abstinence:  Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).
For male study subjects no contraception is required.
5.3 Prohibited Medications and Therapy
Subjects must be able to safely discontinue any prohibited medications or supplements listed in 
Section 5 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 
drug.  Subjects must be consented for the study prior to discontinuing any prohibited medications for 
the purpose of meeting study eligibility.
Contraceptives and/or hormonal replacement therapies containing only progestins (such as those 
containing norethindrone, desogestrel, or levonorgestrel) or those containing progestins with non-
ethinyl estradiol estrogens (e.g., esterified or conjugated) may be used with GLE/PIB at the discretion of 
the Investigator.
5.4 Prior and Concomitant Therapy
The investigator should confirm that a concomitant medication/supplement can be safely administered 
with study drug.  Some medications may require dose adjustments due to the potential for DDIs.


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Any medication/supplement or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or 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 drug.  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 SAE will be 
recorded in eCRF.  The AbbVie Primary Therapeutic Area Medical Director should be contacted if there 
are any questions regarding concomitant or prior therapies.
During the Post-Treatment Period, investigators should reassess concomitant medications/supplements 
and subjects may resume previously prohibited medications/supplements or revert to pre-study doses, 
14 days following discontinuation of study drug, if applicable.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie Emergency 
Medical Contact.
Prior and Concomitant HIV-1 Therapy
If a subject is on an HIV-1 ART regimen, it must include at least 1 of the ARV agents defined in eligibility 
criterion 10.
Subjects will maintain the same dose and dosing interval of their HIV-1 ART regimen upon initiating the 
study drug regimen.
Subjects must remain on the same HIV-1 ART regimen for the entire Treatment Period.  Any change to 
an allowed HIV-1 ART regimen during the Treatment Period must be discussed with the AbbVie 
Therapeutic Area MD prior to the change, unless the change is being made to address an immediate 
safety concern.
Subjects receiving any other HIV-1 ART in addition to those listed in eligibility Criterion 10 would not be 
eligible for enrollment in the study.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following: 
•
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the Investigator or the AbbVie Therapeutic Area Medical Director.
•
The Investigator believes it is in the best interest of the subject.
•
The subject requests withdrawal from the study.
•
Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk.


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•
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk.
•
The subject becomes pregnant while on study drug and the investigator, after discussion with 
the subject, concludes that the benefit of continuing therapy does NOT outweigh the risk.
•
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial.
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.
or
•
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA measurements 
≥100 IU/mL) after HCV RNA < LLOQ during study drug treatment.
When confirmatory testing is required, it should be completed as soon as possible and the subject 
should remain on study drug treatment until the virologic failure criteria has been confirmed.  Subjects 
meeting the virologic failure criteria will be discontinued from study drug and will continue to be 
followed in the Post-Treatment Period for the emergence and persistence of resistant viral variants until 
12 weeks post-treatment.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum (unless otherwise required by local 
regulations), 2 phone calls must be made and 1 certified letter must be sent and documented in the 
subject's source documentation. 
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The Investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the Investigator.
Refer to Section 6.2 for additional discontinuation criteria relating to Toxicity Management.
5.6 Follow-Up for Subject Withdrawal from Study
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment should continue to be followed for all regularly scheduled visits, 
unless they have decided to discontinue the study participation entirely (withdrawal of informed 
consent).  Subjects should be advised on the continued scientific importance of their data even if they 
discontinue treatment with study drug early.
If, during the course of study drug administration, the subject prematurely discontinues (D/C), the 
procedures outlined for the applicable Premature D/C Visit should be completed.  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 


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interfere with the initiation of any new treatments or therapeutic modalities that the investigator feels 
are necessary to treat the subject's condition.  Following discontinuation of study drug, the subject will 
be treated in accordance with the investigator's best clinical judgment.  All attempts must be made to 
determine the date of the last study drug dose and the primary reason for discontinuation of study drug 
or study participation.  The last dose of any study drug and reason for discontinuation will be recorded 
in the eCRF.  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 variants.
If a subject is discontinued from study drug or the Post-Treatment Period with an ongoing adverse event 
or an unresolved laboratory result that is significantly outside of the reference range, the investigator 
will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result or 
adverse event is achieved.
5.7 Study Drug
Identity of Study Drug
Information about the study drug to be used in this study is presented in Table 1.
Table 1.
Identity of Study Drug
Study Drug 
Manufacturer
Mode of 
Administration
Dosage Form
Strength
Glecaprevir/pibrentasvir 
AbbVie
Oral
Film-coated tablet
100 mg/40 mg
Three tablets of GLE/PIB combination will be taken QD, beginning on Day 1 (baseline), and should be 
taken at approximately the same time each day.  The study drug must be taken with food. 
Glecaprevir/pibrentasvir combination tablets will be packaged in bottles with quantities sufficient to 
accommodate the study design.  Each kit label will contain a unique kit number.  This kit number which 
is assigned to a subject identifies the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Each kit will be labelled as required per country requirements.  Labels must 
remain affixed to the kits.  All blank spaces on the label will be completed by the site staff prior to 
dispensing to the subjects.
Subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance.
AbbVie will not supply drug other than GLE/PIB combination. 
5.8 Randomization/Drug Assignment
This is not applicable as this study is non-randomized/open label.


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5.9 Protocol Deviations
The Investigator is responsible for complying with all protocol requirements, written instructions and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the Investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable) and 
AbbVie.
6 SAFETY CONSIDERATIONS 
6.1 Complaints and Adverse Events
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.  Complaints associated with any component of this investigational product 
must be reported to the AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE 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.
An AE 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 AE.  Worsening in severity of a reported AE should be reported as a new AE.  
Laboratory abnormalities and changes in vital signs are considered to be AEs only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, meets protocol specific 
criteria (see Section 6.2 regarding toxicity management) and/or if the investigator considers them to be 
AEs.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.  
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a serious 
adverse event within 24 hours of the site being made aware of the serious adverse event:




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Grading System for Adverse Events (a semi-colon indicates 'or' within the description of the grade).
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
Adverse Event Relationship to Study Drug
For the purpose of medical management, all AEs and laboratory abnormalities that occur during the 
study must be evaluated by the Investigator.  All AEs and laboratory abnormalities deemed "clinically 
significant" based on the medical judgment of the Investigator will be managed and followed to a 
satisfactory clinical resolution.  
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.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  Information regarding a pregnancy occurring up to 30 days after 
end of treatment in a study subject and the outcome of the pregnancy will be collected.
The medical outcome for either mother or infant, meeting any serious criteria including an elective or 
spontaneous abortion, stillbirth, or congenital anomaly is considered an SAE and must be reported to 
AbbVie within 24 hours of the site becoming aware of the event.
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 


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drug is felt to outweigh the potential risk.  If a subject is discontinued, the subject will be monitored for 
SVR in the Post-Treatment Period.
6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described below and in the Operations 
Manual.  This includes the following laboratory abnormalities: 
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also > 2 × baseline 
value, the subject should have a confirmatory ALT measurement performed.
If, the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
!
Complete hepatic questionnaire.
!
Evaluate for alternate etiology of ALT elevation; document in the source, update the 
medical history and concomitant medications eCRF (if applicable), and obtain Anti-hepatitis 
A virus immunoglobulin M (HAV IgM), Anti-hepatitis A virus total (HAV Total), Anti-HBc IgM, 
Anti-HBc Total, Anti-HBs, HBV DNA, HBsAg, Anti-hepatitis E virus immunoglobulin M (HEV 
IgM), Anti-hepatitis E virus immunoglobulin G (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 international 
normalized ratio (INR) within 1 week.  Repeat liver chemistries as indicated until resolution.
Discontinue study drug if any of the following is observed at any time:
•
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
•
Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis.
•
At the discretion of the investigator.
Alternate management of ALT increases is permitted with approval of the AbbVie Therapeutic Area 
Medical Director.
6.3 Product Complaint
A Product Complaint is any complaint 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.
Product Complaints concerning the investigational product must be reported to AbbVie within 24 hours 
of the study site's knowledge of the event.  Product Complaints occurring during the study will be 
followed up to a satisfactory conclusion.


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7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock.  The statistical 
analyses will be performed using a statistical analysis system (SAS) (SAS Institute Inc., Cary, NC, USA).
7.2 Definition for Analysis Populations
The Intention-to-Treat (ITT) population includes all enrolled subjects who received at least 1 dose of 
study drug.  The ITT population will be used for all secondary and exploratory efficacy analyses as well as 
for baseline analyses.
The mITT population includes all enrolled subjects who received at least 1 dose of study drug, excluding 
subjects who did not achieve SVR12 for reasons other than virologic failure.  The mITT population will be 
used for the primary efficacy analysis. 
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug. 
7.3 Statistical Analyses
Primary 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) across genotypes in adults with HCV GT1 – GT6.  The 
primary endpoint will be analyzed based on mITT population. 
The secondary efficacy endpoints of SVR12, on-treatment virologic failure, and post-treatment relapse 
will be analyzed across genotypes in adults with HCV GT1 – GT6 based on ITT population.
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. 
The number and percentage of subjects achieving SVR12 will be summarized along with a two-sided 95% 
confidence interval using the normal approximation to the binomial distribution, unless the number of 
subjects who fail to achieve SVR12 is less than 5, where the Wilson's score method will be used for the 
confidence interval instead.  A summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, other) will be provided.
The efficacy of 8-week treatment duration for subjects with APRI ≤ 1 based on mITT population will be 
established if the lower boundary of two-sided 95% confidence interval for the percentage of subjects 
achieving SVR12 is greater than 92.4% among HCV GT1 – GT6 subjects. 


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The efficacy of 8-week treatment duration for subjects with APRI ≤ 1 based on ITT population will be 
established if the lower boundary of two-sided 95% confidence interval for the percentage of subjects 
achieving SVR12 is greater than 91.4% among HCV GT1- GT6 subjects.
In order to control the Type I error rate, a fixed sequence testing procedure will be used for the SVR12
endpoints.  Only if success has been demonstrated for the primary endpoint of SVR12 based on mITT 
population, will the testing proceed to the first secondary endpoint of SVR12 based on ITT population. 
The multiplicity controlled efficacy endpoints will be tested sequentially in the following order:
1.
Efficacy of the 8-week treatment duration based on mITT population:  If this endpoint is 
statistically significant, then proceed to the following efficacy endpoint.  If this endpoint is 
not statistically significant then stop the testing procedure and declare that no endpoints in 
the study met statistical significance.  
2.
Efficacy of the 8-week treatment duration based on ITT population:  If this endpoint is 
statistically significant, then declare the SVR12 endpoint is statistically significant for both 
mITT and ITT populations.  If not, then announce that SVR12 endpoint is statistically 
significant only for mITT population.
For on-treatment virologic failure and post-treatment relapse, the number and percentage of subjects 
will be summarized along with a two-sided 95% confidence interval using Wilson's score method.
Further details on the primary and other efficacy analyses are provided in the SAP.
Sample Size Estimation
It is planned to enroll approximately 230 adult subjects with chronic HCV GT1 – GT6 infection with APRI 
≤ 1 who are HCV treatment-naïve in the study.  The enrollment will be monitored to have approximately 
maximum 46 GT3-infected subjects (20% of total subjects).
With approximately 230 GT1 – GT6 infected subjects (with 46 GT3 subjects) in mITT analysis, this study 
has approximately 90% power to demonstrate efficacy of the 8-week treatment in terms of SVR12 rate 
(i.e., a two-sided 95% lower confidence bound above 92.4%), assuming that 98% of the GT1, GT2, GT4, 
GT5, and GT6-infected subjects with APRI ≤ 1 and 94% of the GT3-infected subjects with APRI ≤ 1 
achieve SVR12.
With 230 GT1 – GT6 infected subjects (with 46 GT3 subjects) in ITT analysis, this study has approximately 
83% power to demonstrate efficacy of the 8-week treatment in terms of SVR12 rate (i.e., a two-sided 
95% lower confidence bound above 91.4%), assuming that 97% of the GT1, GT2, GT4, GT5, and 
GT6-infected subjects with APRI ≤ 1 and 93% of the GT3-infected subjects with APRI ≤ 1 achieve SVR12.
Efficacy for the 8-week regimen in this study is established by demonstrating similarity to the historical 
control regimen of GLE/PIB administered for 8 weeks in treatment-naïve subjects without cirrhosis.  The 
SVR12 rate of the historical control regimen is calculated, and a threshold is determined by subtracting a 
non-inferiority margin of 6% from the historical SVR12 rate.  Efficacy is established if the lower 95% 
confidence boundary of the SVR12 rate in the 8-week regimen is greater than the threshold.  Efficacy for 
the 8-week regimen in this study is established by demonstrating the lower boundary of 95% CI for 
SVR12 rate is higher than a cut off value (92.4% and 91.4% for mITT and ITT population, respectively).


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In the registrational studies, different SVR12 rates based on mITT population have been observed among 
GT3- and non-GT3-infected treatment-naïve subjects without cirrhosis assigned to 8 weeks of GLE/PIB 
treatment.  In these studies, approximately 98.9% and 96.2% SVR12 has been observed among non-
cirrhotic, treatment naïve chronic HCV GT1, GT2, GT4, GT5, and GT6-infected subjects and GT3 subjects, 
respectively.11-13  Hence, for the non-cirrhotic GT1 – GT6-infected subjects, based on mITT population, 
the historical SVR12 rate of 98.4% is estimated based on a weighted average of 80% GT1, GT2, GT4, GT5, 
and GT6 historical rate and 20% GT3 historical rate.  To establish cut off for efficacy based on mITT 
population, a margin of 6% is applied to the historical control rate of 98.4%, resulting in a threshold of 
92.4%.
Historical SVR12 rate based on ITT population depends on the non-virologic failure in a study.  Study-to-
study variability has been observed in non-virologic failure rates, and is typically around 1%.  The 
observed rate of non-virologic failure in the registrational program is 1.2% (29/2369).11-13  For this 
reason, this study assumes that the historical SVR12 rate based on ITT population for treatment naïve 
non-cirrhotic subjects is 97.4% (with 1% non virologic failure).  To establish cut off for efficacy based on 
ITT population, a margin of 6% is applied to the historical control rate of 97.4%, resulting in a threshold 
of 91.4%.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require review 
and approval by the IEC/IRB before the changes are implemented to the study.  In addition, all changes 
to the consent form will be IEC/IRB approved. 
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International 
Conference for 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 Investigator are specified in Appendix B. 
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie. 


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9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. 
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
12 REFERENCES
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.
Zhang J, Nguyen D, Hu KQ.  Chronic hepatitis c virus infection:  a review of current direct-
acting antiviral treatment strategies.  N Am J Med Sci (Boston).  2016;9(2):47-54.
3.
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):509-516.
4.
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.
5.
World Health Organization.  Guidelines for the screening care and treatment of persons with 
chronic hepatitis C infection.  Updated version, April 2016.  Available at:  www.who.int.  
Accessed on:  01 December 2016.
6.
Chou R, Wasson N.  Blood tests to diagnose fibrosis or cirrhosis in patients with chronic 
hepatitis C virus infection:  a systematic review.  Ann Intern Med.  2013;158(11):807-20.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.
Hepatitis C Virus Infection Consensus Statement Working Group.  Australian 
recommendations for the management of hepatitis C virus infection:  a consensus 
statement 2016.  Melbourne:  Gastroenterological Society of Australia, 2016.
8.
AbbVie.  Glecaprevir/pibrentasvir Investigator's Brochure Edition 2.  06 September 2016.
9.
AbbVie.  Glecaprevir/pibrentasvir Investigator's Brochure Edition 2 Addendum 1.  
November 2016.
10.
Wyles D, Poordad F, Wang S, et al.  SURVEYOR-II, part 3:  efficacy and safety of 
glecaprevir/pibrentasvir (ABT-493/ABT-530) in patients with hepatitis C virus genotype 3 
infection with prior treatment experience and/or cirrhosis.  Hepatology.  
2016;64 (Suppl 1):62A.
11.
Zeuzem S, Feld J, Wang S, et al.  ENDURANCE-1:  a phase 3 evaluation of the efficacy and 
safety of 8- versus 12-week treatment with glecaprevir/pibrentasvir (formerly 
ABT-493/ABT-530) in HCV genotype 1 infected patients with or without HIV-1 co-infection 
and without cirrhosis.  Hepatology.  2016;64 (Suppl 1):132A.
12.
Hassanein T, Wyles D, Wang S, et al.  Glecaprevir/Pibrentasvir demonstrates high SVR rates 
in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis following an 8-week 
treatment duration (SURVEYOR-II, Part 4).  Hepatology.  2016;64 (Suppl 6):1128A.
13.
Foster G, Gane E, Asatryan A, et al.  ENDURANCE-3:  safety and efficacy of 
glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV 
genotype 3-infected patients without cirrhosis.  J Hepatol.  2017;66 (Suppl 1):S33.
14.
European Association of the liver, Asociacion Latinoamericana para el Estudio del Higado.  
EASL-ALEH Clinical Practice Guidelines:  Non-invasive tests for evaluation of liver disease 
severity and prognosis.  J Hepatol.  2015;63:237-64.
15.
US Dept. of Health and Human Services.  Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.  28 May 2009.  Available from:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
ADL
Activities of daily living
AE
Adverse event
ALT
Alanine aminotransferase
APRI
Aminotransferase/platelet ratio index
ART
Anti-retroviral treatment
ARV
Anti-retroviral
AST
Aspartate aminotransferase
BID
Twice daily
CRF
Case report form
CTCAE
Common Terminology Criteria For Adverse Events
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
FIB-4
Fibrosis-4
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GLE
Glecaprevir
GT
Genotype
HAV
Hepatitis A virus
HAV IgM
Hepatitis A virus immunoglobulin M
HBc
Hepatitis B core
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus


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HEV
Hepatitis E virus
HEV IgG
Hepatitis E virus immunoglobulin G
HEV IgM
Hepatitis E virus immunoglobulin M
HIV
Human immunodeficiency virus
HIV-1
Human immunodeficiency virus type 1
ICH
International Conference for Harmonization
IEC
Independent ethics committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
ITT
Intention-to-Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
kPa
kilopascal
L
Liter
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
mITT
Modified Intention-to-Treat
mL
Milliliter
mm
Millimeter
N(t)RTI
Nucleoside/nucleotide reverse transcriptase inhibitor
NS
Nonstructural
NS3
Nonstructural viral protein 3
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
PI
Protease inhibitor
PIB
Pibrentasvir
PO
By mouth
PRO
Patient Reported Outcomes
PT
Post-Treatment
QD
Once daily


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RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR12
Sustained virologic response 12 weeks post dosing
TAF
Tenofovir alafenamide
TDF
Tenofovir disoproxil fumarate
ULN
Upper limit of normal
WHO
World Health Organization
Wk
Week
WOCBP
Woman of childbearing potential


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-133:  Chronic HCV Genotype 1 – 6:  Glecaprevir/Pibrentasvir Once Daily Therapy in 
Subjects with APRI ≤ 1
Protocol Date:  31 July 2017
Clinical research studies sponsored by AbbVie are subject to the International Conference for
Harmonisation (ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the 
study at the site location.  In signing the Investigator Agreement, the investigator is agreeing to the 
following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and Operations Manual, and making changes to a protocol only after notifying AbbVie 
and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except 
when necessary to protect the subject from immediate harm.
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., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
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 protocol and all of its amendments.
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. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Protocol Author, Medical 
Writing
TA MD
Medical Affairs
Statistics
Clinical Pharmacology
Bioanalysis
CPD








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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF 
CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
25 May 2017
The purpose of this Amendment is to correct minor clerical errors for consistency throughout the 
protocol in addition to the following:
1.
Provide clarification as to what dose of rosuvastatin can be taken with GLE/PIB.
!
Updated Section 5, Study Activities to change the allowed concomitant rosuvastatin
dose from 10 mg to 5 mg based upon the anticipated European Union Summary of 
Product Characteristics label recommendation under Subsection 5.1, Eligibility Criteria, 
Concomitant Medications.
2.
Provide clarification and additional information regarding contraception use during the study.
!
Updated Section 5, Study Activities to add Subsection 5.2, Contraception Recommendations.
3.
Provide definition of serious adverse event, adverse event severity grade, and assessments for 
relationship of adverse event to study drug.
!
Updated Section 6, Safety Considerations to add regulatory definition of serious adverse 
events under subsection Medical Complaints/Adverse Events and Serious Adverse Events.
!
Updated Section 6, Safety Considerations to add definition of adverse event severity grade 
under subsection Adverse Event Definition of Severity Grade.
!
Updated Section 6, Safety Considerations to add the definition of reasonable possibility and 
no reasonable possibility under the subsection Adverse Event Severity and Relationship to 
Study Drug.
4.
Provided clarification on the timing to report a serious adverse event
!
Updated Section 6, Safety Considerations, under subsection Medical Complaints/Adverse
Events and Serious Adverse Events, to add the requirement by the Investigator to report a 
serious adverse event to the Sponsor within 24 hours of becoming aware of a serious 
adverse event.
5.
Provide clarification around the risk-based monitoring approach
!
Updated Section 6, Safety Considerations, under subsection Medical Complaints/Adverse 
Events and Serious Adverse Events, to add the statement that adverse events will be 
monitored throughout the study to identify any which may indicate a risk to subjects.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
!
Updated Section 10, Data Quality Assurance, to add statement regarding the use of a quality 
management system to define quality tolerance limits.
6.
Provide clarification on what vital sign measurements will be measured during each Treatment 
and Post-Treatment Follow-up Visit.
!
Updated Appendix D, Activity Schedule to include a list of what vital signs will be measured:  
systolic and diastolic blood pressure, pulse, and body temperature.
7.
Provide clarification that HIV-1 RNA and flow cytometry will be performed at Post-treatment 
Week 4 Visit as well as the Screening Visit.
!
Updated Appendix D, Activity Schedule to add HIV-1 RNA and flow cytometry to the Post-
Treatment Week 4 Visit study activities.



SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-133 – Statistical Analysis Plan
Version 1.0 – 30 Jun 2017
1
1.0
Title Page
Statistical Analysis Plan
Study M16-133
A Single Arm, Open Label, Multicenter Study to 
Evaluate the Efficacy and Safety of Glecaprevir 
(GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults 
with Chronic Hepatitis C Virus (HCV) 
Genotypes 1 – 6 Infection and Aspartate 
Aminotransferase to Platelet Ratio Index (APRI) ≤ 1
Date:  30 Jun 2017
Version 1.0
NCT03212521


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Background.................................................................4
4.1
Objective................................................................................................ 4
4.2
Study Design.......................................................................................... 5
4.2.1
Study Design and Design Diagram ......................................................... 5
4.2.2
Variables Used for Stratification at Randomization (if Applicable)......... 6
4.3
Endpoint................................................................................................. 6
4.3.1
Primary Efficacy Endpoint ..................................................................... 6
4.3.2
Secondary Efficacy Endpoints................................................................ 6
4.3.3
Exploratory Efficacy Endpoints.............................................................. 6
4.3.4
Safety Endpoint...................................................................................... 7
4.4
Sample Size Justification........................................................................ 7
4.5
Interim Analysis ..................................................................................... 8
4.6
Multiplicity Testing Procedures for Type-I Error Control....................... 8
4.7
Missing Data Imputation ........................................................................ 9
5.0
Analysis Populations and Important Subgroups............... 10
5.1
Analysis Populations ............................................................................ 10
5.2
Demographics and Baseline Characteristics.......................................... 11
5.3
Prior, Concomitant, and Post-Treatment Medications ........................... 12
5.4
Subject Disposition............................................................................... 12
5.5
Study Drug Exposure and Compliance ................................................. 13
5.5.1
Exposure .............................................................................................. 13
5.5.2
Compliance .......................................................................................... 13
6.0
Efficacy Analyses................................................................. 13
6.1
General Considerations......................................................................... 13
6.2
Primary Efficacy Analysis.................................................................... 16
6.3
Secondary Efficacy Analyses ............................................................... 17
6.4
Other Efficacy Analyses....................................................................... 17
6.4.1
Resistance Analysis.............................................................................. 18


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6.4.2
Patient Reported Outcomes .................................................................. 19
6.5
Efficacy Subgroup Analyses................................................................. 19
7.0
Safety Analyses.................................................................... 20
7.1
General Considerations......................................................................... 20
7.2
Analysis of Adverse Events.................................................................. 20
7.3
Analysis of Laboratory Data................................................................. 24
7.4
Analysis of Vital Signs and Weight ...................................................... 26
8.0
Analysis Conventions .......................................................... 27
9.0
Summary of Changes ..........................................................30
10.0
References............................................................................31
List of Tables
Table 1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 25
Table 2.
Criteria for Potentially Clinically Significant Vital Sign Values............ 26
Table 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, and PRO Instruments 
(Treatment Period) ............................................................................... 29
Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 29
Table 5.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period) ....................................................................... 30
List of Figures
Figure 1.
Study Design Schematic......................................................................... 5


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses for glecaprevir 
(GLE)/pibrentasvir (PIB) study Protocol M16-133.  It provides high level summaries of 
the planned statistical analyses for key efficacy and safety endpoints and multiplicity 
control strategy, as well as some programming details that are standard for AbbVie's HCV 
programs. 
Unless noted otherwise, all analyses will be performed using SAS® Version 9.4 (SAS 
Institute Inc., Carry, NC 27513) or later under the Unix operating system. 
The SAP will not be updated in the case of future administrative or minor amendments to 
the protocol unless the changes have any impact on the analysis of study data.
4.0
Study Background 
4.1
Objective
The primary objective of this study is: 
●
To demonstrate the efficacy (by achieving high SVR12 rate) and safety of 
8 weeks of treatment with the GLE/PIB combination regimen in treatment-
naïve adults with HCV GT1 – GT6 infection with APRI ≤ 1.  The primary 
efficacy objective will be assessed based on mITT population across genotypes 
HCV GT1 – GT6.
The secondary objectives of this study are:
●
To demonstrate the efficacy (by achieving high SVR12 rate) of 8 weeks of 
treatment with the GLE/PIB combination regimen in treatment-naïve adults 
with HCV GT1 – GT6 infection with APRI ≤ 1 based on ITT population.  
●
Assess the percentage of subjects with HCV on-treatment virologic failure 
across genotypes in adults with HCV GT1 – GT6 infection with APRI ≤ 1 
based on ITT population.


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●
Assess the percentage of subjects with HCV virologic relapse across genotypes 
in adults with HCV GT1 – GT6 infection with APRI ≤ 1 based on ITT 
population.
4.2
Study Design 
4.2.1
Study Design and Design Diagram
The schematic of the study is shown in Figure 1.  Approximately 230 treatment naïve 
subjects with chronic HCV GT1 – GT6 and APRI ≤ 1 (maximum of 20% [46] enrollment 
of GT3-infected subjects), who meet all eligibility criteria, will be enrolled at 
approximately 43 sites worldwide, and will receive GLE/PIB combination 
(300 mg/120 mg) QD for 8 weeks in the treatment period and be followed for an 
additional 12 weeks in the post-treatment period in this non-randomized, open label, 
Phase 3b study.
Figure 1.
Study Design Schematic


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4.2.2
Variables Used for Stratification at Randomization (if 
Applicable)
Not applicable; Study M16-133 is an open label non-randomized study.
4.3
Endpoint
4.3.1
Primary Efficacy Endpoint
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 genotypes in 
adults with HCV GT1 – GT6 based on mITT population.
4.3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
Percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug) across genotypes in adults with HCV 
GT1 – GT6 based on ITT population;
●
Percentage of subjects with on-treatment virologic failure based on ITT 
population;
●
Percentage of subjects with post-treatment relapse based on ITT population.
4.3.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints include:
●
SVR12 in subjects with APRI ≤ 0.7 and in subjects with APRI ≤ 0.5 based on 
ITT population;
●
Percentage of subjects with virologic failure with FibroTest > 0.75 based on 
ITT population;
●
Percentage of subjects with SVR12 by key groups (HCV genotype and subtype; 
age) based on ITT population;
●
Adherence to treatment based on ITT population. 


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4.3.4
Safety Endpoint
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital 
sign measurements, electrocardiogram (ECG), and clinical laboratory testing 
(hematology, chemistry including hepatic function parameters) as a measure of safety and 
tolerability for the entire study duration. 
4.4
Sample Size Justification
It is planned to enroll approximately 230 adult subjects with chronic HCV GT1 – GT6 
infection with APRI ≤ 1 who are HCV treatment-naïve in the study.  The enrollment will 
be monitored to have approximately maximum 46 GT3-infected subjects (20% of total 
subjects).
With approximately 230 GT1 – GT6 infected subjects (including 46 GT3 subjects) in 
mITT analysis, this study has approximately 90% power to demonstrate efficacy of the 
8-week treatment in terms of SVR12 rate (i.e., a two-sided 95% lower confidence bound 
above 92.4%), assuming that 98% of the GT1, GT2, GT4, GT5, and GT6-infected 
subjects with APRI ≤ 1 and 94% of the GT3-infected subjects with APRI ≤ 1 achieve 
SVR12.
With 230 GT1 – GT6 infected subjects (including 46 GT3 subjects) in ITT analysis, this 
study has approximately 83% power to demonstrate efficacy of the 8-week treatment in 
terms of SVR12 rate (i.e., a two-sided 95% lower confidence bound above 91.4%), 
assuming that 97% of the GT1, GT2, GT4, GT5, and GT6-infected subjects with APRI 
≤1 and 93% of the GT3-infected subjects with APRI ≤ 1 achieve SVR12.
Efficacy for the 8-week regimen in this study is established by demonstrating similarity to 
the historical control regimen of GLE/PIB administered for 8 weeks in treatment naïve 
non cirrhotic patients.  The SVR12 rate of the historical control regimen is calculated, and 
a threshold is determined by subtracting a non-inferiority margin of 6% from the historical 
SVR12 rate.  Efficacy is established if the lower 95% confidence boundary of the SVR12
rate in the 8-week regimen is greater than the threshold.  Efficacy for the 8-week regimen 


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in this study is established by demonstrating the lower boundary of 95% CI for SVR12 rate 
is higher than a cut off value (92.4% and 91.4% for mITT and ITT population, 
respectively).
In the registration studies different SVR12 rates based on mITT population have been 
observed among naïve non cirrhotic GT3-infected subjects and non-GT3-infected subjects 
for 8 weeks of GLE/PIB treatment.  In these studies, approximately 98.9% and 96.2% 
SVR12 has been observed among non-cirrhotic, treatment naïve chronic HCV GT1, GT2, 
GT4, GT5, and GT6-infected subjects and GT3 subjects assigned to 8 weeks of treatment, 
respectively.1-3  Hence, for the non-cirrhotic GT1 – GT6-infected subjects, based on mITT 
population, the historical SVR12 rate of 98.4% is estimated based on a weighted average 
of 80% GT1, GT2, GT4, GT5, and GT6 historical rate and 20% GT3 historical rate.  To 
establish cut off for efficacy based on mITT population, a margin of 6% is applied to the 
historical control rate of 98.4%, resulting in a threshold of 92.4%.
Historical SVR12 rate based on ITT population depends on the non-virologic failure in a 
study.  Study-to-study variability has been observed in non-virologic failure rates, and is 
typically around 1%.  The observed rate of non-virologic failure in the registrational 
program is 1.2% (29/2369).1-3  For this reason, this study assumes that the historical 
SVR12 rate based on ITT population for treatment naïve non-cirrhotic subjects is 97.4% 
(with 1% non virologic failure).  To establish cut off for efficacy based on ITT population, 
a margin of 6% is applied to the historical control rate of 97.4%, resulting in a threshold 
of 91.4%.
4.5
Interim Analysis
There is no interim analysis planned for this study. 
4.6
Multiplicity Testing Procedures for Type-I Error Control
In order to control the Type I error rate, a fixed sequence testing procedure will be used 
for the SVR12 endpoints (primary and controlled-secondary efficacy tests of SVR12).  
Only if success has been demonstrated for the primary endpoint of SVR12 based on mITT 


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population, will the testing proceed to the first secondary endpoint of SVR12 based on ITT 
population. 
The multiplicity controlled efficacy endpoints will be tested sequentially in the following 
order:
1.
Efficacy of the 8-week treatment duration based on mITT population:  If this 
endpoint is statistically significant, then proceed to the following efficacy endpoint.  
If this endpoint is not statistically significant then stop the testing procedure and 
declare that no endpoints in the study met statistical significance.  
2.
Efficacy of the 8-week treatment duration based on ITT population:  If this 
endpoint is statistically significant, then declare the SVR12 endpoint is statistically 
significant for both mITT and ITT populations.  If not, then announce that SVR12
endpoint is statistically significant only for mITT population. 
4.7
Missing Data Imputation
Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 8.0.
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.


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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
For EQ-5D-5L index and VAS scores, no imputation will be performed for missing items.  
If a subject starts another treatment for HCV, then all PRO assessment values for this 
subject measured on or after the start date of the new HCV treatment will be excluded 
from analyses. 
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Populations 
The modified Intention-to-Treat (mITT) population includes all enrolled subjects who 
received at least 1 dose of study drug, excluding subjects who did not achieve SVR12 for 
reasons other than virologic failure.  The mITT population will be used for the primary 
efficacy analysis.
The Intention-to-Treat (ITT) population includes all enrolled subjects who received at 
least 1 dose of study drug.  The ITT population will be used for all secondary and 
exploratory efficacy analysis as well as for baseline analyses.
The Safety Population consists of all subjects who received at least 1 dose of study drug.  


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5.2
Demographics and Baseline Characteristics 
Continuous demographic and baseline characteristics include age, weight, height, body 
mass index (BMI), baseline log10 HCV RNA level, APRI, creatinine clearance 
(Cockcroft-Gault calculation), eGFR, platelet count, albumin, CD4+ T-cell count, GGT, 
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);
●
Race (White, Black/African-American, Asian, or other) and (black or 
non-black);
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
●
Geographic region;
●
Country;
●
Baseline BMI (< 30 or ≥ 30 kg/m2);
●
Baseline APRI (≤ 0.7 or > 0.7) and (≤ 0.5 or > 0.5); 
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype;
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL) and 
(< 6,000,000 or ≥ 6,000,000 IU/mL);
●
Baseline FibroTest score (≤ 0.75 or > 0.75) and (≤ 0.48, 0.49 to 0.58, 0.59 to 
0.75, or > 0.75);
●
Former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no);
●
Subject on stable opiate substitution (yes/no).
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum and minimum).   


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5.3
Prior, Concomitant, and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug.  A concomitant medication is defined as any medication that started prior to 
the date of the first dose of study drug and continued to be taken on or after the first dose 
of study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug.  A post-treatment medication for 
the treatment of HCV is defined as any medication taken on or after the last dose of study 
drug and entered as "Post treatment HCV medications" on the eCRF. 
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.  
5.4
Subject Disposition
The number and percentage of subjects who screen failed for any reason, and for each 
screen fail reason, will be summarized for all subjects who screen failed.
For the safety population, the number of subjects in each of the following categories will 
be summarized by investigator 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.
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF).  Similar summaries will be 
provided for discontinuations from the study and study drug interruptions.  Reasons for 
study drug interruptions will be presented in the CSR listings.


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5.5
Study Drug Exposure and Compliance
5.5.1
Exposure
Duration of exposure to study drug is defined for each subject as the last study drug dose 
date minus the first study drug dose date plus 1 day.  The number and percentage of 
subjects in the safety population with study drug duration of ≥ 52 days will be 
summarized.
5.5.2
Compliance
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of tablets dispensed and returned is recorded.  The compliance, defined as 
adherence for study drug (GLE/PIB) during the treatment period, will be calculated as the 
percentage of tablets taken relative to the total tablets expected to be taken.  The total 
number of tablets expected to be taken will be equal to the total number of tablets that 
should have been taken per the protocol for the duration that the subject was in the 
Treatment Period (date of last dose of study drug – date of first dose of study drug + 1).  
Study drug interruptions recorded on the eCRF will not be subtracted from the duration.  
A subject is considered to be compliant (adherent to treatment) if the percentage is 
between 80% and 120%.
6.0
Efficacy Analyses
6.1
General Considerations
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database. 


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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.
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window. 


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Post-treatment relapse (i.e., Relapse12) = confirmed HCV RNA ≥ LLOQ between end
of treatment and 12 weeks after last actual dose of study drug (up to and including the 
SVR12 assessment time point) for a subject with HCV RNA < LLOQ at Final Treatment 
Visit who completed treatment (defined as study drug duration ≥ 52 days), excluding 
reinfection. 
Virologic failure = On-treatment virologic failure or Post-treatment relapse 
(Relapse12)
Only subjects who have at least one post-treatment HCV RNA value will be included in 
the analysis of relapse.  For the analysis of relapse, completion of treatment is defined as 
any subject with study drug duration of 52 days or greater.  If the last available 
post-treatment value is ≥ LLOQ, then the subject will be considered a relapse (i.e., will 
not require confirmation).
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the 
post-treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B gene 
sequences.  Reinfection in the case of the same HCV subtype is defined as a clade switch, 
as indicated by the lack of clustering between the baseline and post-treatment sequences 
by phylogenetic analysis.  If phylogenetic analysis is not possible due to technical 
difficulties, HCV reinfection may be determined with a confirmed HCV genotype or 
subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger 
assay.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);


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2.
Relapse (defined according to the Relapse12 definition for subjects who complete 
treatment);
3.
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] and did not meet the On-treatment virologic 
failure or Relapse12 definition);
4.
HCV reinfection (see definition described earlier);
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR12 non-responder not meeting the definitions of
[1] – [5]). 
6.2
Primary Efficacy Analysis 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  The number and percentage of subjects in the mITT 
population achieving SVR12 will be summarized and a two-sided 95% confidence interval 
will be calculated using the normal approximation to the binomial distribution.  If the 
number of SVR12 non-responders is less than five, then the Wilson's score method will be 
used to calculate the confidence interval.  As a sensitivity analysis, Wilson's score method 
will be used to calculate the confidence interval if the number of SVR12 non-responders is 
greater than or equal to five.
The efficacy of 8-week treatment duration for HCV GT1 – GT6 subjects with APRI ≤ 1 
based on mITT population will be established if the lower boundary of two-sided 95% 
confidence interval for the percentage of subjects achieving SVR12 is greater than 92.4%.
A summary of reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse) in the mITT population will be provided.  A listing of subjects who do not 


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achieve SVR12 by reason for non-response will also be provided.  A listing of subjects 
excluded from the mITT population will be provided.
6.3
Secondary Efficacy Analyses
The number and percentage of subjects in the ITT population achieving SVR12 will be 
summarized and a two-sided 95% confidence interval will be calculated using the normal 
approximation to the binomial distribution.  If the number of SVR12 non-responders is less 
than five, then the Wilson's score method will be used to calculate the confidence interval.  
As a sensitivity analysis, Wilson's score method will be used to calculate the confidence 
interval if the number of SVR12 non-responders is greater than or equal to five.
The efficacy of 8-week treatment duration for HCV GT1 – GT6 subjects with APRI ≤ 1 
based on ITT population will be established if the lower boundary of two-sided 95% 
confidence interval for the percentage of subjects achieving SVR12 is greater than 91.4%.
The number and percentage of subjects, along with two-sided 95% Wilson score intervals,
with on-treatment virologic failure (defined as On-treatment virologic failure) and with 
post-treatment relapse (defined as Relapse12) will be summarized overall for the ITT 
population.
6.4
Other Efficacy Analyses 
The following additional efficacy endpoints will be summarized and analyzed 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;
●
Adherence to treatment;
●
The percentage of subjects in the ITT population with virologic failure by 
baseline FibroTest score (≤ 0.75 or > 0.75);
●
The percentage of subjects in the ITT population with on-treatment virologic 
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The percentage of subjects in the ITT population with post-treatment relapse 
by HCV genotype.
In the above analyses, the percentage of subjects with a two-sided 95% Wilson score 
interval will be summarized.  Imputations for missing data will be performed as described 
in Section 4.7 for SVR, where a missing response will be imputed as a failure after 
performing the described imputation.  All other endpoints will be presented using data as 
observed.
A summary of the subjects who completed treatment and relapsed will be prepared 
displaying the number of subjects relapsing overall and by SVR visit window (within the 
SVR4 window or within the SVR12 window), including the subject number and the SVR 
visit window corresponding to the first occurrence of relapse.  A similar listing will be 
prepared for subjects who prematurely discontinued treatment and relapsed after having 
HCV RNA < LLOQ at their Final Treatment Visit.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum; 
number and percentage) will be presented for exposure during the treatment period.  
Compliance (adherence) will be calculated for each subject and summarized with the 
mean, median, standard deviation, minimum, and maximum for each treatment arm and 
overall.  A listing of compliance for each subject will be provided.  The percentage of 
compliant subjects will be summarized based on data as observed.  An additional 
summary of the percentage of compliant subjects will be provided where subjects who are 
missing study drug accountability records will be imputed as non-compliant.
6.4.1
Resistance Analysis
The following resistance information will be analyzed for all available baseline samples 
from subjects in the study:  1) the prevalence of polymorphisms at signature amino acid 
positions or a key subset of amino acid positions at baseline identified by next-generation 
sequencing (NGS) will be compared to the appropriate subtype specific prototypic 
reference sequence; and, (2) a comparison of SVR12 rates in subjects with or without 


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baseline variants will be conducted.  For subjects not achieving SVR12, treatment-
emergent substitutions at post-baseline time points will be identified by NGS relative to 
the respective baseline sequence and to a subtype-specific reference sequence.
HCV Genotype/Subtype:
Phylogenetic analysis will be conducted on all available HCV sequences from baseline 
samples in order to accurately determine HCV subtype.
6.4.2
Patient Reported Outcomes
The EuroQoL-5 Dimensions-5 Level (EQ-5D-5L) is a health state utility instrument that 
evaluates preference for health status (utility).  The 5 items in the EQ-5D-5L comprise 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) each of which are rated on 5 levels of severity (no problems, slight  
problems, moderate problems, severe problems, unable to do/extreme problems).  
Responses to the 5 items encode a discrete health state which is mapped to a preference 
(utility) specific for different societies.4,5  Subjects also rate their perception of their 
overall health on a separate visual analogue scale (VAS).
Summary statistics (n, mean) at each visit and for change from baseline (n, mean, SD, 
minimum, and maximum) to each visit will be provided for EQ-5D-5L health index score 
and VAS score.
6.5
Efficacy Subgroup Analyses
The number and percentage of subjects with SVR12 in the ITT and mITT populations will 
be presented for the following key subgroups:
●
Baseline APRI (≤ 0.7 or > 0.7) and (≤ 0.5 or > 0.5); 
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype;
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Baseline FibroTest score (≤ 0.75 or > 0.75);
●
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The two-sided 95% Wilson score confidence interval will be produced if there are at least 
10 subjects in the subgroup.
7.0
Safety Analyses
7.1
General Considerations
Safety analyses will be performed using the safety population.
7.2
Analysis of Adverse Events
Adverse events 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.
Treatment-emergent adverse events are defined as any adverse event (AE) with an 
onset date that is after the first dose of study drug and no more than 30 days after the last 
dose of study drug.  Events where the onset date is the same as the study drug start date 
are assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent, unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date).
The number and percentage of subjects with treatment-emergent adverse events will be 
tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT).  The 
system organ classes will be presented in alphabetical order, and the preferred terms will 
be presented in alphabetical order within each system organ class. 
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 adverse event;


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


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●
Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to DAAs (glecaprevir/pibrentasvir);
●
Grade 3 or higher treatment-emergent adverse events;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAA (glecaprevir/pibrentasvir);
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
DAA-related treatment-emergent adverse events leading to discontinuation of 
study drug;
●
Serious treatment-emergent adverse events leading to discontinuation of study 
drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to death.
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be provided.
Adverse Events by PT
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated according to PT and sorted by overall frequency.  Similar summaries 
will be provided for Grade 3 or higher treatment emergent adverse events, DAA related 
treatment-emergent adverse events, DAA-related Grade 3 or higher treatment-emergent 
adverse events, and DAA-related treatment-emergent serious adverse events. 
Adverse Events by Maximum Severity Grade Level
Treatment-emergent adverse events and DAA-related treatment-emergent adverse event 
will be summarized by maximum severity grade.  Each adverse event 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 


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the highest grade level (grade 5).  In this case, the subject will be counted under the 
"Grade 5" category.
Adverse Event by Maximum Relationship
Treatment-emergent adverse events also will be summarized by maximum relationship of 
each preferred term to study drug (DAA), as assessed by the investigator.  If a subject has 
an adverse event 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 adverse event with a relationship assessment of "Reasonable 
Possibility."  In this case, the subject will be counted under the "Reasonable Possibility" 
category.
Other Adverse Events
The number and percentage of subjects experiencing at least one treatment-emergent 
adverse event in the search defined by Product MedDRA Query (PMQ) "Hepatic 
Decompensation and Hepatic Failure" will be presented overall and by SOC and PT.  In 
addition, a listing of treatment-emergent adverse events for subjects meeting the search 
criterion will be provided.
Listing of Adverse Events
The following listings of adverse events will be prepared:
●
All serious adverse events (from the time the subject signed the study-specific 
informed consent through the end of the study),
●
Treatment-emergent serious adverse events,
●
Treatment-emergent adverse events leading to death,
●
Treatment-emergent adverse events leading to discontinuation of study drug,
●
Treatment-emergent adverse events leading to study drug interruption.


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7.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.  The protocol-defined hematology, 
clinical chemistry, and urinalysis laboratory tests will be summarized.  Some of the above 
laboratory variables are calculated by the laboratory vendor including indirect bilirubin, 
creatinine clearance, and eGFR by MDRD.  
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 change 
to Treatment Period visits and change to Post-Treatment Period visits.
Mean 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, change from baseline 
mean, standard deviation, minimum, median, and maximum.
The laboratory parameters defined in Table 1 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 
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Table 1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase 
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin 
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Absolute 
Neutrophil Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Glucose 
(increased)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 – 27.8 mmol/L
> 27.8 mmol/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Assessment of Hepatotoxicity
The number and percentage of subjects with maximum on treatment lab values meeting 
the following criteria for potential hepatotoxicity will be summarized:
●
ALT ≥ 3 × ULN and total bilirubin  ≥ 2 × ULN;
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN;
●
ALT > 5 × ULN and total bilirubin < 2 × ULN;
●
ALT < 3 × ULN and total bilirubin ≥ 2 × ULN.


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The number and percentage of subjects with post-baseline values during the Treatment 
Period meeting the following criteria for hepatic laboratory parameters will be 
summarized:
●
ALT > 5 × ULN and ≥ 2 × baseline;
●
AST > 5 × ULN and ≥ 2 × baseline;
●
Total bilirubin ≥ 2.0 × ULN and > baseline.
7.4
Analysis of Vital Signs and Weight
Vital sign variables are body temperature, sitting systolic blood pressure, sitting diastolic 
blood pressure, sitting pulse rate, and body weight.
The criteria for potentially clinically significant vital sign findings are presented in 
Table 2.
Table 2.
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
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for change to Treatment 
Period visits and change to Post-Treatment Period visits.


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Mean 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, 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 Potentially Clinically Significant (PCS) vital sign values (Table 2) 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.
8.0
Analysis Conventions
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.  The protocol operations manual specifies that all 
Day 1 baseline procedures are to be performed prior to administering the first dose of 
study drug.  Therefore, all Day 1 assessments for which time is not collected will be 
assumed to be pre-dose and the baseline value will be the last non-missing measurement 
collected on or before the first day of study drug administration.
All Day 1 assessments with time available must be before the time of first dose to be 
considered baseline and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 
time or if time is not available, then the average of these measurements will be considered 
the baseline value.  The same baseline value will be used for analyses of the Treatment 
and Post-Treatment Periods.
Safety assessments that are related to a serious adverse event that occurred on the 
first dose day are excluded when applying this algorithm.


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Study Days
Study days are calculated for each time point relative to the first dose of study drug.  
Study days are negative values when the time point of interest is prior to the first study 
drug dose day.  Study days are positive values when the time point of interest is after the 
first study drug dose day.  There is no Study Day 0.  Study Day 1 is the day of the 
first dose of study drug.
Study Drug End Days (Days Relative to the Last Dose of Study Drug) 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.
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.  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.
Definition of Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 3
and Table 4 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.
For laboratory data and vital signs, the time windows specified in Table 3 and Table 5
describes how data are assigned to protocol specified time points.
If more than one assessment is included in a time window, the assessment closest (except 
in analyses of SVR) to the nominal time will be used.  If there are two observations 
equally distant to the nominal time, the latest one will be used in analyses.  For analyses 
of SVR (e.g., SVR12), the last value in the window will be used. 


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If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used 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 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, and PRO Instruments 
(Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 1a
Week 4
28
2 to 42
Week 8
56
43 to 70
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  
Table 4.
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
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
a.
Post-Treatment Visits are applicable to subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4 and SVR12.  Data must also have 
Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last dose of 
study drug.


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Table 5.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period)
Scheduled Time
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Final Post-Treatment Visita
> 2 days after the last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
Vital signs and hematology, chemistry, urinalysis, and coagulation panels are collected at both post-treatment 
visits.  PRO instruments are collected at PTW12/PTDC only.
9.0
Summary of Changes
There have been no changes since the latest version of the protocol.


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10.0
References 
1.
Zeuzem S, Feld J, Wang S, et al.  ENDURANCE-1:  a phase 3 evaluation of the 
efficacy and safety of 8- versus 12-week treatment with glecaprevir/pibrentasvir 
(formerly ABT-493/ABT-530) in HCV genotype 1 infected patients with or 
without HIV-1 co-infection and without cirrhosis.  Hepatology.  
2016;64 (Suppl 1):132A.
2.
Hassanein T, Wyles D, Wang S, et al.  Glecaprevir/pibrentasvir demonstrates high 
SVR rates in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis 
following an 8-week treatment duration (SURVEYOR-II, Part 4).  Hepatology.  
2016;64 (Suppl 6):1128A.
3.
Foster G, Gane E, Asatryan A, et al.  ENDURANCE-3:  safety and efficacy of 
glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve 
HCV genotype 3-infected patients without cirrhosis.  J Hepatol.
2017;66 (Suppl 1):S33.
4.
Szende A, Williams A.  Measuring self-reported population health:  an 
international perspective based on EQ-5D.  EuroQol Group Monographs 
Volume 1.  SpringMed Publishing; 2004.
5.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L user guide:  basic information on 
how to use the EQ-5D-5L instrument, Version 1.0.  Rotterdam, the Netherlands:  
EuroQol Group; 2011.