A Multicenter, Single-Arm Prospective Study to Evaluate Safety and Efficacy of GLE/PIB 8-Week Treatment in Adults and Adolescents With Acute Hepatitis C Virus (HCV) Infection
Phase: PHASE3
Conditions: Hepatitis C Virus (HCV)
Sponsor: AbbVie



  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
10
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
11
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
ADDITIONAL EFFICACY ENDPOINTS
12
3.5
SAFETY ENDPOINTS
13
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
18
5.3
PROHIBITED MEDICATIONS AND THERAPY
20
5.4
PRIOR AND CONCOMITANT THERAPY
20
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
23
5.7
STUDY DRUG
23
5.8
RANDOMIZATION/DRUG ASSIGNMENT
24
5.9
PROTOCOL DEVIATIONS
24
5.10 DATA MONITORING COMMITTEE
24
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
6.2
TOXICITY MANAGEMENT
28
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
29
7.1
STATISTICAL AND ANALYTICAL PLANS
29
7.2
DEFINITION FOR ANALYSIS POPULATIONS
29
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
29
7.4
STATISTICAL ANALYSES FOR EFFICACY
30
7.5
STATISTICAL ANALYSES FOR SAFETY
32
7.6
INTERIM ANALYSIS
33
7.7
OVERALL TYPE I ERROR CONTROL
33
7.8
SAMPLE SIZE DETERMINATION
33
8
ETHICS
34
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
34
8.2
ETHICAL CONDUCT OF THE STUDY
34
8.3
SUBJECT CONFIDENTIALITY
35
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
35
10 DATA QUALITY ASSURANCE
35
11 START AND COMPLETION OF THE STUDY
35
12 REFERENCES
35
LIST OF TABLES
TABLE 1.
SAMPLE SIZE JUSTIFICATION BASED ON PROBABILITY OF OBSERVING ANY TOXICITY
34
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
37
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
40
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APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
41
APPENDIX D.
ACTIVITY SCHEDULE
42
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
44
APPENDIX F.
OPERATIONS MANUAL
46
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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 approximately 1.75 million new infections 
worldwide in 2015 and an estimated 44,700 new infections in the United States (US) in 2017.1,2  There 
are currently no approved direct acting antiviral agent options for use in patients with acute hepatitis C 
virus (HCV) infection.  Because of this, treatment is frequently delayed by 6 months (i.e., until the HCV 
infection is considered chronic).  The majority of new HCV infections today are in people who inject 
drugs (PWID) and men who have sex with men.3  Since PWID are often disconnected from care, waiting 
6 months to confirm chronic infection results in the loss of many such patients to care and accelerates 
community transmission of HCV as the patients infect others during the acute phase.  The Centers for 
Disease Control and Prevention recently reported a dramatic increase in HCV within the US, with new 
HCV cases 4 times higher than they were 10 years ago.2  This jeopardizes the World Health 
Organization's goal of HCV elimination by 2030.
The combination treatment regimen of once daily (QD) glecaprevir (GLE) and pibrentasvir (PIB) at the 
dose of GLE 300 mg and PIB 120 mg (hereafter referred to as GLE/PIB) was initially developed for use in 
chronically infected HCV treatment-naïve (TN) and treatment-experienced (TE) genotype (GT)1 –
GT6-infected adult subjects without cirrhosis or with compensated cirrhosis.  The safety and efficacy of 
the GLE/PIB regimen were demonstrated in 9 registrational and 3 supportive Phase 2 studies in adults 
with chronic HCV.  Subsequent studies have demonstrated the safety and efficacy of GLE/PIB in 
adolescents, and an update to the indication to include adolescents (12 to < 18 years of age) was 
approved by the Food and Drug Administration on April 30, 2019 and in the European Union (EU) on 
March 13, 2019.  Efficacy of GLE/PIB treatment was also demonstrated in Phase 2 and Phase 3 studies in 
chronically HCV-infected adults who were self-reported as current/recent PWID.4
Regulatory approval of antiviral treatment for patients with acute HCV would prevent loss of patients to 
care, simplify decision-making for clinicians in the community setting, shorten the time to treatment of 
HCV infection, and would decrease the risk of community transmission.  The American Association for 
the Study of Liver Diseases and the European Association for the Study of the Liver practice guidelines 
recommend treatment of acute HCV to prevent progression to chronic HCV.5,6  Initial evidence indicates 
that GLE/PIB could be an efficacious and safe treatment for this population.  Additionally, 2 recent 
clinical studies also support that GLE/PIB treatment may be efficacious and safe for use in patients with 
acute HCV:

Martinello et al. evaluated GLE/PIB treatment of 6 weeks duration in 30 acute/recent acquired 
HCV patients, and reported an Intention-to-treat (ITT) sustained virologic response 12 weeks 
post-treatment (SVR12) of 90% and per protocol SVR12 of 96%.7

Chromy et al. evaluated GLE/PIB treatment of 8 weeks duration in 11 patients with acute HCV 
who were also positive for human immunodeficiency virus (HIV), and demonstrated a 100% 
SVR12 rate.8
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The GLE/PIB regimen was well-tolerated in both studies, with no treatment-emergent serious adverse 
events (SAEs) observed.
This study is designed to support treatment of adults and adolescents (≥12 years of age) with acute HCV 
with GLE/PIB 300 mg/120 mg QD, which is currently approved for patients with chronic HCV.
This study aims to provide data to support the treatment of acute HCV patients with GLE/PIB, facilitate 
HCV management in outreach settings, and improve the HCV care cascade.
2.2 Benefits and Risks to Subjects
The GLE/PIB regimen has been well-studied in chronic HCV infection.  The safety and efficacy of the 
GLE/PIB regimen in chronic HCV TN and/or TE HCV GT1 – GT6-infected adults without cirrhosis or with 
compensated cirrhosis, including subjects with severe renal impairment or end-stage renal disease 
(chronic kidney disease Stages 4 or 5), and subjects coinfected with HIV were demonstrated in 
9 registrational studies and 3 supportive Phase 2 studies, resulting in regulatory approvals in multiple 
countries/regions across the globe.  Subsequently, the GLE/PIB regimen was studied in a Phase 2/3 
study in adolescents 12 to < 18 years of age with chronic HCV GT1 – GT6 infection.  The safety and 
efficacy profile of GLE/PIB in adolescents with chronic HCV GT1 – GT6 infection was shown to be similar 
to its safety and efficacy profile established in the adult studies.  Approvals for extension of the GLE/PIB 
treatment regimen to adolescents were granted in multiple countries/regions including the EU, US, 
Japan, and global registrations continue.  Efficacy of GLE/PIB treatment was also demonstrated in 
Phase 2 and Phase 3 studies in chronically HCV-infected adults who were self-reported as current/recent 
PWID.  In clinical trials, the safety and efficacy of GLE/PIB were shown to be similar between subjects 
who self-identified as current/recent PWID, those who were former PWID, and those who did not report 
history of injection drug use.  The safety and efficacy of GLE/PIB were also similar between subjects who 
reported concomitant medication-assisted treatment (MAT) for opioid use disorder and those who did 
not report concomitant MAT.4  The safety data of GLE/PIB from clinical studies describe a well-tolerated 
regimen in chronic HCV populations, including adolescents and PWID patients, with very few risks that 
are mitigated using the product information.  Overall, the use of the GLE/PIB regimen as treatment of 
chronic HCV infection is supported by a favorable benefit-risk profile.
For further details, please see findings from completed studies, including safety data in the current 
GLE/PIB Investigator's Brochure.
Acute HCV infection is generally benign compared with chronic HCV infection, and it is expected that the 
same dose of GLE/PIB (300 mg/120 mg) will be effective in treating acute HCV infection.  Risks 
associated with GLE/PIB, including the risks of toxicity, appear to be limited based on the available data.7  
Given the potential for sustained virologic response (SVR) in the acute HCV infection, the risk-benefit 
assessment is favorable.  Given the potential for SVR in the acute HCV infection, the risk-benefit 
assessment is favorable.
Considering the coronavirus – 2019 (COVID-19) pandemic, the benefit and risk to subjects participating 
in this study have been re-evaluated.  Based on the limited information to date, no additional risk to 
study participants is anticipated with the use of GLE/PIB.  Although there is currently no demonstrated 
activity/efficacy of GLE/PIB against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 
stopping the anti-HCV antiviral treatment may lead to the occurrence of HCV virologic failure and 
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development of resistance.  If a subject in the study has been diagnosed or has symptoms compatible 
with SARS-CoV-2 infection, study drug administration should be maintained, unless a medication needed 
for the treatment of the COVID-19 infection is contraindicated with GLE/PIB or is documented to have 
significant interaction with GLE/PIB.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
The objectives of this study are to assess the safety and efficacy of GLE/PIB 8-week treatment in adults 
and adolescents with confirmed acute HCV infection.
Glecaprevir/pibrentasvir is expected to achieve a high SVR12 rate and an acceptable safety profile in 
adults and adolescents with acute HCV infection.
Primary
The primary objective of this study is to demonstrate the efficacy of 8-week treatment with GLE/PIB in 
adults and adolescents with confirmed acute HCV infection by comparing the SVR12 rate from this study 
to the historical SVR12 rate in subjects with chronic HCV infection who were treated with GLE/PIB.  The 
primary efficacy objective will be assessed based on the ITT population which is defined as all enrolled 
subjects who received at least 1 dose of study drug.
The primary hypothesis is that 8-week treatment with GLE/PIB for subjects in the ITT population is 
superior to an efficacy threshold (described in Section 7.8) based on the historical ITT SVR12 rates of 
treatment with GLE/PIB in subjects with chronic HCV infection.4  This will be shown if the lower bound of 
the 2-sided 95% confidence interval (using Wilson's score method) for the percentage of subjects in the 
ITT population achieving SVR12 is greater than the efficacy threshold.
The estimand corresponding to the primary efficacy objective is the percentage of acutely infected HCV 
subjects assigned 8 weeks of GLE/PIB in the ITT population who achieve SVR12.  Subjects who 
discontinue the study with an unknown SVR12 status will be counted as a failure for SVR12.
Key Secondary
The key secondary objective of this study is the same as the primary objective of this study except that 
the key secondary objective will be assessed in the modified ITT – virologic failure (mITT-VF) population.  
The mITT-VF population is defined as all enrolled subjects who received at least one dose of study drug, 
excluding those who did not achieve SVR12 for reasons other than virologic failure (i.e., those with HCV 
reinfection, those who did not achieve SVR12 due to early premature discontinuation of study drug, and 
those who were missing HCV RNA data in the SVR12 window after backward imputation).
The key secondary hypothesis is that 8-week treatment with GLE/PIB for subjects in the mITT-VF 
population is superior to an efficacy threshold (described in Section 7.8) based on the historical mITT-VF 
SVR12 rates of treatment with GLE/PIB in the chronically-infected HCV population.4  This will be shown if 
the lower bound of the 2-sided 95% confidence interval (using Wilson's score method) for the 
percentage of subjects in the mITT-VF population achieving SVR12 is greater than the efficacy threshold.
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The estimand corresponding to the key secondary efficacy objective is the percentage of acutely 
infected HCV subjects assigned 8 weeks of GLE/PIB in the mITT-VF population (i.e., excluding those in 
the ITT population who did not achieve SVR12 for reasons other than virologic failure) who achieve SVR12.
Supportive Secondary
The other secondary objectives of this study are to determine the on-treatment virologic failure (OTVF), 
post-treatment (PT) relapse, and post-treatment reinfection rates in the ITT population.
Safety
The safety objectives of this study are to examine the safety with respect to alanine aminotransferase 
(ALT) elevations, adverse events (AEs) leading to study drug discontinuation, SAEs, and AEs of hepatic 
decompensation during an 8-week treatment with GLE/PIB in adults and adolescents with confirmed 
acute HCV infection in the Safety Analysis Set (defined as all subjects who received at least 1 dose of 
study drug).
3.2 Primary Endpoint
The primary endpoint is the achievement of SVR12 (defined as HCV RNA < the lower limit of 
quantification [LLOQ] 12 weeks after the last actual dose of study drug) for each subject in the ITT 
population.
3.3 Secondary Endpoints
Key Secondary Endpoint
The key secondary endpoint is achievement of SVR12 for each subject in the mITT-VF population.
Supportive Secondary Endpoints

On-treatment virologic failure (as defined in Section 7.4) for each subject in the ITT population

Post-treatment relapse (Relapse12:  as defined in Section 7.4) for each subject in the ITT 
population who completed treatment as planned (as defined in Section 7.4) with HCV 
RNA < LLOQ at the end of treatment (EOT) and with at least 1 post-treatment HCV RNA value

Post-treatment reinfection with HCV (as defined in Section 7.4) for each subject in the ITT 
population
3.4 Additional Efficacy Endpoints
Additional efficacy endpoints will be specified in the Statistical Analysis Plan (SAP).
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3.5 Safety Endpoints

Alanine aminotransferase elevations of National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03 Grade 1, 2, 3 or 4 with ALT grade increased from 
baseline for each subject in the Safety Analysis Set.

Post-nadir ALT elevation > 3 × upper limit of normal (ULN) with total bilirubin > 2 × ULN for each 
subject in the Safety Analysis Set.

Treatment-emergent hepatic decompensation/hepatic failure events for each subject in the 
Safety Analysis Set.

Treatment-emergent AEs leading to discontinuation of study drug for each subject in the Safety 
Analysis Set

Treatment-emergent SAEs for each subject in the Safety Analysis Set.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This study will be conducted as a Phase 3b, multicenter, single-arm, prospective study to evaluate the 
safety and efficacy of GLE/PIB 8-week treatment in adult and adolescent subjects with acute HCV 
infection.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix F).
See Section 5 for information regarding eligibility criteria.
Figure 1.
Study Schematic
GLE = glecaprevir; PIB = pibrentasvir; PTW = post-treatment week
4.2 Discussion of Study Design
Choice of Control Group
An integrated analysis of Phase 2 and Phase 3 studies of GLE/PIB in chronically HCV-infected adults and 
adolescents who were self-reported as current/recent PWID (referred to hereafter as PWID) versus 
those who were former/non-PWID (referred to hereafter as non-PWID) was performed, and results of 
the analysis are presented in the US Package Insert.4  This analysis will provide the historical efficacy 
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control for the current trial.  The threshold for comparison for the primary efficacy hypothesis will be 
derived from a weighted average of the ITT SVR12 rates in the PWID and non-PWID chronically infected 
populations of subjects.  In the Phase 2 and Phase 3 studies, the overall SVR12 rate was 88.7% (55/62) in 
PWID subjects in the ITT population, with a virologic failure rate of 1.6% (1/62); the overall SVR12 rate 
was 97.8% (4147/4241) in non-PWID subjects in the ITT population, with a virologic failure rate of 1.2% 
(50/4241).  Excluding subjects who failed to achieve SVR12 due to reasons other than virologic failure 
yields SVR12 rates of 98.2% (55/56) for PWID subjects and 98.8% (4147/4197) for non-PWID subjects, for 
the mITT-VF population.  Given that the acute HCV population is comprised primarily of PWID patients 
and the SVR12 rates in the PWID subjects with chronic HCV treated with GLE/PIB are high, an active 
control arm would not provide value in establishing the efficacy of the 8-week GLE/PIB regimen in the 
acute population.  So, the efficacy of GLE/PIB can be established via comparison to a threshold rather 
than to non-inferiority to an active control.  Consequently, the observed SVR12 rates from the chronically 
infected subjects (ITT and mITT-VF populations) will be used as historical controls to provide 
comparators for assessment of GLE/PIB in acutely infected subjects.  A threshold for each of the primary 
and key secondary efficacy analyses of the 8-week GLE/PIB regimen in acute HCV to the historical 
control is determined by subtracting a margin of 6% from the weighted average of the PWID and 
non-PWID historical SVR12 rates.  A margin of 6% is selected to ensure a minimal loss of efficacy of the 
8-week GLE/PIB regimen in acute HCV relative to the historical SVR12 rate in subjects with chronic HCV.  
Details for calculating the efficacy thresholds are provided in Section 7.8.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy and 
safety-related measurements in this study are standard for assessing disease activity in subjects with 
acute HCV.  All clinical and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
This study plans to enroll subjects age 12 years or older who have demonstrated evidence of acute HCV 
infection, who are either without cirrhosis or with compensated cirrhosis and are TN for the current HCV 
infection, in order to assess the safety and efficacy of GLE/PIB in the acute HCV patient population.  
Among people with acute HCV infection, PWID are the most prevalent population and PWID are at high 
risk of community transmission.  Current intravenous drug users of the PWID population are eligible to 
participate in the study.  Treatment of people who are at risk to transmit to other people leads to cost-
savings for society.
Patients with acute hepatitis will likely have significant fluctuation of ALT levels and the peak ALT 
elevation can be > 10 times the ULN.  In order to allow subjects with acute HCV infection to enroll, 
eligibility criteria are adjusted to reflect the characteristics of acute HCV infection.
Selection of Doses in the Study
The doses of GLE (300 mg) and PIB (120 mg) are the approved doses for treatment of chronic HCV 
infection and will be evaluated in the study for acute HCV infection.  Acute HCV infection is generally 
benign compared with chronic HCV infection, and it is expected that the same dose of GLE/PIB 
(300 mg/120 mg) will be effective in treating acute HCV infection.
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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 questions below will result in exclusion from study participation.
Consent
1. Subjects or their legally authorized representative (if permitted per local regulations) must 
voluntarily sign and date an informed consent (and assent for minors as required by applicable 
regulation), approved by an independent ethics committee (IEC)/institutional review board 
(IRB), prior to the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult or adolescent, age 12 years and older.
3. Subject must be able to understand and adhere to the study protocol and study visit schedule 
in the opinion of the investigator.
4. Subject must not have any of the following abnormal laboratory results at screening:

Albumin < 2.8 mg/dL for subjects with cirrhosis, < lower limit of normal for subjects without 
cirrhosis;

International normalized ratio (INR) > 1.5 × ULN, unless subject has known hemophilia or is 
on a stable anticoagulant regimen affecting INR;

Hemoglobin < 10 g/dL;

Platelets < 50,000 cells per mm3 for adult subjects with cirrhosis; < 90,000 cells per mm3 for 
adult subjects without cirrhosis; < 40,000 cells per mm3 for subjects aged < 18 years 
regardless of cirrhosis status;

Calculated creatinine clearance < 30 mL/min.
Subjects who have exclusionary laboratory parameters for hemoglobin and/or calculated creatinine 
clearance are allowed to retest 1 time within the Screening period and must meet all other eligibility 
laboratory criteria on the panel that is repeated.  If the retest result(s) are also exclusionary, the subject 
may not be rescreened or retested again.
Disease/Condition Activity
5. Subject must have evidence of acute HCV infection prior to enrollment.  Evidence of acute 
HCV infection is defined as physician diagnosis of acute HCV infection, quantifiable HCV RNA at 
Screening, and at least 1 of the following:

Negative anti-HCV antibody, HCV RNA and/or HCV core antigen followed by a positive HCV 
RNA or HCV core antigen all within an 8-month period prior to Screening;
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OR

Negative anti-HCV antibody, HCV RNA and/or HCV core antigen followed by a positive HCV 
RNA or HCV core antigen all within an 11-month period prior to Screening; AND risk 
behavior for HCV infection within 6 months prior to positive HCV RNA or HCV core antigen;
OR

Clinical signs and symptoms compatible with acute hepatitis (ALT > 5 × ULN and/or jaundice) 
in the absence of a history of chronic liver disease or other cause of acute hepatitis and 
positive HCV RNA or HCV core antigen all within an 8-month period prior to Screening; AND 
risk behavior for HCV infection within 6 months prior to positive HCV RNA or HCV core 
antigen;
OR

Negative anti-HCV antibody with a positive HCV RNA or HCV core antigen within a 5-month 
period prior to Screening.
6. Negative test result for hepatitis B surface antigen (HBsAg).
7. No evidence of chronic HCV infection for this HCV infection.
8. No known active SARS-CoV-2 infection.  All subjects should undergo viral testing to rule out 
SARS-CoV-2 infection at Screening.  Subjects with active SARS-CoV-2 infection may only rescreen 
after they meet the following SARS-CoV-2 infection viral clearance criteria:

At least 10 days since first polymerase chain reaction (PCR) test result have passed in 
asymptomatic patients; or 10 days have passed since symptom onset and at least 24 hours 
since resolution of fever without use of antipyretics and other symptoms improvement.
9. Subject with HCV/human immunodeficiency virus 1 (HIV-1) co-infection must also meet the 
following criteria:

Naïve to HIV treatment:

Must have a cluster of differentiation 4 (CD4+) count ≥500 cells/mm3 (or CD4+ % ≥29%) 
at Screening;

Have no plan to initiate HIV-1 antiretroviral therapy (ART) treatment while participating 
in this study.

On a stable, qualifying HIV-1 ART regimen for at least 8 weeks prior to Screening:

Must have CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening, and plasma 
HIV-1 RNA < 50 copies/mL at Screening (by the COBAS® Ampliprep/COBAS® Taqman 
HIV-1 Test, v 2.0).

The HIV-1 ART regimen must include at least 1 of the following:

Raltegravir orally (per os) (PO) twice a day (BID)

Dolutegravir PO QD or BID

Rilpivirine PO QD

Elvitegravir/cobicistat PO QD

Bictegravir PO QD
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In addition to the above medications, subjects may take a nucleoside/nucleotide reverse 
transcriptase inhibitor backbone containing any of the following:

Tenofovir disoproxil fumarate PO QD

Tenofovir alafenamide PO QD

Abacavir PO QD or BID

Emtricitabine PO QD

Lamivudine (3TC) PO QD or BID

Alternative HIV-1 ART regimens may be permitted with Sponsor approval.
Subject History
10. Subject must be HCV TN, defined as no prior treatment including interferon for this HCV 
infection.
11. Subject must be documented as either having no cirrhosis or as having compensated 
cirrhosis.  If liver diagnostic tests are indeterminate with available diagnostic methods, subject 
must demonstrate absence of decompensated cirrhosis by evaluating Child-Pugh score.
12. Absence of hepatocellular carcinoma (HCC), for subjects with cirrhosis or with indeterminate 
cirrhosis status, as indicated by a negative ultrasound, computed tomography (CT) scan or 
magnetic resonance imaging (MRI) within 3 months prior to Screening or a negative ultrasound 
at Screening.  Subject who has a positive ultrasound result suspicious of HCC followed by a 
subsequent negative CT scan or MRI or biopsy result will be eligible for the study.
13. No history of liver decompensation.
14. No history of organ transplant.
15. No history of severe life-threatening or other significant sensitivity to any excipients of the 
study drug.
16. Subject must not have clinically significant abnormalities, other than HCV infection, based 
upon the results of a medical history, physical examination, vital signs, laboratory profile, and a 
12-lead electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in 
the opinion of the investigator, including, but not limited to:

Uncontrolled diabetes as defined by a glycated hemoglobin (HbA1c) level > 8.5%.

Active or suspected malignancy or history of malignancy (other than basal cell skin cancer or 
cervical carcinoma in situ) in the past 5 years.

Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, psychiatric, or 
other medical disease or disorder, which is unrelated to the existing HCV infection.
17. Subject must not have cause of liver disease other than HCV infection, including but not 
limited to the following:

Hemochromatosis;

Alpha-1 antitrypsin deficiency;
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
Wilson's disease;

Autoimmune hepatitis;

Alcoholic liver disease;

Cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing 
cholangitis;

Steatosis or steatohepatitis on liver biopsy considered to be the primary cause of the liver 
disease rather than concomitant/incidental with HCV infection.
18. Subject must not have uncontrolled drug use that may impair protocol compliance in the 
opinion of the investigator.
Contraception
19. Female who is not pregnant or breastfeeding, and is not considering becoming pregnant or 
donating eggs during the study or for approximately 30 days after the last dose of study drug.
20.For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
21. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug.  Female subjects of non-childbearing potential do not need to use birth control.
Concomitant Medications
22. Subject must not require chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
23. Subject must not have been treated with any investigational drug within 30 days or 10 half-
lives of the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled 
in another interventional clinical study or was previously enrolled in this study.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, of Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:
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
Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.

Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone (FSH) level > 30 international units (IU)/L.

Premenarchal female (has not met the definition of childbearing potential below)

Females who have not experienced menarche (at least 1 menstrual period).

Females, of Childbearing Potential
Females who have experienced menarche (at least 1 menstrual period) prior to or during the 
study.

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 30 days after the last dose of study drug.

Females must commit to one of the following methods of birth control:

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device.

Intrauterine hormone-releasing system.

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).

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  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).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
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Contraception Requirements for Males
No contraception is required for male subjects.
5.3 Prohibited Medications and Therapy
Subject must be able to safely discontinue any prohibited medications or supplements listed in 
Section 5.1 at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of GLE/PIB and 
not use these during the entire Treatment Period and for 14 days following discontinuation of study 
drug.  Subject must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
In addition to the medications listed in the eligibility criteria, concomitant use of the following is NOT 
allowed:

Any herbal supplements (including milk thistle), red yeast rice (monacolin K), St. John's Wort;

Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin;

Atorvastatin, lovastatin, simvastatin;*

Astemizole, cisapride, terfenadine;

Atazanavir, efavirenz, oxcarbazepine, pitavastatin.
*Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be 
taken with the study drug.  Subjects receiving these statins should either switch to pravastatin or 
rosuvastatin 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug or may 
interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives 
(whichever is longer) prior to the first dose of study drug and until 14 days after the last dose of study 
drug, based on investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, it is 
recommended to reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when 
taking with the study drug.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including COVID-19 vaccines), over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements that the subject is receiving at the time of enrollment or receives 
during the study must be recorded from at least 14 days prior to study drug administration through 
14 days following discontinuation of study drug.  After 14 days post-treatment, antiviral therapies 
related to the treatment of HCV, medications prescribed in association with an SAE, and opiate 
substitution therapy must be recorded.  Nonprescribed illicit drug use must be recorded throughout the 
study.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie Medical Director 
or Scientific Director.  Information regarding potential drug interactions with GLE/PIB can be located in 
the GLE/PIB Investigator's Brochure. 
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COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., messenger RNA, non-replicating 
viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during 
screening or the treatment period, as long as the vaccine is not contraindicated or medically 
inappropriate.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of GLE/PIB on SARS-CoV-2 vaccination is unknown.  Therefore, study drug should 
be administered as follows:

The first dose of study drug GLE/PIB, when possible, is preferred to be given at least ± 7 days 
from any SARS-CoV-2 vaccine administration.

GLE/PIB dosing should not be interrupted due to SARS-CoV-2 vaccine administration.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with HCV and as more data are collected in real-world scenarios and 
clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine electronic Case 
Report Form (eCRF).  Refer to the Operations Manual for instructions on reporting any AEs associated 
with the COVID-19 vaccine.
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 Sponsor.

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 and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

The investigator determines the subject is significantly noncompliant with study procedures.
The following criteria will be considered evidence of HCV OTVF, for the purposes of subject 
management, leading to discontinuation of study drug:
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
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements of 
> 1 log10 IU/mL above nadir) at any time point during treatment; or

Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥100 IU/mL) after HCV RNA < LLOQ during treatment.
Confirmatory testing should be completed as soon as possible and the subject should remain on 
study drug treatment until the OTVF criterion has been confirmed.  Subjects with confirmed 
OTVF will be discontinued from study drug and will continue to be followed in the PT Period for 
the emergence and persistence of resistant viral substitutions until 12 weeks post-treatment.
Subjects who completed treatment with HCV RNA < LLOQ at the end of treatment who 
experience potential virologic failure (HCV RNA ≥ LLOQ) in the PT period should have 
confirmatory testing completed as soon as possible to determine if the subject relapsed.
For HCV/HIV-1 co-infected subjects on stable ART, the criteria for failure to maintain HIV virologic 
suppression is as follows:

HIV-1 RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 2 weeks apart, in a subject 
compliant with their HIV ART therapy.
During the Treatment Period, subjects with confirmed failure to maintain HIV-1 RNA 
suppression should continue study drug treatment unless there is a requirement for prohibited 
concomitant medications.  Clinical management of failure to maintain HIV-1 virologic 
suppression during the study (Treatment Period and PT Period) will be handled by the site 
investigator according to current HIV treatment guidelines and local standard of care.
If the investigator deems it necessary to change the HIV-1 ART regimen or to initiate ART treatment for a 
subject due to safety reasons, the AbbVie Medical Director or Scientific Director must be contacted and 
the change must be approved by AbbVie, unless the change is being made to address an immediate 
safety concern.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone 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 their site if they have safety concerns.  If AbbVie terminates the study for safety
reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored.
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5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
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 subjects 
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 a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after the last 
dose of study drug may be completed to ensure all treatment-emergent AEs/SAEs have been resolved.
5.7 Study Drug
Study drugs refer to drugs that are used (or can be used) in this study to assess the safety and the 
efficacy of the Investigational Product. Investigators will assess the relationship of AEs to the use of 
study drugs. See Section 6.1 (Adverse Event Severity and Relationship to Study Drug) for the list of study 
drugs.
Three tablets of GLE/PIB (i.e., total daily dose of 300 mg/120 mg daily dose), manufactured by AbbVie, 
will be taken orally QD at the same time beginning on Study Day 1 (Baseline) and should be taken at 
approximately the same time each day for a treatment duration of 8 weeks.  The study drug will be 
dosed together with food.  If subjects should forget to take their GLE/PIB at their regularly scheduled 
dosing time, they should take the forgotten dose as soon as they remember as long as it is less than 18 
hours from the regularly scheduled dosing time that GLE/PIB should have been taken.  Otherwise, they 
should take the next dose at the next scheduled dosing time.
If the subject vomits within 3 hours after taking a dose, an additional dose of study drug should be 
taken.  If vomiting occurs more than 3 hours after dosing, an additional dose of study drug is not 
needed. 
Where an interruption is required, the study drugs should not be interrupted for more than 7 days.  If 
study drugs need to be interrupted for more than 7 days, the AbbVie Medical Director or Scientific 
Director should be contacted and consideration should be given to discontinue the subject.
If a subject experiences a severe AE (Grade 3+) or an SAE that the investigator considers to have a 
reasonable possibility of relationship to study drug, the investigator should assess whether the AE can 
be managed medically without interruption of study drug, or whether study drugs should be interrupted 
until the event improves.  If study drugs are interrupted and restarted and the AE recurs, then study 
drugs should be permanently discontinued.
The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
Week 4 and Week 8 Visits during the Treatment Period and at the Premature Discontinuation visit
(Appendix D).  The study site personnel will document compliance.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
AbbVie will provide study drug, GLE/PIB.  AbbVie provided study drug should not be substituted or 
alternately sourced unless otherwise directed by AbbVie.  If a subject is unable to come to the study site 
to pick up their study drug due to COVID-19, a direct-to-patient (DTP) study drug shipment can be made 
from the study site to the subject if allowed by local regulations.  AbbVie will submit any required 
notifications to the regulatory authority as applicable.  Refer to the Operations Manual in Appendix F for 
details on DTP shipment of study drug.
Glecaprevir/pibrentasvir will be packaged in quantities sufficient to accommodate study design.  Each kit 
will be labeled per local requirements and this label must remain affixed to the kit.  Upon receipt, study 
drug should be stored as specified on the label and kept in a secure location.  Each kit will contain a 
unique kit number.  This kit number is assigned to a subject via interactive response technology (IRT) 
and encodes the appropriate study drug to be dispensed at the subject's corresponding study visit.  Site 
staff will complete all blank spaces on the label before dispensing to subjects.  Study drug will only be 
used for the conduct of this study.
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site.  All return or 
destruction procedures will be according to instructions from the sponsor and according to local 
regulations following completion of drug accountability procedures.
5.8 Randomization/Drug Assignment
This is a non-randomized, open-label, single-arm study.  All eligible subjects will receive the same dosage 
of study drug for a duration of 8 weeks.
Details regarding the assignment of subject numbers are provided in Section 6.3 of the Operations 
Manual (Appendix F).
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/independent review board (IRB), regulatory authorities 
(as applicable), and AbbVie.
5.10 Data Monitoring Committee
Not applicable.
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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/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
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 (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.
Reporting will be done via electronic data capture (EDC).  The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie.  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  Product 
complaints occurring during the study will be followed up to a satisfactory conclusion.
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.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
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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, meet protocol-specific criteria (see 
Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs.
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.
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/or 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.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as a SAE within 24 hours of the site being made aware of 
the SAE (refer to Section 4.2 of the Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  After
30 days following the last dose of study drug or completion of study treatment only spontaneously 
reported SAEs will be collected (nonserious AEs will not be collected).  In addition, study procedure-
related serious and nonserious AEs will be collected from the time the subject signs the study-specific 
informed consent.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in an SAE as defined 
above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal relationship 
between the SAE and the investigational medicinal product (IMP) was suspected by 
either the sponsor or the investigator, is unexpected (not listed in the applicable 
Reference Safety Information) and meets one of the above serious criteria.
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the NCI CTCAE (Version 4.03).
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
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Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is
insufficient evidence (information) to suggest a causal relationship.
Study Drugs That Will Be Assessed for the Relationship to Adverse Events
Study Drug Name:
GLE/PIB
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Administration of study drug may be continued at the investigator's 
discretion after discussion with the subject if the benefit of continuing therapy is felt to outweigh the 
risk (Section 5.5).  If a subject is discontinued, the subject will be monitored for SVR in the Post-
Treatment Period as described in Appendix D.
Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will 
be collected for pregnancies occurring up to 30 days after the EOT.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Toxicity Management
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 will be managed and 
followed to a satisfactory clinical resolution.  A toxicity is deemed "clinically significant" based on the 
medical judgment of the investigator.  The table of clinical toxicity grades "NCI CTCAE, Version 4.03" is to 
be used in the grading of AEs and laboratory abnormalities.
The following specific toxicity management guidelines apply to the instances of increases in ALT:
If a subject experiences a post-baseline ALT value ≥ 5 × ULN that is also ≥ 2 × Baseline value, the subject 
should have a confirmatory test performed.  If, the ALT value is confirmed ≥ 5 × ULN, and ≥ 2 × Baseline 
value, the recommendations below should be followed:
If a subject experiences a post-nadir ALT elevation > 3 × ULN with total bilirubin > 2 × ULN, the 
recommendations below should also be followed:

Complete hepatic questionnaire eCRF.
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
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 (HAV) 
immunoglobulin M (IgM), anti-HAV total, anti-hepatitis B virus core (HBc) IgM, anti-HBc total, 
anti-hepatitis B viruses (HBVs), HBV DNA, HBsAg, anti-hepatitis E virus (HEV) IgM, anti-HEV 
immunoglobulin G and HEV RNA, and other additional tests, as appropriate.

Manage the subject as medically appropriate.

Repeat ALT, aspartate aminotransferase (AST), total and fractionated bilirubin, alkaline 
phosphatase and INR within 1 week.  Repeat liver chemistries as indicated until resolution.

Discontinue study drugs 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.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the SAP.
SAS (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all analyses.  All 
confidence intervals will be 2-sided with an alpha level of 0.05.
7.2 Definition for Analysis Populations
The ITT population is defined as all enrolled subjects who received at least 1 dose of study drug.  The ITT 
population will be used for the primary efficacy analysis and other secondary efficacy analyses.
The mITT-VF population is defined as all enrolled subjects who received at least 1 dose of study drug, 
excluding those who did not achieve SVR12 for reasons other than virologic failure (i.e., those with HCV 
reinfection, those who did not achieve SVR12 due to early premature discontinuation of study drug, and 
those who were missing HCV RNA data in the SVR12 window after backward imputation).  The mITT-VF
population will be used for the key secondary efficacy analysis.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
For the primary efficacy analysis, subjects who discontinue the trial with an unknown SVR12 status (after 
applying backward imputation) will be counted as a failure for SVR12.
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7.4 Statistical Analyses for Efficacy
Descriptive statistics will be provided, such as the number of observations, mean, and standard 
deviation for continuous variables and counts and percentages for discrete variables.
The primary and key secondary efficacy analyses will be performed on the ITT and mITT-VF populations, 
respectively, as defined in Section 7.2.  Supportive secondary efficacy analyses will be performed on the 
ITT population.
Intercurrent events will be analyzed as described in Section 7.3.  For the primary efficacy analysis, 
subjects who do not have an SVR12 result after applying backward imputation will be considered a failure 
for SVR12.
No data will be imputed for any efficacy analyses except for analyses of SVR endpoints (HCV RNA data) 
and patient reported outcomes (PRO) questionnaires.  Hepatitis C virus RNA values will be selected for 
the analyses of all SVR endpoints based on defined visit windows.  A backward imputation method will 
be used to impute missing responses for SVR analyses.  Details of the backward imputation method and 
the imputation of missing responses on PRO questionnaires will be described in the SAP.
Summary and Analysis of the Primary Endpoint
The primary endpoint is the achievement of SVR12 (defined as HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug) for each subject in the ITT population.
For the primary efficacy endpoint analysis, the number and percentage of subjects achieving SVR12 will 
be calculated for the ITT population along with a 2-sided 95% confidence interval using Wilson's score 
method.  The superiority of 8-week treatment with GLE/PIB in acute HCV infection to the weighted 
efficacy threshold described in Section 7.8, which is based on the historical ITT SVR12 rate of treatment 
with GLE/PIB in PWID and non-PWID subjects with chronic HCV infection, will be demonstrated if the 
lower bound of the 2-sided 95% confidence interval (using Wilson's score method) for the percentage of 
subjects achieving SVR12 is greater than the weighted efficacy threshold.
In this analysis, subjects who have OTVF, Relapse12, or post-treatment reinfection (defined below), are 
missing SVR12 status after backward imputation, or have early premature discontinuation leading to 
virologic failure will count as SVR12 failures.  A summary of reasons for SVR12 non-response will be 
provided.
Details of the analysis will be documented in the SAP.
Summary and Analysis of Secondary Endpoints
Summary and Analysis of Key Secondary Endpoint
The key secondary endpoint is achievement of SVR12 for each subject in the mITT-VF population.
For the key secondary endpoint analysis, the number and percentage of subjects achieving SVR12 will be 
calculated for the mITT-VF population along with a 2-sided 95% confidence interval using Wilson's score 
method. 
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The superiority of 8-week treatment with GLE/PIB in acute HCV infection to the weighted efficacy 
threshold described in Section 7.8, which is based on the historical mITT-VF SVR12 rate of treatment with 
GLE/PIB for PWID and non-PWID with chronic HCV infection, will be demonstrated if the lower bound of 
the 2-sided 95% confidence interval (using Wilson's score method) for the percentage of subjects 
achieving SVR12 is greater than the efficacy threshold.  The key secondary hypothesis will be tested only 
if the primary efficacy hypothesis is demonstrated according to the fixed-sequence testing procedure 
described in Section 7.7.  Details of the analysis will be documented in the SAP.
Summary and Analysis of Supportive Secondary Endpoints
Supportive secondary endpoints:
1.
On-treatment virologic failure (defined as confirmed increase of > 1 log10 IU/mL above nadir 
during treatment, confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment, or 
HCV RNA ≥ LLOQ at the EOT with at least 6 weeks of treatment) for each subject in the ITT 
population.
2.
Post-treatment relapse (Relapse12:  defined as confirmed HCV RNA ≥ LLOQ between EOT and 
12 weeks after the last dose of study drug [up to and including the SVR12 assessment time 
point], excluding cases of reinfection) for each subject in the ITT population who completed 
treatment as planned (defined as study drug duration ≥ 52 days) with HCV RNA < LLOQ at the 
EOT and with at least 1 post-treatment HCV RNA value.
3.
Post-treatment reinfection with HCV (defined as confirmed HCV RNA ≥ LLOQ in the PT period 
along with the PT detection of a different HCV genotype, subtype, or clade compared with 
baseline) for each subject in the ITT population.
For each secondary endpoint, the number and percentage of subjects in the ITT population meeting the 
endpoint will be calculated along with a 2-sided 95% confidence interval using Wilson's score method.
Details of the analyses will be documented in the SAP.
Summary and Analysis of Additional Efficacy Endpoints
Analysis of additional efficacy endpoints will be described in the SAP.
Subgroup Analysis for Efficacy
Subgroup analyses on the percentage of subjects achieving SVR12 will be performed.  For each subgroup, 
the number and percentage of subjects achieving SVR12 will be calculated for the ITT and mITT-VF 
populations.  For subgroups with at least 5 subjects, a 2-sided 95% confidence interval for the 
percentage will be calculated using Wilson's score method in the ITT and mITT-VF populations.  Analysis 
of SVR12 will be provided for the following subgroups:

HCV genotype and subtype;

Sex;

Age;

Race;
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
Body mass index;

Baseline HCV RNA level;

Baseline platelet count;

Baseline serum albumin;

Baseline ALT;

Baseline total bilirubin;

Geographic region;

Baseline creatinine clearance/estimated glomerular filtration rate;

History of diabetes;

Stable opiate substitution status;

Non-prescribed drug use status;

Baseline aspartate aminotransferase to platelet ratio index (APRI);

Baseline FibroTest;

Baseline Fibrosis-4;

Baseline ALT/AST ratio;

Baseline risk behaviors;

HIV status;

Estimated acute HCV infection duration;

Primary versus re-infection status;

Baseline fibrosis stage;

Baseline cirrhosis status;

Study treatment duration;

Study treatment compliance.
Details of the analyses will be documented in the SAP.
7.5 Statistical Analyses for Safety
The safety endpoints specified in Section 3.1, where AE endpoints will be based on treatment-emergent 
AEs and laboratory endpoints will be based on values collected during treatment, will be analyzed on the 
Safety Analysis Set.  Treatment-emergent AEs are defined as those with onset during GLE/PIB treatment
through 30 days post-dosing.  Laboratory values during treatment are those collected during GLE/PIB 
dosing.  Treatment-emergent hepatic decompensation/hepatic failure events will be identified using the 
AbbVie Product Medical Dictionary for Regulatory Activities (MedDRA) query, including events such as 
ascites, hepatic encephalopathy, esophageal variceal bleeding, and spontaneous bacterial peritonitis.  
For each safety endpoint, the number and percentage of subjects meeting the criteria will be calculated.
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7.6 Interim Analysis
Not applicable for this study.
7.7 Overall Type I Error Control
In order to control the family-wise Type I error rate, a fixed-sequence testing procedure will be used for 
the primary and key secondary efficacy analyses of SVR12 as listed below.  The fixed-sequence testing 
procedure will utilize the sequence of the primary analysis followed by the key secondary analysis.
The multiplicity-controlled efficacy analyses will be performed sequentially in the following order:
1.
Primary:  Superiority of the SVR12 rate of 8-week treatment with GLE/PIB for subjects in the ITT 
population to the efficacy threshold.  If superiority is demonstrated, then proceed to the key 
secondary efficacy analysis.  If superiority is not demonstrated in the primary analysis, then stop 
the testing procedure (i.e., do not perform the key secondary analysis).
2.
Key Secondary:  Superiority of the SVR12 rate of 8-week treatment with GLE/PIB for subjects in 
the mITT-VF population to the efficacy threshold.  If superiority is demonstrated, then declare 
superiority for both the mITT-VF and ITT populations.  If not, then declare that superiority was 
demonstrated only for the ITT population.
7.8 Sample Size Determination
The threshold for comparison for the primary efficacy estimand will be derived from a weighted average 
of the ITT SVR12 rates in the PWID and non-PWID chronically infected populations of subjects who 
received GLE/PIB in Phase 2 and 3 trials.  The ITT SVR12 rate among chronically infected HCV PWID 
(current/recent PWID) is 88.7% and is 97.8% among chronic non-PWID (former/non-PWID) (Mavyret US 
Prescribing Information 2020, Section 14.94).  The threshold for comparison will be calculated by 
(proportion of PWID in the ITT population of this study × 88.7%) + (proportion of non-PWID in the ITT 
population of this study × 97.8%) minus a margin of 6%.  Therefore, the threshold would be 82.7% if all 
subjects in the ITT population of this study are PWID, and it would be 91.8% if all subjects in the ITT 
population of this study are non-PWID.  Similarly, the threshold for the comparison of the key secondary 
estimand will be derived from a weighted average of the mITT-VF SVR12 rates in the PWID and non-PWID 
chronically infected populations.  The mITT-VF SVR12 rate among chronically infected HCV PWID is 98.2% 
and is 98.8% among chronic non-PWID.  The threshold for comparison will be calculated by (proportion 
of PWID in the mITT-VF population of this study × 98.2%) + (proportion of non-PWID in the mITT-VF 
population of this study × 98.8%) minus a margin of 6%.  It follows that the threshold would be 92.2% if 
all subjects in the mITT-VF population of this study are PWID, and it would be 92.8% if all subjects in the 
mITT-VF population of this study are non-PWID.
It is planned to enroll approximately 283 subjects.  Assuming all of the subjects in the ITT population of 
this study are PWID, 283 subjects will provide 80% power to show that an 88.7% SVR12 rate among 
acutely infected HCV subjects in the ITT population is superior to a threshold of 82.7% based on the 
historical ITT SVR12 rate among chronically infected HCV subjects, using a 2-sided 95% confidence 
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interval.  Assuming all of the subjects in the ITT population of this study are non-PWID, 283 subjects will 
provide greater than 95% power to show that a 97.8% SVR12 rate among acutely infected HCV subjects 
in the ITT population is superior to a threshold of 91.8% based on the historical ITT SVR12 rate among 
chronically infected HCV subjects, using a 2-sided 95% confidence interval.
Assuming that approximately 10% of the ITT subjects will not be included in the mITT-VF population and 
that all of the subjects in the mITT-VF population of this study are PWID, a total of 255 subjects will 
provide greater than 95% power to show that a 98.2% SVR12 rate among acutely infected HCV subjects 
in the mITT-VF population is superior to a threshold of 92.2% based on the historical mITT-VF SVR12 rate 
among chronically infected HCV subjects using a 2-sided 95% confidence interval.  Assuming all of the 
subjects in the mITT-VF population of this study are non-PWID, 255 subjects will provide greater than 
95% power to show that a 98.8% SVR12 rate among acutely infected HCV subjects in the mITT-VF 
population is superior to a threshold of 92.8% based on the historical mITT-VF SVR12 rate among 
chronically infected HCV subjects, using a 2-sided 95% confidence interval.
Additionally, the proposed sample size of 283 will provide greater than 94% probability to detect any 
toxicity that has a true incidence rate of at least 1% in subjects with acute HCV infection.  Table 1 shows 
the probability that a given AE or laboratory toxicity would be observed with a sample size of 283 
subjects in the Safety Analysis Set.
Table 1.
Sample Size Justification Based on Probability of Observing Any Toxicity
True Toxicity Rate
Sample Size
Probability of at Least 1 Subject with Toxicity
0.5%
283
75.8%
1%
283
94.2%
2%
283
99.7%
3%
283
100%
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) for review and 
approval.  Approval of both the protocol and the informed consent form(s) must be obtained before any 
subject 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(s) 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 Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
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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.
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).  During the COVID-19 pandemic, remote data review/verification may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
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
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.
12
REFERENCES
1.
World Health Organization. Global Hepatitis Report 2017. Geneva, Switzerland; 2017 2017.
2.
Centers for Disease Control and Prevention. Surveillance for Viral Hepatitis - United States, 2017 
Atlanta, GA: CDC; 2017 [2020 May 13]. Available from: 
https://www.cdc.gov/hepatitis/statistics/2017surveillance/index.htm.
3.
Spearman CW, Dusheiko GM, Hellard M, et al. Hepatitis C. Lancet. 2019;394(10207):1451-66.
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4.
Mavyret (glecaprevir and pibrentasvir) tablets [US Prescribing Information]. North Chicago, IL; 
AbbVie, 2020.
5.
European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J 
Hepatol. 2018;69(2):461-511.
6.
AASLD-IDSA. Hepatitis C guidance:  AASLD-IDSA recommendations for testing, managing, and 
treating hepatitis C.  [updated 24 May 2018; cited 2020 Jun 19]. Available from: 
http://www.hcvguidelines.org.
7.
Martinello M, Orkin C, Cooke G, et al. Short-Duration Pan-Genotypic Therapy With 
Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection. 
Hepatology. 2020;72:7-18.
8.
Chromy D, Mandorfer M, Bucsics T, et al. High efficacy of interferon-free therapy for acute hepatitis 
C in HIV-positive patients. United European Gastroenterol J. 2019;7(4):507-16.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
APRI
Aminotransferase to platelet ratio index
aPTT
Activated partial thromboplastin time
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
BID
Twice a day
BUN
Blood urea nitrogen
CD4+
Cluster of differentiation 4
COVID-19
Coronavirus – 2019
CS
Clinically significant
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
D/C
Discontinuation
DNA
Deoxyribonucleic acid
DTP
Direct-to-patient
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
EQ-5D-5L
EuroQol-5 Dimensions-5 Level
EU
European Union
EudraCT
European Clinical Trials Database
FSH
Follicle-stimulating hormone
FSS
Fatigue Severity Scale
GCP
Good clinical practice
GGT
Gamma-glutamyl transferase
GLE
Glecaprevir
GLE/PIB
Glecaprevir and Pibrentasvir
GT
Genotype
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HAV
Hepatitis A virus
HbA1c
Glycated hemoglobin
HBc
Hepatitis B virus core
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus
HIV-1
Human immunodeficiency virus 1
IASL
International Association of the Study of the Liver
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent ethics committee
IgM
Immunoglobulin M
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intention-to-treat
IU
International unit
LDL
Low density lipoprotein
LLOQ
Lower limit of quantification
MAT
Medication-assisted treatment
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mITT-VF
Modified intention-to-treat analysis set excluding those who did not achieve SVR12 due 
to reasons other than virologic failure
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NCS
Not clinically significant
OTVF
On-treatment virologic failure
PCR
Polymerase chain reaction
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PIB
Pibrentasvir
PO
Orally (per os)
PRO
Patient reported outcomes
PT
Post-treatment or pro-thrombin time
PTW
Post-treatment week
PWID
People who inject drugs
QD
Once daily
RBC
Red blood cell
RNA
Ribonucleic acid
RSI
Reference safety information
SAE
Serious adverse event
SAP
Statistical analysis plan
SAR
Serious adverse reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SUSAR
Suspected unexpected serious adverse reactions
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks post-treatment
TE
Treatment-experienced
TN
Treatment-naïve 
ULN
Upper limit of normal
US
United States
WBC
White blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-350:  A Multicenter, Single-Arm Prospective Study to Evaluate Safety and Efficacy of GLE/PIB 8-Week 
Treatment in Adults and Adolescents with Acute Hepatitis C Virus (HCV) Infection
Protocol Date:  26 August 2022
Clinical research studies sponsored by AbbVie are subject to the ICH GCP and local laws and 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 IRB/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 (within one [1] calendar day to AbbVie, the ethics committees/institutional review 
boards [as required] and other appropriate individuals [e.g., coordinating investigator, institution 
director]):

All changes in the research activity and all unanticipated problems involving risks to human 
subjects or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that 
has the potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
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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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Development
Statistics 
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 1.0
01 March 2021
Version 2.0
02 April 2021
Version 3.0
23 April 2021
Administrative Change 1
01 June 2021
Version 4.0
14 October 2021
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:

Title page:  Added Sponsor name for EU countries.
Rationale:  To clarify Sponsor name for EU countries.

Section 5.1:  Added text to Eligibility Criterion 5 to indicate that subjects must have quantifiable 
HCV RNA at Screening.
Rationale:  To clarify definition of acute HCV infection.

Section 5.1:  Added bictegravir to Eligibility Criterion 9 as a permitted ART.
Rationale:  To clarify that bictegravir is an acceptable component of a qualifying HIV-1 ART 
regimen.

Section 5.1:  Added instructions to Eligibility Criterion 11 for determining absence of 
decompensated cirrhosis.
Rationale:  To clarify subject eligibility if liver diagnostic tests are indeterminate.

Section 5.1:  Added text to Eligibility Criterion 12 to indicate that subjects with indeterminate 
cirrhosis status must demonstrate absence of HCC.
Rationale:  To clarify subject eligibility if liver diagnostic tests are indeterminate.

Section 5.1: Edited text in Eligibility Criterion 23 to update the length of time that subjects must 
not have been treated with any investigational drug prior to the first dose of study drug.
Rationale:  To align the length of time with what is allowed for discontinuation of prohibited 
medications prior to the first dose of study drug. 

Section 5.3:  Added text to describe timing of discontinuation of prohibited medications and to 
indicate that concomitant use of certain medications is not allowed.
Rationale:  To clarify safe discontinuation of prohibited medications and clarify that concomitant 
use of certain medications is not allowed.

Section 5.7:  Added text to describe handling of study drug upon completion or discontinuation 
from study treatment.
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Rationale:  To clarify study drug return or destruction procedures.

Section 5.7 and Section 6.1:  Added text and table to define study drugs.
Rationale:  To clarify study drugs that will be assessed for their relationship to adverse events.

Section 6.1:  Added text to describe collection of SAEs after 30 days following last dose of study 
drug or completion of study treatment.
Rationale:  To clarify what types of AEs will be collected after 30 days following last dose of 
study drug or completion of study treatment.

Section 7.4:  Added subgroups to the list for analysis of efficacy.
Rationale:  To align the subgroups for analysis of efficacy with the SAP.

Section 11:  Added definition of study start and updated definition of end-of-study.
Rationale:  To clarify definitions of study start and end-of-study.

Appendix F:  Removed collection of respiratory rate.
Rationale:  To remove unnecessary vital sign determination.

Appendix B:  Added text describing reporting responsibilities of the investigator.
Rationale:  To clarify the reporting responsibilities of the investigator.

Appendix C and Appendix F:  Modified the list of protocol signatories.
Rationale:  To align with the current team composition and relevant standard operating 
procedures.

Appendix F:  Updated Section 1 contact information.
Rationale:  To reflect current team contact information.

Appendix F:  Added text to describe testing procedures for subjects with indeterminate cirrhosis 
status.
Rationale:  To align with clarified eligibility criteria for subjects with indeterminate cirrhosis 
status.
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