Clinical trial NCT04903626
Conditions: Hepatitis C Virus (HCV)
Keywords: Acute HCV Infection HCV Genotype 1-6 Hepatitis C Glecaprevir Pibrentasvir Mavyret
Sponsor: AbbVie
Start date: 2021-08-24; Completion date: 2024-09-17
Enrollment: 286 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
HCV infection is a global health problem. HCV mainly affects liver cells and causes the liver to become inflamed and damaged. This study will evaluate how safe and effective glecaprevir/pibrentasvir (GLE/PIB) is in adult and adolescent participants with acute HCV infection.

GLE/PIB is an approved drug for the treatment of chronic HCV. Around 283 participants at least 12 years of age with acute HCV Infection will be enrolled in approximately 70 sites worldwide.

Participants will receive oral tablets of GLE/PIB once daily (QD) for 8 weeks and will be followed for 12 weeks after the end of treatment.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, monitoring for side effects and completing questionnaires.

Detailed description:

Arms: arm 1: Participants treated once daily (QD) with glecaprevir/pibrentasvir 300 mg/120 mg for 8 weeks.
Interventions: intervention 1: Glecaprevir/Pibrentasvir (GLE/PIB)
Intervention descriptions: intervention 1: Oral tablets

Protocol documents:
Prot_000.pdf: 


  
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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.
Page 45 of 73
 

SAP_001.pdf: 
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M20-350 – Statistical Analysis Plan
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Statistical Analysis Plan for Study 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
Date: 12 August 2024
Version 4.0
NCT04903626


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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses, and Estimands .................................................. 5
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Choice of Control Group ........................................................................ 8
2.5
Sample Size Determination .................................................................... 8
3.0
Endpoints.............................................................................10
3.1
Primary Endpoint ................................................................................. 10
3.2
Secondary Endpoints............................................................................ 11
3.3
Additional Efficacy Endpoints.............................................................. 11
3.4
Safety Endpoints .................................................................................. 11
4.0
Analysis Populations ...........................................................12
5.0
Subject Disposition..............................................................13
6.0
Study Treatment Duration and Compliance .....................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................14
7.1
Demographics and Baseline Characteristics.......................................... 15
7.2
Medical History.................................................................................... 22
7.3
Prior, Concomitant, and Post-Treatment Medications ........................... 22
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................23
9.0
Efficacy Analyses.................................................................24
9.1
General Considerations......................................................................... 24
9.2
Handling of Missing Data..................................................................... 27
9.3
Primary Efficacy Endpoint and Analyses.............................................. 28
9.3.1
Primary Efficacy Endpoint ................................................................... 28
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 28
9.3.3
Supplementary Analyses of Primary Efficacy Endpoint........................ 29
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 30
9.4.1
Key Secondary Efficacy Endpoint ........................................................ 30


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9.4.2
Main Analysis of Key Secondary Efficacy Endpoint ............................ 30
9.4.3
Supplementary Analyses of Key Secondary Efficacy Endpoint............. 31
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 32
9.5
Additional Efficacy Analyses ............................................................... 33
9.6
Efficacy Subgroup Analyses................................................................. 34
9.7
Resistance Analyses ............................................................................. 37
9.8
Patient Reported Outcomes .................................................................. 41
10.0
Safety Analyses....................................................................42
10.1
General Considerations......................................................................... 42
10.2
Adverse Events..................................................................................... 42
10.2.1
Treatment-Emergent Adverse Events.................................................... 43
10.2.2
Adverse Event Overview...................................................................... 43
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT ...................... 44
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Treatment Discontinuation ................................................................... 45
10.2.5
Adverse Events of Special Interest........................................................ 46
10.2.6
AIDS-Associated Opportunistic Infections ........................................... 46
10.3
Analysis of Laboratory Data................................................................. 47
10.4
Analysis of Vital Signs......................................................................... 50
10.5
Safety Subgroup Analyses.................................................................... 51
11.0
Interim Analyses..................................................................53
12.0
Overall Type-I Error Control.............................................53
13.0
Version History ...................................................................54
13.1
Summary of Changes ........................................................................... 54
14.0
References............................................................................60
15.0
Appendices...........................................................................62


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List of Tables
Table 1.
Sample Size Justification Based on Probability of Observing Any 
Toxicity................................................................................................ 10
Table 2.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Endpoint ................................................................... 29
Table 3.
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Endpoint ............................................................... 31
Table 4.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ...................................................................................... 38
Table 5.
SAP Version History Summary ............................................................ 54
Table B-1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 63
Table B-2.
Criteria for Potentially Clinically Significant Vital Sign Values............ 64
List of Figures
Figure 1.
Study Schematic..................................................................................... 7
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 62
Appendix B.
Laboratory Toxicity Grades and Potentially Clinically Significant 
Criteria for Vital Sign Values ............................................................... 63


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for glecaprevir 
(GLE)/pibrentasvir (PIB) Study 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."
Study M20-350 examines the efficacy and safety of GLE/PIB in adults and adolescents 
with confirmed acute HCV infection.
This SAP provides details to further elaborate the statistical methods outlined in Clinical 
Study Protocol M20-350. The SAP will not be updated in case of future administrative 
changes or amendments to the protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol. Details are outlined in 
Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses, and Estimands
The primary objective is to demonstrate the efficacy of 8-week treatment with GLE/PIB 
in adults and adolescents with confirmed acute HCV infection by comparing the sustained 
virologic response 12 weeks post-treatment (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 intention-to-treat (ITT) 
population which is defined as all enrolled subjects who received at least 1 dose of study 
treatment.
The primary hypothesis is that 8-week treatment with GLE/PIB in the ITT population is 
superior to the efficacy threshold (described in Section 2.4) based on the historical 


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ITT SVR12 rates of treatment with GLE/PIB in subjects with chronic HCV infection.1
This will be shown if the lower bound of the two-sided 95% confidence interval (CI; 
using Wilson's score method2) 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.
The key secondary objective is the same as the primary objective 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 treatment, 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 treatment, 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 2.4) based 
on the historical mITT-VF SVR12 rates of treatment with GLE/PIB in the chronically 
infected HCV population.1 This will be shown if the lower bound of the two-sided 
95% CI (using Wilson's score method2) for the percentage of subjects in the mITT-VF 
population achieving SVR12 is greater than the efficacy threshold.
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.


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The other secondary objectives of this study are to determine the on-treatment virologic 
failure (OTVF), post-treatment relapse, and post-treatment reinfection rates in the 
ITT population.
The safety objectives of this study are to examine the safety with respect to alanine 
aminotransferase (ALT) elevations, adverse events (AEs) leading to study treatment 
discontinuation, serious AEs (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 treatment).
2.2
Study Design Overview
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.
Figure 1.
Study Schematic
GLE  glecaprevir; PIB  pibrentasvir; PTW  post treatment week
2.3
Treatment Assignment and Blinding
All subjects will be assigned to receive 8 weeks of treatment with GLE/PIB.


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2.4
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 people who inject drugs 
(PWID) currently or recently (referred to hereafter as PWID) versus those who 
self-reported as formally or never injecting drugs (referred to hereafter as non-PWID) was 
performed, and results of the analysis are presented in the Mavyret US Prescribing 
Information 2020, Section 14.9.1 This analysis will provide the historical efficacy 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. The observed SVR12 rates from 
subjects with chronic HCV infection (ITT and mITT-VF populations) will be used as 
historical controls to provide comparators for assessment of GLE/PIB in subjects with 
acute HCV. 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% was 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 2.5.
2.5
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. As presented in the 


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Mavyret US Prescribing Information 2020, Section 14.9,1 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). 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 two-sided 95% CI. 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 two-sided 95% CI.
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 


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superior to a threshold of 92.2% based on the historical mITT-VF SVR12 rate among 
chronically infected HCV subjects using a two-sided 95% CI. 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 
two-sided 95% CI. 
Note that for calculation of the efficacy thresholds, PWID is defined as current/recent 
PWID, and non-PWID is defined as former/non-PWID; see SAP Section 7.1 for the 
PWID definitions.
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%
3.0
Endpoints
3.1
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 treatment) for 
each subject in the ITT population.


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3.2
Secondary Endpoints
Key Secondary Endpoint
The key secondary endpoint is the achievement of SVR12 for each subject in the mITT-VF 
population.
Supportive Secondary Endpoints
●
On-treatment virologic failure (defined as confirmed increase of > 1 
log10 IU/mL above nadir during treatment, confirmed HCV RNA 
≥100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥LLOQ at the end of treatment [EOT] with at least 6 weeks of treatment) for 
each subject in the ITT population;
●
Post-treatment relapse (Relapse12: defined as confirmed HCV RNA ≥LLOQ 
between EOT and 12 weeks after the last dose of study treatment [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 treatment duration ≥52 days) with the HCV RNA < LLOQ 
at EOT and with at least 1 post-treatment HCV RNA value;
●
Post-treatment reinfection with HCV (defined as confirmed HCV RNA 
≥LLOQ in the Post-Treatment Period along with the post-treatment detection 
of a different HCV genotype, subtype, or clade compared with baseline) for 
each subject in the ITT population.
3.3
Additional Efficacy Endpoints
Additional efficacy endpoints are described in Section 9.5.
3.4
Safety Endpoints
●
ALT elevations of the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03 Grade 1, 2, 3, or 4 during the 
Treatment Period with ALT grade increased from baseline for each subject in 
the Safety Analysis Set;


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●
Post-nadir ALT elevation > 3 × upper limit of normal (ULN) with total 
bilirubin > 2 × ULN during the Treatment Period 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 treatment for 
each subject in the Safety Analysis Set;
●
Treatment-emergent SAEs for each subject in the Safety Analysis Set.
These endpoints, along with additional safety endpoints based on AEs, laboratory data, 
and vital signs are included in Section 10.2, Section 10.3, and Section 10.4, respectively.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The ITT population is defined as all enrolled subjects who received at least 1 dose of 
study treatment. 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 treatment, 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 treatment, 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 
treatment.


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5.0
Subject Disposition
The number and percentage of subjects who failed to enroll in the study (i.e., failed to 
receive at least 1 dose of study treatment) for any reason and for each reason, will be 
summarized for the set of all subjects who failed to enroll.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be tabulated overall and by investigator:
●
Subjects enrolled/treated (i.e., received at least 1 dose of study treatment) in 
the study;
●
Subjects who completed study treatment;
●
Subjects who prematurely discontinued study treatment;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
●
Subjects in each analysis population (ITT, mITT-VF, and Safety Analysis Set).
The number and percentage of subjects in the Safety Analysis Set who discontinued study 
treatment will be summarized by primary reason (per eCRF). A similar summary will be 
provided for discontinuations from the study. The number and percentage of subjects in 
the Safety Analysis Set with reported study treatment interruptions will be summarized.
Protocol deviations as described in Appendix A will be summarized for the Safety 
Analysis Set by the number and percentage of subjects in each category and in at least one 
category, including a list of subject numbers for each category.
6.0
Study Treatment Duration and Compliance
The duration of study treatment will be summarized for the Safety Analysis Set. Duration 
of treatment is defined for each subject as the last study treatment dose date minus the 
first study treatment dose date plus 1 day.


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Descriptive statistics (number of subjects, mean, standard deviation, median, Q1 and Q3 
of inter-quartile range, minimum, and maximum) will be presented.
Treatment duration also will be summarized with frequencies and percentages using the 
following categories:
●
1 to 15 days, 16 to 35 days, 36 to 55 days, ≥56 days;
●
< 52 days, ≥52 days.
Treatment compliance will be summarized for the ITT population. 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 for study treatment (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 (i.e., 3 tablets 
per day) for the duration that the subject was in the Treatment Period (date of the last dose 
of study treatment
date of first dose of study treatment + 1). Study treatment 
interruptions recorded on the eCRF will not be subtracted from the duration. If the number 
of tablets returned is not available for one or more of the bottles dispensed to a subject, 
then compliance will not be calculated for that subject.
A subject is considered to be compliant if the percentage is between 80% and 120%. 
Compliance will be calculated for each subject and summarized with the number of 
subjects, mean, standard deviation, median, Q1 and Q3 of inter-quartile range, minimum, 
and maximum. The percentage of compliant subjects will be summarized based on the 
data as observed.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, and previous, concomitant and 
post-treatment medications will be summarized for the ITT population. Demographics and 
baseline characteristics will also be summarized for the mITT-VF population. Categorical 


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variables will be summarized with the number and percentage of subjects; percentages 
will be calculated based on the number of non-missing/non-unknown observations. 
Continuous variables will be summarized with descriptive statistics (number of 
non-missing/non-unknown observations, mean and standard deviation, median, 
Q1 and Q3 of inter-quartile range, minimum, and maximum).
7.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for the following groups: 
adolescents (age < 18 years), adults (age ≥18 years), and overall. Summaries of 
demographics and baseline characteristics will also be presented for the following groups: 
current/recent PWID subjects and former/non-PWID subjects using PWID Status 
Classification 1 (see definitions below), subjects with a history of opiate substitution 
therapy use that was ongoing at start of study treatment, and subjects with either no 
history of opiate substitution therapy use or a history of opiate substitution therapy use 
that was not ongoing at start of study treatment.
Continuous demographic variables include age, weight, height, and body mass 
index (BMI). Categorical demographic variables include sex (male or female), race 
(white, black/African-American, Asian, [further categorized as Japanese, Chinese, 
Korean, Taiwanese, or other Asian], American Indian/Alaska native, or native 
Hawaiian/other Pacific Islander; black or non-black), ethnicity (Hispanic/Latino or not 
Hispanic/Latino), age (< 18, 18 to < 40, 40 to < 65, 65 to < 75, ≥75 years; < 18 or 
≥18 years; < 65 or ≥65 years; < 75 or ≥75 years), BMI (< 30 or ≥30 kg/m2), country, 
geographic region (North America, Europe, or rest of world [ROW]), tobacco use 
(current, former, never, or unknown), and alcohol use (current, former, never, or 
unknown).
Continuous baseline characteristics include baseline log10 HCV RNA level, ALT, 
aspartate aminotransferase (AST), bilirubin (total, direct, and indirect), alkaline 
phosphatase, serum creatinine, creatinine clearance (Cockcroft-Gault calculation), 
estimated glomerular filtration rate (eGFR; modification of diet in renal disease [MDRD] 


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equation), platelet count, serum albumin, international normalized ratio (INR), 
homeostasis model of assessment insulin resistance (HOMA-IR), GGT, LDL, HDL, 
FibroTest score, FibroScan score, aspartate aminotransferase to platelet ratio index 
(APRI), Fibrosis-4 (FIB-4), CD4 (for HCV/HIV co-infected subjects), estimated acute 
HCV infection duration, and time since acute HCV infection diagnosis.
Categorical baseline characteristics include:
●
HCV genotype (GT) (1, 2, 3, 4, 5, or 6) and available subtype (as determined 
by the central laboratory);
●
HCV genotype (GT) (1, 2, 3, 4, 5, or 6) and available subtype (final HCV 
genotype and subtype as defined in Section 9.7);
●
Cirrhosis status (cirrhotic, non-cirrhotic, or unknown test results 
indeterminate);
●
Baseline Child-Pugh score (for cirrhotic subjects or subjects with cirrhosis 
status unknown; 5, 6, or > 6)
●
Screening Child-Pugh score (for cirrhotic subjects or subjects with cirrhosis 
status unknown; 5, 6, or > 6)
●
Baseline fibrosis stage (equivalent to Metavir F0 F1, F2, F3, or F4);
●
Baseline HCV RNA level (< LLOQ or ≥LLOQ; < 800,000 or 
≥800,000 IU/mL; < 1,000,000 or ≥1,000,000 IU/mL);
●
Baseline ALT (≤ULN, > ULN to ≤3 × ULN, > 3 × ULN to ≤5 × ULN, 
> 5 × ULN to ≤10 × ULN, or > 10 × ULN);
●
Baseline total bilirubin (< 34.2 or ≥34.2 µmol/L);
●
Baseline creatinine clearance (< 60, ≥60 to < 90, or ≥90 mL/min);
●
Baseline eGFR (< 90 or ≥90 mL/min/1.73 m2);
●
Baseline platelet count (< 100 or ≥100 × 109/L; < 150 or ≥150 × 109/L);
●
Baseline serum albumin (< 35 or ≥35 g/L);
●
Baseline APRI (≤1, > 1 to ≤2, or > 2);
●
Baseline HOMA-IR (< 2 or ≥2 mU × mmol/L2);
●
Baseline FibroTest (< 0.75 or ≥0.75);


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●
Baseline FIB-4 (< 1.45, ≥1.45 to ≤3.25, or > 3.25);
●
Baseline AST/ALT ratio (≤1 or > 1);
●
Baseline HCV/HIV co-infection status (HCV mono-infected or HCV/HIV-1 
co-infected);
●
History of diabetes (yes or no);
●
History of prior HCV infection (yes or no);
●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
drug use (yes, ongoing as of the end of study participation; yes, last dose after 
last dose of study treatment; yes, last dose during study treatment period; yes, 
last dose less than 6 months prior to start of study treatment; yes, last dose 6 to 
12 months prior to start of study treatment; yes, last dose more than 12 months 
prior to start of study treatment; yes, timing of last dose unknown; or no);
●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
injection drug use (yes, ongoing as of the end of study participation; yes, last 
dose after last dose of study treatment; yes, last dose during study treatment 
period; yes, last dose less than 6 months prior to start of study treatment; yes, 
last dose 6 to 12 months prior to start of study treatment; yes, last dose more 
than 12 months prior to start of study treatment; yes, timing of last dose 
unknown; or no);
●
PWID Status Classification 1 PWID classification defined with respect to 
study treatment start (current/recent PWID or former/non-PWID; current 
PWID, recent PWID, former PWID, or non-PWID)
○
Current/recent PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment and ongoing as of end of 
study participation (Current);
●
yes, started prior to start of study treatment with last dose after last 
dose of study treatment (Current);
●
yes, started prior to start of study treatment with last dose during study 
treatment period (Current);
●
yes, started prior to start of study treatment with last dose less than 
6 months prior to start of study treatment (Recent);


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●
yes, started prior to start of study treatment with last dose 6 to 
12 months prior to start of study treatment (Recent).
○
Former/Non-PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment with last dose more than 
12 months prior to start of study treatment (Former);
●
yes, started prior to start of study treatment and timing of last dose 
unknown (Former);
●
yes, started during study treatment period (Non-PWID);
●
yes, started after last dose of study treatment (Non-PWID);
●
no (Non-PWID).
●
PWID Status Classification 2 PWID classification defined with respect to 
study treatment period (current/recent PWID or former/non-PWID; current 
PWID, recent PWID, former PWID, or non-PWID)
○
Current/Recent PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment and ongoing as of end of 
study participation (Current);
●
yes, started prior to start of study treatment with last dose after last 
dose of study treatment (Current);
●
yes, started prior to start of study treatment with last dose during study 
treatment period (Current);
●
yes, started prior to start of study treatment with last dose less than 
6 months prior to start of study treatment (Recent);
●
yes, started prior to start of study treatment with last dose 6 to 
12 months prior to start of study treatment (Recent);
●
yes, started during study treatment period (Current).
○
Former/Non-PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment with last dose more than 
12 months prior to start of study treatment (Former);


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●
yes, started prior to start of study treatment and timing of last dose 
unknown (Former);
●
yes, started after last dose of study treatment (Non-PWID);
●
no (Non-PWID).
●
PWID Status Classification 3 PWID classification defined with respect to 
study participation (current/recent PWID or former/non-PWID; current PWID, 
recent PWID, former PWID, or non-PWID)
○
Current/Recent PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment and ongoing as of end of 
study participation (Current);
●
yes, started prior to start of study treatment with last dose after last 
dose of study treatment (Current);
●
yes, started prior to start of study treatment with last dose during study 
treatment period (Current);
●
yes, started prior to start of study treatment with last dose less than 
6 months prior to start of study treatment (Recent);
●
yes, started prior to start of study treatment with last dose 6 to 
12 months prior to start of study treatment (Recent);
●
yes, started during study treatment period (Current);
●
yes, started after last dose of study treatment (Current).
○
Former/Non-PWID defined with non-prescribed illicit injection drug use 
as:
●
yes, started prior to start of study treatment with last dose more than 
12 months prior to start of study treatment (Former);
●
yes, started prior to start of study treatment and timing of last dose 
unknown (Former);
●
no (Non-PWID).


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●
History of opiate substitution therapy use (yes, ongoing at start of study 
treatment; yes, less than 6 months prior to start of study treatment; yes, 6 to
12 months prior to start of study treatment; yes, more than 12 months prior to 
start of study treatment; yes, timing of last dose unknown; or no);
●
Acute HCV infection criteria met (a. yes, 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; b. yes, 
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 within 6 months prior to positive HCV RNA 
or HCV core antigen; c. yes, 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 within 6 months prior to positive HCV RNA or HCV core 
antigen; d. yes, negative anti-HCV antibody with a positive HCV RNA or 
HCV core antigen within a 5-month period prior to Screening; or, e. no criteria 
met);
●
Risk behavior for acute HCV infection (shared drug-injection equipment, 
shared non-injection drug use equipment, unprotected sexual activity with 
multiple partners, unprotected sexual activity with other male(s), risky tattoos 
or body piercings, shared personal items possibly contaminated with blood, 
healthcare worker with occupational exposure, or other behavior);
●
Grouped risk behavior for acute HCV infection Grouping 1 (contaminated 
needle or IV drug use, contact with infected individual, occupational exposure, 
or other behavior);
●
Grouped risk behavior for acute HCV infection Grouping 2 (drug use, sexual 
transmission, contact by contaminated objects, occupational, or other 
behavior);
●
Estimated acute HCV infection duration (< 3 months, ≥3 months to 
< 6 months, or ≥6 months) across all and by each acute HCV infection 
criteria;
●
Time since acute HCV infection diagnosis (< 3 months or ≥3 months);


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●
Baseline HIV-1 treatment status (for HCV/HIV co-infected subjects: HIV 
Treatment-Naïve or HIV-Treated);
●
Baseline CD4+ T-cell count (for HCV/HIV co-infected subjects: < 200, 200 to 
< 350, 350 to < 500, or ≥500 cells/mm3);
●
Baseline plasma HIV-1 RNA (for HCV/HIV co-infected subjects: < 20 or 
≥20 copies/mL).
Estimated acute HCV infection duration (days) is an estimate of how long a subject has 
been infected with HCV at the time of start of study treatment. The derivation differs 
slightly for each acute infection criteria category. Derivations used for this study were 
adapted from derivations used in the Matthews (2021)3 and Martinello (2019)4 articles. 
For each definition below, the most recent (i.e., closest to study treatment start date) 
negative HCV test of those specified and the earliest (i.e., furthest from study treatment 
start date) positive HCV test of those specified will be used.
a.
For acute infection criteria (a), estimated infection start date is defined as the 
midpoint between the HCV negative test and HCV positive test.
b. For acute infection criteria (b), estimated infection start date is defined as the 
midpoint between the HCV negative test and HCV positive test.
c.
For acute infection criteria (c), estimated infection start date is defined as 
6 weeks (42 days) prior to the date of the HCV positive test.
d. For acute infection criteria (d), estimated infection start date is defined as 
6 weeks (42 days) prior to the date of the HCV positive test.
The estimated duration of infection is defined as (study treatment start date estimated 
infection start date) + 1, in days.
Because a subject may qualify for more than one definition of acute HCV infection, the 
estimated infection duration will be determined using the following priority order for each 
subject: acute infection criteria (d), criteria (a), criteria (b), or criteria (c). For example, if 
a subject meets acute infection criteria (a) and (c), the estimated infection duration 


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associated with criteria (a) will be used. This prioritization will also be used to determine 
which acute HCV infection criteria each subject's estimated duration of infection is 
summarized under.
For categorization of the estimated infection duration, 1 month  31 days (e.g., 3 months 
is 93 days and 6 months is 186 days).
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class (SOC) and preferred 
term (PT)) will be summarized. The SOCs will be presented in alphabetical order, and the 
PTs will be presented in alphabetical order within each SOC. Subjects reporting more 
than one PT within a SOC will be counted only once for that SOC.
7.3
Prior, Concomitant, and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study treatment (GLE/PIB). A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study treatment and continued to be taken on or 
after the first dose of study treatment or any medication that started on or after the date of 
the first dose of study treatment, but not after the date of the last dose of study treatment. 
A post-treatment medication for the treatment of HCV is defined as any medication 
started on or after the date of last dose of study treatment with the indication entered as 
"Hepatitis C."
Prior medications will be divided into the following categories:
●
HCV medications taken for the most recent prior HCV infection;
●
Prior HIV medications taken by subjects with HCV/HIV co-infection at 
baseline;


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●
Non-prescribed illicit drugs overall and by injection or non-injection route and 
specific route within injection and non-injection routes;
●
Opiate substitution therapy medications;
●
All other prior medications.
Concomitant medications will be divided into the following categories:
●
Concomitant HIV medications taken by subjects with HCV/HIV co-infection 
at baseline;
●
Non-prescribed illicit drugs overall and by injection or non-injection route and 
specific route within injection and non-injection routes;
●
Opiate substitution therapy medications;
●
All other concomitant medications.
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 World Health Organization (WHO) Drug Dictionary. Opiate 
substitution therapy and non-prescribed illicit drugs will be summarized as reported.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The primary efficacy endpoint of achievement of SVR12 will be analyzed based on the 
ITT population, and any subject who discontinues the study with an unknown SVR12
status (after applying backward imputation) will be counted as a failure for SVR12. The 
key secondary efficacy endpoint of achievement of SVR12 will be analyzed based on the 
mITT-VF population, and intercurrent events will not have an effect on this analysis.


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9.0
Efficacy Analyses
9.1
General Considerations
All tests and CIs will be two-sided at an alpha level of 0.05.
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Missing data will be imputed as described in Section 9.2 for analyses of the HCV RNA 
endpoints of SVR and virologic failure and the patient reported outcomes (PROs) 
questionnaires.
If a subject starts another treatment for HCV, then all HCV RNA and PRO 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 SVR at all time 
points after the start of the new HCV treatment.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® Quantitative 
HCV 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.
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) 


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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 Treatment Day 36 and 
study treatment duration ≥36 days.
On-Treatment Virologic Failure
Breakthrough or EOT Failure; if a subject meets 
both definitions of Breakthrough and EOT Failure, he or she will be categorized as 
Breakthrough only.
SVR4
HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study treatment) 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 treatment) without any confirmed quantifiable (≥LLOQ) post-treatment value 
before or during that SVR window.
Relapse12
confirmed HCV RNA ≥LLOQ between end of treatment and 12 weeks after 
last actual dose of study treatment (up to and including the SVR12 assessment time point) 
for a subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment 
and has post treatment HCV RNA data available, excluding reinfection as described 
below.
Relapseoverall
confirmed HCV RNA ≥LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment and has 
post treatment HCV RNA data available, excluding reinfection as described below.
Virologic failure through Post-Treatment Week 12
 SVR12 non-responders who 
experience on-treatment virologic failure or Relapse12.


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Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse. For relapse analyses, the completion of treatment is defined as a study 
treatment duration ≥52 days. 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 
subtype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger assay.
Post-treatment relapse is defined as described earlier (Relapse12 and Relapseoverall), and 
no genotype, subtype, or clade switch compared with baseline as determined by 
phylogenetic analysis of the NS3 or NS5A gene sequences. If phylogenetic analysis is not 
possible due to technical difficulties, the subject will be defined as having a 
post-treatment relapse unless an HCV genotype or subtype switch is confirmed by the 
Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger assay.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
HCV reinfection (see definition described earlier);
3.
Relapse12 (see Relapse12 definition);


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4.
Prematurely discontinued study treatment with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study 
treatment [study treatment duration < 52 days] and did not meet the On-treatment 
virologic failure or HCV reinfection definitions);
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study treatment 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]).
For the reasons for SVR12 nonresponse defined above, subjects are only to be counted in 
1 category. Specifically, subjects who were SVR12 non-responders meeting the definition 
of HCV reinfection will be counted in the reinfection category regardless of whether they 
meet the definition of prematurely discontinued study treatment or Relapse12.
9.2
Handling of Missing Data
Missing Data Imputation for SVR
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. A subject with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.


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Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure.
Missing Data Imputation for PRO Questionnaires
The handling of missing data for PROs will be as follows. For EuroQol-5 Dimensions-5 
Level (EQ-5D-5L) index and VAS scores, no imputation will be performed for missing 
items. The missing items of the Fatigue Severity Scale (FSS) questionnaire will be 
imputed with the average score of the answered items as long as more than 50% of the 
items on the FSS are answered.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the achievement of SVR12 (defined as HCV RNA 
< LLOQ 12 weeks after the last actual dose of study treatment) for each subject in the ITT 
population.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 2.


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Table 2.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical Summary
Primary
GLE/PIB 
8 Weeks
SVR12
ITT
Subjects who 
discontinue the 
study with an 
unknown 
SVR12 status 
(after applying 
backward 
imputation) will 
be counted as a 
failure for 
SVR12
Number and percentage of 
subjects who achieve SVR12
along with a two-sided 
95% CI calculated using 
Wilson's score method2
The superiority of 8-week treatment with GLE/PIB in acute HCV infection to the 
weighted efficacy threshold described in Section 2.5, 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 two-sided 95% CI for the 
percentage of subjects achieving SVR12 is greater than the weighted efficacy threshold. 
For the calculation of the efficacy threshold, the proportions of PWID and non-PWID 
subjects in this study will be determined using PWID Status Classification 1 described in 
Section 7.1.
The number and percentage of subjects with each reason for SVR12 non-response will be 
provided. A listing of subjects who do not achieve SVR12 by reason for non-response will 
also be provided.
9.3.3
Supplementary Analyses of Primary Efficacy Endpoint
As a supplementary analysis of the primary endpoint (Supplementary Analysis 1), the 
number and percentage of subjects in the ITT population who achieve SVR12 along with a 
two-sided 95% CI calculated using Wilson's score method will be compared to the 


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efficacy threshold as calculated using the proportions of PWID and non-PWID subjects in 
this study and the PWID Status Classifications 2 and 3 as described in Section 7.1. 
As a supplementary analysis of the primary endpoint (Supplementary Analysis 2), the 
number and percentage of subjects in the ITT population with baseline HCV RNA 
≥LLOQ who achieve SVR12 along with a two-sided 95% CI calculated using Wilson's 
score method will be compared to the efficacy threshold as calculated using the 
proportions of PWID and non-PWID subjects included in this analysis and the PWID 
Status Classifications 1, 2, and 3 as described in Section 7.1. Additionally, the number 
and percentage of subjects with each reason for SVR12 non-response will be provided as 
well as a listing of subjects who do not achieve SVR12 by reason for non-response.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the achievement of SVR12 for each subject in the 
mITT-VF population.
9.4.2
Main Analysis of Key Secondary Efficacy Endpoint
The attributes of the estimand corresponding to the key secondary efficacy endpoint are 
summarized in Table 3.


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Table 3.
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Key 
Secondary
GLE/PIB 
8 Weeks
SVR12
mITT-VF
Not applicable
Number and 
percentage of 
subjects who 
achieve SVR12
along with a 
two-sided 
95% CI 
calculated using 
Wilson's score 
method2
The superiority of 8-week treatment with GLE/PIB in acute HCV infection to the 
weighted efficacy threshold described in Section 2.5, which is based on the historical 
mITT-VF SVR12 rate of treatment with GLE/PIB for PWID and non-PWID subjects with
chronic HCV infection, will be demonstrated if the lower bound of the two-sided 95% CI 
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 12.0. 
For the calculation of the efficacy threshold, the proportions of PWID and non-PWID 
subjects in this study will be determined using PWID Status Classification 1 described in 
Section 7.1.
The number and percentage of subjects with each reason for SVR12 non-response will be 
provided.
9.4.3
Supplementary Analyses of Key Secondary Efficacy 
Endpoint
As a supplementary analysis of the key secondary endpoint, the number and percentage of 
subjects in the mITT-VF population who achieve SVR12 along with a two-sided 95% CI 
calculated using Wilson's score method will be compared to the efficacy threshold as 


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calculated using the proportions of PWID and non-PWID subjects in this study and the 
PWID Status Classifications 2 and 3 as described in Section 7.1.
As a supplementary analysis of the key secondary endpoint, the number and percentage of 
subjects in the mITT-VF population with baseline HCV RNA ≥LLOQ who achieve 
SVR12 along with a two-sided 95% CI calculated using Wilson's score method will be 
compared to the efficacy threshold as calculated using the proportions of PWID and 
non-PWID subjects included in this analysis and the PWID Status Classifications 1, 2, 
and 3 as described in Section 7.1. Additionally, the number and percentage of subjects 
with each reason for SVR12 non-response will be provided.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
The supportive secondary efficacy endpoints are:
●
On-treatment virologic failure (as defined in Section 9.1) for each subject in 
the ITT population;
●
Relapse12 (as defined in Section 9.1) for each subject in the ITT population 
who completed treatment as planned (defined as study treatment duration 
≥52 days) with HCV RNA < LLOQ at EOT and with at least 1 post-treatment 
HCV RNA value;
●
Post-treatment reinfection with HCV (as defined in Section 9.1) for each 
subject in the ITT population.
For the analysis of on-treatment virologic failure, Relapse12, and post-treatment HCV 
reinfection, the number and percentage of subjects in the ITT population will be 
summarized along with a two-sided 95% CI calculated using Wilson's score method.2
Subject numbers of all virologic failures and subjects with post-treatment reinfection will 
be provided.


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9.5
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized for the ITT population:
●
At each post-baseline visit in the Treatment Period, achievement of HCV RNA 
< LLOQ (using data as observed);
●
Achievement of SVR4 (as defined in Section 9.1);
●
Virologic failure through Post-Treatment Week 12 (as defined in Section 9.1);
●
Relapseoverall (as defined in Section 9.1).
For each of the endpoints above, the number and percentage of subjects meeting the 
endpoint will be calculated. For the endpoints of SVR4 and virologic failure, a two-sided 
95% CI will be calculated using Wilson's score method.2 Imputations for missing data will 
be performed as described in Section 9.2 for analysis of SVR4, 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 in the ITT population who completed treatment and relapsed 
(defined as Relapseoverall) will be prepared displaying the number of subjects relapsing 
overall and by SVR visit window (within the SVR4 or SVR12 window or after SVR12
window), including the subject number and the SVR visit window corresponding to the 
first HCV RNA value of those indicating the occurrence of relapse. A similar summary 
will be prepared for subjects in the ITT population who prematurely discontinued 
treatment and relapsed after having HCV RNA < LLOQ at their Final Treatment Visit.
A listing of subjects in the ITT population excluded from the relapse denominator 
(e.g., study treatment duration < 52 days or no post-treatment HCV RNA) will be 
provided, as applicable.
The concordance between SVR4 and SVR12 will be assessed for the ITT population by the 
agreement between SVR4 and SVR12 and the positive predictive value (PPV) and negative 
predictive value (NPV) of SVR4 on SVR12. The agreement between SVR4 and SVR12 is a 
percentage defined as the number of subjects achieving both SVR4 and SVR12 and the 


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number of subjects where both SVR4 and SVR12 are not achieved. The PPV of SVR4 on 
SVR12 is the proportion of subjects who achieve SVR12 out of all subjects who achieved 
SVR4. The NPV of SVR4 on SVR12 is the proportion of subjects who do not achieve 
SVR12 out of all subjects who did not achieve SVR4.
9.6
Efficacy Subgroup Analyses
The number and percentage of subjects achieving SVR12 in the ITT and mITT-VF 
populations will be presented for the following subgroups:
●
HCV GT (1, 2, 3, 4, 5, or 6) and available subtype (final HCV genotype and 
subtype as defined in Section 9.7);
●
Sex (male or female);
●
Age (< 18, 18 to < 40, 40 to < 65, 65 to < 75, ≥ 75 years; < 18 or ≥18 years; 
< 65 or ≥65 years; < 75 or ≥75 years);
●
Race (white, black/African-American, Asian, or other) and (black or 
non-black);
●
BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 800,000 or ≥ 800,000 IU/mL; < 1,000,000 or 
≥1,000,000 IU/mL);
●
Baseline platelet count (< 100 or ≥ 100 × 109/L);
●
Baseline serum albumin (< 35 or ≥ 35 g/L);
●
Baseline ALT (≤ULN, > ULN to ≤ 3 × ULN, > 3 × ULN to ≤5 × ULN, 
> 5 × ULN to ≤10 × ULN, or > 10 × ULN);
●
Baseline total bilirubin (< 34.2 or ≥34.2 µmol/L);
●
Geographic region (North America, Europe, or ROW);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, or ≥90 mL/min);
●
Baseline eGFR (< 90 or ≥90 mL/min/1.73 m2);
●
History of diabetes (yes or no);


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●
History of opiate substitution therapy use (yes, ongoing at start of study 
treatment; yes, less than 6 months prior to start of study treatment; yes, 6 to 
12 months prior to start of study treatment; yes, more than 12 months prior to 
start of study treatment; yes, timing of last dose unknown; or no);
●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
drug use (yes, ongoing as of the end of study participation; yes, last dose after 
last dose of study treatment; yes, last dose during study treatment period; yes, 
last dose less than 6 months prior to start of study treatment; yes, last dose 6 to 
12 months prior to start of study treatment; yes, last dose more than 12 months 
prior to start of study treatment; yes, timing of last dose unknown; or no);
●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
injection drug use (yes, ongoing as of the end of study participation; yes, last 
dose after last dose of study treatment; yes, last dose during study treatment 
period; yes, last dose less than 6 months prior to start of study treatment; yes, 
last dose 6 to 12 months prior to start of study treatment; yes, last dose more 
than 12 months prior to start of study treatment; yes, timing of last dose 
unknown; or no);
●
PWID Status Classification 1 - with respect to study treatment start 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
PWID Status Classification 2 - with respect to study treatment period 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
PWID Status Classification 3 - with respect to study participation 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
Baseline APRI (≤1, > 1 to ≤ 2, or > 2);
●
Baseline FibroTest (< 0.75 or ≥ 0.75);
●
Baseline FIB-4 (< 1.45, ≥ 1.45 to ≤ 3.25, or > 3.25);
●
Baseline AST/ALT ratio (≤ 1 or > 1);


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Risk behavior for acute HCV infection (shared drug-injection equipment, 
shared non-injection drug use equipment, unprotected sexual activity with 
multiple partners, unprotected sexual activity with other male(s), risky tattoos 
or body piercings, shared personal items possibly contaminated with blood, 
healthcare worker with occupational exposure, or other behavior);
●
Grouped risk behavior for acute HCV infection (contaminated needle or 
IV drug use, contact with infected individual, occupational exposure, or other 
behavior);
●
Grouped risk behavior for acute HCV infection (drug use, sexual transmission, 
contact by contaminated objects, occupational, other behavior);
●
Baseline HCV/HIV co-infection status (HCV mono-infected or HCV/HIV-1 
co-infected);
●
Estimated acute HCV infection duration (< 3 months, ≥3 months to 
< 6 months, or ≥6 months) across all and by each acute HCV infection criteria 
used to estimate infection duration;
●
History of prior HCV infection (yes or no);
●
Baseline fibrosis stage (equivalent to Metavir F0 F1, F2, F3, or F4);
●
Baseline cirrhosis status (cirrhotic, non-cirrhotic, or unknown test results 
indeterminate);
●
Treatment duration (< 52 days or ≥52 days);
●
Study treatment compliance (yes or no).
The number and percentage of subjects with each reason for SVR12 non-response will be 
presented for the following subgroups:
●
PWID Status Classification 1 - with respect to study treatment start 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
History of opiate substitution therapy use (yes, ongoing at start of study 
treatment; yes, less than 6 months prior to start of study treatment; yes, 6 to 
12 months prior to start of study treatment; yes, more than 12 months prior to 
start of study treatment; yes, timing of last dose unknown; or no).


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The number and percentage of subjects with on-treatment virologic failure, Relapse12, and 
post-treatment HCV reinfection in the ITT population will be presented for the following 
subgroups:
●
Age (< 18, 18 to < 40, 40 to < 65, 65 to < 75, ≥ 75 years; < 18 or ≥18 years; 
< 65 or ≥65 years; < 75 or ≥ 75 years);
●
PWID Status Classification 1 - with respect to study treatment start 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
PWID Status Classification 2 - with respect to study treatment period 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
PWID Status Classification 3 - with respect to study participation 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
Baseline HCV/HIV co-infection status (HCV mono-infected or HCV/HIV-1 
co-infected).
●
History of opiate substitution therapy use (yes, ongoing at start of study 
treatment; yes, less than 6 months prior to start of study treatment; yes, 6 to 
12 months prior to start of study treatment; yes, more than 12 months prior to 
start of study treatment; yes, timing of last dose unknown; or no);
The two-sided 95% confidence interval using Wilson's score method will be produced if 
there are at least 5 subjects in the subgroup.
9.7
Resistance Analyses
For all subjects, full length NS3/4A and NS5A from baseline samples will be sequenced 
by next generation sequencing (NGS). For subjects who experience virologic failure 
(on-treatment virologic failure or Relapseoverall as defined in Section 9.1), full length 
NS3/4A and NS5A from the first sample after virologic failure with HCV RNA 
≥1000 IU/mL will be sequenced by NGS.


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For all subjects who experience virologic failure for any reason, a listing by subject that 
includes HCV genotype/subtype, reason for non-response, baseline and post-baseline 
resistance data availability, and key baseline characteristics (e.g., sex, age, race, fibrosis 
stage, baseline HCV RNA (log10), and treatment duration (days)) will be produced.
Only samples with an HCV RNA level of ≥1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification. Therefore, if the 
HCV RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥1000 IU/mL will be used.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions for the respective inhibitor class are listed in Table 4. Appropriate 
subtype-specific prototypic reference sequences will be used for comparison with 
sequences from samples.
Table 4.
Signature Amino Acid Positions and the Key Subset of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 
(GT3 only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 
92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93


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The following definitions will be used in the resistance analyses:
●
Baseline polymorphism: a polymorphism by NGS in a baseline sample at a 
detection threshold of ≥ 2% or ≥ 15% (depending on the threshold utilized) 
within a subject's viral population that was not present in the appropriate 
prototypic reference amino acid sequence for a given DAA target (NS3 or 
NS5A).
●
Substitution at signature amino acid position: substitution (relative to
reference) present at a detection threshold of ≥2% within a subject's viral 
population in a baseline or a post-baseline sample at a signature amino acid 
position.
●
Post-baseline substitution: an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥2% of the sequences from the post-baseline sample.
●
Enriched polymorphism: polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post baseline % baseline %) ≥20].
●
Treatment-emergent substitution: A post-baseline substitution or an enriched 
polymorphism.
The following will be provided:
●
Listing by subject of all baseline polymorphisms at signature amino acid 
positions for each DAA target (NS3 and NS5A) at detection threshold of 2%
for subjects in the ITT population.
●
The number and percentage of subjects in the ITT population with baseline 
polymorphisms at signature amino acid positions at detection threshold of 2%
and 15%. This table includes prevalence of each baseline polymorphism, and a 
summary of number of subjects with polymorphisms in NS3 only, in NS5A 
only, any in NS3, any in NS5A, any in NS3 or NS5A, and any in 
NS3 + NS5A.


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●
The number and percentage of subjects in the ITT population with baseline 
polymorphisms at a key subset of amino acid positions in NS3 only, in 
NS5A only, any in NS3, any in NS5A, any in NS3 or NS5A, and any in 
NS3 + NS5A, by subtype, and total (across all subtypes).
●
Listing by subject (and time point) of all treatment-emergent substitutions 
relative to the baseline amino acid sequences for each DAA target (NS3 and 
NS5A) for subjects in the ITT population who experience virologic failure.
●
Listing by subject (and time point) of substitutions at signature amino acid 
positions (relative to reference sequence) for each DAA target (NS3 and 
NS5A) for subjects in the ITT population who experience virologic failure.
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequences from 
baseline samples from all subjects in order to accurately determine genotype/subtype. If 
the phylogenetic analysis is not available, then the result from Sanger sequencing of a 
region of NS5B by AbbVie or by the central laboratory will be used to determine the 
subject's HCV genotype/subtype, if available. Finally, if neither the phylogenetic analysis 
result nor the Sanger sequencing assay result is available, then the Inno-LiPA assay result 
from the central laboratory will be used to categorize the subject. This genotype/subtype 
category (referred to as final genotype/subtype) will be used in efficacy subgroup 
analyses.
In addition, the final genotype/subtype as well as the results from the central laboratory 
(Sanger sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) will be 
summarized as part of the baseline characteristics. A summary of HCV genotype subtype 
as provided by the central laboratory (Sanger sequencing or Inno-LiPA 2.0 Assay [if 
Sanger sequencing not available]) versus phylogenetic analysis also will be provided. 
Listings of HCV genotype and subtype will be provided separately for central laboratory 
results and phylogenetic analysis results.


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9.8
Patient Reported Outcomes
The following instruments will be used to collect PROs: EuroQol-5 Dimensions-5 
Level (EQ-5D-5L) and Fatigue Severity Scale (FSS). Missing data for each measurement 
will be handled as described in Section 9.2.
The 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. Responses to the 5 items encode a discrete health state which is 
mapped to a preference (utility) specific for different societies. Subject's responses to the 
EQ-5D-5L will be combined into a unique health state using a 5-digit code with 1 digit 
from each of the 5 dimensions. The EQ-5D-5L states will be converted into a single 
preference-weighted health utility index score by applying weights.5,6 Subjects also rate 
their perception of their overall health on a separate visual analogue scale (VAS). The 
VAS score will be analyzed separately. Higher health index and VAS scores indicate 
better health. For EQ-5D-5L index and VAS scores, no imputation will be performed for 
missing items.
The FSS measures the impact of fatigue over the past week on specific types of 
functioning. The survey consists of 9 questions using a 7-point Likert scale. A total score 
is calculated as the average of the individual item responses (adding up all the answers 
and dividing by nine). Higher FSS scores indicate a higher degree of impact of fatigue. 
Imputation will be applied to the total score as described in Section 9.2. If a subject starts 
another treatment for HCV, then all PRO values for this subject measured on or after the 
start date of the new HCV treatment will be excluded from analyses.
Summary statistics (number of subjects and mean) at each protocol-specified visit and for 
the change from baseline (number of subjects, mean, SD, minimum and maximum) to 
each applicable post-baseline timepoint will be provided for EQ-5D-5L health index score 
and VAS score and for the FSS total score.


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The following analysis of PROs also will be performed:
●
Number and percentage of subjects who have ever experienced a decrease
from baseline up through each applicable time point of greater than or equal 
to 0.7 in the FSS total score will be calculated along with a two-sided 95% CI 
based on Wilson's score method.2
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of the 
MedDRA coding dictionary used will be noted in the AE tables and in the clinical study 
report. Specific AEs will be counted once for each subject for calculating percentages, 
unless stated otherwise. In addition, if the same AE occurs multiple times within a 
subject, the highest severity and level of relationship to GLE/PIB will be reported.
Participants in clinical trials with HIV-1 may develop infections typically associated with 
acquired immune deficiency syndrome (AIDS). Adverse events that are considered to be 
AIDS-associated opportunistic infections (OIs) as identified by the investigators on the 
AE eCRF will not be included in any analyses of AEs as they will be summarized 
separately (see Section 10.2.6).
Adverse events and AIDS-associated OIs will be summarized for the following groups: 
adolescents (age < 18 years), adults (age ≥18 years), and overall.


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10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with an onset date that is after the first 
dose of study treatment and no more than 30 days after the last dose of study treatment. 
Events where the onset date is the same as the study treatment start date are assumed to be 
treatment-emergent. If an incomplete onset date was collected for an AE, the event will be 
assumed to be treatment-emergent, unless there is other evidence that confirms that the 
event was not treatment-emergent (e.g., the event end date was prior to the study 
treatment start date).
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
●
Treatment-emergent AEs of Grade 3 or higher;
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (GLE/PIB);
●
Treatment-emergent AEs leading to discontinuation of study treatment;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
treatment;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB);
●
Serious treatment-emergent AEs leading to discontinuation of study treatment;
●
Treatment-emergent AEs leading to interruption of study treatment;
●
Treatment-emergent AEs leading to death;
●
Deaths.


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The following listings of AEs will be prepared:
●
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study);
●
Treatment-emergent serious AEs;
●
Treatment-emergent AEs leading to death;
●
Treatment-emergent AEs leading to discontinuation of study treatment;
●
Treatment-emergent AEs leading to study treatment interruption.
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA SOC and PT. The SOCs will be presented in alphabetical order, and 
the PTs will be presented in alphabetical order within each SOC.
Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most severe/highest grade incident for the severity tables and most related incident 
for the relationship tables). Subjects reporting more than one AE within a SOC will be 
counted only once for that SOC. Subjects reporting more than one AE will be counted 
only once in the overall total.
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (GLE/PIB);
●
Grade 3 or higher treatment-emergent AEs;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (GLE/PIB);


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●
Treatment-emergent AEs leading to discontinuation of study treatment;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
treatment;
●
Serious treatment-emergent AEs leading to discontinuation of study treatment;
●
Treatment-emergent AEs leading to interruption of study treatment;
●
Treatment-emergent AEs leading to death.
A listing of treatment-emergent AEs grouped by SOC and PT with subject numbers will 
be created.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
tabulated according to PT and sorted by overall frequency. Similar summaries will be 
provided for Grade 3 or higher treatment-emergent AEs, DAA-related treatment-emergent 
AEs, DAA-related Grade 3 or higher treatment-emergent AEs, and DAA-related 
treatment-emergent serious AEs.
Treatment-emergent AEs and DAA-related treatment-emergent AEs will be summarized 
by maximum severity grade level of each PT, where each AE will be assigned a grade 
level (Grade 1, 2, 3, 4, or 5) by the investigator. Additionally, of the subjects who reported 
at least one treatment-emergent AE, the number and percentage of subjects reporting 
events with a maximum severity of Grade 1, Grade 2, Grade 3, Grade 4, and Grade 5 will 
be calculated.
Treatment-emergent AEs also will be summarized by maximum relationship of each PT 
to study treatment (DAAs), as assessed by the investigator.
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Treatment Discontinuation
SAEs (including deaths) and AEs leading to study treatment discontinuation will be 
summarized by SOC and PT and in listing format as described in Section 10.2.2 and 
Section 10.2.3.


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10.2.5
Adverse Events of Special Interest
For the hepatic decompensation/hepatic failure AE of special interest defined below, the 
number and percentage of subjects experiencing at least one treatment-emergent AE in the 
search will be presented overall and by SOC and PT. In addition, a listing of 
treatment-emergent AEs for subjects meeting the search criterion will be provided. For the 
hepatocellular carcinoma AE of special interest, a listing of all AEs meeting the search 
criterion will be provided.
Hepatic decompensation and hepatic failure:
●
Treatment-emergent events only
●
Product MedDRA Query (PMQ) of "Hepatic decompensation and hepatic 
failure"
Hepatocellular carcinoma:
●
All post-baseline cases, treatment-emergent and non-treatment emergent
●
Search based on specific MedDRA PTs of hepatocellular carcinoma, hepatic 
neoplasm, hepatic cancer, hepatic cancer metastatic, and hepatic cancer 
recurrent.
10.2.6
AIDS-Associated Opportunistic Infections
The number and percentage of subjects experiencing treatment-emergent AIDS-associated 
OIs will be tabulated according to SOC and PT for the HCV/HIV co-infected subjects. 
Subjects reporting more than one AIDS-associated OI for a given PT will be counted only 
once for that term. Subjects reporting more than one AIDS-associated OI within a SOC 
will be counted only once for that SOC. Subjects reporting more than one 
AIDS-associated OI will be counted only once in the overall total. A listing of 
treatment-emergent AIDS-associated OIs will also be generated.


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10.3
Analysis of Laboratory Data
The hematology (including coagulation parameters), clinical chemistry, urinalysis 
(specific gravity and pH only), and total insulin laboratory tests defined in the protocol 
operations manual will be summarized.
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 treatment. 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.
Each laboratory variable will be summarized for all protocol-specified time points 
(starting with Baseline) with the number of non-missing observations, mean and standard 
deviation, median, Q1 and Q3 of inter-quartile range, minimum and maximum. Mean 
change from baseline to each applicable visit, including applicable post-treatment visits, 
will also be summarized for the laboratory parameters of ALT, AST, bilirubin (total, 
direct, and indirect), and alkaline phosphatase, with the number of observations, baseline 
mean, and visit mean. The change from baseline mean, standard deviation, median, 
Q1 and Q3 of inter-quartile range, minimum and maximum will be presented for the mean 
change from baseline.
Changes in hematology (including coagulation parameters), clinical chemistry, and 
urinalysis laboratory parameters will be tabulated using shift tables. Laboratory data 
values will be categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample. A shift table from baseline to minimum value and 
maximum value during the Treatment Period will be created. In this shift table, the 
number and percentage of subjects with baseline values within or above the normal range 
(baseline high or normal) and a minimum value below the normal range (post-baseline 
low) and the number and percentage of subjects with baseline values within or below the 
normal range (baseline low or normal) and a maximum value above the normal range 
(post-baseline high) will be summarized.


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Summaries of graded laboratory parameters and shift from baseline grade (see below) will 
be summarized for the following groups: adolescents (age < 18 years), adults 
(age ≥18 years), and overall.
The laboratory parameters listed in Appendix B will be assigned a toxicity grade of 1, 2, 
3, or 4. The number and percentage of subjects with a maximum toxicity grade of 1, 2, 3 
or 4 will be summarized for the baseline value and for values during the Treatment Period 
for subjects with both a baseline value and at least one post-baseline value during the 
Treatment Period. To be counted, the post-baseline value must have a toxicity grade that 
is more extreme than the toxicity grade corresponding to the baseline value. The summary 
will also include the number and percentage of subjects with a maximum of at least 
Grade 3 for all laboratory parameters in Appendix B. A listing of all relevant laboratory 
parameters will be provided for each subject who had an increase to Grade 2 or higher for 
any laboratory variable in Appendix B.
Shift tables from baseline to maximum value during the Treatment Period will be created 
for ALT and total bilirubin values categorized by toxicity grade. For each baseline grade, 
the frequency and percentage of subjects with maximum Grades of 0, 1, 2, 3, and 4 during 
treatment will be calculated. The number and percentage of those subjects who improved 
from baseline, were the same as baseline, or who worsened from baseline will also be 
calculated.
Shift tables from baseline to the Week 4 and Final Treatment Visits will be created for 
ALT and total bilirubin categorized by toxicity grade. For each baseline grade, the 
frequency and percentage of subjects with Grades of 0, 1, 2, 3, and 4 at the Week 4 and 
Final Treatment Visits will be calculated. The number and percentage of those subjects 
who improved from baseline, were the same as baseline, or who worsened from baseline 
will also be calculated.


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Assessment of Hepatic Laboratory Values
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized for adolescents (age < 18 years), adults 
(age ≥18 years), and overall:
●
Post-nadir (preceding value is lower than the subsequent value) 
ALT > 5 × ULN (regardless of grade change);
●
Total bilirubin ≥2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered);
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin ≤2 × ULN.
Four listings (one for each bullet above) of all liver function tests including ALT, AST, 
total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.
Hepatic Laboratory Abnormalities of Interest
Among the events assessed under "Assessment of Hepatic Laboratory Values," the 
following criteria are of interest:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post nadir ALT > 3 × ULN and a concurrent total bilirubin > 2 × ULN with a 
direct bilirubin:total bilirubin ratio > 0.4.
To support the assessment of hepatic laboratory abnormalities of interest, the following 
potential events will be summarized for adolescents (age < 18 years), adults 
(age ≥18 years), and overall:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN with a direct 
bilirubin:total bilirubin ratio > 0.4.


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Two listings (one for each bullet) of all liver function tests including ALT, AST, total, 
indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline phosphatase 
values will be provided for each subject who met the criterion defined above.
The assessments of hepatic laboratory values and hepatic laboratory abnormalities of 
potential interest will include subjects who have a baseline and at least one post-baseline 
value during the Treatment Period for the respective parameter. Criteria that include both 
ALT and total bilirubin require both parameters to have a baseline and at least one value 
during the Treatment Period. The maximum ratio relative to the ULN will be used to 
determine if subjects meet any of the criteria listed above. The ALT and total bilirubin 
values do not need to be concurrent in order to meet the defined criteria in statistical 
summaries. For ALT, the post-baseline value must represent an increase from the first 
nadir (including baseline) to be counted. First nadir is defined as the last value prior to the 
first increase. For total bilirubin, a subject will be counted if the post-baseline laboratory 
value meets the above criteria regardless of the baseline laboratory value (i.e., the 
post-baseline laboratory value does not need to be worse than the baseline laboratory 
value), except where noted in the criteria above. A confirmed post-nadir increase in ALT 
is defined as two consecutive values of ALT > 5 × ULN after nadir, either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement. A single post-nadir ALT value of greater than 5 × ULN followed by lost to 
follow-up (no additional ALT values) also will be considered as confirmed (i.e., will not 
require confirmation). The ratio of direct to total bilirubin will be calculated using the 
same date/time sample corresponding to the total bilirubin elevation.
10.4
Analysis of Vital Signs
Vital sign variables are body temperature, sitting systolic blood pressure, sitting diastolic 
blood pressure, heart rate, and body weight.
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study treatment. The same baseline value will be used for change to 
Treatment Period visits and change to Post-Treatment Period visits.


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Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
Q1 and Q3 of inter-quartile range, minimum and maximum. Mean change from baseline 
to each applicable visit, including applicable post-treatment visits, will also be 
summarized, with the number of observations, baseline mean, and visit mean. The change 
from baseline mean, standard deviation, median, Q1 and Q3 of inter-quartile range, 
minimum and maximum will be presented for the mean change from baseline.
Vital sign variables will be evaluated based on the potentially clinically significant (PCS) 
criteria presented in Appendix B.
The number and percentage of subjects with on-treatment values meeting the specified 
criteria for PCS vital sign values 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.
10.5
Safety Subgroup Analyses
The following safety summaries will be performed as described above (by adolescents 
(age < 18 years), adults (age ≥ 18 years), and overall) for specific subgroups:
●
Adverse event overview (see Section 10.2.2);
●
Treatment-emergent AEs sorted by descending frequency of MedDRA PT 
(see Section 10.2.3);
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (GLE/PIB) sorted by descending frequency of MedDRA PT 
(see Section 10.2.3);
●
Serious treatment-emergent AEs by MedDRA SOC and PT 
(see Section 10.2.3);
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (GLE/PIB) by MedDRA SOC and PT (see Section 10.2.3);


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●
Treatment-emergent AEs leading to discontinuation of study treatment by 
MedDRA SOC and PT (see Section 10.2.3);
●
Treatment-emergent hepatic decompensation/hepatic failure events by 
MedDRA SOC and PT (see Section 10.2.5);
●
ALT and total bilirubin elevations of the NCI-CTCAE v4.03 Grade 1, 2, 3, 
or 4 during the Treatment Period with grade increased from baseline 
(see Section 10.3);
●
Shift from baseline to maximum value during the Treatment Period for ALT 
and total bilirubin categorized by toxicity grade (see Section 10.3);
●
Shift from baseline to Week 4 and Final Treatment Visits for ALT and total 
bilirubin categorized by toxicity grade (see Section 10.3);
●
Assessment of hepatic laboratory values during the Treatment Period 
(see Section 10.3);
●
Hepatic laboratory abnormalities of interest during the Treatment Period 
(see Section 10.3).
The safety summaries above will be presented for the following subgroups:
●
Baseline HCV RNA (< LLOQ or ≥LLOQ);
●
Age (< 65, ≥65 years);
●
Baseline HCV/HIV co-infection status (HCV mono-infected or HCV/HIV-1 
co-infected);
●
History of opiate substitution therapy use (yes, ongoing at start of study 
treatment; yes, less than 6 months prior to start of study treatment; yes, 6 to 
12 months prior to start of study treatment; yes, more than 12 months prior to 
start of study treatment; yes, timing of last dose unknown, or no);
●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
drug use (yes, ongoing as of the end of study participation; yes, last dose after 
last dose of study treatment; yes, last dose during study treatment period; yes, 
last dose less than 6 months prior to start of study treatment; yes, last dose 6 to 
12 months prior to start of study treatment; yes, last dose more than 12 months 
prior to start of study treatment; yes, timing of last dose unknown; or no);


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●
History (i.e., started prior to start of study treatment) of non-prescribed illicit 
injection drug use (yes, ongoing as of the end of study participation; yes, last 
dose after last dose of study treatment; yes, last dose during study treatment 
period; yes, last dose less than 6 months prior to start of study treatment; yes, 
last dose 6 to 12 months prior to start of study treatment; yes, last dose more 
than 12 months prior to start of study treatment; yes, timing of last dose 
unknown; or no);
●
PWID Status Classification 1 - with respect to study treatment start 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID);
●
PWID Status Classification 2 - with respect to study treatment period 
(current/recent PWID or former/non-PWID; current PWID, recent PWID, 
former PWID, or non-PWID).
11.0
Interim Analyses
No interim analysis is planned for this study.
12.0
Overall Type-I Error Control
In order to control the family-wise Type-I error rate, a fixed-sequence testing procedure7
will be used for the primary and key secondary efficacy analyses of SVR12 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).


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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.
13.0
Version History
Table 5.
SAP Version History Summary
Version
Date
Summary
1.0
13 October 2021
Initial version
2.0
15 November 2023
Version 2.0
3.0
02 July 2024
Version 3.0
4.0
12 August 2024
Version 4.0
13.1
Summary of Changes
The following is a summary of changes between the protocol (protocol version 3.0 
dated 23 April 2021) and SAP version 1.0. These changes were made to provide 
additional information for the specified groups of subjects.
Summaries for adolescents and for adults were added for:
●
Demographics and baseline characteristics summaries;
●
Subgroup analyses of supportive secondary efficacy endpoints;
●
Adverse events summaries.
The following subgroups were added for the summaries of SVR12:
●
Baseline total bilirubin (< 34.2 or ≥34.2 µmol/L);
●
PWID status (current/recent PWID or former/non-PWID);
●
Baseline fibrosis stage (equivalent to Metavir F0 - F1, F2, F3, or F4);
●
Baseline cirrhosis status (cirrhotic or non-cirrhotic);


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●
Treatment duration (< 52 days or ≥52 days);
●
Study treatment compliance (yes or no).
The following subgroup was added for the summaries of the supportive secondary 
endpoints:
●
PWID status (current/recent PWID or former/non-PWID).
The following is a summary of changes between SAP version 1.0 and SAP version 2.0.
●
Throughout
○
Added that Q1 and Q3 of inter-quartile range will be included in numerical 
summaries
●
Rationale: To provide additional summary statistics
●
Section 5.0
○
Clarified that the subjects who failed to enroll in the study are those who 
failed to receive at least one dose of study treatment
●
Rationale: For clarification
●
Section 7.0
○
Added demographics and baseline disease characteristics summaries for 
mITT-VF population
●
Rationale: To provide this information for the key secondary efficacy 
analysis population
●
Section 7.1
○
Added demographics and baseline characteristics summaries to be by 
adult, adolescent, and overall
●
Rationale: To provide this information for the adolescent and adult 
subjects separately
○
Updated cirrhosis status categories to include "unknown 
test results 
indeterminate" and clarified that screening and baseline Child-Pugh score 
includes subjects with cirrhosis status unknown
●
Rationale: To align with protocol-allowed cirrhosis status


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○
Updated categories for baseline HCV RNA level and baseline APRI
●
Rationale: To correct typos
○
Updated history of non-prescribed illicit drug use categories, history of 
non-prescribed illicit injection drug use categories, and PWID status 
categories
●
Rationale: To align with data collection and provide multiple 
definitions of PWID status
○
Added another set of grouped risk behaviors for summarization
●
Rationale: To provide additional information based on different 
groupings of risk behaviors
○
Provided details for calculation of estimated acute HCV infection duration
●
Rationale: To provide details
●
Section 7.3
○
Clarified that any prior and concomitant HIV ART medications will be 
summarized for subjects who are HCV/HIV co-infected at baseline, not 
only those receiving ART at baseline
●
Rationale: For clarification
○
Clarified that opiate substitution therapy and non-prescribed illicit drugs 
will be summarized as reported rather than by generic drug name based on 
the WHO Drug Dictionary
●
Rationale: For clarification
●
Section 9.3.3 and Section 9.4.3
○
Added section describing supplementary analyses of primary endpoint and 
key secondary endpoint
●
Rationale: To add analyses with comparisons to efficacy thresholds 
based on different definitions of PWID status
●
Section 9.6
○
Updated subgroups based on age, baseline HCV RNA level, history of 
non-prescribed illicit drug use, history of non-prescribed illicit injection 
drug use, PWID status, grouped risk behavior categories, HCV/HIV 
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●
Rationale: To align with Section 7.1
○
Updated subgroups based on age and PWID status for summaries of the 
secondary efficacy endpoints
●
Rationale: To align with Section 7.1
○
Updated the subgroup analyses of secondary endpoints to include 
summaries by HCV/HIV co-infection status
●
Rationale: To provide additional information for subjects with and 
without HIV co-infection
●
Section 10.3
○
Clarified that hematology laboratory parameters include coagulation 
parameters and that summaries of laboratory variables over time would 
include summaries for all protocol-specified timepoints
●
Rationale: For clarification
○
Clarified which laboratory parameters would be tabulated using shift tables
●
Rationale: For clarification
○
Added that the summaries of graded laboratory parameters, shifts from 
baseline in graded laboratory parameters, and assessments of hepatic 
laboratory values and hepatic laboratory abnormalities of interest will be 
summarized for adult, adolescent, overall
●
Rationale: To provide this information for the adolescent and adult 
subjects separately
○
Added additional shift tables for baseline to maximum on-treatment, 
Week 4, and Final Treatment Visit values for ALT and total bilirubin 
categorized by toxicity grade
●
Rationale: To provide additional assessments of on-treatment ALT and 
total bilirubin
●
Section 10.5
○
Added Section 10.5 Safety Subgroup Analyses; added analyses of key AE 
and laboratory summaries to be done by adult, adolescent, overall, and by 
subgroups of age, baseline HCV/HIV co-infections status, history of 
non-prescribed illicit drug use, history of non-prescribed illicit injection 
drug use, and PWID status


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●
Rationale: To provide assessments of safety for subgroups of interest
●
Appendix B, Table B-1
○
Added eGFR
●
Rationale: To correct omission
The following is a summary of changes between SAP version 2.0 and SAP version 3.0.
●
Section 2.5
○
Clarified that for calculation of the efficacy thresholds, PWID is defined as 
current/recent PWID, and non-PWID is defined as former/non-PWID
●
Rationale: For clarification
●
Section 6.0
○
Clarified that if the number of tablets returned is not available for one or 
more of the bottles dispensed to a subject, then compliance will not be 
calculated for that subject
●
Rationale: For clarification
○
Added that Q1 and Q3 of inter-quartile range will be included in numerical 
summaries
●
Rationale: To correct omission
●
Section 7.1
○
Added demographics and baseline characteristics summaries for groups of 
subjects based on PWID Status Classification 1 and history of opiate 
substitution therapy use
●
Rationale: To provide additional information for these groups of 
subjects 
○
Added categories of < LLOQ and ≥ LLOQ for baseline HCV RNA level 
●
Rationale: To provide a summary of subjects who had unquantifiable 
or undetectable HCV RNA at baseline
○
Removed antiretroviral (ART) requirement from baseline characteristic 
summary of HIV treatment status


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●
Rationale: To remove limitation to include only ART medications for 
coinfected subjects
●
Section 7.3
○
Removed restriction to include only ART medications in the summaries of 
HIV medications 
●
Rationale: To align with baseline characteristics summary
●
Section 9.3.3 and Section 9.4.4
○
Added supplementary analyses of primary and key secondary endpoints 
excluding those subjects who had baseline HCV RNA < LLOQ
●
Rationale: To provide assessments in subjects who had quantifiable 
HCV RNA at baseline
●
Section 9.6
○
Updated the subgroup analyses of secondary endpoints to include 
summaries by history of opiate substitution therapy
●
Rationale: To provide additional information for subjects with and 
without a history of opiate substitution therapy
○
Added subgroup analyses of reasons for SVR12 non-response for PWID 
status and history of opiate substitution therapy
●
Rationale: To provide additional information for subjects based on 
PWID status and history of opiate substitution therapy
○
Updated subgroup description of estimated infection duration to include 
summaries across all and by each acute HCV infection criteria
●
Rationale: To align with Section 7.1
●
Section 10.3
○
Clarified the data requirements for subjects to be included in the 
summaries of graded laboratory parameters and assessments of hepatic 
laboratory values and hepatic laboratory abnormalities of interest
●
Rationale: For clarification
●
Section 10.5
○
Added baseline HCV RNA < LLOQ or ≥ LLOQ as a safety subgroup 
variable


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●
Rationale: To provide assessments of safety in subjects who had 
quantifiable HCV RNA at baseline and those who did not
○
Added history of opiate substitution therapy as a safety subgroup variable
●
Rationale: To provide assessments of safety in subjects who had a 
history of opiate substitution therapy and those who did not
The following is a summary of changes between SAP version 3.0 and SAP version 4.0.
●
Section 7.1
○
Removed "followed by initiating GLE/PIB treatment" from acute HCV 
infection criteria description
●
Rationale: To align with text in protocol
14.0
References
1.
Mavyret (glecaprevir and pibrentasvir) tablets [US Prescribing Information]. North 
Chicago, IL; AbbVie Inc., 2020.
2.
Newcombe RG. Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Stat Med. 1998;17(8):857-72.
3.
Matthews GV, Bhagani S, Van der Valk M, et al. Sofosbuvir/velpatasvir for 
12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection. 
J Hepatol. 2021;75(4):829-39.
4.
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(1):7-18.
5.
Szende A, Williams A. Measuring self-reported population health: an international 
perspective based on EQ-5D. EuroQol Group Monographs Volume 1. SpringMed 
Publishing; 2004.
6.
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.


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7.
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures. J Stat Plan Inference. 2001;99:25-40.


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15.0
Appendices
Appendix A.
Protocol Deviations
Protocol deviations will be categorized as follows:
●
Subject entered into the study even though they did not satisfy eligibility 
criteria;
●
Subject developed withdrawal criteria during the study and was not 
withdrawn;
●
Subject received the wrong treatment or incorrect dose of study treatment;
●
Subject took a prohibited concomitant medication.


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Appendix B.
Laboratory Toxicity Grades and Potentially Clinically Significant 
Criteria for Vital Sign Values
Table B-1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Absolute 
Neutrophil Count
< LLN – 1.5 × 109/L
< 1.5 –
1.0 × 109/L
< 1.0 –
0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 –
50.0 × 109/L
< 50.0 –
25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 –
2.5 × ULN
> 2.5 × ULN
--
Creatinine 
clearance
< LLN – 60 mL/min
< 60 –
30 mL/min
< 30 – 15 mL/min
< 15 mL/min
eGFR
< 90 – 60
mL/min/1.73 m2
< 60 – 30 
mL/min/1.73 m2
< 30 – 15 
mL/min/1.73 m2
< 15 
mL/min/1.73 m2
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 –
2.0 × 109/L
< 2.0 –
1.0 × 109/L
< 1.0 × 109/L
Lymphocyte
< LLN – 0.8 × 109/L
< 0.8 –
0.5 × 109/L
< 0.5 –
0.2 × 109/L
< 0.2 × 109/L
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Glucose (high)
> ULN – 8.9 mmol/L
> 8.9 –
13.9 mmol/L
> 13.9 –
27.8 mmol/L
> 27.8 mmol/L
Glucose (low)
< LLN – 3.0 mmol/L
< 3.0 –
2.2 mmol/L
< 2.2 –
1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Cholesterol
> ULN –
7.75 mmol/L
> 7.75 –
10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
Triglycerides
> 1.71 – 3.42 mmol/L
> 3.42 –
5.7 mmol/L
> 5.7 –
11.4 mmol/L
> 11.4 mmol/L


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Table B-1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values 
(Continued)
Test
Grade 1
Grade 2
Grade 3
Grade 4
Sodium (low)
< LLN –
130 mmol/L
--
< 130 –
120 mmol/L
< 120 mmol/L
Sodium (high)
> ULN –
150 mmol/L
> 150 –
155 mmol/L
> 155 –
160 mmol/L
> 160 mmol/L
Potassium (low)
< LLN –
3.0 mmol/L
--
< 3.0 – 2.5 mmol/L
< 2.5 mmol/L
Potassium (high)
> ULN –
5.5 mmol/L
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L
> 7.0 mmol/L
Magnesium (low)
< LLN –
0.5 mmol/L
< 0.5 – 0.4 mmol/L
< 0.4 – 0.3 mmol/L
< 0.3 mmol/L
Magnesium (high)
> ULN –
1.23 mmol/L
--
> 1.23 –
3.30 mmol/L
> 3.30 mmol/L
Note:
Criteria from National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03.
Table B-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
Heart 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