Conditions: Hepatitis C Virus (HCV)
Keywords: Chronic Hepatitis C Virus Glecaprevir Pibrentasvir Pharmacokinetic Treatment naïve Treatment experienced Interferon (IFN) Pegylated interferon (pegIFN) Ribavirin (RBV) Sofosbuvir Non-cirrhotic cirrhosis Compensated (Child-Pugh A) cirrhosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
The objectives of this study are to assess the pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir adult formulation in adolescents ages 12 to 17 years and a pediatric formulation of glecaprevir and pibrentasvir in children ages 3 to \< 12 years.

Detailed description:
This was a multicenter study to evaluate the pharmacokinetics (PK), efficacy, and safety of glecaprevir (GLE) and pibrentasvir (PIB) treatment for 8, 12, or 16 weeks in hepatitis C virus (HCV) genotype 1 - 6 (GT1 - GT6)-infected pediatric participants 3 to \< 18 years of age, with or without compensated cirrhosis, with or without human immunodeficiency virus (HIV) coinfection, who are either treatment-naïve (TN), treatment-experienced (TE) with pegylated interferon (pegIFN) with or without ribavirin (RBV), or TE with sofosbuvir (SOF) + RBV with or without pegIFN.

The study was divided into 2 parts, according to the formulation of GLE/PIB administered. Part 1 of the study enrolled HCV GT1 - GT6 infected adolescent participants into the 12 to \< 18 years old age group who were willing to swallow the adult formulation of GLE/PIB (Cohort 1). Part 2 of the study enrolled HCV GT1 - GT6 infected pediatric participants divided into the 9 to \< 12 (Cohort 2), 6 to \< 9 (Cohort 3), and 3 to \< 6 (Cohort 4) years old age groups, to receive the pediatric formulation of GLE + PIB. Part 1 enrolled first and once the pediatric formulation was available enrollment into Part 2 commenced, with each cohort enrolled in parallel.

In each cohort, the first group of participants were enrolled into an intense pharmacokinetics (IPK) portion to characterize the PK and safety in each age group, followed by enrollment into a non-IPK safety/efficacy portion. Study participants enrolled in the IPK portion must have been HIV-negative, treatment-naive, and have an identified HCV genotype. In the IPK portion the first approximately six participants received an initial proposed dose of GLE and PIB based on the child's weight and age at screening. PK samples from these participants were evaluated to determine if therapeutic efficacious exposures were attained, comparable to those of adults, and if any dose adjustments were needed. After the intensive PK analysis results for the first six participants were available, enrollment of the remaining IPK portion resumed with subsequent participants receiving an adjusted final dose as applicable. Additional participants may have been required for further intensive PK analysis per age cohort if therapeutic exposure targets were not achieved.

Enrollment into the non-IPK safety and efficacy portions began when the dosing recommendations per age group based on the PK and clinical data from the IPK analysis were ascertained.

Arms:
arm 1: Adolescents aged 12 to \< 18 years old received the adult formulation of glecaprevir (GLE)/pibrentasvir (PIB) 100 mg/ 40 mg co-formulated film-coated tablets for a once daily (QD) total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. arm 2: Children aged 9 to \< 12 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

The initial proposed dose for children 9 to \< 12 years old (30 to \< 45 kg) was GLE 200 mg + PIB 75 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 250 mg + PIB 100 mg. arm 3: Children aged 6 to \< 9 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

The initial proposed dose for children 6 to \< 9 years old (20 to \< 30 kg) was GLE 160 mg + PIB 60 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 200 mg + PIB 80 mg. arm 4: Children aged 3 to \< 6 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

The initial proposed dose for children 3 to \< 6 years old (12 to \< 20 kg) was GLE 120 mg + PIB 45 mg. After PK analysis from the first 5 enrolled participants the dose was adjusted to GLE 150 mg + PIB 60 mg.

Interventions: intervention 1: Glecaprevir/Pibrentasvir Adult Formulation intervention 2: Glecaprevir + Pibrentasvir Pediatric Formulation
Intervention descriptions: intervention 1: Co-formulated film-coated tablet (100 mg/40 mg) intervention 2: Film-coated pellets/granules (15.67%/8.25%) administered by mixing with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.

Protocol document:
Prot_000.pdf: 
Glecaprevir/Pibrentasvir
M16-123 Protocol Amendment 3
EudraCT 2016-004102-34
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1.0
Title Page
Clinical Study Protocol M16-123
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of 
Glecaprevir/Pibrentasvir in Pediatric Subjects with
Genotypes 1 – 6 Chronic Hepatitis C Virus (HCV) 
Infection (DORA)
Incorporating Administrative Change 1 and 
Amendments 1, 2 and 3
AbbVie Investigational
  Product:
Glecaprevir/Pibrentasvir
Date:
22 March 2019
Development Phase:
2/3
Study Design:
This is a non-randomized, open-label, multicenter study.
EudraCT Number:
2016-004102-34
Investigator(s):
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc.
Sponsor/Emergency 
  Contact:
Associate Medical Director
Infectious Diseases
Development
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Mobile:
Fax:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory 
requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT03067129


Glecaprevir/Pibrentasvir
M16-123 Protocol Amendment 3
EudraCT 2016-004102-34
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
15 December 2016
Amendment 1
10 July 2017
Amendment 1.01
25 July 2017
Amendment 2
09 March 2018
Amendment 2.01
16 March 2018
Administrative Change 1
29 June 2018
The purpose of this amendment is to:
●
Update the proposed dosing for subjects who will enroll in Cohorts 2, 3, and 4 
throughout protocol.
Rationale:  Proposed dosing for subjects in Cohorts 2, 3, and 4 have been 
updated, including in the Dose Selection Strategy in the Introduction, 
Section 3.0, sub-section titled "GLE/PIB Dose Selection Strategy for the 
Pediatric Population."  These are the doses based on the current knowledge of 
the PK and safety of the pediatric doses of glecaprevir and pibrentasvir.
●
Update Section 3.3.
Rationale:  Additional details regarding the pediatric requirement were added 
for completeness.
●
Update Section 5.5.2, Identity of Investigational Products, with the dose and 
storage requirements for the GLE/PIB granules, including the addition of a 
footnote. 
Rationale:  Add the final GLE and PIB doses in mg as packaged into sachets, 
and provide details on the use of the nomenclature "pellets" and "granules" for 
GLE and PIB. The nomenclature is interchangeable, as both terms refer to the 
same pediatric formulation, however, "granules" has been added as this is the 
preferred regulatory term in certain regions. 
●
Update Section 6.1.5 Adverse Event Reporting


Glecaprevir/Pibrentasvir
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Rationale:  The SUSAR reporting process has been added as per updated 
company guidance.
●
Update Section 6.1.7.2 Management of ALT Elevations as per prior 
Administrative Change 1 dated 29 June 2018.
Rationale:  To clarify the title of the eCRF questionnaire that would need to be 
completed in the event of an active Hepatitis B infection.
●
Update the primary contact in Section 7.0.
●
Update Section 8.1.2 Primary, Secondary, and Efficacy Analyses
Rationale:  To add clarification language on the pharmacokinetic analysis, 
and to clarify the section headers.
●
Update Section 8.1.7 Pharmacokinetic and Exposure-Response Analyses
●
Rationale:  To add clarification language on the pharmacokinetic analysis.
●
Update Appendix C Treatment Period footnote j as per prior Administrative 
Change 1 dated 29 June 2018.
Rationale:  To clarify in the table note j that FibroScan completion is required 
6 months prior to screening, consistent with other protocol sections.
●
Update Appendix C Treatment Period footnote h and Post Treatment Period 
footnote b.
Rationale:  To clarify the lab draw procedures for the coagulation panel.
●
Update Appendix C Post Treatment Period footnote f.
Rationale:  To clarify as to when the resistance sample should be drawn 
during the post treatment period.
●
Increase the overall number of subjects that the study will enroll.
Rationale:  To enroll an adequate number of subjects at the final proposed 
dose. 
●
Update Appendix D Estimated Blood Loss for Pediatric Subjects.
Rationale:  To reflect the maximum possible blood loss for visits as per 
updated blood loss calculations.
●
Update typographical errors throughout protocol.


Glecaprevir/Pibrentasvir
M16-123 Protocol Amendment 3
EudraCT 2016-004102-34
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An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


Glecaprevir/Pibrentasvir
M16-123 Protocol Amendment 3
EudraCT 2016-004102-34
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-123
Name of Study Drug:  Glecaprevir 
(GLE)/Pibrentasvir (PIB)
Phase of Development:  2/3
Name of Active Ingredient:
Glecaprevir (GLE)/Pibrentasvir (PIB)
Date of Protocol Synopsis:  22 March 2019
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Glecaprevir/Pibrentasvir in Pediatric Subjects with Genotypes 1 – 6 Chronic Hepatitis C 
Virus (HCV) Infection (DORA)
Objective:  Assess the pharmacokinetics, safety, and efficacy of GLE/PIB in pediatric subjects.
Investigator:  Multicenter
Study Site:  Approximately 40 sites globally
Study Population:  HCV genotype 1 – 6-infected pediatric subjects ≥ 3 to < 18 years of age, who are 
either treatment-naïve, treatment-experienced to interferon (IFN – alpha, beta or pegylated interferon 
[pegIFN]) with or without ribavirin (RBV) or treatment-experienced to sofosbuvir with IFN and/or 
RBV.  Subjects may be non-cirrhotic or have compensated (Child-Pugh A) cirrhosis.  Subjects with 
HCV/HIV-1 co-infection are eligible for study inclusion.
Number of Subjects to be Enrolled:  Approximately 125 subjects
Methodology:  
The study will enroll approximately 125 HCV-infected pediatric subjects, divided into four (4) age 
groups, 3 to < 6, 6 to < 9, 9 to < 12, and 12 to < 18 years of age.  Enrollment will begin in Part 1 of the 
study, into the age group 12 to < 18 years old who are willing to swallow the adult formulation of 
GLE/PIB.  Part 2 of the study will enroll the remaining age groups; those will receive the pediatric 
formulation of GLE/PIB. 
Within each age group, approximately 12 HCV-infected pediatric subjects will be enrolled for intensive 
pharmacokinetics (IPK) in order to adequately characterize the pharmacokinetics (PK) of a particular age 
group for dose confirmation, and the remainder of subjects will be enrolled for the evaluation of safety 
and efficacy of each age group until the total pediatric study population reaches approximately 
125 subjects.  Additional PK assessments will be obtained for subjects enrolled in Japan for the purpose 
of further characterization within Japanese subjects; this is not included within the aforementioned 
12 subjects.
Intensive PK sampling is designed to allow for dose adjustment, based on available pharmacokinetic and 
clinical data to achieve therapeutic exposures that have been safe and efficacious in adult subjects.  Area 
under the concentration curve (AUC) will be the primary measure for dose adjustment.  The duration(s) 
of treatment will be 8, 12, or 16 weeks of therapy dependent on patient genotype, cirrhosis status, and 
prior HCV treatment history.
All subjects who receive at least one dose of study drug will be followed for 144 weeks after completing 
or prematurely discontinuing the study treatment to assess long-term safety and durability of SVR12.


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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female ≥ 3 to < 18 years of age at time of enrollment.
2.
HCV infection demonstrated by positive anti-HCV Ab and HCV RNA ≥ 1000 IU/ mL.
3.
Subject must have a weight consistent with the recommended weight band (Table 12) for their age 
at the time of screening.  Subjects that fall out of the weight band for their age at the time of 
screening may be screened only into the safety and efficacy parts of the study upon TA MD 
approval.
4.
Parent or legal guardian with the willingness and ability to provide written informed consent and 
subject willing and able to give assent, as appropriate for age and country.
Main Exclusion:  
1.
Females who are pregnant or breastfeeding.
2.
Positive test result for Hepatitis B surface antigen (HbsAg) or positive test result for HBV DNA.
3.
Subjects with other known liver diseases.
4.
Decompensated cirrhosis defined as:  presence of ascites, history of variceal bleeding, lab values 
consistent with Child's class B or C cirrhosis.
Investigational Products:
Adult formulation:  Glecaprevir/Pibrentasvir 100 mg/40 mg film-coated 
tablet
Pediatric formulation:  Glecaprevir/Pibrentasvir 15.67%+8.25% film-
coated pellets/granules
Proposed Doses:
Cohort
Age (yrs); 
Weight Band
GLE/PIB Dose
1
12 – < 18; 
≥ 45 kg
300 mg/120 mg
2
9 – < 12 
30 – < 45 kg
250 mg + 100 mg
3
6 – < 9; 
20 – < 30 kg
200 mg + 80 mg
4
3 – < 6; 
12 – < 20 kg
150 mg + 60 mg
  
Mode of Administration:
Oral, taken with food
Duration of Treatment:  All subjects will receive GLE/PIB for 8, 12, or 16 weeks depending on their 
genotype, cirrhosis, and prior treatment experience status.


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Criteria for Evaluation:
Pharmacokinetic:
Plasma concentrations of GLE and PIB will be determined at each study visit for each subject during the 
treatment period.  A single blood sample will be collected without regard to the time of dosing.  For 
those participating in the intensive pharmacokinetic sampling, samples will be collected at the Week 2 
visit immediately prior to dose (0 hour) and at 2, 4, 6, and 12 hours post dose.  The pre-dose blood 
sample (0 hour) will be used for steady state assessment of GLE and PIB.  For subjects enrolled in 
Japan, additional pharmacokinetic sampling will be collected at the Week 2 visit; samples will either be 
collected immediately prior to dose (0 hour) and at 2, 4, 6, and 12 hours post dose, or immediately prior 
to dose (0 hour) and at 2 and 4 hours post dose.
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each treatment and Post-Treatment Period visit.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.  Palatability/acceptability, for the pediatric formulation only, will also be 
assessed.
Resistance:
The polymorphisms at signature resistance-associated amino acid positions at baseline will be tabulated 
and summarized for all subjects receiving study drugs in Part 1.  For subjects in Part 2 of the study, 
baseline polymorphisms will be determined based on availability of samples.  For all subjects who 
experience virologic failure and have an HCV RNA ≥ 1000 IU/mL, post-baseline substitutions relative 
to the baseline sequence and to the appropriate prototypic reference sequence will be tabulated and 
summarized.
Statistical Methods:
Pharmacokinetic:
The primary endpoint will be steady state AUC of GLE and PIB estimated by non-compartmental 
pharmacokinetic analysis or population pharmacokinetic analysis, including AUC at Week 2 in subjects 
with intensive pharmacokinetics samples and AUC in all subjects with or without intensive PK samples.  
The main secondary endpoint is Cmax and clearance of GLE and PIB.  Non-compartmental 
pharmacokinetic analysis or population pharmacokinetic analysis will be performed using intensive or 
overall pharmacokinetic data to facilitate potential GLE and PIB dose modification in each age group.  
The distribution of AUC values for GLE and PIB in each age group corresponding to the final proposed 
doses will be estimated.  The 95% confidence interval for the geometric mean of AUC values will be 
calculated.  Other parameters including Cmax, Ctrough and clearance will be estimated and summarized for 
each age group, and summarized separately for subjects recruited in Japan.


Glecaprevir/Pibrentasvir
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8
Statistical Methods (Continued):
Efficacy:
The secondary endpoint is the percentage of subjects who achieve SVR12 overall and by age group.  The 
percentage will be calculated along with a 2-sided 95% confidence interval calculated using the normal 
approximation to the binomial distribution, unless the number of subjects who fail to achieve SVR12 is 
less than 5, where the Wilson's score method will be used for the confidence interval instead.
Additional secondary endpoints include the percentage of subjects who experience post-treatment 
relapse, the percentage of subjects who experience on-treatment virologic failure (i.e., breakthrough or 
failure to suppress at the end of treatment), and the percentage of subjects with new HCV infection 
(i.e., re-infection) at any time up to the last study visit.
Safety:
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term overall 
and by age group.  Laboratory samples will be collected at Baseline, at Weeks 2, 4, 8, 12 and 16 (if 
applicable depending on treatment duration) and at Post-Treatment Weeks 4 through 144.  Laboratory 
values that are potentially clinically significant, according to predefined criteria, will be identified, and 
the percentage of subjects with potentially clinically significant values during the Treatment Period will 
be summarized overall and by age group.  Palatability/acceptability will be assessed for the pediatric 
formulation only.  Additional summary statistics for safety data will be performed if deemed appropriate.
Resistance:
For all subjects receiving study drugs in Part 1, and subjects with available samples in Part 2 of the 
study, the polymorphisms at signature resistance-associated amino acid positions at baseline identified 
by next generation sequencing (NGS) and comparison to the appropriate prototypic reference sequence 
will be analyzed.
The following resistance information will be analyzed for all subjects receiving study drug who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
substitutions in available post-baseline samples identified by NGS and comparison to the baseline 
sequences, 2) the amino acid substitutions in available post baseline samples at signature resistance-
associated positions identified by NGS, and comparison to the appropriate prototypic reference 
sequence, and 3) the persistence of viral resistance by NGS.  


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M16-123 Protocol Amendment 3
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9
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADR
Adverse Drug Reaction
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AUC
Area under the concentration curve
aPTT
Activated partial thromboplastin time
APRI
Aspartate Aminotransferase to Platelet Ratio Index
ART
Antiretroviral Treatment
AST
Aspartate aminotransferase
BID
Twice Daily
BMI
Body mass index
BSA
Body surface area
BA
Bioavailability
BUN
Blood urea nitrogen
CDC
Center for Disease Control
CI
Confidence interval
CKD
Chronic kidney disease
CRF
Case report form
DAA
Direct-acting antiviral agent
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
DORA
DAA fOr CuRe of HepAtitis
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GLE
Glecaprevir


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GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropic
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV Ab
Human immunodeficiency virus antibody
HIV-1
Human immunodeficiency virus type 1
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
INR
International normalized ratio
IPK
Intensive pharmacokinetic 
iPSP
Initial Pediatric Study Plan
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
IU
International units
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
NS3
Nonstructural viral protein 3
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
PCR
Polymerase chain reaction
pegIFN
Pegylated-interferon alfa-2a or 2b
PI
Protease inhibitor
PIP
Pediatric Investigational Plan
PIB
Pibrentasvir
PK
Pharmacokinetic


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POR
Proof of Receipt
PRO
Patient Reported Outcomes
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SOF
Sofosbuvir
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
SVR4
Sustained virologic response 4 weeks Post-Treatment
SVR12
Sustained virologic response 12 weeks Post-Treatment
SVR24
Sustained virologic response 24 weeks Post-Treatment
TA MD
Therapeutic Area Medical Director 
TE
Treatment-experience
TE-PRS
Treatment-experience to interferon, pegylated interferon, ribavirin and/or sofosbuvir
TN
Treatment-naïve
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Women of Childbearing Potential
Definition of Terms
Study Drugs
Glecaprevir/Pibrentasvir
Screening Period
Up to 42 days prior to Study Day 1
Study Day 1
First day a subject takes study drugs
Treatment Period (TP)
Baseline/Study Day 1 through last dose of study drugs
Post-Treatment Period (PTP)
Day after the last dose of study drugs through Post-Treatment Week 144


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Pharmacokinetic and Statistical Abbreviations
AUC
Area under the concentration curve
Cmax
Maximum observed plasma concentration
Ctrough
Pre-dose trough plasma concentration


Glecaprevir/Pibrentasvir
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms..........................................9
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................31
3.2
Benefits and Risks....................................................................................31
3.3
Pediatric Study Plan and Pediatric Investigational Plan..........................32
4.0
Study Objective......................................................................33
4.1
Primary Objective ....................................................................................33
4.2
Secondary Objective ................................................................................33
5.0
Investigational Plan...............................................................34
5.1
Overall Study Design and Plan:  Description ..........................................34
5.1.1
Screening..................................................................................................38
5.1.1.1
Rescreening..............................................................................................38
5.1.2
Treatment Period (TP) .............................................................................39
5.1.3
Post-Treatment Period .............................................................................41
5.2
Selection of Study Population..................................................................42
5.2.1
Inclusion Criteria .....................................................................................42
5.2.2
Exclusion Criteria ....................................................................................44
5.2.3
Prior and Concomitant Therapy...............................................................46
5.2.3.1
Concomitant HIV-1 Antiretroviral Therapy ............................................47
5.2.3.2
Prior HCV Therapy..................................................................................48
5.2.3.3
Concomitant Therapy...............................................................................49
5.2.3.4
Prohibited Therapy...................................................................................49
5.2.4
Contraception Recommendations and Pregnancy Testing.......................51
5.3
Efficacy, Pharmacokinetic and Safety Assessments/Variables ...............52
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................52
5.3.1.1
Study Procedures .....................................................................................52
5.3.1.2
Meals and Dietary Requirements.............................................................66


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14
5.3.2
Drug Concentration Measurements .........................................................66
5.3.2.1
Collection of Samples for Analysis .........................................................66
5.3.2.2
Handling/Processing of Samples .............................................................68
5.3.2.3
Disposition of Samples ............................................................................68
5.3.2.4
Measurement Methods.............................................................................69
5.3.3
Primary and Secondary Variables............................................................69
5.3.3.1
Primary Variables ....................................................................................69
5.3.3.2
Secondary Variables ................................................................................69
5.3.4
HCV Resistance Variables.......................................................................70
5.3.5
Safety Variables.......................................................................................70
5.3.6
Growth and Development Variables........................................................71
5.3.7
Pharmacokinetic Variables ......................................................................71
5.4
Removal of Subjects from Therapy or Assessment.................................71
5.4.1
Discontinuation of Individual Subjects....................................................71
5.4.1.1
HCV Virologic Failure Criteria ...............................................................72
5.4.1.2
Failure to Maintain HIV Virologic Suppression......................................73
5.4.2
Discontinuation of Entire Study...............................................................74
5.5
Treatments................................................................................................74
5.5.1
Treatments Administered.........................................................................74
5.5.2
Identity of Investigational Products.........................................................76
5.5.2.1
Packaging and Labeling...........................................................................76
5.5.2.2
Storage and Disposition of Study Drugs..................................................77
5.5.3
Method of Assigning Subjects to Treatment Groups...............................78
5.5.4
Selection and Timing of Dose for Each Subject......................................78
5.5.5
Blinding....................................................................................................79
5.5.6
Treatment Compliance.............................................................................79
5.5.7
Drug Accountability.................................................................................80
5.6
Discussion and Justification of Study Design..........................................81
5.6.1
Discussion of Study Design .....................................................................81
5.6.2
Appropriateness of Measurements...........................................................82
5.6.3
Suitability of Subject Population .............................................................82
5.6.4
Selection of Doses in the Study ...............................................................82
5.6.5
Maximum Dose........................................................................................84


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6.0
Complaints .............................................................................84
6.1
Medical Complaints.................................................................................84
6.1.1
Definitions................................................................................................85
6.1.1.1
Adverse Event..........................................................................................85
6.1.1.2
Serious Adverse Events ...........................................................................85
6.1.2
Adverse Event Severity............................................................................87
6.1.3
Relationship to Study Drug......................................................................88
6.1.4
Adverse Event Collection Period.............................................................88
6.1.5
Adverse Event Reporting.........................................................................89
6.1.6
Pregnancy.................................................................................................90
6.1.7
Toxicity Management ..............................................................................91
6.1.7.1
Severe Adverse Events ............................................................................92
6.1.7.2
Management of ALT Elevations..............................................................92
6.2
Product Complaint ...................................................................................93
6.2.1
Definition .................................................................................................93
6.2.2
Reporting..................................................................................................94
7.0
Protocol Deviations................................................................94
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................95
8.1
Statistical and Analytical Plans................................................................95
8.1.1
Demographics ..........................................................................................96
8.1.2
Primary, Secondary, and Efficacy Analyses............................................97
8.1.2.1
Primary Endpoints ...................................................................................97
8.1.2.2
Secondary Endpoints ...............................................................................98
8.1.2.3
Additional Efficacy Endpoints.................................................................99
8.1.2.4
Subgroup Analysis .................................................................................100
8.1.2.5
Sensitivity Analysis ...............................................................................101
8.1.3
Growth and Development......................................................................101
8.1.4
Patient Reported Outcomes....................................................................101
8.1.5
Safety .....................................................................................................102
8.1.5.1
Adverse Events ......................................................................................102
8.1.5.2
Clinical Laboratory Data........................................................................103
8.1.5.3
Vital Signs Data .....................................................................................103


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8.1.6
Resistance Analysis ...............................................................................103
8.1.6.1
HCV Drug-Resistance Analyses............................................................103
8.1.6.2
HIV Drug-Resistance Analyses .............................................................107
8.1.7
Pharmacokinetic and Exposure-Response Analyses .............................107
8.2
Determination of Sample Size ...............................................................109
8.3
Randomization Methods ........................................................................109
9.0
Ethics.....................................................................................109
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................109
9.2
Ethical Conduct of the Study .................................................................110
9.3
Subject Information and Consent...........................................................110
9.3.1
Informed Consent Form and Explanatory Material (Japan Site 
Specific) .................................................................................................111
9.3.2
Revision of the Consent Form and Explanatory Material (Japan 
Site Specific)..........................................................................................112
10.0
Source Documents and Case Report Form 
Completion ...........................................................................112
10.1
Source Documents .................................................................................112
10.2
Case Report Forms.................................................................................112
11.0
Data Quality Assurance ......................................................114
12.0
Use of Information...............................................................114
13.0
Completion of the Study .....................................................114
14.0
Investigator's Agreement....................................................115
15.0
Reference List ......................................................................116
List of Tables
Table 1.
Pediatric Prevalence of HCV in the US (All Genotypes) ........................19
Table 2.
Overview of Clinical Studies by Subject Population...............................23
Table 3.
SVR12 Rates by Treatment Experience and HCV Genotype –
GT1 – 6 (ITT Population, Phase 2 and 3 Analysis Set)...........................24
Table 4.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set) ............................................................................................27
Table 5.
Treatment Regimen and Duration (Excluding Subjects in Japan)...........40


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Table 6.
Treatment Regimen and Duration (Subjects in Japan) ............................40
Table 7.
Prohibited Medications and Supplements................................................50
Table 8.
Clinical Laboratory Tests.........................................................................56
Table 9.
Child-Pugh Classification of Severity of Cirrhosis .................................62
Table 10.
Identity of Investigational Product...........................................................76
Table 11.
Proposed Glecaprevir and Pibrentasvir Doses for the Pediatric 
Population ................................................................................................83
Table 12.
Signature Amino Acid Positions and the Key Subset of Amino 
Acid Positions ........................................................................................104
List of Figures
Figure 1.
Study Schematic.......................................................................................36
Figure 2.
Adverse Event Collection ........................................................................89
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................119
Appendix B.
List of Protocol Signatories....................................................................121
Appendix C.
Study Activities......................................................................................122
Appendix D.
Estimated Blood Loss for Pediatric Subjects.........................................127
Appendix E.
Protocol Amendment:  List of Changes.................................................130


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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 184 million 
individuals infected worldwide.1  There are 7 identified HCV genotypes, with genotype 1 
(GT1) being the most prevalent worldwide.  HCV genotypes 2 (GT2) and 3 (GT3) 
infections are more common in Latin America (5% to 30%), Europe (20% to 40%) and 
Asia (30% to 45%).2-4  HCV GT4 is commonly found in parts of Africa and the Middle 
East, particularly in Egypt, GT5 is primarily found in South Africa, and GT6 is primarily 
found in south-east Asia, and GT7 has recently been described in Central Africa.5
Prevalence data, specific to the pediatric population, is also found in NHANES (Table 1).  
Prevalence estimates based on diagnosed pediatric cases of HCV infection are a small 
fraction compared to the overall anti-HCV antibody prevalence in this population, 
suggesting many children are not diagnosed during childhood.  The most robust estimates 
from NHANES come from NHANES III, which covered the years 1988 to 1994 where 
2,762 and 2,905 children ages 6 to 11 and 12 to 19 years, respectively, were screened.  
The prevalence of anti-HCV antibody was 0.2% for children 6 to 11 years and 0.4% for 
children 12 to 19 years during this timeframe (genotype [GT] was not specified).6  
Estimates from the 1999 through 2002 NHANES survey also indicate a prevalence of 
HCV antibody in 6- to 11-year-olds of 0.2% (95% confidence interval [CI] 0.04%, 0.6%) 
and 0.4% (95% CI 0.2%, 0.9%) in 7- to 19-year-olds (GT not specified).7  Similar low 
anti-HCV antibody prevalence rates of 0.1% were found in a cross-sectional, serologic 
survey of 1,034 urban children aged 1 to 11 years conducted in the years 2000 through 
2002 (GT not specified).8  In addition, a retrospective evaluation of dried heel stick blood 
spots from 2,806 live births in southern California in 2003 found an anti HCV antibody 
prevalence of 0.25% (GT not specified).9


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Table 1.
Pediatric Prevalence of HCV in the US (All Genotypes)
Population (N)
Results
Years
Source
NHANES
6 – 11 y (N = 2762)
12 – 19 y (N = 2905)
Anti-HCV 6 – 11 y 0.2%
(95% CI 0.04, 0.6%)
Anti-HCV 12 – 19 y 0.4%
(95% CI 0.2, 0.9%)
1988 – 1994
Alter 19996
Urban children 1 – 11 y
(N = 1034)
Anti-HCV 0.1%
2000 – 2002
El-Kamary 
20038
Dried heel stick blood spots 
from newborn infants in CA
(N = 2806)
Anti-HCV 0.25%
2003
Bradley 20119
Children < 19 y in Florida
(N = 4,103,700 in 2009)
Anti-HCV 0.035% (i.e., 1444/4, 
201, 700).  Mandatory reporting 
for anti-HCV:  1444 unique reports 
representing 11.7% of the expected 
population based on NHANES III 
estimated pediatric prevalence
2009
Delgado-
Borrego 20127
Optum Insight Beneficiaries
< 18 y (N = 2,229,472)
2 HCV diagnostic codes:  0.004%
2000 – 2009, 
annual 
prevalence for 
2009
Data on file, 
AbbVie
Florida Medicaid 
Beneficiaries < 18 y
(N = 2,493,472 includes 
adults and children; 579 
diagnosed with HCV and 
< 18 y)
2 HCV diagnostic codes:  0.033%
FY 1999 –
2009, annual 
prevalence for 
FY 2008 – 2009
Data on file, 
AbbVie
CI = confidence interval; FY = fiscal year; HCV = hepatitis C virus; NHANES = National Health and Nutrition 
Examination Survey; y = years
According to the Centers for Disease Control (CDC), the incidence of acute HCV 
infection (confirmed and reported) in the general population in the US was highest 
(2.4 cases per 100,000 population) in 1992;10 generally declined until 2003, remained 
relatively stable until 2010, and increased 75% from 2010 to 2012, with the largest 
increases occurring in the population aged 0 to 19 years.10,11  In the population aged 0 to 
19 years in the US, the incidence of acute HCV infection (confirmed and reported) 
decreased from 0.11 to 0.05 cases per 100,000 population from 2000 to 201010 but 
increased from 0.05 to 0.11 cases per 100,000 population from 2010 to 2012.11


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The primary differences in HCV infection between adults and pediatrics are differences in 
the mode of infection (e.g., perinatal transmission in children and increased intravenous 
drug abuse in adults) and natural history of disease.  Studies comparing the natural history 
of HCV infection in both adults and children have been limited by small sample sizes, 
with an average sample size of 22 patients.12  Despite this, progression to advanced liver 
disease appears to be less common in children than in adults, occurring in about 2% of 
pediatric patients.13  Duration of infection appears to be an important factor accounting for 
this difference.14  However, when histology was compared between 21 children and 
52 adults, the children had significantly milder histologic disease and alanine 
aminotransferase (ALT) elevations even after controlling for duration of disease and other 
potentially confounding variables.15  Differences in rates of severe disease and cirrhosis 
between adults and children may also be related to differences in exposure to alcohol, 
drugs, and superinfections more commonly found in adults.16  Extra hepatic 
manifestations of HCV are rare in children, which may also reflect slower disease 
progression in children.17
During the last 10 years, vertical transmission has become the primary mode of 
transmission in children, and transmission via transfusion or health care is exceedingly 
rare in developed countries.18  Therefore, appropriate serologic and virologic screening of 
infants born to HCV-infected mothers is a cornerstone of early diagnosis.  In infants, the 
presence of anti-HCV antibody may be due to passive transplacental passage from the 
mother.  Thus antibody testing for perinatal infection is unreliable until approximately 
12 to 18 months of age.  In patients with detectable antibody, diagnosis of chronic HCV 
infection is generally made by the persistence of HCV ribonucleic acid (RNA) for at least 
6 months.  In perinatal transmission, loss of HCV RNA could reflect transient viremia or 
a resolved infection.  The chronicity rate in perinatal transmission is high; spontaneous 
clearance generally occurs by the third year of life, and clearance beyond age 4 is 
unlikely.
According to the North American Society for Pediatric Gastroenterology, Hepatology, 
and Nutrition (NASPGHAN), all children aged 3 to 17 years who are chronically infected 


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with HCV may be considered candidates for treatment, and should be considered for 
treatment if they develop consistently elevated serum aminotransferase levels or liver 
fibrosis.19  The American Association for the Study of Liver Diseases (AASLD) 
recommends that DAA regimens should be recommended independent of disease severity, 
if a regimen is available dependent upon the child's age group.30  The combinations of 
ledipasvir/sofosbuvir, and sofosbuvir + ribavirin have been approved for use in 
adolescents, though neither combination covers all major genotypes alone.28,29  To date, 
there are no treatment regimens approved for use in HCV-infected patients aged 
< 3 years.  There are several studies of interferon-free regimens in children including 
sofosbuvir/ledipasvir for GT1 (NCT02249182), sofosbuvir (SOF) plus RBV for GT2 and 
3 (NCT02175758), and ombitasvir/paritaprevir/ritonavir with or without dasabuvir for 
GT1 and GT4 (NCT02486406).  Results with direct-acting antiviral (DAA) therapy are 
promising, showing high SVR12 rates in adolescents, similar to adults.  In one clinical 
trial, 100 adolescents with GT1 infection treated with sofosbuvir/ledipasvir achieved an 
SVR12 rate of 97%.21  A high SVR12 rate of 98% has also been in seen adolescents with 
GT2 and GT3 infection after treatment with SOF + RBV.22
AbbVie has developed two "next generation" DAAs Glecaprevir (GLE, formerly known 
as ABT-493), an HCV NS3/4A PI, and pibrentasvir (PIB, formerly known as ABT-530), 
an NS5A inhibitor, for use in combination for the treatment of HCV.  GLE and PIB each 
have potent in vitro antiviral activity against genotypes 1 through 6,23 and a high genetic 
barrier to resistance, with no or little loss of potency against common resistant-associated 
substitutions.  Additive or synergistic in vitro anti-HCV activity has been demonstrated 
with the combination of GLE and PIB.  GLE 100 mg and PIB 40 mg are co-formulated 
into a fixed-dose combination tablet (hereafter referred to as GLE/PIB), which provides 
adult patients with a convenient once-daily (QD), fixed-dose combination treatment 
regimen (three tablets QD) to maximize treatment compliance.  A pediatric formulation 
comprised of film-coated pellets/granules of GLE and PIB, respectively, in a single 
container for a convenient QD oral administration with a dosing vehicle has been 
developed.


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A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data can be found in the Investigator's Brochure.24
Glecaprevir and Pibrentasvir (GLE and PIB)
Overview of GLE/PIB Registrational Phase 3 Program and Supportive Phase 2 
Studies
The GLE/PIB registrational program included a broad subject population including 
subjects with compensated liver disease and subjects with severe renal insufficiency 
across all genotypes using a single GLE/PIB dose of 300 mg/120 mg QD.  Supportive 
Phase 2 studies used the Phase 2 formulation of separate GLE and PIB tablets, with each 
tablet containing 100 mg and 40 mg, respectively.  Treatment arms from these supportive 
Phase 2 studies using the regimen selected for registrational studies (GLE 300 mg plus 
PIB 120 mg) were pooled with arms from the registrational studies for analyses of 
efficacy and safety.  Treatment-naïve (TN) and treatment-experience (TE) subjects to any 
combination of pegylated IFN (pegIFN), RBV, SOF, NS5A inhibitors, or PIs were 
allowed in the program.  In addition, the program included subjects with human 
immunodeficiency virus (HIV) co-infection (Study M13-590), subjects with chronic 
kidney disease [CKD] Stages 4 – 5, including those on hemodialysis (Study M15-462), 
subjects with compensated cirrhosis (Studies M14-172, M15-462, and M14-868 Part 3), 
and subjects with or without cirrhosis who failed a previous regimen containing an NS5A 
inhibitor and/or an NS3/4A PI (Study M15-410).
A total of 2,376 subjects were randomized or enrolled in the registrational studies or 
supportive Phase 2 studies to receive GLE 300 mg QD and PIB 120 mg QD.  Of these, 
2,369 subjects received at least 1 dose of study drug (Table 2).


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


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duration, including any degree of renal impairment, presence of cirrhosis, or human 
immunodeficiency virus type 1 (HIV-1) co-infection (Table 3).
Among subjects with GT3 infection, the pooled SVR12 rates across durations were 95.2% 
among all subjects, 96.6% among cirrhotic subjects, and 100% among subjects with CKD 
Stages 4 – 5.  The SVR12 rates among subjects previously treated with a PI and/or NS5A 
inhibitor were ≥ 89.0% for GT1 and GT4.
Table 3.
SVR12 Rates by Treatment Experience and HCV Genotype –
GT1 – 6 (ITT Population, Phase 2 and 3 Analysis Set)
Genotype
TN
n/N (%)
95% CIa
TE-PRS
n/N (%)
95% CIa
TN + TE-PRS
TE-NS5A 
and/or PIs
n/N (%)
95% CIa
Overall
n/N (%)
95% CIa
Alla
Cirrhotic
n/N (%)
95% CIb
CKD 4–5
n/N (%)
95% CIb
Phase 2 
and 
3 Analysis 
Set
1604/1640 
(97.8)
97.1, 98.5
602/616 
(97.7)
96.6, 98.9
2206/2256 
(97.8)
97.2, 98.4
274/281 
(97.5)
95.7, 99.3
102/104 
(98.1)
95.4, 100.0
101/113 
(89.4)
83.7, 95.1
2307/2369 
(97.4)
96.7, 98.0
GT1
555/561 
(98.9)
98.1, 99.8
326/328 
(99.4)
98.5, 100.0
881/889 
(99.1)
98.5, 99.7
98/101 (97.0)
93.7, 100.0
53/55
(96.4)
91.4, 100.0
97/109 
(89.0)
83.1, 94.9
978/998c
(98.0)
97.1, 98.8
GT2
365/369 
(98.9)
97.9, 100.0
95/97
(97.9)
95.1, 100.0
460/466 
(98.7)
97.7, 99.7
35/35
(100)
100.0, 100.0
16/16
(100)
100.0, 100.0
N/A
460/466 
(98.7)
97.7, 99.7
GT3
499/521 
(95.8)
94.0, 97.5
113/122 
(92.6)
88.0, 97.3
612/643 
(95.2)
93.5, 96.8
112/116 
(96.6)
93.2, 99.9
11/11
(100)
100.0, 100.0
N/A
612/643 
(95.2)
93.5, 96.8
GT4
119/122 
(97.5)
94.8, 100.0
55/56
(98.2)
94.7, 100.0
174/178 
(97.8)
95.6, 99.9
20/20
(100)
100.0, 100.0
20/20
(100)
100.0, 100.0
4/4
(100)
100.0, 100.0
178/182 
(97.8)
95.7, 99.9
GT5
26/26 
(100)
100.0, 100.0
6/6
(100)
100.0, 100.0
32/32
(100)
100.0, 100.0
2/2
(100)
100.0, 100.0
1/1
(100)
100.0, 100.0
N/A
32/32
(100)
100.0, 100.0
GT6
40/41 
(97.6)
92.8, 100.0
7/7
(100)
100.0, 100.0
47/48
(97.9)
93.8, 100.0
7/7
(100)
100.0, 100.0
1/1
(100)
100.0, 100.0
N/A
47/48
(97.9)
93.8, 100.0


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Table 3.
SVR12 Rates by Treatment Experience and HCV Genotype –
GT1 – 6 (ITT Population, Phase 2 and 3 Analysis Set) (Continued)
CI = confidence interval; CKD = chronic kidney disease; GT = genotype; HCV = hepatitis C virus; 
ITT = intention-to-treat; N/A = not applicable; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; 
PRS = regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic 
response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naïve; TE-NS5A and/or PI = TE with 
NS5A inhibitor and/or PI
a.
CI was calculated using a stratum-weighted proportion and variance.
b.
CI was calculated using the normal approximation to the binomial distribution.
c.
Eleven subjects were classified by the central laboratory and treated as GT2 but included here as GT1 due to being 
identified as such by phylogenetic analysis; all 11 subjects achieved SVR12.  
Impact of Baseline Polymorphisms on Treatment Outcome
The association between baseline polymorphisms and treatment outcome in subjects who 
receive GLE 300 mg QD with PIB 120 mg QD in the registrational or supportive Phase 2 
studies was evaluated by conducting an integrated analysis of baseline sequence data.  
Next-generation sequencing (NGS) was conducted on all baseline samples at 15% 
detection threshold at key amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 
31, 58, 92, and 93 in NS5A. 
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% 
(1/34) of subjects with HCV genotype 1, 2, 3, 4, 5 and 6-infection, respectively.  Baseline 
polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% 
(136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV 
genotype 1, 2, 3, 4, 5, and 6-infection, respectively.
The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1, 2, 4, 5, or 6-infected subjects.
Within GT3-infected subjects, baseline polymorphisms in NS3 and the NS5A 
polymorphisms at positions 24, 28, 31, 58, 92, or 93 did not have an impact on treatment 
outcome.  


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Amino Acid Substitutions in Subjects Experiencing Virologic Failure
Among TN and TE-PRS subjects with or without cirrhosis treated for 8, 12, or 16 weeks, 
23 subjects experienced virologic failure (2 with GT1, 2 with GT2, and 19 with GT3).  A 
GT3 infected subject experiencing virologic failure was determined to have been 
re-infected with GT3a virus distinct from the one present at baseline.  Therefore, baseline 
polymorphisms and treatment-emergent substitutions were analyzed for 22 subjects 
experiencing virologic failure. 
Among the 2 GT1-infected subjects, 1 had treatment-emergent substitutions A156V in 
NS3 and Q30R/L31M/H58D in NS5A, and 1 had treatment-emergent Q30R/H58D (while 
Y93N was present at baseline and post-treatment) in NS5A.
Among the 2 GT2-infected subjects, no treatment-emergent substitutions were observed 
in NS3 or NS5A; the prevalent M31 polymorphism in NS5A was present at baseline and 
post-treatment in both subjects.
Among the 18 GT3-infected subjects, the majority of subjects had treatment-emergent 
variants at the time of failure in NS3 (61.1%, 11/18) and NS5A (88.9%, 16/18).  
Treatment emergent NS3 substitutions Y56H/N, Q80K/R, A156G, and Q168L/R were 
observed in 11 subjects, and A166S or Q168R was present at both baseline and 
post-treatment in 5 subjects.  Treatment-emergent NS5A substitutions M28G, A30G/K, 
L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n = 9) or 
Y93H (n = 5) at both baseline and post-treatment.
Integrated Safety Results
A summary of treatment-emergent adverse events (AEs) from pooled analyses of the 
registrational studies and supportive Phase 2 studies along with the AEs occurring with a  
frequency > 5% are headache, fatigue, nausea and diarrhea (Table 4).  The majority of 
subjects experienced an AE, which were mostly considered to be mild in severity by the 
investigator (Grade 1).  Rates of AEs that were serious, led to premature study drug 
discontinuation or had a severity Grade ≥ 3 were low.  Including data from 


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Study M15-462, there were 7 deaths, none of which were related to study drug, and the 
majority occurred several months after the last dose of study drug.
Table 4.
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set)
Phase 2 and 3 Analysis Seta
(N = 2,265)
n (%)
All Adverse Events
DAA-Related Adverse Eventsb
Any AE
1,529 (67.5)
929 (41.0)
An AE Grade ≥ 3
65 (2.9)
4 (0.2)
Any SAE
48 (2.1)
1 (< 0.1)
Discontinuation of study drug 
due to any AE
8 (0.4)
3 (0.1)
All deathsc
6 (0.3)
0
Preferred Termd
Headache
410 (18.1)
298 (13.2)
Fatigue
330 (14.6)
259 (11.4)
Nausea
208 (9.2)
172 (7.6)
Diarrhea
146 (6.4)
86 (3.8)
AE = adverse event; DAA = direct-acting antiviral agent; GLE = Glecaprevir; PIB = Pibrentasvir; SAE = serious 
adverse event
a.
Excludes Study M15-462.
b.
DAAs = GLE, PIB, or GLE/PIB.
c.
Includes nontreatment-emergent deaths.  One additional death occurred in Study M15-462.
d.
DAA-related AEs reported for ≥ 5.0% of subjects in the Phase 2 and 3 Analysis Set.
Adverse events in subjects without cirrhosis (n = 1,977) were similar in type, frequency, 
and severity compared with subjects with cirrhosis (n = 288).  The safety profile in 
subjects with HCV/HIV-1 co-infection (n = 33) was similar to that in HCV mono-infected 
subjects.  Overall, the safety profile of GLE/PIB in the elderly population (≥ 65 years old, 
n = 328) was comparable to the safety profile in the non-elderly population (n = 2,041).


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The frequency and severity of hepatic-related AEs as well as liver chemistry 
abnormalities evaluating potential hepatotoxicity were low across the Phase 2 and 
3 studies.  Liver-related safety results indicated that:
●
Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued 
study drug due to an ALT or bilirubin increase.
○
ALT abnormalities in 3 of these 4 subjects were not clinically significant.
○
One subject experienced concurrent ALT > 3 × ULN (increase from nadir 
grade) and total bilirubin ≥ 2 × ULN in the context of multiple gallstones 
and was not consistent with drug-induced liver injury.
●
Based on exposure-response analyses, no exposure-dependent ALT increases 
were observed in subjects with ALT abnormalities.
●
Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-
related AEs; none were associated with liver disease progression.
●
No subjects experienced drug-related hepatic decompensation.  One subject 
with cirrhosis (Study M14-172) who had known esophageal varices 
experienced an episode of esophageal varices hemorrhage that was considered 
not related to study drug.  Treatment was continued without clinical or 
laboratory signs of liver disease progression.
●
A total of 6 (0.3%) subjects experienced a de novo event of HCC.  In all 
6 subjects, the events were considered related to subject's medical history of 
underlying liver disease and not to GLE/PIB.
In summary, GLE/PIB demonstrated a favorable safety profile similar across durations of 
8, 12, and 16 weeks.  The regimen was well tolerated across a broad and diverse 
population of subjects, including subjects with cirrhosis, HIV co-infection, and CKD 
Stage 4 or 5. 
Common study drug-related AEs occurring in ≥ 5% of subjects were headache, fatigue 
and nausea.  Adverse drug reactions (ADRs) were mostly Grade 1 (mild) in severity.  
Serious AEs and AEs leading to premature study drug discontinuation were rare. 


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There were no hematological or blood chemistry findings of concern or considered likely 
related to treatment.  Unlike other protease inhibitors, no liver-related toxicities and no 
cases consistent with drug-induced liver injury were identified.  
The objectives of this study are to evaluate the efficacy and safety of GLE/PIB used 
together for the treatment of those with chronic HCV GT1 to 6-infection in the pediatric 
population.
Overview of GLE/PIB Phase 3 Clinical Studies in Japan
Two Phase 3 Studies (Studies M15-594 and M15-828) conducted in Japan enrolled 
332 adults with chronic HCV GT1 – GT3 infection who were treated with GLE/PIB 
300/120 mg QD for 8 or 12 weeks.  These studies included treatment-naïve, both IFN 
based-experienced and DAA-experienced subjects, subjects without cirrhosis and with 
compensated cirrhosis, and with or without severe renal impairment.  A high overall 
SVR12 rate of 98.3% was observed across DAA-naïve subjects treated with GLE/PIB at 
the recommended durations regardless of HCV genotype or comorbidities (cirrhosis or 
renal impairment).  In addition, a high SVR12 rate of 93.9% was observed in subjects with 
previous DAA-experience who were treated with GLE/PIB for 12 weeks.
The most common AEs (≥ 5% of subjects) across the two Japan Phase 3 studies were 
nasopharyngitis, pruritis, and headache.  The majority of TEAEs were Grade 1 or 2 in 
severity.  Serious TEAEs, and TEAEs leading to discontinuation of study drug were rare.  
No TEAE deemed related to GLE/PIB occurred in ≥ 5% of subjects across the 
two Japan Phase 3 studies.  There were no hematological or blood chemistry findings of 
concern.  No cases of DILI or hepatic decompensation were identified.  Overall, the type, 
frequency and severity of AEs in subjects with compensated cirrhosis were similar to 
subjects without cirrhosis.  In addition, no unique safety signal or toxicity was identified 
from the use of GLE/PIB in subjects with severe renal insufficiency including those on 
dialysis.


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GLE/PIB Dose Selection Strategy for the Pediatric Population
AbbVie's pediatric formulation development strategy is to develop a dosage form that 
provides suitable and flexible dosing across the pediatric age range of 3 to < 18 years.  
Development of a suitable pediatric formulation was guided by considerations of 
solubility, dose flexibility, stability, compatibility, and ease and reliability of the 
manufacturing process.  It is likely the adult tablets will be suitable for adolescent subjects 
12 years of age and older with weights ≥ 45 kg.  This population is able to swallow tablets 
and utilizing the adult tablet would enable earlier enrollment of this population. In Part 1 
of Study M16-123, a total of 47 adolescent subjects received daily administration of 
GLE/PIB 300 mg/120 mg. PK results showed that the exposures of GLE and PIB in 
HCV-infected adolescent subjects (12 to < 18 years of age) were similar to the exposures 
observed in HCV-infected adult subjects following administration of GLE/PIB 
300 mg/120 mg.
GLE and PIB exhibit low aqueous solubility.  Due to probable requirement of solvent(s) 
that are undesirable for pediatric patients for any oral solution, and 
 
 AbbVie developed a pediatric 
formulation based on the solid oral formulations used to manufacture the adult tablets.  
To provide exposures in pediatric subjects comparable to adult exposures using the 
pediatric formulation, the GLE and PIB dose in pediatric patients of 3 to < 12 years of age
were revised from originally proposed doses.  Preliminary PK results from the initial 


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proposed pediatric doses demonstrated that though GLE and PIB exposures were within 
the range of exposure for efficacy and safety in adults for each of the pediatric cohorts, the 
average exposures in each of the cohorts were lower than the targeted AUC and led to a 
dose adjustment. Additional subjects were enrolled and the intensive PK results obtained, 
and additional population PK modeling performed, confirming that the adjusted doses 
demonstrate exposures that would allow for bridging of adult data, using a 50/20 mg dose 
ratio.  These doses (Table 11) are proposed to be used in the subjects enrolling in the non-
IPK portion of Part 2, in order to confirm that the doses would provide similar exposures 
observed in HCV-infected adult subjects, close to the targeted AUC.
3.1
Differences Statement
This is the first study to evaluate the pharmacokinetics, efficacy and safety of GLE/PIB in 
HCV-infected pediatric subjects (under 18 years old).  The pharmacokinetics, safety, and 
efficacy of the adult formulation of GLE/PIB will be evaluated in Part 1 in 12 to 
< 18 years of age who can swallow the adult formulation.  Part 2 will evaluate the 
pharmacokinetics, safety, and efficacy of the pediatric formulation in 3 to < 12 years of 
age.  The study populations for Part 1 and Part 2 will include GT1 – 6 infected subjects 
with or without compensated cirrhosis.  Those subjects undergoing intensive 
pharmacokinetic (IPK) analysis must be HCV treatment naïve and HIV negative.  
Subjects who are treatment experienced (prior IFN, peg-IFN, RBV, SOF) and/or 
co-infected with HIV-1 may enroll in the safety and efficacy portion of the study.  
Long-term safety and efficacy will be evaluated in a 144-week Post-Treatment Period for 
all subjects enrolled.
3.2
Benefits and Risks
Efficacy of GLE/PIB has been demonstrated in adult subjects with chronic HCV infection 
within the GLE/PIB Registrational program.  Since there is no difference in disease 
symptomatology and only minor differences in the natural progression of disease between 
adults and children, which are largely age related, the effectiveness of GLE/PIB against 
chronic HCV infection is expected to be similar between the two populations.  Part 1 of 


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this study encompasses those who are between the ages of 12 to < 18 years of age, and 
who are able to swallow the adult co-formulated fixed-dose tablets.  Eligible subjects will 
receive GLE/PIB for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, 
and prior treatment experience in accordance with each developmental program (Global 
and Japan) for the use of GLE/PIB in adults.  Part 2 of this study encompasses those who 
are between the ages of 3 to < 12 years of age who will take the pediatric formulation.  
Study drug duration will be for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis 
status, and prior treatment experience in accordance with each developmental program 
(Global and Japan) for the use of GLE/PIB in adults.  
In the pediatric population, the risks associated with GLE/PIB, which have been limited 
and manageable to date, are anticipated to be similar to the adult population.  The efficacy 
of this regimen has not yet been defined in pediatric populations, and it is possible that the 
treatment failure rate may be higher than what was observed in the Phase 3 trials in adults.  
Adverse events that are known, and those not previously described, may occur with the 
combination of the two DAAs, as detailed in the informed consent for this study.  In 
addition, subjects may experience inconvenience or discomfort related to the study visits 
or study procedures.  Additional safety data for each DAA alone and in combination are 
detailed above and in the Investigator's Brochure.
Given the potential high SVR rate in populations of HCV-infected subjects, the benefit-
risk profile for co-administered GLE/PIB as treatment for chronic HCV infection is 
favorable.
3.3
Pediatric Study Plan and Pediatric Investigational Plan
This study design was developed in accordance with the agreed initial Pediatric Study 
Plan (iPSP) and Pediatric Investigational Plan (PIP) for GLE/PIB for the treatment of 
Hepatitis C virus infection (IND Number 127,416, Reference ID:  3959249; EMA 
reference EMEA-001832-PIP01-15).


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The Pediatric Committee (PDCO) of the European Medicines Agency (EMA) issued a 
positive opinion on the PIP for GLE/PIB on April 29, 2016.  Upon AbbVie request, a 
waiver was granted for the pediatric population younger than 3 years of age "on the 
grounds that the specific medicinal product does not represent a significant benefit over 
existing treatment for pediatric patients" in this age group.  
Similarly, on July 15, 2016, the FDA confirmed its agreement with the iPSP for GLE/PIB, 
dated June 16, 2016.  In the agreed iPSP, AbbVie indicated its plans to request a waiver 
for the pediatric population younger than 3 years of age.  On December 14, 2016, AbbVie 
submitted its waiver request as part of the original New Drug Application (NDA) 209394 
(eCTD Sequence 0000).  On August 03, 2017, FDA waived the pediatric requirement for 
children younger than 3 years of age because the necessary studies are impossible or 
highly impracticable (Reference ID:  4134372).
4.0
Study Objective
4.1
Primary Objective
The primary objectives are to:
●
assess the steady state AUC, and to assess the pharmacokinetics (PK) of 
GLE/PIB in pediatric subjects following multiple dosing by age group;
●
evaluate the safety and tolerability of GLE/PIB by age group, cirrhosis status 
and across all subjects
4.2
Secondary Objective
The secondary objectives are to assess:
●
Cmax and clearance of GLE and PIB,
●
The percentage of subjects with sustained virologic response for 12 weeks post 
treatment (SVR12) in HCV GT1 – 6 infected pediatric subjects summarized for 
each age group and overall;


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●
The percentage of subjects with on-treatment HCV virologic failure 
(i.e., breakthrough or failure to suppress at the end of treatment) summarized 
for each age group and overall;
●
The percentage of subjects with post-treatment HCV relapse summarized for 
each age group and overall;
●
The percentage of subjects with new HCV infection (or re-infection) 
summarized for each age group and overall;
●
Pharmacokinetics and emergence/persistence of viral variants in subjects with 
available samples;
●
Palatability/acceptability of pediatric formulation.
The pharmacokinetic primary and secondary objectives for subjects enrolled in Japan will 
be summarized separately.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study is designed to enroll approximately 125 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.  All subjects must 
undergo a mandatory Fibrosis Assessment prior to enrollment into Part 1 or Part 2 of the 
study (refer to Section 5.3.1.1 for more details).
Part 1 of the study allows for enrollment of approximately 44 HCV infected, GT1 – 6 
pediatric subjects into the 12 to < 18 years old age group who weigh ≥ 45 kg and are able 
to swallow (whole tablets – without crushing or breaking) the adult formulation of 
GLE/PIB.  Part 2 of the study allows for enrollment of approximately 81 HCV infected, 
GT1 – 6 pediatric subjects divided into the 3 to < 6, 6 to < 9 and 9 to < 12 years old age 
groups.  Subjects will receive the pediatric formulation of GLE/PIB in Part 2.  


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Each age group in Part 1 and Part 2 will enroll approximately 12 HCV infected subjects to 
adequately characterize the pharmacokinetics of a particular age group.  Those individuals 
will undergo an intensive PK sample draw at the Week 2 visit with blood samples taken 
immediately prior to dose (0 hour) and at 2, 4, 6, and 12 hours post dose.  After the 
approximately first six (6) subjects per age cohort complete the intensive PK at the 
Week 2 visit, the PK samples of those subjects will be analyzed to determine dose 
adjustments of GLE/PIB in an age cohort, if needed.  After the intensive PK analysis 
results are available, enrollment will resume with approximately six (6) additional 
subjects per age cohort and intensive PK of all approximately twelve (12) subjects will be 
evaluated to determine if the study drug doses have achieved therapeutic exposures which 
have been demonstrated to be safe and efficacious in adult subjects.  Additional subjects 
may be required for further intensive PK analysis per age cohort if therapeutic exposure 
targets have not been achieved.  Once doses have been confirmed based on intensive PK 
data for a respective age group, enrollment into the safety/efficacy portion of that age 
group may begin.
For each subject enrolled into the intensive PK portion, the initial dose of GLE/PIB will 
be based on the subject's body weight and age at screening (Table 11).  Enrollment will 
first start into the intensive PK portion of Part 1 for the 12 to < 18 years old age group.  
Once the pediatric study drug formulation is available, Part 2 enrollment will be opened.  
Pediatric subjects will be enrolled first into the intensive PK portion of each of the Part 2 
age groups (3 to < 6, 6 to < 9, and 9 to < 12 years) in parallel.
Enrollment for subjects in Japan in Part 1 and Part 2 will start upon dose confirmation of 
the intensive PK portions of the study.  Eligible Japanese subjects will be given the option 
to participate in Japan specific intensive PK sampling (J-IPK) to maximize data collection 
and to better characterize GLE and PIB exposures in children in Japan.  Consent to collect 
blood samples up to 12 hours post dose (0, 2, 4, 6, and 12 hours) will be requested of all 
participants from Japan.  However, if patients are not willing to participate in the J-IPK 
portion of the study then a reduced number of PK samples will be collected at the Week 2 


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visit immediately prior to dose (0 hour) and at 2 and 4 hours post dose.  At least 2 to 
3 subjects will be enrolled in each of the age cohorts in Part 1 and Part 2 at sites in Japan.
Figure 1.
Study Schematic
The intensive PK portions of Part 1 and Part 2 will allow enrollment of pediatric subjects
with or without compensated cirrhosis who are treatment naïve and who meet the weight 
bands for their age (Table 11).  The HCV genotype must be identified (i.e., Screening 
laboratory result indicating HCV genotype 1, 2, 3, 4, 5, or 6-infection) for those 
participating in the intensive PK portions of the study.  The safety/efficacy portion of both 
Part 1 and Part 2 will include pediatric patients with or without compensated cirrhosis that 
are treatment naïve or treatment experienced (prior IFN [alpha, beta or pegIFN], RBV or 
SOF exposure), with or without HIV-1 co-infection, or subjects with mixed or 
indeterminate HCV genotype.  
Pediatric subjects that fall outside of the weight bands for their age (Table 11) may be 
included in the safety and efficacy parts of Part 1 and Part 2 only with approval of the 
AbbVie Therapeutic Area Medical Director after consideration of risks and benefits.  All 


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subjects will receive GLE/PIB for 8, 12 or 16 weeks, depending on their HCV genotype, 
cirrhosis and prior HCV treatment status.  No dose adjustments of GLE/PIB will be made 
as a consequence of weight change during the Treatment Period.  For patients with an 
indeterminate or mixed genotype including GT3, treatment duration will default to the 
respective GT3 duration based upon treatment-experience and cirrhosis status.  Patients 
with a mixed GT other than GT3, treatment duration will default to the longer treatment 
duration based on GT, treatment-experience and cirrhosis status.
Both Parts 1 and 2 will consist of a Screening Period (Section 5.1.1), a Treatment Period 
(Section 5.1.2), and a Post Treatment Period (Section 5.1.3).  Subjects who prematurely 
discontinue during the Treatment Period in Part 1 or Part 2 will be followed-up in the 
Post-Treatment Period through Week 144.  After completing the Treatment Period in 
Part 1 or Part 2, the subjects will be followed-up for 144 weeks in the Post-Treatment 
Period.  Subjects who prematurely discontinue from the Post-Treatment Period will be 
discontinued from the study.
The pharmacokinetic and clinical data from age groups of 3 to < 6, 6 to < 9, and 9 to 
< 12 years old may be combined for final analyses if exposures from these three (3) age 
groups are comparable to each other.
In both Parts 1 and 2, for each of the analytes (GLE and PIB), the geometric mean and 
individual AUC values from these pediatric subjects from the Week 2 intensive PK 
sampling will be compared with the distribution of individual AUCs across Phase 2/3 
studies in adults on an ongoing basis.  Dose adjustments may be made for each 
component of the DAA regimen if the respective geometric mean AUC in pediatric 
subjects is significantly deviated from the geometric mean AUC values in adults.  
AUC will be the primary measure for dose adjustment.  Other pharmacokinetic exposure 
parameters including Cmax and Ctrough will be considered to provide similar therapeutic 
exposures that have been safe and efficacious in adult subjects. 


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Additional safety and efficacy criteria may be considered for making dose adjustment 
decisions for Parts 1 and 2 to ensure safe and efficacious exposures.  
5.1.1
Screening
Prior to any study specific procedures being performed on the subject at the Screening 
Visit for Part 1 or Part 2, parent(s)/guardian(s) must provide written (signed and dated) 
informed consent and the subject must provide assent (as appropriate for age and country) 
respectively.
Subjects will receive a unique subject number via the Interactive Response Technology 
(IRT) system and will undergo the study procedures identified in Section 5.3.1 associated 
with the Screening Visit.  The investigator or his/her designated and qualified 
representatives will evaluate whether the subject meets all of the eligibility criteria 
specified in Section 5.2.1 and Section 5.2.2 for the Part in which they are enrolling during 
the period from the Screening Visit through Study Day 1 prior to dosing and record the 
results of this assessment and the details of the informed consent and assent process in the 
subject's medical records.
Eligible subjects have up to 42 days following the Screening Visit to enroll into Part 1 or 
Part 2 of the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to retest or rescreen:
●
A positive Hepatitis B surface antigen (HBsAg);
●
Hepatitis B DNA > lower limit of quantitation (LLOQ);
●
A positive serum pregnancy test (if female).
Otherwise, subjects may be retested or rescreened only once before requiring approval 
from the Primary Therapeutic Area Medical Director to rescreen again.
Retesting:


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Subjects who have exclusionary laboratory parameter(s) per Exclusion Criterion 8 
(Section 5.2.2) are allowed to retest on the related panel(s) (e.g., exclusionary albumin 
requires a repeat chemistry panel) within the same screening period and must meet all 
other eligibility laboratory criteria on the panel that is repeated.  If the retest result(s) are 
also exclusionary, the subject may only be rescreened or retested again with approval 
from the Primary Therapeutic Area Medical Director.
Rescreening:
Subjects that exceed the initial 42-day screening period should be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary at the 
first screening attempt (with the exception of HBsAg, Hepatitis B virus (HBV) DNA, and 
positive serum pregnancy test) (Section 5.2.2).
The Primary Therapeutic Area Medical Director should be contacted for approval prior to 
rescreening.  Subjects that are beyond the initial 42-day screening period may still be 
allowed to enroll within a reasonable time period if they continue to meet all eligibility 
criteria and have received approval by the Primary Therapeutic Area Medical Director.  If 
rescreened, the 42 day screening period restarts, and subjects retain their initial subject 
number.
For subjects who rescreen and still do not meet the study eligibility criteria upon 
retest/rescreen, the site personnel must register the subject as a screen failure in both IRT 
and electronic data capture (EDC) systems.
5.1.2
Treatment Period (TP)
After meeting all the eligibility criteria, subjects will be enrolled to a study regimen 
according to their genotype, cirrhosis and prior HCV treatment status as shown in Table 5.  
for global subjects and Table 6 for subjects in Japan.  The treatment duration for subjects 
in Japan is consistent with the currently proposed label in Japan.  There are some minor 
differences from the Global regimen, mostly in subpopulations not common in Japan 


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(e.g., GT5 and 6) after review of the Japan specific Registrational program, consisting of 
majority GT1 and 2.
Table 5.
Treatment Regimen and Duration (Excluding Subjects in Japan)
Patient Population
Duration
GT1 – 6 NC, TN
8 weeks
GT1, 2, 4 – 6 NC, TE
GT1 – 6 C, TN
12 weeks
GT1, 2, 4 – 6 C, TE
GT3 TE
16 weeks
Legend:  C = Cirrhotic; NC = Non-Cirrhotic; TE = Treatment experienced to IFN (alpha, beta or pegIFN) ± RBV or 
SOF/RBV ± pegIFN; TN = Treatment Naïve
Table 6.
Treatment Regimen and Duration (Subjects in Japan) 
Patient Population
Duration
GT1 – 2 NC, TN, TE – IFN
8 weeks
GT1 – 2 C, TN, TE – IFN
12 weeks
GT3 – 6 NC, C, TN, TE – IFN
GT1 – 6 TE – SOF
Legend:  C = Cirrhotic; NC = Non-Cirrhotic; TE – IFN = Japan Treatment experienced to IFN (alpha, beta or pegIFN) ± 
RBV; TE – SOF = Japan Treatment experienced to SOF/RBV; TN = Treatment Naïve
GLE/PIB will be administered as described in Section 5.5.1 (Treatments Administered).  
Subjects and their parent(s)/guardian(s) will receive instructions about the study drugs at 
the Day 1 Visit.  The study drugs will be dispensed at the visits as indicated in 
Appendix C.
After the Day 1 visit, all subjects will continue to return to the site on an outpatient basis 
for the study visits and procedures as identified in Appendix C.  Subjects could also return 
to the site for an unscheduled study visit for additional safety assessments if the 
investigator or sponsor feels it is necessary.  Sites should ensure that subjects adhere to 
the study visits listed in Appendix C.  Subjects who cannot complete their study visit per 
the visit schedule should ensure they do not run out of study drug prior to their next study 


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visit.  Study drug compliance is critical to ensure adequate drug exposure and optimal 
treatment outcome. 
Virologic failure criteria will be evaluated and applied by the Investigator as detailed in 
Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.5.1.  Ideally, this should occur on the day of 
study drug discontinuation, but is recommended to be no later than 2 days after their final 
dose of study drug and prior to the initiation of any other anti-HCV therapy if applicable.  
Following completion or premature discontinuation of study drug treatment, all subjects 
in either Part 1 or Part 2 will be followed in the associated Post-Treatment Period of 
Part 1 or Part 2.
5.1.3
Post-Treatment Period
All subjects who receive at least one dose of the study drug will enter into the 
Post-Treatment Period.  The Post-Treatment will begin the day following the last dose of 
study drug treatment and continue through Week 144 as outlined in Appendix C.  
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a discontinuation visit and undergo the study procedures as outlined in 
Appendix C.
Subjects may also return to the site for an unscheduled study visit for additional safety 
assessments if the investigator or sponsor feels it is necessary.
The Post Treatment Period will assess safety, antiviral response, and growth and 
development.
Growth and development will be assessed using BMI, weight z score, height z score, and 
growth rate at Post-Treatment Weeks 12, 48, 96, 144.  Growth rate is defined as the 
change in height over change in age from the previous visit.


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5.2
Selection of Study Population
The study population in Parts 1 and 2 consists of HCV genotype 1 – 6-infected pediatric 
subjects (ages 3 < 18 years of age) with or without compensated cirrhosis who are naïve 
to HCV treatment or who are IFN (IFN or pegIFN with or without RBV) or SOF/RBV 
treatment experienced.  Subjects who are co-infected with HIV-1 may be enrolled in the 
study.
Subjects who meet the inclusion criteria and who do not meet any of the exclusion criteria 
will be eligible for enrollment into the study.  
5.2.1
Inclusion Criteria
1.
Male or female ≥ 3 to < 18 years of age at time of enrollment.
2.
Willingness to participate in the study for up to 40 months.
3.
If female, subject must be either pre-menarche and not sexually active, 
permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy) OR for Women of Childbearing Potential (WOCBP) practicing at 
least one protocol specified method of birth control (Section 5.2.4), starting at 
Screening through at least 30 days after the last dose of study drug.


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For male subjects, no contraception is required.
4.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.
Females of non-childbearing potential (as defined above) at Screening do not 
require pregnancy testing.
5.
Subject has positive anti-HCV Ab and plasma HCV RNA viral load ≥ 1000 IU/mL 
at Screening Visit.
6.
Chronic HCV infection defined as being positive for anti-HCV antibody (Ab) or 
HCV RNA at least 6 months before Screening.
7.
Subjects participating in the intensive pharmacokinetic part, must be HCV 
treatment-naïve, with or without compensated cirrhosis (Child-Pugh A), HIV-1 
negative and must have a Screening laboratory result indicating HCV genotype 1, 
2, 3, 4, 5, or 6-infection.
8.
Subject screened into the safety and efficacy part must be HCV treatment-naïve 
(i.e., subject has not received a single dose of any approved or investigational anti-
HCV medication) or HCV treatment experienced (subject has failed prior treatment 
with IFN [alpha, beta or pegIFN] with or without RBV or sofosbuvir with RBV 
with or without pegIFN), with or without compensated cirrhosis.  Previous HCV 
treatment must have been completed ≥ 2 months prior to screening.
9.
Subject co-infected with HIV-1 must be on a stable antiretroviral therapy (ART) 
for at least 8 weeks prior to screening, consisting of the qualifying ART regimens 
as outlined in Section 5.2.3.1 (Concomitant HIV-1 Antiretroviral Therapy).  HIV-
co-infected subjects are eligible for enrollment into the safety and efficacy parts of 
the study.
10.
Subjects on a stable ART regimen must have the following:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening, and
●
Plasma HIV-1 RNA less than 50 copies/mL at Screening (by the COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once during the 


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12 months prior to Screening (by an approved plasma HIV-1 RNA quantitative 
assay including but not limited to:  COBAS® Ampliprep/COBAS® Taqman 
HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay).
11.
Subject must have a weight consistent with the recommended weight band 
(Table 11) for their age at the time of screening.  Subjects that fall out of the weight 
band (Table 11) for their age at the time of screening, may be screened into the 
safety and efficacy parts of the study upon therapeutic area medical director (TA 
MD) approval.
12.
For subjects in Part 1:  Willingness to swallow tablets. 
13.
Parent or legal guardian with the willingness and ability to provide written 
informed consent and subject willing and able to give assent, as appropriate for age 
and country.
Rationale for Inclusion Criteria
1, 2, 5 – 12 
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation
3, 4
The impact of GLE/PIB on pregnancies has not been established.  
However, assessment of the complete nonclinical reproductive 
toxicology studies indicates that there is no drug-related effect on 
teratogenicity/fetotoxicity.  In addition, the compounds are non-
genotoxic
13
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.


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2.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
3.
Clinically significant abnormalities or co-morbidities, other than HCV infection 
that make the subject an unsuitable candidate for this study in the opinion of the 
investigator.
4.
Any cause of liver disease other than chronic HCV infection including but not 
limited to the following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Steatohepatitis on liver biopsy considered to be the primary cause of the liver 
disease rather than concomitant/incidental with HCV infection.
5.
Current HBV infection on screening tests, defined as:
●
A positive test result for HBsAg, or 
●
HBV DNA > LLOQ in subjects with isolated positive Anti-HBc (i.e., negative
HBsAg and Anti-Hbs).
6.
Current enrollment in another interventional clinical study, previous enrollment in 
this study, prior or current use of any investigational DAA or commercially 
available anti-HCV agents (other than IFN [alpha, beta or pegIFN], RBV or SOF), 
including telaprevir, boceprevir, ombitasvir, dasabuvir, paritaprevir, ledipasvir, 
velpatasvir, daclatasvir, simeprevir, elbasvir or grazoprevir.
7.
History of solid organ transplant.
8.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Albumin < 2.8 g/dL


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●
Platelets < 40,000 cells per mm3
●
Direct bilirubin > 2.0 mg/dL
9.
Any current or past clinical evidence of Child-Pugh B or C Classification 
(Child-Pugh Score ≥ 7) or clinical history of liver decompensation such as ascites
(noted on physical exam), variceal bleeding or hepatic encephalopathy.
10.
Confirmed presence of hepatocellular carcinoma indicated on imaging techniques 
such as computed tomography (CT) scan or magnetic resonance imaging (MRI) 
within 3 months prior to Screening or on an ultrasound performed at Screening for 
subjects with cirrhosis (a positive ultrasound result will be confirmed with CT scan 
or MRI).
11.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive Glecaprevir/Pibrentasvir.
12.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drugs.
13.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 3, 5, 7 – 13
To ensure safety of the subjects throughout the study
2, 6
To avoid bias for the evaluation of efficacy and safety, including 
concomitant use of other medications
4
To exclude subjects with liver diseases other than chronic HCV GT1 
to 6 infection
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
the consent through the Treatment Period and 30 days after study drugs are stopped, must 
be recorded in the electronic case report form (eCRF) along with the reason for use, 


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date(s) of administration including start and end dates, and dosage information including 
dose, route and frequency.  The investigator should review all concomitant medications 
for any potential interactions.
For subjects on an HIV-1 ART:  information regarding each subjects qualifying, stable 
HIV-1 ART medications including start date, dose and frequency will be recorded into the 
eCRF at Screening.  In addition, subjects will be requested to record in a HIV-1 
Medication Card, the information for the last two doses of their HIV-1 ART medications 
taken (dosing dates, times, and number of pills) prior to the study visits detailed in 
Appendix C, and site personnel will record this information in the eCRF.
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in EDC.  The AbbVie Primary Therapeutic Area Medical Director should be contacted if 
there are any questions regarding concomitant or prior therapies.
5.2.3.1
Concomitant HIV-1 Antiretroviral Therapy
Qualifying HIV-1 Antiretrovirals allowed within this study are as follows:
●
Raltegravir (RAL) PO BID
●
Dolutegravir (DTG) PO QD or PO BID
●
Rilpivirine (RPV) PO QD
●
Tenofovir disoproxil fumarate (TDF) PO QD 
●
Tenofovir alafenamide (TAF) PO QD
●
Abacavir (ABC) PO QD or BID
●
Emtricitabine (FTC) PO QD 
●
Lamivudine (3TC) PO QD or BID


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Subjects receiving any other HIV-1 Antiretroviral in addition to those noted above would 
not be eligible for enrollment in the study.
5.2.3.2
Prior HCV Therapy
For Parts 1 and 2, prior or current use of any investigational or commercially available 
anti-HCV agents other than IFN, pegIFN, RBV, or SOF, excludes a subject from this 
study.  Subjects who previously participated in trials of investigational anti-HCV agents 
may be enrolled if they can produce documentation that they received only placebo or 
only SOF/RBV.
Subjects could be HCV treatment-naïve or prior treatment experienced.  Prior treatment, 
such as interferons, with or without RBV, or SOF plus RBV with or without pegIFN, is 
acceptable.  Subjects will be categorized as:
●
Treatment-naïve:  subject has never received any treatment for HCV infection.
●
Subjects with an allowed prior treatment will be categorized as:
○
Non-responder:  HCV RNA detected at the end of a prior treatment 
course (except for breakthrough, which is captured separately).  These 
subjects are further categorized as:
●
Null responder:  failed to achieve a 1 log10 IU/mL reduction in HCV 
RNA by Week 4 or a 2 log10 IU/mL reduction in HCV RNA by 
Week 12 during a prior treatment course;
●
Partial responder:  achieved at least a 2 log10 IU/mL reduction in HCV 
RNA by Week 12 during a prior treatment course but failed to achieve 
HCV RNA undetectable at the end of treatment;
●
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder.
○
Breakthrough:  confirmed ≥ 1 log10 IU/mL increase from nadir or 
achieved HCV RNA undetectable (or unquantifiable) during a prior 
treatment course but HCV RNA was quantifiable during or at the end of 
treatment.


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○
Relapse:  achieved HCV RNA undetectable at the end of a prior treatment 
course but HCV RNA was detectable following cessation of therapy.
○
Other:  subject received a prior treatment course and reason for not 
achieving SVR is other than above.
○
Unknown:  subject received a prior treatment course and reason for not 
achieving SVR is unknown.
Subjects must have discontinued prior therapy at least 2 months prior to the Screening 
Visit in order to be eligible for the study.
5.2.3.3
Concomitant Therapy
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions (DDI).  
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 14 days following discontinuation 
of study drugs, if applicable.
5.2.3.4
Prohibited Therapy
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 8 at least 14 days or 10 half-lives (whichever is longer) prior to the 
first dose of GLE/PIB and not use these during the entire Treatment Period and for 
14 days following discontinuation of study drugs.


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Table 7.
Prohibited Medications and Supplements
Medication or Supplement Name
Any herbal medicines or 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, etravirine, nevirapine
Pitavastatin, bosentan, oxcarbazepine, silodosin
Ethinyl estradiol-containing contraceptives
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drugs.  Subjects receiving these statins should either (a) switch to pravastatin or rosuvastatin 14 days or 
10 half-lives (whichever is longer) prior to the first dose of study drugs or (b) 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 either 1) reduce or limit the pravastatin 
or rosuvastatin dose in accordance with the GLE/PIB product label (if approved in the country); or 2) reduce the 
pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug if GLE/PIB is 
not yet approved in the country.
Use of ethinyl estradiol containing oral contraceptives with GLE and PIB combination 
was associated with ALT increases in some healthy female subjects.  Hormonal 
contraceptives (including oral, topical [including vaginal rings], injectable, or implantable 
varieties) containing ethinyl estradiol may not be used from 2 weeks prior to the first dose 
of GLE/PIB until 14 days after the end of GLE/PIB dosing.  Progestin-only 
contraceptives, such as those containing norethindrone, desogestrel, or levonorgestrel, 
without ethinyl estradiol, may be used with GLE/PIB.  Hormone replacement therapy 
i.e., estradiol, esterified or conjugated estrogens, as long as they do not contain ethinyl 
estradiol, may be used with GLE/PIB at the discretion of the Investigator.
GLE/PIB is not recommended for use in patients requiring stable cyclosporine doses 
> 100 mg per day.  GLE/PIB may be initiated in subjects receiving cyclosporine ≤ 100 mg 
per day and cyclosporine doses may be adjusted up to 400 mg per day following standard 
therapeutic monitoring practices.


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5.2.4
Contraception Recommendations and Pregnancy Testing
The contraception recommendations in this paragraph are summarized in relation to the 
potential risk of the investigational products used in this study.  All female subjects who 
are experiencing menses or are nearing sexual maturation in the opinion of the 
Investigator, or who are of child-bearing potential should undergo pregnancy testing 
according to Section 5.3.1.1.
If female, subject must be:
●
Pre-menarche and not sexually active, or 
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy), or 
●
Practicing at least one of the following methods of birth control, starting at 
Screening (or earlier) through at least 30 days after stopping study drug.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
●
Progestogen-only oral hormonal contraception, where inhibition of ovulation 
is not the primary mode of action, initiated at least 1 month prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success, and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.  Condom without 
spermicide is acceptable only in countries where spermicide is not available.
●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).


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●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
For Japan specific sites:  Note that both contraceptive sponge and vaginal ring with 
spermicidal jellies or creams are unapproved in Japan.
For male study subjects no contraception is required.
5.3
Efficacy, Pharmacokinetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section with 
the exception of the assessment of concomitant medications (Section 5.2.3), and the 
collection of adverse event information (Section 6.0).  All study data will be recorded in 
the subject's source documentation and then on the appropriate eCRFs, with the exception 
of laboratory data which will be provided to the Sponsor electronically from the 
laboratory(ies).
Informed Consent/Assent 
Signed study-specific informed consent and assent (as appropriate for age and country) 
will be obtained from the parent(s)/guardian(s) and subject before any study procedures 
are performed.  If a subject becomes of legal age during the course of the study, the 
subject will need to be consented using the approved informed consent form.  Details 


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about how informed consent and assent will be obtained and documented are provided in 
Section 9.3.
Medical History
A complete medical history, including history of tobacco, nicotine containing products 
and alcohol use, will be taken from each subject during the Screening Visit.  An updated 
medical history will be obtained prior to study drug administration and will serve as the 
baseline for clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C.  A 
symptom-directed physical examination may be performed at any other visit, when 
necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Vital Signs, Weight, Height and Body Mass Index (BMI)
Body temperature, blood pressure, pulse, body weight, height, and BMI will be measured 
at the visits specified in Appendix C, or upon subject discontinuation.  Blood pressure and 
pulse rate will be measured after the subject has been sitting for at least 3 minutes.  The 
vital signs performed on Study Day 1 will serve as the baseline for clinical assessment.  
Height will be measured standing without shoes using a stadiometer.
12-Lead Electrocardiogram
The ECG obtained at Screening will serve as the baseline assessment.  The ECG should 
be performed prior to blood collection.  An ECG can be performed at subsequent visits if 
deemed clinically necessary.  


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The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date ECG tracings and will provide 
his/her global interpretation as a written comment on the tracing using the following 
categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 8
at the visits indicated in Appendix C.
An overview about the volume of blood drawn for each of the study visits is listed in 
Appendix D of this protocol.  The Investigator/designee should refer to the local 
recommendations on blood drawn in pediatric patients (e.g., the guide on "Ethical 
Considerations for Clinical Trials on Medical Products With the Pediatric Population" or 
"Blood Drawing For Human Subject Research" by Duke University).  The 
Investigator/designee should document exceptions to the local blood loss 
recommendations in the subject's source along with a justification as appropriate.
At the Study Day 1 visit, a blood sample is to be collected prior to the first dose of study 
drug which is to be administered at site during the visit.  Subjects should be reminded to 
eat prior to their first dose of study drug after the sample is collected (e.g., suggest they 
bring a light snack).  Fasting status will be recorded in the source documents and on the 
laboratory requisition.  The baseline laboratory test results for clinical assessment for a 
particular test will be defined as the last measurement prior to the initial dose of study 
drug.


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A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  Instructions regarding the collection, processing, and shipping of these 
samples will be provided by the central laboratory chosen for this study.  The certified 
laboratory chosen for this study is Covance.  Samples will be sent to the following 
address: 
North and South American sites:
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, IN 46214-2985 USA
Tel: (317) 271-1200
Fax: (317) 273-4030
European sites:
Covance Central Laboratory Services
Rue Moïse-Marcinhes 7
1217 Meyrin/Genève-CH
Tel: +41 58-822-7000
Fax: +41 58-822-6999
Japanese sites: 
Covance Central Laboratory Services
c/o BML General Laboratory
1361-1, Matoba, Kawagoe City
Saitama, Japan 350-1101
Tel: +81-3-6837-9536
Fax: +81-3-6220-3667


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Table 8.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Additional Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Prothrombin Time/INRa
Activated partial thromboplastin
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubina,b
Direct and indirect bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Albumina
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Total protein
Glucose
Bicarbonate/CO2
Chloride
Magnesium
Creatinine clearance
(Cockcroft-Gault 
calculation for subjects 
≥12 years old and Schwartz 
formula for those < 12 years 
old)
Alpha2-macroglobulinb
Gamma-glutamyl transferase
(GGT)b
Haptoglobinb
Apolipoprotein A1b
Alpha fetoprotein
Gamma-globulind
Hyaluronated
eGFRJ (MDRD modified)e
Anti-HCV Abc
Anti-HIV Abc
FSHf
Urine and Serum
Human Chorionic
Gonadotropin (hCG)g
HCV RNA
HCV genotype and subtypec
HBsAgc,h
Anti-HBcIgMh
Anti-HBc Totalc,h
Anti-HBsc,h
HBV DNAk
Anti-HAVIgMh
Anti-HAVIgGh
Anti-HEVIgGh
Anti-HEVIgMh
HEV RNAh
HIV-1 RNAi
Flow Cytometryi
HIV Resistancej
Urinalysis
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Also a component of the Child-Pugh Assessment.
b.
Also a component of FibroTest.
c.
Performed at Screening.
d.
For Japan subjects only:  Component of Discriminant Score and collected only if needed during the Screening 
Period.
e.
eGFR calculated by the MDRD formula, modified for the Japanese population.
f.
Performed only at Screening.  FSH will be taken for female subjects aged ≥ 9 to <18 years old.


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Table 8.
Clinical Laboratory Tests (Continued)
g.
Serum and urine pregnancy testing only required for female subjects who are experiencing menses or are nearing 
sexual maturation in the opinion of the PI, or who are of child-bearing potential.
h.
Performed for management of transaminase elevation (Section 6.1.7.2).
i.
Only for HCV/HIV co-infected subjects.
j.
Only in HCV/HIV co-infected subjects who develop plasma HIV-1 RNA level ≥ 500 copies/mL after starting the 
study.
k.
Performed at Screening for subjects who have occult HBV infection (positive Anti-HBc Total with negative 
HBsAg and Anti-HBs) and also performed for management of transaminase elevation (Section 6.1.7.2).
Palatability Questionnaire (Acceptability Questionnaire)
The parent(s)/guardian(s) of the subject will complete a Palatability Questionnaire to 
provide feedback on the perception of the dosage form of the pediatric formulation in 
Part 2.  The parent(s)/guardian(s) of the subject will be asked of their overall impression 
towards the dosage form and the administration via dosing vehicle to the subject; such as 
duration of administration, volume of dosing vehicle, swallowability, and the convenience 
of administration.  
The questionnaire will be completed at the visits as indicated in Appendix C.  The 
parent(s)/guardian(s) will indicate their answers on the questionnaire, which will be kept 
as part of the study record and transcribed into EDC by site personnel.  Site personnel will 
encourage completion of the questionnaire at all applicable visits and will ensure that a 
response is entered for all items. 
Pregnancy Testing
Females of non-childbearing potential (either pre-menarche and not sexually active or 
permanently surgically sterile as defined in Section 5.2.4) at Screening do not require 
pregnancy testing.  All female subjects who are experiencing menses or are nearing sexual 
maturation in the opinion of the Investigator, or who are of child-bearing potential:
●
A serum pregnancy test will be performed for all female subjects of 
childbearing potential at Screening.  Additional urine pregnancy tests will be 


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performed at all visits indicated in Appendix C.  Pregnancy testing is not 
required for females of non-childbearing potential.
●
Urine pregnancy testing will be performed on-site during the study visit if 
there is a scheduled visit.  The pregnancy result will be captured in the source 
document and recorded in the eCRF by site personnel.  If there is not a 
scheduled study visit, subjects may either have pregnancy testing performed at 
the site as an unscheduled study visit or a urine pregnancy test may be 
conducted by the subject at home with a pregnancy test kit provided by the 
site.  If a urine pregnancy test is performed at home, site personnel should 
contact these female study subjects to capture the results of any study-related 
pregnancy tests in the source records only.
●
If a urine pregnancy result is positive, a confirmatory hCG serum test should 
be collected and sent to the central lab.
Concomitant Medication Assessment
Please refer to Section 5.2.3.
Hepatitis B and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.  A positive anti-HIV Ab test must be confirmed for subjects without a previous 
history of HIV infection.  The investigator or his/her representatives must discuss any 
local reporting requirements to local health agencies with the subject's parent(s)/legal 
guardian(s).  The site will report these results per local regulations, if necessary.
HCV Genotype and Subtype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
sample, its genotype/subtype will be determined by a Sanger sequencing assay of a region 
of the NS5B gene by the central laboratory.  


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C.  
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.  
Historical Liver Biopsy or FibroScan or Screening FibroTest
An assessment of liver fibrosis is mandatory prior to enrollment.  Subjects with no history 
of cirrhosis that have not had a liver biopsy within 24 months or FibroScan within 
6 months prior to screening will undergo a non-invasive FibroTest to determine presence 
or absence of cirrhosis. 
Subject must be documented as non-cirrhotic or cirrhotic defined as meeting one of the 
following criteria:
Non-Cirrhotic
●
A liver biopsy within 24 months prior to or during Screening demonstrating 
the absence of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, 
Scheuer, New Inuyama, or Laennec fibrosis score of ≤ 3, Ishak fibrosis score 
of ≤ 4; or
●
A FibroScan® score of < 12.5 kPa within ≤ 6 months of Screening or during 
Screening period; or
●
A Screening FibroTest score of ≤ 0.72


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Cirrhotic
●
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, New Inuyama, or Laennec fibrosis 
score of > 3, Ishak score of > 4 or on a liver biopsy conducted during 
Screening; or
●
A FibroScan® score of ≥ 12.5 kPa within ≤ 6 months of Screening or during 
Screening period; or
●
A Screening FibroTest result that is > 0.72.
The resulting cirrhosis status and HCV genotype/subtype will be documented via 
recording in the Interactive Response Technology (IRT) system for each subject to
determine the duration and regimen of the study drug for each subject.
For subjects participating in sites specific to Japan, cirrhosis determination may be 
performed (in addition to the methods listed above) using the following Discriminant 
Score criteria at the time of screening:
●
Non-Cirrhotic:  screening Discriminant Score (z) less than zero, according to 
the following formula:  z = 0.124 × [gamma-globulin (%)] + 0.001 × 
[hyaluronate (μg × l–1)] –0.075 × [platelet (× 104 cells/mm3)] – 0.413 × gender 
(male, 1; female, 2) – 2.005.
○
Subjects with indeterminate Discriminant Score (score = 0), must have a 
qualifying FibroScan® or liver biopsy.
●
Cirrhotic:  screening Discriminant Score (z) greater than zero, according to the 
following formula:  z = 0.124 × [gamma-globulin (%)] + 0.001 × 
[hyaluronate (μg × l–1)] –0.075 × [platelet (× 104 cells/mm3)] – 0.413 × gender 
(male, 1; female, 2) – 2.005.
○
Subjects with indeterminate Discriminant Score (score = 0), must have a 
qualifying FibroScan® or liver biopsy.


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Longitudinal Fibrotest and APRI
All subjects will undergo assessment of FibroTest and APRI at Screening or Day 1 and 
FibroTest and APRI at PT Weeks 12, 48, 96 and 144 or premature discontinuation.  Any 
subject that does not have a FibroTest and APRI performed during Screening will have 
them performed at Day 1.
Child-Pugh Score and Category
The Child-Pugh score will be calculated and documented prior to Day 1 visit for cirrhotic 
subjects only.  Subjects who were considered to be non-cirrhotic at the screening visit but 
identified as cirrhotic (according to definitions listed here) during the screening process 
will return to the site prior to the Day 1 visit for Child-Pugh assessment.  Any subject with 
a Child-Pugh > 6 prior to the Day 1 visit will no longer be eligible for study participation.
The Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters 
and 2 clinical assessments).  Child-Pugh score will be determined at the screening visit as 
indicated in Appendix C.  The Child-Pugh score will be automatically calculated prior to 
Day 1 by EDC (RAVE) once the investigator or designated site personnel enters the 
subject's parameters (as listed in Table 9).  A total score of 5 – 6 is considered Class A 
(compensated disease); 7 – 9 is Class B (significant functional compromise); and 10 – 15 
is Class C (decompensated disease).


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Table 9.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2
(or suppressed with 
medication)
Grade 3 or 4
(or refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
None:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver and alpha fetoprotein testing will be performed as indicated in Appendix C for 
subjects with compensated cirrhosis only.
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to 
screening) are not required to undergo a screening ultrasound.
A positive ultrasound result suspicious for HCC during the treatment or Post-Treatment 
Period will be confirmed with CT scan or MRI.


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HCV Resistance Testing Plasma Sample
A plasma sample for baseline HCV resistance testing will be collected on Day 1 from all 
subjects in Part 1, and from subjects in Part 2 in which the sample for baseline HCV 
resistance testing will be within the allowable blood volume limits.  HCV resistance 
testing is required for all subjects who meet virologic failure criteria at the visits indicated 
in Appendix C.  Specific instructions for preparation and storage of the samples will be 
provided by the central laboratory, the Sponsor, or its designee.
Flow Cytometry, HIV-1 RNA and HIV Resistance Testing Samples
For subjects co-infected with HIV-1, samples for plasma HIV-1 RNA levels and flow 
cytometry (including but not limited to CD4+ T-cell and CD8+ T-cell counts [absolute 
and percent]) will be obtained at the times specified in Appendix C.  Plasma HIV-1 RNA 
will be measured by the central laboratory using the Roche COBAS AmpliPrep/COBAS 
TaqMan HIV-1 Test, version 2.0 HIV-1 Assay.  Results below the LLOD are reported as:  
"Not Detected."
If a subject's HIV-1 RNA level is ≥ 200 copies/mL, the subject's HIV-1 RNA is to be 
repeated as noted in Section 5.4.1.2.  At the time the repeat plasma HIV-1 RNA is drawn, 
a sample should be obtained for HIV-1 genotypic resistance testing.  If the subject's repeat 
HIV-1 RNA is ≥ 500 copies/mL, the sample obtained for HIV-1 genotypic resistance 
testing may be analyzed.
HIV-1 protease (PR), reverse transcriptase (RT) and integrase (IN) sequences, as 
applicable, will be analyzed by Monogram Biosciences using the GenoSure® Prime drug 
resistance assay.
If the subject's repeat HIV-1 RNA is < 200 copies/mL, then the subject will resume 
routine plasma HIV-1 RNA assessments as shown in Appendix C and described in 
Section 5.4.1.2.


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Specific instructions for preparation and storage of flow cytometry, plasma HIV-1 RNA, 
and HIV resistance samples, if applicable, will be provided by the central laboratory, 
AbbVie, or its designee.
Patient Reported Outcomes (PRO) Instrument (PedsQL)
Subjects will complete the PRO instrument, PedsQL, with the assistance of a 
parent/guardian (where allowed per local regulatory guidelines) on the study days 
specified in Appendix C.  The PRO should be administered as the first procedure at each 
visit.  Subjects will be instructed to follow the instructions provided with the instrument 
and to provide the best possible response to each item.  Site personnel shall not provide 
interpretation or assistance to subjects other than encouragement to complete the tasks.  
Site personnel will encourage completion of each instrument at all applicable visits and 
will ensure that a response is entered for all items.
The PedsQL Generic Core Scales is a 23 item questionnaire designed to measure the core 
dimension of health as defined by the World Health Organization (WHO), in addition role 
(school) functioning.  The PedsQL consists of 4 Multidimensional Scales (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and 
3 Summary Scores (Total Scale Score, Physical Health Summary Score, and Psychosocial 
Health Summary Score).  Completion of the PedsQL should take around 4 minutes to 
complete.  Subjects who are older than 5-years of age and are able to read and understand 
the questions should complete the questionnaire by themselves.  For subjects who are 
5-years of age or younger or who are not comfortable with reading the questions, their 
parent(s)/guardian(s) should complete the parent/guardian proxy-report. 
Assignment of Subject Numbers
A subject number is assigned at screening via IRT system.  Subject numbers will be 
unique 6-digit numbers and will begin with 
 




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Study Drug Compliance
At the Study Drug accountability visits noted in Appendix C, the returned study drug will 
be accounted for by the study site and recorded electronically in the IRT system.  
Additional information regarding treatment compliance can be found in Section 5.5.6. 
5.3.1.2
Meals and Dietary Requirements
Subjects should be reminded that, in order to maximize absorption, each dose of the study 
drugs should be taken with food.  Subjects who participate in the Week 2 intensive PK 
analysis should be instructed to not have a full meal before the visit, so that study drugs 
can be taken with food during the visit.
All study drugs should be dosed together and administered with food, i.e., the morning 
dose of GLE/PIB should be taken together with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of GLE, possible GLE metabolites, PIB, and 
possible PIB metabolites, will be collected by venipuncture at each study visit indicated in 
Appendix C.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, Week 12 and 
Week 16 if applicable.  
Subjects Who Participate in the Intensive PK Sample Collection of Part 1 and 
Part 2, and Subjects in Japan Who Consent to J-IPK:
The PK samples will be collected at the following time points:
●
Day 1:  4 hours post-dose (the morning doses will be administered with food in 
the clinic)
●
Week 2:  immediately prior to dose (0 hour), 2, 4, 6, and 12 hours post dose 
(the morning doses will be administered with food in the clinic)


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●
Other visits (Week 4, 8, 12, and 16 if applicable):  a PK sample regardless of 
the dosing time
Subjects in Japan Unwilling to Participate in J-IPK Sample Collection of Part 1 and 
Part 2:
●
Day 1:  4 hours post-dose (the morning doses will be administered with food in 
the clinic)
●
Week 2:  immediately prior to dose (0 hour), 2 and 4 hours post dose (the 
morning doses will be administered with food in the clinic)
●
Other visits (Week 4, 8, and 12 if applicable):  a PK sample regardless of the 
dosing time
Subjects Who do not require Intensive PK Sample Collection (Not Applicable for 
Subjects in Japan):
The PK samples will be collected at the following time points:
●
Day 1:  4 hours post-dose (the morning doses will be administered with food in 
the clinic)
●
Other visits (Week 2, 4, 8, 12, and 16 if applicable):  a PK sample regardless 
of the dosing time
The date and time of each blood sample collection and the two doses of study drugs prior 
to each blood sample collection will be recorded to the nearest minute in the source 
documents if applicable.  Additionally, the date and time of the two doses of study drugs 
prior to each blood sample collection will be recorded to the nearest minute on the eCRF 
if applicable.  The time that each blood sample is collected will be recorded to the nearest 
minute on the lab requisitions. 
For subjects who participate in the intensive PK sample collection, the maximum amount 
of blood drawn for pharmacokinetic samples will be approximately 10 mL during a 
24-hour period (at Week 2) and approximately 14 mL during the 30-day period from 
Day 1 to Week 4 and additional 2 ml PK blood drawn at each following study visit during 


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treatment period as indicated in Appendix D.  For subjects who participate in the sparse 
PK sample collection, the maximum amount of blood drawn for pharmacokinetic samples 
will be approximately 2 mL at each study visit during treatment period and approximately 
6 mL during the 30-day period from Day 1 to Week 4 as indicated in Appendix D.  
For subjects in Japan who do not consent to intensive PK sample collection, the maximum 
amount of blood drawn for pharmacokinetic samples will be approximately 6 mL during a 
4-hour period (at Week 2) and approximately 10 mL during the 30 day period from Day 1 
to Week 4 and additional 2 mL PK blood drawn at each following study visit during 
treatment period as indicated in Appendix D.  
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of GLE, possible GLE 
metabolites, PIB, and possible PIB metabolites will be provided by the central laboratory, 
the Sponsor, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of GLE, possible GLE 
metabolites, PIB, and possible PIB metabolites will be packed in dry ice sufficient to last 
during transport, and transferred from the study site to the central laboratory.
Specific instructions for shipping to the analytical lab from the central laboratory will be 
provided by the central laboratory, the Sponsor, or its designee. 
The central laboratory will then ship the plasma samples to:


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Sample Receiving
c/o:  Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL 60085
Phone:
Fax:
Email:
An inventory of the samples included will accompany the package and an electronic copy 
of the Manifests (including subject number, study day, the time of sample collection and 
barcode) will be sent to the contact person at 
5.3.2.4
Measurement Methods
Plasma concentrations of GLE and PIB will be determined using validated analytical 
methods under the supervision of the 
  Plasma 
concentrations of possible metabolites of GLE and PIB may also be determined using 
validated or non-validated methods.
5.3.3
Primary and Secondary Variables
5.3.3.1
Primary Variables
The primary PK endpoints from Part 1 and Part 2 are:
Steady state AUC values for GLE and PIB estimated by non-compartmental analysis or 
population pharmacokinetic analysis, including AUC at Week 2 in subjects with intensive 
PK samples and AUC in all subjects with or without intensive PK samples.
5.3.3.2
Secondary Variables
The secondary endpoints in Part 1 and Part 2 are:
●
Cmax and clearance of GLE and PIB at Week 2 
●
Percentage of subjects with SVR12 by age group and overall 


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●
The percentage of subjects with on-treatment virologic failure 
(i.e., breakthrough or failure to suppress at end of treatment) by age group and 
overall
●
The percentage of subjects with post-treatment relapse by age group and 
overall 
●
The percentage of subjects with new HCV infection (i.e., re-infection) at any 
time up to the last study visit by age group and overall
●
Assessment of palatability/acceptability of the pediatric formulation
The pharmacokinetic primary and secondary objectives for subjects enrolled in Japan will 
be summarized separately.
5.3.4
HCV Resistance Variables
For all subjects receiving GLE/PIB and with available samples, baseline polymorphisms 
at signature resistance associated amino acid positions identified by next generation 
sequencing (NGS) and comparison to the appropriate prototypic reference sequence will 
be analyzed.
The following resistance information will be analyzed for subjects receiving GLE/PIB 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid substitutions in available post-baseline samples 
identified by NGS and comparison to the corresponding baseline sequences, 2) the amino 
acid substitutions in available post-baseline samples at signature resistance-associated 
positions identified by NGS and comparison to the appropriate prototypic reference 
sequence, and 3) the persistence of viral substitutions by NGS.
5.3.5
Safety Variables
The following safety evaluations will be analyzed during the study:  adverse events, vital 
signs, physical examination, and laboratory test assessments.  


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5.3.6
Growth and Development Variables
The following evaluations for growth and development outcomes will be analyzed during 
the study:  growth rate, weight and height z score, and BMI standardized score.
5.3.7
Pharmacokinetic Variables
Individual plasma concentrations of GLE and PIB will be measured for Part 1 and Part 2.  
Values for the pharmacokinetic parameters of GLE and PIB including the Cmax, Tmax, 
Ctrough, and area under the concentration curve (AUC) will be determined by non-
compartmental methods using data from subjects who participate in the initial intensive 
PK sample collection and evaluation.  
Individual model-predicted steady-state AUC values for GLE and PIB corresponding to 
the final proposed doses will be estimated by population pharmacokinetic analysis.
Additional parameters may be determined if useful in the interpretation of the data.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If a subject prematurely discontinues during the Treatment Period, Post-Treatment Period 
or the Long-term Follow-up Period, the procedures outlined for the applicable Premature 
D/C Visit should be completed as defined in Appendix C.  Ideally for study drug 
discontinuation, this should occur on the day of study drug discontinuation, but no later 
than 2 days after their final dose of study drug and prior to the initiation of any other 
anti-HCV therapy.  However, these procedures should not interfere with the initiation of 
any new treatments or therapeutic modalities that the investigator feels are necessary to 


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treat the subject's condition.  Following discontinuation of study drug, the subject will be 
treated in accordance with the investigator's best clinical judgment and monitored for 
HCV RNA and the emergence and persistence of resistant viral substitutions in the 
post-treatment period.  The last dose of any study drug and reason for discontinuation 
from the Treatment Period will be recorded in the EDC system.
If a subject has an ongoing adverse event or an unresolved laboratory result that is 
significantly outside of the reference range at the time of study drug discontinuation, the 
investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the DAAs may be continued at 
the investigator's discretion after discussion with the subject and parent(s)/guardian(s), if 
the benefit of continuing DAAs is felt to outweigh the potential risk.  Specific instructions 
regarding subject pregnancy can be found in Section 6.1.6.  Subjects will be monitored for 
SVR in the Post-Treatment Period as described in Section 5.1.3.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of HCV virologic failure for the 
purposes of subject management: 
●
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.
When confirmatory testing is required it should be completed as soon as possible and the 
subject should remain on study treatment until the HCV virologic failure criterion has 
been confirmed.  Subjects meeting a virologic failure criterion will be discontinued from 


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study drug and will continue to be followed in the Post-Treatment Period for the 
emergence and persistence of resistant viral variants until 144 weeks post-treatment.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV-1 RNA will be assessed at scheduled study visits during the Treatment and Post-
Treatment Period, as detailed in Appendix C.
The criteria for failure to maintain HIV virologic suppression among subjects on stable 
ARTs 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.
At the time a confirmatory HIV-1 RNA is drawn, a sample for HIV-1 genotypic resistance 
testing should also be obtained; this sample may be analyzed if the subject's repeat plasma 
HIV-1 RNA is ≥ 500 copies/mL.  A subject should remain on HCV study drug treatment 
and his/her current ART regimen while the failure to maintain HIV virologic suppression 
is being confirmed.  A confirmatory HIV-1 RNA and HIV-1 genotypic resistance blood 
draw can be done as an unscheduled visit.  However, if this blood draw falls on the date of 


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a scheduled study visit (Appendix C), only a single HIV-1 RNA and HIV-1 genotypic 
resistance blood draw needs to be performed at this visit.  
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 (see Section 5.2.3.1) to construct a new HIV ART 
regimen.
Clinical management of failure to maintain HIV-1 virologic suppression during the study 
(Treatment Period and Post-Treatment Period) will be handled by the site investigator 
according to current HIV treatment guidelines and local standard of care.  
If the investigator wishes to change the HIV-1 ART regimen for a subject, it must be 
discussed with the AbbVie Study Designated Physician prior to the change being made, 
unless the change is being made to address an immediate safety concern.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of open-label DAA study drugs (GLE and PIB) will be dispensed in the form 
of adult co-formulated tablets or a pediatric formulation.  Study drugs will be dispensed at 
the visits listed in Appendix C.


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Part 1 Adult Formulations:
The study drug (GLE/PIB) will be dispensed in the form of co-formulated tablets at the 
visits listed in Appendix C.  Subjects will be instructed to take study drugs at the same 
time every day with food.  Subjects will be instructed to swallow study drugs whole.  
Prior to all visits with pharmacokinetic sampling, the date and time of the two previous 
doses will be recorded to the nearest minute in the source documents and the eCRF.
GLE/PIB will be provided by AbbVie as 100 mg/40 mg film-coated tablets.  GLE/PIB 
will be taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) 
QD and with food.
Part 2 Pediatric Formulation:
Glecaprevir and Pibrentasvir (GLE/PIB) will be provided by the Sponsor as separate 
15.67% and 8.25% film-coated pellets/granules.  GLE/PIB will be taken orally and will be 
dosed QD based on body weight/age.
The film-coated pellets/granules are packed in unit doses and are to be administered at 
once QD into a dosing vehicle.  The legal guardian(s) should be counselled by site to 
check that the study drug units have been emptied completely into the dosing vehicle to 
assure the complete dose is taken by the subject.  A reference to the dosing vehicles is 
included in the dosing card to be used for Part 2.
For both Parts 1 and 2, on the morning of Study Day 1, at the site, subjects will be 
administered study drugs by the study site personnel and receive instructions for self-
administration of all study drugs from the Day 1 through study Week 8, 12, or 16, 
depending on subject's genotype, treatment-experience and cirrhosis status, of the 
Treatment Period.  The date and time of administration of the first dose of each drug will 
be recorded in the subject's source and eCRF.


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Following enrollment, the site will use the IRT system for drug dispensation.  Study drugs 
must not be dispensed without contacting the IRT system, and only for subjects enrolled 
in the study through the IRT system.
All subjects who receive at least one dose of study drugs who fail to achieve virologic 
suppression, or who experience virologic breakthrough on DAA therapy will be 
discontinued from treatment and enter the Post-Treatment Period, unless alternative 
management is agreed to with Primary Therapeutic Area Medical Director.  The 
investigator can prescribe another regimen, as deemed appropriate, which will not be 
provided or reimbursed by AbbVie.
5.5.2
Identity of Investigational Products
Information regarding the study drugs to be used in this study is presented in Table 10.
Table 10.
Identity of Investigational Product
Study Part
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
1
GLE/PIB
AbbVie
Oral
film-coated 
Tablets
100 mg/40 mg
2
GLE
AbbVie
Oral
film-coated 
pellets
15.67%
2
PIB
AbbVie
Oral
film-coated 
pellets
8.25%
2
GLE/PIB
AbbVie
Oral
Film-coated 
granulesa
50 mg/20 mg 
unit dose
a.
Film-coated pellets and granules are the same formulation, and the terminology is considered interchangeable.
They are listed separately, however, to reflect the changes in the packaging and labeling from pellets in bottles to 
granules in sachets. 
5.5.2.1
Packaging and Labeling
Adult Formulation:
The adult formulation study drug will be supplied in bottles.


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Each bottle will be labeled per country requirements.
The labels must remain affixed to the bottles.  All blank spaces should be completed by 
site staff prior to dispensing to subject.
Pediatric Formulation:
The pediatric formulation study drug will be supplied in bottles to be used in the intensive 
PK portion of the study.  The study drug to be used in the sparse PK portion will be 
supplied in sachets.
Each study drug unit will be labeled per country requirements.
The labels must remain affixed to the study drug units.  All blank spaces should be 
completed by site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drugs
Study Drug
Storage Conditions
GLE/PIB film-coated Tablets
15° to 25°C (59° to 77°F)
GLE/PIB film-coated pellets
15° to 25°C (59° to 77°F), Protect from moisture
GLE/PIB film-coated granules 
2° to 25°C (36° to 77°F)a
a.
Film-coated pellets and granules are the same formulation and terminology is considered interchangeable. They 
are listed separately, however, to reflect the changes in the packaging and labeling from pellets in bottles to 
granules in sachets.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the AbbVie.  The GLE/PIB Pediatric 
formulation will be supplied in bottles or in sachets in the intensive PK or in the sparse 
PK portions of the study, respectively.  The Pediatric formulation can be administered in a 
dosing vehicle as outlined on the dosing card applicable for Part 2.  Upon receipt of study 
drugs, the site will acknowledge receipt within the IRT system.


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5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria (or who are unable 
to enroll before enrollment has closed), the site personnel must contact the IRT system 
and identify the subject as a screen failure.
First, the subjects in the ≥ 12 to 18 year age group of the intensive PK portion of Part 1 
who are ≥ 45 kg and willing to swallow the adult formulations will be enrolled.  
Enrollment into the safety/efficacy portion of Part 1 will begin when the dosing 
recommendations of GLE/PIB adult formulation are available based on the 
pharmacokinetic and clinical data from the intensive PK part of Part 1 (Section 5.1).  
Enrollment into the intensive PK portion of Part 2 will begin with the current proposed 
doses in Table 11.  Enrollment into the safety/efficacy portion of each of the age groups in 
Part 2 will begin when the dosing recommendations per age group of GLE/PIB pediatric 
formulation are available based on the pharmacokinetic and clinical data from the 
intensive PK part of Part 2 (Section 5.1).  Subjects who are enrolled will retain their 
subject number assigned at the Screening Visit throughout the study.
In Part 1 of the study, the cap on the number of subjects in IRT will be employed to 
ensure that approximately 44 subjects are enrolled.
In Part 2 of the study, caps on the number of subjects in each age group (3 to < 6, 6 to < 9, 
9 to < 12 years of age) will be employed in IRT to ensure that approximately 22 subjects 
on the final recommended dose regardless of prior treatment experience and cirrhotic 
status are enrolled per age group.
Contact information and user guidelines for IRT use will be available for each study site.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.5.  The daily dose for each 
subject in Part 1 will be assigned by IRT as the standard 300/120 mg dosing.  The daily 


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doses for Part 2 of the study will be assigned by IRT as Glecaprevir 15.67% and 
Pibentasvir 8.25%.  
Study drug dosing will be initiated at the Study Day 1 Visit.  GLE/PIB will be dosed QD.  
All study drugs should be dosed together and administered with food at approximately the 
same time every day.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
All study drugs will be dispensed to subjects by study-site personnel under the direction 
of the investigator.  At the start of the study, each subject along with their 
parent(s)/guardian(s) should receive counseling regarding the importance of dosing 
adherence with the treatment regimen with regard to virologic response and potential 
development of resistance.  The start and stop dates of all study drugs will be recorded in 
the source documents and eCRFs.
During the Treatment Period, subjects will be instructed to bring all study drug units (full, 
partial or empty) to the study site at each study visit.  The study site personnel will inspect 
the contents of the study drug units and account for the returned study drug electronically 
at each Study Drug Accountability visit indicated in Appendix C.  If poor adherence is 
noted, the subject and parent(s)/guardian(s) should be counseled and this should be 
documented in the subject's source document.


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5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept per subject by the 
investigator.  An overall accountability of the study drug will be performed and verified 
by the AbbVie monitor throughout the Treatment Period.  The monitor will review study 
drug accountability on an ongoing basis.  Final accountability will be verified by the 
monitor at the end of study drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug unit, the 
IRT system must be contacted and informed of the misplaced or damaged study drug.  If 
the study drug unit is damaged, the subject will be requested to return the remaining study 
drug to the site.  Replacement study drug may only be dispensed to the subject by 
contacting the IRT system.  Study drug replacement(s) and an explanation of the reason 
for the misplaced or damaged study drug(s) will be documented within the subject's 
source.  Date of the first dose and the last dose of the regimen will be documented in the 
subject's source documents and recorded on the appropriate eCRF.
The return status of each study drug unit and the date of reconciliation will be documented 
at Study Drug Accountability Visits in Appendix C.
Detailed instructions regarding study drug accountability are provided below. 
Adult Formulation 
The number of tablets of each type of study drug returned in each bottle will be noted in 
the IRT system and on a drug accountability log (if appropriate).  Labels must remain 
affixed to the bottles.


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Pediatric Formulation
The status of each returned bottle or sachet will be noted in the IRT system and on a drug 
accountability log (if appropriate).  The Investigator/designee must document the status of 
the returned bottles or sachets as "full sealed" or "empty" or "unsealed but not empty" in 
the IRT system.  Labels must remain affixed to the bottles.
Upon completion of or discontinuation from the Treatment Period, all original study drug 
units (containing unused study drugs) will be returned to the Sponsor (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  All empty original study drug units shall be disposed of onsite following 
completion of study drug accountability and reconciliation procedures.  Labels must 
remain attached to the study drug units.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design
The combination regimen of GLE/PIB completed registrational Phase 3 trials in adults in 
several countries including the US, the EU, and Japan.  The dose, durations, and regimens 
have been optimized in adults.  These same durations and regimens are anticipated to be 
similarly successful in children as long as the drug exposures are comparable, so further 
regimen/duration exploration is not warranted.  In addition, no interferon-free regimens or 
ribavirin free regimens are approved for use in children less than 12 years old; the 
historical standard of care (pegIFN/RBV) has notably lower efficacy rates and a worse 
safety profile than the interferon-free DAA regimens and requires longer treatment 
duration, making a comparative study unethical and difficult to enroll.  A non-randomized 
study design with regimens/duration and drug exposure comparable to the recommended 
adult regimens is the best method for evaluation.


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5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.  The PedsQL instrument is 
standard in the literature and thoroughly validated in studies of the pediatric population 
and in pediatric subjects who have chronic health conditions.
5.6.3
Suitability of Subject Population
This is a multicenter, Phase 2/3, open label study in treatment naïve and treatment 
experienced HCV GT1 – 6 infected pediatric subjects, with and without compensated 
cirrhosis, with or without HIV-1 co-infection, designed to evaluate the pharmacokinetics, 
safety, and efficacy of GLE/PIB administered QD for 8, 12 or 16 weeks.  Evaluation for 
the treatment duration is supported by the data from the Registrational program with high 
SVR and favorable safety profile in adults.  Evaluation of the dosages to be used in this 
population is supported by current pharmacokinetic data in adults, based on multiple 
Phase 1 and 2 studies, with modeling to support the intended pediatric dosing. 
This study plans to enroll subjects from ≥ 3 to < 18 years old with genotype 1 – 6 HCV 
infection as agreed upon in the Pediatric Investigation Plans (PIP) and Pediatric Study 
Plan (PSP).  The older subjects who are willing to swallow the adult formulations and are 
≥ 45 kg will be studied using the adult co-formulated tablets.  A pediatric formulation of 
the DAAs has been developed for children in the ≥ 3 to < 12 year old age groups.
5.6.4
Selection of Doses in the Study
In the PIP and the PSP for Glecaprevir/Pibrentasvir, the proposed pediatric doses were 
targeting providing comparable exposures to adult subjects.
AbbVie has developed a separate pediatric formulation for GLE + PIB for use in Part 2 of 
the present study.  
The mg doses for a given weight range for each of the age groups as proposed in the PIP 
and PSP were adjusted to express each age group dose as a multiple of a proposed unit 


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dose of a sachet, which provides a simplified dosing approach for patients and physicians 
and is expected to help reduce potential dispensing and dosing errors while meeting the 
objectives of the weight based dosing.  Given the wide therapeutic window of GLE and 
PIB, the updated doses will not anticipate to change the efficacy/safety profiles.
For the present study, the final proposed doses by weight band range are shown in 
Table 11.
Table 11.
Proposed Glecaprevir and Pibrentasvir Doses for the Pediatric 
Population
Formulation
Age Group (yrs) & 
Weight Band (kg)
Final Proposed Doses (mg)
Glecaprevir
Pibrentasvir
Pediatric formulation
3 to < 6 yr
12 to < 20 kg
150
60
6 to < 9 yr
≥ 20 to < 30 kg
200
80
9 to < 12 yr
≥ 30 to < 45 kg
250
100
Adult formulation
12 to < 18 yr
≥ 45 kg
300
120
The doses of the pediatric formulation were adjusted based upon the intensive 
pharmacokinetic analysis of the first approx. 17 subjects enrolled across the age cohorts.  
The final proposed dosing for each age cohort has been confirmed by additional IPK 
analysis. These drug dose changes are included in this protocol amendment.  Dose 
adjustments were made as necessary to ensure safe and efficacious exposures, but did not 
exceed the adult dose of 300/120 mg of GLE/PIB.
For Part 1, enrollment commenced with pediatric subjects ≥ 12 to < 18 years old who are 
≥45 kg and willing to swallow the adult formulation.  Part 2 enrollment initiated in 
pediatric subjects ≥ 3 to < 12 years old with the pediatric formulation.  Based on current 
modeling and available PK data at the completion of the IPK portion of Part 2, the above 
proposed doses of the pediatric formulation are the target doses for use in children 


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< 12 years of age.  The pharmacokinetic and clinical data will be used to confirm 
appropriate exposure in each of the ≥ 3 to < 12 years old age groups.  
Details on the dose adjustment considerations for Part 1, the enrollment sequence in 
Part 1, and the considerations for enrollment in Part 2 are provided in Section 5.1.
5.6.5
Maximum Dose
For Parts 1 and 2, the maximum dose of GLE and PIB will not exceed 300 mg and 
120 mg per day for 16 weeks.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.1.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.


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All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.1.7 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.


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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).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life 
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.


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6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4).
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity.
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.


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6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
An adverse event where there is evidence to suggest a 
causal relationship between the study drug and the 
adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a 
causal relationship between the study drug and the 
adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
For serious adverse events, if an investigator's opinion of "no reasonable possibility of 
being related to study drug" is given, an "Other" cause of event must be provided by the 
investigator.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related non-serious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (non-serious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  
FAX to:  
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:


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For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
 MD
Associate Medical Director
Infectious Diseases
1 North Waukegan Road
North Chicago, IL 60064
Telephone Contact Information:
Office:
Fax:
Mobile:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
Primary Therapeutic Area Medical Director:
Phone:  
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 


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investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).  If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.4.1.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment. 
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  All adverse events and 
laboratory abnormalities will be managed and followed to a satisfactory clinical 
resolution.  Toxicity is deemed "clinically significant" based on the medical judgment of 
the investigator.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4" is to be used in the grading of 
adverse events and laboratory abnormalities which is available on the Cancer Therapy 
Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Specific toxicity management guidelines apply to the instances of increases in ALT 
(Section 6.1.7.2).
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 Primary 
Therapeutic Area Medical Director should be contacted and consideration should be given 
to discontinue the subject.


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6.1.7.1
Severe Adverse Events
If a subject experiences a severe adverse event (Grade 3+) or a serious adverse event that 
the investigator considers to have a reasonable possibility of relationship to study drug, 
the investigator should assess whether the adverse event 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 adverse event recurs, 
then study drugs should be permanently discontinued.
If a subject experiences a severe adverse event (Grade 3+) or serious adverse event that is 
considered unrelated (no reasonable possibility) to the study drugs, it is not necessary to 
interrupt study drugs unless an interruption is required because of the nature of the event 
(e.g., unable to take oral medications).
The investigator should ensure that all serious adverse events are reported to AbbVie 
within 24 hours of awareness.  Serious adverse event follow-up information, including 
associated dose interruptions (or discontinuations), must be reported to AbbVie within 
24 hours of awareness by entering updated SAE information into the appropriate eCRFs.
Severe adverse events and any associated dose interruptions (or discontinuations) should 
be entered into the appropriate eCRFs.
6.1.7.2
Management of ALT Elevations
If the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Evaluate for alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain additional testing as appropriate.
●
Evaluate for a new viral hepatitis infection, including hepatitis A, B and E.
○
If the subject is found to have an active hepatitis B infection, additional 
evaluation by completion of the eCRF Transaminase Elevations 
Questionnaire should be performed by the investigator.


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●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
international normalized ratio (INR) within 1 week.  Repeat liver chemistries 
as indicated until resolution.
●
Discontinue study 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.
Alternate management of ALT increases is permitted with approval of the Primary 
Therapeutic Area Medical Director.
If the investigator wishes to pursue alternative management of study drugs in the setting 
of confirmed ALT increases described above, then approval of the Primary Therapeutic 
Area Medical Director must be obtained.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any complaint (see Section 6.0 for the definition) related to the 
drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.


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6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitor(s):


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Primary Contact:
Study Management Associate
One North Waukegan Road
North Chicago, IL 60064
Office:
Alternate Contact: 
Study Project Manager
AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen, Germany
Office:
Fax:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The analysis of pharmacokinetic endpoints will be performed when 12 subjects complete 
the 2 week intensive PK (IPK) measurements, and these analyses will be done within each 
age group.  For subjects enrolled in Japan, the pharmacokinetic parameters will be 
summarized separately.
The efficacy, durability of response, resistance, growth and development, patient-reported 
outcomes, and safety analyses will be performed by age group and overall (across Parts 1 
and 2 combined).  
The first interim analysis will occur once all subjects participating in IPK in Part 1 
complete PT Week 12 or prematurely discontinue from the study.  A second interim 
analysis will occur once all subjects in Part 1 complete PT Week 12 or prematurely 
discontinue from the study.  A third interim analysis will occur once all subjects 
participating in the IPK portion in Part 2 complete PT Week 12 or prematurely 
discontinue from the study.  A fourth interim analysis will occur once all subjects in 


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Parts 1 and 2 complete PT Week 12 or prematurely discontinue the study.  Final analysis 
will occur after the completion of the whole study.
SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All statistical tests and all confidence intervals will be two-sided with alpha 
level of 0.05. 
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.
Demographic and efficacy analyses will be performed on the intention-to-treat (ITT) 
population defined as all enrolled subjects who receive at least one dose of study drug, 
unless otherwise specified.
Sensitivity analyses of the SVR12 endpoint, when applicable, will be performed on the 
intention-to-treat population modified to exclude subjects who did not achieve SVR12 for 
reasons other than virologic failure (mITT-VF).
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data).  HCV RNA values will be selected for the analyses of all 
SVR endpoints (e.g., SVR4, SVR12, and SVR24) based on defined statistical visit 
windows.  A backward imputation method will be used to impute missing responses for 
SVR analyses.  Detailed statistical methods for all endpoints will be provided in the 
Statistical Analysis Plan (SAP).
8.1.1
Demographics
Demographics and baseline characteristics will be summarized by age group and overall.  
As a sensitivity analysis, subjects who receive a dose lower than the final dose chosen for 
the subject's age group might be summarized separately.  The baseline value refers to the 
last non-missing measurement collected before the first dose of study drug is received in 
Part 1 or Part 2.  Demographics include age, birth year, weight, height, body mass index 
(BMI), BMI z score (BMI z score will be calculated using WHO published BMI-for-age 


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z-score tables), weight and height z scores (weight and height z scores will be calculated 
using WHO published weight-for-age z-score and height-for-age z-score tables), gender, 
race ethnicity, geographic region and country.  Baseline characteristics will include HCV 
genotype, prior HCV treatment history if applicable, baseline platelets (< 90 or 
≥90 × 109/L), baseline albumin (< 35 or ≥ 35 g/L), baseline alpha fetoprotein (< 20 or 
≥20 ng/mL), baseline HCV RNA levels (continuous) and (< 1,000,000, ≥ 1,000,000 to 
< 2,000,000, ≥ 2,000,000 IU/mL), baseline fibrosis stage (F0-1, F2, F3, F4), baseline 
Fibrotest score, baseline APRI, and baseline Child-Pugh score (non-cirrhotic, 5 or 6).  
Descriptive statistics will be provided, such as the number of observations (N), mean, and 
standard deviation (SD) for continuous variables (e.g., age, weight and height z-score) and 
counts and percentages for discrete variables (e.g., gender and race).
8.1.2
Primary, Secondary, and Efficacy Analyses
The primary and secondary analyses of PK parameters will be performed on subjects in 
the ITT population with available PK samples, unless otherwise specified.
All efficacy analyses will be performed on the ITT population unless otherwise specified.  
Subjects who receive a dose lower than the final dose chosen for the subject's age group 
might be summarized separately.  Efficacy analyses will be performed within each age 
group and overall population.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL that are HCV RNA detected or HCV RNA not detected.  HCV RNA ≥ LLOQ 
are all quantifiable values.
8.1.2.1
Primary Endpoints
The primary endpoint will be steady state AUC of GLE and PIB estimated by non-
compartmental pharmacokinetic analysis or population pharmacokinetic analysis, 


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including AUC at Week 2 in subjects with intensive pharmacokinetics samples and AUC 
in all subjects with or without intensive PK samples.  The 95% confidence interval for the 
geometric mean of AUC values will be calculated.  For subjects enrolled in Japan, the 
pharmacokinetic parameters will be summarized separately.
8.1.2.2
Secondary Endpoints 
The secondary endpoints are:
1.
Cmax and clearance of GLE and PIB at Week 2;
2.
The percentage of subjects with SVR12 by age group and overall; 
3.
The percentage of subjects with on-treatment virologic failure (i.e., breakthrough, 
defined as confirmed increase of > 1 log10 IU/mL above nadir during treatment or 
confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment, or 
HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks of treatment) by 
age group and overall;
4.
The percentage of subjects with post-treatment relapse (defined as confirmed HCV 
RNA ≥ LLOQ between end of treatment and 12 weeks after the last dose of study 
drug among subjects who completed treatment as planned with HCV RNA 
< LLOQ at the end of treatment; excluding subjects who have been shown to be 
re-infected) by age group and overall; 
5.
The percentage of subjects with new HCV infection (i.e., re-infection) at any time 
up to the last visit by age group and overall; 
6.
Assessment of palatability/acceptability of the pediatric formulation by age group 
and overall.
The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the number of subjects who fail to achieve SVR12 is less than 5, where 
the Wilson's score method will be used for the confidence interval instead.


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In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, reinfection, other) will be provided for each age group.
For the analysis of on-treatment virologic failure, relapse, and re-infection, the number 
and percentage of subjects will be summarized along with a two-sided 95% confidence 
interval using Wilson's score method.
For the analysis of post-treatment HCV virologic relapse, completion of treatment is 
defined as any subject with study drug duration of 52 days, 77 days, and 103 days or 
greater for subjects allocated to treatment durations of 8 weeks, 12, and 16 weeks, 
respectively.
For the assessment of palatability/acceptability, the number and percentage of subjects 
with each categorical answer marked will be presented for each question in the 
palatability questionnaire at each applicable treatment visit by age group and overall.  A 
listing of palatability questionnaire results and comments for each applicable subject over 
applicable treatment visits will be produced.
8.1.2.3
Additional Efficacy Endpoints
1.
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit in 
the Treatment Period (using data as observed);
2.
The percentage of subjects with SVR4 by age group and overall;
3.
The percentage of subjects with SVR24 by age group and overall;
4.
The percentage of subjects who relapsed after achieving SVR12 by age group and 
overall;
5.
Change from baseline to all post-baseline visits in Fibrotest score and APRI by age 
group and overall.
All rates will be presented with 2-sided 95% confidence intervals using the Wilson's score 
method.


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In addition, a summary of reason for SVR24 non-response (e.g., on-treatment virologic 
failure, relapse, reinfection, other) will be provided for each age group.
8.1.2.4
Subgroup Analysis 
The number and percentage of subjects with SVR12 will be presented along with the 
2-sided 95% confidence interval for the following subgroups if applicable.  The subgroup 
analysis might be restricted to subjects who receive the final dose for the corresponding 
age group.
●
HCV genotype;
●
Prior HCV treatment history;
○
For treatment experienced subjects, type of non-response to previous 
treatment;
●
Sex (male or female);
●
Baseline fibrosis stage (F0-F1, F2, F3 or F4); 
●
Baseline HCV RNA level (< 1,000,000, ≥ 1,000,000 to < 2,000,000, 
≥2,000,000 IU/mL);
●
Race (Black versus non-black);
●
Ethnicity (Hispanic/Latino versus none);
●
Geographic region (North America, Europe, Japan);
●
Country (as appropriate);
●
Height z-score (< –1, –1 to 1 or > 1);
●
BMI z-score (< 25, ≥ 25 to < 30, or ≥ 30 kg/m2);
●
Drug compliance (< 80% versus ≥ 80%);
●
In adolescents, former injection drug user (yes, within last 12 months; yes, 
more than 12 months ago; or no); 
●
Baseline platelets (< 90, ≥ 90 × 109/L);
●
Baseline albumin (< 35, ≥ 35 g/L).


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The two-sided 95% confidence intervals will be produced using the Wilson's score 
method if there are at least 10 subjects in the subgroups.
8.1.2.5
Sensitivity Analysis
As sensitivity analyses, the number and percentage of subjects in the mITT-VF population 
achieving SVR12, as applicable, will be summarized along with a two-sided 95% 
confidence interval using the normal approximation and a two-sided 95% confidence 
interval using the Wilson's score method.  The two-sided 95% confidence interval using
Wilson's score method will also be calculated as a sensitivity analysis for SVR12 based on 
ITT population.
8.1.3
Growth and Development
The following growth and development endpoints will be calculated in the ITT 
population.
●
Growth rate at Post-Treatment Weeks 12, 48, 96 and 144 (defined as change in 
height over change in age from the previous visit)
●
Weight z score25
●
Height z score25
●
Body mass index (BMI) z score25
Growth rate will be summarized with N, mean and SD together, median and range 
together at each applicable post baseline visit by gender for all and for age group 
separately.  Weight, height and BMI z scores will be summarized with N, mean and SD 
together, median and range together at each applicable post baseline visit for all and by 
age group.  Change from baseline in weight and height will be summarized together with 
other vital signs such as temperature and blood pressure.
8.1.4
Patient Reported Outcomes
At Baseline, End of Treatment, and Post-Treatment, general quality of life will be 
assessed using the PedsQL.  The PedsQL was designed to measure the core dimensions of 


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health, as well as role (school) functioning.  The PedQL consists of 4 multidimensional 
scales (Physical Functioning, Emotional Functioning, Social Functioning, and School 
Functioning) and 3 summary scales (Total Scale Score, Physical Health Summary Score, 
and Psychosocial Health Summary Score).
Across subjects enrolled in Part 1 and 2 (based on ITT population), summary statistics of 
change from baseline (n, mean, SD, minimum and maximum) of 3 summary scale scores 
will be provided by age group and overall.  In addition the same summaries will be 
created separately for subjects who complete all the questionnaires by themselves and for 
subjects whose parent(s)/guardian(s) always complete the parent/guardian proxy-report.
8.1.5
Safety
The secondary safety endpoints are rates of adverse events and clinically significant 
laboratory abnormalities.  All subjects who receive at least one dose of study drug will be 
included in the safety analyses.  The safety analysis will be carried out for all subjects by 
for each age group and overall.  Subjects who receive a dose lower than the final dose 
chosen for the subject's age group might be summarized separately.  A listing of any 
SAEs recorded in the Post-Treatment Period will be included.
8.1.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT).  The tabulation of the number of subjects 
with treatment-emergent adverse events by grade (Grades 1 – 5) and relationship to study 
drug also will be provided.
Additional analyses will be performed if useful and appropriate.


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8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last measurement prior to the initial dose of study drug.  Mean changes from baseline to 
each post baseline visit will be summarized descriptively.
The number and percentage of subjects with post-baseline values meeting pre-specified 
criteria for toxicity grades during treatment will be summarized.
8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, weight, height, 
and BMI from Day 1 to each post baseline visit will be summarized descriptively. 
8.1.6
Resistance Analysis
8.1.6.1
HCV Drug-Resistance Analyses
The secondary endpoint of resistance associated viral variants will be analyzed as follows.  
For all subjects in Part 1 and subjects with available samples in Part 2, full length NS3/4A 
or NS5A from baseline samples will be sequenced by NGS.  For all subjects who 
experience virologic failure (on-treatment virologic failure or post-treatment relapse), full 
length NS3/4A and NS5A genes from the first sample after virologic failure with HCV 
RNA ≥ 1000 IU/mL will be sequenced by NGS.  An appropriate subtype-specific 
prototypic reference sequence will be used for comparison with sequences from samples.  
Subjects treated with study drug who do not achieve SVR12 due to reasons other than 
virologic failure but have a time point with HCV RNA ≥ 1000 IU/mL after treatment 
discontinuation, will have the sample at that time point sequenced. 
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.  Included time 


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points for analyses on samples from subjects who do not achieve SVR12 are 1) the 
sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that resistance-associated 
substitutions were detected by NGS at the time of HCV virologic failure/treatment 
discontinuation.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions are listed in Table 12 Appropriate subtype specific prototypic reference 
sequence will be used for comparison with sequences from samples.
Table 12.
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, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  an amino acid polymorphism by NGS in a baseline 
sample (≥ 2% or ≥ 15% prevalence within a subject's viral population 
depending on polymorphism frequency threshold utilized) that was not present 
in the appropriate prototypic reference amino acid sequence for a given DAA 
target (NS3/4A or NS5A).
●
Polymorphism/substitution at signature amino acid position:  polymorphism 
(relative to reference) present in a baseline or substitution (relative to baseline) 
present in a post-baseline sample at a signature amino acid position.
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.


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●
Enriched polymorphism:  polymorphism present in both the baseline and a 
post-baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post-baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution by NGS:  A post-baseline substitution or an 
enriched polymorphism.
Analysis 1:  The following analyses will be provided for all subjects with baseline 
sequence data, separated by HCV subtype:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A). 
●
A listing of all baseline polymorphisms (15% detection threshold) at non-
signature resistance-associated amino acid positions for each DAA target 
(NS3/4A and NS5A) for subjects who experience virologic failure.
●
A by subject listing of baseline polymorphisms (15% detection threshold) at 
signature amino acid positions in subjects with polymorphisms across both 
NS3 and NS5A, or those with multiple baseline polymorphisms within any one 
target (NS3/4A or NS5A).
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15%.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A, by subtype, and total  
(include all subtypes).
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed as follows:  for each polymorphism, the SVR12 rate will be calculated for 
subjects with and without the polymorphism and the 2 rates will be compared using 
Fisher's exact test.  Analysis will be grouped by HCV subtype and DAA target (NS3/4A 
or NS5A).


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The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
For each signature amino acid position, presence of any polymorphism at that 
position (vs no polymorphism at that position), using detection thresholds of 
both 2% and 15%.  
●
Each individual polymorphism at each signature amino acid position (vs not 
that polymorphism) using detection thresholds of 2% and 15%.
●
Polymorphisms at each non-signature amino acid position at a detection 
threshold of 15%.
Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 
amino acid positions at 15% detection threshold, the SVR12 rate will be calculated, and 
the rates with or without polymorphisms will be compared using Fisher's exact test.  
Analysis will be separated by HCV subtype.  The following tables will be provided:
●
Comparison of SVR12 rates by subtype, and total (include all subtypes)
●
Comparison of SVR12 rates by genotype, and total (include all subtypes)
Analysis 4:  The following analyses will be performed for subjects who do not achieve 
SVR12 and who have post-baseline resistance data available:
●
Listings by subject of all treatment-emergent substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3/4A 
and NS5A).
●
Listings by subject and time point of all post-baseline substitutions at signature 
amino acid positions relative to the baseline amino acid sequence will be 
provided for each DAA target (NS3/4A and NS5A).
The persistence of post-baseline substitutions at signature amino acid positions for each 
target will be assessed by NGS through Post-Treatment Week 144.  A listing by subject 


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and time point of all post-baseline substitutions relative to the baseline amino acid 
sequence will be provided for each DAA target.
If resistance-associated substitutions are not detected in a given target for a subject at the 
time of failure/discontinuation, then that target may not be sequenced in subsequent 
samples from that subject.
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV NS3/4A and/or NS5A sequence from 
baseline samples from subjects in Part 1, and from subjects with available samples  in 
Part 2 in order to accurately determine genotype/subtype.  If the phylogenetic analysis is 
not available, then the result from Sanger sequencing of a region of NS5B by AbbVie or 
by the Central laboratory will be used to determine the subject's HCV genotype/subtype, 
if available.  Finally, if neither the phylogenetic analysis result nor the Sanger sequencing 
assay results is available, then the Inno-LIPA assay results from the Central laboratory 
will be used to categorize the subject.  This information will be presented in summaries of 
efficacy subgroup analyses.
8.1.6.2
HIV Drug-Resistance Analyses
If a subject develops a confirmed, plasma HIV-1 RNA level ≥ 500 copies/mL after 
starting the study, the subject's HIV-1 PR, RT, and/or IN sequences, as applicable, will be 
analyzed by Monogram Biosciences using the GenoSure® Prime drug resistance assays.  
The number of subjects who demonstrate HIV genotypic resistance and the genotypic 
resistant mutations detected in the samples obtained from these subjects will be tabulated 
and summarized.  Resistance will be defined as described by the IAS-USA Panel.26
8.1.7
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of GLE and PIB will be tabulated and summarized for subjects in 
Part 1 and Part 2 by age group, actual dose administered, and overall.


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Non-compartmental pharmacokinetic analysis or population pharmacokinetic analysis will 
be performed to facilitate potential GLE and PIB dose modification in each age group.  
Values for the pharmacokinetic parameters of GLE and PIB including the Cmax, Ctrough, 
and AUC will be tabulated and summarized for subjects by age group, actual dose 
administered, and overall.  Additional parameters or summaries may be determined if 
useful in the interpretation of the data.
Plasma concentration data from Part 1 and Part 2 of this study may be combined with data 
from other studies and analyzed using the following general methodology.
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software.  The structure of the starting 
pharmacokinetic model will be based on the pharmacokinetic analysis of data from 
previous studies.  Apparent oral clearance (CL/F) and apparent volume of distribution 
(V/F) of the PK analytes will be the pharmacokinetic parameters of major interest in the 
NONMEM analyses.  If necessary, other parameters, including the parameters describing 
absorption characteristics, may be fixed if useful in the analysis.  
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.
Relationship between exposure and clinical observations (antiviral activity) will be 
explored.  Exposure-response relationships for primary and secondary efficacy variables 
and/or some safety measures of interest may also be explored.  
The relationship between exposure (e.g., population pharmacokinetic model predicted 
concentrations over time or average concentrations or AUC or trough concentrations of 
the individual model-predicted pharmacokinetic profiles, or some other appropriate 
measure of exposure) and antiviral activity will be explored using graphical and/or 
logistic regression analyses. 


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Additionally, relationship between exposure and efficacy/safety endpoints of interest may 
also be explored.  Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
It is planned to enroll a total of approximately 125 subjects into this study.  The primary 
endpoint will be steady state AUC of GLE and PIB.  Practical considerations include the 
expected larger number of adolescents within this population, in comparison to the 
younger age cohorts.
The proposed sample size of 48 subjects (12 subjects for each age cohort) for intensive 
pharmacokinetic sampling (separate from sampling performed in subjects in Japan) is 
expected to adequately characterize the pharmacokinetics of GLE and PIB to enable dose 
selection in pediatric subjects. 
Approximately 10 subjects will undergo additional PK sampling to support 
characterization of GLE and PIB exposures in children from Japan.
Additional subjects will be enrolled to reach the proposed total of 125 subjects to provide 
safety and efficacy information.
8.3
Randomization Methods
There is no randomization in this study.  Enrolled subjects will receive treatment per the 
planned study schematic outlined in Section 5.1.2.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 


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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP and all other applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject's parent(s)/legal guardian(s) and answer all questions regarding this study.  
Pediatric subjects will be included in all the discussions in order to obtain written assent.  
Prior to any study-related screening procedures being performed on the subject, the 
informed consent statement will be reviewed and signed and dated by subject's 
parent(s)/legal guardian(s) and the person who administered the informed consent, and 


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any other signatories according to local requirements.  Additionally, in keeping with each 
institution's IEC requirements, if applicable, an informed assent form will also be obtained 
by each subject, as appropriate for age and country, prior to any study-related procedures
being performed.  If a subject becomes of legal age during the course of the study, that 
subject will need to be consented using the approved informed consent form.  A copy of 
the informed consent form and assent form will be given to the subject and subject's 
parent(s)/legal guardian(s) and the originals will be placed in the subject's medical record.  
An entry must also be made in the subject's dated source documents to confirm that 
informed consent and assent (if applicable) were obtained prior to any study-related 
procedures and that the subject and parent(s)/legal guardian(s) received signed copies of 
the informed consent and assent forms.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
9.3.1
Informed Consent Form and Explanatory Material (Japan 
Site Specific)
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
Consent to collect samples up to 12-h post dose (0, 2, 4, 6, and 12 hours) will be requested 
of all participants in Japan.  However, if consent and assent cannot be obtained for 12-h
post dose PK sampling, then a reduced PK collection duration (0, 2 and 4 hours) will be 
performed.


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9.3.2
Revision of the Consent Form and Explanatory Material 
(Japan Site Specific)
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 


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collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.


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11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Not applicable for this study.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator/director of 
the site in Japan and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the investigator/director and AbbVie.  The 
investigator/director will provide a final report to the IEC/IRB following conclusion of the 
study, and will forward a copy of this report to AbbVie or their representative.
The investigator/director must submit, maintain, and archive any records related to the 
study according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator/director is not able to retain the records, he/she must notify AbbVie to 
arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for 
Glecaprevir/Pibrentasvir Fixed-Dose Combination.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir 
in Pediatric Subjects With Genotypes 1 – 6 Chronic Hepatitis C 
Virus (HCV) Infection (DORA)
Protocol Date:
22 March 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al. A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
Alter MJ, Kruszon-Moran D, Nainan OV, et al.  The prevalence of hepatitis C virus 
infection in the United States, 1988 through 1994.  N Engl J Med.  
1999;341(8):556-62.
7.
Delgado-Borrego A, Smith L, Jonas MM, et al.  Expected and actual case 
ascertainment and treatment rates for children infected with hepatitis C in Florida 
and the United States:  epidemiologic evidence from statewide and nationwide 
surveys.  J Pediatr.  2012;161(5):915-21.
8.
El-Kamary SS, Serwint JR, Joffe A, et al.  Prevalence of hepatitis C virus infection 
in urban children.  J Pediatr.  2003;143(1):54-9.
9.
Bradley JS, Graham S, Picchio GR, et al.  Prevalence of hepatitis C virus antibody 
in newborn infants in southern California in 2003.  Pediatr Infect Dis J.  
2011;3(7):618-20.


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10.
Centers for Disease Control (CDC).  Viral Hepatitis Surveillance – United States, 
2010.
11.
Centers for Disease Control (CDC).  Viral Hepatitis Surveillance – United States, 
2012.
12.
Micallef JM, Kaldor JM, Dore GJ.  Spontaneous viral clearance following acute 
hepatitis C infection:  a systematic review of longitudinal studies.  J Viral Hepatitis.  
2006;13(1):34-41.
13.
Bortolotti F, Verucchi G, Camma C, et al.  Long-term course of chronic hepatitis C 
in children:  from viral clearance to end-stage liver disease.  Gastroenterology.  
2008;134(7):1900-7.
14.
Guido M, Bortolotti F, Leandro G, et al.  Fibrosis in chronic hepatitis C acquired in 
infancy:  is it only a matter of time?  Am J Gastroenterol.  2003;98(3):660-3.
15.
Murray KF, Finn LS, Taylor SL, et al.  Liver histology and alanine 
aminotransferase levels in children and adults with chronic hepatitis C infection.  
J Pediatr Gastroenterol Nutr.  2005;41(5):634-8.
16.
Jara P, Resti M, Hierro L, et al.  Chronic hepatitis C virus infection in childhood:  
clinical patterns and evolution in 224 white children.  Clin Infect Dis.  
2003;36(3):275-80.
17.
Jonas MM.  Children with hepatitis C.  Hepatology.  2002;36 (5 Suppl 1):S173-8.
18.
Wirth S, Kelly D, Sokal E, et al.  Guidance for clinical trials for children and 
adolescents with chronic hepatitis C.  J Pediatr Gastroenterol Nutr.  
2011;52(2):233-7.
19.
Mack CL, Gonzalez-Peralta RP, Gupta N, et al.  NASPGHAN practice guidelines:  
diagnosis and management of hepatitis C infection in infants, children, and 
adolescents.  J Pediatr Gastroenterol Nutr.  2012;54(6):838-55.
20.
Ghany MG, Nelson DR, Strader DB, et al.  An update on treatment of genotype 1 
chronic hepatitis C virus infection:  2011 practice guideline by the American 
Association for the Study of Liver Diseases.  Hepatology.  2011;54(4):1433-44.


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21.
Younossi ZM, Stepanova M, Balistreri W, et al.  High Efficacy and Significant 
Improvement of Quality of Life (QoL) in Adolescent Pateints with Hepatitis C 
Genotype 1 (GT1) Treated with Sofosbuvir (SOF) and Ledipasvir (LDV).  
Presented at AASLD, November 11-15, 2016, Boston MA.
22.
Schwarz K, Rosenthal P, Gonzalez-Peralta R, et al.  Sofosbuvir + Ribavirin for 12 
or 24 Weeks is Safe and Effective in Adolescents with Genotype 2 or Genotype 3 
Chronic Hepatitis C Infection.  Presnted at AASLD, November 11-15, 2016, 
Boston, MA.
23.
Ng T, Reisch T, Middleton T, et al.  ABT-493, a potent HCV NS3/4A protease 
inhibitor with broad genotype coverage.  Poster presented at:  21st Annual 
Conference on Retroviruses and Opportunistic Infections (CROI); March 03-06, 
2014; Boston, MA.  Poster 636
24.
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's 
Brochure Edition 2.  06 September 2016.
25.
WHO.  Child Growth Standards.  27 April 2006.
26.
Johnson VA, Calvez V, Huldrych GF, et al.  Update of the drug resistance 
mutations in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):4-12.
27.
Report of the paediatric hepatitis C therapy expert meeting.  European Medicines 
Agency, London, 09 December 2014.  21 April 2015.  EMA/87232/2015.
28.
SOVALDI® (sofosbuvir) [Package Insert].  Foster City, CA; Gilead Sciences, Inc., 
2017.
29.
HARVONI® (ledipasvir and sofosbuvir) [Package Insert].  Foster City, CA; Gilead 
Sciences, Inc., 2017.
30.
HCV in Children.  IDSA.  Available from:  https://www.hcvguidelines.org/unique-
populations/children. Updated on: 2018 May 24.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Program Development
Protocol Author Clinical Program 
Development
Therapeutic Area Infectious Disease  
Data and Statistical Sciences
Pharmacokinetics


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Appendix C.
Study Activities
Treatment Period
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8b
Wk 12b
EOT*/Premature D/Cb
Informed Consentc
X
Medical Historyd
X
X
Physical Exame
X
X
X
X
X
X
Vital Signs, Weight, Height, Body Mass Index
X
X
X
X
X
X
X
ECGf
X
Xf
Pregnancy Test (serum [s] urine [u])g
X (s)
X (u)
X (u)
X(u)
X (u)
X (u)
Hematology/Chemistry/Urinalysis/Coagulation Panelh
X
X
X
X
X
X
X
FSHi
X
HbsAg, Anti-HCV Ab, Anti-HIV Ab
X
HCV Genotype and Subtype
X
Historical Liver Biopsy or FibroScan assessment or Screening FibroTest, 
Discriminant Score or liver biopsy for liver cirrhosisj
X
Longitudinal Fibrotest & APRIk
X
Child Pugh Scorel
X
HCC Assessment:  Liver ultrasoundm and Alpha fetoproteinm
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
Adverse Event Assessmentn
X
X
X
X
X
Study Drugs Dispensation
X
X
Xo
Xo
Dispense/Collect/Review Study Drug Dosing Card and HIV-1 Medication 
Card (if applicable)
Xw
X
X
X
Xp
Xp
X


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Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8b
Wk 12b
EOT*/Premature D/Cb
Study Drug Accountability and/or Review of Study Drug Adherence
X
X
X
X
X
PK Sampling
X
Xq
X
X
X
X
HIV RNA Samplesr
X
X
X
X
X
X
Flow Cytometryr
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
Assignment of Subject Number via IRTs
X
Enrollment
X
HCV Resistance Samplet
X
Patient Reported Outcomeu
X
X
Palatability Questionnairev
X
X
D/C = Discontinuation; EOT (End of Treatment) = Final Treatment Visit; Day 1 = Baseline Visit 
*
The EOT visit can be at Week 8, Week 12, or Week 16 in accordance with Section 5.1 and activities should be conducted that are located in the EOT column.  Treatment 
duration will be assigned according to Subjects HCV genotype, cirrhosis and prior HCV treatment experience status. 
a.
All procedures to be performed prior to first dose, with the exception of the PK sample which will be obtained 4 hours post-dose.
b.
The Week 8 study visits apply to all subjects whose treatment duration is 12 weeks and 16 weeks in accordance with Section 5.1.  The Week 12 study visits apply to all 
subjects whose treatment duration is 16 weeks in accordance with Section 5.1.  Subjects who prematurely discontinue the Treatment Period should return to the site to 
complete the Premature D/C Visit Procedures (preferably prior to the initiation of any other anti-HCV therapy).  
c.
Parent(s)/guardian(s) need to sign an IRB/IEC approved informed consent for the study prior to performing any screening or study-specific procedures.  Additionally an 
assent from the subject will be obtained to meet the institution's IEC requirements, as applicable.
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit prior to study drug administration and will serve as the Baseline for 
clinical assessment.
e.
A symptom-directed physical examination may be performed at any other visit, when necessary.
f.
ECG will be measured only in the intensive PK portion of both parts, prior to any blood collection procedures, excluding subjects in Japan.
g.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential should have urine pregnancy testing done through Post-Treatment Week 4.  
Females of non-childbearing potential (as defined per protocol Inclusion Criteria 3) at Screening do not require pregnancy testing.


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h.
For non-cirrhotic subjects:  Coagulation panel performed only at Day 1, at EOT/premature D/C, and as clinically indicated. 
For cirrhotic subjects:  Coagulation panel is required at all treatment visits, including the EOT/premature D/C visit.
i.
FSH for all female subjects aged 9 to < 18 years old.
j.
Subjects with no history of cirrhosis who have not had a liver biopsy within 24 months prior to screening, or Fibroscan within 6 months prior to screening will have a 
screening FibroTest and APRI to determine the presence or absence of cirrhosis for the purpose of treatment assignment.  Subjects who have a liver biopsy or FibroScan 
indicating cirrhosis at any time in the past will not need a Fibrotest and APRI to be performed at screening as evidence of cirrhosis.
k.
Perform a Fibrotest and APRI at Day 1 for any subject who did not have a FibroTest and APRI done during Screening.
l.
Applies only to subjects with cirrhosis.  The Child-Pugh score will be calculated in the EDC RAVE system.  Subjects who were considered to be non-cirrhotic at the 
Screening visit but identified as cirrhotic (according to definitions listed in Section 5.3.1.1) during the screening period will return to the site prior to the baseline visit for 
Child-Pugh assessment.
m.
HCC assessment for subjects with compensated cirrhosis only:  Liver ultrasound will be performed at the screening visit.  Subjects with a historical negative liver ultrasound, 
CT or MRI (within 3 months prior to screening) are not required to undergo a screening ultrasound.
n.
See specific information regarding the adverse event collection in Section 6.1.1.1.
o.
Study drugs are dispensed at Week 8 for subjects on 12 weeks of treatment and at Weeks 8 and 12 for subjects on 16 weeks of treatment.
p.
Dosing card is filled out with date and time (to the nearest minutes) of the 2 doses before PK draws in Part 1 and Part 2.  Dosing cards should not be dispensed at Weeks 8 or 
12 if those are EOT visits for the subject (Section 5.3.1.1).
q.
Intensive PK sampling will be done at Week 2 for the first approximately 12 subjects in each of the age groups and subjects in Japan participating in J-IPK (Section 5.3.2.1).  
Intensive PK samples will be collected at Week 2 visit at time points zero (0) and after two (2), four (4), six (6) and twelve (12) hours of drug intake.  For subjects in Japan 
who will not participate in the J-IPK schedule, samples will be collected at Week 2 visit at time points zero (0) and after two (2) and four (4) hours of drug intake.
r.
Only applicable for HCV/HIV-1 co-infected subject.
s.
The Subject will retain the subject number throughout the course of the study.
t.
Resistance sample will be collected at Day 1.  For a subject who meets virologic failure criteria, a resistance sample must be drawn at the confirmatory visit.  If HCV RNA is 
< 1000 IU/mL in the sample collected at the confirmatory visit, another resistance sample will be collected in the following visit to ensure the HCV RNA is ≥ 1000 IU/mL.
u.
The PRO should be administered as the first study procedure.
v.
Only subjects in Part 2 will complete the palatability questionnaire, at Week 2 and EOT or premature discontinuation visit. 
w.
Dispense HIV-1 Medication Card at screening, if applicable.


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Post Treatment Period
Activity
PT 
Wk 4
PT
Wk 12
PT
Wk 24
PT
Wk 36
PT
Wk 48
PT
Wk 96
PT 
Wk 144
Premature 
D/C
Vital Signs, Weight, Height, Body Mass Index
X
X
X
X
X
X
X
X
Urine Pregnancy Testa
X
Xa
Longitudinal Fibrotest and APRI
X
X
X
X
X
Hematology/Chemistry/Urinalysisb/Coagulation Panelb
X
X
X
X
X
X
HCC Assessment:  Liver Ultrasoundc
X
X
X
X
HCC Assessment:  Alpha fetoproteinc
X
X
X
X
X
Concomitant Medication Assessmentd
X
X
X
X
X
X
X
X
Adverse Event Assessmente
X
X
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
X
HCV Resistance Samplef
X
X
X
X
X
X
X
X
Patient Reported Outcomeg
X
Xg
HIV RNA Samplesh
X
X
Flow Cytometryh
X
D/C = Discontinuation
a.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential should have urine pregnancy testing done through Post-Treatment Week 4.  
Pregnancy testing will be performed at PT Premature D/C visit only if the subject discontinues prior to PT Wk 4.
b.
Urinalysis will not be conducted after the Post-Treatment Week 4 visit.  Urinalysis will be performed at PT Premature D/C visit only if the subject discontinues prior to PT 
Wk 4.  The coagulation panel will be obtained at PTW4 for all patients.  For non-cirrhotic subjects:  Perform the coagulation panel at visits only if clinically indicated after 
post treatment Week 4.
c.
HCC assessment for subjects with compensated cirrhosis only.


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d.
Concomitant medication will be collected for 30 days after study drug has been stopped, thereafter only antiviral medicines taken for the treatment of HCV and medications 
taken for SAEs will be recorded.  See section 5.2.3.
e.
Non-serious AEs and all SAEs will be collected until 30 days post dosing.  Only spontaneously reported SAEs will be collected thereafter.  See Section 6.1.
f.
Resistance samples are only collected for patients that meet virologic failure criteria and should be drawn at the confirmatory visit, and if confirmed, at all subsequent visits.
g.
The PRO should be administered as the first study procedure.  PRO will be accessed at the Premature D/C visit only if the subject discontinues prior to PT Wk 12.
h.
Only applicable for HCV/HIV-1 co-infected subject.


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Appendix D.
Estimated Blood Loss for Pediatric Subjects
Treatment Period – Part 1:  Excluding Subjects in Japan
Screening
Day 1
Wk 2*
Wk 4
Wk 8
Wk 12
Wk 16 
or EOT
Premature 
D/C from 
Treatment
Estimated 
Whole Blood 
Drawn (mL) 
for standard 
tubes
45.3
38.8
23.3
26.3
21.3
21.3
28.8
28.8
*
For those not participating in IPK, the estimated whole blood drawn at Wk 2 is 15.3 mL.
Post-Treatment Period – Part 1:  Excluding Subjects in Japan
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wk 96 
and 144
Premature 
D/C
Estimated Whole 
Blood Drawn (mL) 
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Treatment Period – Part 1:  Subjects in Japan
Screening
Day 1
Wk 2*
Wk 4
Wk 8
Wk 12 
or EOT
Premature 
D/C from 
Treatment
Estimated Whole Blood 
Drawn (mL) for standard 
tubes
52.8
38.8
23.3
26.3
21.3
28.8
28.8
*
For those not participating in J-IPK, the estimated whole blood drawn at Wk 2 is 19.3 mL.


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Post-Treatment Period – Part 1:  Subjects in Japan
Estimated Whole Blood 
Drawn (mL) for 
standard tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
24.3
20.8
8.5
6
17.3
17.3
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Treatment Period – Part 2:  Excluding Subjects in Japan
Estimated 
Whole Blood 
Drawn (mL)
Screening
Day 1
Wk 2*
Wk 4
Wk 8
Wk 12
Wk 16 
or EOT
Premature 
D/C from 
Treatment
for standard tubes
45.3
34.8
23.3
26.3
21.3
21.3
28.8
28.8
for pediatric tubes
32.3
29.2
17.7
22.1
17.1
17.1
23.2
23.2
*
For those not participating in IPK, the estimated whole blood drawn at Wk 2 is 15.3 mL (for standard tubes)/ 
9.7 mL (for pediatric tubes).
Post-Treatment Period – Part 2:  Excluding Subjects in Japan
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
for pediatric tubes
20.1
14.8
5.1
4
9.9
9.9
11.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Treatment Period – Part 2:  Subjects in Japan
Estimated Whole Blood 
Drawn (mL)
Screening
Day 1
Wk 2*
Wk 4
Wk 8
Wk 12 
or EOT
Premature 
D/C from 
Treatment
for standard tubes
52.8
34.8
23.3
26.3
21.3
28.8
28.8
for pediatric tubes
40.8
31.3
20.3
23.3
18.3
25.3
25.3
*
For those not participating in J-IPK, the estimated whole blood drawn at Wk 2 is 19.3 mL (for standard tubes)/ 
16.3 ml (for pediatric tubes).


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Post-Treatment Period – Part 2:  Subjects in Japan
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
for pediatric tubes
21.3
17.8
6
4
13.8
13.8
14.3
An HCV resistance sample may be obtained per protocol in addition to the above blood loss.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.


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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Number of Subjects to be Enrolled:
Previously read:
Approximately 110 subjects
Has been changed to read:
Approximately 125 subjects
Section 1.2  Synopsis
Subsection Methodology:
First paragraph, first sentence previously read:
The study will enroll approximately 110 HCV-infected pediatric subjects, divided into 
four (4) age groups, 3 to < 6, 6 to < 9, 9 to < 12, and 12 to < 18 years of age.
Has been changed to read:
The study will enroll approximately 125 HCV-infected pediatric subjects, divided into 
four (4) age groups, 3 to < 6, 6 to < 9, 9 to < 12, and 12 to < 18 years of age.
Section 1.2  Synopsis
Subsection Methodology:
Second paragraph, first sentence previously read:
Within each age group, approximately 12 HCV-infected pediatric subjects will be 
enrolled for intensive pharmacokinetics (IPK) in order to adequately characterize the 
pharmacokinetics (PK) of a particular age group for dose confirmation, and the remainder 
of subjects will be enrolled for the evaluation of safety and efficacy of each age group 
until the total pediatric study population reaches approximately 110 subjects.  


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Has been changed to read:
Within each age group, approximately 12 HCV-infected pediatric subjects will be 
enrolled for intensive pharmacokinetics (IPK) in order to adequately characterize the 
pharmacokinetics (PK) of a particular age group for dose confirmation, and the remainder 
of subjects will be enrolled for the evaluation of safety and efficacy of each age group 
until the total pediatric study population reaches approximately 125 subjects.  
Section 1.2  Synopsis
Subsection Investigational Products:
"Pediatric formulation:" previously read:
Pediatric formulation:  Glecaprevir/Pibrentasvir 15.67%+8.25% film-coated pellets
Has been changed to read:
Pediatric formulation:  Glecaprevir/Pibrentasvir 15.67%+8.25% film-coated 
pellets/granules
Section 1.2  Synopsis
Subsection Proposed Doses:
Previously read:
Cohort
Age (yrs); 
Weight Band
GLE/PIB Dose
1
12 – < 18; 
≥ 45 kg
300 mg/120 mg
2
9 – < 12 
30 – < 45 kg
200 mg + 75 mg*
3
6 – < 9; 
20 – < 30 kg
160 mg + 60 mg*
4
3 – < 6; 
12 – < 20 kg
120 mg + 45 mg*
*
Exposures of Glecaprevir and Pibrentasvir will be evaluated in approximately 12 subjects with intensive PK 
samples in each Cohort and compared to the exposures observed in Adults.  Following analysis, target doses may 
be adjusted.


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Has been changed to read:
Cohort
Age (yrs); 
Weight Band
GLE/PIB Dose
1
12 – < 18; 
≥ 45 kg
300 mg/120 mg
2
9 – < 12 
30 – < 45 kg
250 mg + 100 mg
3
6 – < 9; 
20 – < 30 kg
200 mg + 80 mg
4
3 – < 6; 
12 – < 20 kg
150 mg + 60 mg
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
NDA
New Drug Application
Section 3.0  Introduction
Sixth paragraph, second and third sentence previously read:
For first-line treatment for chronic HCV infection in children, the American Association 
for the Study of Liver Diseases (AASLD) recommends the combination of pegylated 
interferon 2b (pegIFN-2b) and ribavirin (RBV), which is approved by the United States 
Food and Drug Administration (FDA) for use in children aged 3 to 17 years.20  In 
addition, the combinations of ledipasvir/sofosbuvir, and sofosbuvir + ribavirin have been 
approved for use in adolescents, though neither combination covers all major genotypes 
alone.28,29  
Has been changed to read:
The American Association for the Study of Liver Diseases (AASLD) recommends that 
DAA regimens should be recommended independent of disease severity, if a regimen is 
available dependent upon the child's age group.30  The combinations of 
ledipasvir/sofosbuvir, and sofosbuvir + ribavirin have been approved for use in 
adolescents, though neither combination covers all major genotypes alone.28,29  


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Section 3.0  Introduction
Sixth paragraph, fifth and sixth sentence previously read:
There are several ongoing studies of interferon-free regimens in children including 
sofosbuvir/ledipasvir for GT1 (NCT02249182), sofosbuvir (SOF) plus RBV for GT2 and 
3 (NCT02175758), and ombitasvir/paritaprevir/ritonavir with or without dasabuvir for 
GT1 and GT4 (NCT02486406).  Early results with direct-acting antiviral (DAA) therapy 
are promising, showing high SVR12 rates in adolescents, similar to adults.  
Has been changed to read:
There are several studies of interferon-free regimens in children including 
sofosbuvir/ledipasvir for GT1 (NCT02249182), sofosbuvir (SOF) plus RBV for GT2 and 
3 (NCT02175758), and ombitasvir/paritaprevir/ritonavir with or without dasabuvir for 
GT1 and GT4 (NCT02486406).  Results with direct-acting antiviral (DAA) therapy are 
promising, showing high SVR12 rates in adolescents, similar to adults.  
Section 3.0  Introduction
Seventh paragraph, last sentence previously read:
A pediatric formulation comprised of film-coated pellets of GLE and PIB, respectively, in 
a single container for a convenient QD oral administration with a dosing vehicle has been 
developed.
Has been changed to read:
A pediatric formulation comprised of film-coated pellets/granules of GLE and PIB, 
respectively, in a single container for a convenient QD oral administration with a dosing 
vehicle has been developed.
Section 3.0  Introduction
Subsection GLE/PIB Dose Selection Strategy for the Pediatric Population
Previously read:
AbbVie's pediatric formulation development strategy is to develop a dosage form that 
provides suitable and flexible dosing across the pediatric age range of 3 to < 18 years.  


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Development of a suitable pediatric formulation was guided by considerations of 
solubility, dose flexibility, stability, compatibility, and ease and reliability of the 
manufacturing process.  It is likely the adult tablets will be suitable for adolescent subjects 
12 years of age and older with weights ≥ 45 kg.  This population is able to swallow tablets 
and utilizing the adult tablet would enable earlier enrollment of this population.
GLE and PIB exhibit low aqueous solubility.  Due to probable requirement of solvent(s) 
that are undesirable for pediatric patients for any oral solution, and 
 
, AbbVie developed a pediatric 
formulation based on the solid oral formulations used to manufacture the adult tablets.  
Current dose selection strategy for the purposes of this protocol is based on BSA 
normalization and age appropriate scaling.  The objective was to select a dose for each 
age group in mg that provides exposures in the target range shown to be safe and 
efficacious in adults based on the formulation available currently.  Clinical trial 
simulations have been performed to assist in dose selection in the pediatric population.  
From the clinical trial simulations performed at the proposed GLE and PIB doses in the 
pediatric population, summary statistics for each age group for GLE and PIB and the 
percent of subjects with exposures ≤ 0.5× and ≥ 2× the target AUC were estimated and 
are shown in Table 5.


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Table 5.
Summary Statistics of the Simulations for the Estimated AUC of 
Each Age Group for GLE and PIB
Estimated AUC (ng•hr/mL)
% Subjects with 
Exposures ≤ 0.5× 
and ≥ 2× of the 
Target AUC
Age Group 
(yr)
Dose 
(mg)
5% 
Percentile
Median
Geometric 
Mean
95% 
Percentile
≤ 0.5×
≥ 2×
GLE
≥ 3 to < 6
100
990
5100
5100
26000
27
22
6 to < 9
140
1100
5400
5400
28000
25
24
9 to < 12
175
1000
5300
5300
27000
26
23
12 to < 18
250
1100
5700
5700
29000
23
25
Observed in
Adults
300
980
5300
5500
(Target AUC)
29000
22
22
PIB
≥ 3 to < 6
40
500
1300
1300
3300
14
9
6 to < 9
56
530
1400
1400
3500
12
11
9 to < 12
70
520
1300
1300
3400
13
10
12 to < 18
100
550
1400
1400
3700
10
12
Observed in
Adults
120
590
1400
1400
(Target AUC)
3400
14
12
At the doses listed in Table 5, the geometric mean and median exposures are comparable 
within each age group for GLE and PIB.  The variability in each age group is expected to 
be similar to the variability observed in adults.
The doses shown in Table 5 are based on currently available clearance data in adult 
subjects with HCV infection in Phase 2 studies.  




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and utilizing the adult tablet would enable earlier enrollment of this population. In Part 1 
of Study M16-123, a total of 47 adolescent subjects received daily administration of 
GLE/PIB 300 mg/120 mg. PK results showed that the exposures of GLE and PIB in 
HCV-infected adolescent subjects (12 to < 18 years of age) were similar to the exposures 
observed in HCV-infected adult subjects following administration of GLE/PIB 
300 mg/120 mg.
GLE and PIB exhibit low aqueous solubility.  Due to probable requirement of solvent(s) 
that are undesirable for pediatric patients for any oral solution, and 
 
 AbbVie developed a pediatric 
formulation based on the solid oral formulations used to manufacture the adult tablets.  
To provide exposures in pediatric subjects comparable to adult exposures using the 
pediatric formulation, the GLE and PIB dose in pediatric patients of 3 to < 12 years of age
were revised from originally proposed doses.  Preliminary PK results from the initial 
proposed pediatric doses demonstrated that though GLE and PIB exposures were within 
the range of exposure for efficacy and safety in adults for each of the pediatric cohorts, the 
average exposures in each of the cohorts were lower than the targeted AUC and led to a 
dose adjustment. Additional subjects were enrolled and the intensive PK results obtained, 
and additional population PK modeling performed, confirming that the adjusted doses 
demonstrate exposures that would allow for bridging of adult data, using a 50/20 mg dose 
ratio.  These doses (Table 11) are proposed to be used in the subjects enrolling in the non-


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IPK portion of Part 2, in order to confirm that the doses would provide similar exposures 
observed in HCV-infected adult subjects, close to the targeted AUC.
Section 3.3  Pediatric Study Plan and Pediatric Investigational Plan
Last paragraph
Add:  new third and fourth sentence
On December 14, 2016, AbbVie submitted its waiver request as part of the original New
Drug Application (NDA) 209394 (eCTD Sequence 0000).  On August 03, 2017, FDA 
waived the pediatric requirement for children younger than 3 years of age because the 
necessary studies are impossible or highly impracticable (Reference ID:  4134372).
Section 4.2  Secondary Objective
First paragraph previously read:
The secondary objectives are to assess the efficacy of GLE/PIB by assessing:
Has been changed to read:
The secondary objectives are to assess:
Section 4.2  Secondary Objective
Sixth and seventh bullet previously read:
●
Assess pharmacokinetics and emergence/persistence of viral variants in 
subjects with available samples;
●
Assessment of palatability/acceptability of pediatric formulation.
Has been changed to read:
●
Pharmacokinetics and emergence/persistence of viral variants in subjects with 
available samples;
●
Palatability/acceptability of pediatric formulation.


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Section 5.1  Overall Study Design and Plan:  Description
First paragraph, first sentence previously read:
The study is designed to enroll approximately 110 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Has been changed to read:
The study is designed to enroll approximately 125 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, second sentence previously read:
Part 2 of the study allows for enrollment of approximately 66 HCV infected, GT1 – 6 
pediatric subjects divided into the 3 to < 6, 6 to < 9 and 9 to < 12 years old age groups.
Has been changed to read:
Part 2 of the study allows for enrollment of approximately 81 HCV infected, GT1 – 6 
pediatric subjects divided into the 3 to < 6, 6 to < 9 and 9 to < 12 years old age groups.
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph
Delete:  last sentence
Enrollment into Part 2 may begin upon availability of the pediatric formulation.


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Figure 1.  Study Schematic
Previously read:
Has been changed to read:


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Section 5.2.1  Inclusion Criteria
Criterion 9, first sentence previously read:
Subject co-infected with HIV-1 must be on a stable antiretroviral therapy (ART) for at 
least 8 weeks prior to screening, consisting of the qualifying ART regimens as outlined in 
Section 5.2.4 (Concomitant HIV-1 Antiretroviral Therapy).  
Has been changed to read:
Subject co-infected with HIV-1 must be on a stable antiretroviral therapy (ART) for at 
least 8 weeks prior to screening, consisting of the qualifying ART regimens as outlined in 
Section 5.2.3.1 (Concomitant HIV-1 Antiretroviral Therapy).  
Section 5.3.3  Efficacy Variables
Section title previously read:
Efficacy Variables
Has been changed to read:
Primary and Secondary Variables
Section 5.5.1  Treatments Administered
Subsection Part 2 Pediatric Formulation:
First paragraph, first sentence previously read:
Glecaprevir and Pibrentasvir (GLE/PIB) will be provided by the Sponsor as separate 
15.67% and 8.25% film-coated pellets.  
Has been changed to read:
Glecaprevir and Pibrentasvir (GLE/PIB) will be provided by the Sponsor as separate 
15.67% and 8.25% film-coated pellets/granules.  


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Section 5.5.1  Treatments Administered
Subsection Part 2 Pediatric Formulation:
Second paragraph, first sentence previously read:
The film-coated pellets are packed in unit doses and are to be administered at once QD 
into a dosing vehicle.  
Has been changed to read:
The film-coated pellets/granules are packed in unit doses and are to be administered at 
once QD into a dosing vehicle. 
Table 11.  Identity of Investigational Product
Add:  Study Part "2"
Study Part
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
2
GLE/PIB
AbbVie
Oral
Film-coated 
granulesa
50 mg/20 mg 
unit dose
Table 11.  Identity of Investigational Product
Add:  new table note "a."
Film-coated pellets and granules are the same formulation, and the terminology is 
considered interchangeable. They are listed separately, however, to reflect the changes in 
the packaging and labeling from pellets in bottles to granules in sachets.
Section 5.5.2.2  Storage and Disposition of Study Drugs
Table previously read:
Study Drug
Storage Conditions
GLE/PIB film-coated Tablets
15° to 25°C (59° to 77°F)
GLE/PIB film-coated pellets
15° to 25°C (59° to 77°F), Protect from moisture


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Has been changed to read:
Study Drug
Storage Conditions
GLE/PIB film-coated Tablets
15° to 25°C (59° to 77°F)
GLE/PIB film-coated pellets
15° to 25°C (59° to 77°F), Protect from moisture
GLE/PIB film-coated granules 
2° to 25°C (36° to 77°F)a
a.
Film-coated pellets and granules are the same formulation and terminology is considered interchangeable. They 
are listed separately, however, to reflect the changes in the packaging and labeling from pellets in bottles to 
granules in sachets. 
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Fourth paragraph previously read:
In Part 2 of the study, caps on the number of subjects in each age group (3 to < 6, 6 to < 9, 
9 to < 12 years of age) will be employed in IRT to ensure that approximately 22 subjects 
regardless of prior treatment experience and cirrhotic status are enrolled per age group.
Has been changed to read:
In Part 2 of the study, caps on the number of subjects in each age group (3 to < 6, 6 to < 9, 
9 to < 12 years of age) will be employed in IRT to ensure that approximately 22 subjects 
on the final recommended dose regardless of prior treatment experience and cirrhotic 
status are enrolled per age group.
Section 5.6.4  Selection of Doses in the Study
Second paragraph previously read:
AbbVie has developed a separate pediatric formulation for GLE/PIB for use in Part 2 of 
the present study.  
Has been changed to read:
AbbVie has developed a separate pediatric formulation for GLE + PIB for use in Part 2 of 
the present study.  


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Section 5.6.4  Selection of Doses in the Study
Third paragraph, last sentence previously read:
Given the wide therapeutic window of GLE and PIB, the updated initial doses will not 
anticipate to change the efficacy/safety profiles.
Has been changed to read:
Given the wide therapeutic window of GLE and PIB, the updated doses will not anticipate 
to change the efficacy/safety profiles.
Section 5.6.4  Selection of Doses in the Study
Fourth paragraph previously read:
For the present study, the proposed doses by weight band range are shown in Table 12.
Has been changed to read:
For the present study, the final proposed doses by weight band range are shown in 
Table 11.
Table 12.  Proposed Glecaprevir and Pibrentasvir Doses for the Pediatric Population
Previously read:
Formulation
Age Group (yrs) & 
Weight Band (kg)
Doses (mg)
Glecaprevir
Pibrentasvir
Pediatric formulation
3 to < 6 yr
12 to < 20 kg
120
45
6 to < 9 yr
≥ 20 to < 30 kg
160
60
9 to < 12 yr
≥ 30 to < 45 kg
200
75
Adult formulation
12 to < 18 yr
≥ 45 kg
300
120


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Has been changed to read:
Formulation
Age Group (yrs) & 
Weight Band (kg)
Final Proposed Doses (mg)
Glecaprevir
Pibrentasvir
Pediatric formulation
3 to < 6 yr
12 to < 20 kg
150
60
6 to < 9 yr
≥ 20 to < 30 kg
200
80
9 to < 12 yr
≥ 30 to < 45 kg
250
100
Adult formulation
12 to < 18 yr
≥ 45 kg
300
120
Section 5.6.4  Selection of Doses in the Study
Fourth and fifth paragraph previously read:
The doses of the pediatric formulation may be adjusted dependent upon the intensive 
pharmacokinetic analysis of the first approx. 6 subjects of each of the ≥ 3 to < 12 year old 
age cohorts.  Once final dosing of an age cohort has been confirmed, further drug dose 
changes for an age cohort will be included into a protocol amendment if the final dose 
differs from the current proposed dosing.
For Part 1, enrollment will start with pediatric subjects ≥ 12 to < 18 years old who are 
≥45 kg and willing to swallow the adult formulations.  Part 2 enrollment will start in 
pediatric subjects ≥ 3 to < 12 years old with the pediatric formulation.  Based on current 
modeling and available PK data, the above proposed doses of the pediatric formulation 
are the target doses for use in children < 12 years of age.  The pharmacokinetic and 
clinical data will be used to confirm appropriate exposure in each of the ≥ 3 to < 12 years 
old age groups.  Dose adjustments will be made if necessary to ensure safe and efficacious 
exposures, but not to exceed the adult dose of 300/120 mg of GLE/PIB.
Has been changed to read:
The doses of the pediatric formulation were adjusted based upon the intensive 
pharmacokinetic analysis of the first approx. 17 subjects enrolled across the age cohorts.  


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The final proposed dosing for each age cohort has been confirmed by additional IPK 
analysis. These drug dose changes are included in this protocol amendment.  Dose 
adjustments were made as necessary to ensure safe and efficacious exposures, but did not 
exceed the adult dose of 300/120 mg of GLE/PIB.
For Part 1, enrollment commenced with pediatric subjects ≥ 12 to < 18 years old who are 
≥45 kg and willing to swallow the adult formulation.  Part 2 enrollment  initiated in 
pediatric subjects ≥ 3 to < 12 years old with the pediatric formulation.  Based on current 
modeling and available PK data at the completion of the IPK portion of Part 2, the above 
proposed doses of the pediatric formulation are the target doses for use in children 
< 12 years of age.  The pharmacokinetic and clinical data will be used to confirm 
appropriate exposure in each of the ≥ 3 to < 12 years old age groups.  
Section 6.1.5  Adverse Event Reporting
Last paragraph previously read:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.  
Has been changed to read:
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.


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Section 6.1.7.2  Management of ALT Elevations
Second bullet, sub-bullet previously read:
If the subject is found to have an active hepatitis B infection, additional evaluation with a 
Hepatitis B Questionnaire should be performed by the investigator.
Has been changed to read:
If the subject is found to have an active hepatitis B infection, additional evaluation by 
completion of the eCRF Transaminase Elevations Questionnaire should be performed by 
the investigator.
Section 7.0  Protocol Deviations
"Primary Contact:" previously read:
Study Management Associate
Medical Department
Avenida de Burgos, 91
28050 Madrid, Spain
Office:
Fax:
Has been changed to read:
Study Management Associate
One North Waukegan Road
North Chicago, IL 60064
Office:
Section 8.1.2  Efficacy
Section title previously read:
Efficacy


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Has been changed to read:
Primary, Secondary, and Efficacy Analyses
Section 8.1.2  Efficacy
Add:  new first paragraph
The primary and secondary analyses of PK parameters will be performed on subjects in 
the ITT population with available PK samples, unless otherwise specified.
Section 8.1.2.1  Primary Efficacy Endpoint
Section title previously read:
Primary Efficacy Endpoint
Has been changed to read:
Primary Endpoints
Section 8.1.2.2  Secondary Efficacy Endpoints
Section title previously read:
Secondary Efficacy Endpoints
Has been changed to read:
Secondary Endpoints
Section 8.1.2.2  Secondary Efficacy Endpoints
First paragraph previously read:
The secondary efficacy endpoints are:
Has been changed to read:
The secondary endpoints are:


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Section 8.1.2.3  Additional Efficacy Endpoint
Section title previously read:
Additional Efficacy Endpoint
Has been changed to read:
Additional Efficacy Endpoints
Section 8.1.7  Pharmacokinetic and Exposure-Response Analyses
First paragraph previously read:
Plasma concentrations of GLE and PIB will be tabulated and summarized for subjects in 
Part 1 and Part 2 by age group and overall.
Has been changed to read:
Plasma concentrations of GLE and PIB will be tabulated and summarized for subjects in 
Part 1 and Part 2 by age group, actual dose administered, and overall.
Section 8.1.7  Pharmacokinetic and Exposure-Response Analyses
Third paragraph, first sentence previously read:
Values for the pharmacokinetic parameters of GLE and PIB including the Cmax, Ctrough, 
and AUC will be tabulated and summarized for subjects by age group and overall.  
Has been changed to read:
Values for the pharmacokinetic parameters of GLE and PIB including the Cmax, Ctrough, 
and AUC will be tabulated and summarized for subjects by age group, actual dose 
administered, and overall.  
Section 8.2  Determination of Sample Size
First paragraph, first sentence previously read:
It is planned to enroll a total of approximately 110 subjects into this study.  


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Has been changed to read:
It is planned to enroll a total of approximately 125 subjects into this study.  
Section 8.2  Determination of Sample Size
Last paragraph previously read:
Additional subjects will be enrolled to reach the proposed total of 110 subjects to provide 
safety and efficacy information.
Has been changed to read:
Additional subjects will be enrolled to reach the proposed total of 125 subjects to provide 
safety and efficacy information.
Section 15.0  Reference List
Add:  new Reference 30
HCV in Children.  IDSA.  Available from:  https://www.hcvguidelines.org/unique-
populations/children. Updated on: 2018 May 24.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Program Development
Protocol Author Clinical Program 
Development
Therapeutic Area Infectious Disease  
Data and Statistical Sciences
Pharmacokinetics


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Has been changed to read:
Name
Title
Functional Area
Clinical Program Development
Protocol Author Clinical Program 
Development
Therapeutic Area Infectious Disease  
Data and Statistical Sciences
Pharmacokinetics
Appendix C.  Study Activities
Subsection Treatment Period
Table note "h." previously read:
Non-cirrhotic subjects:  Coagulation panel performed only at Day 1 and as clinically 
indicated. 
Cirrhotic subjects:  Coagulation panel is required at all treatment visits.
Has been changed to read:
For non-cirrhotic subjects:  Coagulation panel performed only at Day 1, at EOT/premature 
D/C, and as clinically indicated. 
For cirrhotic subjects:  Coagulation panel is required at all treatment visits, including the 
EOT/premature D/C visit.
Appendix C.  Study Activities
Subsection Treatment Period
Table note "j." first sentence previously read:
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 
24 months prior to screening, will have a screening FibroTest and APRI to determine the 
presence or absence of cirrhosis for the purpose of treatment assignment.  


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Has been changed to read:
Subjects with no history of cirrhosis who have not had a liver biopsy within 24 months 
prior to screening, or Fibroscan within 6 months prior to screening will have a screening 
FibroTest and APRI to determine the presence or absence of cirrhosis for the purpose of 
treatment assignment.  
Appendix C.  Study Activities
Subsection Post Treatment Period
Activity "Hematology/Chemistry/Urinalysisb/Coagulation Panel" previously read:
Hematology/Chemistry/Urinalysisb/Coagulation Panel
Has been changed to read:
Hematology/Chemistry/Urinalysisb/Coagulation Panelb
Appendix C.  Study Activities
Subsection Post Treatment Period
Table note "b."
Add:  new third and fourth sentence
The coagulation panel will be obtained at PTW4 for all patients.  For non-cirrhotic 
subjects:  Perform the coagulation panel at visits only if clinically indicated after post 
treatment Week 4.
Appendix C.  Study Activities
Subsection Post Treatment Period
Table note "f." previously read:
Resistance samples are only collected for patients that meet virologic failure criteria.
Has been changed to read:
Resistance samples are only collected for patients that meet virologic failure criteria and 
should be drawn at the confirmatory visit, and if confirmed, at all subsequent visits.


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Appendix D.  Estimated Blood Loss for Pediatric Subjects
Subsection Post-Treatment Period – Part 1:  Excluding Subjects in Japan
Previously read:
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wk 96 
and 144
Premature 
D/C
Estimated Whole 
Blood Drawn (mL) 
for standard tubes
24.3
19.0
8.5
6
15.5
15.5
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Has been changed to read:
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wk 96 
and 144
Premature 
D/C
Estimated Whole 
Blood Drawn (mL) 
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Appendix D.  Estimated Blood Loss for Pediatric Subjects
Subsection Post-Treatment Period – Part 1:  Subjects in Japan
Previously read:
Estimated Whole Blood 
Drawn (mL) for 
standard tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
24.3
19.0
8.5
6
15.5
15.5
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.


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Has been changed to read:
Estimated Whole Blood 
Drawn (mL) for 
standard tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
24.3
20.8
8.5
6
17.3
17.3
18.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Appendix D.  Estimated Blood Loss for Pediatric Subjects
Subsection Post-Treatment Period – Part 2:  Excluding Subjects in Japan
Previously read:
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
19.0
8.5
6
15.5
15.5
18.3
for pediatric tubes
20.1
13.4
5.1
4
8.5
8.5
11.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Has been changed to read:
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
for pediatric tubes
20.1
14.8
5.1
4
9.9
9.9
11.3
An HCV resistance sample may be obtained per protocol in addition to the above blood drawn.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.


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Appendix D.  Estimated Blood Loss for Pediatric Subjects
Subsection Post-Treatment Period – Part 2:  Subjects in Japan
Previously read:
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
19
8.5
6
15.5
15.5
18.3
for pediatric tubes
21.3
16
6
4
12
12
14.3
An HCV resistance sample may be obtained per protocol in addition to the above blood loss.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.
Has been changed to read:
Estimated Whole 
Blood Drawn (mL)
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96 
and 144
Premature 
D/C
for standard tubes
24.3
20.8
8.5
6
17.3
17.3
18.3
for pediatric tubes
21.3
17.8
6
4
13.8
13.8
14.3
An HCV resistance sample may be obtained per protocol in addition to the above blood loss.  The estimated whole 
blood drawn for the HCV Resistance sample is 6.0 mL.



SAP_001.pdf: 
Glecaprevir/Pibrentasvir
M16-123 – Statistical Analysis Plan
Version 1.0 – 24 Jan 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-123
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of 
Glecaprevir/Pibrentasvir in Pediatric Subjects with 
Genotypes 1 – 6 Chronic Hepatitis C Virus (HCV) 
Infection
Date:  24 Jan 2018
Version 1.0
NCT03067129


Glecaprevir/Pibrentasvir
M16-123 – Statistical Analysis Plan
Version 1.0 – 24 Jan 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 8
4.4
Planned Interim Analyses and Final Analysis ......................................... 8
5.0
Analysis Populations .............................................................9
5.1
Definition for Analysis Populations ........................................................ 9
5.1.1
Intention-to-Treat (ITT) Population ........................................................ 9
5.1.2
Modified Intention-to-Treat (mITT) Population.................................... 10
5.1.3
Safety Population ................................................................................. 10
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions .......................................................... 10
6.1
Definition of Baseline and End of Treatment Assessment..................... 10
6.1.1
Baseline................................................................................................ 10
6.1.2
Study Days........................................................................................... 11
6.2
Definition of Analysis Windows........................................................... 12
6.3
Missing Data Imputation ...................................................................... 17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications.........................................19
7.1
Demographic and Baseline Characteristics ........................................... 19
7.2
Medical History.................................................................................... 24
7.3
Prior, Concomitant and Post-Treatment Medications ............................ 24
8.0
Patient Disposition............................................................... 25
8.1
Disposition of Safety Population .......................................................... 25
9.0
Study Drug Exposure and Compliance.............................. 26
9.1
Exposure .............................................................................................. 26
9.2
Compliance .......................................................................................... 27
10.0
Efficacy Analysis .................................................................27


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10.1
General Considerations......................................................................... 27
10.2
Handling of Multiplicity....................................................................... 32
10.3
Primary PK and Primary Efficacy Analysis .......................................... 32
10.3.1
Primary PK Analysis ............................................................................ 32
10.3.2
Primary Efficacy Analysis.................................................................... 32
10.4
Secondary PK and Efficacy Analyses ................................................... 33
10.4.1
Secondary PK Analyses........................................................................ 33
10.4.2
Secondary Efficacy Analyses ............................................................... 33
10.5
Sensitivity Analysis for SVR................................................................ 34
10.6
Efficacy Subgroup Analysis ................................................................. 34
10.7
Additional Efficacy Analyses ............................................................... 35
10.8
Resistance Analyses ............................................................................. 37
10.8.1
HCV Drug-Resistance Analyses........................................................... 37
10.9
Growth and Development..................................................................... 42
10.10
Patient Reported Outcomes .................................................................. 42
11.0
Safety Analysis.....................................................................43
11.1
General Considerations......................................................................... 43
11.2
Analysis of Adverse Events.................................................................. 44
11.2.1
Treatment-Emergent Adverse Events.................................................... 44
11.2.2
Tabulations of Treatment-Emergent Adverse Events ............................ 44
11.2.3
Adverse Events of Special Interest........................................................ 47
11.2.4
Listing of Adverse Events..................................................................... 48
11.3
Analysis of Laboratory Data................................................................. 48
11.3.1
Variables and Criteria Defining Abnormality........................................ 48
11.3.2
Statistical Methods ............................................................................... 49
11.4
Analysis of Vital Signs and Weight ...................................................... 52
11.4.1
Variables and Criteria Defining Abnormality........................................ 52
11.4.2
Statistical Methods ............................................................................... 52
12.0
Summary of Changes .......................................................... 52
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP Version 1.0 ............................................................................ 52
13.0
References............................................................................ 53


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List of Tables
Table 1.
Treatment Regimen and Duration (Excluding Subjects in Japan)............ 8
Table 2.
Treatment Regimen and Duration (Subjects in Japan)............................. 8
Table 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, Growth and Development 
Endpoints (Treatment Period)............................................................... 13
Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 14
Table 5.
Laboratory Data, Vital Sign Measurements, Growth and 
Development Endpoints (Except Growth Rate) Visit Windows 
(Post-Treatment Period) ....................................................................... 15
Table 6.
Visit Windows for Growth Rate Calculation (Post-Treatment 
Period) ................................................................................................. 15
Table 7.
Analysis Time Windows for PRO Instruments (Treatment Period) ....... 16
Table 8.
Analysis Time Windows for PRO Instruments (Post-Treatment 
Period) ................................................................................................. 16
Table 9.
Analysis Time Windows for Palatability Questionnaire 
(Treatment Period Only)....................................................................... 17
Table 10.
Analysis Time Windows for Longitudinal Fibrotest and APRI 
(Post-Treatment Period) ....................................................................... 17
Table 11.
Baseline Fibrosis Stage......................................................................... 22
Table 12.
Child-Pugh Classification of Severity of Cirrhosis................................ 23
Table 13.
Medical/Surgical History eCRF............................................................ 24
Table 14.
List of Genotype-Specific Signature Amino Acid Positions and 
Key Subsets of Amino Acid Positions .................................................. 38
Table 15.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 50
List of Figures
Figure 1.
Study Design.......................................................................................... 7


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Statistics and Statistical Programming Departments, or designee, for 
Study M16-123.
Study M16-123 assesses the pharmacokinetics, safety, and efficacy of 
glecaprevir/pibrentasvir (GLE/PIB) in pediatric subjects with chronic hepatitis C virus 
(HCV) genotypes 1 – 6 chronic Infection with or without compensated cirrhosis and with
or without HIV infection, who are HCV treatment-naïve or interferon/pegylated interferon 
(IFN), ribavirin (RBV) and/or sofosbuvir (SOF) treatment-experienced subjects.
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M16-123 Amendment 1 dated 25 July 2017, and 
describes analysis conventions to guide the statistical programming.  Analyses will be 
performed using SAS® Version 9.4 (SAS Institute, Inc., Cary, NC) or later under the 
UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the pharmacokinetics (PK) of GLE/PIB 
by the steady state AUC in pediatric subjects following multiple dosing by age group, and 
evaluate the safety and tolerability of GLE/PIB by age group, cirrhosis status and across 
all subjects. 
The evaluation of the percentage of subjects with sustained virologic response for 
12 weeks post treatment (SVR12) in HCV GT1 – 6 infected pediatric subjects is a part of 
the primary objectives for the US FDA.  For all other countries outside of the US, this 
assessment is a part of the secondary objectives. 


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The secondary objectives are to assess Cmax and clearance of GLE and PIB, the 
percentages of subjects with on-treatment HCV virologic failure summarized for each age 
group and overall, the percentages of subjects with post-treatment HCV relapse 
summarized for each age group and overall, the percentages of subjects with new HCV 
infection (or re-infection) summarized for each age group and overall, the 
emergence/persistence of viral variants in subjects with available samples, and palatability 
of the pediatric formulation.
The growth and development outcomes and patient reported outcomes will also be 
assessed for the glecaprevir/pibrentasvir treatment regimen in the pediatric subjects.
4.2
Design Diagram
This is a Phase 2/3, multicenter, open-label study to evaluate the PK, safety, and efficacy 
of GLE/PIB for 8, 12, or 16 weeks in HCV GT1 – 6 infected pediatric subjects ≥ 3 to 
< 18 years of age, who are either treatment-naïve, treatment-experienced to IFN with or 
without RBV or treatment-experienced to SOF with IFN and/or RBV.  Subjects may be 
non-cirrhotic or have compensated (Child-Pugh A) cirrhosis.  Subjects with HCV/HIV-1 
co-infection are eligible for study inclusion.
The study will enroll approximately 110 HCV-infected pediatric subjects, divided into 
four age groups, 3 to < 6, 6 to < 9, 9 to < 12, and 12 to < 18 years of age.  Enrollment will 
begin in the age group 12 to < 18 years old among subjects who are willing to swallow the 
adult formulation of GLE/PIB (Part 1).  Part 2 of the study will enroll the remaining age 
groups; those will receive the pediatric formulation of GLE/PIB. 
Within each age group, approximately 12 HCV-infected pediatric subjects will be 
enrolled for intensive pharmacokinetics (IPK) in order to adequately characterize the PK 
of a particular age group for dose confirmation, and the remainder of subjects will be 
enrolled for the evaluation of safety and efficacy of each age group until the total pediatric 
study population reaches approximately 110 subjects.  Additional PK assessments will be 
obtained for subjects enrolled in Japan for the purpose of further characterization within 


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Japanese subjects; this is not included within the aforementioned 12 subjects per age 
group.
The study consists of a Treatment Period and a Post-Treatment (PT) Period. 
A study schematic is shown below in Figure 1.
Figure 1.
Study Design
Eligible subjects will be assigned to a treatment regimen according to their HCV 
genotype, cirrhosis status and prior HCV treatment experience as shown in Table 1 for 
global subjects and Table 2 for subjects in Japan.  For patients with an indeterminate or 
mixed genotype, treatment duration will default to the respective GT3 duration based 
upon treatment-experience and cirrhosis status.  The treatment duration for subjects in 
Japan is consistent with the approved label in Japan. 


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Table 1.
Treatment Regimen and Duration (Excluding Subjects in Japan)
Patient Population
Duration
GT1 – 6 NC, TN
8 weeks
GT1, 2, 4 – 6 NC, TE
GT1 – 6 C, TN
12 weeks
GT1, 2, 4 – 6 C, TE
GT3 TE
16 weeks
Legend:  C = Cirrhotic; NC = Non-Cirrhotic; TE = Treatment experienced to IFN (alpha, beta or pegIFN) ± RBV or 
SOF/RBV ± pegIFN; TN = Treatment Naïve
Table 2.
Treatment Regimen and Duration (Subjects in Japan)
Patient Population
Duration
GT1 – 2 NC, TN, TE – IFN
8 weeks
GT1 – 2 C, TN, TE – IFN
12 weeks
GT3 – 6 NC, C, TN, TE – IFN
GT1 – 6 TE – SOF
Legend:  C = Cirrhotic; NC = Non-Cirrhotic; TE – IFN = Japan Treatment experienced to IFN (alpha, beta or pegIFN) ± 
RBV; TE – SOF = Japan Treatment experienced to SOF/RBV ± pegIFN; TN = Treatment Naïve
4.3
Sample Size
The proposed sample size of 48 subjects (approximately 12 subjects for each age cohort 
for IPK sampling with separate from sampling performed in subjects in Japan) is expected 
to adequately characterize the PK of GLE and PIB to enable dose selection in pediatric 
subjects.
4.4
Planned Interim Analyses and Final Analysis
All analyses will be conducted by statisticians and programmers at AbbVie or designees 
according to the methodologies specified in this SAP.  
The first interim analysis will occur once all 12 subjects participating in IPK in Part 1 
complete PT Week 12 or prematurely discontinue from the study.  A second interim 
analysis will occur once all subjects in Part 1 complete PT Week 12 or prematurely 


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discontinue from the study.  A third interim analysis will occur once all subjects 
participating in the IPK portion in Part 2 complete PT Week 12 or prematurely 
discontinue from the study.  A fourth interim analysis will occur once all subjects in 
Parts 1 and 2 complete PT Week 12 or prematurely discontinue the study.  Final analysis 
will occur after the completion of the whole study. 
For each planned interim analysis, data will be locked after performing data cleaning.  
Data after each interim analysis will be added to a new version of the database.  The final 
analysis will be conducted when all subjects enrolled in the study have completed the 
144 week post-treatment visit or prematurely discontinued from the study.  Data after the 
last interim analysis will be added to a new version of the database which will be cleaned 
and locked at the end of the study and included in the final CSR.
There is no intention of stopping the study early based on efficacy findings from the 
interim analyses.  The intention is to follow all subjects who receive study drug for 
144 weeks following treatment.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
If efficacy is determined to be lesser in a dose lower than the final dose, non-safety 
analyses may be performed with the subjects who receive a dose lower than the final dose 
chosen for the subject's age group summarized separately. 
5.1.1
Intention-to-Treat (ITT) Population
All subjects who receive at least one dose of study drug will be included in the ITT 
population.  Demographic, baseline characteristic, exposure, concomitant medication and 
medical history analyses will be performed on the ITT population overall and by age 
group.  Efficacy analyses will be performed on the ITT population.


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5.1.2
Modified Intention-to-Treat (mITT) Population
Sensitivity analyses of SVR12 as described in Section 10.5 will be performed on the ITT 
population modified to exclude subjects who did not achieve SVR12 for reasons other than
virologic failure (mITT-VF). 
5.1.3
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population.  Safety analysis will be performed on the safety population overall and by age 
group.
5.2
Variables Used for Stratification of Randomization
This study is not randomized.  Eligible subjects will be assigned to a treatment regimen 
based on HCV genotype, cirrhotic status, prior HCV treatment experience, and whether 
the subjects are in Japan or not.
6.0
Analysis Conventions
6.1
Definition of Baseline and End of Treatment Assessment
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.  The protocol specifies that all Day 1 assessments 
(other than intensive PK samples) are to be performed prior to administering the first dose 
of study drug.  Therefore, all Day 1 assessments for which time is not collected will be 
assumed to be pre-dose and the baseline value will be the last non-missing measurement 
collected on or before the first day of study drug administration.
All Day 1 assessments with time available must be before the time of first dose to be 
considered baseline, and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 


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time or if time is not available, then the average of these measurements will be considered 
the baseline value.  The same baseline value will be used for analyses of the Treatment 
and Post-Treatment Periods.
Safety assessments that are related to a serious adverse event that occurred on the 
first dose day are excluded when applying this algorithm.
6.1.2
Study Days
Study days are calculated for each time point relative to the first dose of study drug.  
Study days are negative values when the time point of interest is prior to the first study 
drug dose day.  Study days are positive values when the time point of interest is after the 
first study drug dose day.  There is no Study Day 0.  Study Day 1 is the day of the 
first dose of study drug.
Study Drug End Days (Days Relative to the Last Dose of Study Drug)
Study drug end days are calculated for each time point relative to the last dose of study 
drug.  The last day of study drug dosing is defined as Study Drug End Day 0.  Days 
before it have negative study drug end days and days after it have positive study drug end 
days.
Final Treatment Value
The final treatment value is defined as the last non-missing measurement collected after 
Study Day 1 and on or before Study Drug End Day 2.
Final Post-Treatment Value
The final post-treatment value for each subject is the last non-missing measurement 
collected after Study Drug End Day 2 and on or before Study Drug End Day 1,999.


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6.2
Definition of Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 3
and Table 4 describe how HCV RNA and resistance data are assigned to protocol-
specified time points during the Treatment and PT Periods, respectively.  All time points 
and corresponding time windows are defined based on the date/time of blood sample 
collection.
For safety laboratory data, vital signs, and growth and development endpoints (except 
growth rate), the time windows specified in Table 3 and Table 5 describes how data are 
assigned to protocol specified time points.  For the calculation of growth rate only, the 
time window specified in Table 6 will be used to assign height to a specific visit window 
before growth rate will be calculated as the change in height over change in age from the 
previous visit at Post-Treatment Weeks 12, 48, 96, and 144.
For PRO questionnaire, the time windows specified in Table 7 and Table 8 describes how 
data are assigned to protocol specified time points.
For palatability questionnaire, the time windows specified in Table 9 describes how data 
are assigned to protocol specified time points during the treatment period.
For longitudinal Fibrotest and APRI, the time windows specified in Table 10 describes 
how data are assigned to protocol specified time points during the Post-Treatment period.
If more than one assessment is included in a time window, the assessment closest (except 
in analyses of SVR) to the nominal time will be used.  If there are two observations 
equally distant to the nominal time, the latest one will be used in analyses.  For analyses 
of SVR (e.g., SVR12), the last value in the window will be used. 
If multiple measurements are made on the same day for a safety laboratory parameter, a 
vital sign parameter, or a growth and development endpoint, the average of the values will 
be used to calculate descriptive statistics and in analyses of the mean change from 
baseline.


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Table 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, Growth and Development 
Endpoints (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 1a
Week 2
14
2 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12b
84
71 to 98
Week 16c
112
99 to 126
Final Treatment Visitd
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 12-week treatment only.
c.
For 16-week treatment only.
d.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.


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Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,999
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable to subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.


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Table 5.
Laboratory Data, Vital Sign Measurements, Growth and 
Development Endpoints (Except Growth Rate) Visit Windows 
(Post-Treatment Period)
Scheduled Time
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 42
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,999
Final Post-Treatment Visita
> 2 days after the last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
Vital signs and growth and development endpoints are collected at every PT visit; hematology, chemistry, 
urinalysis, and coagulation panels are collected at Post-Treatment Week 4 and PTDC (if subject discontinued 
prior to Post-Treatment Week 4).  For subjects with compensated cirrhosis at baseline, chemistry and 
coagulation panels are collected to calculate the Child Pugh Score. 
Table 6.
Visit Windows for Growth Rate Calculation (Post-Treatment 
Period)
Scheduled Time
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 12
84
3 to 210
Post-Treatment Week 48
336
211 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,999
Final Post-Treatment Visita
> 2 days after the last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
For the calculation of growth rate only, height will be assigned to a visit as described in the table above, then 
growth rate will be calculated as the change in height (millimeter) over the change in age (years) from the 
previous visit.  If height is missing at a visit and/or the previous visit, then growth rate will be missing for the 
visit.


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Table 7.
Analysis Time Windows for PRO Instruments (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 1a
Week 8b
56
2 to 70
Week 12c
84
71 to 98
Week 16d
112
99 to 126
Final Treatment Visite
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 8-week treatment only.
c.
For 12-week treatment only.
d.
For 16-week treatment only.
e.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  PRO instruments are collected at Day 1 and End of Treatment Visit, which can be at Weeks 8, 
12 or 16 depending on treatment assignment. 
Table 8.
Analysis Time Windows for PRO Instruments (Post-Treatment 
Period)
Scheduled Time
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 12
84
3 to 1,999
Final Post-Treatment Visita
> 2 days after the last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  


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Table 9.
Analysis Time Windows for Palatability Questionnaire (Treatment 
Period Only)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Week 2
14
2 to 35
Week 8a
56
36 to 70
Week 12b
84
71 to 98
Week 16c
112
99 to 126
Final Treatment Visitd
2 to ≤ 2 days after last dose of study drug
a.
For 8-week treatment only.
b.
For 12-week treatment only.
c.
For 16-week treatment only.
d.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  Palatability questionnaire are administrated to subjects in Part 2 at Week 2 and End of 
Treatment Visit or premature discontinuation visit.
Table 10.
Analysis Time Windows for Longitudinal Fibrotest and APRI 
(Post-Treatment Period)
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 12
84
3 to 175
Post-Treatment Week 48
336
176 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,999
Final Post-Treatment Visita
> 2 days after the last dose of study drug
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2 for 
all windows.  Study Drug End Day 0 is defined as the day of the last dose of study drug.
6.3
Missing Data Imputation
Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.2.


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For analyses of SVR, subjects' missing visit values will have backward imputation 
applied, if possible.  For backward imputation, if the nearest HCV RNA value after the 
SVR window is unquantifiable or undetectable, then it will be used to impute the HCV 
RNA value in the SVR window.  If a subject is missing an HCV RNA value within the 
appropriate SVR window after performing backward imputation, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value will be missing.  Subjects with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 
failure for summaries of viral response at all time points after the start of the new HCV 
treatment. 
Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure. 
Missing Data Imputation for PRO Questionnaires
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the PedsQL, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that dimension will be considered missing. 
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all PRO data for this subject measured on or after the start date of the new 
HCV treatment will be excluded from analyses.  


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
The ITT population will be used to summarize demographics, baseline characteristics, 
medical history and previous, concomitant, and post-treatment medications; data will be 
summarized across all subjects and by age group. 
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation,
median, maximum and minimum).
Continuous demographic variables include age, weight, height, and body mass index 
(BMI), BMI z score (BMI z score will be calculated using WHO published BMI-for-age 
z score tables),5 weight and height z scores (weight and height z scores will be calculated 
using WHO published weight-for-age z score and height-for-age z score tables.  
Categorical demographic variables include sex, race, black race (black or non-black), 
ethnicity, age category (≥ 3 to < 6 years, ≥ 6 to < 9 years, ≥ 9 to < 12 years, ≥ 12 to 
< 18 years), birth year, weight category (≥ 12 to < 20 kg, ≥ 20 to < 30 kg, ≥ 30 to < 45 kg, 
≥ 45 kg), weight z score category (< –1, –1 to 1, > 1 ), Height z-score category (< –1, –1 
to 1, > 1), BMI z-score category (< –1, –1 to 1, > 1)  country, and geographic region 
(North America, Europe, or Japan).
Weight-for-age reference data are not available beyond age 10 because this indicator does 
not distinguish between height and body mass in an age period where many children are 
experiencing the pubertal growth spurt and may appear as having excess weight (by 
weight-for-age) when in fact they are just tall.  Subjects who are older than 10 years at the 
time of the corresponding weight measurement will be excluded from the summary of 
weight z score.


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When defining geographic region, sites in the United States, Puerto Rico, and Canada will 
be grouped under North America; sites in Belgium, Germany, Russia, Spain and the 
United Kingdom will be grouped under Europe; sites in Japan will be grouped together as 
Japan.
Continuous baseline characteristics include baseline log10 HCV RNA level, creatinine 
clearance, eGFR, platelet count, albumin, GGT, alpha fetoprotein (for cirrhotic subjects 
only), Fibrotest, APRI, FIB-4, AST, ALT, total, direct, and indirect bilirubin for all 
subjects.
Categorical baseline characteristics include: 
●
HCV genotype and subtype (using central laboratory results and final 
genotype/subtype results, see Section 10.8);
●
Prior HCV treatment history (naïve or experienced);
●
For treatment-experienced subjects, type of previous regimen (IFN- or SOF-
based);
●
For treatment-experienced subjects, type of non-response to previous treatment 
(on-treatment nonresponder or breakthrough, post-treatment relapse, or 
unknown/other);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
●
Baseline cirrhosis status (cirrhotic or non-cirrhotic)
●
Baseline HCV RNA level (< 1,000,000 ≥ 1,000,000 to < 2,000,000, 
≥2,000,000 IU/mL);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L); 
●
Baseline albumin (< 35 or ≥ 35 g/L); 
●
Baseline eGFR (< 30, ≥ 30 to < 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2);
●
HIV co-infected subjects (yes/no);
●
History of bleeding disorders (yes/no);
●
History of depression or bipolar disorder (yes/no);
●
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);


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●
Subject on stable opiate substitution (yes/no);
●
Nicotine use (user, ex-user, or non-user);
●
Alcohol use (drinker, ex-drinker, or non-drinker); 
●
Concomitant use of Proton Pump Inhibitors (PPIs).
●
Concomitant use of Statins (yes/no);
In addition, for cirrhotic subjects, the following will be summarized:
●
Baseline Child-Pugh score (5, 6, or > 6),
●
Baseline alpha fetoprotein (< 20 or ≥ 20 ng/mL),
For treatment experienced subjects, any regimen that contains SOF with or without IFN or 
RBV is SOF-based.  Otherwise, any regimen that contains IFN with or without RBV is 
IFN-based.
Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.  Any concomitant medication coded to the WHO Drug 
Dictionary ATC code of C10AA or C10BX will be counted as a statin.
Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores, 
FibroScan scores, or FibroTest scores.  Only one score will be used to categorize each 
subject even if a subject has more than one score recorded.  If a biopsy score is present, 
then it will be used to categorize the subject, regardless of the FibroScan/FibroTest score.  
Similarly, if a FibroScan score is present along with a FibroTest score, then the FibroScan 
score will be used to categorize the subject.  If biopsy and FibroScan scores are not 
present and more than one FibroTest result is available, then the baseline FibroTest result 
(i.e., last non-missing FibroTest result on or before Day 1) will be used to categorize the 
subject.  Subjects will be categorized as F0 – F1, F2, F3, or F4 according to Table 11.


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Table 11.
Baseline Fibrosis Stage
Baseline 
Fibrosis Stage, 
Metavir 
Equivalents
Liver Biopsy Metavir, 
Batts Ludwig, Knodell, 
IASL, Scheuer, New 
Inuyama or Laennec 
Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest*
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥ 8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 12.5
0.59 to 0.72
F4
4
≥ 5
≥ 12, 5
≥ 0.73
*
APRI will not be used to derive Baseline Fibrosis Stage.  However, per inclusion/exclusion criteria, subjects need 
to have concordant FibroTest and APRI scores in order to determine eligibility. 
Presence or absence of cirrhosis will be determined as collected in EDC ("What is the 
subject's cirrhosis status?" – "cirrhotic" or "non-cirrhotic").
Baseline Child-Pugh score is the sum of the points assigned for each of the 
five observed findings as defined in Table 12.


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Table 12.
Child-Pugh Classification of Severity of Cirrhosis
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to 
severe
Hepatic encephalopathy**
None
Grade 1 or 2
(or suppressed with medication)
Grade 3 or 4
(or refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
None:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Baseline APRI and FIB-4 are defined as the equations below.  Subjects who do not have 
concurrent AST and platelet values at baseline will be excluded from the summary of 
baseline APRI.  Age is defined in years at baseline.  Subjects who do not have concurrent
values of AST, ALT, and platelet count at baseline, or subjects who are missing age will 
be excluded from the summary of FIB-4.
APRI =
	
  (/)
	
 (   )(/)
 !!  "#$%  (&'(/))
× 100
FIB-4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10B/L) × CALT (U/L)


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Histories of bleeding disorders and depression or bipolar disorder will be based on the 
Medical History (MH) eCRF, as defined in Table 13.
Table 13.
Medical/Surgical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Bleeding disorders
Blood
Clotting/bleeding problems
Factor deficiency
Hemophilia
Von Willebrand disease
Depression or bipolar disorder
Neurologic and Psychiatric 
System
Bipolar disorder
Depression
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized for all treated subjects.  Subjects reporting more 
than one condition/diagnosis within a body system will be counted only once for that 
body system.
7.3
Prior, Concomitant and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug (GLE/PIB).  A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study drug and continued to be taken on or 
after the first dose of study drug or any medication that started on or after the date of the 
first dose of study drug, but not after the date of the last dose of study drug.  A post-
treatment medication for the treatment of HCV is defined as any medication taken on or 
after the last dose of study drug and entered as "Post-treatment HCV medications" on the 
eCRF.


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The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.  The prior HCV medications taken by 
treatment experienced subjects and collected on the "Last Prior HCV Therapy" and 
"Second to Last Prior HCV Therapy" eCRFs will be summarized separately from other 
prior medications, and will not be included in the summary of all prior and concomitant 
medication.
8.0
Patient Disposition
The number and percentage of subjects who screen failed for any reason will be 
summarized for subjects who screen failed and by each screen fail reason.
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be by investigator for each 
age group and overall.  
●
Enrolled subjects;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug; 
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
●
Subjects ongoing in the Post-Treatment Period (if applicable at the time of 
analysis).
The number and percentage of subjects who discontinued study drug will be summarized
by reason (all reasons) and by primary reason (per eCRF) for each age group and overall.  
Similar summaries will be provided for discontinuations from the study.


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The number and percentage of subjects with reported study drug interruptions will be 
summarized by age group and overall.  Reasons for study drug interruptions will be 
presented in the CSR listings.
9.0
Study Drug Exposure and Compliance
Exposure and compliance will be summarized on the ITT population by age group and 
overall.
9.1
Exposure
The duration of exposure to study drug will be summarized by assigned treatment 
duration for each age group and for all subjects.  Duration of exposure is defined for each 
subject as the last study drug dose date minus the first study drug dose date plus 1 day.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will 
be presented for exposure during the treatment period.
Study drug duration will be summarized with frequencies and percentages using the 
following categories:
●
1 to 30 days
●
31 to 60 days
●
61 to 75 days
●
76 to 90 days
●
91 to 105 days
●
> 105 days
In addition, the number and percentage of subjects with study drug duration of ≥ 52 days 
for subjects assigned to 8 weeks, ≥ 77 days for subjects assigned to 12 weeks and 
≥103 days for subjects assigned to 16 weeks will be summarized by age group and 
overall.


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9.2
Compliance
For the adult formulation, the GLE/PIB tablet, tablet is the dose unit for drug 
accountability.  For the pediatric formulation, bottle/sachet is the dose unit for drug 
accountability and the return status for each dose unit is recorded as either full/sealed, 
empty, or unsealed but not empty separately for glecaprevir and pibrentasvir or for 
glecaprevir and pibrentasvir combined if mixed together.  A bottle/sachet is considered to 
be taken only if the return status is empty.
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of dose units dispensed and returned is recorded.  The compliance for each type 
of dose unit during the treatment period will be calculated as the percentage of dose units 
taken relative to the total dose units expected to be taken.  The total number of dose units 
expected to be taken will be equal to the total number of dose units that should have been 
taken per the protocol for the duration that the subject was in the Treatment Period (date 
of last dose of study drug – date of first dose of study drug + 1).  Study drug interruptions 
recorded on the eCRF will not be subtracted from the duration.
A subject is considered to be compliant if the percentage is between 80% and 120%.  
Compliance will be calculated for each subject and each type of dose unit and 
summarized separately with the mean, median, standard deviation, minimum, and 
maximum for each type of dose unit by age group and overall.  A listing of compliance 
for each subject will be provided.  The percentage of compliant subjects will be 
summarized for each study drug by age group and overall, based on data as observed.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
All efficacy analyses will be performed on the ITT population, unless otherwise specified.


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Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database. 
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).


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EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-treatment virologic failure = Breakthrough or EOT failure; if a subject meets both 
definitions of Breakthrough and EOT failure, he or she will be categorized as 
Breakthrough only. 
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window. 
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of active study drug (up to and including the SVR12 window) for a subject 
with HCV RNA < LLOQ at Final Treatment Visit who completed treatment excluding 
reinfection as described below. 
Relapse24 = confirmed HCV RNA ≥ LLOQ within the SVR24 window for a subject who 
achieved SVR12 and has HCV RNA data available in the SVR24 window, excluding 
reinfection.
Relapseoverall = confirmed HCV RNA ≥ LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment excluding 
reinfection.


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Virologic failure = On-treatment virologic failure or Relapseoverall.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as a 
study drug duration of 52 days or greater for subjects assigned to 8 weeks of treatment, 
77 days or greater for subjects assigned to 12 weeks of treatment, and 103 days or greater 
for subjects assigned to 16 weeks of treatment.  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 active 
treatment in a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with 
the post-treatment detection of a different HCV genotype, subtype, or clade compared 
with baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B 
gene sequences.  Reinfection in the case of the same HCV subtype is defined as a clade 
switch, as indicated by the lack of clustering between the baseline and post-treatment 
sequences by phylogenetic analysis.  If phylogenetic analysis is not possible due to 
technical difficulties, HCV reinfection may be determined with a confirmed HCV 
genotype or subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and no genotype, subtype, or clade switch compared with baseline as 
determined by phylogenetic analysis of the NS3 or NS5A gene sequences.  If 
phylogenetic analysis is not possible due to technical difficulties, the subject will be 
defined as having a post-treatment relapse unless an HCV genotype or subtype switch is 
confirmed by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger assay.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);


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2.
HCV reinfection (see definition described earlier);
3.
Relapse12;
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects assigned to 8 weeks of treatment, 
< 77 days for subjects assigned to 12 weeks of treatment, and < 103 days for 
subjects assigned to 16 weeks of treatment] and did not meet the On-treatment 
virologic failure or reinfection definitions);
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR12 non-responder not meeting the definitions of 
[1] – [5]). 
Reasons for SVR24 Non-Response
Subjects who do not achieve SVR24 (SVR24 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
HCV reinfection;
3.
Relapse12
4.
Relapsed24;
5.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects assigned to 8 weeks of treatment, 
< 77 days for subjects assigned to 12 weeks of treatment, and < 103 days for 
subjects assigned to 16 weeks of treatment] and did not meet the On-treatment 
virologic failure, Relapse12, or Relapse24 definitions);


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6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], [4], or [5]);
7.
Other (defined as any SVR24 non-responder not meeting the definitions of 
[1] – [6]).
For the reasons for SVR12 and SVR24 nonresponse defined above, subjects are only to be 
counted in 1 category.  Specifically, subjects who were SVR12 or SVR24 nonresponders 
meeting the definition of HCV reinfection will be counted in the reinfection category 
regardless of whether they meet the definition of prematurely discontinued study drug, 
relapse12 or relapse24.
10.2
Handling of Multiplicity
There will be no hypothesis testing for the primary and secondary efficacy endpoints.  
Therefore, there will be no adjustment for multiple comparisons.
10.3
Primary PK and Primary Efficacy Analysis
10.3.1
Primary PK Analysis
The primary pharmacokinetic endpoint will be the steady state AUC of GLE and PIB 
estimated by non-compartmental pharmacokinetic analysis or population pharmacokinetic 
analysis.  The 95% confidence interval for the geometric mean of AUC values will be 
calculated.  For subjects enrolled in Japan, the pharmacokinetic parameters will be 
summarized separately.
10.3.2
Primary Efficacy Analysis
For US regulatory agency the efficacy endpoint of SVR12 (HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug) across all subjects in the ITT population is 
considered primary efficacy endpoint.  For all other regulatory agencies the SVR12
efficacy endpoint is considered secondary. 


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The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the number of SVR12 non-responders is less than 5, where the 
Wilson's score method1 will be used to calculate the confidence interval instead.
A summary of reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.  A listing of subjects who do not achieve SVR12 by 
reason for non-response will also be provided.
10.4
Secondary PK and Efficacy Analyses
10.4.1
Secondary PK Analyses
The secondary PK endpoint is:
1.
Cmax and clearance of GLE and PIB
Cmax and clearance values will be estimated by non-compartmental pharmacokinetic 
analysis or population pharmacokinetic analysis.  For subjects enrolled in Japan, the 
pharmacokinetic parameters will be summarized separately.
10.4.2
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment HCV virologic failure (defined 
as On-treatment virologic failure) by age group and overall,
●
The percentage of subjects with post-treatment HCV relapse (defined as 
Relapse12; subjects with reinfection will be summarized separately) by age 
group and overall,
●
The percentage of subjects with re-infection by age group and overall,
●
Assessment of palatability of the pediatric formulation by age group and 
overall.


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The number and percentage of subjects with on-treatment virologic failure, post-treatment 
relapse (Relapse12) and re-infection will be summarized along with two-sided 95% 
confidence interval using Wilson's score method.
For the assessment of palatability, the number and percentage of subjects with each 
categorical answer marked will be presented for each question in the palatability 
questionnaire at each applicable treatment visit by age group and overall.  A listing of 
acceptability questionnaire results and comments for each applicable subject over 
applicable treatment visits will be produced.
10.5
Sensitivity Analysis for SVR
As sensitivity analysis, the number and percentage of subjects in the mITT-VF population 
achieving SVR12, as applicable, will be summarized, along with a two-sided 
95% confidence interval using Wilson's score method.
As a sensitivity analysis, a two-sided 95% confidence interval for the SVR12 rate in the 
ITT population will be calculated using a Wilson score interval if that was not used in the 
primary analysis.
A listings of subject excluded from the mITT-VF population will be provided.
10.6
Efficacy Subgroup Analysis
The percentage of subjects with SVR12 in the ITT population will be calculated along with 
the corresponding 2-sided 95% Wilson score confidence interval for the following 
subgroups if applicable:
●
HCV genotype (1, 2, 3, 4, 5, or 6);
●
Prior HCV treatment history (treatment-naïve or treatment-experienced);
●
For treatment-experienced subjects, type of previous regimen (IFN- or SOF-
based);
●
Sex (male or female);
●
Race (black or non-black);


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●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
●
Geographic region (North America, Europe, Japan);
●
Height z-score (< –1, –1 to 1 or > 1);
●
BMI z-score (< –1, –1 to 1 or > 1);
●
Drug compliance (< 80% versus ≥ 80%)
●
Baseline fibrosis stage (F0 – F1, F2, F3 or F4);
●
Cirrhosis status (yes/no);
●
Baseline HCV RNA level (< 1,000,000, ≥ 1,000,000 to < 2,000,000, 
≥2,000,000 IU/mL);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Injection drug user (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no).
●
Concomitant use of Statins (yes/no);
For subjects with cirrhosis only:
●
Baseline Child-Pugh Score (5, 6, or > 6).
●
Baseline platelets (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
10.7
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized and analyzed for the ITT 
population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed) by age group and overall;
●
The percentage of subjects with SVR12 by age group;
●
The percentage of subjects with SVR4 by age group and overall;


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●
The percentage of subjects with SVR24 by age group and overall;
All rates will be presented with two-sided 95% confidence intervals using the Wilson's 
score method. 
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject number and the SVR visit window corresponding to the first HCV 
RNA value of those indicating the occurrence of relapse.  A similar listing will be 
prepared for subjects who prematurely discontinued treatment and relapsed after having 
HCV RNA < LLOQ at their Final Treatment Visit.  A listing of subjects in the ITT 
population excluded from the relapse denominator (e.g., study drug duration < 52 days for 
subjects assigned to 8 weeks of treatment) will be provided, as applicable.
The number and percentage of subjects who do not achieve SVR24 will be summarized by 
reason for non-response (as defined in Section 10.1).  A listing of subject numbers and 
reason for non-response will be prepared.  
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and the positive predictive value (PPV) and negative predictive value 
(NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is a percentage 
defined as the number of subjects achieving both SVR12 and SVR24 and the number of 
subjects where both SVR12 and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is 
the proportion of subjects who achieve SVR24 out of all subjects who achieved SVR12.  
The NPV of SVR12 on SVR24 is the proportion of subjects who do not achieve SVR24 out 
of all subjects who did not achieve SVR12.  Similarly, the concordance between SVR4 and 
SVR12 will be summarized. 


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10.8
Resistance Analyses
10.8.1
HCV Drug-Resistance Analyses
Full length NS3/4A or NS5A from all available baseline samples will be sequenced by 
next generation sequencing (NGS).  For subjects who experience virologic failure 
(on-treatment virologic failure or post-treatment relapse as defined in Section 10.1), full 
length NS3/4A and NS5A genes from the first available sample after virologic failure 
with HCV RNA ≥ 1000 IU/mL will be sequenced by NGS.  An appropriate subtype 
specific prototypic reference sequence will be used for comparison with sequences from 
samples.  Subjects who experience virologic failure will be referred to as subjects in the 
primary virologic failure (PVF) population, and a listing by subject that includes HCV 
genotype/subtype, IL28B genotype, reason for SVR12 non-response, time point(s) 
sequenced as closest to time of VF, and HCV RNA value at the VF time point(s) will be 
produced for these subjects.  In addition, all listings described below will display HCV 
genotype/subtype and reason for SVR12 non-response in the subject identifier for each 
subject.  A separate listing will summarize all subjects in the PVF population for whom 
no sequencing was performed (e.g., lost to follow-up while HCV RNA ≤ 1000 IU/mL).
Subjects treated with study drug who do not achieve SVR12 due to reasons other than 
virologic failure (prematurely discontinued study drug with no on-treatment virologic 
failure, HCV reinfection, missing SVR12 data or other reasons as described in 
Section 10.1, Reasons for SVR12 Non-Response), but have a time point with HCV RNA 
≥1000 IU/mL after treatment discontinuation, will have the sample at that time point 
sequenced.  These subjects will be referred to as the non-PVF population.  A listing of all 
subjects in the non-PVF population with post-baseline sequencing available will be 
created that is similar to the listing of subjects in the PVF population with post-baseline 
sequencing available.
For each DAA target, signature amino acid positions and a key subset of amino acid 
positions are listed in Table 14.  Appropriate subtype-specific prototypic reference 
sequence will be used for comparison with sequences from samples.


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Table 14.
List of Genotype-Specific Signature Amino Acid Positions and Key 
Subsets of Amino Acid Positions
Genotype
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
NS3/4A
1a
36, 43, 54, 55, 56, 80, 107, 122, 132, 155, 
156, 158, 168, and 170
155, 156, 168
1b
36, 54, 55, 56, 80, 107, 122, 155, 156, 158, 
168, 170, and 175
155, 156, 168
2, 3, 4, 5, 6, 1 – other 
(non 1a/1b)
36, 43, 54, 55, 56, 80, 155, 156, 166 (GT3 
only) and 168
155, 156, 168
NS5A
1a
24, 28, 29, 30, 31, 32, 58, 62, 92, and 93
24, 28, 30, 31, 58, 92, 93
1b
24, 28, 29, 30, 31, 32, 54, 58, 62, 92, and 93
24, 28, 30, 31, 58, 92, 93
2, 3, 4, 5, 6, 1 – other 
(non 1a/1b)
24, 28, 29, 30, 31, 32, 58, 92, and 93
24, 28, 30, 31, 58, 92, 93
Included time points for analyses on samples from subjects who do not achieve SVR12 are 
1) the sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that resistance-associated 
variants were detected at the time of failure/discontinuation. 
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
frequency threshold utilized) that was not present in the appropriate prototypic 
reference amino acid sequence for a given DAA target (NS3/4A or NS5A)
●
Variant at signature amino acid position: variant (relative to reference) present 
by NGS at a detection threshold of 2% or 15% (depending on frequency 
threshold utilized) in a baseline or a post-baseline sample at a signature amino 
acid position
●
Post-baseline variant:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline (< 2%) in the subject and is detectable 
in ≥ 2% of the sequences from the post-baseline sample


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●
Enriched variant:  variant 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 variant by NGS: A post-baseline variant or an enriched 
variant
Analysis will be performed separately for each cohort by HCV genotype/subtype 
within each listing.
Analysis 1:  The following analyses will be performed for all subjects:
●
A listing of all baseline polymorphisms (2% detection threshold) at signature 
amino acid positions for each DAA target (NS3 and NS5A) (ITT). 
●
The number and percentage of subjects with baseline polymorphisms at 
detection-thresholds of 2% and 15% at signature amino acid positions (ITT).  
This table includes prevalence of each baseline polymorphism, and a summary 
of the number of subjects with polymorphisms in NS3 only, NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, and any in NS3 + NS5A.
●
Total number and percentage of subjects with baseline polymorphisms at the 
key subset of amino acid positions in NS3 only, NS5A only, any in NS3, any 
in NS5A, any in NS3 or NS5A, and any in NS3 + NS5A (ITT), by subtype, 
and total.
●
Total number and percentage of subjects with baseline polymorphisms at the 
key subset of amino acid positions in NS3 only, NS5A only, any in NS3, any 
in NS5A, any in NS3 or NS5A, and any in NS3 + NS5A (ITT), by genotype, 
and total.
Analysis 2:  Analysis 2 will be applicable to Cohort 1 only.  The impact of baseline 
polymorphisms on treatment outcome will be assessed for the mITT-VF population as 
follows:  for each polymorphism, the SVR12 rate will be calculated for subjects with and 
without the polymorphism and the two rates will be compared using Fisher's exact test.  
Analysis will be grouped by HCV genotype/subtype and DAA target (NS3 or NS5A).  


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The analysis will include the number of subjects within each genotype/subtype with 
variants in NS3 only, NS5A only, any in NS3, any in NS5A, any in NS3 or NS5A, and 
any in NS3 + NS5A.
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
Polymorphisms at signature amino acid positions (vs no polymorphism at that 
position), using detection thresholds of both 2% and 15%.  The analysis will 
include the 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.
●
Each polymorphism at signature amino acid position (vs not that 
polymorphism) using detection thresholds of 2% and 15%.  The analysis will 
include the 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.
Analysis 3:  Analysis 3 will be applicable to Cohort 1 only.  In subjects with or without 
baseline polymorphisms in NS3 only, in NS5A only, any in NS3, any in NS5A, any in 
NS3 or NS5A, and any in NS3 + NS5A at the key subset of amino acid positions at 15% 
detection threshold, the SVR12 rate will be calculated, and the rates with or without 
polymorphisms will be compared using Fisher's exact test.  Analysis will be separated by 
HCV subtype.  The following tables will be provided (mITT-VF):
●
Comparison of SVR12 rates by subtype, and total (including all subtypes)
●
Comparison of SVR12 rates by genotype, and total (including all genotypes)
Analysis 4:  
The following analyses will be performed for subjects who do not achieve SVR12 (with 
separate summaries for subjects in PVF and non-PVF populations) and have post-baseline 
resistance data available:


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●
Listings by subject of all treatment-emergent variants relative to the baseline 
amino acid sequences will be provided for each DAA target (NS3/4A and 
NS5A). 
●
Listings by subject of all variants at signature amino acid positions in a post-
baseline time point for each DAA target (NS3 and NS5A).
●
The persistence of post-baseline variants at signature resistance-associated 
amino acid positions for each target (NS3 and NS5A) from subjects will be 
assessed at Post-Treatment Week 24.  Listings by subject and time point of all 
treatment-emergent variants will be provided for each DAA target (NS3 and 
NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequence from baseline samples for all 
subjects in Part 1, and from subjects with available sample in Part 2 in order to accurately 
determine subtype.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A, and/or NS5A sequences performed by AbbVie.  If the 
phylogenetic analysis is available, then it will be used to determine the subject's HCV 
genotype and subtype.  If it is not available, then the Sanger sequencing assay result will 
be used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis result nor the Sanger sequencing assay results is 
available, then the Inno-LIPA assay results will be used to categorize the subject.  This 
subtype information will be used in summaries of efficacy subgroup analyses.  The 
baseline characteristic summary will use the results from the central laboratory (Sanger 
sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]).
A summary of HCV 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.


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10.9
Growth and Development
The following growth and development endpoints will be calculated in the ITT 
population.
●
Growth rate at Post-Treatment Weeks 12, 48, 96 and 144 (defined as change in 
height over change in age from the previous visit)
●
Weight z score5
●
Height z score5
●
Body mass index (BMI) z score5
Weight, height, and BMI z scores will be calculated using WHO published weight-for-age 
z score, height-for-age z score, and BMI-for-age z score tables, respectively.  As 
described in Section 7.1, subjects who are older than 10 years at the time of the 
corresponding weight measurement will be excluded from the analyses of weight z score.  
If a subject becomes older than 19 years during the study, the WHO standards at 
19 years old will be used to calculate height z score and BMI z score after 19 years old as 
these WHO standards are very close to the adult standards. 
Growth rate will be summarized with N, mean and SD together, median and range 
together at each applicable post baseline visit by gender for all and for age group 
separately.  Weight, height and BMI z scores will be summarized with N, mean and SD 
together, median and range together at each applicable post baseline visit for all and by 
age group.
10.10
Patient Reported Outcomes
The patient reported outcomes data will be analyzed in the ITT population.
At Baseline, End of Treatment, and Post-Treatment Premature Discontinuation, subjects 
will complete the PRO instrument, PedsQL, with the assistance of a parent/guardian 
(where allowed per local regulatory guidelines).  The PedsQL Generic Core Scales is a 
23 item questionnaire designed to measure the core dimension of health as defined by the 


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World Health Organization (WHO) along with role (school) functioning.  The PedsQL 
consists of 4 Multidimensional Scales (Physical Functioning, Emotional Functioning, 
Social Functioning, and School Functioning) and 3 Summary Scores (Total Scale Score, 
Physical Health Summary Score, and Psychosocial Health Summary Score).  Subjects 
who are older than 5-years of age and are able to read and understand the questions should 
complete the questionnaire by themselves.  For subjects who are 5-years of age or 
younger or who are not comfortable with reading the questions, their parent(s)/guardian(s) 
should complete the parent/guardian proxy-report. 
Across subjects enrolled in Part 1 and 2 (based on ITT population), summary statistics of 
change from baseline to Week 8 (only applicable to subjects assigned to 8 weeks of 
treatment), Week 12 (only applicable to subjects assigned to 12 weeks of treatment), 
Week 16 (only applicable to subjects assigned to 16 weeks of treatment) and Final 
Treatment Visit and Final PT Visit (n, mean, SD, minimum and maximum) of 
3 summary scale scores will be provided by age group and overall.  In addition the same 
summaries will be created separately for subjects who complete all the questionnaires by 
themselves and for subjects whose parent(s)/guardian(s) always complete the 
parent/guardian proxy-report.
If a subject starts another treatment for HCV, then all PRO values for this subject 
measured on or after the start date of the new HCV treatment will be excluded from 
analyses.
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed using the safety population overall and by age group.


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11.2
Analysis of Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The actual version of the MedDRA coding dictionary will be 
noted in the clinical study report.
HIV co-infected subjects are allowed to enroll into the study and the AIDS-associated 
opportunity infections will be flagged on the AE eCRF and in the AE database, which be 
excluded from all AE summary tables and listings.  A separate listing of AIDS-associated 
opportunity infections will be generated for the HIV co-infected subjects if there are HIV 
co-infected subjects enrolled under such conditions. 
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any adverse event with an onset date that is after 
the first dose of study drug and no more than 30 days after the last dose of study drug.  
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  If an incomplete onset date was collected for an adverse event, the 
event will be assumed to be treatment-emergent, unless there is other evidence that 
confirms that the event was not treatment-emergent (e.g., the event end date was prior to 
the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects in each age group and overall with treatment-
emergent AEs will be tabulated by primary MedDRA System Organ Class (SOC) and 
preferred term (PT).  The SOC 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.


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Adverse Event Overview
An overview of AEs will be presented for each age group and overall consisting of the 
number and percentage of subjects experiencing at least one event for each of the 
following AE categories:
●
Any treatment-emergent AE;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs of grade 3 or higher;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAA (glecaprevir/pibrentasvir);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Events by SOC and PT
The following summaries of AEs by SOC and PT will be generated by age group and 
overall:
●
Treatment-emergent adverse events;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs of Grade 3 or higher;


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●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility"
of being related to DAA (glecaprevir/pibrentasvir);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (glecaprevir/pibrentasvir);
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death.
A listing of treatment-emergent AEs grouped by body system and preferred term with 
subject numbers will be created for each age group.
Adverse Events by PT
The number and percentage of subjects experiencing treatment-emergent AEs will be 
tabulated according to PT and sorted by overall frequency across the four age groups.  
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. 
Adverse Events by Maximum Severity Grade Level
Treatment-emergent AEs and DAA-related treatment-emergent AEs will be summarized 
by maximum severity grade level of each PT.  Each AE will be assigned a grade level 
(grade 1, 2, 3, 4, or 5) by the investigator.  If a subject has an AE with unknown severity, 
then the subject will be counted in the severity grade level category of "unknown," even if 
the subject has another occurrence of the same event with a severity present.  The only 
exception is if the subject has another occurrence of the same AE with the highest grade 
level (grade 5).  In this case, the subject will be counted under the "Grade 5" category.


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Adverse Event by Maximum Relationship
Treatment-emergent AEs also will be summarized by maximum relationship of each PT 
to study drug (DAA), as assessed by the investigator.  If a subject has an AE with 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same adverse event with a relationship assessment of "Reasonable Possibility."  In this 
case, the subject will be counted under the "Reasonable Possibility" category.
11.2.3
Adverse Events of Special Interest
Adverse events of special interest included the following:
●
Hepatic decompensation/hepatic failure events, identified using the AbbVie 
Product MedDRA Query (PMQ) for "Hepatic Decompensation and Hepatic 
Failure."
●
Hepatocellular carcinoma events, identified using the preferred terms of 
hepatocellular carcinoma, hepatic neoplasm, hepatic cancer, hepatic cancer 
metastatic, and hepatic cancer recurrent.
For the hepatic decompensation/hepatic failure AE of special interest, the number and 
percentage of subjects experiencing at least one treatment-emergent AE in the search will 
be presented by SOC and preferred term and across all SOCs/preferred terms.  In addition, 
a by-subject listing of treatment-emergent AEs meeting the search criterion will be 
provided.
For the hepatocellular carcinoma AE of special interest, the number and percentage of 
subjects experiencing at least one post-baseline AE in the search will be presented by 
SOC and preferred term and across all SOCs/preferred terms.  In addition, a by-subject 
listing of all post-baseline (i.e., including both treatment-emergent and non-treatment 
emergent) AEs meeting the search criterion will be provided.


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11.2.4
Listing of Adverse Events
The following listings of AEs will be prepared:
●
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
●
Treatment-emergent serious AEs,
●
Treatment-emergent AEs leading to death,
●
Treatment-emergent AEs leading to discontinuation of study drug,
●
Treatment-emergent AEs leading to study drug interruption.
●
Treatment-emergent AEs in each of the AEs of special interest categories.
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.
11.3.1
Variables and Criteria Defining Abnormality
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, reticulocyte count, prothrombin time (PT), international 
normalized ratio (INR), and activated partial thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, sodium, potassium, calcium, inorganic phosphorus, total protein, 
glucose, albumin, chloride, bicarbonate, magnesium, , gamma-glutamyl transferase 
(GGT), alpha fetoprotein, fibrotest, APRI, creatinine clearance (calculated using 
Cockcroft-Gault), and glomerular filtration rate (GFR) for creatinine adjusted for boday
surface area (BSA).
Urinalysis variables include:  specific gravity and pH.


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The central lab calculates the estimated creatinine clearance (CrCl) based on the following 
Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum creatinine 
(mg/dL) × 72].
The central lab calculates the GFR for creatinine adjusted for BSA based on the following 
formula:
GFR for serum adjusted for BSA (mL/min/1.73 m2) = CrCl (mL/min) × 1.73/ 
{[(weight in kg) × (height in meter)]0.5/60}.
11.3.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 
the time of first dose if time is available.  The same baseline value will be used for change 
to Treatment Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable post 
treatment visits, will be summarized for each age group and overall.  Each protocol-
specified laboratory parameter will be summarized with the sample size, baseline mean, 
visit mean, change from baseline mean, standard deviation, minimum, median, and 
maximum.
The laboratory parameters defined in Table 15 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 each age group and overall.  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 


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Table 15.  A listing of all relevant laboratory parameters will be provided for each subject 
who had an increase to Grade 2 or higher for all laboratory variables in Table 15.
Table 15.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase 
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin 
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Absolute 
Neutrophil Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Glucose 
(increased)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 – 27.8 mmol/L
> 27.8 mmol/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Assessment of Hepatic Laboratory Values
The number and percentage of subjects in each age group and overall meeting the 
following criteria during treatment will be summarized:
●
Post nadir (preceding value is lower than the subsequent value) 
ALT > 5 × ULN (regardless of grade change);
●
Total bilirubin ≥ 2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered)
●
Post nadir ALT > 3 × ULN and total bilirubin > 2 × ULN (Hy's law quadrant)


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●
Post nadir ALT > 3 × ULN and total bilirubin ≤ 2 × ULN (Temple's corollary 
quadrant)
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 labs 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 
direct bilirubin/total bilirubin ratio > 0.4 
Two listings (one for each bullet) of all liver function tests including ALT, AST, total, 
indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline phosphatase 
values will be provided for each subject who met the criterion defined above.
For the assessments of hepatic laboratory values and hepatic laboratory 
abnormalities of potential interest, the maximum ratio relative to the ULN will be used 
to determine if subjects meet any of the criteria listed above.  The ALT and total bilirubin 
values do not need to be concurrent in order to meet the defined criteria in statistical 
summaries.  For ALT, the post-baseline value must represent an increase from the 
first nadir (including baseline) to be counted.  First nadir is defined as the last value prior 
to the first increase.  For total bilirubin, a subject will be counted if the post-baseline 
laboratory value meets the above criteria regardless of the baseline laboratory value 
(i.e., the post-baseline laboratory value does not need to be worse than the baseline 
laboratory value), except where noted above.  A confirmed post-nadir increase in ALT is 
defined as two consecutive values of ALT > 5 × ULN after nadir, either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A single post-nadir ALT value of greater than 5 × ULN followed by lost to 


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follow-up (no additional ALT values) also will be considered (i.e., will not require 
confirmation).  The ratio of direct to total bilirubin will be calculated using the same 
date/time sample corresponding to the total bilirubin elevation.
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality
Vital sign variables measured are body temperature, sitting systolic blood pressure, sitting 
diastolic blood pressure, sitting pulse rate, body weight, height, and BMI.
11.4.2
Statistical Methods
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for change to Treatment 
Period visits and change to Post-Treatment Period visits.
Changes from baseline to each post-baseline visit, including applicable post-treatment 
visits, will be summarized for each age group and overall.  Each vital sign parameter will 
be summarized with the baseline mean, visit mean, change from baseline mean, standard 
deviation, minimum, median, and maximum.  
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP Version 1.0
1.
The protocol stated to use Safety Population for Demog/baseline outputs; SAP 
changed these analyses to be run on ITT to align with the new HCV SAP template. 
2.
Protocol Section 8.1.6.2 planned shift tables for clinical laboratory values from 
low/normal to high and high/normal to low; SAP removed these analyses as the 
reference ranges won't work for the pediatric population.


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3.
Protocol Section 8.1.6.3 planned summary table for vital signs meeting Potentially 
Clinically Significant criteria; SAP removed these analyses due to the criteria are 
not applicable to pediatric population.
4.
Protocol Section 8.1.3 planned change from baseline summary statistics for height, 
weight, and BMI z scores; SAP removed these analyses as the summary of the z 
scores at each applicable visit is sufficient.
5.
Updates were made to the subgroup efficacy analysis section to be consistent 
across the HCV glecaprevir/pibrentasvir program.
13.0
References
1.
Newcombe RG.  Two-sided confidence intervals for the single proportion:  
comparison of seven methods.  Stat Med.  1998;17(8):857-72.
2.
Rockstroh JK, Nelson M, Katlama C, et al.  Efficacy and safety of grazoprevir 
(MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV 
co-infection (C-EDGE CO-INFECTION):  a non-randomised, open-label trial.  
Lancet HIV.  2015;2(8):e319-27.
3.
HARVONI® (ledipasvir and sofosbuvir) tablets [package insert].  Foster City, CA; 
Gilead Sciences, Inc., 2016.
4.
Johnson VA, Calvez V, Huldrych GF, et al.  Update of the drug resistance 
mutations in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):4-12.
5.
WHO.  Child Growth Standards.  27 April 2006.