Clinical trial NCT03092375
Conditions: Hepatitis C HCV
Keywords: HCV Previously treated
Sponsor: University of Florida
Start date: 2017-04-20; Completion date: 2020-02-06
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will enroll well-compensated cirrhotic as well as non-cirrhotic subjects treatment experienced with an NS5a Inhibitor + sofosbuvir and will include patients who did not complete the prescribed duration due to adverse event or any reason other than for non/poor compliance. Subjects will be randomized to 12 or 16 weeks of treatment.

Detailed description:
The primary purpose of this study is to compare the efficacy and safety of glecaprevir and pibrentasvir (G/P) for 12 weeks to G/P for 16 weeks in non-cirrhotic NS5A (non-structural protein 5a)-inhibitor plus sofosbuvir ± RBV (Ribavirin) treatment-experienced adults with HCV genotype 1 (GT1) infection, and to compare the efficacy and safety of G/P with RBV for 12 weeks to G/P without RBV for 16 weeks in NS5A-inhibitor plus sofosbuvir (SOF) ± RBV treatment-experienced adults with compensated cirrhosis and GT1 infection.

Arms: arm 1: Non-cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg (3 Glecaprevir/Pibrentasvir (G/P) 100mg/40mg Tablets once-daily by mouth) for 12 weeks. arm 2: Non-cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once-daily by mouth for 16 weeks (G/P 300 mg/120 mg QD for 16 Wks) arm 3: Cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once daily plus Ribavirin 200Mg Tablet (2-3 tablets) twice a day for 12 weeks (G/P 300 mg/120 mg QD + RBV 12 Wks) arm 4: Cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once daily for 16 weeks (G/P 300 mg/120mg QD for 16 Wks)
Interventions: intervention 1: Glecaprevir/Pibrentasvir (G/P) 300mg/120mg intervention 2: Ribavirin 200Mg Tablet
Intervention descriptions: intervention 1: daily intervention 2: Weight-based 1000-1200 mg

Protocol documents:
Prot_000.pdf: 
Protocol  
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Page 1 of 123 
1.0 
Title Page 
Clinical Study Protocol B16-439 
A Phase 3b, Multi-Center, Randomized, Open-Label, Pragmatic Study of 
Glecaprevir/Pibrentasvir (G/P) +/- Ribavirin for GT1 Subjects with Chronic Hepatitis C 
Previously Treated with an NS5A Inhibitor + Sofosbuvir Therapy 
AbbVie Investigational 
Product: 
Glecaprevir, Pibrentasvir 
Date: 
November 20, 2018 (Applicable to sites participating in 
Retreatment sub-study only) 
Development Phase: 
3b 
Study Design: 
Main Study: Randomized open-label, multi-center study. 
Retreatment Sub-study: Open-Label, multi-center study 
Investigators: 
Multi-center.  Investigator information is on file with University 
of Florida. 
IND Sponsor: 
David R. Nelson, MD (UF Hepatology Research at CTRB) 
Sponsor/Emergency 
Contact: 
Phone: 
Fax: 
Mobile: 
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 the Sponsor and AbbVie is permitted without prior written authorization 
from the Sponsor and AbbVie. 
Clinicaltrials.gov Identifier:  NCT03092375


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Page 2 of 123 
 
1. 
Synopsis 
 
IND Sponsor: David 
R. Nelson, MD 
Protocol Number:  B16-439 
Name of Study Drug:  
Glecaprevir (ABT-
493), Pibrentasvir 
(ABT-530), Ribavirin 
(RBV), *Sofosbuvir 
(GS-7977)  
Phase of Development:  3b 
Name of Active 
Ingredient:  ABT-
493, ABT-530, 
ribavirin, *GS-7977  
Date of Protocol Synopsis:  November 20, 2018 
Protocol Title:  A Phase 3b, Multi-Center, Randomized, Open-Label, Pragmatic 
Study of Glecaprevir/Pibrentasvir (G/P) +/- Ribavirin for GT1 Subjects with Chronic 
Hepatitis C Previously Treated with an NS5A Inhibitor + Sofosbuvir Therapy  


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Objectives:   
The primary objectives of this study are to:  
1. Compare the efficacy (SVR12) of G/P given for 12 weeks to non-cirrhotic 
GT1-infected subjects who are treatment-experienced with a NS5A 
inhibitor+SOF±RBV regimen (Arm A) vs. G/P given for 16 weeks (Arm B) 
2. Compare the efficacy (SVR12) of G/P plus RBV given for 12 weeks to GT1-
infected subjects with compensated cirrhosis and who are treatment-
experienced with a NS5A inhibitor+SOF±RBV regimen (Arm C) vs. G/P 
given for 16 weeks (Arm D) 
3. Assess the safety and tolerability of G/P with or without RBV, in these 
subjects with chronic HCV GT1 infection and treatment-experienced with a 
NS5A inhibitor+SOF±RBV regimen. 
 
Investigators:  Multi-center 
Study Sites:  Approximately 35 sites. 
Study Population:   
Main Study: 
Chronic HCV GT1-infected male and female adults, at least 18 years of age, without 
cirrhosis or with compensated cirrhosis and prior NS5A-inhibitor plus sofosbuvir ± 
RBV treatment experience.  
Retreatment sub-study: 
Subjects who experience virologic failure in the Main study 
Number of Subjects to be Enrolled:  up to 225 subjects  
*Applicable to Retreatment sub-study only 


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Methodology: 
 Main Study: 
This is a Phase 3b, randomized, open-label, pragmatic, multicenter study to evaluate 
efficacy and safety of the fixed-dose combination tablets of glecaprevir/pibrentasvir 
with or without RBV in NS5A-inhibitor plus sofosbuvir ± RBV-experienced, chronic 
HCV GT1-infected subjects.  Up to 225 subjects at approximately 35 sites will be 
enrolled into four study arms A, B, C and D.  Up to 150 non-cirrhotic subjects will be 
randomized in a 2:1 ratio to Arms A and B, and up to 75 subjects with compensated 
cirrhosis will be randomized in a 1:1 ratio to Arms C and D.  Randomization will be 
stratified by HCV genotype 1 subtype (1b or non-1b). 
 Subjects without cirrhosis will be randomized 2:1 to: 
Arm A:  G/P 300 mg/120 mg QD for 12 weeks 
Arm B:  G/P 300 mg/120 mg QD for 16 weeks 
Subjects with compensated cirrhosis will be randomized 1:1 to: 
Arm C:  G/P 300 mg/120 mg QD + weight-based RBV BID (1000 mg or 1200 
mg total daily dose) for 12 weeks  
Arm D:  G/P 300 mg/120 mg QD for 16 weeks 
 Subjects who complete or prematurely discontinue the treatment will be followed for 
12 weeks to monitor HCV RNA and to evaluate efficacy and the emergence and 
persistence of viral variants. 
 Scheduled visits for subjects in the planned Treatment Period consist of Day 1, Weeks 
4, 8, 12 for all subjects and Week 16 for subjects in Arms B and D.  During the Post-
Treatment Period, subjects will have visits at Weeks 4 and 12 following completion of 
the Treatment Period.  Efficacy and safety data will be monitored throughout the study.  
These data will enable assessment of virologic stopping, futility, and treatment 
extension criteria as described in the protocol.   


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Retreatment Sub-study 
Subjects who experience virologic failure in the Main study will have the option to 
enter the Retreatment sub-study after experiencing G/P failure and receive 
G/P+SOF±RBV for a total of 16 weeks.  Ribavirin will be used at the discretion of the 
investigator, with particular consideration for a subject who may be at increased risk 
for ribavirin toxicity.    
 Subjects electing to participate in the Retreatment Sub-study will be followed for 
safety and efficacy according to the Main study pragmatic design procedures and 
Study Activities Tables (5 & 6) with exceptions as noted to screening procedures prior 
to re-treatment dosing.  Retreatment eligibility will be determined prior to 
administering G/P+SOF+/-RBV based on Inclusion Criterion 1, 2, 4, 6, 7, 8, 9, and 10 
and Exclusion Criterion 1, 3, 4, 6, 8, 10, 11 and 12 in Sections 5.2.1 and 5.2.2.   


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Diagnosis and Main Criteria for Inclusion/Exclusion:   
Main Inclusion:   
1. Male or female at least 18 years of age at time of screening. 
2. A history of previous treatment with an NS5A-inhibitor plus sofosbuvir 
therapy ± RBV for chronic HCV genotype 1 infection*. 
3. Screening laboratory result indicating chronic HCV GT1 infection*. 
4. Subjects must be able to understand and adhere to the study visit schedule and 
all other protocol requirements and must voluntarily sign and date an informed 
consent. 
    Retreatment Sub-study 
    Subjects who experience virologic failure in the Main study will be considered for 
the Retreatment Sub-study. 
*Applicable during Screening for the Main study only. 
Main Exclusion:   
   1. 
History of severe, life-threatening or other significant sensitivity to any drug. 
 2. 
Female who is pregnant, planning to become pregnant during the study or 
breastfeeding; or male whose partner is pregnant or planning to become 
pregnant during the study. 
 3. 
Clinically significant abnormalities or comorbidities or recent (within 6 months 
prior to study drug administration) history of drug or alcohol abuse that make 
the subjects an unsuitable candidate for this study in the opinion of the 
investigator. 
   4. 
Positive test result at Screening for hepatitis B co-infection (HBsAg positive or   
            Hep B Core Ab -Total positive with detectable HBV DNA) or anti-human  
            immunodeficiency virus antibody (HIV Ab) in patient without known history 
of HIV+ and stable HART therapy*. 
5. 
Prior therapy with HCV PI at any time*. 
6.      History or presence of liver decompensation. 
*Applicable during Screening for the Main study only. 


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Study Drug(s) 
Glecaprevir/pibrentasvir 100 mg/40 mg Tablet 
Ribavirin 200 mg Tablet***  
*Sofosbuvir 400 mg Tablet 
***Ribavirin Dosage Form to be determined by dispensing 
pharmacy during Retreatment sub-study 
Doses: 
Glecaprevir Dose:  300 mg QD 
Pibrentasvir Dose:  120 mg QD 
Glecaprevir/pibrentasvir tablets:  300 mg/120 mg QD (3 
tablets) 
Ribavirin tablets***:  1000 to 1200 mg total daily dose 
divided into two doses BID (5 or 6 tablets total daily dose) at 
the discretion of the PI 
*  Sofosbuvir 400 mg QD 
Mode of 
Administration: 
Oral with food for glecaprevir/pibrentasvir, ribavirin, and 
*Sofosbuvir 
 
Reference Therapy: 
  N/A 
Duration of Treatment: 
Main Study treatment duration is 12 weeks in Arms A and C, and 16 weeks in Arms B 
and D. 
Retreatment sub-study treatment duration is 16 weeks. 
* For Retreatment sub-study only 
Criteria for Evaluation: 
Efficacy:   
Efficacy will be assessed by plasma HCV RNA levels throughout the study. 


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Resistance: 
The following information will be tabulated and summarized:  1) for all subjects with 
available samples, the polymorphisms in NS3 and NS5A (and NS5B for those subjects 
enrolled in the Retreatment sub-study who experience virologic failure) at baseline at 
resistance-associated amino acid positions relative to the appropriate prototypic 
reference sequence, and the impact of baseline polymorphisms on SVR12; and 2) for 
subjects who do not achieve SVR12, all post-baseline substitutions in the NS3 and 
NS5A (and NS5B for those subjects enrolled in the Retreatment sub-study) relative to 
baseline. 
Safety:   
Safety and tolerability will be assessed by monitoring adverse events, physical 
examinations, clinical laboratory tests, and vital signs. 


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Statistical Methods: 
The mITT population for the Main Study will be all subjects enrolled in the Main 
Study receiving at least one dose of study drug categorized according to the treatment 
arm in which they were actually treated, and the Evaluable Patient Population for the 
Retreatment sub-study (EP-RS) will be all subjects who receive at least one dose of 
G/P and of SOF in the Retreatment sub-study. 
Efficacy:   
The primary efficacy endpoints for the mITT population are the difference in SVR12 
(HCV RNA < LLOQ 12 weeks after the last actual dose of study drug) rates between 
Arm A and Arm B in non-cirrhotic subjects, and difference in SVR12 rates between 
Arm C and Arm D in cirrhotic subjects.  
The difference in SVR12 rates will be summarized with a two-sided 95% confidence 
interval for the comparison between Arm A and Arm B in non-cirrhotic subjects, and 
for the comparison between Arm C and Arm D in cirrhotic subjects. The number and 
percentage of subjects achieving SVR12 by treatment arm according to final treatment 
arm assignment of subjects will also be summarized with a two-sided 95% confidence 
interval. The confidence interval for the difference in SVR 12 rates will be calculated 
using Wilson’s score method. The confidence interval for the SVR12 rates by 
treatment arm will be calculated using the normal approximation to the binomial 
distribution if the number of subjects who failed to achieve SVR12 is at least 5. If the 
number of subjects who failed to achieve SVR12 is less than 5, Wilson’s score method 
will be used instead. 
The secondary efficacy variables are: 
1. The difference in SVR12 rates between G/P given for 12 weeks (Arm A and C 
combined) and G/P given for 16 weeks (Arm B and D combined);  
2. The percentage of subjects with on-treatment virologic failure; 
3. The percentage of subjects with post-treatment relapse. 
For the Main study, the differences in the percentages of subjects with on-treatment 
virologic failure or post-treatment relapse for non-cirrhotic subjects (Arm A vs Arm 
B) and subjects with compensated cirrhosis (Arm C vs Arm D) will be summarized 
along with 95% Wilson score intervals.  Additional efficacy endpoints and efficacy 
subgroup analyses will be performed. 
As an additional efficacy endpoint, the percentage of retreated subjects achieving 
SVR12 will be analysed on the EP-RS population overall for the Retreatment sub-
study. 
 


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DAA Resistance: 
For all subjects receiving study drugs and with available samples, the polymorphisms 
at resistance-associated amino acid positions in the NS3 and NS5A (and NS5B for 
those subjects enrolled in the Retreatment sub-study who experience virologic failure) 
proteins at baseline identified by population sequencing or next-generation sequencing 
(NGS) and comparison to the appropriate prototypic reference sequence will be 
analyzed. The impact of baseline polymorphisms on SVR12 will be examined. 
The following resistance information will be analyzed for subjects receiving study 
drugs who do not achieve SVR12 and who have a post-baseline sample with HCV 
RNA ≥ 1000 IU/mL:  1) the amino acid substitutions in NS3 and NS5A (and NS5B for 
those subjects enrolled in the Retreatment sub-study who experience virologic failure) 
in available post-baseline samples identified by population sequencing or NGS and 
comparison to the baseline sequence, 2) the amino acid substitutions in NS3 and 
NS5A (and NS5B for those subjects enrolled in the Retreatment sub-study who 
experience virologic failure) in available post-baseline samples at resistance-
associated positions identified by population sequencing or NGS and comparison to 
the appropriate prototypic reference sequence, and 3) the persistence of viral 
substitutions by population sequencing or NGS. 


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Safety:   
All subjects who receive at least one dose of study drugs will be included in the safety 
analyses.  Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by subject’s final treatment arm 
assignment.  Safety summaries will be provided by treatment group of the Main study 
and overall for the Retreatment sub-study.  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) will be tabulated by primary System Organ 
Class (SOC).  The tabulation of the number of subjects with treatment-emergent 
adverse events also will be provided by grade and relationship to study drug.  Change 
from baseline in laboratory tests to each time point of collection will be summarized 
by subject’s final treatment arm assignment. Laboratory values that show an increase 
in CTCAE grade will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2 
List of Abbreviations, Definitions and Terms 
 
   Abbreviations 
3TC 
Lamivudine 
Ab 
Antibody 
ABC 
Abacvir 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
APRI 
Aminotransferase/platelet ratio index 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
AUC 
Area Under the Concentration Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CCC 
Clinical Coordinating Center 
CKD 
Chronic kidney disease 
CL/F 
Apparent Oral Clearance 
CPK 
Creatine phosphokinase 
CR/CL 
Creatinine clearance 
CRF 
Case report form 
CT 
Computed Tomography 
DAA 
Direct-acting antiviral agent 
D/C 
Discontinuation 
DCV 
Daclatasvir 
DCC 
Data Coordinating Center 


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DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EDTA 
Edetic acid (ethylenediaminetetraacetic acid) 
EHR 
Electronic health record 
EMR 
Electronic medical record 
EOT 
End of treatment 
EP 
Evaluable Population 
EU 
European Union 
FSH 
Follicle stimulating hormone 
FTC 
Emtricitabine 
GAM 
Generalized additive method 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony stimulating factor  
GGT 
Gamma-glutamyl transferase 
GLE 
Glecaprevir 
G/P 
Glecaprevir/Pibrentasvir fixed dose combination 
GT 
Genotype 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 
Hemoglobin A1c 
Glycated haemoglobin 
HIV 
Human immunodeficiency virus 
HIV Ab 
Human immunodeficiency virus antibody 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IFN 
Interferon 


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IL28B 
Interleukin 28B 
IMP 
Investigational Medical Product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
International units 
IUD 
Intrauterine device 
LDV 
Ledipasvir 
LLN 
Lower limit of normal 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantification 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NGS 
Next generation sequencing 
NONMEM 
Non-linear mixed-effect modeling 
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 alfa-2b 
PegIFN/RBV 
Combination of pegylated-interferon alfa-2a or alfa-2b and 
ribavirin 
PI 
Protease Inhibitor 
PIB 
Pibrentasvir 
PK 
Pharmacokinetic 
POR 
Proof of Receipt 
PRS 
IFN, pegIFN, RBV and/or sofosbuvir 


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PT 
Post-Treatment 
QD 
Once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QTc using Fridericia's correction formula 
RBC 
Red blood cells 
RBV 
Ribavirin 
RNA 
Ribonucleic acid 
EP-PCR 
 
Reverse transcriptase PCR 
 
RS 
Retreatment sub-study 
SAD 
Single Ascending Dose 
SAE 
Serious adverse event 
sAFP 
Serum Alpha-Fetoprotein 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System Organ Class/Standard of Care 
SOF 
Sofosbuvir 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR 
Sustained virologic response 
SVR4 
Sustained virologic response 4 weeks post dosing 
SVR12 
Sustained virologic response 12 weeks post dosing 
TAF 
Tenofovir alafenamide 
TDF 
Tenofovir disoproxil fumarate 
ULN 
Upper limit of normal 
V/F 
Apparent Volume of distribution 
WBC 
White blood cells 
 


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Pharmacokinetic and Statistical Abbreviations 
AUC 
Area under the plasma concentration-time curve 
AUC24 
AUC for the 24-hour dosing interval 
β 
Apparent terminal phase elimination rate constant 
CL/F 
Apparent oral plasma clearance 
Cmax 
Maximum observed plasma concentration 
Ctrough 
Pre-dose trough plasma concentration 
t1/2 
Terminal phase elimination half-life 
Tmax 
Time to maximum observed plasma concentration (Cmax) 
 
Definition of Terms 
Study Drug 
Glecaprevir (ABT-493), pibrentasvir (ABT-530), Ribavirin 
(RBV), *Sofosbuvir (GS-7977) 
Study Day 1 
First day of study drug dosing  
Treatment Period 
Day 1 through last dose of study drug 
Post-Treatment 
Period 
Day after the last dose of study drug through Post-Treatment 
Week 12 or Post-Treatment Discontinuation 
 
Note: Differentiation between terms within the Main Study and 
Re-Treatment Substudy will be made with the use of headers 
throughout the protocol 
 
 
 
 


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2.0 Table of Contents 
 
Table of Contents 
1.0 
Title Page ........................................................................................................... 1 
1. 
Synopsis ........................................................................................................................ 2 
1.2 
List of Abbreviations, Definitions and Terms ............................................................. 12 
2.0 
Table of Contents ...............................................................................................17 
3.0 
Introduction.......................................................................................................21 
3.1  
Glecaprevir/Pibrentasvir (G/P) ................................................................................. 22 
3.1.1  
Efficacy ..................................................................................................................................... 23 
3.1.2  
Impact of Baseline Polymorphisms on Treatment Outcome .................................................. 25 
3.1.3  
Amino Acid Substitutions in Subjects Experiencing Virologic Failure ..................................... 25 
3.1.4  
Integrated Safety Results ......................................................................................................... 26 
3.2  
Ledipasvir/Sofosbuvir (LDV/SOF) .............................................................................. 29 
3.3  
PRIORITIZE Study and HCV-TARGET .......................................................................... 30 
3.4  
Study Rationale ........................................................................................................ 30 
3.4.1 Rationale for Retreatment of G/P Failures in this Study .................................................................. 34 
3.5  
Rationale for Pragmatic Design in Phase 3b Study using HCV-TARGET Network and 
Methods ............................................................................................................................. 34 
3.6  
Benefits and Risks .................................................................................................... 36 
4.0 
Study Objective ..................................................................................................37 
4.1 
Primary Objective ..................................................................................................... 37 
4.2 
Secondary Objectives ................................................................................................ 37 
4.3 
Additional Objectives ............................................................................................... 38 
5.0 
Investigational Plan ...........................................................................................38 
5.1       Overall Study Design, Rationale and Plan: Description ................................................ 38 
5.1.1  
Standard of Care Assessments – (patient managed clinically and billed per standard medical 
practice) 41 
5.1.2      Protocol Required Assessments (not billed as standard of care Table 5 and Table 6)................ 42 
5.1.3.    Screening ...................................................................................................................................... 42 
5.1.4   
Treatment Period ..................................................................................................................... 44 
5.1.5      Post-Treatment Period ................................................................................................................. 46 
5.1.6   
Retreatment Sub-study............................................................................................................ 47 
5.2 
Selection of Study Population.................................................................................... 47 
5.2.1 
Inclusion Criteria ........................................................................................................................... 48 
5.2.2 
Exclusion Criteria .......................................................................................................................... 50 


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5.2.3 
Guidance for Determination of Cirrhosis ..................................................................................... 52 
5.2.4  
Prior and Concomitant Therapy ............................................................................................... 53 
5.3 
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables ......... 57 
5.3.1 
Efficacy and Safety Measurements Assessed and Flow Chart ...................................................... 57 
5.3.2 
Efficacy Variables .......................................................................................................................... 68 
5.3.3 
Resistance Variables ..................................................................................................................... 68 
5.3.4 
Safety Variables ............................................................................................................................ 69 
5.4 
Removal of Subjects from Therapy or Treatment Duration Assessment ....................... 69 
5.4.1 
Discontinuation of Individual Subjects ......................................................................................... 69 
5.4.2 
Discontinuation of Entire Study .................................................................................................... 72 
5.5 
Treatments .............................................................................................................. 73 
5.5.1 
Treatments Administered ............................................................................................................. 73 
5.5.1.1          Retreatments Administered .................................................................................................. 74 
5.5.2 
Identity of Investigational Products .............................................................................................. 74 
5.5.3 
Packaging and Labelling ................................................................................................................ 74 
5.5.4 
Method of Assigning Subjects to Treatment Groups- ................................................................... 75 
5.5.5 
Selection and Timing of Dose for Each Subject............................................................................. 76 
5.5.6 
Blinding ......................................................................................................................................... 77 
5.5.7 
Treatment Compliance ................................................................................................................. 77 
5.5.8 
Drug Accountability & Destruction ............................................................................................... 78 
6.0 
Complaints ........................................................................................................81 
6.1 
Medical Complaints .................................................................................................. 81 
6.1.1 
Definitions .................................................................................................................................... 81 
6.1.2 
Adverse Event Severity ................................................................................................................. 84 
6.1.3 
Relationship to Study Drug ........................................................................................................... 84 
6.1.4 
Adverse Event Collection Period ................................................................................................... 85 
6.1.5 
Serious Adverse Event Reporting ................................................................................................. 86 
6.1.6 
Pregnancy ..................................................................................................................................... 86 
6.1.7 
Toxicity Management ................................................................................................................... 87 
6.2. 
Product Complaint .................................................................................................... 88 
6.2.1 
Definition ...................................................................................................................................... 88 
6.2.2 
Reporting ...................................................................................................................................... 88 
7.0 
Protocol Deviations ............................................................................................89 
8.0 
Statistical Methods and Determination of Sample Size .......................................90 
8.1 
Statistical and Analytical Plans .................................................................................. 90 
8.1.1 
Demographics............................................................................................................................... 91 
8.1.2 
Efficacy ......................................................................................................................................... 92 
8.1.3 
Resistance Analyses ...................................................................................................................... 96 
8.2 
Determination of Sample Size ................................................................................... 98 
8.3 
Randomization Methods ........................................................................................... 99 
9.0 
Ethics.................................................................................................................99 
9.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................... 99 


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9.2 
Ethical Conduct of the Study ................................................................................... 100 
9.3 
Subject Information and Consent ............................................................................ 100 
10.0 
Source Documents and Case Report Form Completion ................................... 101 
10.1 
Source Documents .................................................................................................. 101 
10.2 
Case Report Forms .................................................................................................. 102 
10.3 
Centralized Data Abstraction .................................................................................. 103 
10.4 
Submitting Records for Abstraction ........................................................................ 103 
10.5 
Subject Confidentiality Associated with Uploaded Records for Abstraction .............. 104 
10.6 
HIPAA Privacy Rule for Elements of PHI and Uploaded Records for Abstraction........ 105 
11.0 
 Monitoring ............................................................................................................ 106 
12.0 
 Records Retention ................................................................................................. 107 
13.0        Study Drug Records .............................................................................................. 107 
14.0 
 Data Quality Assurance ......................................................................................... 108 
15.0 
 Completion of the Study ........................................................................................ 108 
16.0 
 Investigator's Agreement ............................................................................ 110 
17.0 
 Reference List .............................................................................................. 111 
Appendix A. 
Responsibilities of the Clinical Investigator .......................................... 114 
Appendix B. 
Medicare National Coverage Decision for Clinical Trials ...................... 116 
Qualification Process for Clinical Trials ............................................................................... 119 
Appendix C. 
Methods of Contraceptives ................................................................. 122 
 


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List of Tables 
Table 1. 
Overview of Clinical Studies by Subject Population ........................................... 23 
Table 2. 
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 – 6 (ITT 
Population, Phase 2 and 3 Analysis Set)............................................................................................. 24 
Table 3. 
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 Analysis Set) . 27 
Table 4.  
Prohibited Medications and Supplements ........................................................ 55 
Table 5. 
Study Activities – Treatment Period.................................................................. 57 
Table 6. 
Study Activities – Post-Treatment (PT) Period ............................................. 60 
Table 7. 
Child-Pugh Score for Classification of Severity of Cirrhosis .......................... 62 
Table 8. 
Clinical Laboratory Tests ................................................................................. 63 
Table 9. 
Identity of Investigational Products ................................................................ 74 
 
List of Figures 
Figure 1. 
 Study Schematic ............................................................................................... 39 
 
 


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3.0 
Introduction 
 
Approximately 170 million people worldwide are chronically infected with hepatitis C virus 
(HCV), including approximately 4-5 million in the United States.1-4  The majority of individuals 
infected progress to chronic hepatitis, which can lead to cirrhosis, liver failure, and hepatocellular 
carcinoma (HCC).5  HCV is the leading cause of HCC and indication for liver transplantation in 
most countries, including the United States.5  Recently, the development of oral direct acting anti-
viral therapy has been a major advance for the treatment of HCV with available combinations 
curing the majority of infected patients.6,7  Despite the high sustained virologic response (SVR) 
rates with direct-acting antiviral agents (DAAs), there are patients who fail these combinations and 
there are currently limited approved retreatment options for subjects who failed an NS5A-inhibitor 
all-oral DAA regimen.7-9 
 
Treatment failure in HCV-infected patients is often associated with host (cirrhosis) and/or viral 
factors, including resistant-associated substitutions.10-12 
 
AbbVie recently received FDA approval for two "next generation" DAAs, glecaprevir (GLE, 
formerly known as ABT-493), an HCV NS3/4A protease inhibitor (PI) and pibrentasvir (PIB, 
formerly known as ABT-530), an NS5A inhibitor, for use in combination for the treatment of 
chronic HCV infection, including in subjects with chronic HCV GT1 infection who failed a prior 
NS5A inhibitor-containing regimen without an NS3/4A protease inhibitor.23  GLE and PIB each 
have potent in vitro antiviral activity against genotypes 1 through 613,22 and a high genetic barrier to 
resistance, with no or little loss of potency against common resistant-associated substitutions22.  
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 
herein referred to as G/P, which provides patients with a convenient once-daily (QD), fixed-dose 
combination treatment regimen of three tablets QD to maximize treatment compliance. 
 
 
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology and 


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metabolism, and clinical data can be found in the Investigator's Brochure (applicable to Main Study 
only).13 
 
3.1  
Glecaprevir/Pibrentasvir (G/P) 
 
  Overview of G/P Registration Program and Supportive Studies 
The G/P registration program included a broad subject population including subjects with 
compensated liver disease and subjects with severe renal insufficiency across all 6 major 
genotypes using a single 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 registration studies (GLE 300 mg plus PIB 120 mg) were pooled with arms from the 
registration studies for analyses of efficacy and safety.  Treatment-naïve (TN) and TE subjects to 
any combination of pegylated IFN (pegIFN), RBV, sofosbuvir (SOF), NS5A inhibitors, or PIs 
were allowed in the program.  In addition, the program included subjects with human 
immunodeficiency virus (HIV) coinfection (Study M13-590), subjects with chronic kidney 
disease [CKD] Stages 4 – 5, including those on hemodialysis (Study M15-462), subjects with 
compensated cirrhosis (Studies M14-172, M15-462, and M14-868), 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 registration studies or supportive 
Phase 2 studies to receive G/P 300 mg QD/120 mg QD.  Of these, 2,369 subjects received at least 
1 dose of G/P 300 mg QD/120 mg QD (Table 1). 


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Table 1. 
Overview of Clinical Studies by Subject Population 
Genotype 
Clinical Study  Summary of Study Design  
TN and TE Subjects Without Cirrhosis 
GT1 
M13-590 
G/P 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 
G/P 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 
G/P 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 
G/P 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 compensated Cirrhosis 
GT1, 2, 4, 5, 6 
M14-172 
G/P 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 compensated Cirrhosis 
GT1 – 6 
M15-462 
G/P 300 mg/120 mg QD for 12 weeks (n = 104) 
NS5A Inhibitor and/or PI-Experienced Subjects With or Without compensated Cirrhosis 
GT1, 4 
M15-410 
G/P 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 
 
3.1.1  
Efficacy 
 
In TN or IFN, pegIFN, RBV, and/or SOF treatment-experienced (TE-PRS) subjects, the pooled 
overall SVR12 rates with G/P were > 97% across GT1, 2, 4, 5 and 6 regardless of treatment 
experience, treatment duration, including any degree of renal impairment, presence of cirrhosis, 
or HIV-1 coinfection (Table 2).   
 
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.  


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The SVR12 rates among subjects previously treated with a PI and/or NS5A inhibitor were 
≥ 89.0% for GT1 and GT4. 
Table 2. 
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 – 6 (ITT 
Population, Phase 2 and 3 Analysis Set) 
Genotype 
TN 
n/N (%) 
95% CIa 
TE-PRS 
n/N (%) 
95% CIa 
TN + TE-PRS 
TE-NS5A 
and/or PIs 
n/N (%) 
95% CIa 
Overall 
n/N (%) 
95% CIa 
Alla 
Cirrhotic 
n/N (%) 
95% CIb 
CKD 4 – 5 
n/N (%) 
95% CIb 
Phase 2 
and 3 
Analysis 
Set 
1604/1640 
(97.8) 
97.1, 98.5 
602/616 
(97.7) 
96.6, 98.9 
2206/2256 
(97.8) 
97.2, 98.4 
274/281 
(97.5) 
95.7, 99.3 
102/104  
(98.1) 
95.4, 100.0 
101/113 
(89.4) 
83.7, 95.1 
2307/2369 
(97.4) 
96.7, 98.0 
GT1 
555/561 
(98.9) 
98.1, 99.8 
326/328 
(99.4) 
98.5, 100.0 
881/889 
(99.1) 
98.5, 99.7 
98/101 
(97.0) 
93.7, 100.0 
53/55 
(96.4) 
91.4, 100.0 
97/109 
(89.0) 
83.1, 94.9 
978/998c 
(98.0) 
97.1, 98.8 
GT2 
365/369 
(98.9) 
97.9, 100.0 
95/97  
(97.9) 
95.1, 100.0 
460/466 
(98.7) 
97.7, 99.7 
35/35  
(100) 
100.0, 
100.0 
16/16  
(100) 
100.0, 100.0 
N/A 
460/466 
(98.7) 
97.7, 99.7 
GT3 
499/521 
(95.8) 
94.0, 97.5 
113/122 
(92.6) 
88.0, 97.3 
612/643 
(95.2) 
93.5, 96.8 
112/116 
(96.6) 
93.2, 99.9 
11/11  
(100) 
100.0, 100.0 
N/A 
612/643 
(95.2) 
93.5, 96.8 
GT4 
119/122 
(97.5) 
94.8, 100.0 
55/56  
(98.2) 
94.7, 100.0 
174/178 
(97.8) 
95.6, 99.9 
20/20  
(100)  
100.0, 
100.0 
20/20  
(100)  
100.0, 100.0 
4/4  
(100)  
100.0, 
100.0 
178/182 
(97.8) 
95.7, 99.9 
GT5 
26/26  
(100) 
100.0, 
100.0 
6/6  
(100) 
100.0, 
100.0 
32/32  
(100) 
100.0, 
100.0 
2/2  
(100)  
100.0, 
100.0 
1/1  
(100)  
100.0, 100.0 
N/A 
32/32  
(100)  
100.0, 100.0 
GT6 
40/41  
(97.6) 
92.8, 100.0 
7/7  
(100) 
100.0, 
100.0 
47/48  
(97.9) 
93.8, 100.0 
7/7  
(100) 
100.0, 
100.0 
1/1  
(100) 
100.0, 100.0 
N/A 
47/48  
(97.9) 
93.8, 100.0 
CI = confidence interval; CKD = chronic kidney disease; GT = genotype; HCV = hepatitis C virus; ITT = intention-to-treat; N/A = 
not applicable; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; PRS = regimens containing interferon, pegylated 
interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic response 12 weeks post dosing; TE = treatment-experienced; 
TN = treatment-naïve; TE-NS5A and/or PI = TE with NS5A inhibitor and/or PI 
1. 
CI was calculated using a stratum-weighted proportion and variance. 
2. 
CI was calculated using the normal approximation to the binomial distribution. 
3. 
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 
4. 
Cross reference:  AbbVie, data on file. 
 


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3.1.2  
Impact of Baseline Polymorphisms on Treatment Outcome 
 
The association between baseline polymorphisms and treatment outcome in TN and TE-PRS 
subjects who received G/P 300 mg/120 mg QD in the registration 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.  
3.1.3  
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).  One 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 


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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. 
3.1.4  
Integrated Safety Results 
 
A summary of treatment-emergent adverse events (AEs) from pooled analyses of the registration 
studies and supportive Phase 2 studies are presented in Table 3.  The severity of the underlying 
renal disease and its associated comorbidities in patients with CKD Stages 4 and 5, the frequency 
and severity of the AEs in subjects enrolled Study M15-462 were expected to be higher than in 
subjects enrolled in the other registration studies.  Therefore, the summary of adverse events 
reported in Table 3 does not include the results of Study M15-462. 
 
As shown in Table 3, the AEs occurring with a frequency ≥ 5% are headache, fatigue, nausea and 
diarrhea.  The majority of subjects experienced an AE, which were mostly considered to be mild 
in severity by the investigator (Grade 1).  Rates of AEs that were serious, led to premature study 
drug discontinuation or had a severity Grade ≥ 3 were low.  Including data from Study M15-462, 
there were 7 deaths, none of which were related to study drug, and the majority occurred several 
months after the last dose of study drug.  


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Table 3. 
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 Analysis 
Set) 
 
Phase 2 and 3 Analysis Seta 
(N = 2,265) 
n (%) 
 
All Adverse Events 
DAA-Related Adverse 
Eventsb 
Any AE 
1,529 (67.5) 
929 (41.0) 
An AE Grade ≥ 3 
65 (2.9) 
4 (0.2) 
Any SAE 
48 (2.1) 
1 (< 0.1) 
Discontinuation of study drug due to any AE 
8 (0.4) 
3 (0.1) 
All deathsc 
6 (0.3) 
0 
Preferred 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 non-treatment-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.  
Cross reference:  AbbVie, data on file.  
 
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 G/P in the elderly population (≥ 65 years old, n = 328) was comparable to the 
safety profile in the non-elderly population (n = 2,041). 
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  


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• One subject experienced concurrent ALT > 3 × ULN (increased from nadir grade) and 
total bilirubin ≥ 2 × ULN in the context of multiple gallstones and was not considered to 
have 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 G/P.   
 
In summary, G/P 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, nausea and 
were mostly Grade 1 (mild) in severity.  Serious AEs and AEs leading to premature study drug 
discontinuation were rare.  There were no hematological or blood chemistry findings of concern or 
considered likely related to treatment.  Unlike other protease inhibitors, no liver-related toxicities 
and no cases consistent with drug-induced liver injury were identified. 
 
G/P+SOF+/-RBV for G/P treatment failures 
AbbVie has recently evaluated the safety and efficacy of G/P+SOF+/-RBV in combination in 
patients who had virologic failure following G/P treatment in AbbVie’s registration program.  The 
MAGELLAN-3 study (M15-942) is ongoing and reported to date on a total of 23 subjects 
including 7 GT1-infected patients treated for 16 weeks with G/P+SOF+RBV; 6/7 achieved an 
SVR12 (86%).  The patient who experienced virologic failure relapsed, had GT1a infection, 


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compensated cirrhosis, and had failed a course of LDV/SOF prior to enrolling in the AbbVie parent 
study MAGELLAN-1 (M15-410), where the patient experienced on-treatment failure.  Overall, the 
7 GT1-infected patients enrolled in MAGELLAN-3 had a median of 9 months (min: 6.7/max: 14) 
from time of G/P failure in the AbbVie parent study to start of retreatment in MAGELLAN-3 and 
all had persistent NS5A RASs at baseline prior to retreatment with G/P+SOF+RBV.  Retreatment 
with G/P+SOF+RBV was well tolerated.  There have been no serious adverse events attributed to 
the retreatment regimen and no Grade 3 adverse events. The most common adverse events in >10% 
of subjects were headache, pruritus, dizziness, irritability, fatigue, insomnia and upper respiratory 
tract infection.  There was one grade 3 ALT elevation in a subject with an SAE of cholelithiasis 
that was consistent with biliary obstruction.24   
 
 
3.2  
Ledipasvir/Sofosbuvir (LDV/SOF) 
 
LDV/SOF is a single tablet combining LDV, an NS5A inhibitor, with SOF a nucleotide analog 
HCV NS5B polymerase inhibitor, that was the first fixed dose combination of an all oral DAA 
regimen approved in the US for genotype 1 patients. In the registration clinical trials with 
LDV/SOF, the treatment combination resulted in high SVR rates (≥ 94%) following 8-24 weeks of 
treatment in treatment-naïve and pegIFN and RBV treatment-experienced subjects, irrespective of 
cirrhosis, yet still some patients fail this therapy.14  Subjects with HCV genotype 1 that failed eight 
or twelve weeks of LDV/SOF-containing regimens that were retreated with 24 weeks of LDV/SOF 
had an SVR12 rate of 71% and in this population, the presence of baseline NS5A RAVs was 
associated with virologic failure15.  Post-baseline NS5A and NS5B deep nucleotide sequence 
analysis data (assay sensitivity of 1%) from the 29 genotype 1a LDV/SOF virologic failure subjects 
from Phase 3 showed that 55% (16/29) of subjects had virus with emergent NS5A resistance-
associated substitutions (RAS) K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure.  Five 
of these 16 subjects’ viruses also had baseline NS5A polymorphisms at resistance-associated amino 
acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and 
L31M. Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A 
resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from three of these 7 


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subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most 
common substitution detected at failure was Y93H.14  
 
In the HCV-TARGET observational cohort, treatment failure occurred in 3-5% of 2,099 patients 
treated with LDV/SOF17. Treatment failure was more likely in those with cirrhosis, more advanced 
disease (low albumin and higher bilirubin), and those on concurrent proton pump inhibitors. It can 
be expected that as more patients are treated with DAA therapies, particularly with the widespread 
use of LDV/SOF, the need for retreatment options for patients who fail will increase.  
 
3.3  
PRIORITIZE Study and HCV-TARGET 
 
The PRIORITIZE study and HCV-TARGET represent real-world cohorts to provide well-
characterized patients for a DAA failure clinical trial. In the PRIORITIZE Study approximately 
1250 GT1 patients without a history of decompensated cirrhosis will be randomized to receive 
LDV/SOF, and have virologic, clinical, disease progression, and QOL/PRO data collected for a 5 
year period under a pragmatic design. Each patient will have baseline NS5A testing performed, 
along with a stored sample for research purposes. Upon treatment failure, all patients will have a 
sample collected for resistance testing. Assuming a 5% treatment failure rate, PRIORITIZE will 
generate approximately 65 LDV/SOF treatment failures. HCV-TARGET is an observational cohort 
of patients undergoing DAA therapy. To date, approximately 7,000 patients treated with DAA 
therapy have been enrolled into HCV-TARGET.  Among HCV-TARGET centers, there are more 
than 450 G1 therapy failures, 300 of which failed therapy with an NS5a-I+SOF and represent 
another cohort of DAA failures. Between these two studies, well-characterized NS5a-I/SOF 
failures will be identified to form a unique cohort to rapidly enroll into this DAA failure study. 
 
3.4  
Study Rationale  
 
The FDA approved label duration for NS5A-experienced, PI-naïve subjects with or without 
compensated cirrhosis and HCV GT1 chronic infection is G/P 300 mg/120 mg for 16 weeks.23 
However, the G/P regimen may be further refined based on additional efficacy results in subsets of 


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NS5A inhibitor experienced, PI-naïve HCV GT1 infected subjects. The goals of this study are to 
increase the confidence in real world DAA failure patients who are receiving the recommended 
G/P regimen, to explore a shorter 12-week duration of the G/P regimen in non-cirrhotic subjects, 
and ribavirin-intensification of a shorter 12-week duration of the G/P regimen in subjects with 
compensated cirrhosis. 
 
 
High SVR12 rates were achieved with G/P 300 mg/120 mg when given for 12 and 16 weeks in 
GT1-infected subjects who were NS5A-experienced and PI-naive (SVR12 90.0% 18/20 and 94% 
17/18, respectively, MAGELLAN-1, NCT02446717, AbbVie, data on file). The majority of 
subjects with prior NS5A inhibitor-experience in MAGELLAN-1 Part 1 & 2 combined were 
subjects who failed prior LDV/SOF (Harvoni) treatment: GLE/PIB 300 mg/ 120 mg for 12 weeks 
(n=12, 11 achieved SVR12, 91.7%), GLE/PIB 300 mg/ 120 mg for 16 weeks (n=10, 9 achieved 
SVR12, 90.0%), and G/P 300 mg/ 120 mg plus 800 mg once daily RBV for 12 weeks (n=4, all 4 
achieved SVR12). Among the 42 NS5A-experienced and PI-naïve failures enrolled in 
MAGELLAN-1, 30/31 (96.8%) subjects without cirrhosis and 9/11 (81.8%) of subjects with 
compensated cirrhosis achieved an SVR12.  
 
In MAGELLAN-1, NS5A inhibitor-experienced, PI-naïve subjects without cirrhosis who received 
G/P 300 mg/120 mg for 12 and 16 weeks achieved SVR12 rates of 92.3% (12/13) and 100% 
(14/14), respectively.  As the difference in SVR12 between these two durations was based on a 
single subject that did not achieve SVR, it is hypothesized that 12 weeks treatment duration with 
G/P may provide an effective retreatment option.  Therefore, the present study will evaluate G/P 
for 12 and 16 weeks in a larger patient population to determine if treatment duration may be 
decreased from 16 to 12 weeks in NS5A inhibitor-experienced, PI-naïve subjects without cirrhosis. 
 
MAGELLAN-1 enrolled a total of 11 NS5A inhibitor -experienced, PI-naïve subjects with 
compensated cirrhosis; 85.7% (6/7) and 75.5% (3/4) subjects achieved SVR12 with G/P 300 
mg/120 mg for 12 or 16 weeks, respectively.  The two subjects that did not achieve SVR12 
experienced on-treatment virologic failure and may benefit from the addition of RBV which has 


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been shown to decrease the risk of both on-treatment failure and relapse.16 Therefore, the present 
study will evaluate G/P for 16 weeks and G/P + RBV for 12 weeks in NS5A inhibitor -experienced, 
PI-naïve subjects with compensated cirrhosis. 
 
The objective of this study is therefore to obtain additional data with G/P in NS5A 
inhibitor–experienced, PI-naïve GT1-infected subjects that will help to optimize the G/P regimen 
for this population.  The initial study design did not exclude patients with historical PI exposure 
prior to the NS5A-inbitor exposure as PI resistance has been shown to quickly revert to wild types, 
but did exclude only those who received a PI in combination with a NS5a.  Since the initial study 
launch, G/P has been approved by the FDA and was given a label for NS5A experienced, PI naïve 
patients only; with 16 weeks of therapy. Thus, to minimize treatment failure in this population and 
more accurately reflect FDA label duration, patients with any prior PI exposure will be excluded 
from further recruitment into the study and any patient already enrolled or randomized to a 12- 
week arm will have their treatment extended to 16 weeks duration. 
 
In addition to LDV/SOF-treatment experienced subjects, velpatasvir (VEL)/sofosbuvir (VEL/SOF) 
and daclatasvir (DCV)/sofosbuvir-experienced subjects will be included.  While there is clinical 
evidence that G/P retreatment of LDV/SOF failures can achieve high SVR rates (see above), there 
is no clinical data for G/P in VEL/SOF- or DCV/SOF-experienced subjects. NS5A substitution 
Y93H has been observed in GT1 and GT3 treatment failures with SOF/VEL and confers greater 
than 100-fold reduction in velpatasvir in-vitro susceptibility.19  In GT1a-infected subjects who 
failed a DCV/SOF  regimen NS5A resistance-associated substitutions (including pre-existing 
amino acid polymorphisms or treatment-emergent substitutions): M28T, Q30H/K/R, L31M/V, 
H54R, H58D/P, or Y93C/N were observed. In GT1b failures the P32-deletion was observed. 
Among HCV genotype 1a-infected virologic failure subjects, the most common NS5A amino acid 
substitutions occurred at position Q30 (Q30H/K/R; 73% [8/11], all treatment-emergent).  
Phenotypic analysis of genotype 1a replicons expressing single NS5A M28T, Q30E, Q30H, Q30R, 
L31V, Y93C, Y93H, and Y93N substitutions exhibited 500- 18500-, 1083-, 900-, 2500-, 1367-, 
8500-, and 34833-fold reduced susceptibility to DCV, respectively. For genotype 1b, L31V and 
Y93H single substitutions and L31M/Y93H and L31V/Y93H combinations exhibited 33-, 30-, 


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16000-, and 33667-fold reduced susceptibility to DCV, respectively. The P32-deletion in genotype 
1b reduced DCV susceptibility by >1,000,000-fold.20  None of the studied single NS5A 
substitutions in GT1 at positions 28, 30, 31, and 93 reduced susceptibility to PIB by more than 6-7 
fold22, and there was no single NS5A baseline polymorphism that was associated with a reduced 
SVR12 rate in GT1-infected subjects in the G/P Phase 3 trials (Section 3.1.2).  Furthermore, and 
given the different mechanism of action of GLE when compared to SOF and no cross-resistance 
between SOF and GLE, and GLE with any NS5A inhibitor, the G/P regimen ± RBV should 
provide high SVR rates for VEL/SOF or DCV/SOF-experienced subjects. 
 
In this study, prior GT1-infected NS5A inhibitor + SOF-experienced subjects without cirrhosis will 
be randomized 2:1 to receive G/P for 12 or 16 weeks.  Prior GT1-infected NS5A inhibitor + SOF-
experienced subjects with compensated cirrhosis will be randomized 1:1 to receive 12 weeks of 
G/P with RBV or 16 weeks of G/P.   
 
In the first several years of HCV DAA therapy, more than 50% of patients undergoing treatment 
had evidence of cirrhosis.  With rapid uptake of HCV treatment in this cirrhotic patient population, 
the prevalence of cirrhosis among untreated persons with HCV has decreased substantially to only 
15 to 20%.  This shift in the characteristics of patients presenting for HCV treatment in the US is 
reflected in several other studies including the PRIORITIZE Study mentioned previously (16% 
cirrhosis in over 1200 patients enrolled) and the HCV-TARGET observational registry (15% 
cirrhosis currently with 40% cirrhosis historically). Similar trends in the types of patients treated 
using pharmacy databases (such as TRIO) are evident.  Among the first 130 patients screened for 
this study, 65% have been non-cirrhotic, reflecting the current real-world treatment population in 
DAA failure patients.  Thus, the patient randomization targets have been adjusted and nearly 70% 
non-cirrhotic patients are expected to enroll in this study, thereby matching current observed trends 
in HCV therapy.    
 
In the main study, patients without cirrhosis will be treated with G/P for either 16 or 12 weeks.  
Patients with compensated cirrhosis will be treated for 16 weeks with G/P or 12 weeks with G/P + 
ribavirin.  Ribavirin is an FDA approved drug that is used in combination with other HCV 


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treatments. The approved G/P treatment duration for prior GT1-infected NS5A inhibitor failures 
that are NS3/4A inhibitor naïve and are non-cirrhotic or have compensated cirrhosis is 16 weeks. In 
addition to the approved G/P treatment duration of 16 weeks, a 12-week duration of G/P without 
and with ribavirin is tested for non-cirrhotic and compensated cirrhotic patients, respectively. These 
later treatment arms are considered experimental.  
 
3.4.1 Rationale for Retreatment of G/P Failures in this Study 
 
Combining drugs with different mechanisms of action can increase the probability of achieving a 
sustained virologic response in HCV-infected patients who have failed one or more prior DAA 
therapy.  Data from GT1-infected patients in the MAGELLAN-3 study who failed prior G/P 
therapy support the use of the combination of G/P+SOF±RBV as a viable, well-tolerated 
retreatment option. 
 
3.5  
Rationale for Pragmatic Design in Phase 3b Study using HCV-TARGET 
Network and Methods 
 
The Medicare National Coverage Decision for Clinical Trials provides for a national coverage 
policy covering the routine costs for items and services given to a patient as part of a clinical trial 
(see Appendix B) setting the stage to implement clinical research studies under standard of care 
practice.  Typically, trials designed for regulatory approval are highly controlled and restrictive in 
the patients studied.  By the time of the phase 3b drug development, drug safety and efficacy are 
established from earlier trials yet drugs arrive in the post-marketing environment lacking 
information needed by post-regulatory decision-makers (providers, patients, payers) to guide 
treatment and coverage decisions (no established “real-world” effectiveness).   In 2009, the 
Center for Medical Technology Policy (CMTP) convened a large meeting of experts and 
stakeholders, including the US FDA, to seek input to develop a guidance document to develop 
and implement informative, pragmatic phase 3/3b pharmaceutical trials that satisfy the regulatory 
requirements of the FDA (Effectiveness Guidance Document- Pragmatic Phase 3 
Pharmaceutical Trials:  Recommendations for the design of clinical trials that are more 


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informative for patients, clinicians and payers).  The FDA has issued guidance related to Real 
World Evidence (RWE) use in regulatory decision-making and have stated that “It is important 
that FDA consider the possibilities of using so-called “real world” data as an important tool in 
evaluating not only the safety of medications but also their effectiveness.” The advantage of 
RWE is to produce information needed by the post-regulatory decision makers, which avoids 
delays in coverage decisions and speeds access to beneficial new therapies to a broad range of 
patients. Domains that are most necessary for making post-regulatory decisions that are often 
missing from traditional regulatory trials include generalizability of patient population and 
consistently measured, relevant outcomes. 
 
The HCV-TARGET cohort study has grown into extensive partnership between its academic & 
community centers, the pharmaceutical industry, an HCV community advocate and the FDA.   
The registry has enrolled over 10,000 patients prescribed HCV therapy in the real-world since 
being established in late 2011 and the infrastructure -methods will be leveraged to conduct this 
study. With the Clinical Coordinating Center (CCC) residing at the University of Florida (PI: 
Nelson) and Data Coordinating Center (DCC) at the University of North Carolina at Chapel Hill 
(PI: Fried), HCV-TARGET developed standardized, centralized chart data abstraction methods 
along with data monitoring to increase the efficiency and quality of an observational registry 
while also minimizing costs typically associated with performing post-marketing clinical 
research.  The network hosts databases that are CFR 21 Part 11 compliant and includes MEDRA 
adverse event and WHO drug dictionary coding standardization.  It also has a CDISC compliant 
database allowing the data to be shared directly with the FDA for analyses around safety and 
efficacy as part of a formal MOU (#225-13-0012) executed in 2013 and renewed in 2017.  Thus, 
HCV-TARGET is well positioned to utilize the established observational cohort data collection 
and monitoring methods to act as an Investigator Coordinating Organization (ICO) to implement 
this unique approach to non-IND clinical trials using unlabelled combinations of approved drugs 
and post marketing commitment studies as well as Treatment IND Protocols for Large Population 
Expanded Access Programs (EAP) and late 3b pragmatic clinical trials related to HCV therapy.  
 
 


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3.6  
Benefits and Risks 
 
Main Study 
Potential benefits of treatment with G/P in a NS5A-inhibitor+SOF treatment failure population 
include:  
1. Potential for high SVR in a population with limited treatment options (high unmet need) 
based on results from MAGELLAN-1 which demonstrated a high SVR rate in HCV GT1-
infected subjects with and without compensated cirrhosis who failed prior treatment with a 
NS5A-inhibitor containing regimen.   
2. Potent and pangenotypic antiviral activity in vitro, higher genetic barrier to development of 
drug resistance across genotypes compared to first generation protease and NS5A inhibitors, 
and the convenience of a once daily regimen. 
3. The benefit of shortened therapy for some subjects 
4. The benefit of evaluating a RBV-intensified DAA regimen 
 
The safety of G/P has been established in a diverse population of patients with and without 
compensated cirrhosis in Phase II and III clinical trials (Section 3.1.4) and the overall AE profile 
supports a safe regimen. The most common AEs in greater than 10% of subjects include 
headache and fatigue.  Additional Safety data for G/P and G/P plus RBV are detailed in the 
Investigator’s Brochure (applicable to Main Study Only) and Prescribing Information. The safety 
profile of Ribavirin is well established. RBV is a teratogen (pregnancy category X) and the 
primary toxicity in subjects is reversible hemolytic anemia21. In addition, subjects may 
experience inconvenience or discomfort related to the study visits or study procedures.  
Risks associated with the combination of G/P±RBV, including the risks of toxicity, virologic failure 
and development of resistance-associated substitutions (Section 3.1.3), appear to be limited and 
manageable based upon the available data. Given the potential for high rates of SVR in this 
population of HCV GT 1-infected subjects with limited current treatment options, the risk-benefit 
assessment is favorable. 
 


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Re-treatment sub-study 
Data from the MAGELLAN-3 study support the addition of SOF to G/P±RBV as a retreatment 
option for G/P failures that was well tolerated.24 The risks for treatment with the combination of 
G/P+SOF±RBV include the potential for toxicity, virologic failure and development of additional 
RASs. However, these risks appear to be limited based on available data. Given the potential for 
high rate of SVR in this difficult to treat population of HCV GT 1-infected subjects for whom 
limited data exist regarding retreatment options, the risk-benefit ratio is favorable. 
4.0 
Study Objective 
4.1 
Primary Objective 
 
The primary objectives of this study are to:  
1. Compare the efficacy (SVR12) of G/P given for 12 weeks to non-cirrhotic GT1-infected 
subjects who are treatment-experienced with a NS5A inhibitor+SOF±RBV regimen (Arm 
A) vs. G/P given for 16 weeks (Arm B) 
2. Compare the efficacy (SVR12) of G/P plus RBV given for 12 weeks to GT1-infected 
subjects with compensated cirrhosis and who are treatment-experienced with a NS5A 
inhibitor+SOF±RBV regimen (Arm C) vs. G/P given for 16 weeks (Arm D) 
3. Assess the safety and tolerability of G/P with or without RBV, in these subjects with 
chronic HCV GT1 infection and treatment-experienced with a NS5A inhibitor+SOF±RBV 
regimen. 
4.2 
Secondary Objectives 
 
The secondary objectives are to assess  
1. The difference in  efficacy (SVR12) of G/P±RBV given for 12 weeks (Arms A+C) versus 
G/P±RBV given for 16 weeks (Arms B+D). 
 
 
2. The differences in the percentages of subjects with on-treatment virologic failure for non-
cirrhotic subjects (Arm A vs Arm B) and subjects with compensated cirrhosis (Arm C vs 
Arm D); 


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3. The differences in the percentages of subjects with post-treatment relapse for non-cirrhotic 
subjects (Arm A vs Arm B) and subjects with compensated cirrhosis (Arm C vs Arm D). 
 
4.3 
Additional Objectives 
 
1. To assess the impact of baseline host and viral factors on treatment outcomes, the 
emergence and persistence of viral variants in those with treatment failure in the Main 
study. 
2. To assess safety and efficacy of the retreatment regimen of G/P+SOF±RBV in the 
Retreatment sub-study. 
5.0 
Investigational Plan 
5.1       Overall Study Design, Rationale and Plan: Description 
 
 Main Study 
This Phase 3b study has been designed as a multi-center, randomized, open-label, 
pragmatic study of G/P +/- RBV for 12 weeks or G/P 16 weeks in subjects with chronic 
HCV GT1 infection who are treatment experienced with NS5A inhibitor + SOF therapy.  
Up to 225 subjects with chronic GT1 infection and prior treatment history of a NS5A 
inhibitor +SOF±RBV regimen will be enrolled to receive: 
Arm A: G/P (300mg /120mg QD) for 12 weeks 
Arm B: G/P (300mg /120mg QD) for 16 weeks 
Arm C: G/P (300mg /120mg QD) + wt. based RBV (1000 or 1200mg total daily  
             dose given BID for patients with body weight <75kg or ≥75kg,  
 
 respectively) for 12 weeks 
Arm D: G/P (300mg /120mg QD) for 16 weeks 
 
Randomization scheme: 
-GT1 non-cirrhotic (up to 150) subjects: randomized 2:1 to Arms A or B.  
-GT1 cirrhotic (up to 75) subjects: randomized 1:1 to Arm C or D.  
Randomization will be stratified by HCV GT 1b vs non-1b. 


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The Main study consists of 2 periods: 
Treatment Period: Eligible subjects will be enrolled to receive G/P 300 mg/120 mg QD 
+/- RBV for 12 weeks or G/P for 16 weeks. 
Post Treatment Period: Subjects who complete or prematurely 
discontinue the 
Treatment Period will be followed for 12 weeks after their last dose of study drug to 
evaluate efficacy and to monitor HCV RNA and the emergence and persistence of viral 
substitutions. 
 
 
 
Figure 1.  
Study 
Schematic 
 
The study is designed to enroll up to 225 subjects with a minimum number of 175 subjects to meet 
scientific objectives and 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. 
©
•
•
•
 


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Retreatment Sub-study 
Subjects who experience virologic failure in the Main study will have the option to elect to enter 
the Retreatment sub-study and receive G/P+SOF±RBV for a total of 16 weeks with the start of 
retreatment after experiencing G/P failure.  The use of RBV in the re-treatment regimen is at the 
discretion of the investigator, and in consideration of potential RBV benefit and its risks for 
toxicity as part of the retreatment regimen for the individual subject.  Subjects electing to 
participate in the Retreatment sub-study will be followed for safety and efficacy according to the 
Main study pragmatic design procedures and Study Activities Tables (5 & 6) with exceptions as 
noted to screening procedures prior to re-treatment initiation.  Retreatment eligibility will be 
determined prior to administering G/P+SOF±RBV based on Inclusion Criterion 1, 2, 4, 6, 7, 8, 9, 
and 10, and Exclusion Criterion 1, 3, 4, 6, 8, 10,11 and 12 in Sections 5.2.1 and 5.2.2.   


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Subjects in both the Main Study and the Retreatment sub-study will be consented and enrolled 
prospectively at participating sites. Subjects in the Main Study will be treated with open-label 
G/P +/- RBV according to their randomization while subjects in the Retreatment Sub-Study will 
receive open-label G/P +/- RBV + SOF.  As a pragmatic, phase 3b study both Main and 
Retreatment Sub-Study subjects will be managed clinically per standard of care guidelines (based 
on AASLD/ISDA Guidelines for HCV treatment8) for disease monitoring and HCV treatment.   
To standardize some processes across all subjects, there is protocol required lab safety and 
efficacy monitoring along with required drug dispensing/drug reconciliation intervals outside of 
standard of care. Source data is the original medical record collected as part of standard of care 
HCV treatment except for documentation of protocol inclusion/exclusion criteria, blood sample 
collection, drug dispensing/reconciliation and SAE reporting. All original clinic notes, telephone 
notes, safety and efficacy labs/evaluations collected during standard of care treatment and in the 
post treatment observation period are redacted and submitted according to a contract-defined 
schedule to a central data repository at the University of Florida (UF).  Pertinent data from 
submitted source medical records is abstracted and entered into the database according to uniform 
guidelines by trained staff at the UF Clinical Coordinating Center.  In keeping with the pragmatic 
study design, efficacy and safety outcomes assessments are recommended as part of the subjects’ 
standard clinical follow up and will be collected and analyzed in the submitted medical records.  
5.1.1  
Standard of Care Assessments – (patient managed clinically and billed 
per standard medical practice) 
 
1. Baseline factors (cirrhosis determination- except for Fibrotest to be performed at study 
central laboratory), prior HCV treatment history, medical history, and co-morbid 
conditions 
2. G/P treatment regimen monitoring, RBV treatment regimen monitoring and RBV dose 
adjustments, if applicable 
3. Clinical factors (physical examinations, vital signs) 
4. Adverse events and related management 
5. Concomitant medications 


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5.1.2      Protocol Required Assessments (not billed as standard of care Table 5 
and Table 6) 
 
1. All study required safety and efficacy labs outside of standard of care, including Fibrotest 
and APRI (if assignment of cirrhosis status is unable to be made by site PI). 
2. Baseline NS3 and NS5A sequencing 
3. NS3, NS5A and *NS5B sequencing at evidence of virologic failure 
4. G/P, RBV, *SOF are provided to patients free of charge 
* For Retreatment sub-study only 
 
5.1.3.    Screening 
   
Screening procedures outlined below are required for both subjects of the Main study and 
subjects of the Retreatment sub-study. At the Screening Visit, which will be done in conjunction 
with a standard of care clinical visit, subjects who provide written informed consent (signed and 
dated) prior to any study-specific procedures will receive a unique subject number assigned 
sequentially by the study site. Enrolled subjects will keep their screening number as their subject 
number throughout the Main study and Retreatment sub-study. 
 
The investigator/clinician designee will evaluate whether the subject meets all of the eligibility 
criteria, applicable to the Main study, specified in Section 5.2.1 and Section 5.2.2 during the period 
from the Screening Visit through Study Day 1 prior to dosing, or meets the subset of the inclusion 
criteria 1, 2, 4, 6, 7, 8, 9, and 10 and exclusion criteria 1, 3, 4, 6, 8, 10, 11 and 12 specified in Sections 
5.2.1 and 5.2.2 for eligibility in the Retreatment sub-study. Results of this assessment and the details 
of the informed consent process will be recorded in the subject's medical records or associated 
study source worksheets. Eligible subjects who do not start treatment within 45 days following the 
Screening Visit will require repeat chemistry, hematology, and coagulation labs prior to 
randomization into the Main study or Retreatment sub-study. Enrollment into the Main study is 
competitive; and reasonable effort will be made to start all eligible subjects on therapy, however 


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there is no guarantee for additional treatment starts once full enrolment of n=225 subjects is 
achieved. Enrollment into the Retreatment sub-study is only for subjects who failed treatment in the 
Main study and elect to participate in the Retreatment sub-study. 
 
Medical records to support the medical history will be submitted for centralized data abstraction 
and include clinic visits, telephone contacts, relevant local laboratory testing and 
diagnostic/disease screening results (i.e. fibroscan results, liver biopsy pathology report, 
ultrasound/CT/MRI report for HCC screening, EGD, ECG or other records- if done) collected as 
part of the standard medical care of the subject in the prior 24 months.  The submitted records 
should also include an updated medical history listing and concomitant medication listing. Older 
records (greater than 24 months) to document key medical history and liver disease/HCV 
treatment history will also be submitted for centralized abstraction. 
 
Screening laboratory testing to determine eligibility for the study will be conducted by a central 
laboratory and will include the testing specified in Table 5 and Table 8. For screening lab results 
without specific entry criteria that are abnormal and noted as clinically significant by the study 
investigator, the study investigator or designee will consult with the study medical monitor for 
approval to enroll the patient in the study. 
 
Prior to randomization, subject eligibility will be verified centrally by the CCC.  At a minimum of 
5 business days prior to the scheduled Study Day 1 visit, the site will submit the subject’s 
redacted screening/historical medical records according to HCV-TARGET centralized 
randomization/abstract processes to be verified for meeting enrollment eligibility criteria. After 
being centrally verified as meeting the eligibility criteria, subjects will be randomized centrally 
via the study randomization system.  Sites will receive the respective randomization and subjects 
will be administered study drugs at the site on Study Day 1, with dosing instructions.  
 
5.1.3.1  
Rescreening 
 
Subjects who at Screening have any of the following are not eligible to rescreen or retest: 


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▪ 
HCV genotype does not meet Inclusion Criterion No. 3, Section 5.2.1, or meets 
Exclusion Criterion No. 2, Section 5.2.2. 
 
Otherwise subjects may be retested or rescreened only once. 
 
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on chemistry, 
hematology or coagulation panel(s) (e.g., exclusionary total bilirubin requires a repeat chemistry 
panel) within the same screening period and must meet all eligibility laboratory criteria on any 
panel that is repeated. If the retest result(s) are also exclusionary, the subject may not be 
rescreened or retested again. 
 
Subjects who fail to enroll within 45 days of Screening, may be allowed to rescreen once.  These 
subjects must be rescreened for safety laboratory and eligibility criteria. 
 
For subjects who rescreen or subjects that do not meet the study eligibility criteria upon 
retest/rescreen, the site personnel must contact the sponsor and identify the subject as a screen 
failure. 
 
5.1.4   
Treatment Period 
 
Efficacy and safety outcomes assessments recorded in the medical record as part of the 
subject’s standard clinical management and follow up will be submitted and abstracted 
centrally where available in the medical record, except for protocol defined central laboratory 
assessment collection, drug dispensation and accountability, and required monthly medical 
record source record verification/submission. The schedule of procedures for the study 
 Table 5  - Study Activities) is based on the AASLD guidelines8 for the treatment of HCV, 
which recommends 1) baseline: hepatic fibrosis assessment, drug-drug interaction assessment, 
HCV RNA and genotype/subtype, hepatitis B serologies (HBsAg, anti-HBc, anti-HBs, reflex 
HBVDNA if anti-HBc+) CBC/plts, hepatic function panel, and a calculated glomerular 
filtration rate; 2) on treatment monitoring: HCV RNA and routine CBC/plts, hepatic panel and 


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GFR are recommended at week 4 and as clinically indicated; clinic f/u for assessment is 
typically done at monthly intervals for treatment experienced patients 3) post-treatment 
monitoring: HCV RNA and routine labs are recommended at 12 weeks post-treatment.  G/P ± 
RBV dosing in the Main study, and G/P +SOF ±RBV dosing in the Retreatment sub-study, 
treatment/side effect management, and duration will be recorded in the medical record by the 
site PI and or clinical provider designee and managed according to the AASLD guidelines 
standard of care with additional assessments required by the protocol according to the Study 
Activities Table (Table 5).  
 
Medical records submitted for centralized data abstraction include clinic visits and telephone 
contact as clinically indicated to ensure medication adherence and to monitor for adverse events. 
All original clinic notes, telephone notes, locally available safety labs/evaluations and/or 
diagnostic tests or health screenings collected during HCV treatment period will be submitted 
for chart data abstraction to identify and abstract adverse events, vital signs, physical 
examinations, concomitant medications, HCV RNA, HCV resistance, and clinical laboratory 
tests that were collected as part of standard of care practice. Sites will also perform a monthly 
verification for new clinical interactions that may have occurred in the prior 4 weeks at the time 
the subject visits the site for the monthly central laboratory assessment collection and drug 
dispensing/accountability.  
 
Methods to abstract the assessments are described in a separate Data Abstraction Conventions 
Manual. 
 
Study visits and procedures during the Treatment Period are detailed in Table 5 Section 5.3.1. 
Safety and tolerability will be assessed throughout the study per AASLD guidelines with 
additional assessments required by the protocol according to the Study Activities table (Table 5). 
Central laboratory testing will include chemistry, hematology, PT/INR, and samples for HCV 
RNA analysis as specified in Table 8.  
 
All subjects will continue to return to the site on an outpatient basis as outlined in Table 5. Sites 


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should ensure that subjects adhere to all the study visits for central laboratory sample collection 
and drug dispensing/reconciliation. Subjects who cannot complete their study visit per the visit 
schedule should ensure that they do not run out of study drug prior to their next study visit. 
Compliance is critical to ensure adequate drug exposure. 
 
Virologic stopping 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 Table 5 and as described in 
Section 5.3.1. 
 
5.1.5      Post-Treatment Period 
 
All subjects who received at least one dose of study drug will be monitored in the Post-Treatment 
Period for safety, HCV RNA, and the emergence and persistence of resistance-associated viral 
substitutions for an additional 12 weeks following the last dose of study drug. 
All original clinic notes, telephone notes, locally available safety labs/evaluations and/or 
diagnostic tests or health screenings collected during the post HCV treatment period will be 
submitted for chart data abstraction to identify and abstract adverse events, vital signs, physical 
examinations, concomitant medications, HCV RNA, HCV resistance, and clinical laboratory 
tests that were collected as part of standard of care practice. Sites will also perform a 
verification of the medical records to review for new clinical interactions that may have 
occurred from end of treatment through 12 weeks post treatment which may coincide with 
applicable central laboratory collection visits.  All applicable clinical records for adverse event 
and serious adverse event monitoring in the post treatment period will be submitted for chart 
data abstraction.  
 
The Post-Treatment Period will begin the day following the last dose of study drug treatment. 
Study visits during the Post-Treatment Period are detailed in Table 6 of Section 5.3.1. 
 


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Subjects who prematurely discontinue the Post-Treatment Period should return to the site for a 
Post-Treatment Discontinuation Visit as outlined in Table 6 and will be followed for all post-
treatment safety, HCV RNA, and resistance-associated substitutions according to the post 
treatment period schedule. 
5.1.6   
Retreatment Sub-study 
 
Retreatment Sub-study Dosing and Post-Treatment Period 
The Retreatment sub-study Dosing Period will begin the day the subjects receive the first dose of 
the retreatment regimen of G/P+SOF±RBV through the last dose of retreatment. The Post-
Treatment Period will begin the day following the last dose of study drug treatment. Study visits 
during the Post-Treatment Period are detailed in Table 6 of Section 5.3.1. 
The visit schedules for safety and efficacy evaluations will be based on the Main Study pragmatic 
design procedures and Study Activities Tables (5 & 6) with exceptions as noted to screening 
procedures prior to re-treatment dosing.  
  
Subjects who prematurely discontinue the Retreatment sub-study should return to the site for a 
Retreatment Discontinuation Visit as outlined in Table 6 and will be followed for all post-
retreatment safety, HCV RNA, and resistance-associated substitutions according to the post 
treatment period schedule detailed in the Study Activities Tables (5 & 6). 
 
5.2 
Selection of Study Population 
 
The study population consists of HCV GT1-infected adult male and female subjects including 
those with and without compensated cirrhosis who are prior treatment experienced with an NS5A 
inhibitor+SOF ± RBV. 
 
Subjects who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
enrollment into the study. 
 
 
 


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5.2.1 
Inclusion Criteria 
 
1. 
Voluntary signed and dated written informed consent form in accordance with regulatory 
and institutional guidelines obtained before the performance of any protocol-related 
procedures not part of normal patient care.  
 
2. 
Male or female, at least 18 years of age at time of screening. 
 
3. 
Screening laboratory result indicating HCV GT 1 infection (applicable during Screening 
for Main Study only).   
 
4. 
If cirrhotic, has compensated cirrhosis defined as Child-Pugh score of  6 at screening and 
no current or past clinical evidence of Child-Pugh B or C classification or clinical history 
of liver decompensation including ascites, bleeding varices or hepatic encephalopathy.  In 
patients with history of liver transplantation, hepatic decompensation history for the 
determination of study eligibility will be limited to the period since the liver transplant. 
 
5. 
Treatment experienced with NS5A inhibitor+SOF±RBV regimen and followed in 
PRIORITIZE or HCV-TARGET.  NS5A inhibitor+SOF±RBV treatment -experienced 
subjects not observed in HCV-TARGET or PRIORITIZE can be included if the NS5A 
inhibitor+SOF±RBV regimen and treatment failure is well-characterized in the medical 
records supplied as source from the participating site. Subjects who are treatment 
experienced to LDV/SOF±RBV (Harvoni ®), VEL/SOF±RBV (Epclusa ®), or 
DCV/SOF±RBV will be included (applicable during screening for Main Study only). 
● The subject must not have discontinued the NS5A inhibitor+SOF±RBV treatment for 
known non-compliance  
● The NS5A inhibitor+SOF±RBV regimen must have been taken for at least 4 weeks  
● The subject’s medical records must include sufficient detail of the NS5A 
inhibitor+SOF±RBV therapy treatment experience to confirm eligibility 
 


Protocol  
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6. 
If cirrhotic, absence of HCC as indicated by a negative ultrasound, computed tomography 
(CT) scan or magnetic resonance imaging (MRI) for HCC within 6 months prior to 
Screening or at Screening. Subjects who have an ultrasound with results suspicious of 
HCC followed by a subsequent negative CT or MRI of the liver for HCC will be eligible for 
the study. 
 
7. 
Subjects must be able to understand and adhere to the study visit schedule and all other 
protocol requirements. 
 
8. 
If female, the subject must be either postmenopausal, permanently surgically sterile, or for 
women of childbearing potential must be willing to use protocol specified method(s) of 
contraception (Appendix C) and have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on Day 1 prior to dosing. 
If male, the subject must be surgically sterile, have a female partner who is 
postmenopausal or permanently sterile, or if sexually active with female partner(s) of 
childbearing potential, must be willing to use protocol specified method(s) of contraception 
(Appendix C). 
 
9. 
HIV+ subjects must be on a stable, qualifying HIV-1 ART regimen for at least 8 weeks 
prior to Screening. 
The HIV-1 ART regimen must include at least one of the following ARV agents: 
• 
Raltegravir (RAL) PO BID 
• 
Dolutegravir (DTG) PO QD or PO BID 
• 
Rilpivirine (RPV) PO QD 
• 
Elvitegravir/cobicistat (EVG/COBI) PO QD 
 
In addition to the above medications, subjects may take a nucleoside/nucleotide reverse 
transcriptase inhibitor (N(t)RTI) backbone containing any of the following: 
• 
Tenofovir disoproxil fumarate (TDF) PO QD 
• 
Tenofovir alafenamide (TAF) PO Q  


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• 
Abacavir (ABC) PO QD or BID 
• 
Emtricitabine (FTC) PO QD 
• 
Lamivudine (3TC) PO QD or BID 
Subjects receiving any other HIV-1 ART in addition to those noted above would not be 
eligible for enrollment in the study. 
 
 Subjects on a stable ART regimen must have the following: 
• Two consecutive locally obtained CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) 
closest to the date of the Screening visit; and 
• Two consecutive locally obtained Plasma HIV-1 RNA < 50 copies/mL closest to the 
date of the Screening visit 
 10.  For subjects participating in the Retreatment sub-study, must have failed treatment with 
G/P ±RBV in the Main study.   
 
5.2.2 
Exclusion Criteria 
 
1. 
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during 
the study or for 30 days after the last dose if randomized to G/P or 6 months after the last 
dose if randomized to RBV (or as directed per the local RBV label).  
 
Male subject whose partner is pregnant or planning to become pregnant during the study or 
for 30 days after the last dose if randomized to G/P or 7 months after the last dose of if 
randomized to RBV (or as directed per the local RBV label). 
 
2. 
HCV genotype performed during screening indicating infection with any non-GT1 HCV 
genotype (applicable during screening for Main Study only). 
 
3. 
Requirement for and inability to safely discontinue the medications or supplements listed 
in Table 4 at least 2 weeks or 10 half-lives (whichever is longer) prior to the first dose of 
any study drug. 
 


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4. 
Clinically significant abnormalities or co-morbidities, or recent (within 6 months prior to 
study drug administration) alcohol or drug abuse that make the subject an unsuitable 
candidate for this study in the opinion of the investigator.  
 
5. 
Positive test result at Screening for hepatitis B co-infection (HBsAg positive or Hep B  
Core Ab -Total positive with detectable HBV DNA) or anti-human immunodeficiency 
virus antibody (HIV Ab) in a patient without known history of HIV+ and stable HART 
therapy (applicable during screening for Main Study only). 
 
6. 
Screening laboratory analyses showing any of the following abnormal laboratory results: 
● Total bilirubin ≥ 3.0 mg/dL. 
● Albumin < 2.8 g/dL. 
● Hemoglobin < 11 g/dL for women; < 12 g/dL for men, applicable only to subjects 
receiving RBV  
 
7. 
Prior therapy with a HCV Protease Inhibitor at any time (applicable during screening for 
Main Study only).  
 
8. 
Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 6 weeks (whichever is longer) to study drug 
administration. 
 
9. 
Consideration by the investigator, for any reason, that the subject is an unsuitable candidate  
to receive G/P or, if cirrhotic, RBV (applicable to Main Study only, see exclusion #12 for 
considerations for Retreatment sub-study). 
 
10. History of severe, life-threatening or other significant sensitivity to any excipients of the 
study drugs. 
 
11. Subjects who cannot participate in study per local law. 


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12. For subjects participating in the Retreatment sub-study, consideration by the investigator, 
for any reason, that the subject is an unsuitable candidate to receive G/P plus SOF with or 
without RBV. 
 
 
5.2.3 
Guidance for Determination of Cirrhosis 
 
All patients will be evaluated for the presence of cirrhosis and the final assessment will be 
made by the site PI or clinician designee.  The presence of cirrhosis is defined at screening by 
biopsy and/or a combination of clinical, laboratory, elastography, and imaging criteria 
established a priori.  For post-transplant recipients, cirrhosis determination will be made based 
on medical records post allograft. 
Patients will be determined to have cirrhosis if they have:  
 
1) evidence of stage 4 (Metavir) fibrosis by liver biopsy at any time prior to screening;   
 
2) evidence of stage 3 (Metavir) fibrosis by liver biopsy at any time prior to screening with any 
ONE of the following criteria (for post-transplant recipients, biopsy staging must be from the 
allograft);  
• platelet count <140x 109/L, 
• presence of esophageal varices on esophagogastroduodenoscopy at any time 
     prior to screening, 
• evidence of cirrhosis and/or portal hypertension by imaging studies at any time prior to 
screening, 
• FibroTest® >0.75,  
• Vibration-Controlled Transient Elastography (VCTE) >12.5 kPa, or equivalent magnetic 
resonance elastography (MRE) compatible with stage 4 fibrosis 
 


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3) in the absence of liver biopsy, any TWO of the following criteria:  
•  platelet count <140x 109/L during screening,  
• presence of esophageal varices on esophagogastroduodenoscopy at any time prior to 
screening,  
• evidence of cirrhosis and/or portal hypertension by imaging studies at any time prior to 
screening, 
•  FibroTest® >0.75,  
•  AST:platelet ratio index (APRI) >2 during screening 
• Vibration-Controlled Transient Elastography (VCTE) >12.5 kPa, or equivalent MRE 
compatible with stage 4 fibrosis 
 
If subjects do not meet any of the above definitions of cirrhosis, they will be considered non-
cirrhotic. 
5.2.4  
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 medical 
record along with the reason for use according to standard medical care.  Where the reason for use 
of a concomitant medication or the start/stop date is missing from the submitted medical records, 
the site will be queried.  For the Main study, the investigator/designee should review all 
concomitant medications for any potential interactions with G/P via the DDI tool and the 
MAVYRETTM Prescribing Information23.  For the Retreatment sub-study, the 
investigator/designee should review all concomitant medications for any potential interactions 
with G/P via the DDI tool and the MAVYRETTM Prescribing Information23, and also should 
review all concomitant medications for any potential interactions with sofosbuvir utilizing the 
SovaldiTM Prescribing Information.27 
 
 
During the Post-Treatment Period, all concomitant medications taken will be recorded in the 


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Page 54 of 123 
 
medical record until 30 days following the last dose of study drugs. Only medications taken for 
SAEs and for treatment of HCV will be recorded thereafter. 
 
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapies. 
 
Subjects with HIV-1/HCV co-infection must be on a stable, qualifying HIV-1 ART 
regimen for at least 8 weeks prior to Screening.  If on an HIV-1 ART regimen, it must include at 
least one of the ARV agents as per Inclusion Criterion 9 (Section 5.2.1). 
Subjects will maintain the same dose and dosing interval of their HIV-1 ART regimen upon 
initiating the study drugs regimen.  Subjects should remain on the same HIV-1 ART regimen for 
the entire Treatment Period.  Any change in the HIV-1 ART regimen during  
the Treatment Period must be discussed with the medical monitor prior to the change, unless the 
change is being made to address an immediate safety concern. 
 
Subjects receiving any other HIV-1 ART in addition to those listed in Inclusion Criterion 9 
(Section 5.2.1) would not be eligible for enrollment in the study. 
 
 
5.2.4.1  
Prior HCV Therapy 
 
Subjects must be HCV treatment-experienced with an NS5A-inhibitor+SOF with or without 
RBV.  The subject may also have had an additional past treatment with any HCV regimen that 
did not include administration of a protease inhibitor.  
 
For subjects who had multiple HCV treatment courses, the categorization of previous response 
category will be based on the NS5A inhibitor+SOF treatment. 
 
 
 
 


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 5.2.4.2  
Concomitant Therapy 
 
Subjects should be on stable doses of concomitant medications for at least 2 weeks prior to the 
initiation of study drugs. The investigator should confirm that a concomitant 
medication/supplement can be safely administered with study drugs. Some concomitant 
medications may require dose adjustments due to the potential for drug-drug interactions. 
 
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements, and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses 2 weeks following discontinuation of study 
drugs as applicable. 
5.2.4.3  
Prohibited Therapy 
 
Subjects must be able to safely discontinue any prohibited medications or supplements listed in 
Table 4 at least 2 weeks or 10 half-lives (whichever is longer) prior to the first dose of any study 
drug and not use these during the entire Treatment Period and for 2 weeks following 
discontinuation of study drugs. 
 
Table 4.  
Prohibited Medications and Supplements 
 
Medication or Supplement Name 
red yeast rice (monacolin K), St. John's Wort 
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin 
Atorvastatin, lovastatin, simvastatin* 
Astemizole, cisapride, terfenadine 
Ethinyl estradiol 
Atazanavir, darunavir co-administered with ritonavir, darunavir/r, lopinavir/r, efavirenz, etravirine, 
tipranavir/r, nevirapine 
Azathioprine-if subject is taking RBV 
Amiodarone- Applicable to Retreatment sub-study subjects receiving sofosbuvir 
 
*  Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with the study drugs.  
Subjects receiving these statins should either switch to pravastatin or rosuvastatin prior to the first dose of study drugs or may 
interrupt statin therapy throughout the treatment period and until 14 days after the last dose of study drug, based on investigator's 
judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to reduce the pravastatin dose by 50% or 
limit the rosuvastatin dose to 10 mg QD when taking with the study drugs. 


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Page 56 of 123 
 
Use of high dose (0.035mg) ethinyl estradiol containing oral contraceptives with G/P 
combination was associated with asymptomatic ALT increases (one Grade 3, and one Grade 
2) without concurrent bilirubin increases in 2 healthy female subjects.  Therefore, hormonal 
contraceptives (including oral, topical [including vaginal rings], injectable or implantable 
varieties) containing any ethinyl estradiol may not be used from 2 weeks prior to the first 
dose of study drug until 2 weeks after the end of study drug dosing. Progestin-only 
contraceptives, such as those containing norethindrone, desogestrel, or levonorgestrel, 
without ethinyl estradiol, may be used with G/P. 
 
Post-menopausal hormone replacement therapy, such as with esterified or conjugated 
estrogens, i.e., not containing ethinyl estradiol, may be used with G/P at the discretion of 
the Investigator. 
 
For HCV/HIV-1 coinfected subjects, the investigator must refer to the current package  
  insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 2 weeks prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 30 days following discontinuation of study drugs. G/P is not recommended for use in 
patients requiring stable cyclosporine doses > 100 mg per day.  G/P 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.


 
 
57
5.3 
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables 
 
5.3.1 
Efficacy and Safety Measurements Assessed and Flow Chart 
 
Study procedures described in this protocol are summarized in Table 5 and Table 6 
Table 5. 
Study Activities – Treatment Period for Main study and Retreatment sub-study 
 Subjects assigned to a 12-week treatment duration will not complete the Wk16 EOT visit.  Any patient eligible to receive treatment in the Retreatment 
sub-study will be assessed as noted for screening and according to ALL on-treatment evaluations outlined in the activities table.  
 
 
Activity 
 
Screening 
 
Day 1a 
 
Wk 4 
 
Wk 8 
 
Wk 12 
or 
EOT 
 
Wk 
16 
EOT 
Premature 
D/Cb 
STANDARD OF CARE and documented in Medical Record 
 
 
 
 
 
 
 
Demographics & Medical History (including history of hepatic 
decompensation and Prior HCV Therapy)  
X 
 
Physical Exam & Child-Pugh Score 
X 
As available for abstraction per SOC in the submitted redacted 
medical records 
Vital Signs, Weight, Heightd 
X 
As available for abstraction per SOC in the submitted redacted 
medical records 
Cirrhosis Determination (per Section 5.2.3) 
X 
 
Concomitant Medication Assessment 
Xn 
As available for abstraction per SOC in the submitted redacted 
medical records 
Adverse Event/Serious Adverse Event Assessmente 
Xm 
As available for abstraction per SOC in the submitted redacted 
medical records 
HCC Screening documentation as applicable to subjects with 
cirrhosis (within 6 months of screening)f 
X 
Submit every 6 months imaging per AASLD standard of care 
guidelines for HCC screening 
For HIV co-infected subjects, CD4+ & HIV RNA results 
obtained locally (per Inclusion 9) 
Xp 
As available for abstraction per SOC in the submitted redacted 
medical records 
 


Protocol  
B16-439   November 20, 2018 
 
 
 
Activity 
 
Screening 
 
Day 1a 
 
Wk 4 
 
Wk 8 
 
Wk 12 
or EOT 
 
Wk 16i  
EOT 
Premature 
D/Cb 
REQUIRED ASSESSMENT outside of Standard of Care 
 
 
 
 
 
 
 
Informed Consentc 
X 
 
 
 
 
 
 
Verification of Eligibility/Randomization 
Xj 
 
 
 
 
 
 
Hematology/Chemistry/PT/INRg 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (serum [s]g urine [u]k) for WOCBP only 
X (s) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
HCV Genotype and Subgenotype; HBV serologiesg 
Xo 
 
 
 
 
 
 
HIV Abg,l 
Xo 
 
 
 
 
 
 
FibroTest and APRIg,h 
Xo 
 
 
 
 
 
 
HCV RNA Samplesg 
X 
X 
X 
X 
X 
X 
X 
HCV Resistance Sampleg 
 
X 
X 
X 
X 
X 
X 
Archive Plasma Sampleg 
X 
X 
X 
X 
X 
X 
X 
Study Drugs Dispensed 
 
X 
X 
X 
Xi 
 
 
Randomization Request submitted centrally at least 5 business 
days prior to planned Day 1  
Xj 
 
 
 
 
 
 
Perform Study Drug Accountability and Review of Study 
Drug Adherence 
 
 
X 
X 
X 
X 
X 
Authorization Request for Retreatment 
Xj 
 
 
 
 
 
 
Upload signed central lab reports evaluating clinical significance 
of abnormal results 
X 
X 
X 
X 
X 
X 
X 
Medical Records & Blood sample collection Verification 
Worksheet and Records Submission 
X 
X 
X 
X 
X 
X 
X 
   Wk = Week; EOT = End of treatment; D/C = Discontinuation 
a. 
All procedures to be performed prior to first dose 
b. 
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 


Protocol  
B16-439   November 20, 2018 
 
 
other anti-HCV therapy). 
c. 
Subjects need to sign an IRB/IEC approved informed consent for the study prior to performing any screening or study-specific procedures.  All re-treatment substudy 
subjects will be required to sign additional informed consent inclusive of re-treatment substudy information. 
d. 
Height only collected at Main Study Screening 
e. 
During the treatment period, all SAEs must be collected that occur during the screening period through discontinuation of study treatment and all non-serious AEs must be 
collected that occur from the time of study drug administration through 30 days after discontinuation of dosing. (see Section 6.1.4). 
f. 
Subjects with a historical negative Liver Ultrasound, CT or MRI within 6 months prior to screening for main study and within 6 month prior to screening for the Retreatment 
sub-study are not required to have a screening Liver Ultrasound performed. 
g. 
Collected for central laboratory processing. 
h. 
Fibrotest/APRI will only be collected at the screening visit if the subject does not have a qualifying liver biopsy, Fibroscan, or MRE  
i. 
Only applies if subject assigned to 16-week treatment arm (B or D), and subjects of the Retreatment sub-study  
j. 
Main study: Site must submit documentation that the subject meets all eligibility criteria to the CCC at least business 5 days prior to their Day 1 visit.  Randomization will be 
performed by the CCC.  Retreatment sub-study: Prior to starting treatment, the site will upload subject redacted records to REDCap for verification of eligibility by the CCC.  
Prescription for Sofosbuvir +/- RBV must be included in upload.   
k. 
If the urine pregnancy result is positive, site must confirm immediately with a serum test collected through the central laboratory 
l. 
HIV Ab collected only in subjects without historical positive HIV antibody. 
m.  Non-serious Adverse Events will not be collected between Post-Treatment Week 12 of Main Study and first dose of Retreatment sub-study Dosing Period.  Serious Adverse   
Events will not be collected between Post-Treatment Week 12 of the Main Study and date of informed consent for the Retreatment sub-study 
 
n. 
Concomitant medications will not be collected between Post-Treatment Week 4 of Main Study through 14 days prior to Screening for Retreatment sub-study 
o. 
Not required for Retreatment sub-study 
p. 
As available for abstraction per SOC in the submitted redacted medical records. 


 
 
60
 
Table 6. 
Study Activities – Post-Treatment (PT) Period for Main study and Retreatment sub-study 
 
Activity 
PT Wk 4 
PT Wk 12 
Physical Exam & Child-Pugh Score 
As available for abstraction per 
SOC in the submitted redacted 
medical records 
Vital Signs, Weight 
As available for abstraction per 
SOC in the submitted redacted 
medical records 
Concomitant Medication Assessmenta 
As available for abstraction per 
SOC in the submitted redacted 
medical records 
Adverse Event/Serious Adverse Event Assessmentb 
As available for abstraction per 
SOC in the submitted redacted 
medical records 
Hematology/Chemistry/PT/INRc 
X 
 
HCV RNA Samplesc 
X 
X 
Pregnancy Test (urine [u]) for WOCBP onlye 
X (u) 
X(u)d 
HCV Resistance Samplec 
X 
X 
Archive Plasma Samplec 
X 
X 
Upload signed central lab reports evaluating clinical 
significance of abnormal results 
X 
X 
Medical Records & Blood sample collection Verification 
Worksheet and Records Submission 
X 
X 
For HIV co-infected subjects, CD4+ & HIV RNA results 
obtained locally 
As available for abstraction per 
SOC in the submitted redacted 
medical records 
Wk = Week; PT D/C = Post-Treatment Discontinuation 
a 
Only medications taken for SAEs and for treatment of HCV will be collected after 30 days post-dosing. 
b 
Non-serious AEs will be collected until 30 days post dosing. All SAEs will be collected through PT WK 12. (see Section 6.1.4). 
c 
Collected for central laboratory processing 
d 
Required for WOCBP randomized to RBV arm only, or subjects of Re-treatment study who receive RBV as part of the retreatment regimen 
e 
If the urine pregnancy result is positive, site must confirm immediately with a serum test collected through the central laboratory 
Note: 
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug. 


61 
Protocol  
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5.3.1.1 
Study Procedures 
 
Informed Consent 
 
 Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed. Subjects who failed treatment in the Main study and elect 
participation in the Retreatment sub-study require additional informed consent before any 
procedure of the Retreatment sub-study is performed. 
 Medical History, Physical Examinations, Vital Signs and Weight, Clinical 
Assessment of Hepatic Decompensation 
 
 All original clinic notes, telephone notes, locally available safety labs/evaluations and/or 
diagnostic tests or health screenings collected prior to, during and post HCV treatment 
period will be submitted for chart data abstraction to identify and abstract medical 
history, vital signs, weight (and height historically) and physical examinations that were 
collected as part of standard of care practice.  The medical history listing, assessment for 
historical/current hepatic decompensation and Child Pugh score examination procedures 
will be updated at the standard of care visit where study informed consent is obtained.   
The site will submit medical records created as part of screening/informed consent, as 
well as medical records available in the site medical records system, for up to 24 months 
prior to the study screening.  Older records to document key medical history and liver 
disease/HCV treatment history will also be submitted for centralized abstraction. 
 
Child-Pugh Score and Category 
 
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 visits indicated in 
Table 5 and Table 6. 
 
 


62 
Protocol  
B16-439   November 20, 2018 
 
 
 
Table 7. 
Child-Pugh Score for Classification of Severity of Cirrhosis 
 
 
Points Assigned for Observed Findings 
Parameter 
1 
2 
3 
 
 
Total bilirubin, µmol/L (mg/dL) 
< 34.2 (< 2) 
34.2 – 51.3 (2 – 3) 
> 51.3 (> 3) 
Serum albumin, g/L (g/dL) 
> 35 (> 3.5) 
28 – 35 (2.8 – 3.5) 
< 28 (< 2.8) 
INR 
< 1.7 
1.7 – 2.3 
> 2.3 
Ascites* 
None 
Slight 
Moderate to severe 
Hepatic encephalopathy** 
None 
Grade 1 or 2 (or suppressed 
Grade 3 or 4  or 
with medication)  
 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. 
**    Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram; Grade 1:  restless, 
sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves; Grade 2:  lethargic, time-
disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves; Grade 3:  somnolent, stuporous, 
place-disoriented, hyperactive reflexes, rigidity, slower waves; Grade 4:  unarousable coma, no 
personality/behavior, decerebrate, slow 2 to 3 cps delta activity. 
 
Clinical Laboratory Tests 
 
A central laboratory will be utilized to process and provide results for the clinical laboratory 
tests. Samples will be obtained at a minimum for the central laboratory tests outlined in 
Table 8 at the visits indicated in Table 5 and Table 6. 
 
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  
 
 


63 
Protocol  
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Table 8. 
Clinical Laboratory Tests 
 
Hematology 
Clinical Chemistry 
White Blood Cell (WBC) count 
Red Blood Cell (RBC) count 
Hemoglobin 
Hematocrit  
Platelets 
 Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Bands, if detected   
 
 
Prothrombin Time (PT) 
INR 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
(ALT) 
Aspartate aminotransferase 
(AST)  
Bilirubin, Direct 
Bilirubin, Indirect 
Bilirubin, Total 
Blood Urea Nitrogen (BUN) 
Calcium 
Carbon Dioxide 
Chloride 
Cholesterol 
 Creatinine 
Glucose  
Phosphorus 
Potassium 
Sodium  
Total protein 
Uric Acid 
eGFR by MDRD 
Other Tests 
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG) for females 
(pregnancy) 
HCV RNA 
HCV genotype and subtype 
HBsAg, Hep B Core Ab-Total, 
Hep B Surface Ab 
reflex HBV DNAa 
HIV 1-2b 
APRI and Fibrotest  
     a If HBsAg neg, Hep B Core AB-Total positive at Screening 
      b Only required for subjects without historical positive test result for HIV Ab


64 
Protocol  
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For any laboratory test value outside the reference range that the investigator considers to be 
clinically significant: 
o The investigator will repeat the test through the central laboratory to verify 
the out-of-range value. 
o The investigator will follow the out-of-range value to a satisfactory clinical 
resolution. 
o A laboratory test value that requires a subject to be discontinued from the 
study, a dose modification of RBV, or requires a subject to receive treatment 
will be recorded as an adverse event. 
 
The management of laboratory abnormalities that may occur during the study is described in 
Section 6.1.6 
 
  Contraception Recommendations and Pregnancy Testing  
 
A serum pregnancy test will be performed for all female subjects of childbearing potential at 
Screening. Additional urine pregnancy tests will be performed at all the visits indicated in 
Table 5 and Table 6. Pregnancy testing is not required for females of non-childbearing 
potential. Determination of postmenopausal status will be made during the Screening 
period, based on the subject's history. 
 
Concomitant Medication Assessment 
 
 Excluding the medications and substances listed in Table 4, use of medications 
(prescription or over-the-counter, including vitamins, herbal supplements, and vaccines) 
from the time of signing the consent, through the Treatment Period, and 30 days after study 
drugs are stopped must be recorded in the medical record according to the local standard of 
care.   Only medications taken for SAEs and for treatment of HCV will be abstracted from 
the submitted medical records 30 days after study drugs are stopped as indicated in Table 6 
(Post-Treatment Period).  The concomitant medication listing will be updated in the 
standard of care medical record at the time of informed consent.  All original clinic notes 


65 
Protocol  
B16-439   November 20, 2018 
 
 
and telephone notes collected prior to, during, and post HCV treatment period will be 
submitted for chart data abstraction to identify and abstract concomitant medication(s) that 
were prescribed as part of standard of care practice.   
 
 
Hepatocellular Carcinoma Screening: Liver Ultrasound  
 
In order to monitor for the presence of hepatocellular carcinoma (HCC), per standard of care 
AASLD guidelines, cirrhotic patients must have had an ultrasound, CT, or MRI to screen 
for hepatocellular carcinoma 6 months or less from screening and continued at 6 month 
intervals.  A redacted copy of the imaging findings will be submitted for verification of 
study entry criteria and centralized abstraction. 
 
Enrollment and Assignment of Subject Numbers 
 
Screening numbers will be unique numbers and will be assigned sequentially at the site 
beginning with the first digits representing the investigative site, and the last digits 
representing the subjects at that site. Enrolled subjects will keep their screening number as 
their subject number throughout the Main study and the Retreatment sub-study (if 
applicable).   
 
All screening activities must be completed and reviewed prior to enrollment. Prior to 
randomization, subject eligibility will be verified centrally.  Main Study: At a minimum of 
5 business days prior to the scheduled Study Day 1 visit, the site will submit subject 
redacted screening/historical medical records to be verified for meeting enrollment 
eligibility criteria.  After being centrally verified as meeting the eligibility criteria, subjects 
will be randomized centrally via the study randomization system.  Sites will receive the 
respective randomization and subjects will be administered study drugs at the site on Study 
Day 1, with dosing instructions. Retreatment sub-study: There is no randomization for 
subjects who enter the Retreatment sub-study.  Prior to starting treatment, the site will 
upload subject redacted records to REDCap for verification of eligibility by the CCC.  


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Prescription for Sofosbuvir with or without RBV must be included in upload.   
 
Study Drug Compliance for Kits 
G/P and RBV will be provided for subject dosing to the site. Each subject will have 
compliance documented by the site in the subject's source records for G/P and/or RBV. In 
addition, compliance will be documented for SOF in the Retreatment sub-study. At each 
study drug accountability visit in Table 5, the overall number of tablets*** of G/P, RBV (as 
applicable), and SOF (as applicable) remaining will be recorded in the source along with 
the date of reconciliation and submitted centrally for abstraction. 
 
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). If the LiPA assay is unable to genotype a sample, its genotype will be determined by a 
Sanger sequencing assay of NS5B region. 
 
HCV RNA Levels 
 
Plasma samples for HCV RNA levels will be collected as indicated in Table 5 and Table 6. 
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) 
for this assay (regardless of genotype) are both 15 IU/mL. 


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HCV Resistance Testing Sample 
 
A plasma sample for HCV resistance testing will be collected prior to dosing on Day 1 and 
at the required lab collection visits indicated in Table 5 and Table 6 for each the Main study 
as well as the Retreatment sub-study. Specific instructions for preparation and storage of 
HCV RNA and HCV resistance samples will be provided by the central laboratory. 
 
Archive Plasma Sample 
 
Archive plasma samples will be collected at the study visits, indicated in Table 5 and Table 
6 for the Main study as well as the Retreatment sub-study. Archive plasma samples are 
being collected for possible additional analyses, including but not limited to, study drug or 
metabolite measurements, HCV RNA levels, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing, and other possible predictors of response, as 
determined by AbbVie and the sponsor. Specific instructions for preparation and storage of 
archive samples will be provided by the central laboratory. 
5.3.1.2 
Meals and Dietary Requirements 
 
Tablets*** of G/P and RBV should be taken with food.  In the Retreatment sub-study, SOF 
should be taken daily at the same time as G/P. 
 
5.3.1.3 
Handling/Processing of Samples 
 
Specific instructions for collection of blood samples and subsequent preparation will be 
provided by the central laboratory.


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5.3.2 
Efficacy Variables 
 
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 12 weeks after completion of treatment in both the Main study 
and the Retreatment sub-study. 
5.3.2.1 
Primary Variable 
 
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last actual 
dose of study drug). 
5.3.2.2 
Secondary Variable 
 
The secondary efficacy variables are on-treatment virologic failure and post-treatment 
relapse. 
5.3.3 
Resistance Variables 
 
For all subjects receiving G/P, the substitutions at resistance-associated amino acid positions 
in NS3 and NS5A at baseline identified by population sequencing or NGS and comparison 
to the appropriate prototypic reference sequence will be analysed, along with the impact of 
baseline substitutions on SVR12. 
 
For subjects enrolled in the Retreatment sub-study, the substitutions at resistance-associated 
amino acid positions in NS3 and NS5A (and NS5B for those subjects enrolled in the 
Retreatment sub-study who experience virologic failure) at baseline will be identified by 
population sequencing or NGS, compared to the appropriate prototypic reference sequence, 
along with an analysis of impact of baseline substitutions on SVR12.   
 
The following resistance information will be analyzed for subjects receiving G/P who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL: 1) the 
amino acid substitutions in NS3 and NS5A in available post-baseline samples identified by 
population sequencing or NGS and comparison to the baseline sequence, 2) the amino acid 


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substitutions in NS3 and NS5A in available post-baseline samples at resistance-associated 
positions identified by population sequencing or NGS and comparison to the appropriate 
prototypic reference sequence, and 3) the persistence of viral resistance by population 
sequencing or NGS. 
 
For subjects enrolled in the Retreatment sub-study receiving G/P+SOF±RBV who 
experience virologic failure and who have a post-baseline sample with HCV RNA ≥ 1000 
IU/mL the following resistance information will be analyzed: 1) the amino acid 
substitutions in NS3, NS5A, and NS5B in available post-baseline samples identified by 
population sequencing or NGS and comparison to the baseline sequence, 2) the amino acid 
substitutions in NS3, NS5A, and NS5B in available post-baseline samples at resistance-
associated positions identified by population sequencing or NGS and comparison to the 
appropriate prototypic reference sequence, and 3) the persistence of viral resistance by 
population sequencing or NGS. 
 
5.3.4 
Safety Variables 
 
The following safety evaluations will be performed during the Main study and the 
Retreatment sub-study: adverse events, vital signs & physical examination (abstracted from 
submitted clinical records) and laboratory tests assessments from the central laboratory.  
 
5.4 
Removal of Subjects from Therapy or Treatment Duration 
Assessment 
 
5.4.1 
Discontinuation of Individual Subjects 
 
Each subject has the right to withdraw from the Main study or Re-treatment substudy at any 
time. In addition, the investigator may discontinue a subject from the Main study or Re-
treatment substudy at any time if the investigator considers it necessary for any reason, 
including the occurrence of an adverse event or noncompliance with the protocol. 


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If, during the course of study drug administration, the subject prematurely discontinues, the 
procedures outlined for the applicable Premature D/C Visit should be completed as defined 
in Table 5 and Table 6. Ideally this should occur on the day of study drug discontinuation, 
but no later than 2 days after their final dose of study drug and prior to the initiation of any 
other anti-HCV therapy. However, these procedures should not interfere with the initiation 
of any new treatments or therapeutic modalities that the investigator feels are necessary to 
treat the subject's condition. Following discontinuation of study drug, the subject will be 
treated in accordance with the investigator's best clinical judgment. The last dose of any 
study drug and reason for discontinuation will be recorded in the medical record and 
submitted for centralized abstraction. The subject should then begin the Post-Treatment 
Period where the subject will be monitored for 12 weeks for HCV RNA and the emergence 
and persistence of resistant viral variants. 
 
If a subject is discontinued from study drugs or the Post-Treatment Period with an ongoing 
adverse event or an unresolved laboratory result that is significantly outside of the reference 
range, the investigator will attempt to provide follow-up until a satisfactory clinical 
resolution of the laboratory result or adverse event is achieved. 
 
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of G/P in Main 
study as well as G/P and/or Sofosbuvir in the Retreatment sub-study to that subject may be 
continued at the Principal Investigator's discretion after discussion with the subject, if the 
benefit of continuing prescribed regimen is felt to outweigh the potential risk.  The 
administration of RBV (if applicable) to that subject must be discontinued immediately. 
Specific instructions regarding subject pregnancy can be found in Section 6.1.6. If a subject 
is discontinued, the Subject will be monitored for SVR in the Post-Treatment Period as 
described in Section 5.1.3. 
 
 


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5.4.1.1 
Virologic Stopping Criteria 
 
Individual Patient 
  
Virologic stopping criteria are defined as one of the following: 
 
1. 
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during treatment. 
 
2. 
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, 
 
When confirmatory testing is required it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic stopping criteria has been 
confirmed. Subjects meeting virologic stopping criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistant viral variants until 12 weeks post-treatment.   
 
Treatment Arm Efficacy Adjustment Criteria 
Based on interim virologic data, the following adjustments will be made to individual 
treatment arms within the Main Study.  Treatment Arm Efficacy Adjustment Criteria do 
not apply to the Retreatment sub-study: 
1. 
If more than 2 subjects have confirmed on-treatment virologic failure among the 
first 20 non-cirrhotic subjects with available HCV viral load data across Arms A 
and B, the virologic failures will be examined to determine if all new enrollment 
into the arms should stop and if weight-based twice daily RBV (1000 mg <75 kg or 
1200 mg ≥75 kg body weight total daily dose) should be added to the regimen for 
all future and current subjects in Arm A and Arm B, or a subset of subjects in Arms 
A and B.   Similar analyses will continue every two weeks until all subjects in Arms 
A and B reach the end of treatment.  
2. 
If more than 2 subjects have confirmed post-treatment relapse in the Post-Treatment 


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period among the first 20 subjects in Arm A with available post treatment HCV 
viral load data, the virologic failures will be examined to determine if treatment 
should be extended to 16 weeks for all future and current subjects in Arm A or for a 
subset of subjects in Arm A.  Similar analyses will continue every two weeks until 
all subjects in Arm A reach the end of treatment. 
3. 
If more than 2 subjects have confirmed post-treatment relapse among the first 20 
subjects in Arm C with available post treatment HCV viral load data, the virologic 
failures will be examined to determine if treatment should be extended to 16 weeks 
for all future and current subjects ongoing in Arm C or for a subset of subjects in 
Arm C. Similar analyses will continue every two weeks until all subjects in Arm C 
reach the end of treatment. 
4. 
If more than 2 subjects have confirmed on-treatment virologic failure among the 
first 20 subjects across Arms A, B and D, the virologic failures will be examined to 
determine if weight-based twice daily RBV (1000 mg <75 kg or 1200 mg ≥75 kg 
body weight total daily dose) should be added for all current and future patients in 
Arm D or a subset of subjects in Arm D. Similar analyses will continue every two 
weeks until all subjects in Arms A, B and D reach the end of treatment. 
 
Treatment failures due to non-compliance with study drugs, stopping or holding of study 
drugs due to adverse events, or other reasons for study drug interruptions will not count 
towards virologic failures. 
 
 
5.4.2 
Discontinuation of Entire Study 
 
The sponsor, in agreement with AbbVie, may terminate this study prematurely, either in its 
entirety or the sponsor may terminate this study 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 the sponsor in advance of the intended termination. 


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Advance notice is not required by either party if the study is stopped due to safety 
concerns. If the sponsor terminates the study for safety reasons, the sponsor 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 G/P study drug will be dispensed in the form of co-formulated G/P tablets at 
the visits listed in Table 9. Subjects will be instructed to take study drugs at 
approximately the same time every day with food.  
 
G/P will be provided to the investigator as G/P 100 mg/40 mg tablets. G/P will be taken 
orally as three tablets once daily with food, which corresponds to G/P 300 mg/120 mg 
QD. The maximal dose of G/P is 300mg/120mg for 16 weeks. There is no dose 
adjustment of G/P for any reason in this study. 
 
RBV will be provided to the investigator as 200 mg tablets***. RBV is dosed based on 
weight as 1000 or 1200 mg divided twice daily per local label. For subjects <75 kg, 
RBV may be taken orally as 2 tablets*** in the morning and 3 tablets*** in the evening 
or 3 tablets*** in the morning and 2 tablets*** in the evening which corresponds to a 
1000 mg total daily dose. For subjects weighing ≥75 kg, RBV will be taken orally as 3 
tablets*** in the morning and 3 tablets in the evening which corresponds to a 1200 mg 
total daily dose. RBV should be taken with food. The maximal daily dose of RBV in 
this study is not to exceed 1200 mg for 16 weeks. Based on tolerability, renal function, 
and hemoglobin level, RBV daily dose may be reduced, held, or permanently 
discontinued at the investigator's discretion and in accordance with local RBV 
prescribing information/product label. 
 
All subjects who receive at least one dose of study drug and meet the virologic stopping 


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criteria defined in Section 5.4.1.1 will be discontinued from treatment. 
*** In the Retreatment sub-study, RBV dosage form will be determined by dispensing 
pharmacy. 
5.5.1.1          Retreatments  Administered 
 
The re-treatment study drug regimen of G/P plus SOF ±RBV will be dispensed to 
Retreatment sub-study subjects at the subject’s study site and following study drug 
dispensation schedule of Table 5.  Retreatment regimen is given for 16 weeks.   There is 
no dose adjustment of SOF or G/P for any reason in the Retreatment sub-study. 
 
 
5.5.2 
Identity of Investigational Products 
 
Information about the study drugs to be used in this study is presented in Table 9. 
 
Table 9. 
Identity of Investigational Products 
 
Investigational 
Mode of 
  Dosage 
Product 
Manufacturer 
Administration 
Form 
    
Strength 
Tablets/ 
Capsule***/ 
bottle 
Glecaprevir/ 
Pibrentasvir* 
AbbVie 
Oral 
Tablet 
100 mg/40 
mg 
30 
Ribasphere®* 
Ribavirin** 
As available in 
dispensing pharmacy 
 
Oral 
Tablet/ 
Capsule*** 
200 mg 
168*** 
Sovaldi® 
Sofosbuvir** 
Gilead Sciences, Inc. 
Oral 
Tablet 
400 mg 
28 
Main Study 
*G/P and Ribasphere® dispensed by AbbVie Inc., North Chicago, IL 
Retreatment sub-study 
*G/P dispensed by AbbVie Inc., North Chicago, IL 
**Ribavirin and Sofosbuvir to be dispensed by BioPlus Specialty Pharmacy, Altamonte Springs, FL 
*** RBV dosage form as available in dispensing pharmacy  
 
5.5.3 
Packaging and Labelling 
 


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All study drug will be supplied in bottles.  
 
Each bottle will be labelled as required 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. 
 
 
5.5.3.1 
Storage and Disposition of Study Drugs 
 
 
 
Study Drug 
Storage Conditions 
Glecaprevir/Pibrentasvir 100 mg/40 mg 
15° to 25°C (59° to 77°F) 
Ribasphere® Ribavirin 200 mg (Main 
Study)  
15° to 25°C (59° to 77°F) 
Ribavirin 200 mg (Retreatment sub-
study) 
**** 
Sovaldi®  Sofosbuvir 400 mg 
Room Temperature to below 30°C (86°F) 
 
 
The investigational products are for investigational use only and are to be used only within 
the context of this study. The study drug supplied for this study must be maintained under 
adequate security and stored under the conditions specified on the label until dispensed for 
subject use, destroyed on-site, or returned to AbbVie (or designee). 
**** RBV Storage conditions during the Retreatment sub-study to be provided via FDA-approved 
Prescribing Information.  
5.5.4 
Method of Assigning Subjects to Treatment Groups-  
 
At the Screening Visit, all subjects will be assigned a unique subject number assigned 
sequentially by the study site. Enrolled subjects will keep their screening number as their 
subject number throughout the Main study and the Retreatment sub-study (if applicable). 
 
For subjects who do not meet the study selection criteria, the site personnel will identify 


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the subject as a screen failure by submitting applicable medical records to the central 
abstraction team documenting the screen failure.  Submitted data and reason for screen 
failure will be abstracted centrally.   
 
For enrollment of eligible subjects into the study, subject eligibility will be verified 
centrally by the CCC.  At a minimum of 5 business days prior to the scheduled Study Day 
1 visit, the site will submit the subject’s redacted screening/historical medical records to 
be verified for meeting enrollment eligibility criteria.  After being centrally verified as 
meeting the eligibility criteria, subjects will be randomized centrally via the study 
randomization system (applicable to Main study only).  After verification of subject 
meeting eligibility criteria, study drug will be shipped as a bulk supply from AbbVie and 
BioPlus Specialty Pharmacy Services, Inc. (Re-treatment sub-study only) to study site to 
dispense to eligible study subjects. 
 
Sites will receive the respective randomization and subjects will be administered study 
drugs at the site on Study Day 1, with dosing instructions. 
 
5.5.5 
Selection and Timing of Dose for Each Subject 
 
G/P is a fixed-dose combination tablet of 100 mg glecaprevir and 40 mg Pibrentasvir. The 
dose used for all subjects in this study is 300 mg/120 mg G/P, given together once daily 
with food. The maximum dose of G/P will not exceed 300 mg/120 mg per day for 16 
weeks in the Main study and also in the Retreatment sub-study, if applicable.   
For the Retreatment sub-study, SOF is provided as 400 mg tables and should be taken 
simultaneously with G/P. 
 
Ribavirin (RBV) (if applicable) is provided as 200 mg tablets*** and should be dosed 
BID, e.g., with 2 to 3 tablets*** taken in the morning, and 2 to 3 tablets*** taken in the 
evening based on body weight and must also be taken with food.  For subjects with body 


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weight less than 75kg RBV is dosed at 1000 mg per day (e.g., 400 mg in AM and 600 mg 
in PM, or 600 mg in AM and 400 mg in PM). For subjects with body weight equal or 
greater than 75kg, RBV is dosed at 1200 mg per day (e.g., 600 mg in AM and 600 mg in 
PM). The maximal dose of RBV will not exceed 1200 mg per day for 16 weeks.  
*** RBV dosage form to be determined by dispensing pharmacy. 
 
Study drug dosing will be initiated at the Day 1 Visit in the Main study and the 
Retreatment sub-study if applicable.  Study drug initiation does not need to be witnessed 
at the Day 1 visit. Based on Treatment Arm Efficacy Adjustment criteria in Section 
5.4.1.1, if virologic futility criteria are met, RBV dosing may be added to already ongoing 
or new initiation of G/P dosing in Arms A, B, or D. 
 
 
5.5.6 
Blinding 
 
Both the Main study and Retreatment sub-study will be open-label. 
 
5.5.7 
Treatment Compliance 
 
The investigator or his/her designated and qualified representatives will administer/ 
dispense study drug only to subjects enrolled in the study in accordance with the protocol. 
The study drug must not be used for reasons other than that described in the protocol. 
 
At the start of the study, each subject should receive counselling regarding the importance 
of dosing compliance with the treatment regimen with regard to virologic response and 
potential development of resistance due to poor compliance. 
 
At each study drug dispensing visit during the Treatment Period denoted in Table 5, 
subjects will be instructed to bring all study drug (full, partial or empty) for assessment of 
treatment compliance. Subjects will be instructed to dose from each bottle of study 
medication until the bottle is empty. At post-baseline dispensing visits denoted in Table 


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6, study site personnel will assess subject compliance by inspecting the contents of the 
bottles and record the status of each one, as well as the exact number of remaining 
tablets*** of G/P and/or RBV in the source. Treatment compliance will be based on the 
number of tablets*** dispensed, as recorded in source and the number of remaining 
tablets***.  
***RBV Dosage form to be determined by dispensing pharmacy. 
 
Dosing compliance will also be assessed for patients receiving treatment in the 
Retreatment sub-study.  In addition to G/P and RBV, accounting of SOF dosing will be 
completed and recorded in the study source.  
 
 
5.5.8 
Drug Accountability & Destruction 
 
The investigator/designee will verify that study drug supplies are received intact and in the 
correct amounts. A current (running) and accurate inventory of study drug will be kept by 
the investigator/designee and will include lot number, kit number, number of tablets*** 
dispensed, subject number, initials of person who dispensed study drug and date dispensed 
for each subject. An overall accountability of the study drug will be performed and 
verified by the study monitor. Final accountability will be verified by the monitor at the 
site or via an alternate approved method. 
 
Study drug start dates for each drug and the last dose of the regimen will be documented 
in the subject's source documents.  
 
Upon completion of or discontinuation from the Treatment Period, all original study 
drug bottles (containing unused study drugs) will be destroyed at the study site or 
returned to AbbVie (or its designee). All unused study drugs can only be destroyed 
after being inspected and reconciled by the Study Monitor.  The number of tablets*** of 
each type of study drug returned will be noted in a drug accountability log.  


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On-site destruction is preferred, provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous 
substances. 
• Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to HCV-TARGET. 
• Records are maintained that allow for traceability of each container, including the 
date disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, i.e., incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the 
monitor to review throughout the clinical trial period. 
 
If conditions for destruction cannot be met, the responsible monitor will make 
arrangements for return of all unused and/or partially used study drug to AbbVie (or its 
designee). 
 
It is the investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local, and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept.  Empty containers can only be destroyed on-
site or returned to AbbVie (or its designee) after being inspected and reconciled by the 
monitor at the site or via an alternate approved method.  
***RBV Dosage Forms to be determined by dispensing pharmacy.


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5.5.8.1 
Risk of Development of Resistance-Associated Substitutions 
During Combination DAA Trials 
 
In subjects treated with a DAA, variants with amino acid substitution(s) in the targeted 
protein conferring resistance to the DAA can be selected. For example, in AbbVie HCV 
Phase 3 studies in which patients with GT1 infection were treated with the NS3/4A 
protease inhibitor paritaprevir and NS5A inhibitor ombitasvir, variants that conferred 
resistance to paritaprevir or ombitasvir were detected in patients experiencing virologic 
failure. While data from patients treated with the combination of G/P are limited, it is 
expected that PIB, will be able to suppress the appearance of virus containing resistance-
associated variants in NS3 that confer resistance to GLE, because there should not be any 
cross-resistance in variants resistant to DAAs targeting different proteins. The converse is 
expected to be true as well – GLE should be able to suppress the appearance of virus 
containing NS5A substitutions conferring resistance to PIB. In addition, in vitro resistant 
colony selection studies in HCV replicon cells containing GT1 – 6 NS5A demonstrated 
that PIB had a high genetic barrier to resistance – very few colonies were selected, and 
those that were selected contained NS5A substitutions that conferred only modest levels 
of resistance to PIB. Based on accumulated clinical and in vitro data to date, the risk of 
development of resistant variants to G/P is reduced when compared to treatment with first 
generation protease and NS5A inhibitors. Among the 2258 TN and TE-PRS subjects 
infected with GT1-6 treated with GLE/PIB 300/120 mg included in the integrated 
resistance analysis from the Phase 2 and Phase 3 studies, only 22 (0.97%) experienced 
virologic failure. Among these 22 subjects, treatment-emergent substitutions were 
detected in NS3 in 54.5% (12/22) and in NS5A in 81.8% (18/22). Subjects frequently had 
multiple substitutions in NS5A at the time of failure indicating that, in contrast to first 
generation NS5A inhibitors, single substitutions in NS5A do not confer sufficient 
resistance to allow the virus to overcome PIB drug pressure. These results support the 
prediction that the risk of development of resistance-associated variants with GLE and 
PIB combination treatment is low. 
For subjects enrolled in the Retreatment sub-study, exposure to SOF is not expected to 
result in development of resistant viral variants, due to the high resistance barrier for 
SOF. In clinical studies with LDV/SOF and SOF/VEL, only a small proportion of 
patients who experienced virologic failure had RASs that conferred resistance to SOF at 


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the time of virologic failure.  In analyses of post-treatment resistance from patients in 
phase II/III clinical trials with LDV/SOF25 or SOF/VEL26, among 51/2144 (2.4%) and 
20/1778 (1.1%) patients who experienced virologic failure, respectively, only 1 patient 
harboured virus that contained a RAS that conferred resistance to SOF at the time of 
virologic failure. 
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 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 Section 6.1. 
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 in accordance with standard medical 
practice and the AASLD HCV treatment guidelines.  The adverse events and actions 
taken (concomitant therapy, etc.) identified centrally in the submitted medical records 
generated as part of clinical care will be abstracted into the study database.  The HCV-
TARGET Abstraction Conventions manual will be used to assign adverse event start 
dates for any event abstracted from the medical record without a specific start date noted.  
 
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 


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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 treatment 
regimen. 
 
6.1.1.2 
Serious Adverse Events 
 
If an adverse event meets any of the following criteria, it is to be reported to the sponsor as 
a SAE within 24 hours of the site being made aware of the serious adverse event: 
Death of Subject 
 
An event that results in the death of a subject. 
Life-Threatening 
 
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken. This does not include an event that 
would have been fatal if it had occurred in a more severe 
form. 
Hospitalization or 
Prolongation of 
Hospitalization 
 
An event that results in an admission to the hospital for 
any length of time or prolongs the subject's hospital stay. 
This does not include an emergency room visit or 
admission to an outpatient facility. 
Congenital Anomaly 
 An anomaly detected at or after birth, or any anomaly that 
results in fetal loss. 
Persistent or 
Significant 
Disability/Incapacity 
 
 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject. Disability is not intended to include experiences 
of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle). 
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 


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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. 
 
 
 
Sites will use the SAE reporting template provided by the sponsor to report all SAEs.  If 
an SAE is observed in the submitted clinical records during data abstraction that was 
not previously reported by the site, the site will be queried for the report and supporting 
records.  The query must be responded to within 24 hrs of receipt of the query. 
 
Minimum supporting records required for all SAE reports: 
1. Admit and Discharge note 
2. Daily consult with VS/PE 
3. All labs 
4. Imaging/procedure reports 
5. Medication Administration Record (MAR) 
 
For serious adverse events with the outcome of death, the date and cause of death (if known) 
will be recorded on the appropriate case report form. The site will make all reasonable 
efforts to obtain a death or autopsy certificate, if available. 
 
The following hospitalizations are not considered SAEs: 
• a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
• medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
 


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6.1.2 
Adverse Event Severity 
 
For the purposes of this study, adverse events will be defined and coded centrally based 
on the following definitions: 
 
1. MILD: Adverse events and/or symptoms recorded in the medical record where no 
therapy was given to treat the event or where an over-the-counter 
medication/intervention ONLY was given to treat the event.   
 
2. MODERATE: Adverse events and/or symptoms recorded in the medical record 
requiring prescription medication treatment or any dose reduction in study drug 
ribavirin. 
 
3. SEVERE: Adverse events and/or symptoms requiring any study drug 
discontinuation will be defined and coded as severe.  ANEMIA events requiring 
blood transfusion will be coded as severe. 
 
6.1.3 
Relationship to Study Drug 
 
Assessment of relatedness will be made with respect to both G/P and/or RBV in the Main 
study and both G/P + SOF and/or RBV in the Retreatment sub-study. The 
investigator/clinician designee will use the following definitions to assess the relationship 
of the adverse event to the use of study drug(s): 
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 


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addition, when the investigator has not reported a causality or deemed it not assessable, the 
sponsor will consider the event associated. 
 
For serious adverse events, if an investigator's opinion of relatedness is "no reasonable 
possibility of being related to study drug" an "Other" cause of event must be provided by 
the investigator/clinician designee. 
 
After adverse event data is abstracted from the submitted records, the site investigator/ 
clinician designee will be provided an adverse event listing to assess relationship of the 
adverse event to study drug(s).  Site will be queried to provide adverse event stop 
dates/continuation for any adverse events for which no end date is evident in the 
submitted medical records during the Treatment Period and up to 30 days post treatment.  
 
6.1.4 
Adverse Event Collection Period 
  
From the time of study drug administration until 30 days following discontinuation of 
study treatment has elapsed, all non-serious adverse events will be collected as part of 
standard clinical care in accordance with the AASLD HCV treatment guidelines and 
abstracted from the submitted clinical records. After 30 days following completion of 
study treatment and throughout the Post-Treatment Period, only spontaneously reported 
SAEs will be collected (non-serious AEs will not be collected). 
 
Following the subject’s written consent to participate in the Main study and the 
Retreatment sub-study (as applicable), all SAEs, whether related or not related to study 
drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period 
and through the final study visit. 
 


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If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be submitted within 24 
hours using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
6.1.5 
Serious Adverse Event Reporting 
 
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator/designee will notify the Medical Monitor within 24 hours of the site being 
made aware of the serious adverse event by submitting the available serious adverse event 
data to:  
 
    HCV-TARGET REPORTING CONTACT INFORMATION 
Email to (preferred method):  
 
FAX to: 
 
 
  For safety concerns, contact the physician listed below: 
Primary HCV-TARGET Designated Physician: 
 MD 
Office: 
 
Email:  
 
The HCV-TARGET designated Physician must also report any serious adverse event to 
AbbVie within 24 hours after receipt of the serious adverse event information from the 
study site. 
6.1.6 
Pregnancy 
 
Female subjects randomized or assigned to non-RBV containing regimen in Main study or 
Retreatment sub-study should avoid pregnancy starting with screening and through 30 days 
after completion of study drug. Female subjects randomized or assigned to RBV 
containing regimen in Main study or Retreatment sub-study should avoid pregnancy 
starting with Screening and through 6 months after completion of study drug (or as per 


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local RBV label). Male subjects randomized to G/P in Main study or receiving G/P plus 
SOF in Retreatment sub-study and their partners should avoid pregnancy starting with 
screening and through 30 days after completion of study drug.  Male subjects randomized 
or assigned to RBV containing regimen in Main study or Retreatment sub-study and their 
partners should avoid pregnancy starting with Screening and through 7 months after 
completion of study drug (or as per local RBV label).  
 
Pregnancy in a study subject must be reported to the sponsor within 1 working day of the 
site becoming aware of the pregnancy and should be reported to the Ribavirin Pregnancy 
Registry, as applicable. Administration of G/P in Main study or G/P plus SOF in 
Retreatment sub-study may be continued at the investigator's discretion after discussion 
with the subject, if the benefit of continuing therapy is felt to outweigh the risk (Section 
5.4.1). If a subject is discontinued, the subject will be monitored for SVR in the Post-
Treatment Period as described in Section 5.1.3. 
 
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment for subjects receiving a non-RBV containing regimen or up to 6 months (female 
subjects) or 7 months (male subjects) after the end of treatment for subjects receiving a RBV 
containing regimen. 
 
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 the sponsor 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 Main study or Retreatment sub-study must be evaluated by the 


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investigator/clinician designee. All adverse events and laboratory abnormalities will be 
managed and followed to a satisfactory clinical resolution.  
 
To facilitate this process in a pragmatic study, after adverse event data is abstracted from the 
submitted records, the site investigator/clinician designee will be provided an adverse event 
listing to assess relationship of the adverse event to study drug(s). The site will also upload 
signed central lab reports where the investigator/clinician designee completed the 
evaluation of clinical significance of abnormal results.  Actions taken for clinically 
significant abnormal laboratory results and/or adverse events will be recorded in the site 
medical record or source and uploaded for centralized abstraction. 
 
6.2. 
Product Complaint 
 
6.2.1 
Definition 
 
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
study drug product(s). 
 
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labelling, labelling 
discrepancies/inadequacies in the labelling/instructions (example: printing illegible), 
missing components/product, or packaging issues.  Any product complaints identified 
centrally in the submitted medical records will be abstracted into the study database. 
 
 
6.2.2 
Reporting 
 
Product Complaints concerning the investigational product must be reported to the 
sponsor within 24 hours of the time it is observed or the data is abstracted centrally from 
the submitted medical records via the Product Complaint form. Product Complaints 
occurring during the study will be followed-up to a satisfactory conclusion via specific 


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query to the site for any available clinical information. All follow-up information is to be 
reported to the sponsor and documented in the source medical record.  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/site 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 
 
The investigator should not implement any deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects. When a deviation from the 
protocol is deemed necessary for an individual subject, the investigator must contact the 
following personnel:  
 
If by e-mail: 
 
If by phone: 
 
 
 
 (alternate contact) 
Office: 
 
 
                        Office: 
 
 
Such contact must be made as soon as possible to permit a review by the sponsor to 
determine the impact of the deviation on the subject and/or the study. Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation. 
 


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8.0 
Statistical Methods and Determination of 
Sample Size 
8.1 
Statistical and Analytical Plans 
 
The primary analysis will occur after all subjects in the Main Study have completed the 
PT Week 12 Visit or prematurely discontinued study. The data for subjects treated in the 
Main study will be locked after data cleaning. Data from the Retreatment sub-study will 
be analyzed separately as described below and be included in the end-of study analysis. 
 
The data analysis will be generated using SAS/STAT software, version 9.4 or higher of 
the SAS system for Windows. Copyright © [2001-2012] SAS Institute Inc. SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks 
of SAS Institute Inc., Cary, NC, USA. All statistical tests (if applicable) and confidence 
intervals will be two-sided with an alpha level of 0.05. Descriptive statistics will be 
provided, such as the number of observations (N), mean, and standard deviation (SD) for 
continuous variables and counts and percentages for discrete variables. 
 
The primary efficacy analyses in the Main study will be performed on the intention to 
treat population summarized according to the treatment arm in which the subject actually 
received treatment.  This primary efficacy analysis dataset will be referred to as the 
modified ITT (mITT) population and defined as all enrolled subjects who receive at least 
one dose of study drug according to each subject’s final treatment arm assignment (Arm 
A, Arm B, Arm C or Arm D). Analyses in the Retreatment sub-study will be performed 
overall on the Evaluable Patient population for that sub-study (EP-RS) defined as all 
subjects who receive at least one dose of study drug in the Retreatment sub-study. 
 
The traditional ITT population, which includes all subjects who received at least one dose 
of study drug categorized by the patients’ randomized treatment arm, along with other 
modified ITT populations will be employed in the sensitivity analyses. Specifically, 
sensitivity analyses of the primary endpoint of the Main Study will be performed on the 
following modified ITT populations: 


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1) Modified ITT-Genotype (mITT-GT) Population  
-includes the mITT population (or “as treated”) but excludes subjects with 
genotype other than GT1 infection. 
  
2)  Modified ITT- Genotype and Virologic Failure (mITT- GT-VF) Population 
- includes the mITT-GT population but excludes subjects who did not achieve 
SVR12 for reasons other than virologic failure (mITT-GT-VF), when 
applicable.  
Similarly, for the Retreatment sub-study, sensitivity analyses of the SVR12 endpoint will 
be performed on the EP-RS population modified to exclude subjects other than GT1 (EP-
RS-GT) and further modified to exclude subjects who did not achieve SVR12 for reasons 
other than virologic failure (EP-RS-GT-VF). 
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data). HCV RNA values will be selected for the analyses of all 
SVR endpoints (e.g., SVR4 and SVR12) based on defined visit windows. A backward 
imputation method will be used to impute missing responses for SVR analyses. 
Additional details of analyses to be performed are specified in the Statistical Analysis 
Plan. 
8.1.1 
Demographics 
 
Demographics and baseline characteristics will be summarized for all treated subjects by 
treatment arm for the Main Study and separately on the overall EP-RS population. 
Demographics include age, weight, height, BMI, gender, race, and ethnicity. Baseline 
characteristics will be summarized as continuous variables (where appropriate) and as 
categorical variables, including HCV genotype subtype, most recent HCV treatment 
history, baseline HCV RNA level, and fibrosis stage. 
 
Summary statistics (N, mean, median, SD, and range) will be generated by treatment arm 
for continuous variables (e.g., age and BMI), and the number and percentage of subjects 
will be presented for categorical variables (e.g., sex and race). 


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Study drug exposure and compliance will be summarized by treatment arm and separately 
on the overall EP-RS population. Treatment compliance to study drug will be calculated 
based on the percentage of tablets*** taken relative to the total tablets*** expected to be 
taken for each tablet*** type G/P, RBV, SOF tablets as applicable. A subject is 
considered to be compliant if the percentage is between 80% and 120% for each tablet 
type. Compliance will be calculated for each subject and summarized with the mean, 
median, standard deviation, minimum, and maximum. The percentage of compliant 
subjects will be summarized. 
   ***RBV Dosage Form to be determined by dispensing pharmacy. 
8.1.2 
Efficacy 
 
All efficacy analyses will be performed on the mITT and EP-RS populations, unless 
otherwise specified.  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 Efficacy Endpoints 
 
The primary efficacy endpoints for the mITT population are the difference in SVR12 (HCV 
RNA < LLOQ 12 weeks after the last actual dose of study drug) rates between Arm A and 
Arm B in non-cirrhotic subjects, and difference in SVR12 rates between Arm C and Arm D 
in cirrhotic subjects.  
 
The difference in SVR12 rates will be summarized with a two-sided 95% confidence 
interval for the comparison between Arm A and Arm B in non-cirrhotic subjects, and for 
the comparison between Arm C and Arm D in cirrhotic subjects. The number and 
percentage of subject achieving SVR12 by treatment arm will also be summarized with a 
two-sided 95% confidence interval. The confidence interval for the difference in SVR 12 


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rates will be calculated using Wilson's score method. The confidence interval for the 
SVR12  rates by treatment arm will be calculated using the normal approximation to the 
binomial distribution if the number of subjects who failed to achieve SVR 12 is at least 5. 
If the number of subjects who failed to achieve SVR 12 is less than 5, Wilson’s score 
method will be used instead.  
 
A summary of reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided. 
 
8.1.2.2 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints for the mITT population in the Main Study are: 
 
o 
the difference in SVR12 rates between G/P given for 12 weeks (Arm A and C 
combined) and G/P given for 16 weeks (Arm B and D combined); 
o 
the difference in the percentage of subjects with on-treatment virologic failure 
(confirmed increase of > 1 log10 IU/mL above nadir during treatment, confirmed HCV 
RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA ≥ LLOQ at 
the end of treatment with at least 6 weeks of treatment) between Arm A and Arm B in 
non-cirrhotic subjects, and between Arm C and Arm D in cirrhotic subjects; 
o 
the difference in 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 with reinfection) between Arm A and 
Arm B in non-cirrhotic subjects, and between Arm C and Arm D in cirrhotic subjects. 
 
For the analysis of relapse, completion of treatment is defined as any subject with study 
drug duration of 77 days or greater for 12-week arms (Arms A and C), or 105 days or 
greater for 16-week arm (Arm B and D). 
 
The difference in SVR12 rates between 12 week (Arms A+ C) and 16 week (Arms B+D) 


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treatment durations will be summarized calculated along with a two-sided 95% 
confidence interval using Wilson’s score method. The difference in the percentage of 
subjects with on-treatment virologic failure and post-treatment relapse will be summarized 
with two-sided 95% Wilson score intervals, as will the percentage of subjects with on-
treatment virologic failure and post-treatment relapse in each treatment arm. 
8.1.2.3 
Sensitivity Analysis 
 
As sensitivity analyses, the difference in the percentage of subjects in the mITT-GT and 
mITT-GT-VF populations achieving SVR12 between Arm A and Arm B in non-cirrhotic 
subjects, and between Arm C and Arm D in cirrhotic subjects, as applicable, will be 
summarized. The SVR12 rates in the EP-RS-GT and EP-RS-GT-VF populations overall 
will be calculated. 
8.1.2.4 
Subgroup Analysis 
 
In the mITT population for the Main study, association of the proportions of subjects with 
SVR12 with each of the following subgroups will be compared across treatment arms 
(Arms A and B, and Arm C and D separately) using Zelen’s exact tests.  In addition, two-
sided 95% Wilson score intervals will be calculated for the difference between Arms A 
and B and Arms C and D, for the following subgroups:  
 
o HCV GT1 subtype; 
o Most recent HCV treatment history; 
o All prior HCV treatment history; 
o Type of non-response to NS5A-inhibitor+SOF± RBV treatment; 
o Sex; 
o Age; 
o Race; 
o Ethnicity; 
o BMI; 
o Baseline HCV RNA level; 


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o Baseline platelet count; 
o Baseline albumin; 
o Baseline APRI; 
o Baseline FIB-4; 
o Baseline AST/ALT ratio; 
o Baseline Child-Pugh Score (for cirrhotic subjects only); 
o History of concomitant diseases: (a) diabetes, (b) HIV coinfection (c) post-organ 
transplant;  
o Concomitant use of Proton Pump inhibitors 
o DAA compliance. 
o Baseline resistance polymorphisms (any NS3/4A variant [yes/no]; any NS5A variant 
[yes/no]; any NS3/4A and any NS5A [yes/no], any NS3/4A or any NS5A [yes/no]) 
and [NS3/4A only, NS5A only, both NS3/4A and NS5A, or none]). 
 
The difference in SVR12 rates between G/P given for 12 weeks (Arm A and C combined) 
and G/P given for 16 weeks (Arm B and D combined) will also be examined within the 
combined arms by HCV sub-genotype (1b vs. non-1b). 
 
  Further details about subgroup analyses will be described in the Statistical Analysis Plan. 
 
8.1.2.5 
Additional Efficacy Endpoints 
 
The following additional efficacy endpoints will be summarized for each treatment arm in 
the mITT population and overall in the EP-RS population, as specified below: 
 
o The percentage of mITT subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed); 
o The percentage of mITT subjects with SVR4; 
o The percentage of EP-RS subjects achieving SVR12. 
o The percentage of EP-RS subjects with on-treatment virologic failure and with post-
treatment relapse. 


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In the above analyses for SVR, the percentage of subjects and a two-sided 95% Wilson 
score interval will be summarized. A summary of reasons for SVR non-response will also be 
provided for subjects in the EP-RS populations who do not achieve SVR12. 
 
 
8.1.3 
Resistance Analyses 
 
The following analyses will be performed for all subjects in the mITT population and the 
EP-RS populations separately. In the EP-RS population, baseline polymorphisms in NS3 
and NS5A will be reassessed prior to treatment with G/P + SOF ± RBV.  
 
The HCV NS3 and NS5A amino acid sequences from baseline samples as determined by 
population sequencing or NGS will be compared to the appropriate prototypic reference 
sequence. A listing by subject of all baseline polymorphisms relative to prototypic 
reference sequence at signature amino acid positions will be provided for each DAA target 
(NS3 and NS5A). 
 
The following analyses will be performed for subjects who do not achieve SVR 12 and who 
have post-baseline resistance data available: 
 
(1) The HCV NS3 and NS5A amino acid sequences from the sample closest in time after 
virologic failure or treatment discontinuation with an HCV RNA level of ≥ 1000 IU/mL as 
determined by population sequencing or NGS will be compared to the baseline sequence. 
A  listing by subject 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 
and NS5A). 
 
(2) The HCV NS3 and NS5A amino acid sequences from the sample closest in time after 
virologic failure or treatment discontinuation with an HCV RNA level of ≥ 1000 IU/mL 
will be compared to the appropriate prototypic reference sequence. A listing by subject of 


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all post-baseline substitutions at signature amino acid positions relative to the appropriate 
prototypic reference amino acid sequence will be provided for each DAA target (NS3 and 
NS5A). 
(3) The persistence of post-baseline substitutions at signature amino acid positions for 
each target (NS3 and NS5A) will be assessed by population sequencing or NGS at Post-
Treatment Week 12. A listing by subject and time point of all substitutions relative to the 
baseline amino acid sequence will be provided for each DAA target (NS3 and NS5A). 
 
For subjects who experience virologic failure in the Retreatment sub-study, the NS3, 
NS5A, and NS5B sequences from the baseline sample and from the sample closest in 
time after virologic failure with an HCV RNA level of ≥ 1000 IU/mL will be evaluated as 
described in analyses (1) and (2) above. 
 
8.1.4 
Adverse Events 
 
All subjects who receive at least one dose of study drug will be included in the safety 
analyses. Safety analyses will be conducted separately for the Main study and the 
Retreatment sub-study. 
 
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) for each treatment arm. The tabulation of the 
number of subjects with treatment-emergent adverse events by severity grade and 
relationship to study drug also will be provided. Subjects reporting more than one adverse 
event for a given MedDRA preferred term will be counted only once for that term using 
the most severe grade for the severity grade table and the most related for the relationship 
to study drug table. Subjects reporting more than one type of event within a SOC will be 


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counted only once for that SOC. Selected adverse events will be summarized separately 
for the Re-treatment Substudy. 
 
8.1.5 
Clinical Laboratory Data 
 
Clinical laboratory tests will be summarized at each visit by treatment arm. The baseline 
value will be the last non-missing measurement prior to the initial dose of study drug. 
Mean changes from baseline to each post-baseline visit, including the Final Treatment 
Visit, will be summarized descriptively for each treatment arm. 
 
In addition, the number and percentage of subjects with post-baseline laboratory values 
showing increase in CTCAE toxicity grade during treatment will be summarized by 
treatment arm for the Main study and overall for the Retreatment sub-study. 
 
8.2 
Determination of Sample Size 
 
Based on actual real-world pragmatic enrollment observed in the ongoing study, more 
non-cirrhotics and less compensated cirrhotic subjects are enrolling than was previously 
projected. This will improve precision for the point estimated SVR12 rates of the non-
cirrhotic patient and decrease precision for the point estimated SVR12 rates in 
compensated cirrhotic subjects. For the comparison between Arm A and Arm B in non-
cirrhotic subjects, if the observed SVR12 rate in Arm B is 92%-96%, with 100 subjects in 
Arm A and 50 subjects in Arm B, the half widths of 95% confidence interval of the 
difference between SVR12 rates are displayed in the table below:  
SVR12 in Arm B 
92% 
93% 
94% 
95% 
96% 
Half width (SVR12 in Arm A = SVR12 in Arm 
B) 
0.092 
0.087 
0.081 
0.074 
0.067 
Half width (SVR12 in Arm A = SVR12 in Arm B 
– 1%) 
0.094 
0.088 
0.083 
0.076 
0.069 
Half width (SVR12 in Arm A = SVR12 in Arm B 
– 2%) 
0.095 
0.090 
0.085 
0.078 
0.072 


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For the comparison between Arm C and Arm D in cirrhotic subjects, if the observed 
SVR12 rate in Arm D is 94%-98%, with 40 subjects in Arm C and 40 subjects in Arm D, 
the half widths of the 95% confidence interval of the difference between SVR12 rates are 
displayed in the table below: 
SVR12 in Arm D 
94% 
95% 
96% 
97% 
98% 
Half width (SVR12 in Arm C = SVR12 in Arm D) 
0.104 
0.096 
0.086 
0.075 
0.061 
Half width (SVR12 in Arm C= SVR12 in Arm D – 1%) 
0.108 
0.100 
0.091 
0.081 
0.068 
Half width (SVR12 in Arm C = SVR12 in Arm D – 2%) 
0.112 
0.104 
0.095 
0.086 
0.075 
 
In Study M15-410, subjects with prior NS5A inhibitor experience only (ie. PI naïve) had 
an SVR12 rate of 94.4% for 16 weeks treatment duration.  This SVR12 rate would give 
half widths of 95% confidence intervals of ≤ 11% in most cases where Arm A or Arm C 
are no more that 1% worse than Arm B or Arm D, respectively. 
8.3 
Randomization Methods 
 
The Main study is randomized. In it, eligible subjects without cirrhosis will be 
randomized 2:1 into Arms A and B. Subjects with compensated cirrhosis will be 
randomized 1:1 into Arms C and D.  Randomization will be stratified by HCV genotype 1 
subtype (1b or non-1b) and cirrhosis status. 
The Retreatment sub-study is not randomized; all subjects who experience virologic 
failure in the Main study and consent to the Retreatment sub-study will receive G/P + 
SOF ± RBV for 16 weeks. 
 
 
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 (applicable to Main Study only), the informed 
consent and all other forms of subject information related to the study (e.g., advertisements 
used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. 
The IEC/IRB will review the ethical, scientific and medical appropriateness of the study 


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before it is conducted. IEC/IRB approval of the protocol, informed consent and subject 
information and/or advertising, as relevant, will be obtained prior to the authorization of 
drug shipment to a study site. 
 
Any amendments to the protocol will require IEC/IRB approval prior to implementation of 
any changes made to the study design. The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP. 
 
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 the sponsor. 
 
 
9.2 
Ethical Conduct of the Study 
 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki. Responsibilities of the clinical investigator are specified in Appendix A. 
 
9.3 
Subject Information and Consent 
 
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study. Prior to any study -related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements. A signed 


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copy of the informed consent form will be given to the subject and the original will be 
placed in the subject's medical record. An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any study-
related procedures and that the subject received a signed copy. 
 
 
 
 
 
10.0 
Source Documents and Case Report 
Form Completion 
10.1 
Source Documents 
 
All original clinic notes, telephone notes, locally available safety labs/evaluations 
and/or diagnostic tests or health screenings collected prior to, during and post HCV 
treatment period will be submitted for chart data abstraction to identify and abstract 
medical history, vital signs, weight (and height historically) HCV treatment, dosing, adverse 
events, clinical management and physical examinations that were collected as part of 
standard of care practice.  Additionally, sites will be provided standardized source 
worksheets to manage drug supply, drug accountability and various other study related 
activities that are not routinely covered under clinical care or recorded in the patient 
medical record along with the records associated with central laboratory test collection 
and results.  These documents comprise the study source and will be submitted for 
centralized data abstraction (Section 10.3). 
 
The source documentation for this pragmatic study is largely the medical record 
generated in the clinical management of the subjects.  The Investigator is responsible 
for ensuring that the source data are accurate, legible, contemporaneous, original and 
attributable, whether the data are hand-written on paper or entered electronically. If 
source data are created (first entered), modified, maintained, archived, retrieved, or 
transmitted electronically via computerized systems (and/or any other kind of electronic 


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devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records (EMRs/EHRs), adverse event tracking/reporting, protocol-
required assessments, and/or drug accountability records. 
 
When paper records from such systems are used in place of electronic format to 
perform regulated activities, such paper records should be certified copies. A certified 
copy consists of a copy of original information that has been verified, as indicated by a 
dated signature, as an exact copy having all of the same attributes and information as 
the original. 
 
 
10.2 
Case Report Forms 
 
Case report forms (CRF) are completed for each subject by the centralized data 
abstraction team at the University of Florida.  Site staff is responsible to upload redacted 
records into the applicable case book for each respective patient according to the Study 
Activities Schedule (Table 5). These forms will be used to transmit information collected 
during the study to AbbVie and regulatory authorities, as applicable. The CRF data for 
this study are being collected with an electronic data capture (EDC) system called 
REDCap. REDCap has been used in over 15,360 projects with over 23,000 end users 
across 6 continents.  REDCap is designed for interactive web-based data entry with real-
time field validation.  A dedicated instance of the web-based Research Electronic Data 
Capture (REDCap) data management software package, which is utilized extensively 
throughout the national CTSA program and beyond, is implemented and supported by the 
University of North Carolina –Chapel Hill for the HCV-TARGET registry program. This 
secure server environment housing the database hardware is located within a hardened 
data center on the UNC campus and is governed by standardized University and School 
of Medicine information security guidelines. 


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The “FDA regulation 21 CFR Part 11” details recommendations for electronic records 
and electronic signatures.  According to this regulation, systems generating electronic 
records which are to be considered equivalent to paper records, should be validated, 
produce a time-stamped audit trail of data modifications, require electronic signatures and 
restrict access to authorized users.  The REDCap based data management system 
implemented for the HCV-TARGET registry has been adapted to the specified FDA 
recommendations, and annual internal audits are performed to ensure compliance with 
Title 21 CFR Part 11 is achieved. 
 
10.3 
Centralized Data Abstraction 
 
In order to reduce chart data abstraction errors and inconsistencies and improve data 
quality, the HCV-TARGET Network operations utilizes a specially trained Centralized 
Chart Data Abstraction Service (CDAS) team at the CCC/respective country Abstraction 
Core (CDAS) as the method for chart abstraction. Participating sites upload redacted 
copies of clinically available medical record source data on enrolled subjects into the 
study database. This data includes ALL clinic notes, nursing/staff telephone notes, 
evaluations and lab results generated in standard care to monitor the HCV baseline 
condition, on-treatment safety and efficacy, concomitant therapy, actions taken in 
treatment management as well as outcomes. The CDAS will abstract and enter the data 
from those provided participant medical records into the database and query as needed to 
fill data gaps not addressed by the study Data Abstraction Conventions. 
 
10.4 
Submitting Records for Abstraction 
 
Before submitting records for abstraction, site staff redacts all elements of PHI (see 
Section 10.6) defined by HIPAA except dates of services on all records.  Sites will add 
a study-coded identifier to the submitted records to help maintain subject 


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confidentiality.  Patient identifiers such as patient name, full date of birth, address, etc. 
can be viewed by the DCC or CCC to facilitate onsite and remote monitoring of the 
data and compliance with the protocol, however, with the exception of dates, PHI 
identifiers will not be included on any datasets used for the overall safety and efficacy 
database and analyses, making the database a limited data set.  In instances where a PHI 
identifier other than a date of service is present on a redacted record received for 
CDAS, delegated CDAS personnel will redact that information.   
 
To ensure security with transmitting the records, sites will upload the redacted medical 
records onto the secure study REDCap database. Chart Data Abstractors will access the 
redacted records from this location to abstract the protocol-defined data into the study 
database.  Those records will be maintained by CDAS staff to facilitate data monitoring 
as needed. 
 
The abstracted data is transmitted to the Data Coordinating Center (DCC) via a 
distributed web-based data entry system, REDCap, which is 21 CFR Part 11 validated 
and compliant. 
 
10.5 
Subject Confidentiality Associated with Uploaded Records for 
Abstraction 
 
All patient and study documents are kept confidential. Study sites and the CDAS team 
will be responsible for the confidentiality of the data associated with subjects enrolled 
into this study in the same manner they are responsible for the confidentiality of any 
patient information within their spheres of responsibility. All forms and submitted 
records used for abstraction of the study data will be identified by coded identifiers to 
maintain subject confidentiality. All study staff will identify patients by the patient 
identifier number generated at the study site. 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.  AbbVie (or their representative) will 


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also be allowed access to all source documents pertinent to the study in order to verify 
EDC entries. Participants grant permission to share research data with these entities in 
the consent document. Federal regulations govern the protection of patient’s rights 
relative to data confidentiality and use of research data.   
 
Consent procedures and forms, and the communication, transmission and storage of 
patient data will comply with individual site IRB and federal requirements for 
compliance with HIPPA.  
10.6 
HIPAA Privacy Rule for Elements of PHI and Uploaded Records 
for Abstraction 
 
Established in 1996, the U.S. Department of Health and Human services issued the 
Privacy Rule as part of the Health Insurance Portability and Accountability Act to 
establish a national set of standards for the protection of certain health information.  
This rule protects all “individually identifiable health information” held or transmitted 
by a covered entity or its business associate in any form or media whether electronic, 
paper, or oral.  A list of 18 Identifiers was established: 
 
1. 
Names 
2. 
All geographical subdivisions smaller than a State, including street address, city, 
county, precinct, zip code, and their equivalent geocodes, except for the initial three 
digits of a zip code, if according to the current publicly available data from the Bureau 
of the Census: (1) The geographic unit formed by combining all zip codes with the 
same three initial digits contains more than 20,000 people; and (2) The initial three 
digits of a zip code for all such geographic units containing 20,000 or fewer people is 
changed to 000. 
3. 
All elements of dates (except year) for dates directly related to an individual, 
including birth date, admission date, discharge date, date of death; and all ages over 89 
and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 


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4. 
Phone numbers 
5. 
Fax numbers 
6. 
Electronic mail addresses 
7. 
Social Security numbers 
8. 
Medical record numbers 
9. 
Health plan beneficiary numbers 
10.  Account numbers 
11.  Certificate/license numbers 
12.  Vehicle identifiers and serial numbers, including license plate numbers 
13.  Device identifiers and serial numbers 
14.  Web Universal Resource Locators (URLs) 
15.  Internet Protocol (IP) address numbers 
16.  Biometric identifiers, including finger and voice prints 
17.  Full face photographic images and any comparable images 
18. Any other unique identifying number, characteristic, or code (note this does not 
mean the unique code assigned by the investigator to code the data) 
 
Records submitted for Centralized Abstraction and through RED-I are redacted for 
these PHI identifiers except for dates of service/activities.  In instances where a PHI 
identifier other than a date of service is present on a redacted record delegated CCC 
personnel will redact that information. 
 
11.0 
 Monitoring 
 
The study monitor will review data centrally (remote monitoring) to identify potential 
issues to determine a schedule of on-site visits for targeted review of study records.  
 
The study monitor must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. On-site they will review study records, the 
Investigator Site File, and study medication; discuss the conduct of the study with the 


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investigator; and verify that the facilities remain acceptable.  To supplement routine 
medical monitoring, a data monitoring committee comprised of Dr. Nelson, Dr. Fried 
and at least 3 participating site investigators will review any safety or treatment efficacy 
findings that may affect study-wide dosing decisions and application of futility criteria 
in section 5.4.1.1. 
 
The investigator must notify the sponsor promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to the sponsor. 
 
12.0 
 Records Retention 
 
The investigator must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, or 
for the period specified by the sponsor, whichever is longer. The investigator must 
contact the sponsor prior to destroying any records associated with the study.  The 
sponsor will notify the investigator when the study records are no longer needed. 
 
If the investigator withdraws from the study (eg, relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (eg, another investigator, IRB). 
Notice of such transfer will be given in writing to the sponsor. 
13.0        Study Drug Records 
 
It is the responsibility of the investigator to ensure that a current disposition record of 
study drug (inventoried and dispensed) is maintained at the study site to include study 
drug(s). Records or logs must comply with applicable regulations and guidelines and 
should include: 
• amount received and placed in storage area 
• amount currently in storage area 
• label identification number or batch number 


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• amount dispensed to and returned by each subject, including unique subject 
identifiers 
• amount transferred to another area/site for dispensing or storage 
• nonstudy disposition (eg, lost, wasted) 
• amount destroyed at study site, if applicable 
• amount returned to AbbVie (or designee), if applicable 
• dates and initials of person responsible for Investigational Product dispensing/ 
accountability, as per the Delegation of Authority Form. 
 
The sponsor will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements. 
 
14.0 
 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 electronic CRF. 
 
15.0 
 Completion of the Study 
 
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and sponsor. 
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and sponsor. The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative. 
 
The investigator must retain any records related to the study according to local 
requirements. If the investigator is not able to retain the records, he/she must notify the 
sponsor to arrange alternative archiving options. 
 


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The end-of-study is defined as the date of the last subject's last visit.


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16.0  
Investigator's Agreement 
 
1. I have received and reviewed the MavyretTM Prescribing Information, 
Sovaldi(Sofosbuvir) Prescribing Information, and Ribavirin Prescribing 
Information. 
2. I have read this protocol and agree that the study is ethical. 
3. I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines. 
4. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
5. I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding. 
 
Protocol Title: 
A Phase 3b, Multi-Center, Randomized, Open-Label, Pragmatic 
Study of Glecaprevir/Pibrentasvir (G/P) +/- Ribavirin for GT1 
Subjects with Chronic Hepatitis C Previously Treated with an NS5A 
Inhibitor + Sofosbuvir Therapy  
 
   Protocol Date: 
November 20, 2018 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
 
 
 
 
 
 
 
 
 
 


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17.0  
Reference List 
 
1. World Health Organization. Worldwide Statistics for HCV. Weekly 
Epidemiological Record No. 49. 10 December 1999. 
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, Altria 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. Sy T, Jamal MM. Epidemiology of hepatitis C virus (HCV) infection. Int J Med 
Sci. 2006;3(2):41-6. 
5. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and 
ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis 
C patients with advanced fibrosis. J Hepatol. 2010;52(5):652-7. 
6. Backus LI, Boothroyd DB, Phillips BR, et al. A sustained virologic response 
reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol 
Hepatol. 2011;9(6):509-16. 
7. Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. 
Gastroenterology. 2014;146(5):1176-92. 
8. American Association for the Study of the Liver AASLD Clinical Practise 
Guidelines: Recommendations for Testing, Managing, and Treating Hepatitis C. 
http://www.hcvguidelines.org, accessed September 25,, 2017.  
9. Afdhal N, Reddy KR, Nelson DR, et al.  Ledipasvir and sofosbuvir for previously 
treated HCV genotype 1 infection.  N Engl J Med.  2014;370(16):1483-93. 
10. McPhee F, Friborg J, Levine S, et al.  Resistance analysis of hepatitis C virus NS3 
protease inhibitor asunaprevir.  Antimicrob Agents Chemother.  2012;56(7):3670 
81. 
11. Wong KA, Worth A, Martin R, et al.  Characterization of Hepatitis C virus 
resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-
5885.  Antimicrob Agents Chemother.  2013;57(12):6333-40. 


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12. Krishnan P, Tripathi R, Irvin M, et al.  Lack of impact of baseline 
resistance-associated variants (RAVS) on treatment outcome in the aviator study 
with ABT-450/r, ABT-333, and ABT-267 +/- Ribavirin.  J Hepatol.  
2014;60:S498. 
13. AbbVie. Glecaprevir/Pibrentasvir fixed dose combination Investigator's Brochure 
Edition 2. 06 September 2016. 
14. Harvoni® (ledipasvir and sofosbuvir tablet) US prescribing information. Gilead 
Sciences, Inc., Foster City, CA; revised 06/2016. 
15. Lawitz E, Flamm S, Yang et a. Retreatment of patients who failed 8 or 12 weeks 
of ledipasvir/sofosbuvir for 24 weeks. J Hepatol 62:S192, 2015. 
16.  Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r-ombitasvir and dasabuvir with 
or without ribavirin for HCV. N Engl J Med  2014; 370:1983–92 
17. Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, Kuo 
A, Lok AS, Shiffman ML, Ben Ari Z, Akushevich L, Vainorius M, Sulkowski 
MS, Fried MW, Nelson DR; HCV-TARGET Study Group. Effectiveness of 
Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection 
and Factors Associated With Sustained Virologic Response. Gastroenterology 
2016; 151:1131-1140. 
18. Clinical Trial Facilitation Group (CTFG). Recommendations related to 
contraception and pregnancy testing in clinical trials. 2014. Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
19. Epclusa® (velpatasvir and sofosbuvir tablet) US prescribing information. Gilead 
Sciences, Inc., Foster City, CA; issued 06/2016. 
20. Daklinza® (daclatasvir tablet) US prescribing information. Bristol-Myers Squibb 
Company, revised February 2017. 
21. Ribasphere® (Ribavirin tablet) US prescribing information.  Kadmon 
Pharmaceuticals LLC, 2015. 
22. Ng TI, Krishnan P, Pilot-Matias T,  Kati W, Schnell G, Beyer J, Reisch T, Lu L, 


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Dekhtyar T, Irvin M, Tripathi R, Maring C, Randolph JT, Wagner R, Collins C. In 
Vitro Antiviral Activity and Resistance Profile of the Next Generation Hepatitis C 
Virus NS5A Inhibitor Pibrentasvir. Antimicrob Agents Chemother ePub ahead of 
print, Feb 13, 2017.  
23. Mavyret® (glecaprevir/pibrentasvir tablet) US prescribing information. AbbVie 
Inc., North Chicago, IL issued 08/2018. 
24. Wyles D, Weiland O, Yao B, Reindollar R, Weilert F, Dufour J-F, Gordon S. C., 
Poordad F, Stoehr A,  Brown A, Mauss S, Samanta S, Pilot-Matias T, Rodrigues 
L, Trinh R. Retreatment of hepatitis C virus infection in patients who failed 
glecaprevir/pibrentasvir. J Hepatol 68:S23-S24, 2018. 
25.  Wyles D Dvory Sobol H, Svarovskaia ES Doehle BP, Martin R, Afdhal NH, 
Kowdley KV, Lawitz E, Brainard DM, Miller MD, Gane EJ. Post-treatment 
resistance analysis of hepatitis C virus from phase II and III clinical trials of 
ledipasvir/sofosbuvir J. Hepatol. 66(4):703-710, 2017. 
26.  Hezode C, Reau N, Svarovskaia ES, Doehle BP, Shanmugam R, Dvory-Sobol H, 
Hedskog C, McNally J, Osinusi A, Brainard DM, Miller MD, Mo H, Roberts SK, 
O’Leary JG, Shafram SD, Zeuzem S. Resistance analysis in patients with 
genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III 
studies. J. Hepatol. 68(5):895-903, 2018. 
27. Sovaldi® (sofosbuvir tablet) US prescribing information. Gilead Sciences Inc., 
Foster City, CA, revised 11/2017. 
 
 
 
 
 


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Appendix A. 
Responsibilities of the Clinical Investigator 
 
Clinical research studies managed by HCV-TARGET 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 16.0 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 the sponsor, 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 the 
sponsor and the site director. 
5. 
Reading the information in the Investigator's Brochure (applicable to Main 
Study)/Prescribing Information(s) provided, including the instructions for use and 
the potential risks and side effects of the investigational product(s)/study drugs. 
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 the sponsor and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from the sponsor. 
8. 
Maintaining records demonstrating that an ethics committee reviewed and approved 
the initial clinical investigation and all amendments. 
9. 
Reporting promptly, all changes in the research activity and all unanticipated 


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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 the sponsor. 
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. 
Medicare National Coverage Decision for Clinical Trials 
 
This national coverage policy is based upon the authority found in §1862(a)(1)(E) of the 
Social Security Act (Act). It is binding on all Medicare carriers, fiscal intermediaries, Peer 
Review Organizations, Health Maintenance Organizations, Competitive Medical Plans, 
Health Care Prepayment Plans, and Medicare+Choice organizations (§1852(a)(1)(A) of the 
Act). In addition, an administrative law judge may not disregard, set aside, or otherwise 
review a national coverage decision issued under §1862(a)(1) of the Act. 42 C.F.R. §405.860. 
Clinical Trials 
 
Effective for items and services furnished on or after September 19, 2000, Medicare covers 
the routine costs of qualifying clinical trials, as such costs are defined below, as well as 
reasonable and necessary items and services used to diagnose and treat complications arising 
from participation in all clinical trials. All other Medicare rules apply. 
 
Routine costs of a clinical trial include all items and services that are otherwise generally 
available to Medicare beneficiaries (i.e., there exists a benefit category, it is not statutorily 
excluded, and there is not a national noncoverage decision) that are provided in either the 
experimental or the control arms of a clinical trial except: 
• 
the investigational item or service, itself, 
• 
items and services provided solely to satisfy data collection and analysis needs and 
that are not used in the direct clinical management of the patient (e.g., monthly CT scans for 
a condition usually requiring only a single scan); and 
• 
items and services customarily provided by the research sponsors free of charge for 
any enrollee in the trial. 
 
 
 


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Routine costs in clinical trials include: 
 
• 
Items or services that are typically provided absent a clinical trial (e.g., conventional 
care); 
• 
Items or services required solely for the provision of the investigational item or 
service (e.g., administration of a noncovered chemotherapeutic agent), the clinically 
appropriate monitoring of the effects of the item or service, or the prevention of 
complications; and 
• 
Items or services needed for reasonable and necessary care arising from the provision 
of an investigational item or service--in particular, for the diagnosis or treatment of 
complications. 
  
This policy does not withdraw Medicare coverage for items and services that may be covered 
according to local medical review policies or the regulations on category B investigational 
device exemptions (IDE) found in 42 C.F.R. §405.201-405.215 and 
§411.15 and §411.406. For information about LMRPs, refer to www.lmrp.net, a searchable 
database of Medicare contractors' local policies. 
 
For noncovered items and services, including items and services for which Medicare payment 
is statutorily prohibited, Medicare only covers the treatment of complications arising from the 
delivery of the noncovered item or service and unrelated reasonable and necessary care. 
(Refer to MCM 2300.1 and MIM 3101.) However, if the item or service is not covered by 
virtue of a national noncoverage policy in the Coverage Issues Manual and is the focus of a 
qualifying clinical trial, the routine costs of the clinical trial (as defined above) will be 
covered by Medicare but the noncovered item or service, itself, will not. 
  
 
 


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Requirements for Medicare Coverage of Routine Costs 
 
Any clinical trial receiving Medicare coverage of routine costs must meet the following three 
requirements: 
 
1. The subject or purpose of the trial must be the evaluation of an item or service that 
falls within a Medicare benefit category (e.g., physicians' service, durable medical 
equipment, diagnostic test) and is not statutorily excluded from coverage (e.g., 
cosmetic surgery, hearing aids). 
2. The trial must not be designed exclusively to test toxicity or disease pathophysiology. 
It must have therapeutic intent. 
3. Trials of therapeutic interventions must enroll patients with diagnosed disease rather 
than healthy volunteers. Trials of diagnostic interventions may enroll healthy patients 
in order to have a proper control group. 
 
The three requirements above are insufficient by themselves to qualify a clinical trial for 
Medicare coverage of routine costs. Clinical trials also should have the following desirable 
characteristics; however, some trials, as described below, are presumed to meet these 
characteristics and are automatically qualified to receive Medicare coverage: 
 
1. The principal purpose of the trial is to test whether the intervention potentially 
improves the participants' health outcomes; 
2. The trial is well-supported by available scientific and medical information or it is 
intended to clarify or establish the health outcomes of interventions already in 
common clinical use; 
3. The trial does not unjustifiably duplicate existing studies; 
4. The trial design is appropriate to answer the research question being asked in the trial; 
5. The trial is sponsored by a credible organization or individual capable of executing 


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the proposed trial successfully;  
6. The trial is in compliance with Federal regulations relating to the protection of human 
subjects; and 
7. All aspects of the trial are conducted according to the appropriate standards of 
scientific integrity. 
Qualification Process for Clinical Trials 
 
Using the authority found in §1142 of the Act (cross-referenced in §1862(a)(1)(E) of the 
Act), the Agency for Healthcare Research and Quality (AHRQ) will convene a multi- agency 
Federal panel (the "panel") composed of representatives of the Department of Health and 
Human Services research agencies (National Institutes of Health (NIH), Centers for Disease 
Control and Prevention (CDC), the Food and Drug Administration (FDA), AHRQ, and the 
Office of Human Research Protection), and the research arms of the Department of Defense 
(DOD) and the Department of Veterans Affairs (VA) to develop qualifying criteria that will 
indicate a strong probability that a trial exhibits the desirable characteristics listed above. 
These criteria will be easily verifiable, and where possible, dichotomous. Trials that meet 
these qualifying criteria will receive Medicare coverage of their associated routine costs. This 
panel is not reviewing or approving individual trials. The multi-agency panel will meet 
periodically to review and evaluate the program and recommend any necessary refinements 
to CMS. 
 
Clinical trials that meet the qualifying criteria will receive Medicare coverage of routine costs 
after the trial's lead principal investigator certifies that the trial meets the criteria. This 
process will require the principal investigator to enroll the trial in a Medicare clinical trials 
registry, currently under development. 
 
Some clinical trials are automatically qualified to receive Medicare coverage of their routine 
costs because they have been deemed by AHRQ, in consultation with the other agencies 


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represented on the multi-agency panel to be highly likely to have the above- listed seven 
desirable characteristics of clinical trials. The principal investigators of these automatically 
qualified trials do not need to certify that the trials meet the qualifying criteria, but must 
enroll the trials in the Medicare clinical trials registry for administrative purposes, once the 
registry is established. 
 
Effective September 19, 2000, clinical trials that are deemed to be automatically qualified 
are: 
 
1. 
Trials funded by NIH, CDC, AHRQ, CMS, DOD, and VA; 
2. 
Trials supported by centers or cooperative groups that are funded by the NIH, CDC, 
AHRQ, CMS, DOD and VA; 
3. 
Trials conducted under an investigational new drug application (IND) reviewed by the 
FDA; and 
4. 
Drug trials that are exempt from having an IND under 21 CFR 312.2(b)(1) will be 
deemed automatically qualified until the qualifying criteria are developed and the 
certification process is in place. At that time the principal investigators of these trials must 
certify that the trials meet the qualifying criteria in order to maintain Medicare coverage of 
routine costs. This certification process will only affect the future status of the trial and will 
not be used to retroactively change the earlier deemed status. 
 
Medicare will cover the routine costs of qualifying trials that either have been deemed to be 
automatically qualified or have certified that they meet the qualifying criteria unless CMS's 
Chief Clinical Officer subsequently finds that a clinical trial does not meet the qualifying 
criteria or jeopardizes the safety or welfare of Medicare beneficiaries. 
 
Should CMS find that a trial's principal investigator misrepresented that the trial met the 
necessary qualifying criteria in order to gain Medicare coverage of routine costs, Medicare 


121 
Protocol  
B16-439   November 20, 2018 
 
 
coverage of the routine costs would be denied under §1862(a)(1)(E) of the Act. In the case of 
such a denial, the Medicare beneficiaries enrolled in the trial would not be held liable (i.e., 
would be held harmless from collection) for the costs consistent with the provisions of §1879, 
§1842(l), or §1834(j)(4) of the Act, as applicable. Where appropriate, the billing providers 
would be held liable for the costs and fraud investigations of the billing providers and the 
trial's principal investigator may be pursued. 
 
Medicare regulations require Medicare+Choice (M+C) organizations to follow CMS's 
national coverage decisions. This NCD raises special issues that require some modification of 
most M+C organizations' rules governing provision of items and services in and out of 
network. The items and services covered under this NCD are inextricably linked to the 
clinical trials with which they are associated and cannot be covered outside of the context of 
those clinical trials. M+C organizations therefore must cover these services regardless of 
whether they are available through in-network providers. M+C organizations may have 
reporting requirements when enrollees participate in clinical trials, in order to track and 
coordinate their members' care, but cannot require prior authorization or approval. For the 
initial implementation, Medicare contractors will pay providers directly on a fee for service 
basis for covered clinical trial services for beneficiaries enrolled in M+C plans. 


122 
 
 
 
Appendix C. Methods of Contraceptives 
 
The below listed methods meet the requirements for contraception as per the CTFG 
guidance.18 
 
If female, subject must be either postmenopausal defined as: 
● Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause. 
● Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L. 
 
OR 
● Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
 
           OR for Women of Childbearing Potential 
 ● Agreeing to practice ONE effective method of birth control while receiving G/P or 
G/P + SOF; TWO effective methods of birth control while receiving G/P + RBV, 
or G/P + SOF + RBV (as outlined in the subject information and consent form or 
other subject information documents), starting with Day 1 and for 30 days after 
stopping G/P (if randomized to non-RBV Arm), or G/P + SOF, or 6 months after 
stopping RBV (or per local RBV label). 
○ Progestogen-only hormonal contraception (oral, injectable, implantable) 
    associated with inhibition of ovulation, 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. 
○ Non-ethinyl estradiol hormone-releasing Intrauterine device (IUD) 
○ Non-ethinyl estradiol hormone-releasing Intrauterine hormone-releasing system 
(IUS) 
o Male or female condom with spermicide (male and female condom must not be 
used together) 
o Diaphragm with spermicide 
o Cervical cap with spermicide 
o Contraceptive sponge with spermicide 
○ 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 


123 
 
 
methods] and withdrawal are not acceptable). 
○sexually active with female partners only 
 
Male Subjects 
Subject must be surgically sterile (vasectomy with medical assessment confirming 
surgical success)  
       
     OR   
Have a female partner who is postmenopausal or permanently sterile 
                  (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) 
       
     OR  
if sexually active with female partner(s) of CBP must agree to practice ONE 
effective method of birth control while receiving G/P, or G/P + SOF; or TWO 
effective methods of birth control while receiving G/P + RBV, or G/P + SOF 
+RBV (as outlined in the subject information and consent form or other subject 
information documents), starting with Day 1 and for 30 days after stopping G/P 
(if randomized to non-RBV Arm), or G/P + SOF; or 7 months after stopping 
RBV (or per local RBV label). 
• 
Any approved and commercially available hormonal contraception for 
female partners  
• Any approved and commercially available, including any hormone-
eluting, devices for female partners of male subjects 
• Male or female condom with spermicide (male and female condom must 
not be used together) 
• Female partner using a diaphragm with spermicide 
• Female partner using a cervical cap with spermicide 
• 
Female partner using a contraceptive sponge with spermicide 
• True abstinence: Refraining from heterosexual intercourse-when this is 
in line with the preferred and usual lifestyle of the subject. (Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable). 
sexually active with male partners only 
 
Additionally, male subject agrees not to donate sperm from Study Day 1 through 7 months 
after the last dose of study drug (or as directed by the RBV prescribing information). 

SAP_001.pdf: 
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1 
1.0 
Title Page 
Statistical Analysis Plan 
 A Phase 3b, Multi-Center, Randomized, Open-Label, 
Pragmatic Study of Glecaprevir/Pibrentasvir (G/P) +/- 
Ribavirin for GT1 Subjects with Chronic Hepatitis C 
Previously Treated with an NS5A Inhibitor + 
Sofosbuvir Therapy  
 Clinical Study Protocol B16-439 
March 8, 2019 
Clinicaltrials.gov Identifer: 
NCT03092375


 
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2.0 
Table of Contents 
1.0 
Title Page .................................................................................. 1 
2.0 
Table of Contents ..................................................................... 2 
3.0 
Introduction ............................................................................. 6 
4.0 
Study Objectives, Design and Procedures ............................. 6 
4.1 
Objectives .................................................................................................. 6 
4.2 
Design Diagram ......................................................................................... 7 
4.3 
Sample Size ................................................................................................ 9 
4.4 
Primary Analysis ...................................................................................... 10 
5.0 
Analysis Populations ............................................................. 11 
5.1 
Definition for Analysis Populations ......................................................... 11 
5.1.1 
Intent-to-Treat (ITT) Population and Primary Efficacy Analysis 
Population ................................................................................................ 11 
5.1.2 
Modified Intent-to-Treat (mITT) Populations ......................................... 11 
5.1.3 
Safety Population ..................................................................................... 12 
6.0 
Analysis Conventions ............................................................ 13 
6.1 
Definition of Baseline and End of Treatment Assessment ...................... 13 
6.1.1 
Baseline .................................................................................................... 13 
6.1.2 
Study Days ............................................................................................... 14 
6.2 
Definition of Analysis Windows ............................................................. 15 
6.3 
Missing Data Imputation .......................................................................... 17 
7.0 
Demographics, Baseline Characteristics, Medical 
History, and Other Medications ........................................... 18 
7.1 
Demographic and Baseline Characteristics ............................................. 19 
7.2 
Medical History ....................................................................................... 22 
7.3 
Prior, Concomitant and Post-Treatment Medications .............................. 23 
8.0 
Patient Disposition ................................................................. 23 
9.0 
Study Drug Exposure and Compliance ............................... 25 
9.1 
Exposure .................................................................................................. 25 
9.2 
Compliance .............................................................................................. 26 
10.0 
Efficacy Analysis .................................................................... 26 


 
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10.1 
General Considerations ............................................................................ 26 
10.2 
Handling of Multiplicity .......................................................................... 30 
10.3 
Primary Efficacy Analysis ....................................................................... 30 
10.4 
Secondary Efficacy Analyses................................................................... 31 
10.5 
Efficacy Subgroup Analysis .................................................................... 33 
10.6 
Additional Efficacy Analyses .................................................................. 36 
10.7 
Resistance Analyses ................................................................................. 37 
11.0 
Safety Analysis ....................................................................... 37 
11.1 
General Considerations ............................................................................ 37 
11.2 
Analysis of Adverse Events ..................................................................... 37 
11.2.1 
Treatment-Emergent Adverse Events ...................................................... 38 
11.2.2 
Tabulations of Treatment-Emergent Adverse Events .............................. 38 
11.2.3 
Listing of Adverse Events ........................................................................ 41 
11.3 
Analysis of Laboratory Data .................................................................... 42 
11.3.1 
Variables and Criteria Defining Abnormality .......................................... 43 
11.3.2 
Statistical Methods ................................................................................... 43 
12.0 
References ............................................................................... 46 
Appendix 1. Resistance analysis plan (Version Date:   July 10, 
2017) ........................................................................................ 47 
 
List of Tables 
Table 1. 
Treatment Period Time Windows for Analyses Relating to HCV 
RNA, Resistance Endpoints, and Laboratory Measurements .................. 16 
Table 2. 
Post-Treatment Period Time Windows for Analyses Relating to 
HCV RNA and Resistance Endpoints ...................................................... 16 
Table 3. 
Post-Treatment Visit Windows for Safety Laboratory Data .................... 17 
Table 4. 
Amino Acid Positions by DAA Target for Patients with HCV 
Genotype 1 Infection for Subgroup Analysis .......................................... 20 
Table 5. 
Medical History eCRF ............................................................................. 22 
Table 6. 
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ...................................................................................................... 44 


 
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List of Figures 
Figure 1. 
Study Schematic ......................................................................................... 8 
 
 
 
 


 
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Glossary of Population Definitions 
ITT 
 
All subjects enrolled in the Main Study receiving at least 
one dose of study drug and according to the treatment arm 
to which they were randomized 
mITT 
 
All subjects enrolled in the Main Study receiving at least 
one dose of study drug and according to the treatment arm 
in which they were actually treated. 
mITT-GT 
 
mITT population, excluding subjects with HCV genotypes 
other than genotype 1. 
mITT-GT-VF 
 
mITT-GT population, further excluding subjects with non-
virological failures (e.g., lost to post-treatment follow-up, 
without virological outcome) 
Evaluable population 
Equivalent to the mITT population 
EP-RS 
All subjects enrolled in the Re-Treatment Sub-Study 
receiving at least one dose of study drug (G/P+SOF±RBV 
of a prescribed 16 week regimen, with ribavirin used at the 
discretion of the investigator) 
EP-RS-GT 
 
EP-RS population, excluding subjects with HCV genotypes 
other than genotype 1. 
EP-RS-GT-VF 
 
EP-RS-GT population, further excluding subjects with non-
virological failures (e.g., lost to post-treatment follow-up 
without virological outcome, death, etc.) 
Primary efficacy analysis 
population 
Equivalent to the mITT population 
Safety population 
Equivalent to the mITT population 
 
 
 
 
 


 
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3.0 
Introduction 
This document presents the detailed statistical analyses to be executed by the HCV-
TARGET Data Coordinating Center (DCC) for AbbVie Study B16-439.  This study is 
designed to support comparison of the efficacy, safety, and viral resistance of 
glecaprevir and pibrentasvir (G/P) for 12 weeks to that of G/P for 16 weeks, with and 
without addition of RBV to the treatment regimen. Study subjects will be restricted to 
NS5A-inhibitor plus sofosbuvir ± RBV treatment-experienced adults with HCV 
genotype 1 (GT1) infection and with either no cirrhosis or compensated cirrhosis. An 
overarching description of the study is presented in the Study Protocol (1).  
This Statistical Analysis Plan (SAP) presents formal guidance for the statistical 
programming to produce the results which will address the analyses conventions of the 
study.  Analyses will be performed using SAS® Version 9.4 (SAS Institute, Inc., Cary, 
NC) under the Microsoft Windows operating system.  
4.0 
Study Objectives, Design and Procedures 
4.1 
Objectives 
The primary objectives of this study are to: 
1. Compare the efficacy (SVR12) of G/P administered for 12 weeks to non-cirrhotic 
HCV GT1-infected subjects who are treatment-experienced with a NS5A 
inhibitor+SOF±RBV regimen (Arm A) vs. G/P given for 16 weeks (Arm B)  
2. Compare the efficacy (SVR12) of G/P plus RBV given for 12 weeks to HCV 
GT1-infected subjects with compensated cirrhosis and who are treatment-
experienced with a NS5A inhibitor+SOF±RBV regimen (Arm C) vs. G/P given 
for 16 weeks (Arm D)  


 
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3. Assess the safety and tolerability of G/P with or without RBV, in these subjects 
with chronic HCV GT1 infection and treatment-experienced with a NS5A 
inhibitor+SOF±RBV regimen.  
The secondary objectives are to assess: 
1. the difference in efficacy (SVR12) of G/P±RBV given for 12 weeks (Arms A+C) 
versus G/P±RBV given for 16 weeks (Arms B+D). 
2. the differences in the percentages of subjects with on-treatment virologic failure 
for non-cirrhotic subjects (Arm A vs Arm B) and subjects with compensated 
cirrhosis (Arm C vs Arm D);  
3. the differences in the percentages of subjects with post-treatment relapse for non-
cirrhotic subjects (Arm A vs Arm B) and subjects with compensated cirrhosis 
(Arm C vs Arm D) 
The additional objectives are  
1) to assess the impact of baseline host and viral factors on treatment outcomes,  
2) the emergence and persistence of viral variants in those with treatment failure in this 
treatment regimen, and 
3)  the safety and efficacy of the re-treatment regimen of G/P+SOF±RBV. 
4.2 
Design Diagram 
This Phase 3b study will embrace a multi-center, randomized, open-label, pragmatic 
evaluation of G/P +/- RBV for 12 weeks or G/P 16 weeks in subjects with chronic HCV 
GT1 infection who are treatment experienced with a prior NS5A inhibitor+SOF±RBV 
therapy.   


 
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The main part of this study consists of a Treatment Period of 12 weeks or 16 weeks and 
a Post-Treatment Period of 12 weeks after the last dose of study drug (Figure 1). 
 
Figure 1. 
Study Schematic for the Main Study 
                                 
Randomization will be stratified by HCV genotype 1 subtype (1b or non-1b).  
• HCV GT1 non-cirrhotic subjects (up to 150): randomized 2:1 to Arms A or B..   
• HCV GT1 cirrhotic subjects (up to 75): randomized 1:1 to Arm C or D.  
The initial study design did not exclude patients with historical PI exposure prior to the 
NS5A-inhibitor exposure as PI resistance has been shown to quickly revert to wild 
types, but did exclude only those who received a PI in combination with a NS5a.  Since 
the initial study launch, G/P has been approved by the FDA and was given a label with 
16 weeks of therapy for NS5A experienced, PI naïve patients only.. Thus, to minimize 
treatment failure in this population and more accurately reflect FDA label duration, 
patients with any prior PI exposure will be excluded from further recruitment into the 


 
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study and any patient already enrolled or randomized to a 12- week arm will have their 
treatment extended to 16 weeks duration. 
Subjects who experience virologic failure in the Main Study will have the option to to 
enter the Re-Treatment Sub-Study and receive G/P+SOF±RBV with the start of 
retreatment within 1 year after experiencing G/P failure. Patients who are confirmed by 
phylogenetic analyses to having been re-infected rather than experiencing virological 
failure are excluded. The Treatment Period for the Re-Treatment Sub-Study will be for 
a total of 16 weeks. The Post-Treatment Period for the Re-Treatment Sub-Study will be 
12 weeks following the last dose of the re-treatment regimen. 
 
4.3 
Sample Size 
The objective of this study is to enroll up to 225 subjects.   
For the comparison between Arm A and Arm B in non-cirrhotic subjects, if the 
observed SVR12 rate in Arm B is 92%-96%, with 100 subjects in Arm A and 50 
subjects in Arm B, the half widths of 95% confidence interval of the difference between 
SVR12 rates are displayed in the table below:   
SVR12 in Arm B  
92%  
93%  
94%  
95%  
96%  
Half width (SVR12 in Arm A = SVR12 in Arm  
B)  
0.092 
0.087 
0.081 
0.074 
0.067 
Half width (SVR12 in Arm A = SVR12 in Arm B  
– 1%)  
0.094 
0.088 
0.083 
0.076 
0.069 
Half width (SVR12 in Arm A = SVR12 in Arm B  
– 2%)  
0.095 
0.090 
0.085 
0.078 
0.072 
For the comparison between Arm C and Arm D in cirrhotic subjects, if the observed 
SVR12 rate in Arm D is 94%-98%, with 40 subjects in Arm C and 40 subjects in Arm 


 
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D, the half widths of the 95% confidence interval of the difference between SVR12 
rates are displayed in the table below:  
SVR12 in Arm D  
94%  
95%  96%  
97%  
98%  
Half width (SVR12 in Arm C = SVR12 in Arm D)  
0.104 
0.096 0.086 
0.075 
0.061 
Half width (SVR12 in Arm C= SVR12 in Arm D – 1%)  0.108 
0.100 0.091 
0.081 
0.068 
Half width (SVR12 in Arm C = SVR12 in Arm D – 2%)  0.112 
0.104 0.095 
0.086 
0.075 
  
In a previous study (ref. study M15-410), subjects with prior NS5A inhibitor experience 
only (i.e., PI naïve) had an SVR12 rate of 94.4% for 16 weeks treatment duration.  This 
SVR12 rate would give half widths of 95% confidence intervals of ≤ 11% in most cases 
where Arm A or Arm C are no more that 1% worse than Arm B or Arm D, respectively.  
 
4.4 
Primary Analysis 
Primary data analysis will commence when all subjects in the Main Study have 
completed the Post Treatment Week 12 Visit or have prematurely discontinued the 
study. The data for subjects treated in the Main Study will be preserved after data 
cleaning is completed for the Main study and will be analyzed for the Primary analysis 
clinical study report. Data from the Re-Treatment Sub-Study will be analyzed 
separately. 
An analysis-level dataset will be created, subjected to thorough inter- and intra-
variable evaluation, and independent code assessment to ensure optimal data integrity 
prior to certification for subsequent statistical summaries and analyses. All descriptive 
and inferential statistical evaluations (as applicable) and confidence intervals will be 
two-sided with a significance level (α) of 0.05. Descriptive statistics, including but not 
restricted to number of observations (N), mean, and standard deviation (SD) for 


 
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continuous variables and counts and percentages for discrete variables, will be 
generated to support summary data tabulations and/or graphics.  
 
 
5.0 
Analysis Populations 
5.1 
Definition for Analysis Populations 
5.1.1 
Intention-to-Treat (ITT) Population and Primary Efficacy 
Analysis Population 
 
All randomized subjects who receive at least one dose of study drug in the Main Study 
will comprise the ITT population.  However, in accordance with Protocol Amendment 
10/13/17 the Primary safety and efficacy analyses will be performed on the study 
population “as treated” and summarized according to the treatment arm in which they 
had actually received treatment. The primary efficacy analysis dataset in this pragmatic 
trial, comprised of subjects as treated, will be referred to elsewhere in this document as 
the modified ITT (mITT) population. The traditional ITT population, reflecting the 
patients’ randomized treatment arm, will be employed, along with other modified ITT 
populations, in sensitivity analyses to be discussed later in this document.  
 
5.1.2 
Modified Intent-to-Treat (mITT) Populations 
Sensitivity analyses of the primary endpoint of the Main study will be performed on the 
modified ITT populations as defined below: 


 
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Modified ITT- Genotype (mITT -GT) Population 
As stated in the previous section, the mITT population (or “as treated”) includes all 
subjects representing their actual study regimen and who received at least one dose of 
study drug. The mITT-GT population includes subjects from the mITT population but 
excludes subjects with genotype other than GT1 infection.  
Modified ITT- Genotype and Virologic Failure (mITT- GT-VF) Population 
mITT-GT-VF includes all subjects in the mITT-GT population defined above, but 
excludes subjects who did not achieve SVR12 for reasons other than virologic failure. 
Demographic analyses will also be performed on the mITT population(s). 
5.1.3 
Patient Populations for the Re-Treatment Sub-Study (EP-RS)  
Analyses in the Re-Treatment Sub-Study will be performed overall on the EP-RS 
population, which is defined as all subjects who receive at least one dose of the re-
treatment drug with or without ribavirin as specific by the investigator. 
Sensitivity analyses of the SVR12 endpoint will be performed for the Re-Treatment Sub-
Study on the EP-RS population modified to exclude subjects other than GT1 (EP-RS-
GT) and further modified to exclude subjects who did not achieve SVR12 for reasons 
other than virologic failure (EP-RS-GT-VF). 
5.1.4 
Safety Population 
For the Main Study, all subjects who receive at least one dose of study drug will be 
included in the safety analyses according to their actual treatment arm (mITT≡Safety 
population).   


 
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Safety analyses for the Re-Treatment Sub-Study will be performed on the overall EP-RS 
population as defined above. 
 
6.0 
Analysis Conventions 
6.1 
Definition of Baseline and End of Treatment 
Assessment 
6.1.1 
Baseline 
The baseline result is defined for the Main study as the last non-missing measurement 
collected prior to administering the first dose of study drug.  For subjects who enrolled 
in the Re-Treatment Sub-Study, baseline result is defined as the last non-missing 
measurement collected prior to administering the first dose of re-treatment drug. The 
protocol specifies that all Day 1 assessments shall be performed prior to administering 
the first dose of study drug.  Therefore, all Day 1 assessments for which time is not 
recorded will be assumed to be pre-dose. In this case, the baseline value will be the last 
non-missing result, for a given measurement, collected on or before the first day of 
study drug administration.   
All Day 1 assessments, for which time is recorded, must be before the time of first dose 
to be considered baseline. The last non-missing measurement collected before the date 
and time of the first dose of study drug will be considered the baseline result.  In 
instances where multiple measurements, made prior to dosing, are recorded on the same 
date and with the same time, or without time, the average of these measurements will be 
considered the baseline result.  This same baseline result will be assigned for analyses of 
the Treatment and Post-Treatment Periods. 


 
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Safety assessments related to a serious adverse event occurring on the day of first dose 
of study drug are excluded when applying this algorithm.  
For subjects who enroll in the Re-Treatment Sub-Study and who experience virologic 
failure during the Re-Treatment or Post-Re-Treatment periods, HCV NS3 and NS5A 
resistance analyses will be conducted on the plasma sample collected at the last visit 
prior to the start of the re-treatment and on the first available sample with an HCV viral 
load ≥1000 IU/mL after the time of virologic failure. 
6.1.2 
Study Days 
Study days are determined for each time point (recorded in days) relative to 
administration of the first dose of study drug.  Study days are negative when the time 
point of interest is prior to the first study drug dose day.  Similarly, study days are 
positive 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 are recorded as 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. 


 
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Final Post-Treatment Value 
The final post-treatment value for each subject shall be the last non-missing 
measurement recorded after Study Drug End Day 2 and on or before final study visit. 
6.2 
Definition of Analysis Windows 
For efficacy and resistance analyses for both the Main Study and the Re-Treatment Sub-
Study, the time windows specified in Table 1 and Table 2 represent guidelines for 
assignment of efficacy data to protocol-specified time points during the treatment and 
post-treatment periods, respectively.  All time points and corresponding time windows 
are based on the date/time of blood specimen collection. 
For laboratory data, the time window specified in Table 1 and Table 3 describes how 
data are assigned to protocol specified time points.  
If more than one assessment is included in a time window, the assessment closest 
(except in analyses of SVR outcomes) to the nominal day 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 laboratory measurements are made on the same day for a particular safety or 
vital sign parameter, the average of the values will be used to calculate descriptive 
statistics for that parameter and to support analyses of the mean change from baseline.   


 
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Table 1. 
Treatment Period Time Windows for Analyses Relating to HCV 
RNA, Resistance Endpoints, and Laboratory Measurements  
Scheduled Visit 
Nominal Day (Study Day) 
Time Window (Study Day Range) 
Day 1/Baselinea 
1 
≤ 1a 
Week 4 
28 
14 to 42 
Week 8 
56 
43 to 70 
Week 12 
84 
71 to 98 
Week 16 b 
112 
99 to 126 
Final Treatment Visitc 
2 to ≤ 2 days after last dose of study drug 
a. 
Day of first dose of study drug. 
b. 
For 16-week treatment arms,  and subjects of the Re-Treatment Sub-Study. 
c. 
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2. 
Note: 
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.   
 
Table 2. 
Post-Treatment Period Time Windows for Analyses Relating to 
HCV RNA and Resistance Endpoints 
Scheduled Visita 
Nominal Day 
(Study Drug End Day) 
Time Window 
(Study Drug End Day Range) 
Post-Treatment Week 4 
28 
14 to 56 
Post-Treatment Week 12 
84 
57 to 126 
SVR4 
28 
3 to 56 
SVR12b 
84 
57 to 126 
 
 
 
a. 
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug. 
b. 
For SVR windows, the last value in the window will be used. 
Note: 
The result closest to the scheduled time point will be used, except for SVR4, and SVR12.  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 3. 
Post-Treatment Visit Windows for Safety Laboratory Data  
Scheduled Time 
Nominal Day 
(Study Drug End Day) 
Time Window 
(Study Drug End Days Range) 
Post-Treatment Week 4 
28 
14 to 56 
Post-Treatment Week 12 
84 
57 to 126 
Final Post-Treatment Visita 
> 2 days after 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 are recorded at every PT visit if available in the record; hematology, chemistry, urinalysis, and 
coagulation panels are collected at PTW4 and PTDC (if subject discontinued prior to PTW4).   
 
6.3 
Missing Data Imputation 
Missing SVR Result Imputation 
In this study, it is expected that HCV RNA results will be provided for all subjects by a 
central laboratory. In that regard and where feasible, missing HCV RNA results for 
specific subject visits will be imputed using a backward imputation method according to 
the following backward imputation rules: 
• If the most proximate HCV RNA value beyond the SVR window is “Not 
quantified” or “Target not detected”, then that result will be used to replace a 
missing HCV RNA value within the preceding SVR window.  
• If an HCV RNA value within the SVR window is still missing after performing 
backward imputation, then an HCV RNA value within the SVR window from a 
local laboratory, if present, will be imputed; otherwise, the HCV RNA value in the 
window will remain missing and the SVR status of that patient shall be interpreted 
as a failure. 


 
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• HCV RNA values collected during the Re-Treatment Sub-Study will not be 
imputed backward for the SVR analyses during the Main Study. That is, subjects 
who experience virologic failure in the Main Study will remain as non-SVR for 
the Main Study even if cured in the Re-Treatment Sub-Study. 
Regardless of the imputation method employed, all HCV RNA values for a subject who 
starts a different treatment for HCV measured on or after the start date of the new HCV 
treatment, will be excluded from subsequent analyses (other than the protocol-specified 
re-treatment which will be analyzed separately).  The subject will be considered a 
failure in summaries of viral response at all time points on the current study once new 
HCV treatment has commenced.  
Missing Data Imputation for Virologic Failure 
If HCV RNA results from the central laboratory are missing but a local laboratory result 
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.  
7.0 
Demographics, Baseline Characteristics, Medical 
History, and Other Medications 
Data from the safety population will be used to create demographic and baseline 
characteristic summaries as described below based on the final assigned treatment arm 
for the Main Study. The safety population will be used to summarize medical history 
and previous, concomitant, and post-treatment medications for each treatment arm for 
the Main Study. Similar summaries will be created for the subjects who enroll in the Re-
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7.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristic data will be summarized for all treated subjects 
by treatment arm. Summary statistics (N, mean, median, SD, and range) will be 
generated, by treatment arm, for continuous variables (e.g., age and BMI); number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).  
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, race, black race (black or non-
black), ethnicity, age category (< 65 or ≥ 65 years; < 75 or ≥ 75 years), BMI category (< 
30 or ≥ 30 kg/m2). Continuous baseline characteristics include log10 HCV RNA, eGFR, 
platelet count, albumin, APRI, FIB-4, AST, ALT, ALT/AST and total bilirubin for all 
subjects. Categorical baseline characteristics include:  
● HCV genotype 1 subtype (as determined by the central laboratory); 
● Type of previous regimen (SOF/DCV, SOF/LDV, SOF/VEL, Other); 
● HCV mono-infected vs. HCV/HIV-1 co-infected; 
● HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL);  
● Cirrhosis status (yes/no); 
● History of HCC (yes/no); 
● Child Pugh score for cirrhotic patients only (A, B) 
● Platelet count (< 100 or ≥ 100 × 103/L);  
● Albumin (< 3.5 or ≥ 3.5 g/dL);  
● ALT/AST (< 1 or ≥ 1) 
● eGFR (< 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2); 
● History of diabetes (yes/no); 
● Post organ transplant by transplanted organ (yes/no); 
● Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no); 


 
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● Baseline resistance (as described below). 
 
For the baseline resistance analysis and efficacy subgroup analyses, baseline NS3 and 
NS5A variants are defined based on ≥ 15% NGS detection threshold.  Amino acid 
positions of NS3 and NS5A in genotype 1 subjects for subgroup analysis are listed in 
Table 4. 
Table 4. 
Amino Acid Positions by DAA Target for Patients with HCV 
Genotype 1 Infection for Subgroup Analysis 
Target 
Genotype 
Subgroup Amino Acid Positions 
(All Variants at These Positions Are to Be Included) 
Other Specific 
Variants 
NS3 
1 
155, 156, 168 
 
NS5A 
1a 
28, 30, 31, 93 
H58D, E62A 
 
1b 
31, 93 
 
 
The number and percentage of subjects by treatment arm in the mITT and mITT-GT-VF 
populations will be summarized for the presence of baseline resistance-associated 
variants of: 
● Any NS3 variant at baseline (yes/no); 
● Any NS5A variant at baseline (yes/no); 
● Any NS3 variant at baseline or any NS5A variant at baseline (yes/no); 
● Any NS3 variant at baseline and any NS5A variant at baseline (yes/no). 
● Any NS3 variant at baseline (yes/no) only (without baseline NS5A variants); 
● Any NS5A variant at baseline (yes/no) only (without baseline NS3 variants). 
Differences in proportions of discrete variables will be compared across treatment arms 
and their statistical significance determined with a Mantel-Haenszel chi-square test.  
Comparisons of continuous variables across treatment arms will be conducted with 
general linear modeling or one-way analysis of variance (ANOVA). 


 
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Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI. All patients will be evaluated for the presence of cirrhosis and 
the final assessment will be made by site PI. The presence of cirrhosis is defined at 
screening by biopsy (liver biopsy results up to 3 years prior to screening are acceptable 
if the results showed no cirrhosis) and/or a combination of clinical, laboratory, 
elastography, and imaging criteria established a priori. Patients will be determined to 
have cirrhosis if they have:  
1) Evidence of stage 4 (Metavir) fibrosis by liver biopsy at any time* prior to therapy 
(for post-transplant recipients, biopsy staging should be from the allograft);  
2) Evidence of stage 3 (Metavir) fibrosis by liver biopsy prior to therapy with any one of 
the following criteria (for post-transplant recipients, biopsy staging should be from the 
allograft);  
• Platelet count <140x 109/L during screening,  
• Presence of esophageal varices on esophagogastroduodenoscopy at any time 
• Evidence of cirrhosis and/or portal hypertension by imaging at any time  
• FibroTest® >0.75,  
• Vibration-Controlled Transient Elastography (VCTE) >12.5 kPa, or equivalent 
magnetic resonance elastography (MRE) compatible with stage 4 fibrosis  
 
3) In the absence of liver biopsy, any TWO of the following criteria:  
• Platelets count <140x 109/L during screening,  
• Presence of esophageal varices on esophagogastroduodenoscopy at any time,  
• Evidence of cirrhosis and/or portal hypertension by imaging studies at any time,  
• FibroTest® >0.75,  
• AST to Platelet Ratio Index (APRI)>2 during screening 
• Vibration-Controlled Transient Elastography (VCTE) >12.5 kPa, or equivalent 
MRE compatible with stage 4 fibrosis  
 
 
 


 
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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 =
AST Level (U/L)
AST (Upper Limit of Normal)(U/L)
Platelet Count (109/L)
 × 100 
 
FIB −4 =
Age (years) ×  AST Level (U/L)
Platelet Count (109/L) × ඥALT (U/L)
 
History of diabetes will be based on the Medical History (MH) eCRF, as defined in 
Table 5. 
 
Table 5. 
Medical History eCRF 
 
Medical History eCRF 
Subgroup 
Body System 
Condition/Diagnosis 
Diabetes 
Metabolic 
Diabetes mellitus 
 
 
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 
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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.  A concomitant medication is defined as: 
• Any medication that was 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 as entered on the “Concomitant 
Medications” eCRF. 
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized for each 
treatment arm by generic drug name based on the WHO Drug Dictionary.  Prior 
medications will be divided by the following categories: 
● The prior HCV medications for all subjects; 
● All other prior medications for all treated subjects. 
 
8.0 
Patient Disposition 
The number and percentage of subjects who screen failed for any reason, and for each 
screen fail reason, will be summarized for all subjects who screen failed. 


 
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The number of subjects in each of the following categories will be summarized by 
investigator for each treatment arm and overall.   
● Randomized subjects; 
● Subjects who took at least one dose of the Main study drug; 
● Subjects who completed the Main study drug; 
● Subjects who prematurely discontinued the Main study drug;  
 
A summary of the disposition of subjects in ITT population (by arm as randomized) will 
be created for the subjects who enroll in the main study. 
 
A summary of the disposition of subjects will be created for the subjects who enroll in 
the Re-Treatment Sub-Study: 
• Subjects who took at least one dose of retreatment regimen in the retreatment-
sub-study 
• Subjects who completed the re-treatment sub-study 
• Subjects who prematurely discontinued the re-treatment sub-study 
 
The number and percentage of subjects who discontinued study drug prematurely will 
be summarized by reason (per eCRF) for each treatment arm and overall for the Main 
Study.  Similar summaries will be provided for discontinuations from the study. A 
similar summary of the reasons for discontinuation of retreatment drug will be created 
for the subjects who enroll in the Re-Treatment Sub-Study. 
 
The number and percentage of subjects with reported study drug interruptions will be 
summarized by treatment arm for the Main Study. 


 
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Reasons for study drug interruptions will be presented in the CSR listings. 
 
9.0 
Study Drug Exposure and Compliance 
9.1 
Exposure 
The duration of exposure to study drug is defined for each subject as the last study drug 
dose date minus the first study drug dose date plus 1 day. If any study drug interruptions 
occurred, the days on which subject did not take study drug will be subtracted from the 
duration of exposure. The duration of exposure to study drug will be summarized by 
actual treatment arm and overall for the Main Study on the safety population.  A similar 
summary will be created for the subjects who enroll in the Re-Treatment Sub-Study. 
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 15 days 
● 16 to 30 days 
● 31 to 45 days 
● 46 to 60 days 
● 61 to 76 days 
● 77 to 90 days 
● 91-104 days 
● >= 105 days 
 


 
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9.2 
Compliance 
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of tablets dispensed and returned is recorded.  The compliance for study drug 
will be calculated as the percentage of tablets taken by the subject relative to the total 
tablets expected to be taken.  The total number of tablets expected to be taken will be 
the protocol-specified total number of tablets specified in the Treatment Period (date of 
last dose of study drug – date of first dose of study drug + 1).  The Treatment Period 
will not be adjusted for Study drug interruptions recorded on the eCRF.   
A subject is considered ‘compliant’ if this percentage is between 80% and 120%.  
Compliance will be listed for each subject, and will be summarized by treatment arm as 
mean, median, standard deviation, minimum, and maximum.  The percentage of 
compliant subjects will also be summarized for each treatment arm, based on data as 
recorded (i.e., patients missing any compliance data should not be included).  
10.0 
Efficacy Analysis 
10.1 
General Considerations 
Plasma HCV RNA levels will be determined by certified, central, clinical laboratories 
for each sample collected 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 classified as detectable but are not quantifiable are reported as "< 
15 IU/ML "; those that are not detected are reported as "TARGET 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 ≥ LLOQ are all quantifiable values of 15 IU/mL or greater. 


 
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Missing HCV RNA endpoints of SVR, where encountered in the dataset, will be 
resolved by imputation as described in Section 6.3.   
Definitions for Efficacy Endpoints 
A confirmed quantifiable result during treatment is defined as any two, time-sequential 
and consecutive HCV RNA measurements at or above LLOQ (or 100 IU/mL for 
Breakthrough), either both during treatment, or at the end of treatment measurement 
and at the next consecutive post-treatment measurement.  A confirmed quantifiable 
post-treatment value is defined as any two consecutive post-treatment HCV RNA 
measurements at or above LLOQ. Specific virologic end points, as applied in this 
analysis plan, are defined in detail below.  
Breakthrough: Either 1) Confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < 
LLOQ at some point during the Treatment Period or confirmed increase from nadir in 
HCV RNA (two consecutive measurements > 1 log10 IU/mL above nadir) at any time 
point during the Treatment Period, or 2) a single value indicating viral breakthrough (≥ 
100 IU/mL or > 1 log10 above nadir), followed by patient status of ‘Lost to Follow-up’, 
the latter not requiring confirmation by a proximate measurement). 
EOT failure: HCV RNA ≥ LLOQ at end of treatment and following at least 6 weeks of 
treatment. The HCV RNA value must reflect a plasma specimen collected on or after 
Study Drug Day 36. 
On-treatment virologic failure: Either Breakthrough or EOT (end of treatment) 
failure. 


 
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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 result prior 
to or within the SVR12 window.  
Relapse: confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last dose of study drug (up to and including the SVR12 assessment time point) for a 
subject with HCV RNA < LLOQ at Final Treatment Visit and who completed 
treatment, excluding re-infection as described below.  
Analyses of relapse will include only subjects who have at least one post-treatment 
HCV RNA result.  Completion of treatment is defined as study drug duration of 77 days 
or greater for subjects receiving 12 weeks of treatment, and 105 days or greater for 
subjects receiving 16 weeks of treatment.  If the last available post-treatment value is ≥ 
LLOQ, then the subject will be categorized as a relapse (i.e., confirmation not required).   
HCV re-infection in a subject is defined as: 1) confirmed HCV RNA ≥ LLOQ after the 
end of treatment but for whom HCV RNA < LLOQ at Final Treatment Visit, and 2) 
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.  Re-infection 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 results are unavailable, 


 
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HCV re-infection may be determined with a confirmed HCV genotype or subtype 
switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger assay. 
Post-treatment relapse is defined as described earlier and with no genotype, subtype, or 
clade switch compared with baseline as determined by phylogenetic analysis of the NS3 
or NS5A gene sequences.  If phylogenetic analysis results are unavailable, the subject 
will be categorized 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.  
Treatment failure 
Subjects who do not achieve SVR12 will be assigned type of SVR12 ‘Non-Response’ 
according to the following assignment criteria: 
1. On-treatment virologic failure, per definition above; 
2. HCV re-infection, per definition 
3. Relapse for subjects who complete treatment; 
4. Premature discontinuation of study drug without on-treatment virologic failure 
defined as: 
a. SVR12 non-responder who prematurely discontinued study drug (study 
drug duration < 77 days for subjects receiving 12 weeks of treatment , and 
< 105 days for subjects receiving 16 weeks of treatment) and  
b. On-treatment virologic failure definition not met; 
5. Missing follow-up data in the SVR12 window according to: 


 
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a. Any subject who completed study drug without a virologic result in the 
SVR12 window after applying the imputation rules and  
b. Not meeting the definitions of 1, 2, 3, or 4 
6. Other (i.e., SVR12 non-response not meeting the definitions of 1 – 5) 
 
10.2 
Handling of Multiplicity 
The primary efficacy endpoints (Section 10.3) of the difference in SVR12 rates will be 
assessed for GT1 non-cirrhotic and cirrhotic populations separately. Each of the primary 
endpoints will use 95% confidence intervals without multiplicity adjustment as they are 
on two independent populations. 
10.3 
Primary Efficacy Analysis 
The primary endpoints of this study are:   
1. The difference in SVR12 rates between G/P given for 12 weeks (Arm A) and 
G/P given for 16 weeks (Arm B) to non-cirrhotic GT1infected subjects who are 
treatment-experienced with a NS5A inhibitor+SOF±RBV regimen 
2. The difference in SVR12 rates between G/P plus RBV given for 12 weeks (Arm 
C) and G/P given for 16 weeks (Arm D) to GT1infected subjects with 
compensated cirrhosis and who are treatment-experienced with a NS5A 
inhibitor+SOF±RBV regimen 
 
The difference in SVR12 rates will be summarized with a two-sided 95% confidence 
interval for: 1) the comparison between Arm A and Arm B in non-cirrhotic subjects and  
2) the comparison between Arm C and Arm D in cirrhotic subjects. The number and 


 
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percentage of subject achieving SVR12 by treatment arm will also be summarized with 
a two-sided 95% confidence interval. The confidence intervals for the differences in 
SVR12 rates will be calculated using Wilson's score method. The confidence interval for 
the SVR12 rates by treatment arm will be calculated using the normal approximation to 
the binomial distribution if the number of subjects who failed to achieve SVR12 is at 
least 5. If the number of subjects who failed to achieve SVR12 is less than 5, Wilson’s 
score method will be used instead. A summary of reasons for SVR12 non-response 
(e.g., on-treatment virologic failure, re-infection, relapse, other) will be provided. 
 
10.4 
Secondary Efficacy Analyses 
The secondary endpoints are:  
  
1. The difference in SVR12 rates between G/P given for 12 weeks (Arm A 
and C combined) and G/P given for 16 weeks (Arm B and D combined), 
further differentiated within the combined arms by genetic subtype (1b vs. 
non-1b). 
2. 
The difference in the percentage of subjects with on-treatment virologic 
failure (defined as On-treatment virologic failure in Section 10.1) 
between Arm A and Arm B in non-cirrhotic subjects, and between Arm C 
and Arm D in cirrhotic subjects;  
3. 
The difference in the percentage of subjects with post-treatment relapse 
(defined as relapse in Section 10.1) between Arm A and Arm B in non-
cirrhotic subjects, and between Arm C and Arm D in cirrhotic subjects.   
 


 
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The difference in SVR12 rates will be summarized with a two-sided 95% confidence 
interval using Wilson’s score method the comparison between 12 week (Arms A+C) and 
16 week (Arms B+D) treatment durations. The difference in the percentage of subjects 
with on-treatment virologic failure and post-treatment relapse between Arms A and B 
and between Arms C and D will be summarized with two-sided 95% Wilson score 
intervals, as will the percentage of subjects with on-treatment virologic failure and post-
treatment relapse in each arm.  
Treatment effects will be evaluated based on a 2-sided significance level (α= 0.050, 
rounded to three decimal places), and all efficacy analyses will be performed on the 
mITT population, unless otherwise specified.   
Sensitivity analyses will be performed that summarize the difference, and provide 95% 
Wilson’s score confidence intervals of the percentage of subjects in the ITT, mITT-GT 
and mITT-GT-VF populations achieving SVR12 between Arm A and Arm B in non-
cirrhotic subjects, and between Arm C and Arm D in cirrhotic subjects, as applicable.   
The following sensitivity analyses will assess difference in SVR12 rates between 
treatment arms or treatment durations.  
● Differences in proportions of subjects achieving SVR12 will be computed 
between Arms A and B and Arms C and D using contrasts within a logistic 
regression model. Treatment arm and HCV genotype 1 subtype as contrast 
factor;  baseline log10 HCV RNA level will be included in the model as a 
continuous covariate. Contrast and parameter estimates will also be reported 
for each arm pair (A/B or C/D) 
● The difference in SVR12 rates between Arms A and B and Arms C and D will 
be determined using a stratum-adjusted Mantel-Haenszel (MH) proportion 


 
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with a continuity correction for variance, adjusting for each of the 
randomization stratum. 
● The difference in proportions of SVR12 rates will be determined for 12-week 
vs. 16-week treatment durations using contrasts within a logistic regression 
model with cirrhosis status and HCV genotype 1 subtype (e.g., 1b, non-1b) as 
factors. Contrast and parameter estimates will also be reported. 
 
The SVR12 rates and accompanying 95% Wilsons’ score method confidence intervals) 
in the EP-RS-GT and EP-RS-GT-VF populations overall will also be calculated, 
10.5 
Efficacy Subgroup Analysis 
In the mITT population for the Main study, association of the proportions of subjects 
with SVR12 with each of the following subgroups will be compared across treatment 
arms (Arms A and B, and Arm C and D separately) using Zelen’s exact tests.  In 
addition, two-sided 95% Wilson score intervals will be calculated for the difference 
between Arms A and B and Arms C and D, for the following subgroups:  
  
• 
HCV GT1 subtype (1b or non-1b); 
• 
Treatment duration (12-week or 16-week) 
• 
Most recent HCV treatment history (i.e., specific NS5A inhibitor with SOF 
combination); 
• 
Time from end of prior NS5A inhibitor +SOF combination treatment to start 
of main study treatment with G/P (e.g., <365 days and >365 days). 
• 
Sex (male or female); 
• 
Age (< 65 or ≥ 65 years; < 75 or ≥ 75 years); 
• 
Race (White, Black/African-American, Asian, or other) and (black or 
non-black); 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 


 
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• 
BMI (< 30 or ≥ 30 kg/m2); 
• 
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL); 
• 
Baseline platelet count (< 100 or ≥ 100 × 109/L); 
• 
Baseline albumin (< 35 or ≥ 35 g/L); 
• 
Baseline APRI  (< 1.0 or ≥ 1.0); 
• 
Baseline FIB-4 (< 1.45, ≥ 1.45 to ≤ 3.25, or > 3.25); 
• 
Baseline AST/ALT ratio (< 1.0 or ≥ 1.0); 
• 
Baseline Child-Pugh Score (A/B; for cirrhotic subjects only); 
• 
History of concomitant diseases: (a) diabetes (yes/no), (b) HIV co-infection 
(yes/no) (c) post-organ transplant by transplanted organ (yes/no) 
HCC(yes/no); 
• 
Concomitant use of Proton Pump inhibitors (yes/no); 
• 
DAA compliance (yes/no);  
• 
Baseline resistance polymorphisms (any NS3/4A variant [yes/no]; any NS5A 
variant [yes/no]; any NS3/4A and any NS5A [yes/no], any NS3/4A or any 
NS5A [yes/no]) and [NS3/4A only, NS5A only, both NS3/4A and NS5A, or 
none]). 
 
Within each subgroup, the percentage of subjects meeting SVR12 within each arm and 
the difference between treatment arms will be calculated, as will the corresponding two-
sided 95% Wilson score intervals. Also within each subgroup, the percentage of subjects 
meeting SVR12 within combined Arm A+ArmC and ArmB+ArmD will be calculated, 
as will the corresponding two-sided 95% Wilson score intervals.   A test of homogeneity 
will be conducted (Zelen's exact test) to evaluate whether differences between treatment 
arms (Arm A vs. Arm B, and Arm C vs. Arm D, separately) are consistent across 
subgroups.  Tests will be conducted at the nominal 0.05 level.  The 2-sided 95% Wilson 


 
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score confidence intervals will be produced if there are at least 10 subjects in each 
subgroup.  
For the subgroup analyses, the presence of baseline resistance-associated 
polymorphisms is defined in Section 7.1; this subgroup analysis will be conducted on 
the mITT and mITT-GT-VF populations. All other subgroup analysis will be conducted 
on the mITT population.  
 
Subgroup analysis will also be performed on relevant combinations of subgroup 
variables if deemed clinically meaningful.   
Extending the results of the univariate subgroup analyses, a stepwise logistic regression 
model will be used to explore the associations between each of the subgroup variables, 
actual treatment arm and SVR12 by fitting a logistic regression model on all subjects in 
the mITT-GT-VF population.  Among all candidate predictors, continuous 
measurements will be used where possible (e.g., continuous baseline log10 HCV RNA 
level, continuous age, continuous BMI) in the logistic regression model.  For the 
variables on presence of baseline resistance-associated variants, only the unique 
variables (NS3 only vs. NS5A only vs. both NS3 and NS5A vs. none) will be used in 
the logistic regression model.  A stepwise logistic regression approach will be used to 
assess the strength of each subgroup variable in predicting SVR12, with a significance 
level of 0.10 to enter and remain in the model.  
A similar analysis will be conducted among the subjects in the mITT-GT-VF population 
with GT1a. 


 
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Finally, logistic regression models will be used to explore the associations of baseline 
RAPs in NS5A using the Key Subset of amino acid positions (Appendix 1) among the 
subjects in the mITT-GT-VF population with GT1a. First, a univariate logistic 
regression will explore whether the number of linked baseline NS5A RAPs (0, 1, 2, 3, 
or more than 3) is associated with SVR12.  Secondly the association of  any RAP in 
NS5A at each of the amino acids positions in the Key Subset (Appendix 1) with SVR12 
will be explored using a stepwise logistic regression approach with a significance level 
of 0.10 to enter and remain in the model. 
 
10.6 
Additional Efficacy Analyses 
The following additional efficacy endpoints will be summarized by treatment arm for 
the mITT population or for the EP-RS population overall, as specified below:  
• 
The percentage of mITT subjects with HCV RNA < LLOQ at each post-
baseline visit in the Treatment Period (using data as observed); 
• 
The percentage of mITT subjects with SVR4;  
• 
 The percentage of EP-RS subjects achieving SVR12. 
• 
The percentage of EP-RS subjects with on-treatment virologic failure or with 
post-treatment relapse. 
 
In the above analyses for SVR, the percentages of subjects and two-sided 95% Wilson 
score intervals will be summarized. A summary of reasons for SVR non-response will 
also be provided. 
 
 


 
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10.7 
Resistance Analyses 
Except for the summary of baseline resistance associated polymorphisms and subgroup 
analysis of SVR12, the resistance analyses will be performed for all subjects in the 
mITT population and the EP-RS populations separately per attached Resistance 
Analysis Plan (Appendix 1). In the EP-RS population, presence of polymorphisms in 
NS3 and NS5A will be reassessed prior to treatment with G/P + SOF ± RBV in the Re-
Treatment Sub-Study. 
 
11.0 
Safety Analysis 
11.1 
General Considerations 
Safety data will be summarized for each treatment arm using safety population (as 
defined in section 5.1.4); all AE related analyses are for the safety population of the 
Main Study unless otherwise specified; all laboratory data related analyses are for the 
safety population of the Main Study unless otherwise specified. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) Organ Class 
(SOC) and preferred term. The actual version of the MedDRA coding dictionary will be 
noted in the clinical study report. 
 
11.2 
Analysis of Adverse Events 
 


 
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11.2.1 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events are defined as any adverse event (AE) with an onset 
date that is on or after the first dose of study drug and no more than 30 days after the last 
dose of study drug. If an incomplete onset date was recorded 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 with treatment-emergent adverse events will be 
tabulated by treatment arm and overall for the Main Study and overall for the 
Retreatment Substudy by primary MedDRA System Organ Class (SOC) and preferred 
term (PT). The system organ classes will be presented in alphabetical order, and the 
preferred terms will be presented in alphabetical order within each system organ class. 
The tabulation of the number of subjects with treatment-emergent adverse events by 
severity grade and relationship to study drug also will be provided. Subjects reporting 
more than one adverse event for a given MedDRA preferred term will be counted only 
once for that term using the most severe grade for the severity grade table and the most 
related for the relationship to study drug table. Subjects reporting more than one type of 
event within a SOC will be counted only once for that SOC (most severe/highest grade 
incident for the severity tables and most related incident for the relationship tables). 
Subjects reporting more than one AE will be counted only once in the overall total. 
Adverse Event Overview 
A tabulation of adverse events (AE) will be presented by treatment arm and overall for 
the Main Study and for the single Re-Treatment Sub-Study arm, and will consist of the 


 
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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 
DAA (G/P); 
● Severe Treatment-emergent AEs; 
● Serious treatment-emergent AEs; 
● Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAA (G/P); 
● Treatment-emergent AEs leading to discontinuation of study drug; 
● DAA-related treatment-emergent AEs leading to discontinuation of study 
drug; 
● Treatment-emergent Severe AEs with a "reasonable possibility" of being 
related to DAA (G/P); 
● 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 Preferred Term (MedDRA) 
The following summaries of AEs by SOC and Preferred Term will be generated by 
treatment arm and overall: 
● Treatment-emergent adverse events (for the Main Study and the Retreatment 
substudy); 
● Treatment-emergent adverse events occurring in 5% or more of Safety 
population in any of the Arms (for the Main Study and the Retreatment 
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● Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs (G/P) (for the Main study, and broken down by relationship to 
G/P or, SOF, or Ribavirin in the Re-treatment Sub-study as applicable); 
● Serious treatment-emergent adverse events; 
● Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to DAAs (G/P); 
● Severe treatment-emergent adverse events; 
● Treatment-emergent adverse events leading to discontinuation of study drug; 
● DAA-related treatment-emergent adverse events leading to discontinuation of 
study drug; 
● Treatment-emergent severe adverse events with a "reasonable possibility" of 
being related to DAAs (G/P); 
● Serious treatment-emergent adverse events leading to discontinuation of study 
drug; 
● Treatment-emergent adverse events leading to interruption of study drug; 
● Treatment-emergent adverse events leading to death. 
 
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be created by treatment arm for the Main Study and for 
the single Retreatment Substudy arm. 
Adverse Events by Preferred Term 
The number and percentage of subjects experiencing treatment-emergent adverse 
events by treatment arm and overall in the Main study will be tabulated according to 
Preferred Term and sorted by overall frequency for the total number of subjects overall.  
Similar summaries will be provided for Severe  treatment-emergent adverse events, 
DAA related treatment-emergent adverse events, DAA related treatment-emergent 
serious adverse event, and DAA-related Severe  treatment-emergent adverse events.  


 
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Adverse Events by Maximum Severity Grade Level 
Treatment-emergent adverse events and DAA-related treatment-emergent adverse 
events will be summarized by maximum severity level of each preferred term by 
treatment arm and overall in the Main study.  Each adverse event will be assigned a 
Severity 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 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 (Severe).  In this case, the subject will be counted 
under the "Severe" category. 
Adverse Event by Maximum Relationship 
Treatment-emergent adverse events also will be summarized by maximum relationship 
of each preferred term to study drug (DAA), as assessed by the investigator, by 
treatment arm and overall in the Main study.  If a subject has an adverse event with 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same adverse event with a relationship assessment of "Reasonable Possibility."  In this 
case, the subject will be counted under the "Reasonable Possibility" category. 
 
11.2.3 
Listing of Adverse Events 
The following listings of adverse events will be prepared: 
● All serious adverse events (from the time the subject signed the study-specific 
informed consent through the end of the study), 
● Treatment-emergent serious adverse events, 


 
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● Treatment-emergent adverse events leading to death, 
● Treatment-emergent adverse events leading to discontinuation of study drug, 
● Treatment-emergent adverse events leading to study drug interruption. 
 
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. Clinical laboratory tests will be 
summarized at each visit by treatment arm and overall in the Main study. The baseline 
value will be the last non-missing measurement prior to the initial dose of study drug. 
Mean changes from baseline to each post-baseline visit, including the Final Treatment 
Visit and Final Post Treatment Visit, will be summarized descriptively for each 
treatment arm.  
In addition, the number and percentage of subjects with post-baseline laboratory values 
showing increase in CTCAE toxicity grade during treatment will be summarized by 
treatment arm and overall for the Main Study as well as for the single Re-Treatment 
Sub-Study arm.  
Baseline results falling on Day 1 must also be attributable to specimens collected prior 
to the first dose, if determinable.  In all cases, this same baseline value will be used for 
Change to Treatment Period 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 treatment arm.  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 
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11.3.1 
Variables and Criteria Defining Abnormality 
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, prothrombin time (PT), and international normalized ratio 
(INR). 
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, 
phosphorus, uric acid, cholesterol, total protein, glucose, albumin, chloride, 
bicarbonate, and estimated glomerular filtration rate (eGFR) calculated using the 
modification of diet in renal disease (MDRD) equation defined below. 
Some of the above laboratory variables are calculated by the laboratory vendor 
including indirect bilirubin, and eGFR by MDRD.  The central lab calculates eGFR by 
MDRD using the following equation, where serum creatinine is measured in mg/dL 
and age is measured in years: 
GFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1.154 × (Age)–0.203 × 1.212 (if 
Black) × 0.742 (if Female). 
11.3.2 
Statistical Methods 
The laboratory parameters defined in Table 6 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 treatment arm.  The post-baseline value must be in a 
toxicity grade that is more extreme than the toxicity grade corresponding to the baseline 
value to be counted.  The summary will also include the number and percentage of 
subjects with a maximum of at least Grade 3 for all laboratory parameters in Table 6.  A 


 
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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 6. 
Table 6. 
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values 
Test 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT/SGPT  
> ULN – 3 × ULN 
> 3 – 5 × ULN 
> 5 – 20 × ULN 
> 20 × ULN 
AST/SGOT  
> ULN – 3 × ULN 
> 3 – 5 × ULN 
> 5 – 20 × ULN 
> 20 × ULN 
Alkaline 
Phosphatase  
> ULN – 2.5 × ULN 
> 2.5 – 5 × ULN 
> 5 – 20 × ULN 
> 20 × ULN 
Total Bilirubin 
> ULN – 1.5 × ULN 
> 1.5 – 3 × ULN 
> 3 – 10 × ULN 
> 10 × ULN 
Hemoglobin  
< LLN – 100 g/L 
< 100 – 80 g/L 
< 80 g/L 
-- 
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 
eGFR 
< LLN – 60 mL/min 
< 60 – 30 mL/min 
< 30 – 15 mL/min 
< 15 mL/min 
Cholesterol 
> ULN – 7.75 mmol/L 
> 7.75 – 
10.34 mmol/L 
> 10.34 – 
12.92 mmol/L 
> 12.92 mmol/L 
Albumin 
< LLN – 30 g/L 
< 30 – 20 g/L 
< 20 g/L 
-- 
 
Assessment of Hepatotoxicity  
The number and percentage of subjects in each treatment arm  and overall in the Main 
Study  and overall in the Retreatment Sub-Study with maximum on-treatment lab values 
meeting the following criteria will be summarized: 
● ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN; 
● ALT ≥ 3 × ULN and total bilirubin < 2 × ULN; 


 
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● ALT > 5 × ULN and total bilirubin < 2 × ULN; 
● ALT < 3 × ULN and total bilirubin ≥ 2 × ULN. 
 
The maximum ratio relative to the ULN will be used to determine if subjects meet the 
criteria listed above.  The ALT and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  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). 
A listing of all 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 
any of the criteria defined above.  The listings will be reviewed to assess bilirubin (e.g., 
mixed or direct predominance) and temporal relationships for subjects with ALT ≥ 3 × 
ULN and total bilirubin ≥ 2 × ULN. 
The number and percentage of subjects with post-baseline values during the Treatment 
Period meeting the following criteria will be summarized: 
● ALT > 5 × ULN and ≥ 2 × baseline; 
● AST > 5 × ULN and ≥ 2 × baseline; 
● Total bilirubin ≥ 2.0 × ULN and > baseline. 
 
As noted above, a post-baseline value must be more extreme than the baseline value to 
be considered.  A separate listing will be provided that presents all lab values for the 
subjects meeting any of these criteria during treatment. 


 
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12.0 
References 
1. 
(Study protocol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 1. Resistance analysis plan (Version Date:   July 10, 2017) 
1. Main Study Patient Cohort (NS5A + SOF experienced): 4 arms, GT1a and GT1b 
a. G/P x 12 wks, non-cirrhotic 
b. G/P x 16 wks, non-cirrhotic 
c. G/P + RBV x 12 wks, compensated cirrhosis 
d. G/P x 16 wks, compensated cirrhosis 
2. Samples for resistance analysis 
a. Baseline samples for all patients 
b. Earliest time point at treatment failure (and sequential samples, if 
available) from patients who failed G/P treatment 
c. In the ITT-RS population, presence of polymorphisms in NS3 and NS5A 
will be reassessed prior to treatment with G/P + SOF ± RBV in the Re-
Treatment Sub-Study. 
3. Signature Amino Acid Positions and the Key Subset of Amino Acid Positions 
(provided by AbbVie) 
Genotype, 
Target 
Signature Amino Acid Positions 
Key Subset of Amino Acid 
Positions 
GT1, NS3 
36, 43 (GT1a only), 54, 55, 56, 80, 155, 
156, 168 
155, 156, 168 
GT1, NS5A 
24, 28, 29, 30, 31, 32, 58, 62, 92, 93 
24, 28, 30, 31, 58, 92, 93 


 
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4. Methods: Quantitative resistance analysis and mutation linkage – methods of Liu 
et al. 2016 (PMID 26645605) 
a. Primer-ID approach  
i. Advantages 
1. More accurate quantification of proportion of RASs  
2. Improved sensitivity and specificity 
b. Illumina paired-end sequencing, consensus clustering, bioinformatics 
analysis 
c. Reference sequence: H77 or CON-1 
d. Query each AA position (list provided by AbbVie) 
i. Signature AA positions 
ii. Key subset of AA positions 
e. Raw data output 
i. For each AA position, polymorphism relative to the reference 
sequence (and for treatment failures, baseline sequence) and read 
abundance (after consensus clustering) will be reported 
 
 


 
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5. Analysis plan for baseline RAPs (separately for mITT population or EP-RS 
population) 
a. Primary analysis 
i. Initial filtering 
1. 2% threshold -> generate a table of all RAPs present at 
>=2%  
2. 15% threshold -> generate a table of all RAPs present at 
>=15%  
ii. Analysis output (will be done for both 2% and 15% cutoff) 
1. List of patients with RAPs, including specific substitutions 
and % reads 
2. Prevalence of specific RAPs in all patients at baseline, 
stratified by treatment arms and GT1a vs GT1b 
3. Proportion of patients with no NS3 or NS5A RAP, NS3 
RAP only, NS5A RAP only, and both NS3 and NS5A RAPs 
a. Will generate separate reports for “any signature AA 
position” and for “key subset of AA position” 
b. Exploratory analysis 
i. Initial filtering 


 
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1. 1% filter to remove potential/equivocal erroneous resistance 
calls due to technical artifacts from 
amplification/sequencing 
ii. Analysis output (reads >=1% will be reported as % abundance) 
1. Linkage of RASs within each target 
a. Example A 
i. Data 
1. Q30H (4.7%)/Q30N 
(83%)/Q30S(12%) 
2. Y93H (100%) 
ii. Linkage analysis will be reported as 
1. Q30H/Y93H (4.7) 
2. Q30N/Y93H (83%) 
3. Q30S/Y93H (12%) 
b. Example B 
i. Data 
1. R30Q (72%) 
2. Y93H (68%) 
ii. Linkage analysis based on sequence analysis 


 
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1. Y93H (2.7%) 
2. R30Q (6%) 
3. R30Q/Y93H (65%) 
2. Linkage of RASs between targets (NS3 and NS5A) 
a. Our current methods cannot definitively demonstrate 
linkage by analysis of sequence reads (NS3 and 
NS5A are in two different amplicons), and thus, if 
possible, will infer linkage based on % reads 
b. Example 
i. Data 
1. NS3 R155K (8%) 
2. NS5A Y93H (99%) 
ii. Linkage analysis 
1. NS3 R155K/NS5A Y93H (~8%) 
 
6. Analysis plan for impact of baseline RASs on G/P efficacy (SVR12; mITT-GT-
VF population or EP-RS-GT-VF population) 
a. Filtering of dataset 
i. Apply 2% and 15% threshold to define presence/absence of each 
RAP 


 
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ii. Four separate “baseline RAP datasets” will be generated, using the 
following filters: 
1. 2% threshold, including signature RAPs 
2. 2% threshold, including key RAPs only 
3. 15% threshold, including signature RAPs 
4. 15% threshold, including key RAPs only 
b. Primary analysis 
i. mITT-GT-VF analysis: 1) population, stratified by treatment arms 
(x4) and GT1 subtype (x2); 2) population, stratified by treatment 
duration (x2) and GT1 subtype (x2) 
ii. For each of the four “baseline RAP datasets” (above), will perform 
the following comparisons with respective to SVR12, using 
Fisher’s Exact Test 
1. Patients with and without NS3 only baseline RAPs  
2. Patients with and without NS5A only baseline RAPs 
3. Patients with and without both NS3 and NS5A baseline 
RAPs 
iii. For each NS3 and NS5A “Signature RAP”, defined by 2% and 15% 
threshold, will perform the following comparisons with respective 
to SVR12 
1. Patients with and without specific “Signature RAP” 


 
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2. Patients with only 1 and with >1 NS5A “Signature RAP” 
c. Exploratory analysis 
i. Depending on the number of treatment failures, will use their 
baseline and treatment failure RAP dataset to guide the selection of 
RAP linkage and abundance for further analysis 
 
7. Analysis plan for patients with treatment failure (separately for mITT population 
or EP-RS population) 
a. Data 
i. For each signature position 
1. Presence/absence of RAP (according to 2% and 15% 
threshold) 
2. Changes in the read abundance of RAP (based on % reads) 
3. Characterize RAP linkage, if any 
ii. “Treatment emerging RAP” will be defined as 
1. Absent at baseline, present at treatment failure (2%, 15% 
threshold) 
2. Present at both baseline and treatment failure (2%, 15% 
threshold), but % read increase by >=20% 
b. Primary analysis 


 
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i. List of patients with RAPs including specific substitutions and % 
reads 
ii. Comparison of baseline vs treatment failure samples (as well as all 
subsequent samples, if available) will be performed for each 
Signature position 
iii. Phylogenetic analysis of NS3 and NS5A sequences to exclude re-
infection 
c. Exploratory analysis 
i. Examine and compare AA changes in all positions between 
baseline vs treatment failure with respective to changes in AA and 
read abundance