Clinical trial NCT02692703
Conditions: Chronic Hepatitis C HCV Hepatitis C Virus
Keywords: HCV Treatment Experienced Hepatitis C HCV Genotype 3 Without cirrhosis Non-cirrhotic HCV Genotype 2 Renal Transplant HCV Treatment Naive Post transplant HCV Genotype 6 Liver Transplant HCV Genotype 5 HCV Genotype 4 Kidney Transplant HCV Genotype 1
Sponsor: AbbVie
Start date: 2016-04-22; Completion date: 2017-06-29
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety and efficacy of 12 weeks of treatment of ABT-493/ABT-530 (glecaprevir/pibrentasvir) in adults who are post primary orthotopic liver or renal transplant with chronic hepatitis C virus (HCV) infection.

Detailed description:

Arms: arm 1: Glecaprevir/pibrentasvir (300 mg/120 mg) coformulated once daily (QD) for 12 weeks.
Interventions: intervention 1: glecaprevir/pibrentasvir
Intervention descriptions: intervention 1: Tablet; glecaprevir coformulated with pibrentasvir

Protocol documents:
Prot_000.pdf: 
ABT-493/ABT-530
M13-596 Protocol Amendment 2
EudraCT 2015-005616-14
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1.0
Title Page
Clinical Study Protocol M13-596
A Single-Arm, Open-Label, Multicenter Study to 
Evaluate the Safety and Efficacy of 
ABT-493/ABT-530 in Adult Post-Liver or Post-Renal 
Transplant Recipients with Chronic Hepatitis C Virus 
Genotype 1 – 6 Infection (MAGELLAN-2)
Incorporating Amendments 1 and 2
AbbVie Investigational
  Product:
ABT-493/ABT-530
Date:
21 June 2016
Development Phase:
3
Study Design:
This is an open label, multicenter study
EudraCT Number:
2015-005616-14
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc. (AbbVie)*
Sponsor/Emergency 
  Contact:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02692703


ABT-493/ABT-530
M13-596 Protocol Amendment 2
EudraCT 2015-005616-14
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date 
Original
28 January 2016
Amendment 1
26 May 2016
The purpose of this amendment is to:
●
Update Section 3.0, Introduction, and Section 5.2.3.2, Management of 
Immunosuppressant Agent Dosing.
Rationale:  The protocol has been updated to provide clarification regarding 
cyclosporine dose adjustment during the Treatment Period for subjects 
requiring maintenance titration as per usual transplant standard of care.  The 
dosing recommendation of 100 mg total daily dose is based upon the Phase 1 
drug-drug interaction studies (Studies M13-584, M13-605) that examined 
cyclosporine doses of 100 mg and 400 mg, as described within the protocol.  
Stable dosing at or below cyclosporine 100 mg/day was selected as the entry 
criteria (Inclusion Criterion 14), as this dose demonstrated only mild 
increases in ABT-493 exposure when coadministered with ABT-493 and 
ABT-530.  Although larger increases in ABT-493 exposure were observed with 
the cyclosporine 400 mg dose, all study drugs were well tolerated in both 
studies and no safety signals were identified.  Coadministration with ABT-493 
and ABT-530 did not affect exposure of cyclosporine at either dose level.
While the recommended dose of cyclosporine at the time of entry into the study 
(Inclusion Criterion 14) remains the same, clarification is needed for a subject 
who has entered into the study at a daily cyclosporine dose of 100 mg or less 
and requires an increase in the maintenance cyclosporine dose during the 
period of ABT-493/ABT-530 administration to > 100 mg/day.  Cyclosporine 
doses > 400 mg have not been formally evaluated in DDI studies with 
ABT-493 and ABT-530, and cyclosporine doses should not exceed 400 mg/day 
when coadministered with ABT-493/ABT-530 under any circumstances.  
Contact with the Therapeutic Area MD should be made for any case requiring 
titration of the cyclosporine maintenance dose to greater than 100 mg to 


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discuss proper management of concurrent therapies in order to prevent 
unnecessary discontinuation of study drug and risk of resistance development 
due to incomplete therapy.
●
Update Section 5.2.2, Exclusion Criteria, Criterion 7.
Rationale:  Clarification that concurrent liver disease other than HCV as an 
exclusionary criteria is applicable in the post-transplant period.
●
Update Section 5.1.2, Treatment Period, and Section 5.3.1.1, Study 
Procedures.
Rationale:  To clarify that the Immunosuppressive dosing diary completion 
begins during the screening period. 
●
Update Appendix B, List of Protocol Signatories.
Rationale:  To correct the typographical error.
●
Minor clerical updates made throughout the protocol.
Rationale:  For clarification and consistency throughout the protocol.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix E.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-596
Name of Study Drug:  ABT-493/ABT-530
100 mg/40 mg tablets (ABT-493/ABT-530) 
Phase of Development:  3
Name of Active Ingredient:  ABT-493, ABT-530
Date of Protocol Synopsis:  21 June 2016
Protocol Title:  A Single-Arm, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of 
ABT-493/ABT-530 in Adult Post-Liver or Post-Renal Transplant Subjects with Chronic Hepatitis C 
Virus Genotype 1 – 6 Infection (MAGELLAN-2)
Objectives:  The primary objectives of this study are to compare the 12-week sustained virologic 
response, SVR12 (HCV RNA < LLOQ 12 weeks following therapy) of 12 weeks of treatment with the 
ABT-493/ABT-530 combination regimen in adults with HCV genotype 1 – 6 infection who are post 
primary orthotopic liver transplant or renal transplant to a pre-defined threshold, based on the historical 
SVR12 rates for the current standard of care regimens (sofosbuvir/ledipasvir plus ribavirin or sofosbuvir 
plus daclatasvir plus RBV) and to assess the safety of treatment with the ABT-493/ABT-530 combination 
regimen for 12 weeks in adults with HCV genotype GT1 – 6 infection and post primary orthotopic liver 
transplant or renal transplant.
Investigators:  Multicenter
Study Sites:  Approximately 30 sites globally
Study Population:  Adults at least 18 years of age with chronic HCV genotype (GT) 1 – 6 infection who 
are post primary liver or renal transplant.
Number of Subjects to be Enrolled:  Approximately 90 subjects (including a minimum of 15 post-renal 
transplant subjects) and a maximum of approximately 50 subjects with HCV GT1 infection).
Methodology:  
This is a Phase 3, single arm, open-label, multicenter study to evaluate the safety and efficacy of 
ABT-493/ABT-530 for 12 weeks in chronic HCV GT1 – 6 infected subjects who have received a primary 
liver or renal transplant, and who are either HCV treatment-naïve or prior treatment experienced with 
IFN or pegIFN with or without RBV or sofosbuvir with RBV with or without pegIFN (except GT3 
infected subjects, who must be treatment-naïve).
The study will consist of 2 periods:
Treatment Period:
Eligible subjects will be enrolled to receive 12 weeks of ABT-493/ABT-530 300 mg/120 mg once daily 
(QD) for 12 weeks.
Scheduled visits for subjects in the Treatment Period consist of Day 1, Day 3 and Weeks 1, 2, 4, 6, 8, and 
12.  Study procedures, including assessment of adverse events, vital signs, study drug adherence, 
concomitant medications, HCV RNA, HCV resistance, ABT-493/ABT-530 and immunosuppressant 
concentrations, pharmacokinetic assays, and clinical laboratory tests, will be conducted at each visit.
Post-Treatment Period:
Subjects who complete or prematurely discontinue the Treatment Period will be followed for 24 weeks to 
monitor safety, HCV RNA levels, and the emergence and persistence of resistant viral variants.


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Methodology (Continued):
During the Post-Treatment Period, all subjects will have visits at Day 3 and Weeks 1, 2, 4, 8, 12, and 24 
following completion of the Treatment Period.  Study procedures to monitor safety, HCV RNA, and the 
emergence and persistence of resistant virus will be conducted during these visits.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female, at least 18 years of age at time of screening.
2.
Screening laboratory result indicating HCV GT1 – 6 infection.
3.
Subject is a recipient of a cadaveric or living donor liver transplant which was a consequence of 
HCV infection ≥ 3 months prior to screening Or Subject received a cadaveric or living donor kidney 
at least ≥ 3 months before screening.
4.
Subjects must be documented as non-cirrhotic. 
5.
Subject is currently taking a stable immunosuppression regimen based on tacrolimus, sirolimus, 
everolimus, mycophenolate mofetil (MMF), mycophenolic acid, azathioprine and/or cyclosporine.
Main Exclusion:  
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
2.
Clinical history of fibrosing cholestatic hepatitis post-transplant.
3.
Re-transplantation of the liver or kidney.
4.
Steroid resistant rejection of the transplanted liver or kidney, or a history of rejection treated with 
high dose steroid within 3 months of screening.
5.
History of post-transplant complications related to hepatic or renal vasculature.
Investigational Products:
ABT-493/ABT-530 100 mg/40 mg Film-coated tablet  
Dose:
ABT-493/ABT-530:  300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Dose:
N/A
Mode of Administration:
N/A
Duration of Treatment:  Subjects will receive ABT-493/ABT-530 for 12 weeks.
Criteria for Evaluation:
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.


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Criteria for Evaluation (Continued):
Pharmacokinetic:
Individual plasma concentrations of ABT-493 and ABT-530, and possible metabolites of ABT-493 and 
ABT-530 will be tabulated and summarized.  Individual blood concentrations of immunosuppressants; 
cyclosporine, sirolimus, everolimus, and/or tacrolimus, will also be tabulated and summarized.
Patient Reported Outcomes (PROs):
Health state utility will be measured using the EuroQol-5-Dimensions-3 Level (EQ-5D-3L) instrument.  
The Fatigue Severity Scale (FSS) will be used to measure the severity of fatigue and its effect on lifestyle 
and activities.  The Short Form 36 Version 2 Health Status Survey (SF-36v2) will be used to assess the 
functional health and well-being of subjects. 
Resistance:
The following information will be tabulated and summarized:  1) for all subjects with available samples, 
the variants at baseline at signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference sequence; and 2) for subjects who do not achieve SVR12, post-baseline variants 
relative to baseline.
Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects with SVR12 (HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug) for all intent-to-treat (ITT) subjects treated with 
ABT-493/ABT-530.  Non-inferiority of the SVR12 rate for the ABT-493/ABT-530 regimen compared to 
the historical SVR12 rate for the current standard of care regimens (based on SVR12 rates for 
SOF/ledipasvir (LDV) plus RBV or SOF plus daclatasvir (DCV) plus RBV 
 
 will be tested.  The number and percentage of subjects achieving SVR12
will be summarized and a two-sided 95% confidence interval will be calculated using the Normal 
approximation to the binomial distribution unless the SVR12 rate for the primary is 100%, where the 
Wilson's score method will be used for the confidence intervals instead.  The lower confidence bound of 
the 2-sided 95% CI (LCB) for the percentage of subjects achieving SVR12 must exceed 86% to achieve 
non-inferiority.
The secondary efficacy endpoints are:
!
The percentage of subjects with on-treatment virologic failure,
!
The percentage of subjects with post-treatment relapse.
The number and percentage of subjects meeting each secondary efficacy endpoint will be summarized 
along with 95% Wilson score confidence intervals.
Additional efficacy endpoints include:  percentage of subjects with HCV RNA < LLOQ at each post-
baseline visit during treatment period, percentage of DAA naïve subjects with on-treatment virologic 
failure and relapse, SVR4, SVR24, and the percentage of subjects who relapsed after achieving SVR12; the 
number and percentage of subjects meeting each additional efficacy endpoint will be summarized along 
with 95% Wilson score confidence intervals.


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentration of ABT-493, ABT-530, and their possible metabolites will be tabulated for each 
subject.  Summary statistics will be computed for each time and visit.  Population pharmacokinetic 
analyses will be performed using the actual sampling time relative to dosing.  Pharmacokinetic models 
will be built using a non-linear mixed-effect modeling approach.  Individual blood concentrations of 
immunosuppressants, cyclosporine, sirolimus, everolimus, and/or tacrolimus, will also be tabulated and 
summarized.
PROs: 
Change from baseline in the patient reported outcome summary measures will be summarized 
descriptively.  In addition, the proportion of patients achieving a minimal important difference will be 
identified.
Resistance:
For all subjects receiving study drug, the HCV variants at signature resistance-associated amino acid 
positions at baseline identified by population or deep sequencing and comparison to the appropriate 
prototypic reference sequence will be analyzed.
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 
variants in available post-baseline samples identified by population or deep sequencing and comparison 
to the baseline sequences, 2) the amino acid variants in available post baseline samples at signature 
resistance-associated positions identified by population or deep sequencing, and comparison to the 
appropriate prototypic reference sequence, and 3) the persistence of post-baseline viral resistance by 
population or deep sequencing.
Safety:
All subjects who receive at least one dose of study drug will be included in the safety analyses.  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) will be tabulated by primary System Organ Class (SOC) and 
MedDRA preferred term.  The tabulation of the number of subjects with treatment-emergent adverse 
events also will be provided by severity grade and relationship to study drug.  Change from baseline in 
laboratory tests and vital signs measurements to each time point of collection will be summarized, and 
values that are potentially clinically significant, according to predefined criteria, will be summarized.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APRI
Aminotransferase/platelet ratio index 
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
BID
Twice Daily
BMI
Body Mass Index
BUN
Blood urea nitrogen
CNI
Calcineurin Inhibitors
CPK
Creatine phosphokinase
CR/CL
Creatinine clearance
CRF
Case report form
CT
Computed Tomography
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DCV
Daclatasvir
DNA
Deoxyribonucleic acid
EC
Ethics Committee 
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EQ-5D-3L
EuroQol 5 Dimensions 3 Levels Health State Instrument
EU
European Union
FSS
Fatigue Severity Scale
GAM
Generalized additive method
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype


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HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
Hemoglobin A1c
Glycated hemoglobin
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
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
MedDRA
Medical Dictionary for Regulatory Activities
NONMEM
Non-linear mixed-effect modeling
MMF
Mycophenolate mofetil
mTOR
Mammalian target of rapamycin
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
PK
Pharmacokinetic


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POR
Proof of Receipt
PRO
Patient Reported Outcome
PR
pegIFN/RBV
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
ROC
Receiver Operating Characteristic
SAE
Serious adverse event
SF-36v2
Short Form 36-Version 2 Health Status Survey
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOF
Sofosbuvir
SOC
System Organ Class/Standard of Care
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
SVR24
Sustained virologic response 24 weeks post dosing
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
Wk
Week
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
WPAI
Work Productivity and Activity Index


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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
CI
Confidence Interval
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
Ctrough
Pre-dose trough plasma concentration
LCB
Lower confidence bound
ITT
Intent-to-Treat
SD
Standard Deviation
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration (Cmax)
Definition of Terms
Study Drug
ABT-493, ABT-530
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 24 
or Post-Treatment Discontinuation


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms..........................................8
2.0
Table of Contents...................................................................12
3.0
Introduction ...........................................................................17
3.1
Differences Statement..............................................................................23
3.2
Benefits and Risks....................................................................................23
4.0
Study Objective......................................................................24
4.1
Primary Objective ....................................................................................24
4.2
Secondary Objective ................................................................................24
5.0
Investigational Plan...............................................................25
5.1
Overall Study Design and Plan:  Description ..........................................25
5.1.1
Screening..................................................................................................26
5.1.1.1
Retest/Rescreening...................................................................................27
5.1.2
Treatment Period......................................................................................28
5.1.3
Post-Treatment Period .............................................................................29
5.2
Selection of Study Population..................................................................30
5.2.1
Inclusion Criteria .....................................................................................30
5.2.2
Exclusion Criteria ....................................................................................33
5.2.3
Prior and Concomitant Therapy...............................................................35
5.2.3.1
Prior HCV Therapy..................................................................................36
5.2.3.2
Management of Immunosuppressant Agent Dosing................................37
5.2.3.3
Concomitant Therapy...............................................................................39
5.2.3.4
Prohibited Therapy...................................................................................39
5.2.4
Contraception Recommendations and Pregnancy Testing.......................40
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables.............................................................................42
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................42
5.3.1.1
Study Procedures .....................................................................................42
5.3.1.2
Meals and Dietary Requirements.............................................................53


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5.3.1.3
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples ....................................................................................53
5.3.1.4
Optional Sample for Pharmacogenetic Exploratory Research.................53
5.3.2
Drug Concentration Measurements .........................................................54
5.3.2.1
Collection of Samples for Analysis .........................................................54
5.3.2.2
Handling/Processing of Samples .............................................................55
5.3.2.3
Disposition of Samples ............................................................................55
5.3.2.4
Measurement Methods.............................................................................55
5.3.3
Efficacy Variables....................................................................................55
5.3.3.1
Primary Variable......................................................................................55
5.3.3.2
Secondary Variable(s)..............................................................................56
5.3.4
Resistance Variables ................................................................................56
5.3.5
Safety Variables .......................................................................................56
5.3.6
Pharmacokinetic Variables ......................................................................56
5.3.7
Pharmacogenetic  Exploratory Research Variables .................................57
5.4
Removal of Subjects from Therapy or Assessment .................................57
5.4.1
Discontinuation of Individual Subjects....................................................57
5.4.1.1
Virologic Failure Criteria.........................................................................59
5.4.2
Discontinuation of Entire Study...............................................................59
5.5
Treatments................................................................................................60
5.5.1
Treatments Administered.........................................................................60
5.5.2
Identity of Investigational Products .........................................................61
5.5.2.1
Packaging and Labeling...........................................................................61
5.5.2.2
Storage and Disposition of Study Drug ...................................................61
5.5.3
Method of Assigning Subjects to Treatment ...........................................62
5.5.4
Selection and Timing of Dose for Each Subject ......................................62
5.5.5
Blinding....................................................................................................62
5.5.6
Treatment Compliance.............................................................................62
5.5.7
Drug Accountability.................................................................................63
5.6
Discussion and Justification of Study Design..........................................64
5.6.1
Discussion of Study Design .....................................................................64
5.6.2
Appropriateness of Measurements...........................................................66
5.6.3
Suitability of Subject Population .............................................................66


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5.6.4
Selection of Doses in the Study ...............................................................67
5.6.4.1
Rationale for Duration Selections............................................................69
5.6.4.2
Risk of Development of Resistance Mutations During 
Combination DAA Trials.........................................................................69
6.0
Complaints .............................................................................70
6.1
Medical Complaints.................................................................................71
6.1.1
Definitions................................................................................................71
6.1.1.1
Adverse Event..........................................................................................71
6.1.1.2
Serious Adverse Events ...........................................................................72
6.1.2
Adverse Event Severity............................................................................73
6.1.3
Relationship to Study Drug......................................................................74
6.1.4
Adverse Event Collection Period.............................................................75
6.1.5
Adverse Event Reporting.........................................................................75
6.1.6
Pregnancy.................................................................................................77
6.1.7
Toxicity Management ..............................................................................77
6.1.7.1
Management of Increases in ALT............................................................78
6.1.8
Renal Transplant Management of Proteinuria .........................................80
6.2
Product Complaint ...................................................................................81
6.2.1
Definition .................................................................................................81
6.2.2
Reporting..................................................................................................81
7.0
Protocol Deviations................................................................82
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................82
8.1
Statistical and Analytical Plans................................................................82
8.1.1
Demographics ..........................................................................................83
8.1.2
Efficacy....................................................................................................84
8.1.2.1
Primary Efficacy Endpoints.....................................................................85
8.1.2.2
Secondary Efficacy Endpoints.................................................................85
8.1.2.3
Sensitivity Analysis .................................................................................86
8.1.2.4
Subgroup Analysis ...................................................................................86
8.1.2.5
Additional Efficacy Endpoints.................................................................87
8.1.3
Patient Reported Outcomes......................................................................88
8.1.4
Resistance Analysis .................................................................................89


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8.1.5
Safety .......................................................................................................92
8.1.5.1
Adverse Events ........................................................................................92
8.1.5.2
Clinical Laboratory Data..........................................................................92
8.1.5.3
Vital Signs Data .......................................................................................93
8.1.6
Pharmacokinetic and Exposure-Response Analyses ...............................93
8.2
Determination of Sample Size .................................................................95
8.2.1
Justification of Success Criterion and Non-Inferiority Margin for 
SVR12 .......................................................................................................96
9.0
Ethics.......................................................................................97
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................97
9.2
Ethical Conduct of the Study ...................................................................97
9.3
Subject Information and Consent.............................................................98
10.0
Source Documents and Case Report Form 
Completion .............................................................................99
10.1
Source Documents ...................................................................................99
10.2
Case Report Forms...................................................................................99
11.0
Data Quality Assurance......................................................100
12.0
Use of Information...............................................................100
13.0
Completion of the Study .....................................................101
14.0
Investigator's Agreement....................................................102
15.0
Reference List ......................................................................103
List of Tables
Table 1.
Prohibited Medications and Supplements................................................40
Table 2.
Clinical Laboratory Tests.........................................................................46
Table 3.
Identity of Investigational Products .........................................................61
List of Figures
Figure 1.
Study Schematic.......................................................................................26
Figure 2.
Adverse Event Collection ........................................................................75


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EudraCT 2015-005616-14
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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................106
Appendix B.
List of Protocol Signatories....................................................................108
Appendix C.
Study Activities – Treatment Period......................................................109
Appendix D.
Study Activities – Post-Treatment (PT) Period .....................................112
Appendix E.
Protocol Amendment:  List of Changes.................................................114


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3.0
Introduction
End stage liver disease due to chronic hepatitis C virus (HCV) infection is a common 
indication for liver transplantation, accounting for up to 30% of all liver transplants.1  In 
HCV-infected individuals, recurrent infection of the new graft occurs in almost all liver 
transplant recipients.  HCV infection is typically more aggressive in the post-transplant 
population than in other HCV-infected populations, with 30% of transplant recipients 
developing cirrhosis within 5 years, and is a frequent cause of graft loss.  HCV infection 
significantly impacts both patient and allograft survival in the liver transplant population, 
a trend that is also seen in the renal transplant population.2-6  Within the renal transplant 
population, HCV seroprevalence is up to 22% in kidney recipients, and those who are 
HCV positive have lower long term survival rates when compared to the HCV negative 
renal transplant population, with 15 year survival rates of 78% versus 94.5%, respectively.  
Thus, safe and effective treatment of HCV in the post-renal and liver transplant 
populations is of clinical importance.
HCV infection is a global health problem, with over 130 – 184 million individuals 
infected worldwide.7  There are 7 identified HCV genotypes,8 with genotype 1 (GT1) 
being most prevalent worldwide, including in the United States.  Depending on various 
risk factors, between 10% and 40% of patients with chronic HCV infection will develop 
cirrhosis.9  Death related to the complications of cirrhosis may occur at an incidence of 
approximately 4% per year; hepatocellular carcinoma occurs in this population at an 
estimated incidence of 1% to 5% per year.9 Patients diagnosed with hepatocellular 
carcinoma have a 33% probability of death during the first year.9  Successful treatment of 
HCV has been shown to significantly reduce the risk of disease progression and related 
mortality as well as the development of hepatocellular carcinoma.10,11
Interferon (IFN)-based therapies in the post-liver transplant setting have historically been 
associated with low SVR rates, partly due to the treatment limiting toxicities associated 
with IFN and ribavirin (RBV)12 though even these regimens are associated with improved 
long-term outcomes.  In the renal transplant setting, IFN can be deleterious to the 


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allograft, and should be avoided.6  Currently approved interferon (IFN)- and, in some 
cases, ribavirin (RBV)-free combination regimens consisting of 2 or more potent direct 
acting antiviral agents (DAAs) represent overall substantial progress in the treatment of 
HCV infection compared with previous IFN-based therapy for most HCV populations 
outside of the transplant population.  The current IFN-free DAA combination treatment 
regimens have substantially increased SVR12 rates in pegIFN/RBV-naïve and 
-experienced patients, shortened the duration of treatment, and improved the safety and 
tolerability of treatment relative to IFN-containing regimens.  Improved SVR, shorter 
treatment durations and improved safety and tolerability have also been described in the 
post-transplant population with these regimens.13-16  
Despite the advances in IFN-free regimens, not all are equally potent across all HCV 
genotypes and subtypes, and across all subpopulations, including patients who have failed 
previous DAA-based regimens, patients with severe renal impairment, post-transplant 
patients and patients with decompensated cirrhosis, leaving important medical needs 
unaddressed.  Currently available treatments in the transplant populations still require 
RBV for most recommended regimens,17 and can potentially be associated with 
significant drug interactions, particularly with calcineurin inhibitors (CNIs).
In addition, more convenient and tolerable regimens are also needed in order to improve 
patient compliance and by extension, increase the chances of cure.  Features of such a 
regimen include low pill burden and once daily dosing, pan-genotypic coverage and 
RBV-free dosing.  AbbVie is currently developing two "next generation" DAAs, 
ABT-493 (NS3/4A PI) and ABT-530 (NS5A inhibitor), as combination therapy for 
chronic HCV infection.  These DAAs are denoted as "next generation" compounds 
because each demonstrated potent antiviral activity against all major HCV GTs in vitro 
with no or little loss of potency against known common single resistant variants.
ABT-493 and ABT-530
ABT-493 is an NS3/4A PI with potent and pan-genotypic activity.  It demonstrates a high 
genetic barrier to resistance with activity against common variants that emerge following 


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exposure to first generation PIs.  ABT-530 is an NS5A inhibitor with pan-genotypic 
activity and a high genetic barrier to resistance maintaining activity against all common 
single nucleotide change resistance-associated variants in NS5A in all GTs.  ABT-530 is 
> 100-fold more active than the first generation NS5A inhibitors (ombitasvir, daclatasvir, 
and ledipasvir) against single key resistance-associated variants.  Additive or synergistic 
in vitro anti-HCV activity has been demonstrated with the combination of ABT-493 and 
ABT-530, depending on the concentrations tested.
In general, ABT-493 and ABT-530 in combination has been well tolerated when 
administered to over 250 healthy volunteers and 270 HCV-infected subjects. When 
ABT-493 was given in combination with ABT-530 in healthy volunteers, results showed 
that ABT-493 exposures were not significantly changed when co-administered with 
ABT-530 (≤ 31% difference); however, the exposure of ABT-530 increased in an 
ABT-493-dose-dependent manner (from 1.5-fold at 100 mg ABT-493 up to 3- to 4-fold at 
400 mg ABT-493).
Studies M14-867 and M14-86818,19 are Phase 2b studies designed to assess the efficacy, 
safety and pharmacokinetics of the combination of ABT-493 and ABT-530 in 
non-cirrhotic subjects with HCV GT1 – 6 infection.  In these studies, subjects received 
12 weeks of ABT-493 and ABT-530 with or without ribavirin.  
In Study M14-867 Part 1, the combination of ABT-493 and ABT-530 demonstrated high 
rates of SVR12 in treatment-naïve (98%) and treatment-experienced (100%) HCV 
GT1-infected subjects.  In Study M14-868, preliminary results across dose regimens in 
GT2 and GT3 demonstrated SVR12 of 89% – 97% (excluding non-virologic failures).  To 
date, safety data across 274 subjects in Part 1 of Studies M14-867 and M14-868 
encompassing 274 subjects show that the most frequently reported adverse events were 
fatigue, nausea, and headache (occurring in > 5% of subjects) with the majority being 
Grade 1 or 2 in severity.  Among these 274 subjects, there have been 4 (1.5%) 
treatment-emergent SAEs reported (all assessed as not related to ABT-493 or ABT-530):  
pneumonia, atrial fibrillation, B-cell lymphoma, and metastatic prostate cancer.  
Two subjects (0.7%; 2/274) had treatment-emergent adverse events leading to treatment 


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discontinuation.  One subject with history of irritable bowel disease discontinued for 
Grade 2 AE of abdominal pain assessed as having a reasonable possibility of relatedness 
to both the DAAs and RBV.  The abdominal pain for this subject resolved after 
discontinuation from study drugs.  The other subject discontinued for the aforementioned 
Grade 4 SAE of B-cell lymphoma for the purposes of initiating chemotherapy.
In both Studies M14-867 and M14-868, in all subjects with baseline ALT elevations, the 
ALT levels showed a trend toward normal or became normal with DAA treatment, and 
there have been no on-treatment ALT elevations above baseline.  Other laboratory 
abnormalities were infrequent and were primarily associated with well-described 
hemolytic effect of RBV, manifesting as Grade 1 anemia in a total of 4 subjects, all 
occurring in the RBV-containing arms Study M14-868.  Observed total bilirubin 
elevations were Grade 1 or 2 with predominantly indirect fraction, were mostly isolated 
occurrences, and normalized or stabilized with continued DAA therapy.  Total bilirubin 
elevations were primarily observed in the RBV-containing arms.
In Part 2 of Study M14-867,18 a total of 34 GT1-infected subjects without cirrhosis 
received ABT-493 and ABT-530 for 8 weeks.  Among enrolled subjects, there are 
29 treatment-naïve subjects.  Thirty-three of the 34 (97%) subjects achieved SVR12.  
One subject discontinued from study drug due to the non-DAA related SAE of 
adenocarcinoma but did achieve SVR4; the subject subsequently died due to the 
aforementioned SAE prior to the post-treatment Week 12 visit.  There have been no other 
SAEs, discontinuations due to adverse events or deaths.  Adverse events have been mostly 
Grade 1 or Grade 2, with the most frequently reported adverse events being fatigue, 
diarrhea and nausea.  There have been no on-treatment ALT elevations above baseline.  
This study also contains arms to evaluate genotypes 4 – 6 (total 34 patients), who received 
ABT-493 and ABT-530 for 12 weeks, and have achieved SVR4 of 100%. 


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DDI STUDIES WITH CYCLOSPORINE AND TACROLIMUS
Phase 1 drug-drug interaction studies of ABT-493/ABT-530 have been conducted with 
tacrolimus and cyclosporine (CsA) in healthy volunteers.  The pharmacokinetic results 
from these studies are summarized below: 
Tacrolimus Phase 1 Data (Study M13-592):  The effect of the combination of 300 mg 
ABT-493 and 120 mg ABT-530 at steady-state on the pharmacokinetics of a single dose 
of 1 mg tacrolimus and vice-versa was evaluated in healthy subjects.  A single dose of 
1 mg tacrolimus did not affect the steady-state exposures of 300 mg ABT-493 and 120 mg 
ABT-530.  Tacrolimus exposures increased by 50% when co-administered with ABT-493 
and ABT-530.  All study drugs were well-tolerated and no safety concerns were 
identified.  Based on these results, the following dosing recommendations for tacrolimus 
management during treatment with ABT-493 and ABT-530 are recommended in this 
study:
●
For subjects who are initiating therapy with tacrolimus, the initial dose should 
be selected from the lower end of the recommended range as per the 
tacrolimus label (e.g., 0.10 mg/kg/day for adult liver transplant recipients).  
●
For subjects already taking tacrolimus, dosing should continue with close 
monitoring of tacrolimus trough levels and tacrolimus dose adjustment as 
needed.  
Cyclosporine Phase 1 Data (Studies M13-584 and M13-605):  Study M13-584 
evaluated the effect of co-administration of single-dose and multiple-doses of 300 mg 
ABT-493 and 120 mg ABT-530 with a single dose of 100 mg cyclosporine.  
Pharmacokinetic results showed that a single dose of cyclosporine modestly increased the 
steady-state exposures of ABT-493 by 30% – 34% and of ABT-530 by 11% – 26%.  The 
exposures of cyclosporine following a single dose of 100 mg were minimally affected by 
co-administration of single or steady-state doses of ABT-493 and ABT-530 (≤ 14% 
increase).  All study drugs were well-tolerated and no safety concerns were identified.


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Study M13-605 evaluated the interaction between a single dose of 300 mg ABT-493 and 
120 mg ABT-530 and a single dose of 400 mg cyclosporine in healthy subjects.  
Preliminary pharmacokinetic results from this study showed that cyclosporine exposures 
were not affected by co-administration with ABT-493 and ABT-530.  However, the 
exposures of ABT-493 increased 4.5 to 5.1-fold, and for ABT-530 increased 22% to 88% 
following co-administration of a single dose of 400 mg cyclosporine.  All study drugs 
were well-tolerated and no safety concerns were identified.
Based on pharmacokinetic results from these two studies, the following recommendations 
are made for cyclosporine management during treatment with ABT-493 and ABT-530:
●
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should 
not exceed 100 mg once daily for entry into the study. If the cyclosporine 
maintenance dose needs to be increased to a total daily dose greater than 
100 mg during the Treatment Period, discussion with the Therapeutic Area 
Medical Director should occur.  Dosages of cyclosporine > 400 mg are not 
allowed during the Treatment Period.
Study M13-596 is a single-arm, multi-center, open label, Phase 3 study intended to 
evaluate the safety and efficacy of ABT-493/ABT-530 administered for 12 weeks in adult 
post-liver or post-renal transplant subjects with chronic HCV GT1 – 6 infection who are 
treatment-naïve or treatment-experienced with pegIFN or IFN with or without RBV or 
sofosbuvir with RBV with or without pegIFN (except GT3 infected subjects who must be 
treatment naïve).  Additional discussion and justification of study design may be found in 
Section 5.6.1.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, drug-drug interaction and clinical data can be found in the 
ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure.20


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3.1
Differences Statement
The current study (Study M13-596) is the first study to evaluate the safety and efficacy of 
the ABT-493/ABT-530 combination regimen in chronic HCV GT1 – 6 infected, 
post-primary orthotopic liver or renal transplant subjects.  The ongoing Phase 2b studies 
(Studies M14-867 and M14-868) were designed to assess the efficacy, safety and 
pharmacokinetics of the combination regimen of ABT-493 and ABT-530 administered for 
12 and 8 weeks in subjects with HCV GT1 – 6 infection and provide the main supporting 
data and rationale of the advancement of the ABT-493/ABT-530 fixed dose combination 
regimen into this Phase 3 study.  Study M13-596 will evaluate the co-formulated, fixed 
dose combination tablet of ABT-493/ABT-530 intended for marketing.  Other ongoing 
Phase 3 studies within the program, including other special populations, exclude 
post-transplant subjects, thus the need for a dedicated study in this population.
3.2
Benefits and Risks
Preliminary efficacy data in Studies M14-867 and M14-868 demonstrated high rates of 
SVR12 (89% to 100% SVR4 or SVR12) in subjects with HCV GT1 – 6 infection without 
cirrhosis who received ABT-493 in combination with ABT-530 for 12-weeks.  
One hundred percent of subjects (n = 40) who received ABT-493 200 mg + ABT-530 
120 mg × 12 weeks in Study M14-867 achieved SVR12.  Preliminary safety data across 
the GT1 – 3 arms in Part 1 of Studies M14-867 and M14-868 using a regimen containing 
ABT-493 at a 300 mg dose (n = 89) demonstrate an acceptable safety profile.
In the post liver and renal transplant population, the risks associated with ABT-493 and 
ABT-530, including the risks of toxicity and virologic failure, are anticipated to be limited 
and manageable based on the results of the Phase 2 trials which are summarized in the 
Introduction (Section 3.0).  The efficacy of this regimen has not yet been defined in this 
population, and it is possible that the treatment failure rate may be higher than what was 
observed in the Phase 2 trials for the non-immunosuppressed populations.  Although the 
present study is limited to subjects without cirrhosis, hepatic decompensation and/or graft 
failure can still occur in the post-transplant population.  Other risks include the potential 


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for alterations in immunosuppressant exposures, specifically tacrolimus, sirolimus, and 
everolimus, though the risk will be mitigated with close monitoring of 
immunosuppressant drug levels.  However, as RBV-free treatment options are limited 
within this patient population, the potential benefits of treatment outweigh the potential 
risks.  
Adverse events that are known, and those not previously described, may occur with the 
combination of the two DAAs, as detailed in the informed consent for this study.  In 
addition, subjects may experience inconvenience or discomfort related to the study visits 
or study procedures.  Additional safety data for each DAA alone and the combination of 
ABT-493 and ABT-530 are detailed in Section 3.0 and in the Investigator's Brochure.
Given the potential high SVR rate in populations of HCV-infected subjects, the 
benefit-risk profile for co-administered ABT-493 and ABT-530 as treatment for chronic 
HCV infection is favorable.
4.0
Study Objective
4.1
Primary Objective
The primary objectives of this study are to compare the 12-week sustained virologic 
response, SVR12 (HCV RNA < LLOQ 12 weeks following therapy) of 12 weeks of 
treatment with the ABT-493/ABT-530 combination regimen in adults with HCV genotype 
GT1 – 6 infection who are post primary orthotopic liver transplant or renal transplant to a 
pre-defined threshold, based on the historical SVR12 rates for the current standard of care 
regimens (sofosbuvir/ledipasvir plus ribavirin or sofosbuvir plus daclatasvir plus RBV) 
and to assess the safety of treatment with the ABT-493/ABT-530 combination regimen 
for 12 weeks in adults with HCV genotype GT1 – 6 infection and post primary orthotopic 
liver transplant or renal transplant.
4.2
Secondary Objective
The secondary objectives are to assess:


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●
The percentages of subjects with on-treatment virologic failure.
●
The percentages of subjects with post-treatment relapse.
Additional objectives are to assess pharmacokinetics and emergence/persistence of viral 
variants in these treatment regimens.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study was designed to enroll approximately 90 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.  The number of 
GT1 subjects included will be a maximum of approximately 50 subjects for the overall 
study to ensure enrollment of other genotypes.  A minimum of 15 post-renal transplant 
subjects will be included in the study.
This is a Phase 3, single arm, open-label, multicenter study to evaluate the safety and 
efficacy of ABT-493/ABT-530 in chronic HCV GT1 to 6-infected non-cirrhotic (F0-F3) 
subjects who have received a primary orthotopic liver or renal transplant who are either 
HCV treatment-naïve or prior treatment-experienced with IFN or pegIFN with or without 
RBV or sofosbuvir with RBV with or without pegIFN (except GT3-infected subjects who 
must be treatment-naïve). 
This study consists of 2 Periods:
●
Treatment Period:  Enrolled subjects will receive 12 weeks of 
ABT-493/ABT-530.
●
Post-Treatment Period:  Subjects who complete or prematurely discontinue the 
treatment period will be followed for 24 weeks after their last dose of study 
drug to evaluate efficacy and to monitor HCV RNA and the emergence and 
persistence of viral variants. 


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A study schematic is shown below in Figure 1.
Figure 1.
Study Schematic
The primary analysis will occur after all subjects have completed the Post-Treatment 
Week 12 Visit or prematurely discontinued from the study.
5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures will receive a unique subject number via the 
Interactive Response Technology (IRT) system and will undergo the study procedures
identified in Section 5.3.1.1.  The investigator will evaluate whether the subject meets all 
of the eligibility criteria 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, and will record the results 
of this assessment and the details of the informed consent process in the subject's medical 
records.  Eligible subjects have up to 42 days following the Screening Visit to enroll into 
the study.
An immunosuppression regimen diary will be provided to subjects during screening to 
begin recording all cyclosporine, sirolimus, everolimus, and/or tacrolimus (CNI/mTOR) 
dosing information including date, time, and dose. 
For subjects who do not meet the study eligibility criteria or for eligible subjects that are 
not able to enroll due to enrollment being completed, the site personnel must register the 
subject as a screen failure in both IRT and EDC systems.


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5.1.1.1
Retest/Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
A positive Hepatitis B surface antigen (HBsAg);
●
A positive HIV-1 Ab test;
●
HCV genotype indicating co-infection with more than one HCV genotype;
●
A positive serum pregnancy test (if female).
Otherwise, subjects may be retested or rescreened only once before requiring approval 
from the Primary Therapeutic Area Medical Director to rescreen again.
Retesting:
Subjects who have exclusionary laboratory parameter(s) per Exclusion Criterion 9, 
Section 5.2.2 are allowed to retest on the related panel(s) (e.g., exclusionary ALT requires 
a repeat chemistry panel) within the same screening period and must meet all other 
eligibility laboratory criteria on the panel that is repeated.  If the retest result(s) are also 
exclusionary, the subject may only be rescreened or retested again with approval from the 
Primary Therapeutic Area Medical Director.
Rescreening:
Subjects that exceed the initial 42-day screening period should be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary at the 
first screening attempt (with the exception of HIV, HBV, HCV genotype and subtype, 
follicle stimulating hormone (FSH), which do not need to be repeated).  The FibroScan 
and liver biopsy do not need to be repeated for rescreened subjects provided that the date 
of the liver biopsy is within 6 months of the rescreening date and the FibroScan is within 
3 months of the rescreening date (Section 5.1.1).
The Primary Therapeutic Area Medical Director should be contacted for approval prior to 
rescreening.  Subjects that are beyond the initial 42-day screening period may still be 
allowed to enroll within a reasonable time period if they continue to meet all eligibility 


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criteria and have received approval by the Primary Therapeutic Area Medical Director.  If 
rescreened, the 42 day screening period restarts, and subjects retain their initial subject 
number.
For subjects who rescreen and still do not meet the study eligibility criteria upon 
retest/rescreen, the site personnel must register the subject as a screen failure in both IRT 
and EDC systems. 
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT on Study Day 1.  
Subjects will be administered study drugs at the site on Study Day 1, and given 
instructions about the administration of study drugs, immunosuppression medication and 
dosing schedule.
Subject immunosuppression dosing regimen diaries will be maintained throughout the 
trial, for all subjects taking cyclosporine, sirolimus, everolimus, and/or tacrolimus during 
the Screening, Treatment and Post-Treatment periods.  All doses of these medications are 
to be recorded in the diary, including dosage strength, date, and time.  The information 
collected in the diaries will be reviewed during each study visit and recorded in the eCRF 
in addition to the local laboratory immunosuppression level results.  Diaries should be 
dispensed, collected and reviewed at each study visit as indicated in Appendix C and 
Appendix D.  Subjects should be reminded to bring the diary to each study visit.
At any time during the treatment period, the investigator may perform supplemental 
immunosuppression level testing as an unscheduled visit.
Refer to Section 5.2.3.2 (Management of Immunosuppressive Agent Dosing) for details 
regarding management of the immunosuppressive regimen (CNI and mTOR) during the 
treatment period.  
Study visits and procedures during the Treatment Period are detailed in Appendix C.  
Safety and tolerability will be assessed throughout the study.  Laboratory testing will 


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include chemistry, hematology, coagulation panel and urinalysis as specified in Table 2.  
Plasma samples for pharmacokinetic analysis (including optional samples for intensive 
PK analysis) and HCV RNA analysis will be collected as detailed in Section 5.3.1.1 and 
Section 5.3.2, respectively.  Blood samples for optional pharmacogenetic analysis will be 
collected as detailed in Appendix C.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all the study visits.  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 
study drug exposure. 
The virologic failure criteria will be evaluated and applied by the investigator as detailed 
in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.4.1.  Subjects who prematurely discontinue 
from study treatment will continue to be followed in the Post-Treatment Period (see 
Section 5.1.3).
5.1.3
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 viral 
variants for an additional 24 weeks following the last dose of study drug.  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 Appendix D and 
Section 5.3.1.1.
On Day 1 of the Post-Treatment Period, it is recommended that the pre-study dose of 
immunosuppressants tacrolimus, sirolimus, everolimus and cyclosporine be resumed.  
Further modifications in tacrolimus, sirolimus, everolimus and cyclosporine dosing or 


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dose frequency should be guided by measuring trough level testing.  During the 
post-treatment period, the investigator may need to monitor and adjust the dosing of 
cyclosporine, tacrolimus, everolimus, and sirolimus for study subjects.
Subjects who prematurely discontinue the Post-Treatment Period should return to the site 
for a Post-Treatment discontinuation visit as outlined in Appendix D.
5.2
Selection of Study Population
The study population will consist of chronic HCV-infected GT1 – 6 males and females, 
who have received a primary orthotopic liver transplant or primary renal transplant, are 
non-cirrhotic (F0-F3), and who are either HCV treatment-naïve or prior 
treatment-experienced with IFN or pegIFN with or without RBV or sofosbuvir with RBV 
with or without pegIFN (except for GT3 subjects who must be treatment-naïve).
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Male or female at least 18 years of age at time of Screening.
2.
If female, subject must be either postmenopausal (defined in Section 5.2.4), OR 
permanently surgically sterile OR for Women of Childbearing Potential practicing 
at least one protocol specified method of birth control (see Section 5.2.4), starting 
at Study Day 1 through at least 30 days after the last dose of study drug. 
For male subjects, no contraception is required.
3.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.  Females of 
non-childbearing potential (either postmenopausal or permanently surgically sterile 
as defined in Section 5.2.4) at Screening do not require pregnancy testing.
4.
Screening laboratory result indicating HCV GT 1, 2, 3, 4, 5 or 6 infection.


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5.
Subject has positive anti-HCV Ab and plasma HCV RNA viral load ≥ 1000 IU/mL 
at Screening Visit.
6.
Chronic HCV infection defined as one of the following:
●
Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before 
Screening, or 
●
A liver biopsy consistent with chronic HCV infection, or 
●
Abnormal alanine aminotransferase (ALT) levels for at least 6 months before 
Screening.
7.
Subject must be HCV treatment-naïve (i.e., subject has not received a single dose 
of any approved or investigational anti-HCV medication) or HCV 
treatment-experienced (subject has failed prior treatment with IFN or pegIFN with 
or without RBV or sofosbuvir with RBV with or without pegIFN), pre- or post-
transplant.  Previous HCV treatment must have been completed ≥ 2 months prior to 
screening.  GT3 subjects must be treatment-naïve.
8.
Body Mass Index (BMI) is ≥ 18.0 kg/m2 at the time of Screening.  BMI is 
calculated as weight measured in kilograms (kg) divided by the square of height 
measured in meters (m).
9.
Subjects must be documented as non-cirrhotic defined as meeting one of the 
following criteria:
●
A liver biopsy within 6 months prior to or during Screening demonstrating the 
absence of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, 
Scheuer, or Laennec fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; or
●
A FibroScan® score of < 12.5 kPa within 3 months of Screening or during the 
Screening Period; 
○
Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6), must 
have a qualifying liver biopsy; or
●
A screening FibroTest score of ≤ 0.48 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) < 1.


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○
Subjects with indeterminate FibroTest (0.48 < result < 0.75), or conflicting 
FibroTest and APRI results (e.g., FibroTest ≤ 0.48, but APRI ≥ 1) must 
have a qualifying liver FibroScan® or biopsy.
Liver biopsy results will supersede Fibrotest®/APRI or FibroScan® results and 
be considered definitive.  FibroScan® results will supersede Fibrotest®/APRI 
results for the determination of absence of cirrhosis.
10.
Subjects must voluntarily sign and date an informed consent form, approved by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the 
initiation of any screening or study-specific procedures.
11.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
12.
Subject is a recipient of a cadaveric or living donor liver transplant which was a 
consequence of HCV infection ≥ 3 months prior to screening Or Subject received a 
cadaveric or living donor kidney at least ≥ 3 months before screening.
13.
For subjects with a history of hepatocellular carcinoma (HCC):  Subject is a 
recipient of a cadaveric or living donor liver transplant ≥ 3 months prior to 
screening as a consequence of hepatocellular carcinoma (HCC) in the setting of 
chronic HCV will be eligible if there is not a clinical diagnosis of recurrent HCC 
post-liver transplant.
14.
Subject is currently taking a stable immunosuppressant regimen based on 
tacrolimus, sirolimus, everolimus, mycophenolate mofetil (MMF), azathioprine, 
cyclosporine and/or mycophenolic acid.  Corticosteroids such as prednisone or 
prednisolone are permitted as components of the immunosuppressant regimen 
providing the dose is no more than 10 mg/day at the time of screening.  
Cyclosporine must be at a maintenance dose of 100 mg or less per day.
Rationale for Inclusion Criteria
1, 4 – 7, 9, 12, 13
In order to select the appropriate subject population with 
appropriate disease characteristics for evaluation


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8, 14
For the safety of study subjects
2, 3
The impact of ABT-493 and ABT-530 on pregnancies is unknown
10, 11
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
2.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
3.
Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti 
human immunodeficiency virus antibody (HIV Ab).
4.
HCV genotype performed during screening indicating co-infection with more than 
one HCV genotype or if HCV genotype is indeterminate.
5.
Requirement for and inability to safely discontinue the medications or supplements 
listed in Table 1 the protocol (Section 5.2.3.4) at least 2 weeks or 10 half-lives 
(whichever is longer) prior to the first dose of any study drug.
6.
Clinically significant abnormalities, other than HCV infection, that make the 
subject an unsuitable candidate for this study in the opinion of the investigator, 
including, but not limited to:
●
Active or suspected malignancy.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, 
psychiatric, metabolic, or other medical disease or disorder, which is unrelated 
to the existing HCV infection.


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●
Uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) 
level > 8.5% at the Screening Visit.
7.
Any cause of liver disease post transplantation other than chronic HCV infection 
including but not limited to the following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Steatohepatitis on liver biopsy considered to be the primary cause of the liver 
disease rather than concomitant/incidental with HCV infection.
8.
Clinical history of Fibrosing cholestatic hepatitis at any time post-transplant.
9.
Screening laboratory analyses showing any of the following abnormal laboratory 
results: 
●
ALT and AST > 10 × ULN
●
Albumin < 3.5 g/dL
●
Hemoglobin < 10 g/dL 
●
Platelets < 70,000 
●
Calculated creatinine clearance (using Cockcroft-Gault method) of 
< 30 mL/min
●
Direct bilirubin > 2 mg/dL
●
International Normalized Ratio (INR) > 1.5 ULN
10.
Clinical history of acute renal failure in the 3 months prior to screening.
11.
Re-transplantation of the liver or kidney. 
12.
Recipient of liver or kidney from a donor with known HIV infection and/or HBV 
surface antigen positive.
13.
Steroid resistant rejection of the transplanted liver or kidney, or a history of 
rejection treated with high dose steroid within 3 months of screening.


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14.
History of post-transplant complications related to hepatic or renal vasculature.
15.
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) prior to 
study drug administration. 
16.
Receipt of any other investigational or commercially available direct acting 
anti-HCV agents other than sofosbuvir (e.g., telaprevir, boceprevir, simeprevir, 
paritaprevir, daclatasvir, ledipasvir, ombitasvir, elbasvir or dasabuvir).  
17.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-493/ABT-530.
18.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drugs.
19.
Subjects who cannot participate in the study per local law.
Rationale for Exclusion Criteria
1, 6, 9, 11, 13 – 19
In order to ensure safety of the subjects throughout the 
study
2, 5, 10, 12
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
3, 4, 7, 8, 12
To exclude subjects with HIV or liver diseases other than 
chronic HCV GT1 – 6 infection
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from the time of signing 
consent, or received during the study, through the Treatment Period and 30 days after 
study drugs are stopped, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 


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and frequency.  The investigator should review all concomitant medications for any 
potential drug-drug interactions.  
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in EDC.
The Primary Therapeutic Area Medical Director should be contacted if there are any 
questions regarding prior or concomitant therapy(ies).
5.2.3.1
Prior HCV Therapy
Subjects must be HCV treatment-naïve or treatment-experienced, with the exception of 
HCV GT3 treatment-experienced subjects who will not be eligible.  Subjects will be 
considered treatment-experienced, if they have previously received HCV treatment with 
IFN or pegIFN with or without RBV or sofosbuvir with RBV with or without pegIFN.  
Receipt of any other investigational or commercially available direct acting anti-HCV 
agents other than sofosbuvir is not allowed.
Subjects will be categorized as:
●
Treatment-naïve: subject has never received any treatment for HCV infection.
●
Subjects with an allowed prior treatment will be categorized as:
○
Non-responder:  HCV RNA detected at the end of a prior treatment 
course (except for breakthrough, which is captured separately).  These 
subjects are further categorized as:
●
Null responder:  failed to achieve a 1 log10 IU/mL reduction in HCV 
RNA by Week 4 or a 2 log10 IU/mL reduction in HCV RNA by 
Week 12 during a prior treatment course; 


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●
Partial responder:  achieved at least a 2 log10 IU/mL reduction in HCV 
RNA by Week 12 during a prior treatment course but failed to achieve 
HCV RNA undetectable at the end of treatment; 
●
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder. 
○
Breakthrough:  confirmed ≥ 1 log10 IU/mL increase from nadir or 
achieved HCV RNA undetectable (or unquantifiable) during a prior 
treatment course but HCV RNA was quantifiable during or at the end of 
treatment. 
○
Relapse:  achieved HCV RNA undetectable at the end of a prior treatment 
course but HCV RNA was detectable following cessation of therapy.
○
Other:  subject received a prior treatment course and reason for not
achieving SVR is other than above.
○
Unknown:  subject received a prior treatment course and reason for not 
achieving SVR is unknown.
Subjects must have completed or discontinued prior therapy at least 2 months prior to the 
Screening Visit in order to be eligible for the study.
5.2.3.2
Management of Immunosuppressant Agent Dosing
Drug-drug interaction studies have been conducted for ABT-493/ABT-530 
co-administered with cyclosporine or tacrolimus and are detailed, along with the dosing 
recommendations during the Treatment Period as follows:
Dosing recommendations for tacrolimus management during treatment with ABT-493 and 
ABT-530 in this study are:
●
For subjects who are initiating therapy with tacrolimus, the initial dose should 
be selected from the lower end of the recommended range as per the 
tacrolimus label (e.g., 0.10 mg/kg/day for adult liver transplant recipients).
●
For subjects already taking tacrolimus, dosing should continue with close 
monitoring of tacrolimus trough levels and tacrolimus dose adjustment as 
needed.


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Dosing recommendations for cyclosporine management during treatment with ABT-493 
and ABT-530 in this study are:
●
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should 
not exceed 100 mg once daily for entry into the study. If the cyclosporine 
maintenance dose needs to be increased to a total daily dose greater than 
100 mg during the Treatment Period, discussion with the Therapeutic Area 
Medical Director should occur.  Dosages of cyclosporine > 400 mg are not 
allowed during the Treatment Period.
For mTOR inhibitors, as the metabolic profile for both sirolimus and everolimus are 
similar to tacrolimus, management of sirolimus and everolimus will be similar to 
tacrolimus (refer to Section 3.0 for additional information).
●
For subjects who are initiating therapy with sirolimus or everolimus, the initial 
dose should be selected from the lower end of the recommended range as per 
the sirolimus and everolimus labels.
●
For subjects already taking sirolimus or everolimus, dosing should continue 
with close monitoring of drug trough levels and dose adjustment as needed.
During this study, the dosing of tacrolimus, cyclosporine, sirolimus and everolimus will 
be informed by scheduled blood level testing.  Tacrolimus, cyclosporine, sirolimus and 
everolimus blood level testing may be performed at any time during the study at the 
investigator's discretion.  Where possible, it is recommended that CNI and mTOR 
medications be taken with study drugs in the morning with food.  Based on in vitro 
drug-drug interaction studies, no potential interaction is expected with azathioprine, MMF 
and mycophenolic acid.  Subjects may be on azathioprine, MMF, and/or mycophenolic 
acid as per the investigator's discretion.  Monitoring of azathioprine, MMF, and/or 
mycophenolic acid levels beyond what is standard and clinically indicated is not required.
CNI dosing in the study is guided by the recommended dose reductions based on healthy 
volunteer data and modeled to achieve trough levels appropriate in the post-transplant 
setting. Clinical experience suggests some differences may be observed between patients 


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in relation to cyclosporine or tacrolimus dosing and associated trough levels.  Therefore 
CNI and mTOR dosing will be guided by frequent trough level estimates, particularly 
during the first weeks of treatment administration, and by the investigators clinical 
experience in the management of CNI and mTOR medications in liver or renal transplant 
recipients.
On Day 1 of the Post-Treatment Period, it is recommended that the pre-study dose of 
immunosuppressants tacrolimus, sirolimus, everolimus and cyclosporine be resumed.  
Further modifications in tacrolimus, sirolimus, everolimus and cyclosporine dosing or 
dose frequency should be guided by measuring trough levels.
5.2.3.3
Concomitant Therapy
Subjects should be on a stable dose of concomitant medications for at least 2 weeks prior 
to initiation of study drugs.  The investigator should confirm that a concomitant 
medication/supplement can be safely administered with study drugs.  Some medications 
may require dose adjustments due to the potential for drug-drug interactions.  
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, 30 days following discontinuation 
of study drugs, if applicable.
5.2.3.4
Prohibited Therapy
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 1 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 
30 days following discontinuation of study drugs.


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Table 1.
Prohibited Medications and Supplements
Medication or Supplement Name
Any herbal supplements (including milk thistle), red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
*
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 30 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.
Use of ethinyl estradiol containing oral contraceptives with ABT-493 and ABT-530 
combination was associated with ALT increases in some healthy female subjects.  
Hormonal contraceptives (including oral, topical [including vaginal rings], injectable, or 
implantable varieties) containing ethinyl estradiol may not be used from 2 weeks prior to 
the first dose of ABT-493/ABT-530 until 30 days after the end of ABT-493/ABT-530 
dosing.  Progestin-only contraceptives, such as those containing norethindrone, 
desogestrel, or levonorgestrel, without ethinyl estradiol, may be used with 
ABT-493/ABT-530.  Post-menopausal hormone replacement therapy i.e., estradiol, 
esterified or conjugated estrogens, as long as they do not contain ethinyl estradiol, may be 
used with ABT-493/ABT-530 at the discretion of the Investigator.
The chronic use of systemic immunosuppressants other than those from the anti-rejection 
regimen is prohibited from 2 weeks prior to the first dose of study drug and until 30 days 
after the last dose of study drug including, but not limited to, corticosteroids (prednisone 
equivalent of > 10 mg/day for > 2 weeks), or monoclonal antibodies (e.g., infliximab).
5.2.4
Contraception Recommendations and Pregnancy Testing
If female, subject must be either postmenopausal defined as:


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●
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).
●
Practicing at least one of the following methods of birth control, on Study 
Day 1 (or earlier) through at least 30 days after the last dose of study drug.
○
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.
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
Progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action, initiated at least 1 month prior 
to Study Day 1.
○
Male or female condom with or without spermicide. Condom without 
spermicide is acceptable only in countries where spermicide is not 
available. 
○
Cap, diaphragm or sponge with spermicide.
○
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
○
True abstinence:  Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).


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For male study subjects no contraception is required. 
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C (Treatment Period) and Appendix D
(Post-Treatment Period).
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.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including date of transplant, type of donor (deceased or 
living), history of tobacco, alcohol and drug use, will be taken at Screening.  The subject's 
medical history will be updated at the Study Day 1 Visit.  This updated medical history 
will serve as the baseline for clinical assessment.
For all subjects, prior IFN-based HCV treatment history and type of prior treatment 
response should be collected and recorded in source documentation according to the 
categories listed in Section 5.2.3.1.  Data should be collected and recorded for each 
subject for both pre and post renal and liver transplant settings.  Reasonable effort should 
be made to obtain and document this information.


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Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Height will be measured only at Screening.  
Vital Signs and Weight
Body temperature, blood pressure, pulse and body weight will be measured at each study 
visit as specified in Appendix C and Appendix D or upon subject discontinuation.  Blood 
pressure and pulse rate should be measured after the subject has been sitting for at least 
3 minutes.  The subject will wear lightweight clothing and no shoes during weighing.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at Screening.  The ECG should be performed 
prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant


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Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.  
Local Therapeutic Monitoring for Cyclosporine, Sirolimus, Everolimus, and/or 
Tacrolimus 
Blood samples for immunosuppressant trough level estimation will be submitted to the 
investigative site's local laboratory for subjects taking cyclosporine, tacrolimus, 
everolimus and sirolimus as indicated in Appendix C and Appendix D and at any other 
time points that the investigator deems necessary.  For each immunosuppressant level 
blood draw, the result, the date and time of the sample collection and details regarding 
immunosuppressant dosing will be recorded in the electronic case report form (eCRF).
Investigators will use the local laboratory results for management of immunosuppressant 
related adverse events or dose modifications during the study.  A central laboratory will 
be utilized to process and provide results for all other clinical laboratory tests.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 2
at the visits indicated in Appendix C and Appendix D.
Blood samples for serum chemistry tests should be collected following a minimum 8-hour 
fast prior to study drug intake (with the exception of the Screening Visit, which may be 
non-fasting).  Subjects whose visits occur prior to the morning dose of study drug should 
be instructed to fast after midnight until the blood sample is collected in the morning and 
thereafter take their study medications with food.  Subjects whose visits occur following 
the morning dose of study drug should be instructed to fast after breakfast until the study 
visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected prior to 
the first dose of study drug.  Blood samples should still be drawn if the subject did not fast 
for at least 8 hours.  Fasting or non-fasting status will be recorded in the source 
documents and on the laboratory requisition.  The baseline laboratory test results for 


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clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A central laboratory will be utilized to process and provide results for all other clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Samples will be sent to the following addresses:
Covance
8211 SciCor Drive
Indianapolis, IN  46214 USA
(For sites in North America)
Covance
7 rue Moise-Marcinhes
1217 Meyrin
Geneva Switzerland
(For sites in Europe)
Covance (Asia) Pte Ltd
1 International Business Park
The Synergy
Singapore  609917
(For sites in Asia Pacific)


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Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Reticulocyte count
Prothrombin Time/INR
Activated partial thromboplastin
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Direct and indirect bilirubin
Total bilirubin
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Calcium
Inorganic phosphate
Sodium
Potassium
Cholesterol
Low Density Lipoproteins (LDL)a,b
High Density Lipoprotein (HDL)b
Chloride
Bicarbonate
Magnesium 
Total Insulin
Total protein
Glucose
Triglycerides
Gamma-glutamyl transferase (GGT)
Creatinine clearance 
(Cockcroft-Gault calculation
HBsAgc
Anti-HCV Abc
Anti-HIV Abc
Opiatesc
Barbituratesc
Amphetaminesc
Cocainec
Benzodiazepinesc
Alcoholc
Phencyclidinec
Propoxyphenec
Methadonec
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG) for 
femalesd
FSHh
HCV RNA
Hepatitis B Panele
Hemoglobin A1Cc
IL28B
HCV genotype and subtypec
Pharmacogenetic sample 
(optional)
Alpha2-macroglobulinf
Haptoglobinf
Apolipoprotein A1f
Alpha fetoproteinc
Cyclosporine levelg
Tacrolimus levelg
Everolimus levelg
Sirolimus levelg
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Directly measured.
b.
Performed only at Baseline.
c.
Performed only at Screening.
d.
Pregnancy testing is not required for females of non-childbearing potential. 
e.
Performed for management of transaminase elevation (Section 6.1.7.1). 
f.
Component of FibroTest and collected only if needed during the Screening Period.
g.
Therapeutic monitoring only performed locally during the study for purposes of immunosuppression dose 
management.
h.
Only performed if requested during screening for post-menopausal women < 55 to verify FSH level if site does not 
have one available.


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For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug 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 6.1.7.
Pregnancy Test
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 visits indicated in 
Appendix C.  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.
Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.  The investigator must discuss any local reporting requirements to local health 
agencies with the subject.  The site will report these results per local regulations, if 
necessary.  The HIV results will not be reported by the central laboratory to the clinical 
database.
Urine Screens for Drugs of Abuse
Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse.  
The panel for drugs of abuse will minimally include the drugs listed in Table 2.  Any 
positive result must be assessed for clinical significance.


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These analyses will be performed by the certified central laboratory chosen for the study.
Liver Diagnostic Testing
At Screening, it is recommended that subjects should otherwise meet all of the inclusion 
criteria and none of the exclusion criteria before undergoing a liver biopsy.
Subjects who have not had a qualifying liver biopsy within the previous 6 months or who 
have not had a qualifying FibroScan within the previous 3 months but otherwise meet all 
of the inclusion criteria and none of the exclusion criteria will undergo liver biopsy or 
non-invasive testing (FibroTest and APRI or FibroScan) for assessment of cirrhosis prior 
to enrollment.  Selection of liver biopsy or non-invasive testing performed should be 
based on local standard practice.
Subject will be considered to be non-cirrhotic and eligible for the study if they meet at 
least one of the criteria listed in the Inclusion Criterion 9 (Section 5.2.1).  
Patient Reported Outcomes (PRO) Instruments (Questionnaires)
Subjects will complete the self-administered PRO instruments (where allowed per local 
regulatory guidelines) on the study days specified in Appendix C and Appendix D.  
Subjects should be instructed to follow the instructions provided with the instruments and 
to provide the best possible response to each item.  Site personnel shall not provide 
interpretation or assistance to subjects other than encouragement to complete the tasks.  
Subjects who are functionally unable to read any of the instruments may have site 
personnel read the questionnaires to them.  Site personnel will encourage completion of 
each instrument at all specified visits and will ensure that a response is entered for all 
items.
PRO instruments should be consistently presented as listed in Appendix C and 
Appendix D, so that subjects complete the questionnaires in the following order:  the 
SF-36v2, FSS and EQ-5D-3L.  The PRO instruments should be completed prior to study 


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drug administration on Day 1 and prior to any discussion of adverse events or any review 
of laboratory findings, including HCV RNA levels.
Short Form 36 (SF-36) – Version 2 Health Survey
The SF-36v2 is a general Health Related Quality of Life (HRQoL) instrument with 
extensive use across a broad variety of health conditions and is the standard in 
literature for HCV.  The SF-36v2 instrument comprises 36 total items (questions) 
targeting a subject's functional health and well-being in 8 domains (physical 
functioning, role physical, bodily pain, general health, vitality, social functioning, role 
emotional and mental health).  Domain scores are also aggregated into a Physical 
Component Summary score and a Mental Component Summary score.  Higher 
SF-36v2 scores indicate a better state of health.  The SF-36v2 should require 
approximately 10 minutes to complete.
Fatigue Severity Scale (FSS)
The FSS measures the impact of fatigue over the past week on specific types of 
functioning (e.g., motivation, exercise, physical functioning, carrying out duties, 
interfering with work, family, or social life).  The survey consists of 9 questions using 
a 7 point Likert scale.  A total score is calculated as the average of the individual item 
responses.  The scale's psychometric properties have been confirmed in chronic 
hepatitis C and other diseases.  The FSS should require approximately 5 minutes to 
complete.
EuroQol-5 Dimensions-3 Level (EQ-5D-3L)
The EQ-5D-3L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) each of which are 
rated on 3 levels of severity (no problems, some problems, unable to do/extreme 
problems).  Responses to the 5 items encode a discrete health state which is mapped to 
a preference (utility) specific for different societies.  Subjects also rate their perception 


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of their overall health on a separate visual analogue scale (VAS).  The EQ-5D-3L 
should require approximately 5 minutes to complete.
Enrollment and Assignment of Subject Numbers
All screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet all the Inclusion Criteria and none of the Exclusion Criteria at Screening will 
proceed to enrollment via the IRT system on Study Day 1.
Subject numbers will be unique 6-digit numbers and will begin with 100301 with the 
first three digits representing the investigative site, and the last three digits representing 
the subjects at that site.  Enrolled subjects will keep their subject number throughout the 
study.  
Study Drug Compliance for Kits
Individual bottles of ABT-493/ABT-530 will be provided for subject dosing to the site.  
Each subject will have compliance documented by the site in the subject's source notes for 
ABT-493/ABT-530.  At each Study Drug Accountability Visit listed in Appendix C, the 
overall number of tablets of ABT-493/ABT-530 remaining in each bottle will be recorded 
and entered in the IRT system along with the date of reconciliation.
Additional information regarding treatment compliance can be found in Section 5.5.6.
HCV Genotype and Subtype
Plasma samples for HCV genotype and subtype determination will be collected at 
Screening.  Genotype and subtype will be assessed using the Versant® HCV Genotype 
Inno LiPA Assay, Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, 
Tarrytown, NY) by the central laboratory.  If the LiPA assay is unable to genotype a 
sample, its genotype/subtype will be determined by a Sanger sequencing assay of a region 
of the NS5B gene by the central laboratory.  


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
Appendix D.  Plasma HCV RNA levels will be determined for each sample collected by 
the central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV 
Quantitative Test, v2.0.  The lower limit of detection (LLOD) and lower limit of 
quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.  
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Day 1 
and at the study visits indicated in Appendix C and Appendix D.  Specific instructions for 
preparation and storage of HCV RNA and HCV resistance samples will be provided by 
the central laboratory, AbbVie, or its designee.
Archive Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Appendix C and 
Appendix D.  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 or measures of disease progression, as determined by 
AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.
Immunosuppression Regimen Dosing Diary 
A subject immunosuppression regimen dosing diary will be provided to all subjects taking 
cyclosporine, sirolimus, everolimus, and/or tacrolimus during Screening and for 30 days 
into the Post-Treatment period.  All doses of these immunosuppressive medications will 
be recorded in the diary by study subjects, including dosage strength, date, and time.  The 
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in the eCRF along with the local laboratory therapeutic monitoring laboratory results.  
Site personnel will provide training on its proper use and subjects will be instructed to 
complete the required information and ensure that entries are accurate and current at all 
times.  
Diaries should be dispensed, collected and reviewed at each study visit as appropriate as 
indicated in Appendix C and Appendix D.  Subjects should be reminded to bring the 
completed diary to each study visit.
Study Drug Dosing Card
Subjects will be provided with self-administration instructions and study drug dosing 
cards to record the exact date, time (record to the nearest minute) and number of tablets of 
study drug administration (ABT-493/ABT-530) for the last 2 doses of each study drug 
taken prior to the scheduled pharmacokinetic sample collection during the Treatment 
Period.
The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
●
The study coordinator should make sure the subject is given the dosing card at 
the visits listed in Appendix C and that instruction is provided to the subject 
regarding proper study drug administration relative to the pharmacokinetic 
blood collection and documentation of dosing times on the dosing card.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.


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5.3.1.2
Meals and Dietary Requirements
Study drug (i.e., ABT-493/ABT-530) tablets should be dosed together and taken with 
food.  When an immunosuppressant medication is scheduled to be taken, per direction 
from the investigator, the medication should be administered with the study drug.
5.3.1.3
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples 
Specific instructions for collection, storage and shipment of pharmacogenetic samples will 
be provided by the central laboratory, AbbVie, or its designee.
IL28B Sample
One (required) whole blood sample for DNA isolation will be collected from each subject 
at Study Day 1 for Interleukin 28B (IL28B) pharmacogenetic analysis.  If the IL28B 
pharmacogenetic sample is not collected on Day 1, it may be collected at any other visit 
during the study.  This sample will not be used for any testing other than IL28B 
genotypes.
5.3.1.4
Optional Sample for Pharmacogenetic Exploratory Research 
Subjects will have the option to provide samples for optional pharmacogenetic 
exploratory research.  Subjects may still participate in the main study even if they decide 
not to participate in this optional exploratory research.
An optional whole blood sample for DNA isolation will be collected on Day 1 from each 
subject who consents to provide samples for exploratory research.  If the sample is not 
collected on Day 1, the sample may be collected at any time throughout the study.
AbbVie (or people or companies working with AbbVie) will store the optional 
pharmacogenetic exploratory research samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
ABT-493/ABT-530 (or drugs of this class) or this disease and related conditions 
continues, but for no longer than 20 years after study completion.  The procedure for 


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obtaining and documenting informed consent for exploratory research samples is 
discussed in Section 9.3.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assays of ABT-493, ABT-530 and their possible 
metabolites will be collected by venipuncture at each study visit indicated below and in 
Appendix C.
Subjects who do not participate in Optional Intensive PK sampling:
●
At all Treatment Period visits, except for Study Day 1, a single blood sample 
(3 mL) will be collected without regard to the time of dosing.  
●
The date and time of blood sample collection and the two previous doses of the 
study drug will be recorded to the nearest minute in the source documents.  
Additionally, the date and time of the two previous doses of the study drug 
will be recorded to the nearest minute on the eCRF.
Subjects who consent to participate in Optional Intensive PK sampling: 
●
On Study Day 1 and the Week 4 visit, subjects will have their dose 
administered by study site personnel with food.  Blood samples will be 
collected on Study Day 1 at 2, 4 and 6 hours post-dose and at the Week 4 Visit 
immediately prior to dose (0 hour) and 2 and 4 hours post-dose.
○
The date and time of site-administered dose, blood sample collection and 
the two previous doses of study drug (for Week 4 Visit only) will be 
recorded to the nearest minute in the source documents.  Additionally, the 
date and time of the site-administered dose and two previous doses (for 
Week 4 Visit only) will be recorded in the eCRF.
●
At all other Treatment Period visits, a single blood sample (3 mL) will be 
collected without regard to the time of dosing.
○
The date and time of blood sample collection and the two previous doses 
of the study drug will be recorded to the nearest minute in the source 


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documents.  Additionally, the date and time of the two previous doses of 
the study drug will be recorded to the nearest minute on the eCRF.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-493 and ABT-530 
will be provided by the central laboratory, the Sponsor, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, their 
possible metabolites and archive plasma samples will be packed in dry ice sufficient to 
last during transport, and transferred from the study site to the central laboratory.
The central laboratory will then ship the ABT-493 and ABT-530 samples to the reference 
laboratories following separately provided instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of ABT-493 and ABT-530 will be determined using validated 
assay methods under the supervision of the Drug Analysis Department at AbbVie.  
Plasma concentrations of possible metabolites of any analytes listed above may also be 
determined using either validated or non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 24 weeks after completion of treatment.
5.3.3.1
Primary Variable
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).


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5.3.3.2
Secondary Variable(s)
The secondary efficacy variables are on-treatment virologic failure and post-treatment 
relapse.
Additional efficacy variables include:  SVR4, SVR24, and the percentage of subjects who 
relapsed after achieving SVR12.
5.3.4
Resistance Variables
For all subjects receiving ABT-493/ABT-530, the variants at signature 
resistance-associated amino acid positions at baseline identified by population or deep 
sequencing and comparison to the appropriate prototypic reference sequence will be 
analyzed.
The following resistance information will be analyzed for subjects receiving 
ABT-493/ABT-530 who do not achieve SVR12 and who have a post-baseline sample with 
HCV RNA ≥ 1000 IU/mL:  1) the amino acid variants in available post-baseline samples 
identified by population or deep sequencing and comparison to the baseline sequence, 
2) the amino acid variants in available post-baseline samples at signature resistance 
associated positions identified by population or deep sequencing and comparison to the 
appropriate prototypic reference sequence, and 3) the persistence of viral resistance by 
population or deep sequencing.
5.3.5
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, ECG, and laboratory tests assessments.
5.3.6
Pharmacokinetic Variables
Individual plasma concentrations of ABT-493 and ABT-530 and possible metabolites of 
ABT-493 and ABT-530 will be tabulated and summarized.  Individual blood 


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concentrations of immunosuppressants, cyclosporine, sirolimus, everolimus, and/or 
tacrolimus, will also be tabulated and summarized.
5.3.7
Pharmacogenetic  Exploratory Research Variables
IL28B status will be determined for each subject and analyzed as a factor contributing to 
the subject's response to study treatment.  These IL28B GT results may be analyzed as 
part of a multi-study assessment of IL28B and response to ABT-493, ABT-530, or drugs 
of these classes.  The results may also be used for the development of diagnostic tests 
related to IL28B and study treatment, or drugs of these classes.  The results of additional 
IL28B pharmacogenetic analyses may not be reported with the clinical study report.
Optional pharmacogenetic samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be 
analyzed as part of a multi-study assessment of factors influencing the subjects' response 
to the study drug (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods or technologies.  The results 
from these analyses are exploratory in nature and may not be included with the study 
report.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If, 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 Appendix C.  Ideally this should occur on the day of study drug 


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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 EDC (electronic data capture) system.  The subject should then begin the 
Post-Treatment Period where the subject will be monitored for 24 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 study drug 
may be continued at the Principal Investigator's discretion after discussion with the 
subject, if the benefit of continuing study drug is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  If a 
subject is discontinued, subject will be monitored for SVR in the Post-Treatment Period 
as described in Section 5.1.3.
For subjects who are receiving study drugs and experience an episode of rejection of the 
transplanted liver or kidney that is presumed or histologically confirmed, the Primary 
Therapeutic Area Medical Director should be contacted to discuss the planned evaluation 
and/or treatment plan.  Subjects who are receiving study drugs and experience an episode 
of rejection of the transplanted liver or kidney that is presumed or histologically 
confirmed may continue the study drugs per investigator discretion.  Should there be a 
need to discontinue the study drugs, the subject should enter the Post-Treatment Period.  
Treatment(s) of a rejection episode, e.g., by use of corticosteroids or other agents, will be 


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captured in eCRF as part of the adverse event reporting.  Alternative management of study 
drug in this setting requires Primary Therapeutic Area Medical Director approval.
For subjects discontinuing study drugs, investigators should be aware of the potential for 
consequent alterations in immunosuppressant levels and should ensure that a plan is in 
place for appropriate immunosuppressant dose modification in the PTP and this plan 
should be discussed with the study subject.  See Section 5.2.3.2 for further information on 
the management of immunosuppressants.
5.4.1.1
Virologic Failure Criteria
The following criteria will be considered evidence of HCV virologic failure for the 
purposes of subject management:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurements of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment.
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic failure criteria has been 
confirmed.  Subjects meeting the virologic failure criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistant viral variants until 24 weeks post-treatment. 
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 


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concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
The study drug (ABT-493/ABT-530) will be dispensed in the form of co-formulated 
tablets at the visits listed in Appendix C.  Subjects will be instructed to take study drugs at 
the same time every day with food.  Prior to all visits with pharmacokinetic sampling, the 
date and time of the two previous doses will be recorded to the nearest minute in the 
source documents and the eCRF.
ABT-493/ABT-530 will be provided by AbbVie as 100 mg/40 mg Film-coated tablets.  
ABT-493/ABT-530 will be taken orally at ABT-493 300 mg/ABT-530 120 mg (three × 
ABT-493 100 mg/ABT-530 40 mg tablets) QD and with food.
Subjects will be instructed to take study medication at the same time(s) every day.  All 
compounds including cyclosporine, sirolimus, everolimus, tacrolimus, azathioprine, 
MMF, and mycophenolic acid should be taken together with food.  This is important as 
taking the DAAs in combination with the immunosuppressants at different times can 
significantly impact the levels of the immunosuppressant medications.
Investigators should inform subjects in advance of Study Day 1 of the plan for 
cyclosporine, sirolimus, everolimus or tacrolimus management during the study, e.g., an 
investigator may wish to instruct a subject not to take their morning CNI/mTOR dose 
prior to the site visit on Study Day 1.
Beginning with Study Day 1, the site will use the IRT system to obtain the study drug kit 
numbers to dispense at the study visits specified in Appendix C.  Study drug must not be 
dispensed without contacting the IRT system.  Study drug may only be dispensed to 
subjects enrolled in the study through the IRT system.  The site will also contact the IRT 


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system to provide study drug return information for each kit at the visits specified in 
Appendix C.  At the end of the Treatment Period or at the Premature D/C Visit from the 
Treatment Period, the site will contact the IRT system to provide the discontinuation visit 
date information and study drug return information for each kit.
All subjects who receive at least one dose of study drug and meet the virologic failure 
criteria defined in Section 5.4.1.1 will be discontinued from treatment. 
5.5.2
Identity of Investigational Products
Information about the study drugs to be used in this study is presented in Table 3.
Table 3.
Identity of Investigational Products
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
ABT-493/ABT-530
AbbVie
Oral
Film-coated Tablet
100 mg/40 mg
5.5.2.1
Packaging and Labeling
All study drugs will be supplied in bottles.
Each bottle will be labeled 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.
5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions
ABT-493/ABT-530 bottles
15° to 25°C (59° to 77°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 or returned to AbbVie.


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5.5.3
Method of Assigning Subjects to Treatment 
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of the IRT system.  For subjects who do not meet the study selection criteria, the site 
personnel must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive unique study drug kit numbers.  The study drug 
kit numbers will be assigned according to schedules computer-generated before the start 
of the study by the AbbVie Statistics Department.  
Contact information and user guidelines for IRT use will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
5.5.4
Selection and Timing of Dose for Each Subject
Study drug dosing will be initiated at the Study Day 1 Visit.  ABT-493/ABT-530 will be 
dosed every morning with food.  Study drug and allowed immunosuppressants 
(cyclosporine, everolimus, sirolimus, tacrolimus, azathioprine, MMF, and mycophenolic 
acid) should be taken together with food at approximately the same times in the morning 
every day.  This is important as taking the DAAs in combination with the 
immunosuppressants at different times can significantly alter the level of the 
immunosuppressants. 
Selection of the doses for this study is discussed in Section 5.5.4.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 


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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 counseling 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 visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial or empty) for assessment of treatment 
compliance.  At post-baseline dispensing visits denoted in Appendix C, study site 
personnel will assess subject compliance by inspecting the contents of the bottles and 
recording the status of each one, the site will record the exact number of remaining tablets 
of ABT-493/ABT-530 in IRT.  Treatment compliance will be based on the number of 
tablets dispensed, as recorded in IRT, and the number of remaining tablets.  If poor 
compliance is noted, the subject should be counseled and this should be documented in 
the subject's source.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include lot number, kit number, number of tablets dispensed, subject number, initials 
of the 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 AbbVie monitor 
throughout the Treatment Period.  The monitor will review study drug accountability on 
an ongoing basis.  Final accountability will be verified by the monitor at the end of study 
drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug bottle of 
ABT-493/ABT-530 the IRT system must be contacted and informed of the misplaced or 


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damaged study drug.  If the bottle is damaged, the subject will be requested to return the 
remaining study drug to the site.  Replacement study drug may only be dispensed to the 
subject by contacting the IRT system.  Study drug replacement(s) and an explanation of 
the reason for the misplaced or damaged study drug(s) will be documented within the IRT 
system.  The study drug start date and the last dose of the regimen will be documented in 
the subject's source documents and recorded on the appropriate eCRF.  The status of each 
bottle, number of tablets remaining in each one returned, and the date of reconciliation 
will be documented in the IRT system.  The monitor will review study drug accountability 
on an ongoing basis.
Upon completion of or discontinuation from the Treatment Period, all original study drug 
bottles (containing unused study drugs) will be returned to AbbVie (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  The number of tablets of each type of study drug returned in each bottle will 
be noted in the IRT system or on a drug accountability log (if appropriate).  Labels must 
remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design 
This is a multicenter, Phase 3 single arm, open-label study in treatment naïve and prior 
IFN and/or pegIFN with or without RBV or sofosbuvir with RBV with or without pegIFN 
treatment-experienced, HCV GT1 – 6-infected adult subjects without cirrhosis designed to 
evaluate the safety and efficacy of ABT-493/ABT-530 300/120 mg administered QD for 
12 weeks in subjects who are post primary liver or post renal transplant.  Evaluation for 
the 12 week treatment duration in the current study is supported by preliminary data from 
the Phase 2b Studies M14-867 and M14-868, with high SVR in GT1 – 6 non-cirrhotic 
populations.  Drug-drug interactions between ABT-493/ABT-530 and tacrolimus and 
cyclosporine have been evaluated in multiple Phase 1 studies.  Active comparator and 
Placebo controlled trials are ongoing in current Phase 3 Studies M15-464 and M13-594.  


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As this study is to evaluate the safety and efficacy of the combination in the 
Post-transplant subpopulation, a single arm study was chosen, as placebo or active 
comparator arms may not yield additional information from that being obtained by the 
aforementioned ongoing studies.  In addition, the potential to eradicate HCV infection 
while avoiding the limitations and toxicities of both IFN and RBV could represent a 
significant advance in treatment options in this population.  Given these considerations, 
the absence of randomization, blinding, and control groups is appropriate.  
Efficacy for the 12-week regimen in this study will be established by demonstrating non-
inferiority to a historical control regimen because the SVR12 rate for the current standard 
of care regimens of SOF/LDV plus RBV or SOF plus DCV plus RBV for 12 weeks in the 
post-transplant population is sufficiently high (95%).  The justification of the historical 
control SVR12 rate and the non-inferiority margin of 8% is described in Section 8.2.1.
This study will evaluate the potential to eradicate HCV starting in the early post-transplant 
period by treating subjects as early as 3 months post-transplant.  Given the universal 
recurrence of HCV after transplantation and the accelerated rate of fibrosis and disease 
course, it is desirable to have the option to eradicate HCV before or after transplantation, 
e.g., in the post-transplant period.  Treatment in the early post-transplant period, prior to 
onset of histologic disease, may be called preemptive therapy.  Prior to transplant, 
individuals with Childs B or C stage cirrhosis who are awaiting transplantation may 
become too medically unstable, e.g., because of fluctuating hepatic and/or renal function, 
to complete a full treatment course prior to transplantation.  Therefore, an important
option for some patients would be to eradicate HCV soon after transplantation, preferably 
before there is evidence of graft fibrosis and potentially prior to detectable HCV induced 
hepatic injury.  Histologic features of hepatitis develop in about 75% of recipients in the 
first 6 months following liver transplantation.6  Therefore, this study will evaluate the 
treatment of patients starting at 3 months post-transplant, after the immediate 
post-transplant period and when its attendant complications have been addressed and 
immunosuppression regimens are typically stable.  In this setting with a recent hepatic 


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graft in situ, subjects are generally anticipated to have limited hepatic disease with a high 
likelihood of achieving SVR.  
This study will also evaluate the potential to eradicate HCV in the post-renal transplant 
population.  Given the impact of HCV nephropathy on the implanted graft, in addition to 
ongoing liver disease (which has not been treated, thus the liver would be susceptible to 
the natural course of HCV infection), it is desirable to have the option to eradicate HCV 
after transplantation, as up to 28% of renal transplant recipients will die of chronic liver 
disease.  Given the high seroprevalence of HCV in the renal transplant population, there
remains a need for HCV treatment, as the kidney is the most commonly transplanted 
organ. 
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.
The EQ-5D-3L, SF-36 v2 and the FSS instruments are standard in the literature and 
thoroughly validated.
5.6.3
Suitability of Subject Population
The selection of post-transplant liver and renal subjects infected with HCV GT1 – 6 will 
allow for the assessment of safety, efficacy and pharmacokinetics of the combination 
ABT-493/ABT-530 regimen for the duration of 12 weeks.
This study will enroll subjects who are naïve to HCV treatment or who have received 
prior treatment limited to sofosbuvir with RBV with or without pegIFN or IFN-based 
treatment for their HCV infection; this will include "pegIFN/RBV-null-responders" who 
have been considered the most difficult to cure amongst the IFN-experienced subjects.  
Preliminary data from Study M14-867 Part 1 shows no difference in efficacy in subjects 
with HCV GT1 when comparing treatment-naïve subjects (49 of 50 with SVR12) and 
pegIFN/RBV null responders (28 of 28 with SVR12).  Similarly, preliminary data from 


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Study M14-867 Part 2 Arm K shows no difference in efficacy in HCV GT1 subjects when 
comparing treatment-naïve subjects (28 of 28 with SVR12) and treatment-experienced 
subjects (5 of 5 with SVR12) with available post-treatment Week 12 data.  This study will 
specifically exclude subjects with any prior exposure to DAA treatment other than 
sofosbuvir as the effect of possible viral mutants on efficacy of ABT-493/ABT-530 is not 
fully understood.
This study will enroll HCV-infected subjects without cirrhosis based on the safety and 
efficacy of ABT-493/ABT-530 demonstrated in non-cirrhotic subjects in Phase 2b 
Studies M14-867 and M14-868.  HCV GT 3, treatment-experienced subjects with 
cirrhosis are excluded from this study, as this sub-population of HCV-monoinfected 
subjects is currently being evaluated in the ongoing Part 3 of Study M14-868 to identify 
the optimal treatment duration in this sub-population.
The age range selected for this study, at least 18 years of age, is also intended to be 
representative of the target population.  Similarly, a substantial portion of the HCV 
infected population have a relatively high BMI, and given the acceptable safety and 
pharmacokinetic profiles of ABT-493 and ABT-530 in Phase 1 and 2 studies, this 
protocol will enroll subjects with a BMI ≥ 18 kg/m2.
HCV-infected subjects who are on stable opiate (methadone or buprenorphine/naloxone) 
maintenance therapy will be allowed to enroll in this study based on the results from 
Study M13-602 which evaluated the pharmacokinetic, pharmacodynamic, safety and 
tolerability of the co-administration of buprenorphine/naloxone or methadone and the 
DAAs (ABT-493 + ABT-530) in adult subjects on stable opioid maintenance therapy and 
demonstrated acceptable safety and no relevant pharmacokinetic or pharmacodynamic 
interactions.
5.6.4
Selection of Doses in the Study
High observed SVR rates (≥ 96%) across HCV genotypes and cirrhotic and non-cirrhotic 
populations from the Phase 2b studies supported evaluating ABT-493 300 mg and 


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ABT-530 120 mg in HCV GT1 – 6, post-liver or post-renal transplant subjects.  To date, 
the observed SVR rates are consistent with exposure-response model predicted values.  
Based on results from exposure-response analyses and clinical trial simulations, 
ABT-493/ABT-530 300/120 mg for 12 weeks is predicted to achieve high SVR in 
post-liver or post-renal transplant population.  Adding ribavirin to the regimen or 
extending the duration to 16 weeks are not expected to significantly increase the SVR. 
ABT-493 and ABT-530 regimens including the proposed 300 mg/120 mg 
ABT-493/ABT-530 QD regimen have been well-tolerated and safe across all Phase 2b 
study arms including cirrhotic subjects.  All ABT-493 and ABT-530 doses studied had a 
similar safety profile.  The most frequently reported adverse events were fatigue, nausea 
and headache and were mostly Grade 1 or 2 in severity.  In all subjects with baseline ALT 
elevations, ALT levels normalized or trended toward normal with DAA treatment, and 
there have been no on-treatment ALT elevations above baseline grade. 
●
Clinical studies evaluating DDI between ABT-493 + ABT-530 and 
immunosuppressant drugs including tacrolimus and cyclosporine have been 
conducted.  Results from these studies showed ABT-493 and ABT-530 did not 
affect cyclosporine exposure, but increased tacrolimus exposure by 50%.  
ABT-493 and ABT-530 exposures were not affected by tacrolimus.  
Cyclosporine 100 mg slightly increased exposure of ABT-493 by 37% and 
ABT-530 by 22%.  High dose of cyclosporine (400 mg) significantly increased 
exposure of ABT-493 (up to 5.1-fold) and ABT-530 (up to 88%).  This study 
will evaluate the treatment of patients in the early post-transplant period 
(> 3 months post liver transplant) but after the immediate post-transplant 
period and when its attendant complications have been addressed and CNI 
based immunosuppression is typically stable.  As the recommended dose of 
cyclosporine used in this population is 75 to 150 mg BID, in order to maintain 
trough concentration (Ctrough) of 75 to 125 ng/mL, no dose adjustment is 
needed for ABT-493 and ABT-530.  A co-formulated bilayer tablet of 
ABT-493 and ABT-530 will be used in this Phase 3 study.  Preliminary 
pharmacokinetic results of the Phase 3 HME bilayer tablet formulation 
administered under fasting conditions showed approximately 50% lower 


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bioavailability compared to the Phase 2 formulation at the ABT-493 300 mg + 
ABT-530 120 mg dose.  When the Phase 3 HME bilayer tablet was 
administered under non-fasting conditions, exposures became relatively 
similar to the reference Phase 2 formulation.  Hence, the Phase 3 
co-formulated ABT-493 and ABT-530 HME Bilayer Tablet formulation 
should be administered with food (300/120 mg, 3 × 100/40 mg tablets) to 
provide DAA exposures that are similar to those of the Phase 2 formulations.  
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for 
12 weeks.
5.6.4.1
Rationale for Duration Selections
Treatment duration of 12 weeks for this Phase 3 study is supported based on available 
data (all SVR4 and available SVR12 rates) from 12-week treatment groups receiving 
ABT-493/ABT-530 300 mg/120 mg combinations in Phase 2 Studies M14-867 and 
M14-868 in HCV GT1- to 6-infected non-cirrhotic patients.  The combination of 
ABT-493/ABT-530 in these patients achieved > 93% SVR4 or SVR12.  Study M14-867 
also demonstrated efficacy with a shorter duration of 8 weeks of treatment, with 33 of 34 
achieving SVR12 (97%), in the GT1 infected subjects without cirrhosis.  Though the 
8 week treatment duration has demonstrated high SVR rates, as the post-transplant 
population has been associated with lower overall SVR rates historically compared to the 
non-transplant mono-infected population, the longer 12 week duration was selected for 
this study.
5.6.4.2
Risk of Development of Resistance Mutations 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 


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failure.  While data from patients treated with the combination of ABT-493 and ABT-530 
are limited, it is expected that ABT-530, an NS5A inhibitor, will be able to suppress the 
appearance of virus containing resistance-associated variants in NS3 that confer resistance 
to ABT-493, 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 –
ABT-493 should be able to suppress the appearance of virus containing NS5A variants 
conferring resistance to ABT-530.  In addition, in vitro resistant colony selection studies 
in HCV replicon cells containing GT1 – 6 NS5A demonstrated that ABT-530 had a high 
genetic barrier to resistance – very few colonies were selected, and those that were 
selected contained NS5A variants that conferred only modest levels of resistance to 
ABT-530.  It remains to be seen whether the development of resistance in subjects treated 
with ABT-530 resembles that seen in vitro.  Based on accumulated clinical and in vitro 
data to date, the risk of development of resistant variants during ABT-493 and ABT-530 
combination trials is reduced when compared to treatment with first generation protease 
and NS5A inhibitors.  For example, in Phase 2b Study M14-867 Part 1 evaluating the 
combination of ABT-493 and ABT-530 in 79 GT1-infected subjects without cirrhosis for 
a 12 week duration, only 1 subject experienced virologic failure, and preliminary 
sequencing results indicated that treatment-emergent NS5A RAVs were detected at the 
time of failure in this subject.  These results support the prediction that the risk of 
development of resistance-associated variants with ABT-493 and ABT-530 combination 
treatment is low.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.8.  For product complaints, please refer to Section 6.2.


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6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 


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medical intervention, meets protocol specific criteria (see Section 6.1.7 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4).
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity.
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).


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Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
For serious adverse events, if an investigator's opinion of relatedness is "no reasonable 
possibility of being related to study drug" an "other" cause of event must be provided by 
the investigator.


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6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected). 
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.


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Email:  
FAX to
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
Telephone Contact Information:
Office:
Fax:
Mobile:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup Primary 
Therapeutic Area Medical Director:
Phone:  


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The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.  
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Administration of study drug may be continued at the 
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. 
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  All adverse events and 
laboratory abnormalities will be managed and followed to a satisfactory clinical 
resolution.  A toxicity is deemed "clinically significant" based on the medical judgment of 
the investigator.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4" is to be used in the grading of 
adverse events and laboratory abnormalities which is available on the Cancer Therapy 
Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.


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Specific toxicity management guidelines apply to the instances of increases in ALT 
(Section 6.1.7.1)
Because of the potential impact of interruption/discontinuation of study drugs on 
immunosuppressant levels, when an interruption/discontinuation is anticipated or required 
by protocol, investigators should ensure that a plan for appropriate immunosuppressant 
dose modification is in place and that this has been communicated with the subject.  
Similarly for those recommencing study drugs after an interruption, the investigator 
should ensure that a plan for appropriate immunosuppressant dose adjustment is in place 
and that this has been communicated with the subject.  Where an interruption is required 
the study drugs should not be interrupted for more than 7 days.  If study drugs need to be 
interrupted for more than 7 days, the Primary Therapeutic Area Medical Director should 
be contacted and consideration should be given to discontinue the subject.
6.1.7.1
Management of Increases in ALT
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also 
> 2 × baseline value, the subject should have a confirmatory ALT measurement 
performed.  
If the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, the 
recommendations below should be followed:
●
Evaluate for alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain additional testing as appropriate (e.g., hepatitis B panel).
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drugs if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis.
○
At the discretion of the investigator.


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Alternate management of ALT increases is permitted with approval of the Primary 
Therapeutic Area Medical Director.
If at any time an investigator suspects rejection of the transplanted liver or kidney while 
the subject is receiving study drug, then dose adjustment of immunosuppressants may be 
performed per the investigator's usual practice and the event captured on eCRF.  If the 
abnormality is non-responsive to immunosuppressant adjustment and/or if the investigator 
wishes to empirically augment the immunosuppressive regimen, e.g., by commencement 
of high dose steroids or to add specific anti-rejection agents but without the availability of 
a biopsy of the transplanted organ confirming rejection, then discontinuation of study 
drugs should be considered by the investigator.  If the investigator wishes to pursue 
alternative management of study drugs in this setting the Primary Therapeutic Area 
Medical Director should be contacted to obtain approval.
If a biopsy of the transplanted organ is performed as part of the evaluation of rejection and 
the histologic findings are consistent with rejection as determined by the local pathologist, 
the investigator should follow the usual management of rejection and continuation of 
study drugs should be per investigator discretion.  If the investigator wishes to pursue 
alternative management of study drugs in the setting of histologically confirmed rejection, 
then the Primary Therapeutic Area Medical Director should be contacted to obtain 
approval.  Biopsy tissue from the transplanted organ obtained during the trial to evaluate 
rejection or other pathologic process should be read locally and the result recorded in the 
subject source documents.  Because of the potential impact of discontinuation (or 
interruption) of study drugs on immunosuppressant levels, investigators should ensure 
that a plan for appropriate immunosuppressant dose modification is in place and that this 
plan is communicated to the subject.
If the findings of a liver biopsy are not consistent with liver rejection or if the clinical 
suspicion of rejection is low or the biopsy results are pending and the subject experiences 
an ALT level ≥ 5 × ULN that is ≥ 2 × baseline, confirmatory chemistry testing should be 
performed.  If the ALT level is confirmed ≥ 5 × ULN and ≥ 2 × baseline and the HCV 


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RNA is declining or is undetectable, then management should be per above.  If a liver 
biopsy has not been performed, consideration should be made to performing a liver 
biopsy.
If the investigator wishes to pursue alternative management of study drugs in the setting 
of confirmed ALT increases described above, then approval of the Primary Therapeutic 
Area Medical Director must be obtained.
6.1.8
Renal Transplant Management of Proteinuria
Renal transplant subjects will undergo a urinalysis at each study visit as part of the 
surveillance for renal injury including renal graft rejection.  If new onset or increased 
proteinuria is identified it is recommended that this be evaluated further and in 
conjunction with the patient's nephrologist.  If further work up confirms a new or 
increased proteinuria that is considered to be clinically significant, e.g., urine 
protein/creatinine ratio or 24-hour urine protein > 1 g on two or more occasions, then 
further evaluation for possible renal graft rejection or HCV associated renal disease is 
recommended and consideration should be given to the performance of an allograft biopsy 
with immunofluorescence and electron microscopy per KDIGO Clinical Practice 
Guidelines.  In the setting of confirmed renal rejection, continuation of the study drugs 
should be per investigator discretion.  If the investigator wishes to pursue alternative 
management of study drugs in the setting of histologically confirmed rejection, then the 
Primary Therapeutic Area Medical Director should be contacted to obtain approval.  
Biopsy tissue from the transplanted organ obtained during the trial to evaluate rejection or 
other pathologic process should be read locally and the result recorded in the subject 
source documents.  Because of the potential impact of discontinuation (or interruption) of 
study drugs on immunosuppressant levels, if study drugs are discontinued or interrupted, 
investigators should ensure that a plan for appropriate immunosuppressant dose 
modification is in place and that this plan is communicated to the subject.


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6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality of the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.


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7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitor(s):
Primary Contact:
Office:
Fax:
Alternate Contact:
Office:
Fax:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued the study.  The data for the primary analysis will be locked after 
data cleaning.  Data after PT Week 12 will be added to a new version of the database 
which will be cleaned and locked at the end of the study.


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SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All statistical tests 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.
Analyses will be performed on the intent-to-treat (ITT) population defined as all enrolled 
subjects who receive at least one dose of study drug, unless otherwise specified.  
Sensitivity analyses of the primary endpoint, SVR12, when applicable, will be performed 
on the ITT population modified to exclude subjects not of eligible genotypes 
(e.g., according to phylogenetic analyses) (mITT-GT), and on the mITT-GT population 
modified to exclude subjects who did not achieve SVR12 for reasons other than virologic 
failure (mITT-GT-VF).  
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data) and PRO questionnaires.  HCV RNA values will be selected 
for the analyses of all SVR endpoints (e.g., SVR4, SVR12, and SVR24) based on defined 
visit windows.  A backward imputation method will be used to impute missing responses 
for SVR analyses.  Imputation of missing responses on PRO questionnaires is described in 
Section 8.1.3.
8.1.1
Demographics
Demographics, baseline characteristics, study drug exposure and compliance will be 
summarized for the ITT population.  Demographics will include age, weight, height, BMI, 
gender, race, and ethnicity.  Baseline characteristics will be summarized as continuous 
variables (where appropriate) and as categorical variables, including all subgroup 
variables defined in Section 8.1.2.4, and include HCV genotypes and subtypes, IL28B 
genotype, prior HCV treatment history (including timing of prior HCV treatment, 
i.e., pre- or post-transplant), baseline HCV RNA level, fibrosis stage (F0-F1, F2, F3 or F4 
[if applicable]), baseline homeostasis model of assessment – insulin resistance 


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(HOMA-IR), tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or 
non-drinker) status, former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no), use of stable opiate substitution, history of diabetes, baseline 
metabolic syndrome, history of bleeding disorders, history of depression or bipolar 
disorder, history of cardiovascular disease, type of transplant (liver or kidney), prior 
dialysis (hemodialysis, peritoneal dialysis, other) in renal transplant subjects, donor type 
(living or deceased), time since transplantation (months), immunosuppressant medication, 
and geographic region.
Summary statistics (N, mean, median, SD, and range) will be generated 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).  
Study drug exposure and compliance will be summarized for all treated subjects.  
Treatment compliance to study drug will be calculated based on the percentage of tablets 
taken relative to the total tablets expected to be taken.  A subject is considered to be 
compliant if the percentage is between 80% and 120%.  Compliance will be calculated for 
each subject and summarized with the mean, median, SD, minimum, and maximum.  The 
percentage of compliant subjects will be summarized. 
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, 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.
IL28B will be resulted as C/C, C/T, or T/T by the central laboratory.


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8.1.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug) in the ITT population.  The number and percentage of subjects 
in the ITT population achieving SVR12 will be summarized with a two-sided 95% 
confidence interval, calculated using the normal approximation to the binomial 
distribution.  If the SVR12 rate is 100%, then the Wilson's score method will be used to 
calculate the confidence interval.
The lower confidence bound of the 2-sided 95% CI (LCB) for the percentage of subjects 
achieving SVR12 must exceed 86% to achieve non-inferiority to the standard of care.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
the percentage of subjects with on-treatment virologic failure (defined as 
confirmed increase of > 1 log10 IU/mL above nadir during treatment, 
confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks 
of treatment), and 
●
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 with HCV RNA 
< LLOQ at the end of treatment; subjects with reinfection will be summarized 
separately).
For the analysis of relapse, completion of treatment is defined as any subject with study 
drug duration of 77 days or greater.
The number and percentage of subjects will be summarized along with two-sided 95% 
Wilson score confidence intervals.


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In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, other) will be provided.
8.1.2.3
Sensitivity Analysis
As sensitivity analyses, the percentage of subjects in the mITT-GT and mITT-GT-VF 
populations achieving SVR12, as applicable, will be summarized.
The Wilson score confidence interval will also be calculated as a sensitivity analysis for 
the primary endpoint of SVR12.
8.1.2.4
Subgroup Analysis
The percentage of ITT subjects with SVR12 will be calculated, as will the corresponding 
two-sided 95% Wilson score confidence intervals for the following subgroups.  
●
HCV genotype (1, 2, 3, 4, 5, or 6) and subtype;
●
Prior HCV treatment history;
○
For treatment-experienced subjects, type of non-response to previous 
treatment (on-treatment nonresponder or breakthrough, post-treatment 
relapse, or unknown/other);
●
Prior sofosbuvir (SOF) experience (DAA naïve, SOF experienced);
●
Organ transplant type (liver or kidney);
●
IL28B genotype (CC or non-CC) and (CC, CT, or TT);
●
Sex (male or female);
●
Age (< 65 or ≥ 65 years) and (< 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);
●
BMI (< 25, ≥ 25 to < 30, or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 6,000,000 or ≥ 6,000,000 IU/mL) and 
(< 2,000,000, ≥ 2,000,000 to < 6,000,000, ≥ 6,000,000 to < 10,000,000, or 
≥10,000,000 IU/mL);


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●
Baseline HOMA-IR (< 2 or ≥ 2 mU × mmol/L2) and (< 3 or 
≥3 mU × mmol/L2);
●
Baseline fibrosis stage (F0 – F1, F2, F3, or F4 [if applicable]);
●
Baseline platelet count (< 100 or ≥ 100 × 109/L) and (< 120 or ≥ 120 × 109/L);
●
Baseline albumin (< LLN or ≥ LLN);
●
Baseline GGT (≤ ULN or > ULN);
●
Baseline LDL (< 88, ≥ 88 to < 119, or ≥ 119 mg/dL);
●
Baseline APRI (< 1 or ≥ 1);
●
Baseline FIB-4  (< 1.45, ≥ 1.45 to ≤ 3.25, or > 3.25);
●
Baseline AST/ALT ratio  (< 1 or ≥ 1);
●
Geographic region (North America, Europe, Rest of world);
●
Country (as appropriate);
●
History of diabetes (yes/no);
●
History of bleeding disorders (yes/no);
●
History of depression or bipolar disorder (yes/no);
●
History of cardiovascular disease (yes/no);
●
Baseline metabolic syndrome (yes/no);
●
Former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no);
●
Subject on stable opiate substitution (yes/no);
●
Presence of baseline resistance-associated variants (yes/no);
●
Compliance to study drug (yes/no).
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized for the ITT population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);


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●
The percentage of DAA naïve subjects with on-treatment virologic failure;
●
The percentage of DAA naïve subjects with post-treatment relapse;
●
The percentage of subjects with SVR4;
●
The percentage of subjects with SVR24;
●
The percentage of subjects who relapse after achieving SVR12.
In the above analyses for SVR and relapse, the percentage of subjects with a two-sided 
95% Wilson score confidence interval will be summarized.  The percentage of sofosbuvir 
experienced subjects achieving SVR12 will be summarized as applicable.
8.1.3
Patient Reported Outcomes
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that domain will be considered missing.  The missing items of the FSS questionnaire 
will be imputed with the average score of the answered items as long as more than 50% of 
the items on the FSS are answered.  For EQ-5D-3L index and VAS scores, no imputation 
will be performed for missing items.  
The mean change from baseline to each applicable post-baseline time point in the 
SF-36v2 Mental Component Summary (MCS) and Physical Component Summary (PCS) 
scores; FSS total score; EQ-5D-3L health index score and VAS score will be summarized 
descriptively at each visit and for change from baseline to each visit. 
The following analyses of PROs will be performed:
●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable time point of greater than or 
equal to 2.5 points in the SF-36 MCS and PCS;


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●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable time point of greater than or 
equal to 5 points in the SF-36 domain scores;
●
Cumulative number and percentage of subjects who have ever experienced an 
increase from baseline up through each applicable time point of greater than or 
equal to 0.7 in the FSS total score.
Additional analyses of PROs may be performed as useful and appropriate.
8.1.4
Resistance Analysis
The DNA encoding NS3 amino acids 1 – 181 and NS5A amino acids 1 – 215 will be 
sequenced by population or deep sequencing for analysis of baseline samples from all of 
the SVR-achieving subjects.  For subjects who experienced virologic failure (on-treatment 
virologic failure or post-treatment relapse), full length NS3/4A and NS5A genes from 
their baseline samples will be sequenced by population or deep sequencing. For each 
DAA target, resistance-associated signature amino acid variants will be identified by 
AbbVie Clinical Virology.  An appropriate prototypic reference sequence will be used for 
comparison with sequences from samples.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of virologic failure or treatment discontinuation is < 1000 IU/mL, 
the sample closest in time after failure/discontinuation with an HCV RNA level 
≥1000 IU/mL will be used.  Included time points for analyses on samples from subjects 
who do not achieve SVR12 are 1) the sample closest in time after failure/discontinuation 
with an HCV RNA level of ≥1000 IU/mL, and 2) 24 weeks post-DAA treatment, 
provided that resistance-associated variants were detected by either population or deep 
sequencing at the time of failure/discontinuation.  
The following definitions will be used in the resistance analyses:


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●
Baseline variant:  a variant (by population or deep sequencing) in a baseline 
sample determined by comparison of the amino acid sequence of the baseline 
sample to the appropriate prototypic reference amino acid sequence for a given 
DAA target.
●
Post-baseline variant by population or deep sequencing:  an amino acid variant 
detected by population or deep sequencing in a post-baseline time point sample 
that was not detected by population or deep sequencing at baseline in the 
subject.
●
Enriched variant by deep sequencing:  post-baseline variant that is enriched by 
at least 20% relative to baseline sequence (post-baseline % – baseline % ≥ 20).
●
Treatment-emergent variant: Enriched variant or a post-baseline variant.
●
Emerged variant by population or deep sequencing:  a treatment emergent 
variant that is observed in 2 or more subjects of the same HCV subtype by 
population or deep sequencing.
●
Linked variant by population or deep sequencing:  2 or more signature 
resistance associated or emerged resistance-associated amino acid variants 
identified within a target by population or deep sequencing, and no mixture of 
amino acids is detected at either position.
The following analyses will be performed for all subjects:
●
The HCV amino acid sequence as determined by population or deep 
sequencing at baseline will be compared to the appropriate prototypic 
reference amino acid sequence.  A listing by subject of all baseline variants 
relative to prototypic reference sequence at signature resistance associated 
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 SVR12 and 
have post-baseline resistance data available:
●
The HCV amino acid sequence as determined by population or deep 
sequencing on 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 baseline and appropriate prototypic reference amino acid sequence.  


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Listings by subject of all post-baseline variants detected by population or deep 
sequencing relative to the baseline amino acid sequences will be provided for 
each DAA target (NS3 and NS5A).  Listings by subject of all emerged variants 
by population or deep sequencing, by amino acid position and variants within 
a DAA target in a post-baseline sample relative to the baseline amino acid 
sequence will be provided for each DAA target.  In addition, listings by 
subject of all post-baseline variants (by population or deep sequencing) at 
signature resistance-associated amino acid positions relative to the appropriate 
prototypic reference amino acid sequences will be provided for each DAA 
target (NS3 and NS5A).
●
Linkage between emerged or signature variants by population or deep 
sequencing will also be evaluated.  A listing by subject and time point of the 
linked variants by population or deep sequencing for each target will be 
provided.
●
The persistence of post-baseline variants at signature resistance-associated 
amino acid positions for each target (NS3 and NS5A) will be assessed by 
population or, deep sequencing at Post-Treatment Week 24.  Listings by 
subject and time point of all post-baseline variants relative to the baseline 
amino acid sequence will be provided for each DAA target (NS3 and NS5A).
●
If resistance-associated variants are not detected by either population or, deep 
sequencing in a given target for a subject at the time of failure/discontinuation, 
then that target may not be sequenced in subsequent samples from that subject.
Replicon EC50 values may not be obtainable for all samples, but for samples where 
phenotype data are obtained, the fold change in EC50 levels at each post-baseline time 
point where phenotypic analysis was performed will be compared both to baseline and 
prototypic standards.
Phylogenetic analysis will be conducted on HCV sequence from available baseline 
samples from all non-GT1 subjects in order to accurately determine their subtypes.  The 
resulting subtype information will be presented in summaries of baseline characteristics 
and efficacy subgroup analyses.


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8.1.5
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.
8.1.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT).  The tabulation of the number of subjects 
with treatment-emergent adverse events by 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 
tables.  Subjects reporting more than one type of event within a SOC will be counted only 
once for that SOC.
8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  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 Final Treatment Visit, will be summarized 
descriptively. 
Laboratory data values will be categorized as low, normal, or high based on reference 
ranges of the laboratory used in this study.  The number and percent of subjects who 
experience post-baseline shifts in clinical laboratory values from low/normal to high and 
high/normal to low based on the normal range will be summarized.
In addition, the number and percentage of subjects with post-baseline values meeting 
pre-specified criteria for Potentially Clinically Significant (PCS) laboratory values or 
toxicity grades will be summarized. 


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8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each post-baseline visit, including Final Treatment Visit, will be 
summarized descriptively.  The number and percentage of subjects with post-baseline 
values meeting pre-defined criteria for PCS vital signs values during treatment will be 
summarized.  
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of ABT-493 and ABT-530 and possible metabolites and 
pharmacokinetic parameter values for ABT-493 and ABT-530 will be tabulated for each 
subject and group.  Blood concentrations of cyclosporine, tacrolimus, everolimus and 
sirolimus will be tabulated for each subject and group.  Summary statistics will be 
computed for each time and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of 
major interest in the NONMEM analyses.  If necessary, other parameters, including the 
parameters describing absorption characteristics, may be fixed if useful in the analysis.  
The evaluation criteria described below will be used to examine the performance of 
different models.
●
The objective function of the best model is significantly smaller than the 
alternative model(s).


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●
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept 
and a slope of one) than the alternative model(s).
●
Visual inspection of model fits, standard errors of model parameters and 
change in inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates of CL/F and V/F with potentially 
physiologically relevant or clinically meaningful covariates (such as subject age, sex, 
body weight, concomitant medications, laboratory markers of hepatic or renal function, 
etc.) will be explored using either stepwise forward selection method, or generalized 
additive method (GAM) or another suitable regression/smoothing method at a 
significance level of 0.05.  After identification of all relevant covariates, a stepwise 
backward elimination of covariates from the full model will be employed to evaluate the 
significance (at P < 0.005, corresponding to an increase in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
In general, all continuous covariates will be entered in the model, initially in a linear 
fashion, with continuous covariates centered around the median value.  Linear or 
non-linear relationships of primary pharmacokinetic parameters with various covariates 
may also be explored.  For example:
TVCLi = Theta(1) + Theta(2) (Comedication [1,2,…]) + Theta(3) (WTi-median value) + 
Theta(4) (AGEi – median value).
Where TVCLi = Typical value of clearance for an individual1, Theta(1) is the intercept 
and Theta(2) – (4) are regression parameters relating the fixed effects (weight and age 
centered on the median value) to clearance.


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The relationship between exposure and clinical observations (antiviral activity) will be 
explored.  Exposure-response relationships for primary and secondary efficacy variables 
and/or some safety measures of interest may also be explored.
The relationship between exposure (e.g., population pharmacokinetic model predicted 
concentrations over time or average concentrations or AUC or trough concentrations of 
the individual model-predicted pharmacokinetic profiles, or some other appropriate 
measure of exposure) and antiviral activity will be explored.  
Logistic regression analyses will explore the relationship between exposure and one or 
more virologic endpoints (e.g., SVR12, relapse following end of treatment and 
breakthrough on treatment).
Additionally, relationship between exposure and safety endpoints of interest may also be 
explored.  Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
It is planned to enroll approximately 90 subjects with a minimum of 15 post-renal 
transplant subjects and a maximum of approximately 50 subjects with HCV genotype 1 
infection.  The primary efficacy endpoint of SVR12 will be assessed for the ITT 
population.  For the primary efficacy endpoint of SVR12, with a sample size of 90 subjects 
and assuming that 96% of the subjects will achieve SVR12, this study has greater than 
90% power to show non-inferiority to the historical SVR12 rate of 94% (based on the 
lower bound of a normal approximation of a single binomial proportion confidence 
interval being above a threshold of 86%) using a one-sample test for superiority using 
EAST 6.3.
No adjustment for dropouts is applicable because subjects who do not have data at 
Post-Treatment Week 12 (after imputing) are counted as failures for SVR12.


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8.2.1
Justification of Success Criterion and Non-Inferiority Margin 
for SVR12
The primary efficacy endpoint analysis of SVR12 is a non-inferiority test of the SVR12 rate 
in this study to the historical SVR12 rate of 94% (based on the lower bound of a normal 
approximation of a single binomial proportion confidence interval being above a threshold 
of 86%) using a one-sample test for superiority. 
The 86% threshold was established by applying an 8% non-inferiority margin to a 
historical SVR12 rate of 94%.
 
 
 
 
The 8% non-inferiority margin is based on the paucity of data in non-GT1 liver transplant 
recipients and renal transplant recipients regardless of genotype and the potential benefit 
of a RBV-free regimen.  
●
Most data published on the post-transplant population to date, including the 
studies that were used to establish the historical control rate for this study, are 
in GT1 subjects who have received a liver transplant.  
●
The current standard-of-care regimens used for historical comparison all 
include RBV.  Given the ABT-493/ABT-530 regimen is RBV-sparing, a 
slightly wider non-inferiority margin compared to the margin used in other 
AbbVie Phase 3 studies with ABT-494/ABT-530 was considered, as a small 
decrement in efficacy may be outweighed by an improvement in safety offered 
with the avoidance of RBV in a patient population more susceptible to RBV-
related toxicity.  


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to 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 AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.


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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 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.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
The optional pharmacogenetic and intensive PK analysis will only be performed if the 
subject has voluntarily signed and dated the IRB/IEC approved pharmacogenetic 
informed consent and intensive PK informed consent respectively, after the nature of the 
testing has been explained and the subject has had an opportunity to ask questions.  The 
subject must provide consent specific to pharmacogenetic testing and intensive PK before 
the testing is performed.  If the subject does not consent to the additional pharmacogenetic 
and/or intensive PK testing it will not impact the subject's participation in the study.
In the event a subject withdraws from the main study, optional pharmacogenetic 
exploratory research samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for the optional samples.  If consent is withdrawn for the 
optional sampling, the subject must inform their study doctor, and once AbbVie is 
informed, the optional samples will be destroyed.  However, if the subject withdraws 
his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.


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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 


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performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional pharmacogenetic exploratory research 
samples from this study will be experimental in nature and the results will not be suitable 
for clinical decision making or patient management.  Hence, the subject will not be 
informed of individual results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, researchers will have no access to subject 
identifiers.  Individual results will not be reported to anyone not directly involved in this 
research other than for regulatory purposes.  Aggregate data from optional 
pharmacogenetic exploratory research may be used in scientific publications or presented 
at medical conventions.  Optional pharmacogenetic exploratory research information will 
be published or presented only in a way that does not identify any individual subject.


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  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 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-493/ABT-530 
Fixed-Dose Combination.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Single-Arm, Open-Label, Multicenter Study to Evaluate the Safety 
and Efficacy of ABT-493/ABT-530 in Adult Post-Liver or 
Post-Renal Transplant Recipients with Chronic Hepatitis C Virus 
Genotype 1 – 6 Infection (MAGELLAN-2)
Protocol Date:
21 June 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
OPTN & SRTR Annual Data Report 2012.  
http://optn.transplant.hrsa.gov/converge/data/annualReport.asp.
2.
Forman LM, Lewis JD, Berlin JA, et al.  The association between hepatitis C 
infection and survival after orthotopic liver transplantation.  Gastroenterology.  
2002;122(4):889-96.
3.
Lucey MR, Terrault N, Ojo L, et al.  Long-term management of the successful 
adult liver transplant:  2012 practice guideline by the American Association for the 
Study of Liver Diseases and the American Society of Transplantation.  Liver 
Transpl.  2013;19(1):3-26.
4.
Berenguer M, Prieto M, Rayón JM, et al.  Natural history of clinically compensated 
hepatitis C virus-related graft cirrhosis after liver transplantation.  Hepatology.  
2000;32 (4 Pt 1):852-8.
5.
Kalambokis G, Manousou P, Samonakis D, et al.  Clinical outcome of HCV-related 
graft cirrhosis and prognostic value of hepatic venous pressure gradient.  Transpl 
Int.  2009;22(2):172-81.
6.
Kidney Disease:  Improving Global Outcomes (KDIGO) Transplant Work Group.  
KDIGO clinical practice guideline for the care of kidney transplant recipients.  
American Journal of Transplantation.  2009;9 (Suppl 3):S1-S157.
7.
World Health Organization.  Worldwide Statistics for HCV.  Weekly 
Epidemiological Record No. 49.  10 December 1999.
8.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment Web 
resource.  Hepatology.  2014;59(1):318-27.
9.
European Association for Study of Liver.  EASL Clinical Practice Guidelines:  
Management of hepatitis C virus infection.  J Hepatol.  2014;60(2):392-420.


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10.
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.
11.
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.
12.
Berenguer M, Palau A, Aguilera V, et al.  Clinical benefits of antiviral therapy in 
patients with recurrent hepatitis C following liver transplantation.  Am J 
Transplant.  2008;8(3):679-87.
13.
Charlton M, Gane E, Manns MP, et al.  Sofosbuvir and ribavirin for treatment of 
compensated recurrent hepatitis C virus infection after liver transplantation.  
Gastroenterology.  2015;148(1):108-17.
14.
Curry MP, Forns X, Chung RT, et al.  Sofosbuvir and ribavirin prevent recurrence 
of HCV infection after liver transplantation: an open-label study.  
Gastroenterology.  2015:148(1):100-7.
15.
Fagiuoli S, Ravasio R, Lucà MG, et al.  Management of hepatitis C infection 
before and after liver transplantation.  World J Gastroenterol.  
2015;21(15):4447-56.
16.
Forns X, Charlton M, Denning J, et al.  Sofosbuvir compassionate use program for 
patients with severe recurrent hepatitis C after liver transplantation.  Hepatology.  
2015;61(5):1485-94.
17.
European Association for Study of Liver.  EASL recommendations on treatment of 
hepatitis C 2015.  J Hepatol.  2015;63(1):199-236.
18.
Poordad F, et al.  98%-100% SVR4 in HCV genotype 1 non-cirrhotic 
treatment-naïve or pegylated interferon/ribavirin null-responders with the 
combination of the next generation NS3/4A protease inhibitor ABT-493 and NS5A 
inhibitor ABT-530.  Presented at 66th Annual AASLD, November 15, 2015, San 
Franscisco, CA.


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19.
Kwo P, et al.  Surveyor-II:  High SVR4 rates achieved with the next generation 
NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic 
treatment-naïve and treatment experienced patients with HCV genotype 3 
infection.  Presented at 66th Annual AASLD, November 17, 2015, San Franscisco, 
CA.
20.
AbbVie.  Investigator's Brochure for ABT-493/ABT-530 Fixed-Dose Combination 
Edition 1.  23 September 2015.


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


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Bioanalysis
Statistics
Clinical
Global Drug Supply Management


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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 1a
Study 
Day 3
Wk 1
Optional 
Day 10 for 
Mgmt of 
Immuno-
suppressive 
Meds
Wk 2
Wk 4
Wk 6
Wk 8
Wk 12 
EOT or 
Premature 
D/C from 
Treatmentb
Unsched 
Visit for 
Mgmt of 
Immuno-
suppressive 
Meds
Informed Consentc
X
Medical Historyd
X
X
Physical Exam 
X
X
X
Vital Signs, Weight, Heighte
X
X
X
X
X
X
X
X
X
X
X
ECG
X
Hematology/Chemistry/Urinalysis/Coagulation 
Panel
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])f
X (s)
X (u)
X (u)
X (u)
X (u)
HBsAg, Anti-HCV Ab, Anti-HIV Ab
X
Drug/Alcohol Screen
X
Alpha fetoprotein
X
Hemoglobin A1Cg
X
HCV Genotype and Subtype 
X
FibroTest and APRI or FibroScan or Liver 
Biopsyh
X
IL28B Samplei
X
Optional Exploratory Pharmacogenetic Samplei
X
Total Insulin
X


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Activity
Screening
Day 1a
Study 
Day 3
Wk 1
Optional 
Day 10 for 
Mgmt of 
Immuno-
suppressive 
Meds
Wk 2
Wk 4
Wk 6
Wk 8
Wk 12 
EOT or 
Premature 
D/C from 
Treatmentb
Unsched 
Visit for 
Mgmt of 
Immuno-
suppressive 
Meds
Sample for cyclosporine, tacrolimus, 
everolimus, sirolimus therapeutic drug 
monitoring (Local Lab)j
Xj
X
X
X
X
X
X
X
X
X
X
Immunosuppressive Regimen Dose 
Modification Review
X
X
X
X
X
X
X
X
X
X
Immunosuppression Regimen Dosing Diary 
dispensation, review and collectionk
X 
(Dispense 
only)
X
X
X
X
X
X
X
X
X
X
Study Drug Dosing Card dispensation, review 
and collection
X 
(Dispense 
only)
X
X
X
X
X
X
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessmentl
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes Instruments 
(PROs)m
X
X
Study Drugs Dispensed
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
X
X
X
Study Drug Accountability and Review of 
Study Drug Adherencen
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic Samples DAAc,p
Xo
X
X
X
X
Xo
X
X
X


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Wk = Week; EOT = End of treatment; D/C = Discontinuation
a.
All procedures to be performed prior to first dose, with the exception of the additional (optional) post-dose pharmacokinetic intensive samples (Section 5.3.2.1).
b.
Subjects who prematurely discontinue from the study during the Treatment Period should return to the site to complete the Premature D/C from Treatment Visit Procedures 
(preferably prior to the initiation of any other anti-HCV therapy).
c.
Subjects need to sign and date an IRB/IEC approved informed consent for the study (prior to performing any screening or study-specific procedures) and the optional 
pharmacogenetic and intensive pharmacokinetic sample(s), if applicable.
d.
A complete medical history will be taken at Screening and will be updated at the Study Day 1 Visit.
e.
Height will be measured at the Screening Visit only. 
f.
Pregnancy testing is not required for women not of childbearing potential as defined in Inclusion Criterion 2. 
g.
For subjects with history of Diabetes Mellitus.
h.
For subjects who have not had a qualifying liver biopsy within the previous 6 months or a qualifying FibroScan within the previous 3 months.
i.
If the IL28 sample or the optional Pharmacogenetic sample are not collected at Study Day 1, they may be collected at any other visit during the study.
j.
Sample for cyclosporine, tacrolimus, everolimus, or sirolimus, blood concentrations at screening may take place as an unscheduled visit so the subjects screening day 
CNI/mTOR dose is not interrupted.
k.
The Immunosuppression Regimen Dosing Diary will be provided to study subjects taking an immunosuppressive regimen containing cyclosporine, sirolimus, everolimus, 
and/or tacrolimus during the screening visit and subsequent visits as indicated.  The diaries will be reviewed for completeness and accuracy between study visits and collected 
by site staff after review.
l.
See specific information regarding adverse event collection in Section 6.1.1.1.
m.
PROs should be administered before any study procedures and in the order listed as per Section 5.3.1.1.
n.
Subjects should bring all study drug to every visit for the site to review adherence.  However, the site will record the number of tablets returned only at the Study Drug 
Accountability Visits at Weeks 4, 8 and 12 or Premature D/C.
o.
For subjects participating in Optional Intensive PK sampling, intensive PK samples will be drawn on Day 1 at 2, 4 and 6 hours post-dose and on Week 4 at 0 (immediately 
prior to dose), 2, and 4 hours post the dose administered during the visit. Subjects not participating in intensive PK will not have a sample drawn at Day 1.
p.
Detail regarding timing of samples is provided in Section 5.3.2.1.


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Appendix D.
Study Activities – Post-Treatment (PT) Period
Activity
PT 
Day 3
PT Wk 
1
PT Wk 
2
PT Wk 
4
PT Wk 
8
PT Wk 
12
PT Wk 
24 or PT 
D/Ca
Unsched Visit for 
Mgmt of 
Immunosuppressive 
Meds
Vital Signs and Weight
X
X
X
X
X
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation 
Panel
X
X
X
X
X
X
Pregnancy Test (urine)b
X (u)
X (u)
PRO Instrumentsc
X
X
Concomitant Medication Assessment
X
X
X
Xd
Xd
Xd
Xd
Xd
Adverse Event Assessmente,f
X
X
Xe
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
Cyclosporine, tacrolimus, everolimus, sirolimus 
therapeutic drug monitoring (Local Lab)
X
X
X
X
X
Immunosuppression Regimen Dosing Diary 
dispensation, review and collectiong
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit procedures.
b.
Urine pregnancy testing is not required in the PT Period for women that are not of childbearing potential.
c.
PROs should be administered before any study procedures and in the order listed as per Section 5.3.1.1.
d.
Only medications taken for SAEs and for treatment of HCV will be collected after 30 days post-dosing. 


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e.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.
f.
Only SAEs will be collected after the 30 days post dosing (see Section 6.1.4).
g.
The Immunosuppression Regimen Dosing Diary will be provided to study subjects taking an immunosuppressive regimen containing cyclosporine, sirolimus, everolimus, 
and/or tacrolimus during the screening visit and subsequent visits as indicated.  The diaries will be reviewed for completeness and accuracy between study visits and collected 
by site staff after review.
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.


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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 3.0  Introduction
Subsection DDI STUDIES WITH CYCLOSPORINE AND TACROLIMUS
Fifth paragraph, bullet previously read:
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should not exceed 
100 mg once daily
Has been changed to read:
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should not exceed 
100 mg once daily for entry into the study. If the cyclosporine maintenance dose needs to 
be increased to a total daily dose greater than 100 mg during the Treatment Period, 
discussion with the Therapeutic Area Medical Director should occur.  Dosages of 
cyclosporine > 400 mg are not allowed during the Treatment Period.
Section 5.1.2  Treatment Period
Second paragraph, first sentence previously read:
Subject immunosuppression dosing regimen diaries will be maintained throughout the 
trial, for all subjects taking cyclosporine, sirolimus, everolimus, and/or tacrolimus during 
both the Treatment and Post-Treatment periods.  
Has been changed to read:
Subject immunosuppression dosing regimen diaries will be maintained throughout the 
trial, for all subjects taking cyclosporine, sirolimus, everolimus, and/or tacrolimus during 
the Screening, Treatment and Post-Treatment periods.  


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Section 5.2.1  Inclusion Criteria
Criterion 3, last sentence previously read:
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined above) at Screening do not require pregnancy testing.
Has been changed to read:
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing.
Section 5.2.2  Exclusion Criteria
Criterion 7 previously read:
Any cause of liver disease other than chronic HCV infection including but not limited to 
the following:
Has been changed to read:
Any cause of liver disease post transplantation other than chronic HCV infection 
including but not limited to the following:
Section 5.2.2  Exclusion Criteria
Criterion 9, second bullet previously read:
Albumin < 3.5 mg/dL
Has been changed to read:
Albumin < 3.5 g/dL
Section 5.2.3.2  Management of Immunosuppressant Agent Dosing
Third paragraph, bullet previously read:
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should not exceed 
100 mg once daily.


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Has been changed to read:
The dose of cyclosporine with ABT-493/ABT-530 (300/120 mg QD) should not exceed 
100 mg once daily for entry into the study. If the cyclosporine maintenance dose needs to 
be increased to a total daily dose greater than 100 mg during the Treatment Period, 
discussion with the Therapeutic Area Medical Director should occur.  Dosages of 
cyclosporine > 400 mg are not allowed during the Treatment Period.
Section 5.3.1.1  Study Procedures
Subsection Immunosuppression Regimen Dosing Diary
First paragraph, first sentence previously read:
A subject immunosuppression regimen dosing diary will be provided to all subjects taking 
cyclosporine, sirolimus, everolimus, and/or tacrolimus during the Treatment period and 
for 30 days into the Post-Treatment period.  
Has been changed to read:
A subject immunosuppression regimen dosing diary will be provided to all subjects taking 
cyclosporine, sirolimus, everolimus, and/or tacrolimus during Screening and for 30 days 
into the Post-Treatment period.  
Section 5.3.1.1  Study Procedures
Subsection Immunosuppression Regimen Dosing Diary
Last paragraph, last sentence previously read:
Subjects should be reminded to bring the diary to each study visit.
Has been changed to read:
Subjects should be reminded to bring the completed diary to each study visit.



SAP_001.pdf: 
ABT-493/ABT-530
M13-596 – Statistical Analysis Plan
Version 1.0 – 27 October 2016
1
1.0
Title Page
Statistical Analysis Plan
Study M13-596
A Single-Arm, Open-Label, Multicenter Study to 
Evaluate the Safety and Efficacy of 
ABT-493/ABT-530 in Adult Post-Liver or Post-Renal 
Transplant Recipients with Chronic Hepatitis C Virus 
Genotype 1 – 6 Infection (MAGELLAN-2)
Date:  27 October 2016
NCT02692703


ABT-493/ABT-530
M13-596 – Statistical Analysis Plan
Version 1.0 – 27 October 2016
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................5
4.1
Objectives ..................................................................................................5
4.2
Design Diagram .........................................................................................6
4.3
Sample Size................................................................................................6
4.3.1
Justification of Non-Inferiority Margin for SVR12 ....................................7
4.4
Primary Analyses .......................................................................................8
5.0
Analysis Populations ...............................................................8
5.1
Definition for Analysis Populations...........................................................8
5.1.1
Intention-to-Treat (ITT) Population...........................................................8
5.1.2
Modified Intention-to-Treat (mITT) Populations ......................................8
5.1.3
Safety Population.......................................................................................9
5.2
Variables Used for Stratification of Randomization..................................9
6.0
Analysis Conventions ..............................................................9
6.1
Definition of Baseline and End of Treatment Assessment ........................9
6.1.1
Baseline......................................................................................................9
6.1.2
Study Days...............................................................................................10
6.2
Definition of Analysis Windows .............................................................10
6.3
Missing Data Imputation..........................................................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications...........................................14
7.1
Demographic and Baseline Characteristics .............................................15
7.2
Medical History .......................................................................................19
7.3
Prior, Concomitant and Post-Treatment Medications..............................20
8.0
Patient Disposition.................................................................20
8.1
Disposition of Safety Population .............................................................21
9.0
Study Drug Exposure and Compliance...............................21
9.1
Exposure ..................................................................................................21
9.2
Compliance ..............................................................................................22


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10.0
Efficacy Analysis....................................................................23
10.1
General Considerations............................................................................23
10.2
Handling of Multiplicity ..........................................................................27
10.3
Primary Efficacy Analysis .......................................................................27
10.4
Secondary Efficacy Analyses...................................................................27
10.5
Sensitivity Analyses for SVR ..................................................................28
10.5.1
Imputation Approaches............................................................................28
10.6
Efficacy Subgroup Analysis ....................................................................29
10.7
Additional Efficacy Analyses ..................................................................30
10.8
Resistance Analyses.................................................................................32
10.8.1
Presence of Baseline Resistance-Associated Variants.............................37
10.9
Patient Reported Outcomes......................................................................39
11.0
Safety Analysis.......................................................................40
11.1
General Considerations............................................................................40
11.2
Analysis of Adverse Events.....................................................................40
11.2.1
Treatment-Emergent Adverse Events ......................................................40
11.2.2
Tabulations of Treatment-Emergent Adverse Events..............................41
11.2.3
Listing of Adverse Events........................................................................44
11.3
Analysis of Laboratory Data....................................................................44
11.3.1
Variables and Criteria Defining Abnormality..........................................44
11.3.2
Statistical Methods...................................................................................45
11.4
Analysis of Vital Signs and Weight.........................................................47
11.4.1
Variables and Criteria Defining Abnormality..........................................47
11.4.2
Statistical Methods...................................................................................48
12.0
Summary of Changes ............................................................49
12.1
Summary of Changes Between the Latest Version of Protocol and 
SAP ..........................................................................................................49
13.0
References...............................................................................49


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List of Tables
Table 1.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements and PRO Instruments
(Treatment Period)...................................................................................11
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)...........................................................................12
Table 3.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period)...........................................................................13
Table 4.
Baseline Fibrosis Stage............................................................................18
Table 5.
Medical History eCRF .............................................................................19
Table 6.
List of Genotype-Specific Signature Amino Acid Positions and a 
Key Subset of Amino Acid Positions ......................................................33
Table 7.
Resistance-Associated Variants by DAA Target and HCV 
Genotype..................................................................................................38
Table 8.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................46
Table 9.
Criteria for Potentially Clinically Significant Vital Sign Values.............48
List of Figures
Figure 1.
Study Schematic.........................................................................................6


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Statistics and Statistical Programming Departments, or designee, for 
Study M13-596.  Study M13-596 examines the safety and efficacy of 12 weeks of 
treatment with the ABT-493/ABT-530 combination regimen in adults with HCV GT1 – 6 
infection who are DAA-naïve and post primary orthotopic liver transplant or renal 
transplant.
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M13-596 Amendment 1 dated 26 May 2016 and 
describes analysis conventions to guide the statistical programming.  Analyses will be 
performed using SAS® Version 9.3 (SAS Institute, Inc., Cary, NC) or later under the 
UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to compare the 12-week sustained virologic 
response, SVR12 (HCV RNA < LLOQ 12 weeks following therapy) of 12 weeks of 
treatment with the ABT-493/ABT-530 combination regimen in adults with HCV GT1 – 6 
infection and post primary orthotopic liver transplant or renal transplant to a pre-defined 
threshold, based on the historical SVR12 rates for the current standard of care regimens 
(sofosbuvir/ledipasvir plus ribavirin or sofosbuvir plus daclatasvir plus RBV) and to 
assess the safety of treatment with the ABT-493/ABT-530 combination regimen for 
12 weeks in adults with HCV GT1 – 6 infection and post primary orthotopic liver 
transplant or renal transplant.
The secondary objectives are to assess the percentage of subjects with on-treatment 
virologic failure, and the percentage of subjects with post-treatment relapse.


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The pharmacokinetics and the emergence and persistence of viral variants for this 
treatment regimen also will be assessed.
4.2
Design Diagram
This is a Phase 3, single arm, open-label, multicenter study evaluating the safety and 
efficacy of ABT-493/ABT-530 for 12 weeks, in GT1 – 6 HCV-infected non-cirrhotic (F0-
F3) subjects who have received a primary orthotopic liver or renal transplant who are 
either HCV treatment-naïve or prior treatment-experienced with IFN or pegIFN with or 
without RBV or sofosbuvir with RBV with or without pegIFN (except GT3-infected 
subjects who must be treatment-naïve).
This study consists of a Treatment Period and a Post-Treatment (PT) Period.
The study is designed to enroll approximately 90 subjects to meet scientific and regulatory 
objectives without enrolling an undue number of subjects in alignment with scientific and 
ethical considerations.
Figure 1.
Study Schematic
4.3
Sample Size
It is planned to enroll approximately 90 subjects with a minimum of 15 post-renal 
transplant subjects and a maximum of approximately 50 subjects with HCV genotype 1 
infection in this study.  The primary efficacy endpoint of SVR12 will be assessed for the 
ITT population.  For the primary efficacy endpoint of SVR12, with a sample size of 
90 subjects and assuming that 96% of the subjects will achieve SVR12, this study has 


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greater than 90% power to show non-inferiority to the historical SVR12 rate of 94% (based 
on the lower bound of a normal approximation of a single binomial proportion confidence 
interval being above a threshold of 86%) using a one-sample test for superiority using 
EAST 6.3. 
The 86% threshold was established by applying an 8% non-inferiority margin to the 
historical SVR12 rate of 94% 
 
 
 
 
No adjustment for dropouts is applicable because subjects who do not have data at Post-
Treatment Week 12 (after imputing) are counted as failures for SVR12.
4.3.1
Justification of Non-Inferiority Margin for SVR12
The 8% non-inferiority margin is based on the paucity of data in non-GT1 liver transplant 
recipients and renal transplant recipients regardless of genotype and the potential benefit 
of a RBV-free regimen.
●
Most data published on the post-transplant population to date, including the 
studies that were used to establish the historical control rate for this study, are 
in GT1 subjects who have received a liver transplant. 
●
The current standard-of-care regimens used for historical comparison all 
include RBV.  Given the ABT-493/ABT-530 regimen is RBV-sparing, a 
slightly wider non-inferiority margin compared to the margin used in other 
AbbVie Phase 3 studies with ABT-494/ABT-530 was considered, as a small 
decrement in efficacy may be outweighed by an improvement in safety offered 
with the avoidance of RBV in a patient population more susceptible to RBV 
related toxicity.


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4.4
Primary Analyses
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued the study.  For the primary analysis, data will be locked after 
performing data cleaning.  Results from the primary analysis (e.g., SVR12 data) will be 
described in the primary clinical study report (CSR) that is planned to be included as part 
of submissions to regulatory agencies to support possible labeling changes.
The final analysis will be conducted when all subjects enrolled in the study have 
completed the 24 week post-treatment visit or prematurely discontinued from the study.  
Data after the primary analysis will be added to a new version of the database which will 
be cleaned and locked at the end of the study and included in the final CSR.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
ITT population.  Efficacy analyses will be performed on the ITT population.
5.1.2
Modified Intention-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 as described in Section 10.5, when applicable, will be 
performed on the ITT population modified to exclude subjects not of an eligible genotype 
(e.g., subjects of multiple/mixed genotypes or treatment-experienced subjects who were 
determined to be GT3 according to LiPA, Sanger or phylogenetic analyses as described in 
Section 10.8 under HCV Genotype/Subtype) (mITT-GT), and on the mITT-GT 
population further modified to exclude subjects who did not achieve SVR12 for reasons 
other than virologic failure (mITT-GT-VF).  


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5.1.3
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population.  Safety and demographic analyses will be performed on the safety population.  
5.2
Variables Used for Stratification of Randomization
This study is not randomized.  Eligible subjects will be enrolled into a single arm.
6.0
Analysis Conventions
6.1
Definition of Baseline and End of Treatment Assessment
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.  The protocol specifies that all Day 1 assessments 
(other than optional intensive PK samples) are to be performed prior to administering the 
first dose of study drug.  Therefore, all Day 1 assessments for which time is not collected 
will be assumed to be pre-dose and the baseline value will be the last non-missing 
measurement collected on or before the first day of study drug administration.
All Day 1 assessments with time available must be before the time of first dose to be 
considered baseline and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 
time or if time is not available, then the average of these measurements will be considered 
the baseline value.  The same baseline value will be used for analyses of the Treatment 
and Post-Treatment Periods.
Safety assessments that are related to a serious adverse event that occurred on the 
first dose day are excluded when applying this algorithm.


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6.1.2
Study Days
Study days are calculated for each time point relative to the first dose of study drug.  
Study days are negative values when the time point of interest is prior to the first study 
drug dose day.  Study days are positive values when the time point of interest is after the 
first study drug dose day.  There is no Study Day 0.  Study Day 1 is the day of the 
first dose of study drug.
Study Drug End Days (Days Relative to the Last Dose of Study Drug)
Study drug end days are calculated for each time point relative to the last dose of study 
drug.  The last day of study drug dosing is defined as Study Drug End Day 0.  Days 
before it have negative study drug end days and days after it have positive study drug end 
days.
Final Treatment Value
The final treatment value is defined as the last non-missing measurement collected after 
Study Day 1 and on or before Study Drug End Day 2.
Final Post-Treatment Value
The final post-treatment value for each subject is the last non-missing measurement 
collected after Study Drug End Day 2 and on or before Study Drug End Day 999.
6.2
Definition of Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 1
and Table 2 describe how efficacy data are assigned to protocol-specified time points 
during the Treatment and PT Periods, respectively.  All time points and corresponding 
time windows are defined based on the date/time of blood sample collection.
For laboratory data vital signs and PRO measurements, the time windows specified in 
Table 1 and Table 3 describes how data are assigned to protocol specified time points.


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If more than one assessment is included in a time window, the assessment closest (except 
in analyses of SVR) to the nominal time will be used.  If there are two observations 
equally distant to the nominal time, the latest one will be used in analyses.  For analyses 
of SVR (e.g., SVR12), the last value in the window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used to calculate descriptive 
statistics and in analyses of the mean change from baseline.  For summaries of shifts from 
baseline and potentially clinically significant values, multiple values on the same day will 
not be averaged; all values will be considered for these analyses.
Table 1.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements and PRO Instruments
(Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 1a
Day 3
3
2 to 5
Week 1
7
6 to 8
Day 10
10
9 to 12
Week 2
14
13 to 21
Week 4
28
22 to 42
Week 6
42
43 to 49
Week 8
56
50 to 70
Week 12
84
71 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  PRO instruments are collected at Day 1 and End of Treatment Visit (Week 12) only.


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Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 2
14
3 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24
168
127 to 999
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable 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, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.


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Table 3.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period)
Scheduled Time
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Vital Sign
Post-Treatment Day 3
3
3 to 5
Post-Treatment Week 1
7
6 to 10
Post-Treatment Week 2
14
11 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24
168
127 to 999
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 collected at every PT visit; hematology, chemistry, urinalysis, and coagulation panels are 
collected at every PT visit except PTW8 and PTW12.  PRO instruments are collected at PTW12 and PTW24 
(or PTDC) only. 
6.3
Missing Data Imputation
Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.2.
For analyses of SVR, subjects missing visit values will have backward imputation 
applied, if possible.  For backward imputation, if the nearest HCV RNA value after the 
SVR window is unquantifiable or undetectable, then it will be used to impute the HCV 
RNA value in the SVR window.  If a subject is missing an HCV RNA value within the 
appropriate SVR window after performing backward imputation, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value will be missing.  Subjects with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.


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Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 
failure for summaries of viral response at all time points after the start of the new HCV 
treatment.
Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure.
Missing Data Imputation for PRO Questionnaires
The handling of missing data for patient reported outcomes (PROs) will be as follows.  If 
a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the 
missing items will be imputed with the average score of the answered items in the same 
scale.  In cases where the respondent did not answer at least 50% of the items, the score 
for that domain will be considered missing.  The Mental and Physical Component 
Summary measures will not be computed if any domain is missing.  The missing items of 
the FSS questionnaire will be imputed with the average score of the answered items as 
long as more than 50% of the items on the FSS are answered.  For EQ-5D-3L index and 
VAS scores, no imputation will be performed for missing items.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
Demographics and baseline characteristics will be summarized on the safety population 
overall and by type of transplant (liver or kidney). 
The safety population will be used to summarize medical history and previous, 
concomitant, and post-treatment medications.


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7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum and minimum).
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  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), country, and geographic region (North America, Europe, or rest of 
world [ROW]).
When defining geographic region, sites in the United States, Canada, and Puerto Rico will 
be grouped under North America; sites in Italy, Spain, and the United Kingdom will be 
grouped under Europe; sites in Australia, New Zealand, and Taiwan will be grouped 
together as ROW).
Continuous baseline characteristics include baseline log10 HCV RNA level, homeostasis 
model of assessment – insulin resistance (HOMA-IR), creatinine clearance, eGFR, 
platelet count, albumin, GGT, LDL, HDL, APRI, FIB-4, AST, ALT, total, direct, indirect 
bilirubin, and time since transplantation (months).
Categorical baseline characteristics include:
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (as determined by the 
central laboratory);
●
Prior HCV treatment history (treatment-naïve or treatment-experienced);
○
For treatment-experienced subjects, type of previous regimen (IFN-, SOF-
based, or other);
○
For treatment experienced subjects, type of non-response to previous 
treatment (on-treatment non-responder or breakthrough, post-treatment 
relapse, or unknown/other);


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○
For treatment-experienced subjects, occurrence of prior HCV treatment 
relative to renal or liver transplant (pre-transplant or post-transplant);
●
Prior HCV DAA treatment history:
○
DAA-naïve (i.e., treatment naïve or treatment-experienced with IFN or 
pegIFN with or without RBV);
○
SOF-experienced (i.e., treatment-experienced with sofosbuvir with RBV 
with or without pegIFN); 
○
Other DAA-experienced (i.e., treatment-experienced with DAA drugs 
other than sofosbuvir);
●
IL28B genotype (CC, CT, or TT; CC or non-CC);
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL; < 6,000,000 or 
≥ 6,000,000 IU/mL);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4 [if 
applicable]);
●
Baseline platelet count (< 90 or ≥ 90 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
History of diabetes (yes/no);
●
History of bleeding disorders (yes/no);
●
History of depression or bipolar disorder (yes/no);
●
History of cardiovascular disease (yes/no);
●
Type of transplant (liver or kidney),
○
For renal transplant subjects, prior dialysis type (hemodialysis, peritoneal 
dialysis, other, or not done);
●
Donor type (living or deceased);
●
Immunosuppressant medication (Tacrolimus, Cyclosporine, other);
●
Injection drug user (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Subject on stable opiate substitution (yes/no);


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●
Tobacco use (user, ex-user, or non-user);
●
Alcohol use (drinker, ex-drinker, or non-drinker);
●
Concomitant use of Proton Pump Inhibitors (PPIs).  
Summaries of baseline resistance are described in Section 10.8.
Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.
If the IL28B genotype result is not available from a sample collected on Day 1, then a 
result available from a sample collected at any time during the study will be used to 
summarize IL28B genotype.  IL28B rs12979860 will be resulted as C/C, C/T, or T/T by 
the central laboratory.
HOMA-IR is defined as fasting glucose (mmol/L) × fasting insulin (μIU/mL) ÷ 22.5.  
Subjects who do not have concurrent fasting glucose and fasting insulin values at baseline 
will be excluded from the summary of baseline HOMA-IR.
Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores, 
FibroScan scores, or FibroTest scores.  Only one score will be used to categorize each 
subject even if a subject has more than one score recorded.  If a biopsy score is present, 
then it will be used to categorize the subject, regardless of the FibroScan/FibroTest score.  
Similarly, if a FibroScan score is present along with a FibroTest score, then the FibroScan 
score will be used to categorize the subject.  If biopsy and FibroScan scores are not 
present and more than one FibroTest result is available, then the baseline FibroTest result 
(i.e., last non-missing FibroTest result on or before Day 1) will be used to categorize the 
subject.  Subjects will be categorized as F0 – F1, F2, F3, or F4 according to Table 4.
All subjects will be categorized as not having cirrhosis (cirrhosis = no) since this study 
excludes subjects with cirrhosis.


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Table 4.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, Batts 
Ludwig, Knodell, IASL, 
Scheuer, or Laennec Score
Liver Biopsy 
Ishak Score
FibroScan 
(kPa)
FibroTest*
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 12.5
0.59 to 0.74
F4
4
≥ 5
≥ 12.5
≥ 0.75
*
APRI will not be used to derive Baseline Fibrosis Stage.  However, per inclusion/exclusion criteria, subjects need 
to have concordant FibroTest and APRI scores in order to determine eligibility.
Immunosuppressant medications (i.e., Cyclosporine, Sirolimus, Everolimus and 
Tacrolimus) are captured on the "Immunosuppression Regimen Dosing Diary" eCRF.  
Other immunosuppressant medications are captured on the "Concomitant Medications and 
Supplements" eCRF.
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 
baseline values of AST, ALT, and platelet count 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 (10!/L)
× 100
FIB-4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10!/L) × *ALT (U/L)
Histories of diabetes, bleeding disorders, depression or bipolar disorder, and 
cardiovascular disease will be based on the Medical History (MH) eCRF, as defined in 
Table 5.


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Table 5.
Medical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Diabetes
Metabolic
Diabetes mellitus
Bleeding disorders
Blood
Clotting/bleeding problems
Factor deficiency
Hemophilia
Von Willebrand disease
Depression or bipolar disorder
Neurologic and Psychiatric 
System
Bipolar disorder
Depression
Cardiovascular disease
Cardiovascular
Angina
Cardiac arrhythmia
Cardiovascular disease
Congenital heart disease
Congestive heart failure
Coronary artery disease
Hypertension
Myocardial infarction
Myocarditis
Peripheral vascular disease-arterial
Peripheral vascular disease-venous
Valvular heart disease
Vasculitis
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.


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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 (ABT-493/ABT-530).  A concomitant medication is defined as any medication 
that started prior to the date of the first dose of study drug and continued to be taken on or 
after the first dose of study drug or any medication that started on or after the date of the 
first dose of study drug, but not after the date of the last dose of study drug.  A 
post-treatment medication for the treatment of HCV is defined as any medication taken on 
or after the last dose of study drug and entered as "Post-treatment HCV medications" on 
the eCRF.
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.  The prior HCV medications taken by the 
treatment experienced subjects will be summarized separately from other prior 
medications.  
The number and percentage of subjects taking concomitant immunosuppressant 
medications will be summarized separately from other concomitant medications. 
The number and percentage of subjects with immunosuppressant medication dosage 
increase and decrease, respectively, at each post-baseline visit in the treatment period will 
be summarized by each immunosuppressant medication as captured on the 
"Immunosuppression Regimen Dosing Diary" eCRF (i.e., Cyclosporine, Sirolimus, 
Everolimus and Tacrolimus).
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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8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized overall 
and by investigator.
●
Subjects enrolled in this study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
●
Subjects ongoing in the Post-Treatment Period at the time of the primary 
analysis.
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF).  Similar summaries will be 
provided for discontinuations from the study.
The number and percentage of subjects with reported study drug interruptions will be 
summarized.
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 will be summarized for the safety population.  
Duration of exposure is defined for each subject as the last study drug dose date minus the 
first study drug dose date plus 1 day.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will 
be presented for exposure during the treatment period.


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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 75 days
●
76 to 90 days
●
> 90 days
In addition, the number and percentage of subjects with study drug duration of ≥ 77 days 
will be summarized.  
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 
(ABT-493/ABT-530) during the treatment period will be calculated as the percentage of 
tablets taken relative to the total tablets expected to be taken.  The total number of tablets 
expected to be taken will be equal to the total number of tablets that should have been 
taken per the protocol for the duration that the subject was in the Treatment Period (date 
of last dose of study drug – date of first dose of study drug + 1).  Study drug interruptions 
recorded on the eCRF will not be subtracted from the duration.  
A subject is considered to be compliant if the percentage is between 80% and 120%.  
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 for study drug, based on data as observed.  An additional summary of the 
percentage of compliant subjects will be provided where subjects who are missing study 
drug accountability records will be imputed as non-compliant.


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10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
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HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-treatment virologic failure = Breakthrough or EOT failure.
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of study drug (up to and including the SVR12 assessment time point) for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment 
(defined as study drug duration ≥ 77 days), excluding reinfection as described below.
Relapse24 = confirmed HCV RNA ≥ LLOQ within the SVR24 window for a subject who 
achieved SVR12 and has HCV RNA data available in the SVR24 window, excluding 
reinfection.


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Relapseoverall = confirmed HCV RNA ≥ LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment (defined as study 
drug duration ≥ 77 days), excluding reinfection.
Virologic failure = On-treatment virologic failure or Relapseoverall.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as any 
subject with study drug duration of 77 days or greater.  If the last available post-treatment 
value is ≥ LLOQ, then the subject will be considered a relapse (i.e., will not require 
confirmation).
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the post 
treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B gene 
sequences.  Reinfection in the case of the same HCV subtype is defined as a clade switch, 
as indicated by the lack of clustering between the baseline and post-treatment sequences 
by phylogenetic analysis.  If phylogenetic analysis is not possible due to technical 
difficulties, HCV reinfection may be determined with a confirmed HCV genotype or 
subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger 
assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and no genotype, subtype, or clade switch compared with baseline as 
determined by phylogenetic analysis of the NS3 or NS5A gene sequences.  If 
phylogenetic analysis is not possible due to technical difficulties, the subject will be 
defined as having a post-treatment relapse unless an HCV genotype or subgenotype 
switch is confirmed by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger 
assay. 


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


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[study drug duration < 77 days] and did not meet the On-treatment virologic 
failure, Relapse12, or Relapse24 definitions);
5.
HCV reinfection;
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], [4], or [5]);
7.
Other (defined as any SVR24 non-responder not meeting the definitions of 
[1] – [6]).
10.2
Handling of Multiplicity
No adjustment for multiple comparisons is used in this open-label single-arm study.
10.3
Primary Efficacy Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug) in the ITT population.  The number and percentage of subjects 
in the ITT population achieving SVR12 will be summarized with a two-sided 95% 
confidence interval, calculated using the normal approximation to the binomial 
distribution.  If the SVR12 rate is 100%, then the Wilson's score method will be used to 
calculate the confidence interval.  
The lower confidence bound of the 2-sided 95% CI (LCB) for the percentage of subjects 
achieving SVR12 must exceed 86% to achieve non-inferiority to the standard of care.
10.4
Secondary Efficacy Analyses
Two secondary efficacy endpoints will be summarized:
●
the percentage of subjects with on-treatment virologic failure (defined as 
On-treatment virologic failure);


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●
the percentage of subjects with post-treatment relapse (defined as Relapse12; 
subjects with reinfection will be summarized separately).
The number and percentage of subjects with on-treatment virologic failure and 
post-treatment relapse (Relapse12) will be summarized with two-sided 95% Wilson score 
intervals.  
In addition, a summary of reasons for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, other) will be provided.
10.5
Sensitivity Analyses for SVR
The following analysis approaches will be used as sensitivity analyses for the SVR12 rate.  
●
A two-sided 95% confidence interval for the SVR12 rate in the ITT population 
will be calculated using a Wilson score interval.
●
The SVR12 rate in the mITT-GT and mITT-GT-VF populations, as applicable, 
will be calculated, as well as the corresponding two-sided 95% confidence 
interval using a Wilson score interval and a Normal approximation to the 
binomial distribution.
Listings of subjects excluded from the mITT-GT and mITT-GT-VF populations will be 
provided, as applicable.
10.5.1
Imputation Approaches
In addition to imputing SVR12 as described in Section 6.3, SVR12 will be presented using 
the following other methods to impute missing HCV RNA values:
●
imputing any missing HCV RNA values in the SVR12 window by carrying 
forward the last non-missing (post-baseline) HCV RNA value prior to the 
SVR12 window.
●
impute as described in Section 6.3 but treat SVR12 non-responders who were 
categorized as "prematurely discontinued study drug with no on-treatment 


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virologic failure" or "missing follow-up data in the SVR12 window" as 
successes.
For each of these, the percentage of subjects with SVR12 will be presented along with 
two-sided 95% Normal and Wilson score confidence intervals.
10.6
Efficacy Subgroup Analysis
The percentage of ITT subjects with SVR12 will be calculated, as will the corresponding 
two-sided 95% Wilson score confidence intervals for the following subgroups:
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (as defined in 
Section 10.8);
●
Prior HCV treatment history (treatment-naïve or treatment-experienced);
○
For treatment-experienced subjects, type of previous regimen (IFN- or 
SOF-based);
○
For treatment-experienced subjects, occurrence of prior HCV treatment 
relative to renal or liver transplant (pre-transplant or post-transplant);
●
Type of organ transplant (liver or kidney);
●
Type of immunosuppressant medications (Tacrolimus, Cyclosporine, or other);
●
IL28B genotype (CC or non-CC);
●
Sex (male or female);
●
Age (< 65 or ≥ 65 years) and (< 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);
●
Baseline BMI (< 30, or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL) and 
(< 6,000,000, or ≥6,000,000 IU/mL);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4 [if 
applicable]);
●
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●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2); 
●
Geographic region (North America, Europe, Rest of world);
●
Country (as appropriate);
●
History of diabetes (yes/no);
●
Former injection drug user (yes, within last 12 months; yes, more than 
12 months ago; or no);
●
Subject on stable opiate substitution (yes/no);
●
Presence of baseline resistance-associated variants (any NS3/4A variant 
[yes/no]; any NS5A variant [yes/no]; any NS3/4A and any NS5A variant 
[yes/no], any NS3/4A or any NS5A variant [yes/no]), and (NS3/4A variant 
only, NS5A variant only, both NS3/4A and NS5A, or none);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no).
The 2-sided 95% Wilson score confidence interval will be produced if there are at least 
10 subjects in the subgroup.
For the subgroup analyses, the presence of baseline resistance-associated variants as listed 
above are defined in Section 10.8.1; this subgroup analysis will be performed in the 
mITT-GT-VF population.
10.7
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of DAA-naïve subjects with on-treatment virologic failure;
●
The percentage of DAA-naïve subjects with post-treatment relapse;
●
The percentage of subjects with SVR4;
●
The percentage of subjects with SVR24;


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●
The percentage of subjects who relapsed after achieving SVR12 (Relapse24);
●
The percentage of subjects with virologic failure through Post-Treatment 
Week 12 (i.e., the SVR12 non-responders due to on-treatment virologic failure 
or Relapse12)
In the above analyses for SVR, virologic failure, and relapse, the percentage of subjects 
with a two-sided 95% Wilson score interval will be summarized.  Imputations for missing 
data will be performed as described in Section 6.3 for analysis of SVR, where a missing 
response will be imputed as a failure after performing the described imputation.  All other 
endpoints will be presented using data as observed.
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject number and the SVR visit window corresponding to the 
first occurrence of relapse.  A similar listing will be prepared for subjects who 
prematurely discontinued treatment and relapsed after having HCV RNA < LLOQ at their 
Final Treatment Visit.
The number and percentage of subjects who do not achieve SVR12 will be summarized by 
reason for non-response (as defined in Section 10.1).  A listing of subject numbers and 
reason for non-response will be prepared.  A similar summary and listing will be prepared 
for subjects who do not achieve SVR24.
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and the positive predictive value (PPV) and negative predictive value 
(NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is a percentage 
defined as the number of subjects achieving both SVR12 and SVR24 and the number of 
subjects where both SVR12 and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is 
the proportion of subjects who achieve SVR12 and SVR24 out of all subjects who achieved 
SVR12.  The NPV of SVR12 on SVR24 is the proportion of subjects who neither achieve 


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SVR12 nor SVR24 out of all subjects who did not achieve SVR12.  Similarly, the 
concordance between SVR4 and SVR12 will be summarized. 
10.8
Resistance Analyses
For all subjects, full length NS3/4A or NS5A from baseline samples will be sequenced by 
next generation sequencing (NGS).  For subjects who experience virologic failure (on-
treatment virologic failure or post-treatment relapse as defined in Section 10.1), full 
length NS3/4A and NS5A genes from the first sample after virologic failure with HCV 
RNA ≥ 1000 IU/mL will be sequenced by NGS.  An appropriate subtype specific 
prototypic reference sequence will be used for comparison with sequences from samples.  
Subjects who experience virologic failure will be referred to as subjects in the primary 
virologic failure (PVF) population, and a listing by subject that includes HCV subtype, 
IL28B genotype, reason for SVR12 non-response, time point(s) sequenced as closest to 
time of VF, and HCV RNA value at the VF time point(s) will be produced for these 
subjects.  In addition, all listings described below will display HCV subtype and reason 
for SVR12 non-response in the subject identifier for each subject.  A separate listing will 
delineate all subjects in the PVF population for whom no sequencing was performed 
(e.g., lost to follow-up while HCV RNA ≤ 1000 IU/mL).
Subjects treated with study drug who do not achieve SVR12 due to reasons other than 
virologic failure (prematurely discontinued study drug with no on-treatment virologic 
failure, HCV reinfection, missing SVR12 data or other reasons as described in 
Section 10.1, Reasons for SVR12 Non-Response), but have a time point with HCV RNA 
≥1000 IU/mL after treatment discontinuation, will have the sample at that time point 
sequenced.  These subjects will be referred to as the non-PVF population.  A listing of all 
subjects in the non-PVF population with post-baseline sequencing available will be 
created that is similar to the listing of subjects in the PVF population with post-baseline 
sequencing available.


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


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frequency threshold utilized) within a subject's viral population in a baseline or 
a post-baseline sample at a signature amino acid position
●
Post-baseline variant:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline (< 2%) in the subject and is detectable 
in ≥ 2% of the sequences from the post-baseline sample
●
Enriched variant:  variant present in both the baseline and a post-baseline 
sample whose prevalence in the post-baseline sample is at least 20 percentage 
points greater than the prevalence in the baseline sample [(post-baseline % –
baseline %) ≥ 20]
●
Treatment-emergent variant by NGS: A post-baseline variant or an enriched 
variant
Analysis will be Performed Separately for each HCV Subtype Within each Listing.  
Analysis 1:  The following analyses will be performed for all subjects:
●
A listing of all baseline variants (≥ 2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A) (ITT). 
●
A listing of all baseline variants (≥ 15% detection threshold) at non-signature 
resistance-associated amino acid positions for each DAA target (NS3/4A and 
NS5A) for subjects in PVF population.
●
A listing of baseline variants (≥ 15% detection threshold) at signature amino 
acid positions in subjects with variants across both NS3 and NS5A, or those 
with multiple baseline variants within any one target (NS3 or NS5A) (ITT 
population).
●
The number and percentage of subjects with baseline variants at detection-
thresholds of ≥ 2% and ≥ 15% for variants at signature amino acid positions 
(ITT).  This table includes prevalence of each baseline variant, and a summary 
of number of subjects with variants in NS3 only, NS5A only, and NS3 + 
NS5A.  Include the number of GT2 – 6 subjects with variants in NS3 only, 
NS5A only, any in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + 
NS5A.


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●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A (ITT), by subtype, and total.
●
Total number and percentage of subjects with baseline polymorphisms at a key 
subset of amino acid positions in NS3 only, in NS5A only, any in NS3, any in 
NS5A, any in NS3 or NS5A, any in NS3 + NS5A (ITT), by genotype, and 
total.
Analysis 2:  The impact of baseline variants on treatment outcome will be assessed for 
mITT-GT-VF population as follows:  for each variant, the SVR12 rate will be calculated 
for subjects with and without the variant and the 2 rates will be compared using Fisher's 
exact test.  Analysis will be grouped by HCV subtype and DAA target (NS3/4A or 
NS5A).  The analysis will include total number of subjects within each subtype with any 
variant within NS3, any variant within NS5A, and with variants in NS3 + NS5A.
The following will be included in the analyses of impact of baseline variants on treatment 
outcome:
●
Variants at signature amino acid positions (vs no variant at that position), 
using detection thresholds of both 2% and 15%.  The analysis will include the 
number of subjects with variants in NS3 only, in NS5A only, any in NS3, any 
in NS5A, any in NS3 or NS5A, any in NS3 + NS5A. 
●
Variants at each non-signature amino acid position at a detection threshold of 
15%.
●
Each variant at signature amino acid position (vs not that variant) using 
detection thresholds of 2% and 15%.  The analysis will include the number of 
subjects with variants in NS3 only, in NS5A only, any in NS3, any in NS5A, 
any in NS3 or NS5A, any in NS3 + NS5A.
Analysis 3:  In subjects with or without polymorphisms in NS3 only, in NS5A only, any 
in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A at the key subset of 
amino acid positions at 15% detection threshold, the SVR12 rate will be calculated, and 
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Analysis will be separated by HCV subtype.  The following tables will be provided 
(mITT-GT-VF):
●
Comparison of SVR12 rates by subtype, and total (include all subtypes)
●
Comparison of SVR12 rates by genotype, and total (include all subtypes)
Analysis 4 (will be available in the primary CSR and will updated in the final CSR 
for the study):
The following analyses will be performed for subjects who do not achieve SVR12 (with 
separate summaries for subjects in PVF and non-PVF populations) and have post-baseline 
resistance data available:
●
Listings by subject of all treatment-emergent variants relative to the baseline 
amino acid sequences will be provided for each DAA target (NS3/4A and 
NS5A). 
●
Listings by subject of all variants at signature amino acid positions in a post-
baseline time point for each DAA target (NS3/4A and NS5A).
●
The persistence of post-baseline variants at signature resistance-associated 
amino acid positions for each target (NS3 and NS5A) from subjects will be 
assessed at Post-Treatment Week 24.  Listings by subject and time point of all 
treatment-emergent variants will be provided for each DAA target (NS3 and 
NS5A).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequence from baseline samples from all 
subjects in order to accurately determine subtype.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A, and/or NS5A sequences performed by AbbVie.  If the 


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phylogenetic analysis is available, then it will be used to determine the subject's HCV 
genotype and subtype.  If it is not available, then the Sanger sequencing assay result will 
be used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis result nor the Sanger sequencing assay results is 
available, then the Inno-LIPA assay results will be used to categorize the subject.  This 
subtype information will be presented in summaries of efficacy subgroup analyses.  The 
baseline characteristic summary will use the results from the central laboratory (Sanger 
sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]).
This subtype information will be presented in summaries of efficacy subgroup analyses.  
The baseline characteristic summary will use the results from the central laboratory 
(Sanger sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]).
A summary of HCV subtype as provided by the central laboratory (Sanger sequencing or 
Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) versus phylogenetic analysis 
also will be provided.
10.8.1
Presence of Baseline Resistance-Associated Variants
For the efficacy subgroup analyses defined in Section 10.6, any NS3/4A variant and any 
NS5A variant are defined as follows, where baseline resistance-associated variants based 
on ≥ 15% NGS detection threshold are considered.  Signature amino acid positions of 
NS3/4A and NS5A by HCV genotype are listed in Table 7.


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Table 7.
Resistance-Associated Variants by DAA Target and HCV Genotype 
Target
Genotype
Signature Amino Acid Positions 
(All Variants at These 
Positions Are to Be Included)
Other Specific Variants
NS3/4A
1, 2, 3, 4, 5, 6
155, 156, 168
NS5A
1a
28, 30, 31, 93
H58D, E62A
1b
31, 93
2
24, 28, 30, 92, and 93
3
24, 28, 30, 31, 58, and 93
4
24, 28, 30, 31, and 93
5
24, 28, 30, 31, 58, 92, and 93
6
24, 28, 30, 31, 58, 92, and 93
For example, according to Table 7, all subjects with any baseline variant at amino acid 
positions 155, 156, or 168 will be counted as having any NS3/4A variant at baseline; any 
HCV genotype 2 subjects with any baseline variant at amino acid positions 24, 28, 30, 92, 
or 93 will be counted as having any NS5A variant at baseline.
The number and percent of subjects in the mITT-GT-VF population will be summarized 
for the presence of baseline resistance-associated variants of:
1.
Any NS3/4A variant at baseline (yes/no);
2.
Any NS5A variant at baseline (yes/no);
3.
Any NS3/4A variant at baseline or any NS5A variant at baseline (yes/no); 
4.
Both NS3/4A and NS5A variant at baseline (i.e., any NS3/4A variant at baseline 
and any NS5A variant at baseline) (yes/no);
5.
Presence or absence of any variant 
5a. Any NS3/4A variant at baseline only (i.e., without baseline NS5A variants);
5b. Any NS5A variant at baseline only (i.e., without baseline NS3/4A variants); 
5c. Both NS3/4A and NS4A variant at baseline; 


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5d. None (i.e., no baseline variant in either NS3/4A or in NS5A at baseline).
10.9
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  
SF-36 version 2 (SF-36v2), Fatigue Severity Scale (FSS), and EuroQol-5 Dimensions-3 
Level (EQ-5D-3L).
Subject's responses to the EQ-5D-3L will be combined into a unique health state using a 
5-digit code with 1 digit from each of the 5 dimensions.  The EQ-5D-3L states will be 
converted into a single preference-weighted health utility index score by applying 
weights.1,2  The VAS score will be analyzed separately.
The SF-36v2 measures dimensions of a patient's functional health and well-being in 
8 domains and also provides 2 summary scores that characterize a patient's mental 
(Mental Component Summary; MCS) and physical (Physical Component Summary; PCS) 
health status.  Imputation will be applied to each domain as described in Section 6.3.  The 
score for each of the 8 domains ranges from 0 to 100 and will be normalized according to 
the user manual.3  The standardization of the normalized scores will provide the 
norm-based scores with a mean of 50 and a SD of 10.  The two summary scores are based 
on the norm-based scores.  Per the SF-36v2 instrument manual, score for any item with 
multiple responses will be set to "missing."  Subject's responses to the SF-36v2 will be 
summarized for the PCS and MCS measures and eight individual domain measures.
The FSS measures the impact of fatigue over the past week on specific types of 
functioning.  The survey consists of 9 questions using a 7-point Likert scale.  A total score 
is calculated as the average of the individual item responses (adding up all the answers 
and dividing by nine).  Higher FSS scores indicate a higher degree of impact of fatigue.  
Imputation will be applied to the total score as described in Section 6.3.
Summary statistics (n and mean) at each visit and for change from baseline (n, mean, SD, 
minimum and maximum) to each visit will be provided for the SF-36v2 (MCS and PCS) 


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scores; FSS total score; and EQ-5D-3L health index score and VAS score and will be 
summarized descriptively at each visit and for change from baseline to each visit.  
The following analyses of patient reported outcomes (PROs) also will be performed:
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable time point of greater than or equal to 
2.5 points in the SF-36 MCS and PCS, along with two-sided 95% Normal CI;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable time point of greater than or equal to 
5 points in the SF-36 domain scores, along with two-sided 95% Normal CI;
●
Number and percentage of subjects who have ever experienced an increase 
from baseline up through each applicable time point of greater than or equal to 
0.7 in the FSS total score, along with two-sided 95% Normal CI.
If a subject starts another treatment for HCV, then all PRO values for this subject 
measured on or after the start date of the new HCV treatment will be excluded from 
analyses.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized using the safety population.
11.2
Analysis of Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
clinical study report.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events are defined as any adverse event (AE) with an onset 
date that is after the first dose of study drug and no more than 30 days after the last dose 
of study drug.  Events where the onset date is the same as the study drug start date are 


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assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent, unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT).  The system organ classes will be presented 
in alphabetical order, and the preferred terms will be presented in alphabetical order 
within each system organ class.
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent adverse event;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent adverse events of Grade 3 or higher;
●
Serious treatment-emergent adverse events;
●
Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
DAA-related treatment-emergent adverse events leading to discontinuation of 
study drug;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAA (ABT-493/ABT-530);
●
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;


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●
Deaths.
Adverse Events by SOC and PT
Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most severe/highest grade incident for the severity tables and most related incident 
for the relationship tables).  Subjects reporting more than one AE within an SOC will be 
counted only once for that SOC.  Subjects reporting more than one AE will be counted 
only once in the overall total.
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs (ABT-493/ABT-530);
●
Serious treatment-emergent adverse events;
●
Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to DAAs (ABT-493/ABT-530);
●
Grade 3 or higher treatment-emergent adverse events;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
DAA-related treatment-emergent adverse events leading to discontinuation of 
study drug;
●
Serious treatment-emergent adverse events leading to discontinuation of study 
drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to death.
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be created.


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Adverse Events by PT
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated according to PT and sorted by overall frequency.  Similar summaries 
will be provided for Grade 3 or higher treatment-emergent adverse events, DAA-related 
treatment-emergent adverse events, DAA-related Grade 3 or higher treatment-emergent 
adverse events, and DAA-related treatment-emergent serious adverse events.
Adverse Events by Maximum Severity Grade Level
Treatment-emergent adverse events and DAA-related treatment-emergent adverse events 
will be summarized by maximum severity grade level of each preferred term.  Each 
adverse event will be assigned a grade level (Grade 1, 2, 3, 4, or 5) by the investigator.  If 
a subject has an AE with unknown severity, then the subject will be counted in the 
severity grade level category of "unknown," even if the subject has another occurrence of 
the same event with a severity present.  The only exception is if the subject has another 
occurrence of the same AE with the highest grade level (Grade 5).  In this case, the 
subject will be counted under the "Grade 5" category.
Adverse Event by Maximum Relationship
Treatment-emergent adverse events also will be summarized by maximum relationship of 
each preferred term to study drug (DAA), as assessed by the investigator.  If a subject has 
an adverse event with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same adverse event with a relationship assessment of "Reasonable 
Possibility."  In this case, the subject will be counted under the "Reasonable Possibility" 
category.
Other Adverse Events
The number and percentage of subjects experiencing at least one treatment-emergent 
adverse event in the search defined below by Product MedDRA Query (PMQ) will be 


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presented overall and by SOC and PT.  In addition, a listing of treatment-emergent 
adverse events for subjects meeting the search criterion will be provided.
"Hepatic Decompensation and Hepatic Failure" (PMQ)
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,
●
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.
11.3.1
Variables and Criteria Defining Abnormality
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, reticulocyte count, prothrombin time (PT), international 
normalized ratio (INR), and activated partial thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, sodium, potassium, calcium, inorganic phosphorus, cholesterol, 
total protein, glucose, triglycerides, albumin, chloride, bicarbonate, magnesium, total 
insulin, gamma-glutamyl transferase (GGT), creatinine clearance (calculated using 


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Cockcroft-Gault), and estimated glomerular filtration rate (eGFR) calculated using the 
modification of diet in renal disease (MDRD) equation defined below.
Urinalysis variables include:  specific gravity, ketones, pH, protein, blood, glucose, 
urobilinogen, bilirubin, leukocyte esterase, and microscopic (reflexly performed if other 
variables are abnormal).
Some of the above laboratory variables are calculated by the laboratory vendor including 
indirect bilirubin, creatinine clearance, 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).
The central lab calculates the estimated creatinine clearance (CrCl) based on the following 
Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum 
creatinine (mg/dL) × 72].
11.3.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 
the time of first dose if time is available.  The same baseline value will be used for change 
to Treatment Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable 
post-treatment visits, will be summarized.  Each protocol-specified laboratory parameter 
will be summarized with the sample size, baseline mean, visit mean, change from baseline 
mean, standard deviation, minimum, median, and maximum.  


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The laboratory parameters defined in Table 8 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.  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 8.  A listing of all relevant laboratory 
parameters will be provided for each subject who had an increase to Grade 2 or higher for 
all laboratory variables in Table 8.
Table 8.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Absolute Neutrophil 
Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Creatinine clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Albumin
< LLN – 30 g/dL
< 30 – 20 g/L
< 20 g/L
--
Assessment of Hepatic Laboratory Parameters
The number and percentage of subjects 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;
○
ALT > 5 × ULN and total bilirubin < 2 × ULN;
●
ALT < 3 × ULN and total bilirubin ≥ 2 × ULN.  


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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.
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality
Vital sign variables are body temperature, sitting systolic blood pressure, sitting diastolic 
blood pressure, sitting pulse rate, and body weight.


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The criteria for potentially clinically significant vital sign findings are presented in 
Table 9.
Table 9.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic Blood Pressure
≤ 90 mmHg AND A decrease of 
≥ 20 mmHg from baseline
≥ 180 mmHg AND An increase of 
≥20 mmHg from baseline
Diastolic Blood Pressure
≤ 50 mmHg AND A decrease of 
≥ 15 mmHg from baseline
≥ 105 mmHg AND An increase of 
≥15 mmHg from baseline
Pulse Rate
≤ 50 bpm AND A decrease of 
≥15 bpm from baseline
≥ 120 bpm AND An increase of 
≥15 bpm from baseline
Weight
A decrease of ≥ 15% from 
baseline
An increase of ≥ 15% from baseline
Body Temperature
> 38.3°C AND An increase of 
≥1.1°C from baseline
11.4.2
Statistical Methods
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for change to Treatment 
Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable post 
treatment visits, will be summarized.  Each vital sign parameter will be summarized with 
the baseline mean, visit mean, change from baseline mean, standard deviation, minimum, 
median, and maximum.  
The number and percentage of subjects with on-treatment values meeting the specified 
criteria for Potentially Clinically Significant (PCS) vital sign values (Table 9) will be 
summarized.  A post-baseline value must be more extreme than the baseline value to be 
considered a PCS finding.  A separate listing will be provided that presents all vital sign 
values for the subjects meeting PCS criteria during treatment.


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12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and SAP
1.
Updates were made to the resistance analysis plan to be consistent across the HCV 
ABT-493/ABT-530 program.
2.
Updates were made to the subgroup efficacy analysis section to be consistent 
across the HCV ABT-493/ABT-530 program
13.0
References
1.
Szende A, Williams A.  Measuring self-reported population health:  an 
international perspective based on EQ-5D.  EuroQol Group Monographs 
Volume 1.  SpringMed Publishing; 2004.
2.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L user guide:  basic information on 
how to use the EQ-5D-5L instrument, Version 1.0.  Rotterdam, the Netherlands:  
EuroQol Group; 2011.
3.
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's manual for the SF-36v2 health 
survey.  2nd ed.  Lincoln, RI:  QualityMetric Incorporated; 2007.