Conditions: Hepatitis C Virus (HCV)
Keywords: Chronic Hepatitis C Virus (HCV) Genotype 1 to 6 Cirrhosis Compensated Cirrhosis Human Immunodeficiency Virus co-infection Treatment-naïve treatment-experienced interferon Asian
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 160
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of glecaprevir/pibrentasvir (ABT-493/ABT-530) in chronic hepatitis C virus (HCV) genotype (GT)1 to GT6-infected Asian participants with compensated cirrhosis with or without human immunodeficiency virus (HIV) co-infection who are HCV treatment-naïve or treatment-experienced with interferon (IFN) (alpha, beta or pegylated interferon \[pegIFN\]) with or without ribavirin (RBV) OR sofosbuvir with RBV with or without IFN.

Detailed description:

Arms:
arm 1: Participants received oral glecaprevir/pibrentasvir 300 mg/120 mg once daily (QD) for 12 or 16 weeks. Participants received treatment for 12 weeks with the exception of treatment-experienced, genotype 3-infected participants who received treatment for 16 weeks.

Interventions: intervention 1: Glecaprevir/Pibrentasvir
Intervention descriptions: intervention 1: Coformulated tablet for oral administration

Protocol document:
Prot_000.pdf: 
ABT-493, ABT-530
M15-593 Protocol
1
1.0
Title Page
Clinical Study Protocol M15-593
An Open-Label Study to Evaluate the Efficacy and 
Safety of ABT-493/ABT-530 in Treatment-Naïve and 
Treatment-Experienced Asian Adults With Chronic 
Hepatitis C Virus Genotype (GT) 1 to GT6 Infection 
With Compensated Cirrhosis and With or Without 
Human Immunodeficiency Virus Co-Infection
AbbVie Investigational
  Product:
ABT-493, ABT-530
Date:
03 April 2017
Development Phase:
3
Study Design:
This is an open-label multicenter study.
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.
NCT03235349


ABT-493, ABT-530
M15-593 Protocol
2
1.1
Synopsis
AbbVie Inc.
Protocol Number:  M15-593
Name of Study Drug:  ABT-493/ABT-530
Phase of Development:  3
Name of Active Ingredient:  ABT-493, ABT-530
Date of Protocol Synopsis:  03 April 2017
Protocol Title:  An Open-Label Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in 
Treatment-Naïve and Treatment-Experienced Asian Adults With Chronic Hepatitis C Virus 
Genotype (GT) 1 to GT6 Infection With Compensated Cirrhosis and With or Without Human 
Immunodeficiency Virus Co-Infection
Objectives:  The primary objectives of this study are to assess the efficacy (SVR12, [HCV RNA < lower 
limit of quantification {LLOQ} 12 weeks after the last actual dose of study drug]) and safety following 
12 or 16 weeks of treatment with the ABT-493/ABT-530 combination regimen in treatment-naïve or 
treatment-experienced adults with chronic hepatitis C virus (HCV) GT1 to GT6 infection with 
compensated cirrhosis with or without human immunodeficiency virus (HIV) co-infection.
The secondary objectives are to assess the percentage of subjects with on-treatment HCV virologic 
failure, the percentage of subjects with post-treatment relapse of HCV infection, and the percentage of 
HCV/HIV co-infected subjects achieving SVR12.
An additional objective is to assess the pharmacokinetics of ABT-493 and ABT-530 in 
Asian HCV-infected adults.
Investigators:  Multicenter
Study Sites:  Approximately 35 sites.
Study Population:  Chronic HCV GT1, 2, 3, 4, 5 or 6-infected Asian male and female adults aged 
18 years or older, with compensated cirrhosis, with or without HIV co-infection who are HCV 
treatment-naïve or treatment-experienced to interferon (IFN) (alpha, beta or pegylated interferon 
[pegIFN]) with or without ribavirin (RBV) OR sofosbuvir with RBV with or without IFN.
Number of Subjects to be Enrolled:  Approximately 160 subjects
Methodology:  
This is a Phase 3, single-arm, open-label, multicenter study to evaluate the efficacy and safety of
ABT-493/ABT-530 in chronic HCV GT1 to GT6-infected subjects with compensated cirrhosis with or 
without HIV co-infection who are HCV treatment-naïve or treatment-experienced with IFN (alpha, beta 
or pegIFN) with or without RBV OR sofosbuvir with RBV with or without IFN.
Approximately 160 subjects meeting the eligibility criteria will be enrolled.  A minimum of 
60 GT1-infected subjects, a minimum of 36 GT2-infected subjects and approximately 24 GT3-, 4-, 5- or 
-6-infected subjects from China will be enrolled into this study.  Approximately 30 GT1-infected subjects 
and approximately 10 GT2-infected subjects will also be enrolled into this study from the regional Asian 
country of South Korea.  Of the approximately 160 subjects, a maximum of 16 HCV/HIV co-infected 
subjects will be enrolled.


ABT-493, ABT-530
M15-593 Protocol
3
Methodology (Continued):  
This study will consist of two periods:
Treatment Period:  Eligible subjects will be enrolled and will receive ABT-493/ABT-530 300 mg/120 mg 
once daily (QD) for either 12 or 16 weeks.  Treatment duration will differ among subjects based on HCV 
GT and HCV treatment experience (12 weeks of treatment for GT1, 2, 3, 4, 5 and 6-infected subjects 
with the exception of 16 weeks for treatment-experienced GT3-infected subjects.). 
Scheduled visits for subjects assigned to receive 12 weeks of treatment will consist of Day 1 and 
Weeks 1, 2, 4, 8 and 12.  For subjects assigned to receive 16 weeks of treatment, scheduled visits will 
consist of Day 1 and Weeks 1, 2, 4, 8, 12 and 16.  Study procedures, including assessment of adverse 
events, vital signs, adherence, concomitant medications, HCV RNA, HCV resistance, HIV-1 RNA and 
HIV resistance (as applicable), pharmacokinetic assays, and clinical laboratory tests will be conducted at 
each visit.
Post-Treatment Period:  Subjects who complete the Treatment Period, experience on treatment virologic 
failure, or otherwise prematurely discontinue the Treatment Period will be followed for 24 weeks to 
monitor safety and to evaluate efficacy and the emergence and/or persistence of HCV 
resistance-associated substitutions. 
Baseline HCV resistance samples will be collected for all subjects, but HCV resistance analysis of 
baseline and post-baseline samples will be performed only for subjects who experience virologic failure.
During the Post-Treatment Period, all subjects will have visits at Weeks 4, 12, and 24 following 
completion of the Treatment Period.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female of Asian descent and at least 18 years of age at time of Screening.
2.
If female, subject must be either (as defined in Section 5.2.4 of the protocol) postmenopausal, OR 
permanently surgically sterile OR for Women of Childbearing Potential practicing at least 
one protocol specified method of birth control starting at Study Day 1 (or earlier) through at least 
30 days after the last dose of study drug.
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 the protocol) at Screening do not 
require pregnancy testing.
4.
Screening laboratory result indicating HCV GT1, 2, 3, 4, 5 or 6-infection.
5.
Subject has positive HCV antibody (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 HCV Ab or HCV RNA at least 6 months before Screening; or
●
A liver biopsy consistent with chronic HCV infection 
7.
Subject must be HCV treatment-naïve (i.e., subject has not received any approved or investigational 
HCV treatment) or treatment-experienced (i.e., subject has failed prior HCV treatment with IFN 
[alpha, beta or pegIFN] with or without RBV OR sofosbuvir with RBV with or without IFN.  
Previous HCV treatment must have been completed ≥ 8 weeks prior to screening.


ABT-493, ABT-530
M15-593 Protocol
4
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
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.
Compensated cirrhosis defined as Child-Pugh score of ≤ 6 at Screening and no current or past 
clinical evidence of Child-Pugh B or C Classification or clinical history of liver decompensation 
including ascites noted on physical exam, bleeding varices, use of diuretics for ascites, or hepatic 
encephalopathy.
10. Subject must have documented cirrhosis at any time previously or at Screening by meeting one of 
the following criteria:
●
Histologic diagnosis of cirrhosis on a liver biopsy e.g., a METAVIR, Batts-Ludwig, Knodell, 
IASL, Scheuer, or Laennec fibrosis score of > 3 or Ishak fibrosis score of > 4; or
!
A screening FibroTest score of ≥ 0.75 and Aspartate Aminotransferase to Platelet Ratio Index 
(APRI) > 2; or
o
Subjects with indeterminate FibroTest (0.48 < result < 0.75), or discordant FibroTest and 
APRI results (e.g., FibroTest ≥ 0.75, but APRI ≤ 2) must have a qualifying FibroScan® or 
liver biopsy.
!
FibroScan score ≥ 14.6 kPa.
o
Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6) must have qualifying 
liver biopsy.
11. Absence of hepatocellular carcinoma (HCC) as indicated by Serum Alpha-Fetoprotein (sAFP) 
< 100 ng/mL at Screening and a negative ultrasound, computed tomography (CT) scan or magnetic 
resonance imaging (MRI) for HCC within 12 weeks prior to Screening or at Screening.  Subjects 
who have an ultrasound with results suspicious of HCC followed by a subsequent negative CT or 
MRI of the liver for HCC will be eligible for the study.
12. 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.
13. Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements. 
In addition to Inclusion Criteria 1 through 13, subjects enrolled with HCV GT1 to 6 and HIV-1 co-
infection, must also meet the following criteria per local standard practice:
14. Positive test result for Human Immunodeficiency Virus antibody (HIV Ab) at Screening.
15. Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to initiate ART 
treatment while participating in this study) 
or
On a stable, qualifying HIV-1 ART regimen (allowed regimens will be based on AbbVie approval) 
for at least 8 weeks prior to screening.
16. Subjects naïve to ART must have CD4+ count ≥ 500 cells/mm3 (or CD4+ % ≥ 29%) at Screening.


ABT-493, ABT-530
M15-593 Protocol
5
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
17. Subjects on stable ART must have the following:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening; and
!
Plasma HIV-1 RNA below LLOQ by an approved plasma HIV-1 RNA quantitative assay 
(including but not limited to:  Roche COBAS® Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) 
at Screening and at least once during the 12 months prior to Screening.
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.
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 hepatitis B virus (HBV) 
DNA > LLOQ if HBsAg is negative.
4.
HCV genotype performed during screening indicating co-infection with more than one HCV 
genotype.
5.
Requirement for and inability to safely discontinue contraindicated medications or supplements 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 or HCV/HIV co-infection, based upon 
the results of a medical history, physical examination, vital signs, laboratory profile, and a 12-lead 
electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in the opinion 
of the investigator, including, but not limited to:
●
Uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) level > 8.5% at 
the Screening Visit.
●
Active or suspected malignancy or history of malignancy (other than basal cell skin cancer or 
cervical carcinoma in situ) in the past 5 years.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, psychiatric, or other 
medical disease or disorder, which is unrelated to the existing HCV infection.
7.
Any cause of liver disease other than chronic HCV-infection, including but not limited to the 
following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Steatohepatitis on liver biopsy considered to be the primary cause of the liver disease rather than 
concomitant/incidental with HCV infection


ABT-493, ABT-530
M15-593 Protocol
6
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
8.
Screening laboratory analyses showing any of the following abnormal laboratory results:
●
ALT > 10 × upper limit of normal (ULN)
●
AST > 10 × ULN
●
Estimated Glomerular filtration rate adjusted for the Chinese population (eGFR) 
< 50 mL/min/1.73 m2 as estimated by the MDRD method, modified for the Chinese population 
(C-MDRD), according to the following formula:
eGFR = 175 × (Serum Creatinine)–1 234 × (Age)–0 179 × (0.79 if Female)
●
Total bilirubin > 3.0 ULN
●
Albumin < 2.8 g/dL 
●
International normalized ratio (INR) > 2.3, unless subject has known hemophilia or is on a 
stable anticoagulant regimen affecting INR
●
Hemoglobin < 11 g/dL for women; < 12 g/dL for men
●
Platelets < 60,000 cells per mm3
●
Absolute neutrophil count (ANC) < 1000 cells/μL.
9.
History of solid organ transplantation.
10. 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.
11. Requirement for chronic use of systemic immunosuppressants, including but not limited to, 
corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab).
12. Chronic human immunodeficiency virus, type 2 (HIV-2) infection.
13. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to 
receive ABT-493/ABT-530.
14. History of severe, life-threatening or other significant sensitivity to any excipients of the study drugs.
15. Patients who can't participate in study per local law.
Additional Exclusion Criteria for Subjects with HCV/HIV Co-Infection:
16. For subjects on stable ART, taking anti-retroviral agent(s) other than those permitted based on 
AbbVie approval.
17. Treatment for an AIDS-associated opportunistic infection (OI) within 12 months of Screening or 
prophylaxis for an AIDS-associated opportunistic infection within 6 months of Screening.
18. Diagnosis of any clinical AIDS-defining event within 12 months prior to Screening.  A list of these 
events may be found in Appendix D of the protocol.
Investigational Products:
ABT-493/ABT-530 100 mg/40 mg Film-coated tablet
Dose(s):
ABT-493/ABT-530 300 mg/120 mg QD (3 tablets)
Mode of Administration:
Oral


ABT-493, ABT-530
M15-593 Protocol
7
Duration of Treatment:  Subjects will receive ABT-493/ABT-530 for 12 or 16 weeks.  Treatment 
duration will differ among subjects based on HCV genotype and treatment experience (12 weeks of 
treatment for GT1, 2, 3, 4, 5 and 6-infected subjects with the exception of 16 weeks for treatment-
experienced GT3-infected subjects).
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment Period and Post-Treatment Visit 
throughout the study.  
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-Lead ECGs, and vital signs.
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.
Resistance:
For subjects receiving active study drugs who experience virologic failure, the following HCV resistance 
information will be tabulated and summarized:  1) HCV amino acid variants at baseline at signature 
resistance-associated positions relative to the appropriate prototypic reference sequence; 2) HCV amino 
acid variants relative to the baseline sequence in available post-baseline samples; and 3) HCV amino 
variants at signature resistance-associated positions relative to the appropriate prototypic reference 
sequence in available post-baseline samples.
HIV-1 drug resistance genotyping for protease, reverse transcriptase and integrase sequences may be 
performed for protocol-defined eligible specimens.
Pharmacokinetic: 
Individual plasma concentrations of ABT-493 and ABT-530, and possible metabolites of ABT-493 and 
ABT-530 will be tabulated and summarized.  Values for pharmacokinetic parameters of ABT-493, 
ABT-530 and possible metabolites of ABT-493 and ABT-530 including apparent oral clearance (CL/F) 
and apparent volume of distribution (V/F) will be estimated using population pharmacokinetic modeling 
procedures.
Plasma concentrations of HIV-1 ARVs for individual subjects or a group of subjects or for the entire 
study may be analyzed based on safety, HCV RNA and/or plasma HIV-1 RNA results.
Statistical Methods:
The primary analysis will occur after all subjects have completed the Post-Treatment (PT) Week 12 Visit 
or prematurely discontinued the study.  The data for the primary analysis will be locked after data 
cleaning.  Data collected after this lock will be added to a new version of the database which will be 
cleaned and locked at the end of the study.
Data across subjects of all genotypes will be combined for analysis, unless otherwise indicated.  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.


ABT-493, ABT-530
M15-593 Protocol
8
Statistical Methods (Continued):
Efficacy:
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study 
drug).  The number and percentage of subjects achieving SVR12 will be presented along with a two-sided 
95% confidence interval (CI) for the percentage.
The normal approximation to the binomial distribution will be used to calculate the CI unless the rate for 
the primary endpoint is 100%, in which case the Wilson's score method will be used for the calculation of 
the CI.  No hypothesis will be tested.
The secondary efficacy endpoints are:
!
The percentage of subjects with on-treatment HCV 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 of HCV infection (defined as confirmed 
HCV RNA ≥ LLOQ between end of treatment and 12 weeks after the last dose of study drug 
among subjects who completed treatment as planned with HCV RNA < LLOQ at the end of 
treatment excluding  re-infection), and
●
The percentage of HCV/HIV co-infected subjects achieving SVR12.
For the secondary endpoints, the number and percentage of subjects will be presented along with 95% 
Wilson score CIs.
Additional efficacy endpoints include:  SVR4, SVR24, and the percentage of subjects who relapsed after 
achieving SVR12.
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 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 
meet toxicity grades or are potentially clinically significant, respectively, according to predefined criteria, 
will be summarized.
PROs:  
Changes from baseline to each applicable visit in the patient reported outcome (PRO) summary measures 
will be summarized.
Resistance:  
For all subjects receiving study drugs who experience HCV virologic failure, the HCV amino acid 
variants at signature resistance-associated positions in NS3 and NS5A at baseline identified by 
population or deep sequencing and comparison to the appropriate prototypic reference sequence will be 
analyzed.


ABT-493, ABT-530
M15-593 Protocol
9
Statistical Methods (Continued):
Resistance (Continued):  
The following resistance information will be analyzed for subjects receiving active study drugs who 
experience HCV virologic failure, and who have an available post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the HCV amino acid variants in NS3 and NS5A  identified by population or deep 
sequencing and comparison to the baseline sequence, 2) the HCV amino acid variants in available post-
baseline samples at signature resistance-associated positions in NS3 and NS5A identified by population 
or deep sequencing and comparison to the appropriate prototypic reference sequence, and 3) the 
persistence of HCV viral amino acid variants NS3 and NS5A by population or deep sequencing.
If any subject on stable HIV-1 ART develops a confirmed, quantifiable plasma HIV-1 RNA level (HIV-1 
RNA ≥200 copies/mL at one assessment and ≥ 500 copies/mL on repeat testing) after starting the study, 
the HIV-1 protease, reverse transcriptase and integrase sequences may be analyzed.  
Pharmacokinetic:  
Individual plasma concentration of ABT-493, possible ABT-493 metabolites, ABT-530, and possible 
ABT-530 metabolites will be tabulated and summarized for each visit.  Additional summaries and 
analyses of concentration data may be performed if appropriate and useful in the interpretation of the 
data.  Population pharmacokinetic analyses will be performed using the actual sampling time relative to 
dosing.  Pharmacokinetic models will be built using a non-linear mixed-effects modeling approach. 


ABT-493, ABT-530
M15-593 Protocol
10
1.2
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
ART
Antiretroviral therapy
AUC
Area Under the Concentration Curve
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence interval
CL/F
Apparent Oral Clearance
CPK
Creatine phosphokinase
CRF
Case report form
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
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
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus


ABT-493, ABT-530
M15-593 Protocol
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hCG
Human Chorionic Gonadotropin
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
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NONMEM
Non-linear mixed-effect modeling
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
OATP
Organic anion transporting polypeptide
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
PR
pegIFN/RBV
PRO
Patient Reported Outcome
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin


ABT-493, ABT-530
M15-593 Protocol
12
RNA
Ribonucleic acid
SAE
Serious adverse event
SAS
Statistical Analysis System
SD
Standard Deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
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
TDF
Tenofovir disoproxil fumarate
TE-PRS
Treatment-experienced with regimens containing interferon, pegylated 
interferon, ribavirin, and/or sofosbuvir
ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
WOCBP
Women of childbearing potential
Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
AUC24
AUC for the 24-hour dosing interval
β
Apparent terminal phase elimination rate constant
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
Ctrough
Pre-dose trough plasma concentration
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration (Cmax)


ABT-493, ABT-530
M15-593 Protocol
13
Definition of Terms
Study Drug
ABT-493 and 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


ABT-493, ABT-530
M15-593 Protocol
14
2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Synopsis................................................................................................. 2
1.2
List of Abbreviations and Definition of Terms...................................... 10
2.0
Table of Contents ................................................................ 14
3.0
Introduction......................................................................... 19
3.1
Differences Statement .......................................................................... 32
3.2
Benefits and Risks................................................................................ 33
4.0
Study Objective ................................................................... 33
4.1
Primary Objective ................................................................................ 33
4.2
Secondary Objective............................................................................. 34
5.0
Investigational Plan.............................................................34
5.1
Overall Study Design and Plan:  Description ........................................ 34
5.1.1
Screening ............................................................................................. 35
5.1.1.1
Rescreening.......................................................................................... 36
5.1.2
Treatment Period.................................................................................. 36
5.1.3
Post-Treatment Period.......................................................................... 37
5.2
Selection of Study Population............................................................... 38
5.2.1
Inclusion Criteria.................................................................................. 38
5.2.2
Exclusion Criteria................................................................................. 41
5.2.3
Prior and Concomitant Therapy............................................................ 44
5.2.3.1
Prior HCV Therapy .............................................................................. 45
5.2.3.2
Prior and Concomitant HIV-1 Therapy................................................. 46
5.2.3.3
Concomitant Therapy........................................................................... 46
5.2.3.4
Prohibited Therapy............................................................................... 47
5.2.4
Contraception Recommendations ......................................................... 49
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 51
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 51
5.3.1.1
Study Procedures.................................................................................. 51
5.3.1.2
Meals and Dietary Requirements.......................................................... 61
5.3.1.3
Blood Samples for Pharmacogenetic Analysis ...................................... 61


ABT-493, ABT-530
M15-593 Protocol
15
5.3.2
Drug Concentration Measurements....................................................... 62
5.3.2.1
Collection of Samples for Analysis....................................................... 62
5.3.2.2
Handling/Processing of Samples........................................................... 63
5.3.2.3
Disposition of Samples......................................................................... 63
5.3.2.4
Measurement Methods ......................................................................... 64
5.3.3
Efficacy Variables................................................................................ 64
5.3.3.1
Primary Variable .................................................................................. 64
5.3.3.2
Secondary Variable .............................................................................. 64
5.3.4
HCV Resistance Variables.................................................................... 64
5.3.5
HIV Resistance Variables..................................................................... 65
5.3.6
Safety Variables ................................................................................... 65
5.3.7
Pharmacokinetic Variables ................................................................... 65
5.3.8
Pharmacogenetic Variables................................................................... 66
5.4
Removal of Subjects from Therapy or Assessment ............................... 66
5.4.1
Discontinuation of Individual Subjects ................................................. 66
5.4.1.1
HCV Virologic Stopping Criteria ......................................................... 67
5.4.1.2
Failure to Maintain HIV Virologic Suppression.................................... 68
5.4.2
Discontinuation of Entire Study............................................................ 69
5.5
Treatments ........................................................................................... 70
5.5.1
Treatments Administered...................................................................... 70
5.5.2
Identity of Investigational Product........................................................ 70
5.5.2.1
Packaging and Labeling........................................................................ 71
5.5.2.2
Storage and Disposition of Study Drug................................................. 71
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 71
5.5.4
Selection and Timing of Dose for Each Subject .................................... 72
5.5.5
Blinding ............................................................................................... 72
5.5.6
Treatment Compliance ......................................................................... 72
5.5.7
Drug Accountability ............................................................................. 73
5.6
Discussion and Justification of Study Design........................................ 74
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 74
5.6.2
Appropriateness of Measurements........................................................ 80
5.6.3
Suitability of Subject Population .......................................................... 80
5.6.4
Selection of Doses in the Study ............................................................ 81


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5.6.4.1
Rationale for Dose Selections............................................................... 81
5.6.4.1.1
ABT-493 and ABT-530 Doses ............................................................. 81
5.6.4.2
Rationale for Duration Selections ......................................................... 84
5.6.4.3
Risk of Development of Resistance Mutations During 
Combination DAA Trials ..................................................................... 85
6.0
Complaints........................................................................... 86
6.1
Medical Complaints ............................................................................. 87
6.1.1
Definitions ........................................................................................... 87
6.1.1.1
Adverse Event...................................................................................... 87
6.1.1.2
Serious Adverse Events........................................................................ 88
6.1.2
Adverse Event Severity ........................................................................ 89
6.1.3
Relationship to Study Drug................................................................... 90
6.1.4
Adverse Event Collection Period.......................................................... 91
6.1.5
Adverse Event Reporting...................................................................... 91
6.1.6
Pregnancy............................................................................................. 93
6.1.7
Toxicity Management........................................................................... 93
6.1.7.1
Management of Increases in ALT......................................................... 94
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections ....................................................................... 94
6.2
Product Complaint................................................................................ 95
6.2.1
Definition............................................................................................. 95
6.2.2
Reporting ............................................................................................. 95
7.0
Protocol Deviations ............................................................. 96
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 96
8.1
Statistical and Analytical Plans............................................................. 96
8.1.1
Demographics ...................................................................................... 97
8.1.2
Efficacy................................................................................................ 98
8.1.2.1
Primary Efficacy Endpoint ................................................................... 99
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 99
8.1.2.3
Sensitivity Analysis.............................................................................100
8.1.2.4
Subgroup Analysis ..............................................................................100
8.1.2.5
Additional Efficacy Endpoints.............................................................101


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8.1.3
Patient Reported Outcomes .................................................................102
8.1.4
HCV and HIV Resistance Analyses.....................................................103
8.1.5
Safety..................................................................................................105
8.1.5.1
Adverse Events....................................................................................105
8.1.5.2
Clinical Laboratory Data .....................................................................105
8.1.5.3
HIV-1 RNA Data ................................................................................106
8.1.5.4
Vital Signs Data ..................................................................................106
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................106
8.2
Determination of Sample Size .............................................................108
8.3
Randomization Methods......................................................................109
9.0
Ethics.................................................................................. 109
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................109
9.2
Ethical Conduct of the Study...............................................................110
9.3
Subject Information and Consent.........................................................110
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 111
10.1
Source Documents...............................................................................111
10.2
Case Report Forms..............................................................................111
11.0
Data Quality Assurance .................................................... 112
12.0
Use of Information ............................................................ 112
13.0
Completion of the Study ................................................... 113
14.0
Investigator's Agreement.................................................. 114
15.0
Reference List.................................................................... 115
List of Tables
Table 1.
Prohibited Medications and Supplements ............................................. 48
Table 2.
Clinical Laboratory Tests ..................................................................... 54
Table 3.
Child-Pugh Classification of Severity of Cirrhosis................................ 57
Table 4.
Identity of Investigational Products ...................................................... 71
Table 5.
Overview of Clinical Studies by Subject Population (Phase 2 and 
3 Analysis Set) ..................................................................................... 75


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Table 6.
Summary of SVR12, On-Treatment Virologic Failure, and 
Post-Treatment Relapse in TN and TE Non-GT3-Infected 
Subjects by Cirrhosis Status (TN + TE-PRS Subjects, Phase 2 and 
3 Analysis Set) ..................................................................................... 77
Table 7.
SVR12 Rates by Prior Treatment Experience, HCV Genotype, and 
Duration for Non-GT3-Infected Subjects (ITT Population, 
Phase 2 and 3 Analysis Set).................................................................. 78
Table 8.
Summary of SVR12, On-Treatment Virologic Failure, and 
Post-Treatment Relapse in TN and TE GT3-Infected Subjects by 
Cirrhosis Status and Treatment Duration (ITT Population, Phase 2 
and 3 Analysis Set)............................................................................... 79
Table 9.
Recommended Treatment Duration for Subjects with Cirrhosis............ 80
List of Figures
Figure 1.
HCV Genotypes Distributions in China ................................................ 21
Figure 2.
Study Schematic................................................................................... 35
Figure 3.
Adverse Event Collection..................................................................... 91
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................119
Appendix B.
List of Protocol Signatories .................................................................121
Appendix C.
Study Activities – Treatment Period ....................................................122
Appendix D.
List of AIDS-Associated Opportunistic Infections ...............................127


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with over 
184 million individuals infected worldwide.1  There are 7 identified HCV genotypes, with 
genotype (GT) 1 being the most prevalent worldwide.  HCV GTs 2 and 3 infections are 
more common in Latin America (5% to 30%), Europe (20% to 40%) and Asia (30% to 
45%).2-4  HCV GT4 is commonly found in parts of Africa and the Middle East, 
particularly in Egypt, GT5 is primarily found in South Africa, and GT6 is primarily found
in south-east Asia.5  Depending on various risk factors, between 10% and 40% of patients 
with chronic HCV infection will develop cirrhosis6 GT7 has recently been described in 
Central Africa.7
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.6  Patients diagnosed with hepatocellular 
carcinoma have a 33% probability of death during the first year.6  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.7,8
In Asia, sub-genotypes 1b, 2a, 2b, 3a, and GT6 are the most common causes of HCV 
infections.3  The frequency of HCV infection in China varies by geographical region 
within the country, age, and population groups.  In a report in 2007, the national 
prevalence in adults was estimated to be 1% to 1.9% (ranging from 0.29% to 9.6% in 
various geographic areas).3  The most common HCV GTs in China are GT1 (67%) and 
GT2 (14%).3
Epidemiology of HCV in China
Chronic HCV infection is recognized as an important cause of chronic hepatitis, cirrhosis, 
and hepatocellular carcinoma in China.9  Epidemiological studies in the mid-1990s 
reported a national prevalence of 3.2%,10 but other reports suggested a prevalence ranging 
from 0.29% to 9.6%.11


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These studies showed that the frequency of HCV infection in China varied by 
geographical region within the country, age, and population groups and also between rural 
and metropolitan areas.  With the Yangtze River as the boundary, the prevalence rate in 
northern China (3.6%) was higher than southern China (2.9%).10  Anti-HCV positive rates 
were reported to increase gradually with age, from 2% in 1 year old to 3.9% in 50 to 
59 year old groups, respectively.10  A study of individuals > 55 years old in the rural 
Henan province found a prevalence of 9.6%,12 while Liu et al documented a prevalence of 
0.9% in persons 25 to 65 years old in Anyang.13
In 2006, the National Nutritional Survey estimated that the overall national prevalence is 
approximately 0.43%, which represents approximately 5.1 million Chinese infected with 
HCV.14  A recent study reported that 25 million Chinese were infected with HCV 
chronically and advanced liver diseases were frequently detected.15  Among human 
immunodeficiency virus (HIV)-positive Chinese patients, it is estimated that 60% to 90% 
are co-infected with HCV.14  Among patients with chronic hepatitis B, it is estimated that 
11% to 15% are co-infected with HCV.16,17  In addition, 50% of the patients receiving 
dialysis in China are reported to be infected with HCV.14  Together, these data suggest 
that a significant number of Chinese patients are at risk for the morbidity and mortality 
associated with HCV infection.
An important epidemiologic feature of HCV infections in China is the distribution of GTs 
(Figure 1).  HCV sub-genotype 1b is the most common GT in China with a prevalence of 
66%,18 but it has been reported to be as high as 90% in some areas of southern China.14  
HCV GT2 is the second most common GT, with a prevalence of 14%,18 increasing 
gradually from southern to northern China (Figure 1).14
Other HCV GTs include GT6, which is detected in approximately 10% of cases, 
especially in the south region of China; and GT3 which is reported in approximately 4.3% 
of the cases in China.18  Majority of these chronic HCV-infected patients in China have 
IL28B CC genotype.15


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Figure 1.
HCV Genotypes Distributions in China
In summary, the current epidemiology data indicate that HCV infections are an important 
public health problem in China and that the most prevalent GTs in the general population 
countrywide are HCV sub-genotype 1b and GT2.  HCV GT3 and 6 are detected in the 
southern region of China, but their frequency is reported to be increasing in recent years.
Cirrhosis in China
In China, hepatitis virus B and C remain the primary etiological factors for hepatic 
cirrhosis, and a recent increase in alcoholic cirrhosis has also been noted.19,20  In a study 
of liver cirrhosis over 10 consecutive years in southern China, the distribution of 
etiological agents leading to complication of liver cirrhosis (LC) was as follows:  viral 
hepatitis, 80.62% (hepatitis B virus [HBV] 77.22%, hepatitis C virus [HCV] 2.80%, 
[HBV + HCV] 0.58%); alcohol.21  Moreover, studies have reported that different 


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etiologies tend to result in different complications; for example, HCC occurs more often 
in viral hepatitis LC cases than in alcoholic and autoimmune LC cases, but the exact 
relationship between the LC etiology and complications has not been verified by clinical 
research on a large sample.22,23
HCV-Infection Treatment Options
Until recently, in most countries, treatment of HCV GT1 infection employed a single 
direct-acting antiviral agent (DAA) plus pegylated interferon and ribavirin (PR).  
However, interferon (IFN)-based treatment regimens are associated with considerable, 
often treatment limiting toxicities (fever, chills, rigor, fatigue, depression, and anemia).24
An oral fixed-dose combination of sofosbuvir and ledipasvir (NS5A inhibitor) was 
approved in the United States (US) and Europe for the treatment of GT1 and GT4 HCV 
infection for non-cirrhotic and cirrhotic patients.25  The combination achieves SVR12 of 
94% – 96% in treatment-naïve GT1 patients with and without cirrhosis and rates of 93% 
in HCV GT4 infected patients with or without cirrhosis.  In addition, an IFN-free
combination of ombitasvir (NS5A inhibitor), paritaprevir (protease inhibitor), dasabuvir 
(non-nucleoside NS5b polymerase inhibitor) and ritonavir, given with or without ribavirin 
(RBV), was also approved in the US and Europe for the treatment of chronic HCV GT126
and the dual combination of ombitasvir and paritaprevir/ritonavir with RBV is approved 
for treatment of non-cirrhotic GT4 infection in the US26 and for both cirrhotic and 
non-cirrhotic GT4 infected patients in the European Union (EU).27  When given for 
12 weeks, the dual regimen with RBV achieves 100% SVR12 (sustained virologic 
response 12 weeks post dosing) rates in the HCV GT4 infected patients without 
cirrhosis28 and 96% to 100% SVR (sustained virologic response) rates in those with 
cirrhosis when given for 12 or 16 weeks respectively.29
Although IFN-free therapies are available for the treatment of GT2 and GT3 infection 
using sofosbuvir plus RBV,30 SVR rates were lower for PR-treatment experienced 
patients with or without cirrhosis.30


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Daclatasvir, an NS5A inhibitor, to be used in combination with sofosbuvir, has been 
approved in the US for treatment of GT3 HCV infection.  However, SVR was found to be 
substantially reduced in patients with compensated cirrhosis.31
The current standard of care for the treatment of chronic HCV infection in China is 
pegylated interferon (pegIFN) combined with RBV for 24 weeks to 72 weeks, depending 
upon the patient's HCV GT, disease status, and response to past treatment(s).  SVR rates 
range from 60% to 75% among GT1b-infected patients and 75% to 85% among primarily 
GT2-, GT3-, and GT6-infected patients;32,33 however, the pegIFN/RBV regimen has a 
well-described burden of toxicity (e.g., severe cytopenia and depression) and cumbersome 
weekly injections, in addition to a long duration of treatment.  Many patients requiring 
treatment are ineligible, and frequently toxicity is treatment limiting.  Treatment of 
chronic HCV in China could be significantly improved with the availability of a 
pangenotypic, all-oral, pegIFN-free regimen that has a higher SVR rate, a better safety 
profile, and shorter treatment durations.  To this end, AbbVie is developing ABT-530, a 
next generation NS5A inhibitor, and ABT-493, a next generation protease inhibitor (PI), 
to be used in combination with each other, for the treatment of chronic HCV.
ABT-493
ABT-493 is an NS3/4A PI with potent and pangenotypic activity.  It demonstrates a high 
genetic barrier to resistance and maintains activity against common variants that emerge 
following exposure to first generation PIs.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data can be found in the Investigator's Brochure.34
ABT-530
ABT-530 is an NS5A inhibitor with potent and pangenotypic activity.  It demonstrates a 
high genetic barrier to resistance and maintains activity against all common single 
nucleotide change resistance-associated substitutions in NS5A in all GTs.  ABT-530 is 


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> 100-fold more active than the first generation NS5A inhibitors (ombitasvir, daclatasvir, 
and ledipasvir) against key resistance-associated substitutions.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data can be found in the current Investigator's Brochure.35
ABT-493 and ABT-530
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.36
ABT-493 and ABT-530 combination has been well tolerated when administered to over 
590 healthy volunteers in Phase 1 studies (including Japanese and Han Chinese subjects 
living in the United States).  In addition, 166 subjects were exposed to ABT-493 
monotherapy and 198 subjects were exposed to ABT-530 monotherapy in Phase 2 studies.  
When ABT-493 was given in combination with ABT-530 in healthy volunteers, ABT-493 
exposures were not significantly changed by 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).
The combination of ABT-493 and ABT-530 has also been evaluated in overseas Han 
Chinese subjects at various dose combination levels (ABT-493 + ABT-530:  100 mg + 
120 mg, 200 mg + 120 mg, 300 mg + 120 mg, 200 mg + 80 mg, and 700 mg + 160 mg) in 
Studies M14-066 and M15-432.  Results from these 2 studies showed no observed ethnic 
differences for ABT-493 and ABT-530 at doses evaluated.
The safety profile of co-administered ABT-493 and ABT-530 in healthy volunteers in 
these studies is consistent with that of the individual compounds.
For a more detailed discussion of drug-drug interaction studies please refer to the 
Investigator's Brochures for the respective compounds.37


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ABT-493 + ABT-530 Combination in HCV-Infected Subjects
Data from Global Phase 2b studies demonstrated robust efficacy results for 300 mg 
ABT-493 in combination with 120 mg ABT-530 across HCV GTs with favorable safety 
profiles in HCV-infected subjects.  Thus, this dose combination was proposed for the 
Phase 3 clinical program studies. 
Phase 3 dose and treatment durations for the planned Phase 3 studies were based on 
available SVR4 and SVR12 data from ABT-493 and ABT-530 combination Phase 2b 
studies (Studies M14-867 and M14-868 (Parts 1 and 2)) and exposure-response modeling 
and simulations of antiviral activity.  Based on the results from the Phase 2b studies, 
Studies M14-867 and M14-868 (Parts 1 and 2), the 300 mg dose of the ABT-493 and 
120 mg dose of ABT-530 in combination was proposed for all global registrational 
studies.  This dose had been demonstrated to be efficacious for the proposed Phase 3 
study populations with the planned study duration and would reduce chances of virologic 
failures across GTs and difficult-to treat patient populations to maximize the chance for 
SVR.  Importantly, ABT-493 and ABT-530 regimens including the proposed 
300 mg/120 mg ABT-493/ABT-530 QD regimen had 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 300 mg ABT-493 and 120 mg ABT-530 dose are 
also supported by the exposure-response analyses and SVR simulations to achieve higher 
SVR rates than using lower doses of respective DAAs in the planned Phase 3 populations.  
Based on all current data available, AbbVie believes the combination of 300 mg ABT-493 
and 120 mg ABT-530 provides optimal balance for efficacy, safety, and regimen 
simplicity. 
The 6 Global Phase 3 trials include a study in HCV GT1 – 6 in patients with Renal 
Impairment (Study M15-462), a study in HCV GT1 comparing 8 versus 12 weeks in 
subjects without cirrhosis (Study M13-590), a placebo controlled comparator trial in HCV 
GT2-infected subjects without cirrhosis (Study M15-464), an active comparator trial with 
daclatasvir plus sofosbuvir for 12 weeks in GT3 subjects without cirrhosis 
(Study M13-594), a dedicated GT4 – 6 non-cirrhotic trial for 12 weeks (Study M13-583) 


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and a 12 week treatment duration Phase 3 evaluating subjects with HCV GT1, 2, 5 – 6 
with compensated cirrhosis (Study M14-172).
Three additional Phase 3 studies were initiated in 2Q2016.  The objective of these studies 
is to assess the efficacy and safety of the combination of ABT-493 and ABT-530 in 
special populations and include:  HCV GT1 – 6 subjects who are status post liver 
transplantation (Study M13-596), HCV GT1 – 6 subjects with HIV/HCV co-infection 
(Study M14-730), and a study in HCV GT3 subjects with or without cirrhosis (expansion 
of Study M14-868).  
Phase 2 Studies that were subsequently expanded (Studies M14-867 and M14-868) 
assessed efficacy, safety and pharmacokinetics of combination of ABT-493 and ABT-530 
in HCV GT1 (Study M14-867 Part 1) or GT2 or 3-infected (Study M14-868 Part 1) in 
treatment-naïve and PR-experienced non-cirrhotic subjects, respectively, GT4 – 6 
(Study M14-867 Part 2) or GT2- or 3-infected (Study M14-868 Parts 1, 2, and 3) 
treatment-naïve and PR-experienced subjects with and without cirrhosis.  
In Study M14-867 Part 1, HCV GT1-infected subjects received 12 weeks of ABT-493 
200 mg QD + ABT-530 120 mg QD (Arm A) or ABT-493 200 mg + ABT-530 40 mg QD 
(Arm B).  One hundred percent (100%) (40/40) of subjects treated with ABT-493 200 mg 
QD + ABT-530 120 mg QD for 12 weeks and 97% (38/39) of subjects treated with 
ABT-493 200 mg QD + ABT-530 40 mg QD for 12 weeks achieved SVR12.  One subject 
in Arm B experienced relapse at Post-Treatment Week 4.
In Study M14-867 Part 2, HCV GT1-infected subjects without cirrhosis received 8 weeks 
of ABT-493 300 mg QD + ABT-530 120 mg 100% (34/34) achieved SVR4 and 97% 
(33/34) achieved SVR12.  The one subject who did not achieve SVR12 died due to 
adenocarcinoma in the abdomen which was deemed not related to study drugs, but did 
have HCV RNA undetectable at last visit.  In Study M14-867 Part 2, treatment-naïve and 
PR-experienced HCV GT1-infected subjects with compensated cirrhosis received either 
12 weeks of ABT-493 200 mg QD + ABT-530 120 mg, 96% (26/27) achieved SVR12
with one subject who relapsed at Week 4 post treatment completion.


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In Study M14-867 Part 2, HCV GT4 – 6 infected treatment-naïve and PR-experienced 
non-cirrhotic subjects were treated with ABT-493 300 mg QD + ABT-530 120 mg QD for 
12 weeks.  All 34 subjects (22 with HCV GT4 infection, 1 with HCV GT5 infection, and 
11 with HCV GT6 infection) achieved SVR12. 
In Study M14-868 Part 1, HCV GT2- and GT3 subjects were randomized to receive 
12 weeks of the combination regimen of ABT-493 (200 or 300 mg) and ABT-530 (40 or 
120 mg) with or without twice-daily, weight based RBV (1000 or 1200 mg total daily 
dose).  
Among 74 subjects with HCV GT2 infection in Part 1 of Study M14-868, no subject has 
experienced on treatment virologic failure or post-treatment relapse.  Excluding 
one subject who was lost to follow-up, all 73 subjects with HCV GT2 infection achieved 
SVR12.  The SVR12 rates for each of the treatment regimens were 96% (24/25) (including 
a subject who was lost to follow-up) of subjects treated with ABT-493 300 mg QD + 
ABT-530 120 mg QD for 12 weeks, 100% (24/24) of subjects treated with ABT-493 
200 mg QD + ABT-530 120 mg QD for 12 weeks and 100% (25/25) of subjects treated 
with ABT-493 200 mg QD + ABT-530 120 mg QD + RBV for 12 weeks.
One hundred twenty-one (121) subjects with HCV GT3 infection were treated in Part 1 of 
Study M14-868.  Among all subjects receiving the regimen tested in this study, 
i.e., ABT-493 300 mg and ABT-530 120 mg without RBV for 12 weeks, 93% 
(28/30 subjects) achieved SVR12.  One subject in this arm had no data available (HCV 
RNA < LLOQ at most recent visit) through Post-Treatment Week 12 and was counted as 
an SVR12 non-responder.  One subject in this arm experienced relapse at Post-Treatment 
Week 4.
In Study M14-868 Part 2, among 29 treatment-naïve non-cirrhotic subjects with GT3 
infection treated for 8 weeks with ABT-493 300 mg QD + ABT-530 120 mg QD, no 
subject experienced on-treatment virologic failure or post-treatment relapse.  One of the 
29 subjects had missing SVR12 data.  Among 24 treatment-naïve cirrhotic subjects with 


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GT3 infection treated for 12 weeks with ABT-493 300 mg QD + ABT-530 120 mg QD, 
no subject experienced on-treatment virologic failure or post-treatment relapse.  
In Study M14-868 Part 3, GT3-infected subjects with treatment experience and/or 
cirrhosis were treated with ABT-493/ABT-530 300 mg/120 mg QD for 12 and/or 
16 weeks.  Treatment-naïve GT3-infected subjects with cirrhosis achieved a SVR12 rate of 
98% (39/40) and treatment-experienced subjects with cirrhosis achieved a SVR12 rate of 
96% (45/47) following 12 and 16 weeks of treatment with ABT-493/ABT-530 
300 mg/120 mg QD, respectively, with no virologic failures among treatment-naive 
subjects with cirrhosis.  The relapse rate among treatment-experienced subjects with 
cirrhosis following 16 weeks of treatment was 2% (1/46).  Among treatment-experienced 
subjects without cirrhosis, the SVR12 rates for the 12-week and 16-week regimens were 
91% (20/22) and 96% (21/22), respectively.
To date, safety data across all Part 1 arms in Studies M14-867 and M14-868 
encompassing 274 subjects treated with ABT-493 at doses 200 and 300 mg and ABT-530 
at doses 40 and 120 mg (with and without RBV in Study M14-868) for 12 weeks show 
that the most frequently reported adverse events were fatigue, nausea, and headache 
(occurring in > 5% of subjects).  Most of them were Grade 1 or 2 in severity.  There were 
no increases in the frequency or severity of any adverse event between the different 
regimens of ABT-493 200 mg plus 40 mg or 120 mg ABT-530, and ABT-493 300 mg 
plus 120 mg ABT-530.
Of the 274 subjects, there have been 4 (1.5%) treatment-emergent SAEs reported 
combined (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 discontinuation.  Both were 
GT3-infected subjects (ABT-493/ABT-530 [200 mg/120 mg] QD + RBV) of 
Study M14-868.  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.  Baseline alanine aminotransferase (ALT) elevations for this 
subject normalized during treatment and there were no on-treatment ALT elevations 


ABT-493, ABT-530
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above baseline; subject had total bilirubin elevations that were primarily indirect.  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.  The ALT normalization 
pattern was similar across all arms (i.e., both ABT-493 and ABT-530 dose levels) in both 
studies.  Other laboratory abnormalities were infrequent and were primarily associated 
with the well-described hemolytic effect of RBV, manifesting as Grade 1 anemia in total 
of 4 subjects, all occurring in Study M14-868 RBV-containing arms.  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.
The safety of the combination regimen of ABT-493 and ABT-530 in subjects with 
compensated cirrhosis is investigated in Study M14-867 Part 2 (ABT-493/ABT-530 
[200 mg/120 mg] QD for 12 weeks) and Study M14-868 Part 2 (ABT-493/ABT-530 
[300 mg/120 mg] QD for 12 weeks with and without ribavirin or for 16 weeks without 
ribavirin).  Based on 82 subjects with compensated cirrhosis enrolled in these arms who 
have received 4 weeks or more of treatment, the ABT-493 and ABT-530 regimen has 
demonstrated a favorable safety profile in this patient population.  The majority of adverse 
events have been Grade 1 or 2 and there have been no treatment discontinuations.
A detailed discussion of the preclinical pharmacology and toxicology, in vitro virology 
and metabolism, and clinical data for ABT-493, ABT-530 and the combination of 
ABT-493 and ABT-530 can be found in the ABT-493 and ABT-530 Fixed-Dose 
Combination Investigator's Brochure.
AbbVie evaluated the combination of ABT-493 (300 mg QD) + ABT-530 (120 mg QD) 
in healthy Western subjects in Phase 1 drug-drug interaction (DDI) studies and in Han 


ABT-493, ABT-530
M15-593 Protocol
30
Chinese, Japanese and Caucasians in Study M15-432.  Based on cross-study comparison, 
the exposures (Cmax and AUC24) in Japanese and Han Chinese subjects were comparable 
to the exposures observed in Western subjects.  Overall, results from these studies 
demonstrate similar pharmacokinetic profiles between Han Chinese and Caucasian 
subjects and support parallel approach in the proposed China development strategy 
utilizing the Global Phase 3 dose.
AbbVie's IFN-free combination regimen of ABT-493 and ABT-530 provides a 
compelling opportunity for improving the treatment of HCV-infected patients in China 
and meeting significant unmet medical needs of these patients.  The proposed regimen 
provides for an all oral, IFN-free treatment that is simpler, safer, shorter and more 
efficacious than currently available injection-based regimens for the treatment of HCV 
GT1 – 6.
Antiretroviral Therapy (ART) Drug-Drug Interaction Studies with ABT-493 and 
ABT-530
Phase 1 DDI studies of the ABT-493 + ABT-530 combination with HIV antiretroviral 
(ARV) drugs have been conducted in healthy volunteers and/or HIV-1 infected subjects.
The ABT-493 + ABT-530 combination had no clinically meaningful impact on the 
exposures (≤ 80%) of evaluated ARV regimens:  rilpivirine, raltegravir, dolutegravir, 
abacavir, lamivudine, ritonavir-boosted protease inhibitors (darunavir, lopinavir), 
elvitegravir, emtricitabine and tenofovir disoproxil fumarate (TDF).  
Based on Phase 1 DDI studies, the exposures of ABT-493 and ABT-530 were not affected 
by rilpivirine and raltegravir.
Dolutegravir, lamivudine and abacavir (Triumeq®) coadministered with ABT-493 + 
ABT-530 was evaluated in a DDI study (Study M15-584 Arm 2).  Coadministration was 
safe and well tolerated with mild adverse events reported.  The exposures of dolutegravir, 
lamivudine and abacavir were similar with and without coadministration with ABT-493 


ABT-493, ABT-530
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31
and ABT-530 (≤ 13% difference).  ABT-493 and ABT-530 exposures were slightly lower 
(25% to 28%) when administered with dolutegravir, lamivudine and abacavir. 
ABT-493 is a substrate of an organic anion transporting polypeptide (OATP), therefore 
OATP inhibitors may increase the exposures of ABT-493.  When ABT-493 + ABT-530 
was administered with cyclosporine (400 mg), an OATP inhibitor, ABT-493 exposure 
increased to 5.1-fold to that of DAAs administered alone.  The observed increase in 
exposure, however, was not associated with clinically significant safety findings.  
Protease inhibitors as a class have potential to inhibit OATP, thus the larger exposure 
increases in ABT-493 with ritonavir boosted protease inhibitors than with ritonavir alone 
may result from interaction of ABT-493 with both the protease inhibitor and ritonavir 
components.  Cobicistat has been shown in vitro and in vivo to have similar cytochrome 
P-450 enzyme and transporter inhibition potential as ritonavir.
When ABT-493 was administered with ritonavir, exposure of ABT-493 was 2-fold of 
ABT-493 exposure alone.  Coadministration of ABT-493 + ABT-530 with ritonavir 
boosted protease inhibitors, darunavir QD or lopinavir BID, increased ABT-493 
exposures, AUC and Cmax, to 3- to 5-fold and 2.6 to 4.4-fold, respectively, while 
exposures of ABT-530 were similar with and without darunavir QD (≤ 16% change) and 
increased to 1.4 to 2.5-fold with lopinavir BID.  The exposures of lopinavir (≤ 24% 
increase) or darunavir (< 30% increase) were comparable with and without DAA 
coadministration.  Both the regimens (darunavir QD or lopinavir BID) tested were well 
tolerated with mild adverse events.  Therefore, coadministration of ritonavir-boosted PIs 
is not recommended with ABT-493/ABT-530.  Coadministration of ABT-493 + ABT-530 
with ritonavir boosted atazanavir was studied in a DDI study that was terminated early 
due to an increase in ABT-493 exposure up to 16-fold and ABT-530 exposure up to 
3-fold with Grade 1 and 2 increases in ALT and Grade 2 to 3 increase in total bilirubin 
(predominately indirect).  Therefore, coadministration of atazanavir is contraindicated 
with ABT-493/ABT-530.


ABT-493, ABT-530
M15-593 Protocol
32
The combination of ABT-493 +ABT-530 was evaluated with Genvoya® (elvitegravir 
150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg QD).  
Coadministration was safe and well tolerated, with mild adverse events reported and 
one grade 3 neutropenia deemed related to the combination of Genvoya®, ABT-493 and 
ABT-530 in a black male subject with a low baseline ANC, leading to premature study 
drug discontinuation.  The ABT-493 exposure increased to 3-fold and the ABT-530 
exposure increased by 57%, with clinically insignificant increases in elvitegravir,
cobicistat, tenofovir and emtricitabine exposures.  Thus, cobicistat boosted elvitegravir 
will be allowed with ABT-493/ABT-530.
Efavirenz induces P-gp and exposures of ABT-493 and ABT-530 in the presence of 
efavirenz were approximately 3- and 2-fold lower, respectively, and thus coadminstration 
of efavirenz and efavirenz-containing regimens is not recommended with 
ABT-493/ABT-530. 
In summary, coadministration of HIV-PIs alone, ritonavir-boosted PIs and efavirenz is not 
recommended with ABT-493/ABT-530.  Based on the above information, cobicistat-
boosted elvitegravir, dolutegravir, abacavir, lamivudine, rilpivirine and raltegravir are 
allowed.
For a more detailed discussion of drug-drug interaction studies please refer to the 
ABT-493 and ABT-530 Fixed-Dose Combination Investigator's Brochures.37
3.1
Differences Statement
The current study (Study M15-593) is the Phase 3 study evaluating the efficacy, safety 
and pharmacokinetics of the combination of ABT-493/ABT-530 in 160 Asian subjects 
with chronic HCV GT1, 2, 3, 4, 5 or 6-infection who are HCV-treatment naïve or 
-experienced, with compensated cirrhosis and with or without HIV co-infection.  The 
current study will evaluate the selected dose and regimen of ABT-493/ABT-530 
300 mg/120 mg QD using the co-formulated, fixed dose combination tablet intended for 
marketing for 12 or 16 (for GT3 treatment-experienced) weeks in Asian subjects.  The 


ABT-493, ABT-530
M15-593 Protocol
33
diverse subject population to be enrolled will be representative of the intended population 
of subjects infected with a broad range of HCV GTs and will allow evaluation of the 
safety and efficacy of ABT-493/ABT-530 in Asian subjects.
3.2
Benefits and Risks
Potential benefits of treatment with ABT-493/ABT-530 include:  Potent and 
pan-genotypic antiviral activity in vitro, higher genetic barrier to development of drug 
resistance across GTs compared to first generation protease and NS5A inhibitors, no need 
for RBV, 12 or 16 weeks of treatment, and the convenience of a once-daily regimen.  
Adverse events that are known, and those not previously described, may occur with 
ABT-493/ABT-530 as detailed in the informed consent of 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-530 
and ABT-493 are detailed in Section 3.0 and in the Investigator's Brochures for the 
respective compounds. 
Risks associated with ABT-493 and ABT-530, including the risks of toxicity, virologic 
failure and development of resistant mutations (Section 5.6.4), appear to be limited and 
manageable based upon the available data.  Given the potential for SVR in this population 
of HCV GT1, 2, 3, 4, 5 and 6-infected subjects, the risk-benefit assessment is favorable.
4.0
Study Objective
4.1
Primary Objective
The primary objectives of this study are to assess the efficacy (SVR12, [HCV RNA 
< lower limit of quantification {LLOQ} 12 weeks after the last actual dose of study drug]) 
and safety following 12 or 16 weeks of treatment with the ABT-493/ABT-530 
combination regimen in treatment-naïve and treatment-experienced adults with chronic 
HCV GT1 to GT6-infection with compensated cirrhosis and with or without HIV co-
infection.


ABT-493, ABT-530
M15-593 Protocol
34
4.2
Secondary Objective
The secondary objectives are to assess:
●
The percentage of subjects with on-treatment HCV virologic failure;
●
The percentage of subjects with post-treatment relapse of HCV infection;
●
The percentage of HCV/HIV co-infected subjects achieving SVR12.
An additional objective is to assess the pharmacokinetics of ABT-493 and ABT-530 in 
Asian HCV-infected adults.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, single-arm, open-label, multicenter study to evaluate the efficacy, safety 
and pharmacokinetics of ABT-493/ABT-530 in chronic HCV GT1 to GT6-infected Asian 
adult subjects with compensated cirrhosis with or without HIV co-infection who are HCV 
treatment-naïve or treatment-experienced with IFN (alpha, beta or pegIFN) with or 
without RBV OR sofosbuvir with RBV with or without IFN.
This study will consist of 2 periods as follows:
Treatment Period:  Eligible subjects will be enrolled and will receive 
ABT-493/ABT-530 300 mg/120 mg QD for either 12 or 16 weeks.  Treatment 
duration will differ among subjects based on HCV GT and HCV treatment experience 
(12 weeks of treatment for GT1, 2, 3, 4, 5 and 6-infected subjects with the exception 
of 16 weeks for treatment-experienced GT3-infected subjects).
Post-Treatment Period:  Subjects who complete the Treatment Period, experience-on 
treatment virologic failure, or otherwise prematurely discontinue the Treatment Period 
will be followed for 24 weeks to monitor safety and to evaluate efficacy and the 
emergence and/or persistence of HCV resistance-associated substitutions.


ABT-493, ABT-530
M15-593 Protocol
35
Figure 2.
Study Schematic
Approximately 160 subjects meeting the eligibility criteria will be enrolled.  A minimum 
of 60 GT1-infected subjects, a minimum of 36 GT2-infected subjects and approximately 
24 GT3, 4, 5 or -6-infected subjects from China will be enrolled into this study. 
Approximately 30 GT1-infected subjects and approximately 10 GT2-infected subjects 
will also be enrolled into this study from the regional Asian country of South Korea.  Of 
the approximately 160 subjects, a maximum of 16 HCV/HIV co-infected subjects will be 
enrolled.
The study is designed to enroll approximately 160 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
scientific and 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.
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.  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 


ABT-493, ABT-530
M15-593 Protocol
36
subject's medical records.  Eligible subjects have up to 35 days following the Screening 
Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who at Screening have any of the following are not eligible to rescreen or retest:
●
HCV GT does not meet Inclusion Criterion 4, Section 5.2.1, or meets 
Exclusion Criterion 4, Section 5.2.2.
Otherwise subjects may be retested or rescreened only once.
Subjects who have exclusionary laboratory parameter(s) are allowed to retest on the 
related panel(s) (e.g., exclusionary ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on any panel that is 
repeated.  If the retest result(s) are also exclusionary, the subject may not be rescreened.  
Subjects that are rescreened outside of the initial 35 day screening period must be 
rescreened for all laboratory and eligibility criteria, not just those that were exclusionary.
For subjects who rescreen or subjects that do not meet the study eligibility criteria, the site 
personnel must contact the IRT and identify the subject as a screen failure.
5.1.2
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT.  Subjects will be 
administered study drug at the site on Study Day 1, with dosing instructions.
Study visits and procedures during the Treatment Period are detailed in Section 5.3.1.1
Appendix C.  Safety and tolerability will be assessed throughout the study. Laboratory 
testing will include chemistry, hematology, 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 5.3.2 and 
Section 5.3.1.1, respectively.


ABT-493, ABT-530
M15-593 Protocol
37
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 study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out 
of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
HCV Virologic stopping criteria will be evaluated and applied by the investigator as 
detailed in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation (D/C) Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.4.1.
5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug and either complete treatment or 
prematurely discontinue the study drug will be monitored in the Post-Treatment Period for 
safety, HCV RNA and the emergence and persistence of resistant viral variants, plasma 
HIV-1 RNA and HIV resistance (as applicable), and PROs 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 C.
Some of the Post-Treatment Period study visits and visit activities (including but not 
limited to vital signs, clinical laboratory tests and concomitant medication assessment) 
may be conducted in the home or non-hospital/clinic environment at the request of the 
investigator and with the agreement of the subject.
Subjects who prematurely discontinue the Post-Treatment Period should return to the site 
for a Post-Treatment D/C visit as outlined in Appendix C.


ABT-493, ABT-530
M15-593 Protocol
38
5.2
Selection of Study Population
The study population consists of chronic HCV GT1, 2, 3, 4, 5 or 6-infected Asian, male 
and female adults, with compensated cirrhosis, with or without HIV co-infection who are 
HCV treatment-naïve or treatment-experienced to IFN (alpha, beta or pegIFN) with or 
without RBV OR sofosbuvir with RBV with or without IFN.
5.2.1
Inclusion Criteria
1.
Male or female of Asian descent and at least 18 years of age at time of Screening.
2.
If female, subject must be either (as defined in Section 5.2.4) postmenopausal, OR 
permanently surgically sterile OR for Women of Childbearing Potential (WOCBP) 
practicing at least one protocol specified method of birth control, starting at Day 1 
(or earlier) through at least 30 days after the last dose of study drug.
No male contraception is required if the male subject has a female partner who is 
postmenopausal or permanently sterile (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
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 the protocol) at Screening do not require pregnancy 
testing.
4.
Screening laboratory result indicating HCV GT1, 2, 3, 4, 5 or 6-infection.
5.
Subject has positive HCV antibody (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 HCV Ab or HCV RNA at least 6 months before Screening; or
●
A liver biopsy consistent with chronic HCV infection;


ABT-493, ABT-530
M15-593 Protocol
39
7.
Subject must be HCV treatment-naïve (i.e., subject has not received any approved 
or investigational HCV treatment) or treatment-experienced (i.e., subject has failed 
prior HCV treatment with IFN [alpha, beta or pegIFN] with or without RBV OR 
sofosbuvir with RBV with or without IFN).  Previous HCV treatment must have 
been completed ≥ 8 weeks prior to screening.
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.
Compensated cirrhosis defined as Child-Pugh score of ≤ 6 at Screening and no 
current or past clinical evidence of Child-Pugh B or C Classification or clinical 
history of liver decompensation including ascites noted on physical exam, bleeding 
varices, use of diuretics for ascites, or hepatic encephalopathy.
10.
Subject must have documented cirrhosis at any time previously or at Screening by 
meeting one of the following criteria:
●
Histologic diagnosis of cirrhosis on a liver biopsy e.g., a METAVIR, 
Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3 or 
Ishak fibrosis score of > 4; or
●
A screening FibroTest score of ≥ 0.75 and Aspartate Aminotransferase to 
Platelet Ration Index (APRI) > 2; or
○
Subjects with indeterminate FibroTest (0.48 < result < 0.75), or discordant 
FibroTest and APRI results (e.g., FibroTest ≥ 0.75, but APRI ≤ 2) must 
have a qualifying FibroScan® or liver biopsy
●
FibroScan score ≥ 14.6 kPa.
○
Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6) must 
have qualifying liver biopsy.
11.
Absence of hepatocellular carcinoma (HCC) as indicated by Serum Alpha 
Fetoprotein (sAFP) < 100 ng/mL at Screening and a negative ultrasound, computed 
tomography (CT) scan or magnetic resonance imaging (MRI) for HCC within 
12 weeks prior to Screening or at Screening.  Subjects who have an ultrasound with 


ABT-493, ABT-530
M15-593 Protocol
40
results suspicious of HCC followed by a subsequent negative CT or MRI of the 
liver for HCC will be eligible for the study.
12.
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.
13.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
In addition to Inclusion Criteria 1 through 13, subjects enrolled with HCV GT1 to 6 and 
HIV-1 co-infection, must also meet the following criteria per local standard practice:
14.
Positive test result for Human Immunodeficiency Virus antibody (HIV Ab) at 
Screening.
15.
Naïve to treatment with any antiretroviral therapy (ART) (and have no plans to 
initiate ART treatment while participating in this study) 
or
On a stable, qualifying HIV-1 ART regimen (allowed regimens will be based on 
AbbVie approval) for at least 8 weeks prior to screening.  
16.
Subjects naïve to ART must have CD4+ count ≥ 500 cells/mm3 (or CD4+ % 
≥29%) at Screening.
17.
Subjects on stable ART must have the following:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening; and
●
Plasma HIV-1 RNA below LLOQ by an approved plasma HIV-1 RNA 
quantitative assay (including but not limited to:  Roche COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) at Screening and at least 
once during the 12 months prior to Screening.


ABT-493, ABT-530
M15-593 Protocol
41
Rationale for Inclusion Criteria
1, 4 – 7, 9 – 11, 
14 – 17
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation
2, 3
The impact of ABT-493 and ABT-530 on pregnancies is unknown
8
For the safety of study subjects
12, 13
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
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 
hepatitis B virus (HBV) DNA > LLOQ if HBsAg is negative.
4.
HCV genotype performed during screening indicating co-infection with more than 
one HCV genotype.
5.
Requirement for and inability to safely discontinue contraindicated 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.
6.
Clinically significant abnormalities, other than HCV infection or HCV/HIV 
co-infection, based upon the results of a medical history, physical examination, 
vital signs, laboratory profile, and a 12-lead electrocardiogram (ECG) that make 
the subject an unsuitable candidate for this study in the opinion of the investigator, 
including, but not limited to:


ABT-493, ABT-530
M15-593 Protocol
42
●
Uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) 
level > 8.5% at the Screening Visit.
●
Active or suspected malignancy or history of malignancy (other than basal cell 
skin cancer or cervical carcinoma in situ) in the past 5 years.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, 
psychiatric, or other medical disease or disorder, which is unrelated to the 
existing HCV infection.
7.
Any cause of liver disease other than chronic HCV-infection, including but not 
limited to the following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Steatohepatitis on liver biopsy considered to be the primary cause of the liver 
disease rather than concomitant/incidental with HCV infection
8.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
ALT > 10 × upper limit of normal (ULN)
●
AST > 10 × ULN
●
Estimated Glomerular filtration rate adjusted for the Chinese population 
(eGFR) < 50 mL/min/1.73 m2 as estimated by the MDRD method, modified 
for the Chinese population (C-MDRD), according to the following formula:
eGFR = 175 × (Serum Creatinine)–1.234 × (Age)–0.179 × (0.79 if Female)
●
Total bilirubin > 3.0 ULN
●
Albumin < 2.8 g/dL
●
International normalized ratio (INR) > 2.3, unless subject has known 
hemophilia or is on a stable anticoagulant regimen affecting INR
●
Hemoglobin < 11 g/dL for women; < 12 g/dL for men
●
Platelets < 60,000 cells per mm3


ABT-493, ABT-530
M15-593 Protocol
43
●
Absolute neutrophil count (ANC) < 1000 cells/μL.
9.
History of solid organ transplantation.
10.
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.
11.
Requirement for chronic use of systemic immunosuppressants, including but not 
limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
azathioprine, or monoclonal antibodies (e.g., infliximab).
12.
Chronic human immunodeficiency virus, type 2 (HIV-2) infection.
13.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-493/ABT-530.
14.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drugs.
15.
Patients who can't participate in study per local law.
Additional Exclusion Criteria for Subjects with HCV/HIV-1 Co-infection:
16.
For subjects on stable ART, taking anti-retroviral agent(s) other than those 
permitted based on AbbVie approval.
17.
Treatment for an AIDS-associated opportunistic infection (OI) (Appendix D) 
within 12 months of Screening or prophylaxis for an AIDS-associated 
opportunistic infection within 6 months of Screening.
18.
Diagnosis of any clinical AIDS-defining event within 12 months prior to 
Screening.  A list of these events may be found in Appendix D.


ABT-493, ABT-530
M15-593 Protocol
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Rationale for Exclusion Criteria
1, 6, 8, 9, 13 – 18
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
To exclude subjects with hepatitis B and liver diseases other than 
HCV
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or traditional Chinese medicine and/or herbal supplements) that the subject 
is receiving from the time of signing the consent through the Treatment Period and 
30 days after study drugs are stopped, must be recorded in the electronic case report form 
(eCRF) along with the reason for use, date(s) of administration including start and end 
dates, and dosage information including dose, route and frequency.  The investigator 
should review all concomitant medications for any potential interactions.
Information regarding each subject's qualifying, stable HIV-1 ART medications (allowed 
regimens will be based on AbbVie approval) including start date, dose and frequency will 
be recorded into the eCRF at screening.  In addition, subjects will be requested to record 
information for the last two doses of their HIV-1 ART medications taken (dosing date, 
times, and number of pills) prior to the study visits detailed in Appendix C and site 
personnel will record this information in the eCRF.
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  Only medications taken for SAEs and for 
treatment of HCV and HIV will be recorded thereafter.
The AbbVie Primary Therapeutic Area Medical Director (TA MD) should be contacted if 
there are any questions regarding concomitant or prior therapies.


ABT-493, ABT-530
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45
5.2.3.1
Prior HCV Therapy
Subjects will be considered treatment-experienced if they have failed prior HCV treatment 
with IFN [alpha, beta or pegIFN] with or without RBV OR sofosbuvir with RBV with or 
without IFN.  Previous HCV treatment must have been completed ≥ 8 weeks prior to the 
Screening Visit.
Subjects will be categorized as follows:
●
Treatment-naïve:  subject never received any treatment for HCV injection.
●
Subjects with an allowed prior treatment will be categorized as follows:
○
Non-responder:  HCV RNA detected at the end of a prior treatment 
course (except for breakthrough, which is captured separately).  These 
subjects are further categorized as:
●
Null responder:  failed to achieve a 1 log10 IU/mL reduction in HCV 
RNA by Week 4 or a 2 log10 IU/mL reduction in HCV RNA by 
Week 12 during a prior treatment course;
●
Partial responder:  achieved at least a 2 log10 IU/mL reduction in HCV 
RNA by Week 12 during a prior treatment course but failed to achieve 
HCV RNA undetectable at the end of treatment;
●
Unknown or Unable to Specify:  insufficient data to categorize as null 
or partial responder.
○
Breakthrough:  confirmed ≥ 1 log10 IU/mL increase from nadir or 
achieved HCV RNA undetectable (or unquantifiable) during a prior 
treatment course but HCV RNA was quantifiable during or at the end of 
treatment.
○
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.


ABT-493, ABT-530
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46
Subjects must have discontinued prior HCV therapy at least 8 weeks prior to the 
Screening Visit in order to be eligible for the study.
5.2.3.2
Prior and Concomitant HIV-1 Therapy
Subjects with HCV/HIV co-infection who are not naïve to HIV ARTs must be on a stable, 
qualifying HIV-1 ART regimen (allowed regimens will be based on AbbVie approval) for 
at least 8 weeks prior to screening.
Information regarding each subject's qualifying, stable HIV-1 ART medications including 
start date, dose and frequency will be recorded into the eCRF at screening.  In addition, 
subjects will be requested to record information for the last two doses of their HIV-1 ART 
medications taken (dosing date, times, and number of pills) prior to the study visits during 
the Treatment Period and Post-Treatment Period detailed in Appendix C and site 
personnel will record this information in the eCRF.
Study participants should plan to remain on the same HIV-1 ART regimen for the entire 
study (Treatment Period and Post-Treatment Period).  Any change in the HIV-1 ART 
regimen during the Treatment Period must be discussed with the primary AbbVie TA MD 
prior to the change being made, unless the change is being made to address an immediate 
safety concern.
5.2.3.3
Concomitant Therapy
Subjects should be on stable doses of concomitant medications for at least 2 weeks prior 
to the initiation of study drugs (8 weeks prior to screening for HIV ARTs).  The 
investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs.  Some concomitant medications may require dose 
adjustments due to the potential for drug-drug interactions.  The investigator can also 
review the label(s) for the concomitant medication(s) for additional information.


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The use of hepato-protective medication (e.g., Sho-saiko-to, Milk thistle, ursodeoxycholic 
acid, glycyrrhizin acid, SAMe, etc.) is allowed, provided that the drug does not meet any 
other exclusion criterion.
A subject on a stable dose of a hepato-protectant should have been on the same dose for at 
least 2 weeks prior to study entry, which begins when the subject signs the informed 
consent.  In addition, the subject should maintain the hepato-protectant at the same dose 
throughout the whole study until the end of the Post-Treatment period.  If any change to 
hepato-protectant dosing is needed, the investigator should contact the AbbVie TA MD to 
discuss prior to taking action.
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 after 30 days following 
discontinuation of study drugs, as 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
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Efavirenz containing regimens
*
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 the 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, such as with 
esterified or conjugated estrogens, i.e., not containing ethinyl estradiol, may be used with 
ABT-493/ABT-530 at the discretion of the Investigator.  
Anti-HCV medications other than those specified in the protocol will not be allowed 
anytime during the Treatment Period.
The chronic use of systemic immuno-suppressants 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), 
azathioprine, or monoclonal antibodies (e.g., infliximab).


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For HCV/HIV-1 Co-Infected Subjects
The investigator must refer to the current package insert(s) or product label(s) of the 
subject's ART regimen for a complete list of prohibited medications.
5.2.4
Contraception Recommendations
If female, subject must be either:
●
Postmenopausal defined as:
○
Age ≥ 55 years with no menses for 12 or more months without an 
alternative medical cause.
○
Age < 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
●
Women of Childbearing Potential (WOCBP):
○
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), excluding ethinyl 
estadiol.
●
Male or female condom with or without spermicide.
●
Cap, diaphragm or sponge with spermicide.


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●
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).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
If the male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.
If the male subject is sexually active with female partner(s) of childbearing potential, he 
must agree from Study Day 1 through 90 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing 
potential).
●
True abstinence:  Refraining from heterosexual intercourse – when this is in 
line with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
●
Additionally, male subject agrees not to donate sperm from Study Day 1 
through 90 days after the last dose of study drug.


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5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures are described in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
Informed Consent Information
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 history of alcohol, tobacco and nicotine-containing 
product use, will be taken at Screening.  The medical history will be updated on Study 
Day 1.  The medical history obtained prior to the first dose of study drug will serve as the 
baseline for clinical assessment.
Physical Examination
Physical examinations will be performed at visits specified in Appendix C or upon subject 
discontinuation.  A symptom-directed physical examination will be performed 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 dosing will be recorded as adverse events.
Height will be measured only at Screening.  Waist circumference will be measured at the 
Screening Visit, but if it is not measured at Screening, it may be measured on Study 
Day 1.


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Vital Signs and Weight
Body temperature, blood pressure, pulse and weight will be measured at each study visit 
as specified in Appendix C or upon subject discontinuation.  The subject will wear 
lightweight clothing and no shoes during weighing.  Blood pressure and pulse rate will be 
measured after the subject has been sitting for at least 3 minutes.  The vital signs 
measurements on Study Day 1 will serve as the baseline measurements for clinical 
assessment.
12-Lead Electrocardiogram (ECG)
A single 12-lead resting ECG will be obtained at the visits indicated in Appendix C or 
upon subject discontinuation.  The ECG obtained at Screening will serve as the baseline 
measurement for clinical assessment.  The ECG should be performed prior to blood 
collection.
Each ECG will be evaluated by an appropriately qualified physician at the site ("local 
reader"), preferably a cardiologist.  This reading of the ECG will be used by the 
investigator for subject safety assessments, including adverse event determination and 
management, and decision on whether a subject will be discontinued from the study.
The local reader will sign and date all the ECGs collected in this study and provide a 
global interpretation for each ECG using the following categories:
●
Normal ECG
●
Abnormal ECG – Not clinically significant (NCS)
●
Abnormal ECG – Clinically significant (CS)
All local reader's evaluations of ECGs will be entered into the electronic source 
documents, electronic case report forms or paper case report forms.  All ECG source 
documentation will be retained at the study site.  The automatic cardiograph reading 
(i.e., cardiograph-generated measurements and interpretations) will not be collected for 
analysis.


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Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests listed in Table 2 at 
the visits indicated in Appendix C.
The 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 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 the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be
found in the laboratory manual provided by the central laboratory chosen for this study.  
The certified laboratory chosen for this study is Covance.


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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, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Reticulocyte count
Prothrombin Time/INR
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine aminotransferase 
(SGPT/ALT)
Aspartate aminotransferase 
(SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric Acid
Cholesterol
Total protein
Glucose
Triglycerides
Low Density Lipoproteins 
(LDL)a,b
High Density Lipoprotein 
(HDL)b
Albumin
Chloride
Bicarbonate
Magnesium
Total insulin
Gamma-glutamyl transferase 
(GGT)
Creatine phosphokinase (CPK)
Follicle stimulating hormone 
(FSH)c
Creatinine clearance (Cockcroft 
Gault calculation)
eGFR (C-MDRD)d
HBsAge
HBV DNA (if HBsAg is 
negative)e
HCV Abe
HIV Abe
Opiatese
Barbituratese
Amphetaminese
Cocainee
Benzodiazepinese
Alcohole
Phencyclidinee
Propoxyphenee
Methadonee
Hemoglobin A1Ce
HCV genotype and subtypee
Urine and Serum:
Human Chorionic
Gonadotropin (hCG) for 
femalesf
Hepatitis B Panelg
HCV RNA
Plasma HIV-1 RNAh
HIV-1 genotypic resistance 
testing (if applicable)h
IL28B
CD4,h CD4%h
CD8,h CD8%h
CD4:  CD8h
Alpha fetoprotein
Alpha2-macroglobulini
Haptoglobini
Apolipoprotein A1i
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Directly Measured.
b.
Performed only at Baseline.
c.
FSH at Screening only for female subjects to assess postmenopausal state.
d.
eGFR calculated by the MDRD formula, modified for the Chinese population (C-MDRD).
e.
Performed only at Screening.
f.
Pregnancy testing is not required for females of non-childbearing potential.


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Table 2.
Clinical Laboratory Tests (Continued)
g.
Performed for management of transaminase elevations (Section 6.1.7.1).
h.
Only for HCV/HIV co-infected subjects.
i.
Component of FibroTest collected only if needed during the Screening Period.
For any laboratory test value outside the reference range that the investigator considers 
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.  Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.  Additional 
urine pregnancy tests will be performed at all the 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.
Concomitant Medication Assessment
Use of medications (prescription or over-the-counter, including vitamins, herbal 
supplements, and vaccines) from the time of signing the consent, through the Treatment 
Period and 30 days after study drugs are stopped must be recorded in the eCRF at each 
study visit indicated in Appendix C (Treatment Period).  Thereafter, only medications 


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taken for SAEs and treatment of HCV and HIV will be recorded in the eCRF at each 
study visit indicated in Appendix C (Post-Treatment Period).
Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), HBV DNA (if HBsAg is negative), HCV Ab and 
HIV Ab tests will be performed at Screening.  The tests will be performed by a certified 
laboratory.  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.  
Urine Screens for Drugs of Abuse
A urine screen for drugs of abuse will be performed at Screening.  The panel for drugs of 
abuse will minimally include drugs listed in Table 2.  Any positive result must be assessed 
for clinical significance.
These analyses will be performed by the certified central laboratory chosen for the study.
Liver Diagnostic Testing
Subjects who have not had a qualifying liver biopsy within the previous 24 months or 
who have not had a qualifying FibroScan® within the previous 6 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.
Biopsy results as per METAVIR, Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec 
gradings with fibrosis score of > 3 (including 3 – 4 or 3/4), or Ishak grading with fibrosis 
score of > 4 are acceptable for ascertaining presence of compensated cirrhosis.  Subjects 
with historical liver FibroScan® or biopsy results are acceptable if these were conducted 
within 6 or 24 months from Screening, respectively, and the results are not exclusionary.  
In a subject with an indeterminate FibroTest result (0.48 < result < 0.75), or conflicting 


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FibroTest and APRI results (e.g., FibroTest ≥ 0.75, but APRI ≤ 2) at Screening, liver 
FibroScan® or biopsy can be performed during Screening to ascertain the presence or 
absence of cirrhosis.  Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6) 
may only be enrolled if they have a qualifying liver biopsy performed within 24 months 
prior to or during Screening.
Child-Pugh Score and Category
The Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters 
and 2 clinical assessments; Table 3).  Child-Pugh score will be determined at the visits 
indicated in Appendix C.
Table 3.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2 (or suppressed 
with medication)
Grade 3 or 4 (or 
refractory)
*
None; Slight ascites = Ascites detectable only by ultrasound examination; Moderate ascites = Ascites manifested 
by moderate symmetrical distension of the abdomen; Severe ascites = Large or gross ascites with marked 
abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram; Grade 1:  restless, 
sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves; Grade 2:  lethargic, time-disoriented, 
inappropriate behavior, asterixis, ataxia, slow triphasic waves; Grade 3:  somnolent, stuporous, place-disoriented, 
hyperactive reflexes, rigidity, slower waves; Grade 4:  unarousable coma, no personality/behavior, decerebrate, 
slow 2 to 3 cps delta activity.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Study 
Day 1 prior to dosing to confirm the subject has not progressed to hepatic decompensation 
since Screening.


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Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
In order to monitor for the presence of hepatocellular carcinoma (HCC), alpha fetoprotein 
will be assayed and an ultrasound of the liver will be performed as indicated in 
Appendix C.  A positive Ultrasound result suspicious for HCC at screening will be 
confirmed with CT scan or MRI during the screening period.  Suspicious ultrasound 
lesions confirmed by CT or MRI are exclusionary.
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.  Subjects should be 
instructed to follow the instructions provided with each instrument and to provide the best 
possible response to each item.  Site personnel shall not provide interpretation or 
assistance to subjects other than encouragement to complete the tasks.  Subjects who are 
functionally unable to read any of the instruments may have site personnel read the 
questionnaires to them.  Site personnel should encourage completion of each instrument at 
all specified visits and should ensure that a response is entered for all items.
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.  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 of their overall health on a separate visual analogue scale (VAS).  
The EQ-5D-3L should require approximately 5 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 


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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.
PRO instruments should be completed prior to drug administration on Study Day 1 and 
prior to any discussion of adverse events or any review of laboratory findings, including 
HCV RNA levels.
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.
Screening numbers will be unique 6-digit numbers and will begin with 100201 with the 
first three digits representing the investigative site, and the last three digits representing 
the subject at that site.  Enrolled subjects will keep their screening number as their subject 
number throughout the study.
Study Drug Compliance for Kits
Individual kits 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 in Appendix C, the overall 
number of tablets of ABT-493/ABT-530 remaining in each kit will be recorded in the 
source and entered in the IRT system along with the date of reconciliation.
HCV Genotype and Sub-Genotype
Plasma samples for HCV genotype and sub-genotype determination will be collected at 
Screening.  Genotype and sub-genotype will be assessed using the appropriate assay by 
the central laboratory.


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C.  
Plasma HCV RNA levels will be determined by an approved HCV RNA quantitative 
assay for each sample collected by the central laboratory including but not limited to 
Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v 2.0.
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Study 
Day 1 and at the study visits indicated in Appendix C.  Specific instructions for 
preparation and storage of HCV RNA and HCV resistance samples will be provided by 
the central laboratory, AbbVie, or its designee.
Flow Cytometry, HIV-1 RNA and HIV Resistance Testing Samples
Samples for plasma HIV-1 RNA levels and flow cytometry (including but not limited to 
CD4+ T-cell and CD8+ T-cell counts [absolute and percent]) will be obtained at the times 
specified in Appendix C.
If a subject who is on stable HIV-1 ART has an HIV-1 RNA level ≥ 200 copies/mL, the 
subject's HIV-1 RNA is to be repeated as noted in Section 5.4.1.2.  At the time the repeat 
plasma HIV-1 RNA is drawn, a sample may be obtained for HIV-1 genotypic resistance 
testing.  If the subject's repeat HIV-1 RNA is ≥ 500 copies/mL, the sample obtained for 
HIV-1 genotypic resistance testing may be analyzed as indicated by local standard of care.
If the subject's repeat HIV-1 RNA is < 200 copies/mL, then the subject will resume 
routine plasma HIV-1 RNA assessments as shown in Appendix C and described in 
Section 5.4.1.2.
Specific instructions for preparation and storage of flow cytometry, plasma HIV-1 RNA, 
and HIV resistance samples, if applicable, will be provided by the central laboratory, 
AbbVie, or its designee.


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Archive Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Appendix C.  
Archive plasma samples are being collected for possible additional analyses, including but 
not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, HCV resistance testing, and other possible predictors 
of response, as determined by AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.
5.3.1.2
Meals and Dietary Requirements
Study drug (i.e., ABT-493/ABT-530) tablets should be taken with food.
5.3.1.3
Blood Samples for Pharmacogenetic Analysis
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 Study 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 GTs.
Optional Sample for Pharmacogenetic Analysis
A separate (optional) whole blood sample for DNA isolation will be collected at baseline 
on Study Day 1 from each subject who consents.  If the optional pharmacogenetic sample 
is not collected on Study Day 1, it may be collected at any other visit during the study.  
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.  Samples collected in China will be shipped frozen to the central laboratory in 
China and then to an AbbVie designated laboratory in China for long-term storage.  


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Samples collected outside of China will be sent to an AbbVie designated laboratory 
outside of China for long term storage.  All samples will be stored in a secure storage 
space with adequate measures to protect confidentiality.  The samples will be retained 
while research on ABT-493 and ABT-530 or drugs for the treatment of HCV continues 
but no longer than 5 years after completion of this study and all study endpoint data are 
analyzed.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of ABT-493, possible ABT-493 metabolites, 
ABT-530, possible ABT-530 metabolites and HIV-1 ART regimens will be collected by 
venipuncture at each study visit indicated 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 for ABT-493/ABT-530 without regard to the time of 
dosing.  For co-infected subjects only, an additional blood sample (4 mL) will 
be collected for possible HIV-1 ART assays.
●
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 (3 mL each) 
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.  
For co-infected subjects only, an additional blood sample (4 mL) will be 
collected at each timepoint.


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○
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 for ABT-493/ABT-530 without regard to the time of dosing.  For 
co-infected subjects only, an additional blood sample (4 mL) will be collected 
for possible HIV-1 ART assays.
○
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.
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 
(and their possible metabolites) and HIV-1 ART regimens will be provided by the central 
laboratory, AbbVie, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of ABT-493 and ABT-530 
(and their possible metabolites), HIV-1 ART regimens 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, ABT-530 and HIV-1 ART samples to 
the reference laboratories following separately provided instructions.


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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.
Plasma concentrations of HIV-1 ART regimens for individual subjects, a group of 
subjects or for the whole study may be analyzed based on safety, HCV RNA and plasma 
HIV-1 RNA results.  The plasma concentrations of HIV-1 ART regimens will be 
determined, if necessary, at a separate laboratory using validated assay methods under the 
supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
HCV virologic response will be assessed by plasma HCV RNA levels in IU/mL at various 
time points from Study Day 1 through 24 weeks after completion or discontinuation of 
treatment.
5.3.3.1
Primary Variable
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).
5.3.3.2
Secondary Variable
The secondary efficacy variables are on-treatment HCV virologic failure and post-
treatment relapse of HCV infection (excluding re-infection), and SVR12 for HCV/HIV co-
infected subjects.
5.3.4
HCV Resistance Variables
For all subjects receiving study drugs who experience virologic failure, the HCV amino 
acid variants at signature resistance-associated positions in NS3 and NS5A at baseline 


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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 experience virologic failure and who have an available post-baseline sample with 
HCV RNA ≥ 1000 IU/mL:  1) the HCV amino acid variants in NS3 and NS5A identified 
by population or deep sequencing and comparison to the baseline sequence, 2) the HCV 
amino acid variants at signature resistance-associated amino acid positions in NS3 and 
NS5A identified by population or deep sequencing and comparison to the appropriate 
prototypic reference sequence, and 3) the persistence of HCV viral amino acid variants in 
NS3 and NS5A by population or deep sequencing.
5.3.5
HIV Resistance Variables
If any subject on stable HIV-1 ART develops a confirmed, quantifiable plasma HIV-1 
RNA level (HIV-1 RNA ≥ 200 copies/mL at one assessment and ≥ 500 copies/mL on 
repeat testing) after starting the study, the HIV-1 protease, reverse transcriptase and 
integrase sequences may be analyzed as indicated by local standard of care practices.
5.3.6
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, ECG, and laboratory tests assessments.
HIV virologic response will be assessed by plasma HIV-1 RNA levels in copies/mL at 
various time points from Study Day 1 through 24 weeks after completion of treatment.
5.3.7
Pharmacokinetic Variables
Individual plasma concentrations of ABT-493 and ABT-530 (and their possible 
metabolites) will be tabulated and summarized.  Plasma concentrations of HIV-1 ARVs 
for individual subjects, a group of subjects or for the whole study may be analyzed based 
on HCV RNA and/or plasma HIV-1 RNA results and summarized.


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5.3.8
Pharmacogenetic 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.
DNA samples from subjects who separately consent for additional pharmacogenetic 
analysis may be sequenced and data analyzed for genetic factors contributing to the 
disease or to the subject's response to study treatment, in terms of pharmacokinetics, 
efficacy, tolerability and safety.  Such genetic factors may include genes for drug 
metabolizing enzymes, drug transport proteins, genes within the target pathway, or other 
genes believed to be related to drug response.  Some genes currently insufficiently 
characterized or unknown may be understood to be important at the time of analysis.  
Pharmacogenetic analyses will be limited to ABT-493 and ABT-530, drugs of this class, 
HCV and related conditions.  Pharmacogenetic analyses will not be done to determine a 
subject's predisposition to unrelated diseases.  Pharmacogenetic analyses will take place at 
an AbbVie designated laboratory in China and data will be exported to AbbVie in the 
United States.
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 


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defined in Appendix C.  Ideally this should occur on the day of study drug 
discontinuation, but no later than 2 days after their final dose of study drug and prior to 
the initiation of any other anti-HCV therapy.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  The last dose of any study drug and reason for discontinuation will be recorded 
in the electronic data capture (EDC) system.  The subject should then begin the 
Post-Treatment Period where the subject will be monitored for 24 weeks for HCV RNA, 
the emergence and/or persistence of resistant viral variants, plasma HIV-1 RNA, HIV 
resistance (as applicable) and PROs.
If a subject is discontinued from the Post-Treatment Period, the subject should return for 
Post-Treatment Discontinuation procedures as defined in Appendix C.  The reason for 
discontinuation will also be recorded in the Study Discontinuation eCRF. 
If a subject is discontinued from study drug 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 DAAs to 
that subject may be continued at the Principal Investigator's discretion after discussion 
with the subject, if the benefit of continuing DAAs is felt to outweigh the potential risk.  
Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  Subjects 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3.
5.4.1.1
HCV Virologic Stopping Criteria
HCV virologic stopping criteria are defined as follows: 


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●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurements of > 1 log10 IU/mL above nadir) at any time point during 
treatment; or 
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during treatment.
When confirmatory testing is required it should be completed as soon as possible and the 
subject should remain on study treatment until the HCV virologic stopping criterion has 
been confirmed.  Subjects meeting a virologic stopping criterion 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, plasma HIV-1 RNA, HIV resistance 
(as applicable) and PROs until 24 weeks post-treatment.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV-1 RNA will be assessed at each scheduled study visit during the Treatment Period 
and Post-Treatment Period, as detailed in Appendix C.
For HCV/HIV-1 Co-Infected Subjects on Stable ART
The criteria for failure to maintain HIV virologic suppression is as follows:
●
HIV-1 RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 
2 weeks apart, in a subject compliant with their HIV ART therapy.
At the time a confirmatory HIV-1 RNA is drawn, a sample for HIV-1 genotypic resistance 
testing may also be obtained; this sample may be analyzed if the subject's repeat plasma 
HIV-1 RNA is ≥ 500 copies/mL.  A subject should remain on HCV study drug treatment 
and his/her current ART regimen while the failure to maintain HIV virologic suppression 
is being confirmed.  A confirmatory HIV-1 RNA and HIV-1 genotypic resistance blood 
draw can be done as an unscheduled visit.  However, if this blood draw falls on the date of 
a scheduled study visit (Appendix C), only a single HIV-1 RNA and HIV-1 genotypic 
resistance blood draw needs to be performed at this visit.  


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Clinical management of failure to maintain HIV-1 virologic suppression during the study 
(Treatment Period and Post-Treatment Period) will be handled by the site investigator 
according to current HIV treatment guidelines and local standard of care.  
If the investigator wishes to change the HIV-1 ART regimen for a subject, it must be 
discussed with the AbbVie TA MD prior to the change being made, unless the change is 
being made to address an immediate safety concern.
During the Treatment Period, subjects with confirmed failure to maintain HIV-1 RNA 
suppression should continue study drug treatment unless there is a requirement for
prohibited concomitant medications (Section 5.2.3.2 and Section 5.2.3.4) to construct a 
new HIV ART regimen.
For HCV/HIV-1 Co-Infected Subjects Naïve to ART
Clinical management of ART-naïve co-infected subjects during the study (Treatment 
Period and Post-Treatment period) will be handled by the site investigator according to 
current HIV treatment guidelines and local standard of care.  During the Treatment 
Period, if an investigator deems it necessary to initiate HIV-1 ART for a subject, 
continuation of study drug treatment must be discussed with the AbbVie TA MD prior to 
ART initiation.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.


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5.5
Treatments
5.5.1
Treatments Administered
Each dose of study drug (ABT-493/ABT-530) will be dispensed in the form of film-
coated 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.  For subjects participating in 
Intensive PK sampling on Study Day 1 and at the Week 4 visit, they will have their dose 
administered by study site personnel after food and blood samples are collected for assay 
of study drugs.  The date and time of dosing and blood sample collection will be recorded 
to the nearest minute in the source document.
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 as ABT-493 300 mg/ABT-530 120 mg (three × 
ABT-493 100 mg/ABT-530 40 mg tablets) QD and with food.  
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.  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 visit date information and study drug return 
information for each kit (Section 5.5.7).
All subjects who receive at least one dose of study drug and meet the HCV virologic 
stopping criteria or fail to maintain HIV virologic suppression should follow instructions 
in Section 5.4.1.1 and Section 5.4.1.2, respectively.
5.5.2
Identity of Investigational Product
Information about the study drugs to be used in this study is presented in Table 4.


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Table 4.
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.
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, 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 


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of the study by the AbbVie Statistics Department.  Upon receipt of study drug, the site 
will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.  
All three tablets of ABT-493/ABT-530 will be dosed together QD.  All subjects should 
take all doses of study medications with food.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing adherence with the treatment regimen with regard to virologic response and 
potential development of resistance due to poor compliance.
At each study drug accountability visit during the Treatment Period see (Appendix C), 
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 record the status of each one, as well as the exact number of 


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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 via 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 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 
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.  Study drug start dates for each drug 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 
AbbVie and according to local regulations following completion of drug accountability 


ABT-493, ABT-530
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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 and Choice of Control Groups
The selection of the treatment regimen is based on Phase 2 and Phase 3 studies which 
indicate that the combination of ABT-493/ABT-530 300/120 mg QD is generally safe and 
is optimal to achieve SVR in HCV GT1 – 6 infected subjects.
The current study (Study M15-593) is a multicenter, open-label Phase 3 study to evaluate 
the safety and efficacy of the combination of ABT-493/ABT-530 (300/120 mg) QD 
combination in treatment naïve or treatment-experienced (i.e., alpha, beta or pegylated 
interferon [pegIFN]) with or without RBV OR sofosbuvir with RBV with or without IFN 
HCV GT1 – 6 infected Asian adult subjects with compensated cirrhosis, with or without 
HIV co-infection.  The treatment duration is 12 weeks with the exception of treatment-
experienced GT3 HCV cirrhotic subjects who will receive 16 weeks of treatment.
The Phase 2 and 3 Analysis Set (integrated) from the global clinical development program 
includes all subjects who received doses of ABT-493 300 mg QD and ABT-530 120 mg 
QD either from registrational studies or in supportive Phase 2 studies.  Efficacy data 
through Post Treatment Week 12 for all subjects in the Phase 2 and 3 Analysis Set were 
included for the primary (SVR12) and secondary (on-treatment virologic failure and post-
treatment relapse) endpoints.  The Phase 2 and 3 Analysis Set organized by subject 
population is displayed in Table 5.  Subjects were considered treatment-experienced if 
they had failed regimens containing interferon, pegylated interferon, ribavirin, and/or 
sofosbuvir (TE-PRS).


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Table 5.
Overview of Clinical Studies by Subject Population (Phase 2 and 3 
Analysis Set)
Genotype
Clinical Study
Summary of Study Design
TN and TE Subjects Without Cirrhosis
GT1
M13-590*
ABT-493/ABT-530 300 mg/120 mg QD for 8 (n = 351) or 
12 weeks (n = 352)
M14-867
ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks (n = 34)
GT2
M15-464
ABT-493/ABT-530 300 mg/120 mg QD (n = 202) or placebo 
(n = 100) for 12 weeks
M14-868
ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks (n = 199) or 
12 weeks (n = 25)
GT3
M13-594
ABT-493/ABT-530 300 mg/120 mg QD for 8 (n = 157) or 
12 weeks (n = 233) or SOF 400 mg + DCV 60 mg QD for 
12 weeks (n = 115) (all subjects in study were TN)
M14-868
ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks (n = 29; TN 
only), 12 weeks (n = 76), or 16 weeks (n = 22; TE only)
GT4, GT5, GT6
M13-583
ABT-493/ABT-530 300 mg/120 mg QD for 12 weeks (n = 121)
M14-867
ABT-493/ABT-530 300 mg/120 mg QD for 12 weeks (n = 32)
M14-868
ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks (n = 58)
TN and TE Subjects With Cirrhosis
GT1, GT2, GT4, 
GT5, GT6
M14-172
ABT-493/ABT-530 300 mg/120 mg QD for 12 weeks (n = 146)
GT3
M14-868
ABT-493/ABT-530 300 mg/120 mg QD for 12 weeks (n = 64; TN 
only) or 16 weeks (n = 51; TE only)
Subjects With CKD Stages 4 – 5 With or Without Cirrhosis
GT1 – GT6
M15-462
ABT-493/ABT-530 300 mg/120 mg QD for 12 weeks (n = 104)
NS5A Inhibitor and/or PI-Experienced Subjects With or Without Cirrhosis
GT1, GT4
M15-410
ABT-493/ABT-530 300 mg/120 mg QD for 12 (n = 66) or 
16 weeks (n = 47)
CKD = chronic kidney disease; DCV = daclatasvir; GT = genotype; NS5A = nonstructural viral protein 5A; 
PI = protease inhibitor; QD = once daily; SOF = sofosbuvir; TE = treatment-experienced; TN = treatment-naïve
*
HCV monoinfected or HIV-coinfected.
Treatment durations were selected based on Phase 2 and 3 Analysis Set (from 12-week or 
16 week treatment groups receiving ABT-493/ABT-530 300/120 mg combinations in 


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HCV GT1, GT2, GT3, GT4, GT5, and GT6-infected patients with cirrhosis, with or 
without previous treatment experience (Table 6, Table 7 and Table 8).


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Table 6.
Summary of SVR12, On-Treatment Virologic Failure, and Post-Treatment Relapse in TN and TE
Non-GT3-Infected Subjects by Cirrhosis Status (TN + TE-PRS Subjects, Phase 2 and 3 Analysis Set)
Endpoint
n/N (%)
GT1
GT2
GT4
GT5
GT6
8 
Weeks
12 
Weeks
Overall
8 
Weeks
12 
Weeks
Overall
8 
Weeks
12 
Weeks
Overall
8 
Weeks
12 
Weeks
Overall
8 
Weeks
12 
Weeks
Overall
Subjects Without Cirrhosis
SVR12
383/387 
(99.0)
400/401 
(99.8)
783/788 
(99.4)
193/197 
(98.0)
232/234 
(99.1)
425/431 
(98.6)
43/46 
(93.5)
111/112 
(99.1)
154/158 
(97.5)
2/2 
(100)
28/28 
(100)
30/30 
(100)
9/10 
(90.0)
31/31 
(100)
40/41 
(97.6)
OTVF
1/387 
(0.3)
0/401
1/788 
(0.1)
0/197
0/234
0/431
0/46
0/112
0/158
0/2
0/28
0/30
0/10
0/31
0/41
Relapse12
0/384
0/400
0/784
2/195 
(1.0)
0/232
2/427 
(0.5)
0/45
0/111
0/156
0/2
0/27
0/29
0/10
0/30
0/40
Subjects With Cirrhosis
SVR12
N/A
98/101 
(97.0)
98/101 
(97.0)
N/A
35/35 
(100)
35/35 
(100)
N/A
20/20 
(100)
20/20 
(100)
N/A
2/2 
(100)
2/2 
(100)
N/A
7/7 
(100)
7/7 
(100)
OTVF
N/A
0/101
0/101
N/A
0/35
0/35
N/A
0/20
0/20
N/A
0/2
0/2
N/A
0/7
0/7
Relapse12
N/A
1/98 
(1.0)
1/98 
(1.0)
N/A
0/35
0/35
N/A
0/19
0/19
N/A
0/2
0/2
N/A
0/7
0/7
GT = genotype; HCV = hepatitis C virus; N/A = not applicable; OTVF = on-treatment virologic failure; PRS = regimens containing interferon, pegylated interferon, ribavirin, 
and/or sofosbuvir; Relapse12 = relapse before or during the SVR12 window; RNA = ribonucleic acid; SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-
experienced; TN = treatment-naïve
Note:
Data for Relapse12 includes subjects with end-of-treatment response and post-treatment HCV RNA data.


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Table 7.
SVR12 Rates by Prior Treatment Experience, HCV Genotype, and Duration for Non-GT3-Infected Subjects 
(ITT Population, Phase 2 and 3 Analysis Set)
Treatment Group
n/N (%)
GT1
GT2
GT4
GT5
GT6
8 Weeks
12 Weeks
8 Weeks
12 Weeks
8 Weeks
12 Weeks
8 Weeks
12 Weeks
8 Weeks
12 Weeks
TN
245/248 
(98.8)
310/313 
(99.0)
172/174 
(98.9)
193/195 
(99.0)
36/39 
(92.3)
83/83
(100)
2/2
(100)
24/24 
(100)
7/8 
(87.5)
33/33 
(100)
TE-PRS
138/139 
(99.3)
188/189 
(99.5)
21/23 
(91.3)
74/74
(100)
7/7
(100)
48/49 
(98.0)
N/A
6/6
(100)
2/2
(100)
5/5
(100)
TN + TE-PRS
All
383/387 
(99.0)
498/502 
(99.2)
193/197 
(98.0)
267/269 
(99.3)
43/46 
(93.5)
131/132 
(99.2)
2/2
(100)
30/30 
(100)
9/10 
(90.0)
38/38 
(100)
Difference %
(8-week – 12 week)
95% CI
–0.7
(–2.1, 0.6)
–1.4
(–4.4, 1.7)
–5.6
(–14.1, 2.9)
0.0
(–73.3, 73.3)
–10.5
(–37.8, 16.9)
CI = confidence interval; GT = genotype; HCV = hepatitis C virus; ITT = intention-to-treat (all subjects who received at least 1 dose of study drug); N/A = not applicable; 
PRS = regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-experienced; 
TN = treatment-naïve


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Table 8.
Summary of SVR12, On-Treatment Virologic Failure, and Post-Treatment Relapse in TN and TE
GT3-Infected Subjects by Cirrhosis Status and Treatment Duration (ITT Population, Phase 2 and 3 Analysis 
Set)
Endpoint
n/N (%)
TN
TE-PRS
8 Weeks
12 Weeks
12 Weeks
16 Weeks
Subjects Without Cirrhosis
SVR12
177/186 (95.2)
258/270 (95.6)
44/49 (89.8)
21/22 (95.5)
OTVF
1/186 (0.5)
1/270 (0.4)
1/49 (2.0)
0/22
Relapse12
5/178 (2.8)
3/257 (1.2)
4/48 (8.3)
1/22 (4.5)
Subjects With Cirrhosis
SVR12
N/A
64/65 (98.5)
N/A
48/51 (94.1)
OTVF
N/A
0/65
N/A
1/51 (2.0)
Relapse12
N/A
0/64
N/A
2/50 (4.0)
GT = genotype; ITT = intention-to-treat (all subjects who received at least 1 dose of study drug); N/A = not applicable; OTVF = on-treatment virologic failure; 
PRS = regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir; Relapse12 = relapse before or during the SVR12 window; 
SVR12 = sustained virologic response 12 weeks postdosing; TE = treatment-experienced; TN = treatment-naïve


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Treatment-experienced GT3-infected subjects with and without cirrhosis were evaluated 
for 12-week and 16-week durations of treatment.  Among TE GT3-infected subjects 
without cirrhosis, the SVR12 rates were higher in subjects treated for 16 weeks (95.5%) 
compared to 12 weeks (89.8%).  Subjects with cirrhosis treated for 16 weeks achieved a 
high (94.1%) SVR12 rate, similar to subjects without cirrhosis (95.5%).  These results in 
GT3-infected subjects support the use of 16 weeks of treatment in TE GT3-infected 
subjects with or without cirrhosis.
Based on the efficacy data presented above, the 12-week treatment duration is anticipated 
to achieve high SVR rates in GT1, 2, 3, 4, 5 and 6 infected treatment-naïve and
-experienced subjects with compensated cirrhosis, with the exception of 16 weeks for 
treatment-experienced GT3-infected subjects (Table 9).
Table 9.
Recommended Treatment Duration for Subjects with Cirrhosis
Patient Population
Recommended Treatment Duration for Subjects with Cirrhosis
Treatment-Naive
12 weeks
Treatment-Experienced*
12 weeks (16 weeks for GT3)
*
Treatment-experienced to interferon (IFN) (alpha, beta or pegylated interferon [pegIFN]) with or without ribavirin 
(RBV) OR sofosbuvir with RBV with or without IFN.
Since this study will enroll more than one genotype, there is no single standard of care for 
comparison.  A placebo-controlled study is not considered to be appropriate in HCV 
subjects with compensated liver disease because they have greater risk of progression to 
decompensated liver disease with treatment delays for a placebo group.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA and HIV-1 RNA assays are standard and validated.
5.6.3
Suitability of Subject Population
This study plans to enroll HCV GT1, 2, 3, 4, 5, and 6-infected subjects with cirrhosis who 
are treatment-naïve or treatment-experienced to prior HCV therapy with or without HIV 


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co-infection in order to assess the safety, pharmacokinetics and antiviral activity of 
ABT-493/ABT-530.  Subjects who are treatment-naïve as well as those who received 
prior treatment with IFN (alpha, beta or pegylated interferon [pegIFN]) with or without 
RBV OR sofosbuvir with RBV with or without IFN for their HCV infection are included 
in the study in order to evaluate the efficacy of ABT-493/ABT-530 regimen in this 
diverse cohort of HCV GT1 – 6-infected subjects.  Subjects who have failed treatment 
with a PI or NS5A inhibitor alone or in combination with interferon (with or without 
RBV) will not be permitted to enroll. 
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 evaluating the pharmacokinetic, pharmacodynamic, safety and tolerability 
effects of the coadministration of buprenorphine/naloxone or methadone and the DAAs 
(ABT-493 + ABT-530) in adult subjects on stable opioid maintenance therapy showing 
acceptable safety and no relevant pharmacokinetic or pharmacodynamic interactions.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
The doses of 300 mg ABT-493 and 120 mg ABT-530 were selected to optimize efficacy 
of the combination while maintaining an acceptable safety profile.
5.6.4.1.1
ABT-493 and ABT-530 Doses
Based on the results from the Phase 2b studies, Studies M14-867 and M14-868, the 
300 mg dose of ABT-493 and 120 mg dose of ABT-530 in combination has been selected 
for Phase 3 studies in HCV GT1 to 6 cirrhotic and non-cirrhotic populations and is also 
applicable for this Asian regional Phase 3 study.  This dose has been demonstrated 
efficacious for the proposed Phase 3 study populations with the planned study duration 
and would reduce chance of virologic failure across genotypes and difficult-to-treat 
patient populations to maximize the chance for SVR.  Importantly, ABT-493 and 
ABT-530 regimens including the proposed 300 mg/120 mg ABT-493/ABT-530 QD 


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regimen have been well-tolerated and safe across all Phase 2b study arms including 
cirrhotic subjects. 
Further detailed rationale is provided below:
●
In Phase 1 studies, no ethnic difference was observed in ABT-493 and 
ABT-530 exposures for Han Chinese, Japanese and Caucasian subjects living 
in the United States.
●
Based on in vitro studies, both ABT-493 and ABT-530 demonstrated strong 
pan-genotypic anti-viral activity.  ABT-530 demonstrated strong 
pan-genotypic anti-viral activity in vitro.  Given the potent in vitro efficacy 
across GTs and high SVR rates of 93% – 100% observed to date across dose 
groups in Phase 2 studies in GT1, GT2 and GT3-infected non-cirrhotic 
patients, the ABT-493/ABT-530 dose of 300 mg/120 mg is expected to 
provide sufficient exposure to achieve significant antiviral potency in GT1-, 
GT2-, GT3-, GT4-, GT5- and GT6-infected subjects.
●
Maximization of SVR rate:  based on results from Part 1 and Part 2 of the 
Phase 2b studies, the combination of ABT-493/ABT-530 has demonstrated 
100% response rates for 12 weeks of treatment duration at ABT-493/ABT-530 
200/120 mg QD in HCV GT1, GT2 and with ABT-493/ABT-530 300/120 mg 
QD in GT4 to GT6-infected non-cirrhotic subjects.  GT1-infected subjects 
with compensated cirrhosis achieved an SVR4 rate of 96% with a 12-week 
regimen of ABT-493 200 mg and ABT-530 120 mg.  These Phase 2b clinical 
results are consistent with exposure-response modelling and simulations of 
antiviral activity in GT1, GT2, and GT4-infected subjects with compensated 
cirrhosis which suggest that treatment with the combination of ABT-493 and 
ABT-530 for 12 weeks in this population will achieve close to 100% 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, the ALT levels 
have normalized or trended toward normal with DAA treatment, and there 


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have been no on-treatment ALT elevations above baseline grade.  There were 
no patients with clinically relevant treatment-emergent alanine 
aminotransferase elevations from baseline to date among approximately 
500 patients in the Phase 2 trials including approximately 82 patients with 
compensated cirrhosis with at least 8 weeks of treatment (55 of them receiving 
300/120 mg QD dose).
●
Preliminary pharmacokinetic data demonstrates that ABT-493 exposures 
following 200 mg QD dosing in cirrhotic subjects are approximately 3-fold 
higher than those in non-cirrhotics.  Based on the integrated pharmacokinetic 
exposures of ABT-493 and safety data in healthy subjects across 100 mg to 
1200 mg dose range, ALT elevations ≥ Grade 2 are only anticipated to occur 
when ABT-493 AUC is higher than 190,000 ng•h/mL, which is 33× higher 
than the projected geometric mean AUC exposure at ABT-493 300 mg in 
non-cirrhotic subjects.
●
ABT-530 had shown to be safe and well tolerated at 600 mg QD multiple 
dosing and MTD was not achieved.  Although ABT-493 300 mg increases 
ABT-530 exposure at 120 mg by 4-fold, the increased ABT-530 exposure was 
still less than the exposures of ABT-530 600 mg QD in Study M13-356 and no 
significant safety signal was observed in healthy subjects and HCV infected 
patients.  No clinically meaningful adverse events or laboratory abnormalities 
were observed in any ABT-530 120 mg dose groups in Phase 2 
Studies M14-867 and M14-868.
●
For HIV-HCV co-infected subjects, extensive drug-drug interaction studies 
have been conducted between HIV-1 ART regimens and ABT-493 + ABT-530 
combinations.  The allowed HIV-1 ART regimens in the study are not 
anticipated to significantly interact with ABT-493 and ABT-530.
●
A film-coated 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 
 bilayer tablet formulation administered under fasting conditions showed 
approximately 35% to 56% lower bioavailability compared to the Phase 2 
formulations at the ABT-493/ABT-530 dose of 300 mg/120 mg.  When the 
Phase 3 bilayer tablet was administered under non-fasting conditions, 
exposures became comparable to the Phase 2 formulation.  Hence, the Phase 3 


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co-formulated ABT-493/ABT-530 bilayer tablet must be administered with 
food to provide desirable DAA exposures.
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for up 
to 16 weeks.
5.6.4.2
Rationale for Duration Selections
Treatment duration for this Asian regional Phase 3 study was determined based on study 
results from the Global program.  The treatment duration differs among subjects based on 
HCV GT and treatment-experience (12 weeks of treatment for treatment-naïve and 
treatment-experienced GT1, 2, 3, 4, 5 and 6-infected subjects with the exception of 
16 weeks for treatment-experienced GT3-infected subjects).
For cirrhotic subjects, efficacy data of the 200 mg/120 mg dose in GT1-infected cirrhotic 
subjects and safety and efficacy data of the 300 mg/120 mg dose in GT3-infected cirrhotic 
subjects from Part 2 of Phase 2b studies would support efficacy and safety in cirrhotic 
subjects across GT1, GT2, and GT4 to GT6.
Efficacy results from Part 2 of Study M14-867 in GT1 cirrhotic subjects showed 96% 
SVR12 for ABT-493 200 mg + ABT-530 120 mg QD administered for 12 weeks, which is 
in line with the clinical exposure-response simulation predicted range.  In addition, 
efficacy results from Part 2 of Study M14-868 in GT3 cirrhotic subjects showed 100% 
SVR4 for ABT-493 300 mg + ABT-530 120 mg QD administered for 12 weeks.  Based on 
simulations conducted to predict SVR rates of 300 mg/120 mg ABT-493/ABT-530 for 12 
and 16 weeks in HCV GT1 subjects with cirrhosis, this ABT-493/ABT-530 dose could 
provide improved SVR rates compared to lower doses and a duration of 12 weeks could 
achieve an SVR rate close to 100% in cirrhotic subjects with HCV GT1 infection.  A 
longer duration (e.g., 16 weeks) of 300 mg/120 mg ABT-493/ABT-530 QD treatment is 
not expected to provide a significant improvement in the SVR rate (in GT1).  Similar to 
GT1, the predicted SVR rates for GT2-infected subjects with cirrhosis following 
300 mg/120 mg ABT-493/ABT-530 QD treatment for 12 weeks is 98%.  This dose is also 


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anticipated to yield a high SVR rate following a 12-week treatment duration in the GT4 to 
GT6-infected cirrhotic population.
In Part 3 of Study M14-868, high efficacy was demonstrated with the ABT-493/ABT-530 
300 mg/120 mg QD regimen in HCV GT3-infected subjects with cirrhosis and/or 
treatment experience following 12 and/or 16 weeks of treatment.  SVR12 rates > 95% 
were observed in treatment-naive and treatment-experienced subjects with cirrhosis 
following 12 and 16 weeks of treatment, respectively.  
Treatment-naïve HCV GT3-infected subjects with cirrhosis treated for 12 weeks achieved 
high efficacy (SVR12 rate of 98%) with no virological failures observed.  Treatment-
experienced HCV GT3-infected subjects with cirrhosis treated for 16 weeks achieved 
SVR12 rate of 96%, with a low rate of relapse (2%).  Among treatment-experienced 
subjects without cirrhosis, the 16-week regimen appeared to have a slightly higher SVR12
rate (96%) and a slightly lower relapse rate (5%) than the 12-week regimen.  Treatment 
with the shorter duration of 12 weeks resulted in a slightly lower SVR12 rate (91%) and a 
slightly higher relapse rate (9%) compared to the 16 week regimen.  There was a 
comparable safety profile for GT3 treatment-experienced subjects regardless of duration 
of treatment with study drug (12 or 16 weeks) and between subjects with or without 
cirrhosis.
Overall, the SVR12 rates for the GT3-infected treatment-experienced cohort, with and 
without cirrhosis, in the 16-week arm (SVR12 of 96% [66/69]) demonstrates that 16 weeks 
of treatment maximizes efficacy and is the most appropriate duration for this hardest-to-
treat population.  
5.6.4.3
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 


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resistance to paritaprevir or ombitasvir were detected in patients experiencing virologic 
failure.  While resistance data from patients treated with the combination of ABT-530 and 
ABT-493 are limited, it is expected that ABT-530, an NS5A inhibitor, will be able to 
suppress the appearance of virus containing resistance-associated substitutions 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, the combination of ABT-493 and ABT-530 achieved 
high SVR rates with few virologic failures in DAA-naïve patients with HCV genotype 1, 
2, 3, 4, 5, or 6 infection in the Phase 3 registrational studies.  These results support the 
prediction that the risk of development of resistance-associated substitutions 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 AbbVie (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 AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be adverse events only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, meet 


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protocol specific criteria (see Section 6.1.7 regarding toxicity management) and/or if the 
investigator considers them to be AEs.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
AE if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure 
is being done will be considered an AE.
6.1.1.2
Serious Adverse Events
If an AE 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 SAE.
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 SAEs 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 AE 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 AEs.  Below are the 
general grading categories.  However, the investigator should always search NCI CTCAE 
for a given diagnostic/symptomatic AE term to identify and apply specific grading details 
for that AE entity.
Grading system for AEs (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 AE 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.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.


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6.1.4
Adverse Event Collection Period
All SAEs as well as protocol-related nonserious AEs (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 AEs 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 3.
Figure 3.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a SAE, whether associated with study drug or not, the Investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the electronic data capture (EDC) system.  SAEs 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 SAE.


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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:
Fax:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
In emergency situations involving study subjects when the primary TA MD is not 
available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline where 
your call will be re-directed to a designated backup AbbVie TA MD:
Phone:  


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AbbVie 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 AE.  However, the medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, stillbirth or congenital anomaly is considered a SAE 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 AEs and laboratory abnormalities that occur 
during the study must be evaluated by the investigator.  All AEs and laboratory 
abnormalities will be managed and followed to a satisfactory clinical resolution.  A 
toxicity is deemed "clinically significant" based on the medical judgment of the 
investigator.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4" is to be used in the grading of AEs 
and laboratory abnormalities and 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).
6.1.7.1
Management of Increases in ALT
If a subject experiences a post-baseline increase in ALT to > 5 × ULN and also > 2 × the 
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 × the baseline value, the 
recommendations below should be followed:
●
Complete hepatic questionnaire; 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, etc.).
●
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.
Alternate management of ALT increases is permitted with approval of the AbbVie TA 
MD.
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections
HIV-1 infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  These known AIDS-associated opportunistic infections (OI) are 
listed in Appendix D.38  The events listed in Appendix D will be summarized as HIV 
related events, not as AEs.  These OIs will be collected from the time of study drug 
administration until 30 days following discontinuation of study drug.


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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 
biologic or drug component of the product(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to AbbVie 
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 AbbVie (or an authorized 
representative) and documented in source as required by AbbVie.  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 assigned Site Monitor and the following AbbVie Team 
Members:
Primary Contact:
Alternate Contact:
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.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation.
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 


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data cleaning.  Data collected after this lock will be added to a new version of the 
database which will be cleaned and locked at the end of the study.  
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 categorical variables.
Data across subjects of all genotypes will be combined for analysis, unless otherwise 
indicated.  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 efficacy endpoint, when applicable, will be 
performed on the ITT population modified to exclude subjects of multiple genotypes 
according to the central laboratory or 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 across the set of all subjects for the ITT and mITT population(s).  
Demographics include age (continuous; < 65 or ≥ 65 years; < 75 or ≥ 75 years), weight, 
height, waist circumference, BMI (continuous; < 25, ≥ 25 to < 30, or ≥ 30 kg/m2), sex, 
race, ethnicity, type of Asian descent, and geographic region.  Baseline characteristics will 


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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 genotype 
and available subtype, prior HCV treatment history, baseline HIV co-infection status, HIV 
ART at baseline, IL28B genotype (CC, CT, or TT; CC or non-CC), baseline HCV RNA 
level, baseline homeostasis model of assessment – insulin resistance (HOMA-IR), 
baseline Child-Pugh score (5, 6, or > 6), tobacco (user, ex-user, or non-user) and alcohol 
use (drinker, ex-drinker, or non-drinker) status, injection drug use, (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, and use of hepato-
protectants at baseline.
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.  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 will be considered 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 calculated 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.
The summaries described above will also be performed for each geographic region.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.


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Plasma HCV RNA levels will be determined by an approved HCV RNA quantitative 
assay for each sample collected by the central laboratory (including but not limited to 
Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v 2.0). 
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  The number and percentage of subjects achieving SVR12 will 
be presented along with a two-sided 95% confidence interval (CI) for the percentage.  
The normal approximation to the binomial distribution will be used to calculate the CI 
unless the rate for the primary endpoint is 100%, in which case the Wilson's score method 
will be used for the calculation of the CI.  No hypothesis will be tested.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment HCV 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 as planned with HCV 
RNA < LLOQ at the end of treatment, excluding re-infection), and
●
The percentage of HCV/HIV co-infected subjects (determined at Screening) 
achieving SVR12.
For the analysis of relapse, a subject enrolled to receive 12 weeks of treatment is 
considered to have completed treatment if study drug duration is 77 days or more, and a 
subject enrolled to receive 16 weeks of treatment is considered to have completed 
treatment if study drug duration is 105 days or more.


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The percentages of subjects with on-treatment virologic failure, post-treatment relapse, 
and SVR12 will be calculated along with two-sided 95% Wilson score confidence 
intervals.
In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection) will be provided for the set of all subjects and for the set of 
HCV/HIV co-infected subjects.
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.
8.1.2.4
Subgroup Analysis
The percentage of subjects with SVR12 will be calculated, as will the corresponding 
two-sided 95% Wilson score CIs, for subgroups based on the following factors for the 
ITT and mITT population(s): 
●
Geographic region;
●
HCV genotype and available subtype;
●
Prior HCV treatment history;
●
For treatment-experienced subjects, type of prior treatment experience;
●
For treatment-experienced subjects, type of non-response to previous 
treatment;
●
Baseline HIV co-infection status;
●
IL28B genotype;
●
Sex;
●
Age;
●
Type of Asian descent;
●
Baseline BMI;
●
Baseline HCV RNA levels;
●
Baseline HOMA-IR;


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●
Baseline platelet count;
●
Baseline albumin;
●
Baseline GGT;
●
Baseline LDL;
●
Baseline APRI;
●
Baseline FIB-4;
●
Baseline AST/ALT ratio;
●
Baseline alpha fetoprotein (AFP);
●
Baseline Child-Pugh Score;
●
Baseline AFP, platelet count and albumin;
●
History of diabetes;
●
History of bleeding disorders;
●
History of depression or bipolar disorder;
●
Baseline metabolic syndrome;
●
History of cardiovascular disease;
●
Injection drug use;
●
Baseline stable opiate substitution use;
●
Baseline hepato-protectant medication use;
●
Study drug compliance.
Further details about subgroup analyses will be described in the Statistical Analysis Plan 
(SAP).
8.1.2.5
Additional Efficacy Endpoints
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 subjects with SVR4;
●
The percentage of subjects with SVR24;


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●
A summary of reason for SVR4 and SVR24 non-response (e.g., on-treatment 
virologic failure, relapse, re-infection);
●
The percentage of subjects who relapsed after achieving SVR12.
In the above analyses for SVR and relapse, the percentage of subjects will be calculated 
along with a two-sided 95% Wilson score confidence interval.  The summaries listed 
above will also be presented by geographic region.
Additionally, the secondary endpoints will be summarized by geographic region, and the 
subgroup and sensitivity analyses will be performed separately for each geographic 
region.
The additional endpoints along with the secondary endpoints of on-treatment virologic 
failure and post-treatment relapse will also be summarized for the HCV/HIV co-infected
subjects.  The sensitivity analyses will also be performed for the HCV/HIV co-infected 
population.
8.1.3
Patient Reported Outcomes
The handling of missing data for patient reported outcomes (PROs) will be as follows.  
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 will be summarized descriptively for the FSS total score 
and the EQ-5D-3L health index score and VAS score at each visit.  
The cumulative number and percentage of subjects who have ever experienced an 
increase from baseline in the FSS total score of greater than or equal to 0.7 through each 
applicable time point will also be calculated.
The analyses described above will also be performed separately for each geographic 
region.  Additional analyses of PROs will be performed as useful and appropriate.


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8.1.4
HCV and HIV Resistance Analyses
For subjects who, experience virologic failure (on treatment virologic failure or post-
treatment relapse), full length NS3/4A and NS5A genes from their available 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 available samples from 
subjects who do not achieve SVR12 are 1) the sample closest in time after 
failure/discontinuation with an HCV RNA level of ≥ 1000 IU/mL, and 2) 24 weeks 
post-DAA treatment, provided that resistance-associated substitutions were detected by 
either population or deep sequencing at the time of failure/discontinuation.
The following definitions will be used in the resistance analyses:
●
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.
●
Emerged variant by population or deep sequencing:  a post-baseline variant 
that is observed in 2 or more subjects of the same HCV sub-genotype by 
population or deep sequencing.


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The following analyses will be performed for all subjects who experience virologic 
failure:
The HCV amino acid sequence as determined by population or deep sequencing of 
available baseline samples 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 experience virologic failure 
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 with an HCV RNA level of 
≥1000 IU/mL will be compared to the baseline and appropriate prototypic reference 
amino acid sequence.  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 amino acid variants (by population or deep sequencing) at signature 
resistance associated positions relative to the appropriate prototypic reference amino 
acid sequence will be provided for each DAA target (NS3 and NS5A).
The persistence of post-baseline variants at signature resistance-associated amino 
acid positions for each target (NS3 and NS5A) 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).


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If resistance-associated substitutions are not detected by either population or deep 
sequencing in a given target for a subject at the time of failure, then that target may not be 
sequenced in subsequent samples from that subject.
HIV-1 drug resistance genotyping for protease, reverse transcriptase and integrase may be 
performed for protocol defined eligible specimens.
8.1.5
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.  Safety data will be summarized for the set of all subjects, separately for each 
geographic region, and for the set of HCV/HIV co-infected subjects. 
8.1.5.1
Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of subjects with treatment-emergent 
AEs (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.  The tabulation of the number of subjects with 
treatment-emergent AEs by severity grade and relationship to each study drug (DAAs) 
also will be provided.  Subjects reporting more than one AE for a given MedDRA 
preferred term will be counted only once for that term using the event with the most 
severe grade from the severity grade table and the most related event from 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 test values 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.


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Laboratory data values will be categorized as low, normal, or high based on reference 
ranges of the laboratory used in this study.  Shift tables from baseline to minimum value 
and from baseline to maximum value will be created.  The shift tables will cross-tabulate 
the frequency of subjects with baseline values below/within/above the normal range 
versus minimum/maximum post-baseline values below/within/above the normal range.
In addition, the number and percentage of subjects with post-baseline values during the 
Treatment Period meeting pre-specified criteria for potentially clinically significant 
laboratory values or toxicity grades will be calculated.
8.1.5.3
HIV-1 RNA Data
For the HCV/HIV co-infected subjects who were on stable HIV-1 ART at initiation of 
study drug, the number and percentage of subjects with 2 consecutive HIV-1 RNA values 
≥ 200 copies/mL during the Treatment Period will be calculated.
8.1.5.4
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 potentially clinically significant vital signs values 
will be summarized. 
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of ABT-530 and ABT-493 and possible metabolites and 
pharmacokinetic parameter values for ABT-493 and ABT-530 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.


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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).
●
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 CL/F and V/F values with only 
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.


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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 individual, 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.
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 160 subjects.  The sample size for this study is 
driven by the expected sample size requirements for each genotype and geographical 
region for this secondary indication.  No formal hypothesis is being tested in this study.  If 


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the observed SVR12 rate in this study is 95% among 160 subjects, then the two-sided 95% 
CI calculated using the normal approximation for a single binomial proportion is 91.6% to 
98.4%.
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be enrolled into a single arm.
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 International Conference on 
Harmonization (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.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A 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.
Optional pharmacogenetic and optional intensive PK samples will only be collected if the 
subject has voluntarily signed and dated a separate informed consent, approved by an 
IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  The separate pharmacogenetic and intensive PK informed 
consents must be signed before the samples are collected and testing is performed.  If the 
subject does not consent to either pharmacogenetic or intensive PK testing, it will not 
impact the subject's participation in the study.


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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 optional pharmacogenetic research that may be done using DNA samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, neither the investigator nor the subject 
will 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 research may be used in scientific publications or presented at medical 
conventions.  Optional pharmacogenetic 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.


ABT-493, ABT-530
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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-493 and 
ABT-530.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-Label Study to Evaluate the Efficacy and Safety of 
ABT-493/ABT-530 in Treatment-Naïve and Treatment-Experienced 
Asian Adults With Chronic Hepatitis C Virus Genotype (GT) 1 to 
GT6 Infection With Compensated Cirrhosis and With or Without 
Human Immunodeficiency Virus Co-Infection
Protocol Date:
03 April 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Mohd Hanafiah K, Groeger J, Flaxman AD, et al.  Global epidemiology of 
hepatitis C virus infection:  new estimates of age-specific antibody to HCV 
seroprevalence.  Hepatology.  2013;57(4):1333-42.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al.  A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Smith DB, Bukh J, Kuiken C, et al.  Expanded classification of hepatitis C virus 
into 7 genotypes and 67 subtypes:  updated criteria and genotype assignment web 
resource.  Hepatology.  2014;59(1):318-27.
6.
European Association for Study of Liver.  EASL Clinical Practice Guidelines: 
management of hepatitis C virus infection.  J Hepatol.  2014;60(2):392-420.  
Erratum in:  J Hepatol.  2014;61(1):183-4.
7.
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.
8.
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.
9.
Tao Q, Wang Y, Wang H, et al.  Seroepidemiology of HCV and HBV infection in 
northern China.  Gastroenterol Jpn.  1991;26 (Suppl 3):156-8.


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10.
Expert Committee on Chronic Hepatitis C Antiviral Therapy.  Expert consensus for 
antiviral therapy for chronic hepatitis C.  Chin J Clin Infect Dis.  2009;3(3):343-52  
(electronic edition).
11.
Zhao S, Jiang T, Li R, et al.  HCV infection in voluntary donors and its influence 
on recruitment of donors in Chongqing area.  Zhongguo Shi Yan Xue Ye Xue Za 
Zhi.  2008;16(3):676-80.
12.
Zhang M, Sun X, Mark S, et al.  Hepatitis C virus infection, Linxian, China.  
Emerg Infect Dis.  2005;11(1):17-21.
13.
Liu F, Chen K, He Z, et al.  Hepatitis C seroprevalence and associated risk factors, 
Anyang, China.  Emerg Infect Dis.  2009;15(11):1819-22.
14.
Zhuo H, Lu S, Wang T.  Chronic hepatitis C and progress of anti-viral drugs 
research.  Chemical Drugs, Division II-CDE/SFDA.  2012.
15.
Wei L, Lopez-Talaver JC, Rao H, et al.  Prevalence of HCV viral and host IL28B 
genotypes in China.  Poster presented at:  62nd Annual Meeting of the American 
Association for the Study of Liver Disease (AASLD 2011); November 4-8, 2011; 
San Francisco, CA.  Poster 412.
16.
Li W, Zhu Y, Hua Z.  [Exploration on the association between the pattern of HBV 
markers and infection of HCV among population] [article in Chinese].  Zhonghua 
Liu Xing Bing Xue Za Zhi.  1994;15(4):212-4.
17.
Chen X, Xuan M, Wu D. [Study of superinfection of HBV and HCV] [article in 
Chinese].  Zhonghua Liu Xing Bing Xue Za Zhi.  1999;20(3):141-3.
18.
Lu L, Nakano T, He Y, et al.  Heptitis C virus genotype distribution in China; 
predominance of closely related subtype 1b isolates and existence of new 
genotype 6 variants.  J Med Virol.  2005;75(4):538-49.
19.
Friedman SL.  Seminars in medicine of the Beth Israel Hospital, Boston.  The 
cellular basis of hepatic fibrosis.  Mechanisms and treatment strategies.  N Engl J 
Med.  1993;328(25):1828-35.


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20.
Zhang Y, Pu XX, Zhao JY, et al.  The differences in cirrhosis and primary cancer 
of liver caused by ethanol, HCV and HBV.  Shijie Huaren Xiaohua Zazhi.  
1999;7:572.
21.
Wang X, Lin SX, Tao J, et al.  Study of liver cirrhosis over ten consecutive years in 
Southern China.  World J Gastroenterol.  2014;20(37):13546-55.
22.
Perz JF, Armstrong GL, Farrington LA, et al.  The contributions of hepatitis B 
virus and hepatitis C virus infections to cirrhosis and primary liver cancer 
worldwide.  J Hepatol.  2006;45(4):529-38.
23.
Mueller S, Millonig G, Seitz HK.  Alcoholic liver disease among 502 villages in 
southern Taiwan.  J Gastroenterol Hepatol.  2007;22:92-8.
24.
COPEGUS (ribavirin) [US prescribing information].  South San Francisco, CA; 
Genentech USA, Inc., 2013.
25.
HARVONI® (ledipasvir and sofosbuvir) tablets [package insert].  Foster City, CA; 
Gilead Sciences, Inc., 2015.
26.
Viekira Pak™ (ombitasvir, paritaprevir and ritonavir tablets; dasabuvir tablets) 
[Summary of Product Characteristics].  North Chicago, IL; AbbVie Inc., 2015.
27.
VIEKIRAX™ tablets (ombitasvir/paritaprevir/ritonavir) [Summary of Product 
Characteristics].  Maidenhead, UK; AbbVie Ltd., 2015.
28.
Technivie (ombitasvir, paritaprevir and ritonavir) [US prescribing information].  
North Chicago, IL, AbbVie Inc., 2015.
29.
Asselah T, Hassanein TI, Qaqish RB.  Efficacy and safety of 
ombitasvir/paritaprevir/ritonavir co-administered with ribavirin in adults with 
genotype 4 chronic hepatitis C infection and cirrhosis (AGATE-I).  66th Annual 
Meeting of the American Association for the Study of Liver Diseases.  
November 13-17, 2015; Boston, MA.  Abstract 714.
30.
SOVALDI® (sofosbuvir) Tablets [package insert].  Foster City, CA; Gilead 
Sciences, Inc., 2014.
31.
DAKLINZA™ (daclatasvir) [package insert].  Princeton, NJ; Bristol-Myers Squibb 
Company, 2015.


ABT-493, ABT-530
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32.
American Association for the Study of Liver Diseases.  Recommendations for 
Testing, Managing, and Treating Hepatitis C.  August 2015.
33.
European Association for the Study of the Liver.  EASL recommendations on 
treatment of hepatitis C.  April 2015.
34.
AbbVie.  ABT-493 Investigator's Brochure Edition 4.  14 September 2015.
35.
AbbVie.  ABT-530 Investigator's Brochure Edition 4.  16 September 2015.
36.
AbbVie.  R&D/13/030.  Combination of ABT-530 and ABT-493 in HCV replicon 
cells.  2013.
37.
AbbVie.  ABT-493 and ABT-530 Dose Combination Investigator's Brochure
Edition 2.  06 September 2016.
38.
Guidelines for Prevention and Treatment of Opportunistic Infections in 
HIV-Infected Adults and Adolescents.  Available from:  
http://aidsinfo.nih.gov/guidelines.
39.
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm.


ABT-493, ABT-530
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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.


ABT-493, ABT-530
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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.


ABT-493, ABT-530
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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Clinical
CPPM
Statistics
Bioanalysis
Clinical Drug Supply Management


ABT-493, ABT-530
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Appendix C.
Study Activities – Treatment Period
Activity
Screening
Day 
1a
Wk 
1
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 12 EOT*/Wk 16 EOT* or 
Premature D/C from Treatmentb
Informed Consentc
X
Medical Historyd
X
X
Physical Examination
X
X
X
Vital Signs, Weight, Waist Circumference,e Heighte
X
X
X
X
X
X
X
X
ECG 
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
X
X
X
X
X
X
X
FSHf
X
Pregnancy Test (serum [s] urine [u])g
X (s)
X (u)
X (u)
X (u)
X (u)
X (u)
HBsAgh HBV DNA h , HCV Ab, HIV Ab Tests
X
Drug/Alcohol Screen
X
HbA1Ci
X
HCV Genotype and Sub-genotype
X
FibroTest and APRI, FibroScan®j or Liver Biopsyj
X
IL28B Samplek
X
Optional Pharmacogenetic Samplec,k
X
Total Insulin
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
X
Adverse Event Assessmentl
X
X
X
X
X
X
X
X
Patient Reported Outcomes Instruments (PROs)m
X
X
X
Dispense Study Drug
X
X
X
Xn
Study Drug Accountabilityo and Review of Study Drug Adherence
X
X
Xo
Xo
Xo
Xo


ABT-493, ABT-530
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Activity
Screening
Day 
1a
Wk 
1
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 12 EOT*/Wk 16 EOT* or 
Premature D/C from Treatmentb
HCV RNA Sample
X
X
X
X
X
X
X
X
HIV-1 RNAp,q
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
Flow Cytometry Samplep
X
X
X
X
X
Pharmacokinetic Samples for subjects who do not participate in the 
Optional Intensive PK samplingr
X
X
X
X
X
X
Pharmacokinetic Samples for subjects who do participate in the 
Optional Intensive PK samplingr
Xs
X
X
Xs
X
X
X
Child-Pugh Score
X
X
Clinical Assessment of Hepatic Decompensation
X
HCC Screening:  Liver Ultrasound
X
Alpha Fetoprotein
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
*
The EOT visit can be at Weeks 12 or 16 depending on treatment assigned.
a.
All procedures to be performed prior to first dose, with exception of the additional (optional) post-dose pharmacokinetic samples (Section 5.3.2.1).
b.
Subjects who prematurely discontinue the Treatment Period should return to the site to complete the Premature Discontinuation Visit Procedures (preferably prior to the 
initiation of any other anti-HCV therapy).
c.
Subjects need to sign an IRB/IEC approved informed consent for the study (prior to performing any screening or study-specific procedures) and the optional Pharmacogenetic 
Sample and Intensive PK 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.  Waist circumference will be measured at the Screening Visit, but if it is not measured at Screening, it may be measured 
on Day 1.
f.
Only at Screening, for female subjects to assess postmenopausal state.


ABT-493, ABT-530
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g.
Pregnancy testing is not required for females of non-childbearing potential as defined in Inclusion Criterion 3. 
h.
Perform the test for HBV DNA if HBsAg is negative. 
i.
For those with history of diabetes mellitus. 
j.
For subjects who have not had a qualifying liver biopsy within the previous 24 months or a qualifying FibroScan® within the previous 6 months. 
k.
If the sample is not collected at Study Day 1, it may be collected at any other visit during the study.
l.
See specific information regarding adverse event collection in Section 6.1.4.
m.
PROs should be administered before any study procedures.  EOT PROs are at Week 12 EOT or Week 16 EOT, as applicable. 
n.
Applicable only to those subjects enrolled into a 16-week treatment. 
o.
Subjects should bring all the study drug to the study drug accountability visits at Weeks 4, 8, 12, EOT or Premature D/C.  The site will record the number of tablets returned 
only at these visits.
p.
HCV/HIV co-infected subjects only.
q.
For HCV/HIV co-infected subjects on stable ART:  As detailed in Section 5.4.1.2, a repeat HIV-1 RNA blood draw to confirm a HIV-a RNA result of ≥ 200 copies/mL can 
be done as an unscheduled visit, but must be performed at least 2 weeks apart from the prior HIV-1 RNA result.  At the time the repeat plasma HIV-1 RNA is drawn, a sample 
may be obtained for HIV-1 resistance testing.  If the confirmatory HIV-1 RNA lab draw falls on the date of a scheduled study visit, only a single HIV-1 RNA and HIV-1 
resistance blood draw is needed at the visit.
r.
Details regarding timing of PK samples are provided in Section 5.3.2.1.
s.
For subjects participating in Optional Intensive PK sampling, additional PK samples will be drawn on Study Day 1 at 2, 4 and 6 hours post-dose and on Week 4 visit 
immediately prior to dose (0 hour) and 2 and 4 hours post-dose during the visit.


ABT-493, ABT-530
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Study Activities – Post Treatment Period
Activity
PT Week 4
PT Week 12
PT Week 24 or PT D/Ca
Vital Signs and Weight
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
Xb
Pregnancy Test (urine)c
X (u)
X (u)b
Concomitant Medication Assessmentd
X
X
PRO Instrumentse
X
X
Adverse Event Assessmentf,g
X
X
X
HCV RNA Samples
X
X
X
HIV-1 RNAh,i
X
X
X
HCV Resistance Sample
X
X
X
Flow Cytometry Sampleh
X
X
X
Archive Plasma Sample
X
X
X
Child-Pugh Score
X
X
Alpha Fetoprotein
X
X
PT = Post Treatment
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT Discontinuation Visit procedures.
b.
Hematology/Chemistry/Urinalysis/Coagulation Panel and Pregnancy Test are only required at Post-Treatment Discontinuation if subject discontinued prior to PT Week 4.
c.
Pregnancy testing is not required in the PT Period for women that are not of childbearing potential.
d.
Only medications taken for SAEs and treatment of HCV and HIV will be collected after 30 days post-dosing.
e.
PROs should be administered before any study procedures.
f.
All AEs (whether solicited or spontaneously reported by the subject) will be collected until 30 days post dosing.


ABT-493, ABT-530
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g.
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) (Section 6.1.4).
h.
HCV/HIV co-infected subjects only.
i.
For HCV/HIV co-infected subjects on stable ART:  As detailed in Section 5.4.1.2, a repeat HIV-1 RNA blood draw to confirm a HIV-a RNA result of ≥ 200 copies/mL can 
be done as an unscheduled visit, but must be performed at least 2 weeks apart from the prior HIV-1 RNA result.  At the time the repeat plasma HIV-1 RNA is drawn, a sample 
may be obtained for HIV-1 resistance testing.  If the confirmatory HIV-1 RNA lab draw falls on the date of a scheduled study visit, only a single HIV-1 RNA and HIV-1 
resistance blood draw is needed at the visit.
Note:
Day 1 of the Post-Treatment Period will be defined as the day after the last dose of study drug.


ABT-493, ABT-530
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Appendix D.
List of AIDS-Associated Opportunistic Infections
Collection of data regarding known AIDS-associated opportunistic infections is covered 
in Section 6.1.8.
●
Aspergillosis
●
Bartonellosis
●
Candidiasis (*Bronchi; *Esophagus; *Lungs; Oropharyngeal [Thrush]; 
*Trachea; Vulvovaginal [Persistent, Frequent, or Poorly Responsive to 
Therapy])
●
*Coccidioidomycosis
●
*Cryptococcosis
●
*Cryptosporidiosis
●
Cytomegalovirus (*Retinitis; *Cytomegalovirus Disease [other than liver, 
spleen or nodes])
●
Enteric infections, Recurrent (Bacterial)
●
Herpes Simplex Virus (*Bronchitis; *Esophagitis; *Pneumonitis; *Chronic 
Ulcer[s] [> 1 month in duration])
●
*Histoplasmosis
●
Human Herpesvirus-8 Disease (Kaposi Sarcoma, Primary Effusion 
Lymphoma, Multicentric Castleman's Disease)
●
Human Papilloma Virus Infections
●
*Isosporiasis (Cystoisosporiasis)
●
Microsporidiosis
●
*Mycobacterium avium – Complex Disease (Disseminated)
●
*Mycobacterium tuberculosis – Infection and Disease
●
*Pneumonia
●
*Pneumonia, recurrent bacterial (and/or other respiratory infections including 
sinusitis, bronchitis, otitis)
●
*Progressive multifocal leukoencephalopathy (JC Virus Infection)
●
Syphilis


ABT-493, ABT-530
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●
*Toxoplasma Gondii Encephalitis
●
Varicella Zoster Virus Diseases
*
AIDS-defining event as described by CDC Surveillance Case Definition of 1993.
Note:
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871 htm.39



SAP_001.pdf: 
ABT-493, ABT-530
M15-593 Statistical Analysis Plan
Version 1.0 – 18 Jan 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M15-593
An Open-Label Study to Evaluate the Efficacy and 
Safety of ABT-493/ABT-530 in Treatment-Naïve and 
Treatment-Experienced Asian Adults With Chronic 
Hepatitis C Virus Genotype (GT) 1 to GT6 Infection 
With Compensated Cirrhosis and With or Without 
Human Immunodeficiency Virus Co-Infection
Date:  18 Jan 2018
Version 1.0
NCT03235349


ABT-493, ABT-530
M15-593 Statistical Analysis Plan
Version 1.0 – 18 Jan 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 7
4.4
Planned Analyses ................................................................................... 7
5.0
Analysis Populations .............................................................8
5.1
Definitions of 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, Final Treatment, and Final Post-Treatment 
Assessments ........................................................................................... 9
6.1.1
Baseline.................................................................................................. 9
6.1.2
Study Days........................................................................................... 10
6.2
Definition of Analysis Windows........................................................... 10
6.3
Missing Data Imputation ...................................................................... 14
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications.........................................15
7.1
Demographic and Baseline Characteristics ........................................... 15
7.2
Medical History.................................................................................... 24
7.3
Prior, Concomitant and Post-Treatment Medications ............................ 24
8.0
Subject Disposition..............................................................25
8.1
Disposition of Safety Population .......................................................... 25
9.0
Study Drug Exposure and Compliance..............................26
9.1
Exposure .............................................................................................. 26
9.2
Compliance .......................................................................................... 27


ABT-493, ABT-530
M15-593 Statistical Analysis Plan
Version 1.0 – 18 Jan 2018
3
10.0
Efficacy Analysis .................................................................27
10.1
General Considerations......................................................................... 27
10.2
Handling of Multiplicity....................................................................... 32
10.3
Primary Efficacy Analysis.................................................................... 32
10.4
Secondary Efficacy Analyses ............................................................... 33
10.5
Sensitivity Analyses for SVR12............................................................. 33
10.5.1
Imputation Approaches......................................................................... 34
10.6
Efficacy Subgroup Analysis ................................................................. 34
10.7
Additional Efficacy Analyses ............................................................... 36
10.8
Resistance Analyses ............................................................................. 38
10.9
Patient Reported Outcomes .................................................................. 44
11.0
Safety Analysis.....................................................................45
11.1
General Considerations......................................................................... 45
11.2
Analysis of Adverse Events.................................................................. 45
11.2.1
Treatment-Emergent Adverse Events.................................................... 45
11.2.2
Tabulations of Treatment-Emergent Adverse Events ............................ 46
11.2.3
Listings of Adverse Events................................................................... 50
11.3
Analysis of Laboratory Data................................................................. 50
11.3.1
Variables and Criteria Defining Abnormality........................................ 50
11.3.2
Statistical Methods ............................................................................... 54
11.4
Analysis of Vital Signs and Weight ...................................................... 55
11.4.1
Variables and Criteria Defining Abnormality........................................ 55
11.4.2
Statistical Methods ............................................................................... 56
11.5
Analysis of Child-Pugh Score............................................................... 57
11.6
Analysis of HIV-1 RNA and Flow Cytometry Data .............................. 57
12.0
Summary of Changes .......................................................... 58
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ............................................................................................... 58
13.0
References............................................................................60


ABT-493, ABT-530
M15-593 Statistical Analysis Plan
Version 1.0 – 18 Jan 2018
4
List of Tables
Table 1.
Analysis Time Windows for HCV RNA and Resistance 
Endpoints, Safety Laboratory and Vital Sign Measurements, 
Child-Pugh Score, and PRO Instruments (Treatment Period)................ 12
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 12
Table 3.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements, Child-Pugh Score, and PRO Instruments 
(Post-Treatment Period) ....................................................................... 13
Table 4.
Analysis Time Windows for HIV-1 RNA and Flow Cytometry 
Measurements (Treatment Period)........................................................ 13
Table 5.
Analysis Time Windows for HIV-1 RNA and Flow Cytometry 
Measurements (Post-Treatment Period)................................................ 14
Table 6.
Child-Pugh Classification of Severity of Cirrhosis................................ 19
Table 7.
Baseline Fibrosis Stage......................................................................... 20
Table 8.
Clinical Identification of Metabolic Syndrome ..................................... 21
Table 9.
Medical History Categories .................................................................. 22
Table 10.
List of Signature Amino Acid Positions and a Key Subset of 
Amino Acid Positions........................................................................... 39
Table 11.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values .................................................................................................. 52
Table 12.
Criteria for Potentially Clinically Significant Vital Sign Values............ 56
List of Figures
Figure 1.
Study Schematic..................................................................................... 7


ABT-493, ABT-530
M15-593 Statistical Analysis Plan
Version 1.0 – 18 Jan 2018
5
3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Statistics and Statistical Programming Departments for Study M15-593.  
Study M15-593 evaluates the efficacy, safety, and pharmacokinetics of 
ABT-493/ABT-530 in chronic hepatitis C virus (HCV) genotype (GT) 1 to GT6-infected 
Asian adult subjects with compensated cirrhosis with or without human 
immunodeficiency virus (HIV) co-infection who are HCV treatment-naïve or treatment-
experienced with interferon (IFN) (alpha, beta or pegylated-IFN [pegIFN]) with or 
without ribavirin (RBV) OR sofosbuvir (SOF) with RBV with or without IFN.
This SAP provides details to further elaborate the statistical methods outlined in Clinical 
Study Protocol M15-593 incorporating Administrative Change No. 1 dated 
02 October 2017 and Administrative Change No. 2 dated 12 January 2018, 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.
This SAP does not include the analysis plan for the pharmacokinetic data.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the efficacy (SVR12, [HCV RNA 
< lower limit of quantification {LLOQ} 12 weeks after the last actual dose of study drug]) 
and safety following 12 or 16 weeks of treatment with the ABT-493/ABT-530 
combination regimen in treatment-naïve and treatment-experienced adults with chronic 
HCV GT1 to GT6-infection with compensated cirrhosis and with or without HIV co-
infection.
The secondary objectives are to assess:
●
The percentage of subjects with on-treatment HCV virologic failure;


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●
The percentage of subjects with post-treatment relapse of HCV infection;
●
The percentage of HCV/HIV co-infected subjects achieving SVR12.
An additional objective is to assess the pharmacokinetics of ABT-493 and ABT-530 in 
Asian HCV-infected adults.
4.2
Design Diagram
This is a Phase 3, single-arm, open-label, multicenter study to evaluate the efficacy, safety 
and pharmacokinetics of ABT-493/ABT-530 in chronic HCV GT1 to GT6-infected Asian 
adult subjects with compensated cirrhosis with or without HIV co-infection who are HCV 
treatment-naïve or treatment-experienced with IFN (alpha, beta or pegIFN) with or 
without RBV OR sofosbuvir with RBV with or without IFN.  This study consists of a 
Treatment Period and a Post-Treatment (PT) Period.  The study schematic is presented in 
Figure 1.
The study is designed to enroll approximately 160 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
scientific and ethical considerations.  From China, a minimum of 60 GT1-infected 
subjects, a minimum of 36 GT2-infected subjects and approximately 24 GT3, 4, 5 or 
6-infected subjects will be enrolled into this study.  From the regional Asian country of 
South Korea, approximately 30 GT1-infected subjects and approximately 
10 GT2-infected subjects will also be enrolled into this study.  Of the approximately 
160 subjects, a maximum of 16 HCV/HIV co-infected subjects will be enrolled.


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Figure 1.
Study Schematic
All subjects in this study are to have compensated cirrhosis.  Treatment experienced 
GT3-infected subjects will receive 16 weeks of treatment; all other subjects will receive 
12 weeks of treatment.
4.3
Sample Size
It is planned to enroll approximately 160 subjects.  The sample size for this study is 
driven by the expected sample size requirements for each genotype and geographical 
region for this secondary indication.  No formal hypothesis is being tested in this study.  If 
the observed SVR12 rate in this study is 95% among 160 subjects, then the two-sided 95% 
confidence interval (CI) calculated using the normal approximation for a single binomial 
proportion is 91.6% to 98.4%.
4.4
Planned Analyses
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued the study.  The primary analysis will summarize data through 
PT Week 12.  The data for the primary analysis will be locked after data cleaning, and 
data collected after this lock will be added to a new version of the database.  Results from 
the primary analysis will be described in the primary clinical summary report (CSR) and 
submitted to regulatory agencies as part of a marketing authorization submission.


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The final analysis will be conducted after all subjects enrolled in the study have 
completed the PT Week 24 Visit or prematurely discontinued the study.  The data for the 
final analysis will be cleaned and locked at the end of the study and included in the final 
CSR.
All analyses will be conducted by statisticians and programmers at AbbVie (or their 
designees) according to the methodologies specified in this SAP.  There is no intention of 
shortening the follow-up time of subjects based on efficacy findings from the primary 
analysis.  All subjects who receive study drug will be followed for 24 weeks following 
treatment.  Therefore, no statistical adjustment will be employed due to the primary 
analysis.
5.0
Analysis Populations
5.1
Definitions of 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 and analyses of compliance data will be performed on 
the ITT population, unless otherwise specified.
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 of multiple genotypes 
according to the central laboratory or phylogenetic analyses  or subjects who received 
incorrect duration of treatment due to incorrect classification of GT or treatment 
experience at screening (mITT-GT), and on the mITT-GT population modified to exclude 
subjects who did not achieve SVR12 for reasons other than virologic failure (i.e., subjects 
with reasons other than on-treatment HCV virologic failure and relapse) (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.  Analyses of safety; demographics; baseline characteristics; medical history; 
prior, concomitant, and post-treatment medications; and study drug exposure will be 
performed on the safety population.  The safety population will be the same as the ITT 
population for this study.
5.2
Variables Used for Stratification of Randomization
This study is not randomized.  Eligible subjects will be enrolled into a single arm. 
Therefore, no variables were used for stratification of randomization.
6.0
Analysis Conventions
6.1
Definition of Baseline, Final Treatment, and Final
Post-Treatment Assessments
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.  The protocol specifies that all Day 1 assessments 
(other than intensive PK samples) are to be performed prior to administering the first dose 
of study drug.  Therefore, all Day 1 assessments for which time is not collected will be 
assumed to be pre-dose and the baseline value will be the last non-missing measurement 
collected on or before the first day of study drug administration.
All Day 1 assessments with time available must be before the time of first dose to be 
considered baseline, and the last non-missing measurement collected before the date and 
time of the first dose of study drug will be considered the baseline value.  If multiple 
measurements that are prior to dosing are recorded on the same date and with the same 
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 PT Periods.


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Safety assessments that are related to a serious adverse event that occurred on the 
first dose day are excluded when applying this algorithm.
6.1.2
Study Days
Study Days (Days Relative to the First Dose of Study Drug)
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 PT 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.


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For safety laboratory data, vital signs, Child-Pugh score, and PRO instruments, the time 
windows specified in Table 1 and Table 3 describe how data are assigned to protocol-
specified time points.
For samples of plasma HIV-1 RNA and flow cytometry (including but not limited to 
CD4+ T-cell and CD8+ T-cell counts [absolute and percent]), the time windows specified 
in Table 4 and Table 5 describe how data are assigned to protocol-specified time points.
If more than one assessment is included in a time window, the assessment closest (except 
in analyses of SVR) to the nominal time will be used.  If there are two observations 
equally distant to the nominal time, the latest one will be used in analyses.  For analyses 
of SVR (e.g., SVR12), the last value in the window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter, a 
vital sign parameter, or a flow cytometry 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, graded laboratory values and potentially clinically 
significant values, multiple values on the same day will not be averaged; all values will be 
considered for these analyses.


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Table 1.
Analysis Time Windows for HCV RNA and Resistance Endpoints, 
Safety Laboratory and Vital Sign Measurements, Child-Pugh 
Score, and PRO Instruments (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Week 16b
112
99 to 126
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 16-week treatment only.  
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the last dose of study drug.
Note:
For all windows, data must be on or before Study Drug End Day 2.  The result closest to the scheduled time 
point will be used.  PRO instruments are collected at Day 1, Week 4 and End of Treatment Visit; Total 
insulin, Child-Pugh score and alpha fetoprotein are collected at Day 1 and End of Treatment Visit.
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 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24b
168
127 to 999
SVR4
c
28
3 to 56
SVR12
c
84
57 to 126
SVR24
b,c
168
127 to 210
a.
PT Visits are applicable for subjects who received at least one dose of study drug.
b.
Not included in primary CSR.
c.
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.  For all 
windows, data must occur after Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the 
last dose of study drug.


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Table 3.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements, Child-Pugh Score, and PRO Instruments
(Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24b
168
127 to 999
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
PT Visits are applicable for subjects who received at least one dose of study drug.
b.
Not included in primary CSR.
c.
The last value within the PT Period window will be used to define the Final PT Visit value.  The lower bound of 
this Final window is Study Drug End Day 3.  Study Drug End Day 0 is defined as the day of the last dose of study 
drug.
Note:
The result closest to the scheduled time point will be used.  For all windows, data must occur after Study Drug 
End Day 2.  Vital signs are collected at every PT visit; hematology, chemistry, urinalysis, and coagulation 
panel are collected at PT Week 4 or PT D/C (if subject discontinued prior to PT Week 4); the coagulation 
panel, total bilirubin, and serum albumin are also collected at PT Week 12 and PT Week 24; PRO instruments, 
Child-Pugh score and alpha fetoprotein are collected at PT Week 12 and PT Week 24 (or PT/DC).
Table 4.
Analysis Time Windows for HIV-1 RNA and Flow Cytometry 
Measurements (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 2
14
2 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Week 16b
112
99 to 126
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug. 
b.
For 16-week treatment only.
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the last dose of study drug. 
Note:
Time windows specified in this table are for HCV/HIV co-infected subjects only.  For all windows, data must 
be on or before Study Drug End Day 2.  The result closest to the scheduled time point will be used.  Flow 
cytometry samples are collected at Day 1, Week 4, Week 12, and End of Treatment Visit. 


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Table 5.
Analysis Time Windows for HIV-1 RNA and Flow Cytometry 
Measurements (Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24b
168
127 to 999
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
Not included in primary CSR.
c.
The last value within the PT Period window will be used to define the Final PT Visit value.  The lower bound of 
this Final window is Study Drug End Day 3.  Study Drug End Day 0 is defined as the day of the last dose of study 
drug.
Note:
Time windows specified in this table are for HCV/HIV co-infected subjects only.  The result closest to the 
scheduled time point will be used.  For all windows, data must occur after Study Drug End Day 2.   
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.  A subject with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 


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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 PT 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.  
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. 
If a subject starts another treatment for HCV, then all PRO assessment values for this 
subject measured on or after the start date of the new HCV treatment will be excluded 
from analyses.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
The safety population will be used to summarize demographics and baseline 
characteristics, medical history and previous, concomitant, and PT medications for the set 
of all subjects and for the geographic region of China.
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects in each category.  Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean, 
standard deviation, median, maximum and minimum).


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Continuous demographic variables include age, weight, height, waist circumference, and 
body mass index (BMI).  Categorical demographic variables include sex, age category 
(< 65 or ≥ 65 years; < 75 or ≥ 75 years), BMI category (< 25, ≥ 25 to < 30, or 
≥30 kg/m2), race, ethnicity, type of Asian descent (Chinese or Korean), and geographic 
region. 
Continuous baseline characteristics include baseline log10 HCV RNA level, FibroTest 
score, alpha fetoprotein, homeostasis model of assessment – insulin resistance
(HOMA-IR), total INR, platelet count, albumin, GGT, LDL, HDL, APRI, FIB-4, AST, 
ALT, AST/ALT ratio, creatinine clearance (by Cockcroft-Gault formula, defined below), 
eGFR (using the modification of diet in renal disease [MDRD] formula modified for the 
Chinese population [C-MDRD], defined below), total, direct, and indirect bilirubin.
Categorical baseline characteristics include:
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (as determined by the 
central laboratory);
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (final HCV genotype 
and subtype as defined in Section 10.8);
●
Prior HCV treatment history (naïve or experienced);
○
For treatment-experienced subjects, type of prior treatment experience 
(IFN-based or SOF-based; subjects who received SOF will be categorized 
as SOF-based);
○
For treatment experienced subjects, type of non-response to previous 
treatment (on-treatment non-responder or breakthrough, post-treatment 
relapse, or unknown/other);
●
HCV genotype (as determined by the central laboratory) and prior HCV 
treatment history;
●
HCV genotype (final HCV genotype as defined in Section 10.8) and prior 
HCV treatment history;
●
Screening HIV co-infection status (HCV mono-infected or HCV/HIV
co-infected);


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●
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; < 10,000,000 or ≥ 10,000,000 IU/mL)
●
Baseline HOMA-IR (< 2 or ≥ 2 mU × mmol/L2);
●
Baseline platelet count (< 100 or ≥ 100 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline alpha fetoprotein (< 20 or ≥ 20 ng/mL);
●
Baseline Child-Pugh score (5, 6, or > 6);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, F4 [if 
applicable]);
●
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);
●
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Baseline stable opiate substitution use (yes/no);
●
Baseline hepato-protectant medication use (as determined by investigator on 
concomitant medication eCRF, yes/no);
●
Tobacco use (user, ex-user, or non-user);
●
Alcohol use (drinker, ex-drinker, or non-drinker); 
●
Baseline total bilirubin (< 34.2 or ≥ 34.2 umol/L);
●
Baseline total INR (< 1.7 or ≥ 1.7);
●
Baseline creatinine clearance (Cockcroft-Gault) (< 60, ≥ 60 to < 90, or 
≥90 mL/min);
●
Baseline eGFR (C-MDRD) (< 60, ≥ 60 to < 90, or ≥ 90 mL/min/1.73 m2);
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no).


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The demographic and baseline characteristics specified above, along with the following, 
will be summarized for subjects with HCV/HIV co-infection at Screening for the overall 
safety population and for the geographic region of China:
●
HIV-1 treatment status (antiretroviral therapy [ART]-Naïve, ART-Treated);
●
HIV-1 ART regimen (e.g., raltegravir [RAL], dolutegravir [DTG], rilpivirine 
[RPV]) for those receiving ART (as determined by investigator on 
concomitant medication eCRF) at baseline;
●
Baseline CD4+ T-cell count (continuous; and < 200, 200 to < 350, 350 to 
< 500, or ≥500 cells/mm3).
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 during the Screening 
period, then a result available from a sample collected at any time during the study will be 
used to summarize IL28B genotype.
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 Child-Pugh score is determined by the Day 1 assessment of ascites and hepatic 
encephalopathy along with the baseline values of total bilirubin, serum albumin, and 
international normalized ratio (INR).  The Child-Pugh score is the sum of the points 
assigned for each of the five observed findings as defined in Table 6.


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Table 6.
Child-Pugh Classification of Severity of Cirrhosis
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L 
(mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L 
(g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic 
encephalopathy**
None
Grade 1 or 2 
(or suppressed with 
medication)
Grade 3 or 4 (or 
refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
None:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Baseline 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 7.
All subjects in this study will be categorized as having cirrhosis (cirrhosis = yes) since 
this study excludes subjects who do not have cirrhosis.


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Table 7.
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 < 14.6
0.59 to 0.72
F4
4
≥ 5
≥ 14.6
≥ 0.73
Baseline APRI and FIB-4 are calculated by 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)
The central laboratory calculates the estimated creatinine clearance (CrCl) based on the 
following Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum 
creatinine (mg/dL) × 72].
The central laboratory calculates eGFR by C-MDRD using the following equation, where 
serum creatinine is measured in mg/dL and age is measured in years:
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine)–1.234 × (Age)–0.179 × (0.79 if 
female).


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Subjects will be classified as having metabolic syndrome if at least 3 of the 
5 characteristics in Table 8 are present.
Table 8.
Clinical Identification of Metabolic Syndrome
Risk Factor
Defining Level in Conventional Units
Defining Level in SI Units
Abdominal obesity, given as 
waist circumference
Men
> 40 in
> 102 cm
Women
> 35 in
> 88 cm
Triglycerides
≥ 150 mg/dL
≥ 1.695 mmol/L
HDL cholesterol
Men
< 40 mg/dL
< 1.03452 mmol/L
Women
< 50 mg/dL
< 1.29315 mmol/L
Blood pressure (BP)
Systolic BP ≥ 130 mm Hg or Diastolic BP ≥85 mm Hg
Fasting glucose
≥ 100 mg/dL
≥ 5.5507 mmol/L
Reference:  Grundy 20041
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA); the actual version of the MedDRA coding dictionary will be noted in the 
clinical study report.  Histories of diabetes, bleeding disorders, depression or bipolar 
disorder, and cardiovascular disease will be defined by a subject having medical history 
coded to at least 1 preferred term within any of the high level terms specified for the 
category in Table 9.


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Table 9.
Medical History Categories
Medical History eCRF
Category
MedDRA High Level Term
Name
Diabetes
Diabetic complications cardiovascular
Diabetic complications dermal
Diabetic complications gastrointestinal
Diabetic complications NEC
Diabetic complications neurological
Diabetic complications ophthalmic
Diabetic complications renal
Diabetes mellitus (incl subtypes)
Hyperglycaemic conditions NEC
Bleeding disorders
Coagulation factor deficiencies
Coagulopathies
Platelet disorders NEC
Thrombocytopenias
Coagulation disorders congenital
Depression or bipolar disorder
Depressive disorders
Bipolar disorders
Mood alterations with manic symptoms
Cardiovascular disease
Coronary artery disorders NEC
Ischaemic coronary artery disorders
Cardiac conduction disorders
Rate and rhythm disorders NEC
Supraventricular arrhythmias
Ventricular arrhythmias and cardiac arrest


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Table 9.
Medical History Categories (Continued)
Medical History eCRF
Category
MedDRA High Level Term
Name
Cardiovascular disease (continued)
Congenital cardiac malpositions and transpositions
Congenital cardiac structural defects NEC
Congenital cardiovascular disorders NEC
Cardiac disorders congenital NEC
Cardiac hypoplasias congenital
Cardiac malpositions congenital
Cardiac septal defects congenital
Cardiac valve disorders congenital
Cardiovascular disorders congenital NEC
Great vessel disorders congenital
Multiple cardiac abnormalities congenital
Persistent foetal circulation disorders
Heart failure signs and symptoms
Heart failures NEC
Left ventricular failures
Right ventricular failures
Accelerated and malignant hypertension
Renal hypertensions
Vascular hypertensive disorders NEC
Coronary necrosis and vascular insufficiency
Infectious myocarditis
Noninfectious myocarditis
Peripheral vasoconstriction, necrosis and vascular insufficiency
Aortic valvular disorders
Cardiac valve disorders NEC
Mitral valvular disorders
Pulmonary valvular disorders
Tricuspid valvular disorders
Aortic inflammatory disorders
Arterial inflammations
Vasculitides NEC


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7.2
Medical History
Medical history data will be coded using the MedDRA coding dictionary; the actual 
version of the MedDRA coding dictionary will be noted in the clinical study report.  
Medical history data will be summarized and presented using MedDRA System Organ 
Class (SOC) and preferred term.  The SOCs will be presented in alphabetical order and 
the preferred terms will be presented in alphabetical order within each SOC.  The number 
and percentage of subjects with a particular preferred term will be summarized.  Subjects 
reporting more than one preferred term within a SOC will be counted only once for that 
SOC.
7.3
Prior, Concomitant and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study 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.
Hepatoprotective medications taken at baseline will be summarized by generic drug name.
Prior medications will be divided into the following categories:
●
Prior HCV medications taken by treatment-experienced subjects;
●
Prior HIV medications taken by HCV/HIV co-infected subjects receiving ART 
(as determined by investigator on concomitant medication eCRF) at baseline;
●
All other prior medications for all treated subjects.
Concomitant medications will be divided into the following categories:
●
Concomitant HIV medications taken by HCV/HIV co-infected subjects;


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●
All other concomitant medications for all treated subjects.
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.  
8.0
Subject 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 and for subjects 
who screen failed within each geographic region (China and South Korea).
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized by 
investigator and across all investigators for the set of all subjects and by geographic 
region.
●
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 (if applicable at the time of 
analysis).
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF) for the set of all subjects and for 
the geographic region of China.  Similar summaries will be provided for discontinuations 
from the study.


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The number and percentage of subjects with reported study drug interruptions will be 
summarized for the set of all subjects and for the geographic region of China.  
Reasons for study drug interruptions will be presented in the CSR listings.
9.0
Study Drug Exposure and Compliance
9.1
Exposure
The safety population will be used to summarize duration of exposure to study drug for 
the set of all subjects and for the geographic region of China.  Duration of exposure is 
defined for each subject as the last study drug dose date minus the first study drug dose 
date plus 1 day.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will 
be presented for exposure during the treatment period.
Study drug duration will be summarized with frequencies and percentages using the 
following categories:
●
1 to 15 days
●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days
●
91 to 105 days
●
> 105 days
In addition, the number and percentage of subjects with study drug duration of ≥ 77 days 
and ≥ 105 days will be summarized.


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9.2
Compliance
At each Study Drug Dispensation visit the number of tablets dispensed is automatically 
calculated according to the number of bottles dispensed, and at each Study Drug 
Accountability visit (starting with the Week 4 visit), the total number of tablets 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 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.
The ITT population will be used to perform the summaries described above for the overall 
set of subjects and for the geographic region of China.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
A 2-sided significance level of 0.050 (when rounded to three decimal places) will be used 
to determine statistical significance (where applicable), and all efficacy analyses will be 
performed on the ITT population, unless otherwise specified.


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Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED " or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
IL28B rs12979860 will be resulted as C/C, C/T, or T/T by the central laboratory.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).


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


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Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analyses of relapse, completion of treatment is defined as a 
study drug duration of 77 days or greater for subjects assigned to 12 weeks of treatment 
and 105 days or greater for subjects assigned to 16 weeks of treatment.  If the last 
available post-treatment value is ≥ LLOQ, then the subject will be considered a relapse 
(i.e., will not require confirmation).
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of 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.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
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1.
On-treatment HCV virologic failure (see On-treatment HCV virologic failure
definition; if a subject meets both definitions of Breakthrough and EOT failure, 
he or she will be categorized as Breakthrough only);
2.
Relapse12;
3.
Prematurely discontinued study drug with no on-treatment HCV virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 77 days for subjects assigned to 12 weeks of treatment, and 
< 105 days for subjects assigned to 16 weeks of treatment] and did not meet the 
On-treatment HCV 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 HCV virologic failure (see On-treatment HCV virologic failure
definition; if a subject meets both definitions of Breakthrough and EOT failure, 
he or she will be categorized as Breakthrough only);
2.
Relapse12;
3.
Relapse24;
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
[study drug duration < 77 days for subjects assigned to 12 weeks of treatment, and 


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< 105 days for subjects assigned to 16 weeks of treatment] and did not meet the 
On-treatment HCV virologic failure or Relapse24 definitions);
5.
HCV reinfection (see definition described earlier);
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], [4], or [5]);
7.
Other (defined as any SVR24 non-responder not meeting the definitions of [1] –
[6]).
For the reasons for SVR12 and SVR24 nonresponse defined above, subjects are only to be 
counted in 1 category.  For example, the categories of premature discontinuation and 
reinfection are mutually exclusive.  Thus, subjects who are SVR12 or SVR24
nonresponders meeting the definition of HCV reinfection will be counted in the 
reinfection category and will not be counted in any other category (as in the example, 
even if such a subject appears to meet the definition of prematurely discontinued study 
drug with no on-treatment HCV virologic failure, the subject would be counted in the 
reinfection category only).
10.2
Handling of Multiplicity
There will be no hypothesis testing for the primary and secondary efficacy endpoints.  
Therefore, there will be no adjustment for multiple comparisons.
10.3
Primary Efficacy Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  The number and percentage of subjects in the ITT population 
achieving SVR12 will be summarized with a two-sided 95% CI, 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.2 No hypothesis 
will be tested.


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10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
the percentage of subjects with on-treatment HCV virologic failure (defined as 
On-treatment HCV virologic failure);
●
the percentage of subjects with post-treatment relapse (defined as Relapse12; 
subjects with reinfection will be summarized separately);
●
the percentage of HCV/HIV co-infected subjects (determined at Screening) 
achieving SVR12.
The numbers and percentages of subjects with on-treatment HCV virologic failure, 
post-treatment relapse (Relapse12), and SVR12will be calculated along with two-sided 
95% Wilson score CIs.2  
In addition, a summary of reasons for SVR12 non-response (e.g., on-treatment HCV 
virologic failure, relapse, re-infection, other) will be provided for the set of all subjects 
and for the set of HCV/HIV co-infected subjects.  Listings of subject numbers with reason 
for non-response will be prepared.
10.5
Sensitivity Analyses for SVR12
Two-sided 95% CIs for the primary endpoint SVR12 rate will be calculated using both the 
normal approximation to the binomial distribution and the Wilson score method.2
Analyses of the primary endpoint will also be performed on the mITT-GT and 
mITT-GT-VF populations.  Both two-sided 95% normal approximation and Wilson score 
CIs will be provided for each of these sensitivity analyses.
The analyses described above will also be performed for the geographic region of China.
For each sensitivity analysis, a two-sided 95% CI will be produced only if there are at 
least 10 subjects in the summary.


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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 in the ITT population 
will be presented using the following other methods to impute missing HCV RNA values:
●
impute 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 
virologic failure" or "missing follow-up data in the SVR12 window" as 
successes.
For each of these, the number and percentage of subjects with SVR12 will be presented 
along with two-sided 95% CIs using both the normal approximation to the binomial 
distribution and the Wilson score method.  These analyses will be performed for the set of 
all subjects and for the geographic region of China.
10.6
Efficacy Subgroup Analysis
Subgroup analyses will be performed for the primary efficacy endpoint of SVR12.
Within each subgroup, the number and percentage of subjects achieving SVR12 will be 
calculated for the ITT population.  The 2-sided 95% Wilson score CI will be produced if 
there are at least 10 subjects in the subgroup.
The following subgroups will be analyzed:
●
HCV genotype (1, 2, 3, 4, 5, or 6) and available subtype (based on the latest 
determination of genotype from the baseline sample [by the central laboratory 
or by phylogenetic analysis, with preference given to the phylogenetic analysis 
results] at the time of the primary SVR12 analysis);


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●
Prior HCV treatment history (treatment-naïve or treatment-experienced);
●
For treatment-experienced subjects, type of prior treatment experience (IFN-
or SOF-based);
●
For treatment experienced subjects, type of non-response to previous treatment 
(on-treatment non-responder or breakthrough, post-treatment relapse, or 
unknown/other);
●
Screening HIV co-infection status (HCV mono-infected or HCV/HIV co-
infected);
●
IL28B genotype (CC or non-CC);
●
Sex (male or female);
●
Age (< 65 or ≥ 65 years) and (< 75 or ≥ 75 years);
●
Geographic region (China or South Korea);
●
Type of Asian descent (Chinese or Korean);
●
Baseline BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA level (< 1,000,000 or ≥ 1,000,000 IU/mL; < 6,000,000 or 
≥ 6,000,000 IU/mL; < 10,000,000 or ≥ 10,000,000 IU/mL);
●
Baseline HOMA-IR (< 2 or ≥ 2 mU × mmol/L2);
●
Baseline platelet count (< 100 or ≥ 100 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline alpha fetoprotein (< 20 or ≥ 20 ng/mL);
●
Baseline Child-Pugh score (5, 6, or > 6);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, or ≥ 90 mL/min);
●
Baseline eGFR by C-MDRD (< 60, ≥ 60 to < 90, or ≥ 90 mL/min/1.73 m2);
●
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);
●
Injection drug use (yes, within last 12 months; yes, more than 12 months ago; 
or no);


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●
Baseline stable opiate substitution use (yes/no);
●
Baseline hepato-protectant medication use (yes/no);
●
Study drug compliance (yes/no);
●
Concomitant use of PPIs (yes/no).
The summaries described above will be performed for the set of all subjects and for the 
geographic region of China.
A logistic regression model will be used to explore the associations between each of the 
subgroup variables and SVR12 by fitting a logistic regression model on all subjects in the 
mITT-GT-VF population.  Among all candidate predictors, continuous measurements will 
be used where possible (e.g., continuous baseline log10 HCV RNA level, continuous age, 
continuous BMI) in the logistic regression model.  A stepwise logistic regression 
approach will be used to assess the strength of each subgroup variable in predicting 
SVR12, with a significance level of 0.10 to enter and remain in the model.
10.7
Additional Efficacy Analyses
The ITT population will be used to summarize the following additional efficacy endpoints 
for the set of all subjects and for the geographic region of China:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects with SVR4;
●
A summary of reasons for SVR4 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection, other);
●
The percentage of subjects with HCV virologic failure through PT Week 12 
(i.e., the SVR12 non-responders due to on-treatment virologic failure or 
Relpase12);
●
The percentage of subjects with SVR24*;
●
A summary of reasons for SVR24 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection, other)*;


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●
The percentage of subjects who relapsed after achieving SVR12 (Relapse24).
*
These endpoints will be summarized for the HCV/HIV co-infected subjects (determined at Screening) within the 
populations/groups identified above.
In the above analyses for SVR, HCV virologic failure, and relapse, the number and 
percentage of subjects along with a two-sided 95% Wilson score CI will be calculated.  
Imputations for missing data will be performed as described in Section 6.3 for analysis of 
SVR, HCV virologic failure, and relapse.  All other endpoints will be presented using data 
as observed.  
As additional endpoints, the secondary endpoints will be summarized for the geographic 
region of China.  A summary of the subjects who completed treatment and relapsed 
(defined as Relapseoverall) will be prepared displaying the number of subjects relapsing 
overall and by SVR visit window (within the SVR4, SVR12, SVR24 windows or after 
SVR24 window), including the subject number and the SVR visit window corresponding 
to the first HCV RNA value of those indicating the occurrence of relapse.  A similar 
listing will be prepared for subjects who prematurely discontinued treatment and relapsed 
after having HCV RNA < LLOQ at their Final Treatment Visit.  These summaries will be 
performed for the overall ITT population and for the geographic region of China within 
the ITT population.
Listings of subject numbers with reason for non-response will be prepared for the SVR 
endpoints.
The concordance between SVR12 and SVR24 will be assessed by the agreement between 
SVR12 and SVR24 and the positive predictive value (PPV) and negative predictive value 
(NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is a percentage 
defined as the number of subjects achieving both SVR12 and SVR24 and the number of 
subjects where both SVR12 and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is 
the proportion of subjects who achieve SVR24 out of all subjects who achieved SVR12.  
The NPV of SVR12 on SVR24 is the proportion of subjects who do not achieve SVR24 out 
of all subjects who did not achieve SVR12.  Similarly, the concordance between SVR4 and 


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SVR12 will be summarized.  These summaries will be performed for the overall ITT 
population and for the geographic region of China within the ITT population.
For each additional analysis, if applicable, a two-sided 95% CI will be produced only if 
there are at least 10 subjects in the summary.
10.8
Resistance Analyses
For subjects who enroll in South Korea, full length NS3/4A and NS5A from baseline 
samples will be sequenced by next generation sequencing (NGS).  For subjects who enroll 
in South Korea who experience HCV virologic failure (on-treatment HCV 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 next generation sequencing (NGS).  For genotype 1-infected 
subjects experiencing virologic failure who enroll in China, amino acids 1 – 181 in NS3 
and 1 – 215 in NS5A from the baseline sample and the first sample after virologic failure 
with HCV RNA ≥ 1000 IU/mL will be sequenced by population sequencing.  An 
appropriate subtype-specific prototypic reference sequence will be used for comparison 
with sequences from samples.  Subjects who experience HCV 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 HCV virologic failure, and HCV RNA value at 
the HCV virologic failure 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 from South Korea and GT1-infected subjects from China treated with active 
study drug who do not achieve SVR12 and who do not meet the above criteria for the PVF 
population (i.e., prematurely discontinue study drug with no on-treatment HCV virologic 
failure, have HCV reinfection, are missing SVR12 data or have other reasons as described 


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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.  For subjects who are lost to follow-up with less than 6 weeks of therapy 
while not virally suppressed (e.g., HCV RNA never < LLOQ or have increase in viral 
load post-nadir), the sample at the latest available time point with HCV RNA 
≥1000 IU/mL and the corresponding baseline sample will be 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.  For each DAA 
target, signature amino acid positions and a key subset of amino acid positions are shown 
in Table 10.  Appropriate subtype-specific prototypic reference sequences will be used for 
comparison with sequences from samples.
Table 10.
List of Signature Amino Acid Positions and a Key Subset of Amino 
Acid Positions
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1, NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 132 
(GT1a only), 155, 156, 158, 168, 170, 175 (GT1b only)
155, 156, 168
GT1, NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 93
GT2, 4, 5, 6, 
NS3
36, 43, 54, 55, 56, 80, 155, 156, 168
155, 156, 168
GT2, 4, 5, 6, 
NS5A
24, 28, 29, 30, 31, 32, 58, 62, 92, 93
24, 28, 30, 31, 58, 92, 93
GT3, NS3
36, 43, 54, 55, 56, 80, 155, 156, 166, 168
155, 156, 168
GT3, NS5A
24, 28, 29, 30, 31, 32, 58, 92, and 93
24, 28, 30, 31, 58, 92, 93
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 


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with an HCV RNA level of ≥ 1000 IU/mL, and 2) 24 weeks post-DAA treatment, 
provided that resistance-associated substitutions were detected at the time of 
failure/discontinuation.
The following definitions will be used in the resistance analyses by population 
sequencing:
●
Baseline polymorphism:  a polymorphism 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 substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline in the subject.
The following definitions will be used in the resistance analyses by NGS:
●
Baseline polymorphism:  a polymorphism in a baseline sample (≥ 2% or 
≥15% prevalence within a subject's viral population depending on frequency 
threshold utilized) that was not present in the appropriate prototypic reference 
amino acid sequence for a given DAA target (NS3/4A or NS5A).
●
Substitution at signature amino acid position:  substitution (relative to 
reference) present at a detection threshold of ≥ 2% or ≥ 15% (depending on 
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 substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the sample.
●
Enriched substitution:  a substitution present at both baseline and in a post-
baseline sample whose prevalence in the post-baseline sample is at least 
20 percentage points greater than the prevalence in the baseline sample 
[(post-baseline % – baseline %) ≥ 20].
●
Treatment-emergent substitution by NGS: a post-baseline substitution or an 
enriched substitution.


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Analysis will be performed separately for each HCV subtype and treatment duration 
within each listing
Analysis 1:  The following analyses will be performed for subjects who enroll in South 
Korea:
●
A listing of all baseline polymorphisms (≥ 2% detection threshold) at signature 
amino acid positions for each DAA target (NS3 and NS5A) (ITT population). 
●
The number and percentage of subjects with baseline polymorphisms at 
detection-thresholds of ≥ 2% and ≥ 15% at signature amino acid positions (ITT 
population).  This table includes prevalence of each baseline polymorphism, 
and a summary of number of subjects with polymorphisms in NS3 only, in 
NS5A only, any in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 and 
NS5A.
●
Total number and percentage of subjects with baseline polymorphisms at the 
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 and NS5A (ITT population) 
by genotype, subtype, and total.
Analysis 2:  The impact of baseline polymorphisms on treatment outcome will be 
assessed for mITT-GT-VF population for subjects who enroll in South Korea as follows:  
for each polymorphism, the SVR12 rate will be calculated for subjects with and without 
the polymorphism and the 2 rates will be compared using Fisher's exact test.  Analysis 
will be grouped by HCV subtype, treatment duration, and DAA target (NS3 or NS5A).  
The following will be included in the analyses of impact of baseline polymorphisms on 
treatment outcome:
●
Polymorphisms at signature amino acid positions (vs. no polymorphisms at 
that position), using detection thresholds of both ≥ 2% and ≥ 15%.  The 
analysis will include the number of subjects with polymorphisms in NS3 only, 
in NS5A only, any in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + 
NS5A.


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●
Each polymorphism at signature amino acid position (vs not that 
polymorphism) using detection thresholds of ≥ 2% and ≥ 15%.  The analysis 
will include the number of subjects with polymorphisms in NS3 only, in NS5A 
only, any in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A.
Analysis 3:
In subjects who enroll in South Korea, the SVR12 rate will be calculated and compared 
using Fisher's exact test between subjects with or without polymorphisms at 15% 
detection threshold in NS3 only, in NS5A only, any in NS3, any in NS5A, any in NS3 or 
NS5A, any in NS3 and NS5A at the key subset of amino acid positions.  Analysis will be 
performed by HCV genotype, subtype, and overall on the mITT-GT-VF population.
Analysis 4:
The following analyses will be performed for subjects who enroll in South Korea 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 substitutions relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3 and 
NS5A). 
●
Listings by subject of all substitutions at signature amino acid positions in a 
post-baseline time point for each DAA target (NS3 and NS5A).
Analysis 5:  For subjects who enroll in China who experience virologic failure and 
have sequence data available, the following analyses will be conducted:
●
A listing of all baseline polymorphisms at signature amino acid positions for 
each DAA target (NS3 and NS5A). 
●
Listings by subject of all post-baseline substitutions relative to the baseline 
amino acid sequence will be provided for each DAA target (NS3 and NS5A).
●
Listings by subject of all emerged substitutions, by amino acid position and 
substitution within a DAA target in a post-baseline sample relative to the 


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baseline amino acid sequence will be provided for each DAA target (NS3 and 
NS5A).
●
Listings by subject of all post-baseline substitutions at signature amino acid 
positions relative to the appropriate prototypic reference amino acid sequence 
will be provided for each DAA target (NS3 and NS5A).
If resistance-associated substitutions are not detected in a given target for a subject at the 
time of failure/discontinuation, then that target may not be sequenced in subsequent 
samples from that subject.
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequence from all available baseline 
samples from subjects who enroll in South Korea and genotype 1-infected subjects 
experiencing virologic failure who enroll in China in order to accurately determine 
subtype.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A, and/or NS5A sequences performed by AbbVie.  If the 
phylogenetic analysis is available, then it will be used to determine the subject's HCV 
genotype and subtype.  If it is not available, then the Sanger sequencing assay result will 
be used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis result nor the Sanger sequencing assay results is 
available, then the Inno-LIPA assay results will be used to categorize the subject.  This 
subtype information will be 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.


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HIV Drug-Resistance Analyses
If any subject on stable HIV-1 ART develops a confirmed, quantifiable plasma HIV-1 
RNA level (HIV-1 RNA ≥ 200 copies/mL at one assessment and ≥ 500 copies/mL on 
repeat testing) after starting the study, the HIV-1 protease, reverse transcriptase and/or 
integrase sequences, as applicable, will be analyzed by Monogram Biosciences using the 
GenoSure® Prime drug resistance assays for subjects from South Korea.  The number of 
subjects who demonstrate HIV genotypic resistance and the genotypic resistant mutations 
detected in the samples obtained from these subjects will be tabulated and summarized in 
the final CSR, as applicable.  Resistance will be defined as described by the IAS-USA 
Panel.3
10.9
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs): 
EuroQol-5 Dimensions-3 Level (EQ-5D-3L) and Fatigue Severity Scale (FSS).
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.4,5  The VAS score will be analyzed separately.  For EQ-5D-3L index and VAS 
scores, no imputation will be performed for missing items.
The FSS measures the impact of fatigue over the past week on specific types of 
functioning.  The survey consists of 9 questions using a 7-point Likert scale.  A total score 
is calculated as the average of the individual item responses (adding up all the answers 
and dividing by nine).  Higher FSS scores indicate a higher degree of impact of fatigue.  
Imputation will be applied to the total score as described in Section 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 EQ-5D-3L health index score 
and VAS score and for the FSS total score.


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The number and percentage of subjects who have ever experienced an increase from 
baseline in the FSS total score of greater than or equal to 0.7 through each applicable 
timepoint will also be calculated, along with two-sided 95% CIs based on the normal 
approximation to the binomial distribution.
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.
The ITT population will be used to perform the analyses described above for the set of all 
subjects and for the geographic region of China.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized using the safety population.  Safety data will be 
summarized for the set of all subjects and for the geographic region of China.
11.2
Analysis of Adverse Events
Adverse events (AEs) will be coded using the MedDRA coding dictionary.  The actual 
version of the MedDRA coding dictionary will be noted in the CSR.
HIV-1-infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  A list of these known AIDS-associated opportunistic infections 
(OIs) is contained in Appendix D of the study protocol.  AEs that are identified by the 
investigators as AIDS-associated OIs will not be included in any analyses of AEs, but will 
be summarized separately for the HCV/HIV co-infected subjects.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with an onset date that is after the 
first dose of study drug and no more than 30 days after the last dose of study drug.  Events 
where the onset date is the same as the study drug start date are assumed to be treatment-


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emergent.  If an incomplete onset date was collected for an AE, the event will be assumed 
to be treatment-emergent, unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term.  The SOCs will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.
Subjects reporting more than one AE for a given preferred term will be counted only once 
for that term (most severe/highest grade incident for the severity tables and most related 
incident for the relationship tables).  Subjects reporting more than one AE within a SOC 
will be counted only once for that SOC.  Subjects reporting more than one AE will be 
counted only once in the overall total.
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; this 
overview will also be presented for the set of HCV/HIV co-infected subjects within the 
populations/groups specified in Section 11.1:
●
Any treatment-emergent AE;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (ABT-493/ABT-530);
●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (ABT-493/ABT-530);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (ABT-493/ABT-530);


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●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Events by SOC and Preferred Term
The following summaries of AEs by SOC and preferred term will be generated:
●
Treatment-emergent AEs (will also be presented for the set of HCV/HIV 
co-infected subjects);
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (ABT-493/ABT-530);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent AEs leading to discontinuation of study drug;
●
DAA-related treatment-emergent AEs leading to discontinuation of study 
drug;
●
Serious treatment-emergent AEs leading to discontinuation of study drug;
●
Treatment-emergent AEs leading to interruption of study drug;
●
Treatment-emergent AEs leading to death.
A listing of treatment-emergent AEs grouped by SOC and preferred term with subject 
numbers will be created.


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Adverse Events by Preferred Term
The following summaries of AEs tabulated according to preferred term and sorted by 
overall frequency will be generated:
●
Treatment-emergent AEs (will also be presented for the set of HCV/HIV 
co-infected subjects within the populations/groups specified in Section 11.1);
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
DAAs (ABT-493/ABT-530);
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to DAAs (ABT-493/ABT-530);
●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to DAAs (ABT-493/ABT-530).
Adverse Events by Maximum Severity Grade Level
Treatment-emergent AEs and DAA-related treatment-emergent AEs will be summarized 
by maximum severity grade level of each preferred term.  Each AE will be assigned a 
grade level (Grade 1, 2, 3, 4, or 5) by the investigator.  If a subject has an AE with 
unknown severity, then the subject will be counted in the severity grade level category of 
"unknown," even if the subject has another occurrence of the same event with a severity 
present.  The only exception is if the subject has another occurrence of the same AE with 
the highest grade level (Grade 5).  In this case, the subject will be counted under the 
"Grade 5" category.
Adverse Events by Maximum Relationship
Treatment-emergent AEs also will be summarized by maximum relationship of each 
preferred term to study drug (DAAs), as assessed by the investigator.  If a subject has an 
AE with unknown relationship, then the subject will be counted in the relationship 
category of "unknown," even if the subject has another occurrence of the same event with 


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a relationship present.  The only exception is if the subject has another occurrence of the 
same AE with a relationship assessment of "Reasonable Possibility."  In this case, the 
subject will be counted under the "Reasonable Possibility" category.
Adverse Events of Special Interest
The AEs of special interest include the following:
●
"Hepatic Decompensation and Hepatic Failure" defined by the Product 
MedDRA Query (PMQ);
●
"Hepatocellular Carcinoma" defined by the MedDRA preferred terms: 
hepatocellular carcinoma, hepatic neoplasm, hepatic cancer, hepatic cancer 
recurrent, and hepatic cancer metastatic.
For the hepatic decompensation/hepatic failure AE of special interest, the number and 
percentage of subjects experiencing at least one treatment-emergent AE in the search will 
be presented by SOC and preferred term and across all SOCs/preferred terms.  In addition, 
a by-subject listing of treatment-emergent AEs meeting the search criterion will be 
provided.
For the hepatocellular carcinoma AE of special interest, a by-subject listing of all post-
baseline (i.e., including both treatment-emergent and non-treatment emergent) AEs 
meeting the search criterion will be provided.
Adverse Events by HIV-1 ART Regimen
For the HCV/HIV co-infected subjects who were on HIV-1 ART at initiation of study 
drug, treatment-emergent AEs also will be summarized for the subgroups defined by the 
HIV-1 ART regimen (e.g., RAL, DTG, RPV) the subjects were receiving at study drug 
initiation.  For each HIV-1 ART regimen, the number and percentage of subjects 
experiencing treatment-emergent AEs will be tabulated according to SOC and preferred 
term.


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AIDS-Associated Opportunistic Infections
The number and percentage of subjects experiencing treatment-emergent AIDS-associated 
OIs will be tabulated according to SOC and preferred term for the HCV/HIV co-infected 
subjects (determined at Screening).  Subjects reporting more than one AIDS-associated OI 
for a given preferred term will be counted only once for that term.  Subjects reporting 
more than one AIDS-associated OI within a SOC will be counted only once for that SOC.  
Subjects reporting more than one AIDS-associated OI will be counted only once in the 
overall total.
11.2.3
Listings of Adverse Events
The following listings of AEs will be prepared:
●
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
●
Treatment-emergent serious AEs,
●
Treatment-emergent AEs leading to death,
●
Treatment-emergent AEs leading to discontinuation of study drug,
●
Treatment-emergent AEs leading to study drug interruption,
●
AEs (treatment-emergent or all, as applicable) in each of the AEs of special 
interest categories,
●
Treatment-emergent AIDS-associated OIs.
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to a serious AE, will be used in all analyses.
11.3.1
Variables and Criteria Defining Abnormality
Hematology variables to be summarized 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 


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(PT), international normalized ratio (INR), and activated partial thromboplastin time 
(aPTT).
Chemistry variables to be summarized 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, uric acid, cholesterol, total protein, glucose, triglycerides, albumin, chloride, 
bicarbonate, magnesium, total insulin, gamma-glutamyl transferase (GGT), alpha 
fetoprotein, creatinine clearance (calculated using Cockcroft-Gault), estimated glomerular 
filtration rate (eGFR) calculated using the modification of diet in renal disease (MDRD) 
formula modified for the Chinese population (C-MDRD), and creatine phosphokinase 
(CPK).
Urinalysis variables to be summarized include:  specific gravity and pH.
The definitions of toxicity grades for laboratory parameters are presented in Table 11.


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Table 11.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
White blood 
cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Absolute 
Neutrophil 
Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN –
75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 
109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Glucose (high)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 –
27.8 mmol/L
> 27.8 mmol/L
Glucose (low)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
eGFR 
(C-MDRD)
< LLN –
60 mL/min/1.73 m2
< 60 –
30 mL/min/1.73 m2
< 30 –
15 mL/min/1.73 m2
< 15 mL/min/1.73 m2
Cholesterol
> ULN –
7.75 mmol/L
> 7.75 – 10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Lymphocyte
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
aPTT
> ULN – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Sodium (low)
< LLN – 130 mmol/L
--
< 130 – 120 mmol/L
< 120 mmol/L
Sodium (high)
> ULN –
150 mmol/L
> 150 – 155 mmol/L
> 155 – 160 mmol/L
> 160 mmol/L
Potassium (low)
< LLN – 3.0 mmol/L
--
< 3.0 – 2.5 mmol/L
< 2.5 mmol/L
Potassium 
(high)
> ULN – 5.5 mmol/L
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L
> 7.0 mmol/L


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Table 11.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values 
(Continued)
Test
Grade 1
Grade 2
Grade 3
Grade 4
Triglycerides
> 1.71 –
3.42 mmol/L
> 3.42 – 5.7 mmol/L
> 5.7 – 11.4 mmol/L
> 11.4 mmol/L
Magnesium 
(low)
< LLN – 0.5 mmol/L
< 0.5 – 0.4 mmol/L
< 0.4 – 0.3 mmol/L
< 0.3 mmol/L
Magnesium 
(high)
> ULN –
1.23 mmol/L
--
> 1.23 –
3.30 mmol/L
> 3.30 mmol/L
CPK
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 10 × ULN
> 10 × ULN
Assessments of hepatotoxicity will be made based on a single laboratory parameter 
collected at any post-baseline visit through the Final Treatment visit using the following 
criteria:
●
ALT > 5 × ULN and ≥ 2 × baseline;
●
Total bilirubin ≥ 2 × ULN and > baseline;
●
Total bilirubin ≥ 2 × ULN and > baseline and direct/total bilirubin ratio > 0.4;
●
Increase from nadir by grade in ALT: 
○
ALT > 3 – 5 × ULN (Grade 2);
○
> 5 – 20 × ULN (Grade 3);
○
> 20 × ULN (Grade 4).
The direct/ total bilirubin ratio will be calculated using the same date/time sample 
corresponding to the total bilirubin elevation.  For the summary of increase from nadir by 
grade in ALT, the post-baseline value must represent an increase from the first nadir 
(including baseline) to be counted, where the grade of the post-baseline value must be 
more extreme than the grade of the nadir value.  First nadir is defined as the last value 
prior to the first increase.  The maximum ratio relative to the ULN will be used to 
determine if subjects meet the criteria listed above.


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Assessments of hepatotoxicity will also be made based on multiple laboratory parameters 
collected at any post-baseline visit through the Final Treatment visit using the following 
criterion:
●
ALT > 3 × ULN (Grade 2+ and increase from nadir grade) and total bilirubin 
≥2 × ULN.
For the criterion based on multiple laboratory parameters, the analysis will check to see if 
the subject meets the ALT and total bilirubin portions of the criterion at any time within 
the Treatment Period (i.e., draw dates do not need to be concurrent).  The maximum ratio 
relative to the ULN for each parameter will be used to determine if the subject meets the 
criterion listed above.  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.  The grade of the post-baseline ALT value must be at least
Grade 2 and more extreme than the grade of the nadir value.  For total bilirubin, a subject 
or event will be counted if the post-baseline laboratory values meet 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).
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 all 
summaries of the data from the Treatment and Post-Treatment Period visits.
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; and change from baseline 
mean, standard deviation, minimum, median, and maximum. 
Plots of mean change (± standard error) from baseline to each visit will be presented for 
ALT and bilirubin (total, direct, and indirect).


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Hematology and chemistry data values will be categorized as low, normal, or high based 
on the normal ranges of the laboratory used for each sample.  Shift tables from baseline to 
minimum value and from baseline to maximum value during treatment (Study Drug End 
Day ≤ 2) will be created.  The shift tables will cross-tabulate the frequency of subjects 
with baseline values below/within/above the normal range versus minimum/maximum 
post-baseline values below/within/above the normal range. 
The laboratory parameters listed in Table 11 will be categorized according to the toxicity 
grades defined in the table.  The number and percentage of subjects with a maximum 
toxicity grade of 1, 2, 3 or 4 during treatment will be calculated.  To be counted, the 
post-baseline value must have a toxicity grade that is more extreme than the toxicity grade 
corresponding to the baseline value.  For each laboratory parameter in Table 11, the 
summary will also include the number and percentage of subjects with a maximum of at 
least Grade 3.  These summaries will also be presented for the set of HCV/HIV 
co-infected subjects (determined at Screening) within the populations/groups specified in 
Section 11.1.  A listing of all relevant laboratory parameters will be provided for each 
subject who had an increase to Grade 2 or higher for any laboratory variable in Table 11.
For the assessments of hepatotoxicity based on single and multiple laboratory parameters, 
the number and percentage of subjects meeting the criterion during treatment will be 
calculated for each criterion.  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 single or multiple 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 (or ALT Grade 2+) and total bilirubin 
≥2 × ULN.
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 (PCS) vital sign findings are presented in 
Table 12.
Table 12.
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 all summaries of the 
data from the Treatment and Post-Treatment Period visits.
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; and 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 PCS vital sign values (Table 12) will be calculated.  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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11.5
Analysis of Child-Pugh Score
Child-Pugh scores will be categorized as 5, 6, > 6, or missing at baseline and each 
protocol-specified post-baseline visit, including applicable post-treatment visits.  Shift 
tables from baseline to each post-baseline visit will be created.  The shift tables will cross-
tabulate the frequency of subjects with baseline values in each category versus the post-
baseline categories.  For each baseline category and across the baseline categories, the 
percentage of subjects in each post-baseline category (excluding the post-baseline 
category of missing) will be calculated. 
11.6
Analysis of HIV-1 RNA and Flow Cytometry Data
Plasma HIV-1 RNA will be measured by the central laboratory using the Roche COBAS 
AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0.  For specimens with HIV-1 RNA 
results that are detectable but not quantifiable, the results are reported as "< 20 CP/ML 
HIV-1 RNA DETECTED;" for specimens with no HIV RNA detected, the results are 
reported as "NO HIV-1 RNA DETECTED."  Subjects will also have blood samples 
drawn and archived.  These samples may be used for other analyses including drug 
resistance testing.  These samples may be tested at the discretion of AbbVie.
For the HCV/HIV co-infected subjects (determined at Screening) who are on HIV-1 ART 
at initiation of study drug, the number and percentage of subjects with 2 consecutive 
HIV-1 RNA values ≥ 200 copies/mL during the Treatment Period will be calculated; only 
data from the central laboratory will be included in this analysis.  A listing of subjects 
with a plasma HIV-1 RNA value ≥ 200 copies/mL at any baseline or post-baseline visit 
during the study will be provided.
For the HCV/HIV co-infected subjects (determined at Screening), changes from baseline 
to each post-baseline visit, including applicable post-treatment visits, in CD4+ T-cell 
count (absolute and percentage), CD8+ T-cell count (absolute and percentage), and 
lymphocytes (count) will be summarized.  Each parameter will be summarized with the 
sample size; baseline mean; visit mean; and change from baseline mean, standard 
deviation, minimum, median, and maximum.


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12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP
1.
Modified the definitions of the mITT populations to also exclude subjects who 
received incorrect duration of treatment due to incorrect classification of GT or 
treatment experience at enrollment.
2.
Removed the analyses of demographics, baseline characteristics, study drug 
exposure and compliance for the mITT populations because it is expected that 
these populations will be very similar to the ITT population.
3.
Replaced analyses by geographic region with analyses for the geographic region of 
China because analyses for the subset of subjects from China, rather than analyses 
by geographic region, are required by the regulatory agency.  Certain analyses of 
subject disposition and SVR12 will be performed by geographic region.
4.
Added additional analyses of categorical baseline characteristics for subjects with 
HCV/HIV co-infection at Screening to provide additional information for the 
HCV/HIV co-infected population.
5.
Added analyses of SVR12 for the geographic region of China to sensitivity analysis 
to address regulatory requirements for China-specific analyses.
6.
Added additional imputation approaches to the sensitivity analysis of the primary 
endpoint to align with the HCV ABT-493/ABT-530 program.
7.
Removed the subgroup analysis of the primary endpoint for the mITT populations 
to align with the HCV ABT-493/ABT-530 program.
8.
Added the additional efficacy analysis of the percentage of subjects with HCV 
virologic failure through PT Week 12 to align with the HCV ABT-493/ABT-530 
program.
9.
Removed several of the additional efficacy analyses to be performed on the 
HCV/HIV co-infected population because the number of HCV/HIV co-infected 


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subjects is anticipated to be lower than had been expected at the time the protocol 
was written.
10.
Removed word "cumulative" from the analysis of subjects who have ever 
experienced an increase from baseline in the FSS total score of greater than or 
equal to 0.7 through each applicable timepoint to align with the HCV 
ABT-493/ABT-530 program.
11.
Specified the assays used by the central laboratory for the HCV RNA and HIV-1 
RNA samples and the HIV-1 resistance testing, along with the LLOD and LLOQ 
for the HCV RNA assay.  This information was not known at the time of protocol 
development.
12.
Removed several of the safety analyses to be performed on the HCV/HIV 
co-infected population because the number of HCV/HIV co-infected subjects is 
anticipated to be lower than had been expected at the time the protocol was written.
13.
Added analysis of laboratory assessments of hepatotoxicity to align with the HCV 
ABT-493/ABT-530 program.
14.
Added plots of mean change (± standard error) from baseline for ALT and bilirubin 
(total, direct, and indirect) to align with the HCV ABT-493/ABT-530 program. 
15.
Added shift tables for Child-Pugh score to align with the HCV ABT-493/ABT-530 
program.
16.
Added analyses of CD4+ T-cell count, CD8+ T-cell count, and lymphocytes for the 
HCV/HIV co-infected population to align with the HCV ABT-493/ABT-530 
program.


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13.0
References
1.
Grundy SM, Brewer HB Jr, Cleeman JI, et al.  Definition of metabolic syndrome:  
report of the National Heart, Lung, and Blood Institute/American Heart 
Association conference on scientific issues related to definition.  Circulation.  
2004;109(3):433-8.
2.
Newcombe RG.  Two-sided confidence intervals for the single proportion:  
comparison of seven methods.  Stat Med.  1998;17(8):857-72.
3.
2017 update of the drug resistance mutations in HIV-1.  Top Antivir Med.  2017; 
24(4):132-41.  Available from:  https://www.iasusa.org/sites/default/files/tam/24-4-
132.pdf.
4.
Szende A, Williams A.  Measuring self-reported population health:  an 
international perspective based on EQ-5D.  EuroQol Group Monographs 
Volume 1.  SpringMed Publishing; 2004.
5.
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.