Clinical trial NCT02723084
Conditions: Chronic Hepatitis C Virus Hepatitis C Virus
Keywords: Hepatitis C Virus Non-cirrhotic Hepatitis C Genotype 2 Chronic Hepatitis C Virus Hepatitis C
Sponsor: AbbVie
Start date: 2016-04-08; Completion date: 2017-03-24
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase 3 study is to evaluate the efficacy and safety of ABT-493/ABT-530 in comparison to sofosbuvir plus ribavirin for 12 weeks in Hepatitis C Virus (HCV) Genotype 2 (GT2) infected participants.

Detailed description:
This was a randomized, open-label, active-control, multicenter study to evaluate efficacy, safety, and pharmacokinetics of ABT-493/ABT-530 in chronic HCV GT2-infected direct-acting antiviral agent (DAA) treatment-naïve Japanese adult participants without cirrhosis. The participants were randomized in a 2:1 ratio to ABT-493/ABT-530 for 8 weeks (Arm A) and sofosbuvir plus ribavirin for 12 weeks (Arm B).

Arms: arm 1: Co-formulated ABT-493/ABT-530 (300 mg/120 mg) administered once daily (QD) for 8 weeks in HCV genotype (GT) 2 -infected, DAA treatment-naïve participants without cirrhosis. arm 2: sofosbuvir (400 mg) QD co-administered with weight based ribavirin (RBV) 600-1000 mg divided twice daily (BID) for 12 weeks in HCV GT2 -infected, DAA treatment-naïve participants without cirrhosis.
Interventions: intervention 1: ABT-493/ABT-530 intervention 2: sofosbuvir (SOF) intervention 3: ribavirin (RBV)
Intervention descriptions: intervention 1: Co-formulated tablet intervention 2: Tablet intervention 3: Capsule

Protocol documents:
Prot_001.pdf: 
ABT-493, ABT-530
M15-828 Protocol Amendment 2
1
1.0
Title Page
Clinical Study Protocol M15-828
A Randomized, Open-Label, Active Comparator, 
Multicenter Study to Evaluate the Efficacy and 
Safety of ABT-493/ABT-530 in Japanese Adults with 
Genotype 2 Chronic Hepatitis C Virus Infection 
(CERTAIN-2)
Including Administrative Change 1 and 
Amendments 1 and 2
AbbVie Investigational
  Product:
ABT-493/ABT-530
Date:
17 June 2016
Development Phase:
3
Study Design:
This is a randomized, open-label, active comparator, multicenter 
study.
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie GK*
Sponsor/Emergency 
  Contact:
Urgent contact during business 
hours:
Urgent contact after 
business hours (at night 
or on holidays):
* 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.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date 
Original
18 December 2015
Administrative Change 1
19 May 2016
Amendment 1
29 January 2016
The purpose of this amendment is to:
●
Update to how subjects will be randomized.
Rationale:  To provide clarification on the stratification/randomization of 
subjects using Screening HCV RNA values.
●
Update to Section 5.2.3.1, Prior HCV Therapy.
Rationale:  To provide additional guidance how subjects will be categorized.
●
Update to Section 5.3.5, Safety Variables.
Rationale:  To provide clarification on safety variables.
●
Correct inconsistencies and typographical errors throughout the protocol.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix D.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
3
1.2
Synopsis
AbbVie GK
Protocol Number:  M15-828
Name of Study Drug:  ABT-493/ABT-530
Phase of Development:  3
Name of Active Ingredient:  ABT-493, ABT-530
Date of Protocol Synopsis:  17 June 2016
Protocol Title:  A Randomized, Open-Label, Active Comparator, Multicenter Study to Evaluate the 
Efficacy and Safety of ABT-493/ABT-530 in Japanese Adults with Genotype 2 Chronic Hepatitis C 
Virus Infection (CERTAIN-2)
Objective:  
The primary objectives of this study are to assess the efficacy (sustained virologic response 12 weeks 
post treatment, SVR12) and safety of 8 weeks of treatment with the combination regimen 
ABT-493/ABT-530 in comparison to sofosbuvir (SOF) plus ribavirin (RBV) for 12 weeks in HCV 
GT2-infected subjects.
Investigators:  Multicenter, investigator information on file at AbbVie
Study Sites:  Approximately 60 sites.
Study Population:  DAA treatment-naïve, HCV GT2-infected non-cirrhotic Japanese adults, at least 
18 years of age at time of Screening.
Number of Subjects to be Enrolled:  Approximately 120 subjects.
Methodology:  
This is a Phase 3, randomized, open-label, active-control, multicenter study to evaluate the efficacy, 
safety and pharmacokinetics of ABT-493/ABT-530 for 8-weeks compared to the treatment regimen 
currently approved in Japan of sofosbuvir plus ribavirin for 12 weeks in chronic HCV GT2-infected 
DAA treatment-naïve subjects without cirrhosis.
The study will consist of:
Treatment Period
HCV GT2-infected DAA treatment-naïve subjects (including subjects who are interferon [IFN] treatment 
experienced with or without RBV) without cirrhosis will be randomized in a 2:1 ratio to one of the 
two treatment arms:

Arm A:  ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks (80 subjects)

Arm B:  SOF 400 mg QD plus RBV (600 – 1000 mg based on weight divided BID) for 
12 weeks (40 subjects)
The randomization will be stratified by prior IFN-experience (naïve versus experienced) and Screening 
HCV RNA (< or ≥ 6 million IU/mL).
Scheduled visits for subjects in the Treatment Period who are assigned to the 8-week regimen of 
ABT-493/ABT-530 consist of Day 1 and Weeks 1, 2, 4 and 8.  For subjects assigned to the 12-week 
regimen of SOF plus RBV, scheduled visits in the Treatment Period consist of Day 1 and Weeks 1, 2, 4, 
8 and 12.  Study procedures, including assessment of adverse events, vital signs, treatment adherence, 
concomitant medications, HCV RNA, pharmacokinetic assays for ABT-493, ABT-530 and active 
comparators, and clinical laboratory tests, will be conducted at each visit.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
4
Methodology (Continued):
Post-Treatment Period
Subjects who complete the Treatment Period, experience on treatment virologic failure, or prematurely 
discontinue study drug will be followed for 24 weeks to monitor safety, HCV RNA levels, and to 
evaluate efficacy and the emergence and persistence of viral resistance-associated variants.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Japanese male or female subjects at least 18 years of age at time of screening.
2.
Female who is:

not of childbearing potential, defined as:
o
postmenopausal for at least 2 years prior to screening (defined as amenorrheic for longer 
than 2 years, age appropriate and confirmed by a follicle-stimulating hormone [FSH] level 
indicating a postmenopausal state), or
o
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy) or has a vasectomized partner(s);

of childbearing potential and sexually active with male partner(s):
o
currently using at least one effective method of birth control at the time of screening and 
agrees to practice one effective method of birth control for subjects randomized to Arm A 
and two effective methods of birth control for subjects randomized to Arm B while 
receiving study drugs (non-hormonal intrauterine device [IUD], subject or partner[s] using 
condoms, contraceptive sponge, diaphragm, or vaginal ring with spermicidal jellies or 
creams), starting with Screening and for 30 days after stopping study drug  for Arm A 
subjects and 6 months after stopping study drug  for Arm B subjects.  (Note that both 
contraceptive sponge and vaginal ring with spermicidal jellies or creams are unapproved in 
Japan.)
3.
Sexually active males must be surgically sterile, or if sexually active with female partner(s) of 
childbearing potential must agree to practice one effective form of birth control (partner[s] using IUD 
[including those containing hormonal contraceptives], subject or partner[s] using condoms, 
contraceptive sponge, diaphragm, or vaginal ring with spermicidal jellies or creams), starting with 
Screening and through 30 days after stopping study drug  for Arm A subjects and 6 months after 
stopping study drug  for Arm B subjects.  (Note that both contraceptive sponge and vaginal ring with 
spermicidal jellies or creams are unapproved in Japan.)
4.
Screening central laboratory result indicating HCV GT2 infection without co-infection of any other 
genotype.
5.
Subject has positive anti-HCV Ab and plasma HCV RNA viral load ≥ 1000 IU/mL at Screening 
Visit.
6.
Chronic HCV infection defined as one of the following:

Positive for anti-HCV antibody (Ab) and/or HCV RNA at least 6 months before Screening.

A liver biopsy consistent with chronic HCV infection.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
7.
Subject must be HCV DAA treatment-naïve (i.e., patient has not received a single dose of any 
approved or investigational DAA).  Prior HCV treatment using IFNs with or without ribavirin is 
acceptable.  Previous HCV IFN based treatment must have been completed ≥ 2 months prior to 
screening.
8.
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.
9.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements.
10. Subject must be documented as non-cirrhotic, defined as meeting one of the following criteria:

A liver biopsy within 24 months prior to or during screening demonstrating the absence of 
cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, Scheuer, New Inuyama or Laennec 
fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; 

A FibroScan® score of < 12.5 kPa within 6 months of Screening or during the Screening Period; 
o
Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6), must have a qualifying 
liver biopsy.

A screening FibroTest score of ≤ 0.72 and Aspartate Aminotransferase to Platelet Ratio Index 
(APRI) ≤ 2;
o
Subjects with indeterminate FibroTest, or conflicting FibroTest and APRI results 
(e.g., FibroTest ≤ 0.72, but APRI > 2 or FibroTest ≥ 0.73, but APRI ≤ 2) must have a 
qualifying FibroScan® or liver biopsy.

A screening Discriminant Score (z) less than zero, according to the following formula:  
z = 0.124 × [gamma-globulin (%)] + 0.001 × [hyaluronate (µg×l–1)] -0.075 × [platelet 
(× 104 cells/mm3)] – 0.413 × gender (male, 1; female, 2) – 2.005.
o
Subjects with indeterminate Discriminant Score (score = 0), must have a qualifying 
FibroScan® or liver biopsy.
Main Exclusion:  
1.
Female who is pregnant, planning to become pregnant during the study, or breastfeeding; or male 
whose partner is pregnant or planning to become pregnant during the study. 
2.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol in the opinion of the investigator.
3.
Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti human 
immunodeficiency virus antibody (HIV Ab).
4.
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.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
5.
Clinically significant abnormalities, other than HCV-infection, based upon the results of a medical 
history, physical examination, vital signs, laboratory profile, and a 12-lead electrocardiogram (ECG) 
that make the subject an unsuitable candidate for this study in the opinion of the investigator, 
including but not limited to:

Uncontrolled diabetes as defined by a glycated hemoglobin (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, or any history of HCC. 

Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, psychiatric, or other 
medical disease or disorder, which is unrelated to the existing HCV infection.
6.
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, or steatohepatitis considered to be the primary cause of the liver disease 
rather than concomitant/incidental with HCV infection.
7.
History of solid organ transplantation.
8.
Receipt of any investigational product within a time period equal to 10 half-lives of the product, if 
known, or a minimum of 6 weeks (whichever is longer) prior to study drug administration.
9.
Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to 
receive ABT-493/ABT-530.
10. History of severe, life-threatening or other significant sensitivity to any excipients of the study drug.
11. Patients who can't participate in study per local law.
12. Any current or past clinical evidence of decompensated liver disease such as ascites noted on 
physical exam, hepatic encephalopathy or esophageal variceal bleeding.
13. Screening laboratory analyses showing any of the following abnormal laboratory results:

Creatine Clearance (CrCl) ≤ 50 mL/min

Albumin:  < LLN 

International normalized ratio (INR):  ≥ 1.2 (Subjects with a known inherited blood disorder and 
INR ≥ 1.2 may be enrolled with permission of the AbbVie TA MD.)

Hemoglobin:  < 12 g/dL

Platelets:  < 90,000 cells per mm3
Investigational Products:
ABT-493/ABT-530 100 mg/40 mg tablet
Doses:
ABT-493/ABT-530 300 mg/120 mg QD (3 × 100 mg/40 mg tablets)
Mode of Administration:
Oral after food
Reference Therapy:
sofosbuvir (SOF) 400 mg tablet plus ribavirin (RBV) 200 mg capsule
Doses:
SOF 400 mg QD plus RBV 600 – 1000 mg based on weight divided BID
Mode of Administration:
Oral


ABT-493, ABT-530
M15-828 Protocol Amendment 2
7
Duration of Treatment:  Subjects will receive ABT-493/ABT-530 for 8 weeks.  Subjects will receive 
SOF plus RBV for 12 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects receiving 
ABT-493/ABT-530 with available samples, the variants at baseline at signature resistance-associated 
amino acid positions relative to the appropriate prototypic reference sequence; and 2) for subjects 
receiving any study drugs who do not achieve SVR12, post-baseline variants relative to baseline.
Pharmacokinetic:
Individual plasma concentrations of ABT-493, ABT-530, SOF, GS-331007, RBV and their possible 
metabolites will be tabulated and summarized.  Values for pharmacokinetic parameters of ABT-493, 
ABT-530, SOF, GS-331007, RBV and their possible metabolites including apparent clearance (CL/F) 
and apparent volume of distribution (V/F) will be estimated using population pharmacokinetic modeling 
procedures.
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.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Statistical Methods:
Efficacy:
The ITT population will include all randomized subjects who receive at least one dose of study drug.  
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study 
drug).  
The primary efficacy endpoint is:

Non-inferiority of ABT-493/ABT-530 for 8-weeks (Arm A) to SOF/RBV for 12 weeks (Arm B) 
in SVR12 using a non-inferiority margin of 10%.
For the primary efficacy endpoint to show non-inferiority in the SVR12 rate of ABT-493/ABT-530 for 
8-weeks (Arm A) to that of SOF/RBV for 12 weeks (Arm B), the percentage of subjects achieving SVR12
will be calculated for each arm and a two-sided 95% confidence interval for the difference in SVR12 rates 
(Arm A minus Arm B) will be calculated using the normal approximation to the binomial distribution.  
All subjects in the ITT population will be used when calculating SVR12.  If the lower bound of the 
confidence interval for the difference is above the non-inferiority margin of –10%, then 
ABT-493/ABT-530 for 8 weeks will be considered non-inferior to SOF plus RBV for 12-weeks.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
8
Statistical Methods (Continued):
Efficacy (Continued):
The following secondary endpoints will be summarized:

the percentage of subjects achieving SVR12 in Arm A;

the percentage of subjects with on-treatment virologic failure (defined as confirmed increase of 
> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA ≥ 100 IU/mL after HCV 
RNA < LLOQ during treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 
6 weeks of treatment), and 

the percentage of subjects with post-treatment relapse (defined as confirmed HCV RNA 
≥LLOQ between end of treatment and 12 weeks after the last dose of study drug among 
subjects who completed treatment as planned with HCV RNA < LLOQ at the end of treatment; 
excluding subjects who have been shown to have been reinfected).
For the first secondary efficacy endpoint, the percentage of subjects in Arm A achieving SVR12 and a 
two-sided 95% confidence interval will be calculated using the normal approximation to the binomial 
distribution, unless the rate for SVR12 is 100%, then the Wilson's score method will be used for the 
confidence interval instead.  
For the analysis of relapse, completion of treatment is defined as any subject assigned to the 12-week 
treatment (Arm B) with study drug duration of 77 days or greater; or any subject assigned to the 8-week 
treatment (Arm A) with study drug duration of 52 days or greater.
The percentage of subjects with on-treatment virologic failure, or post-treatment relapse will be 
summarized for each treatment arm.  Two-sided 95% confidence intervals will be provided for the 
percentages within treatment arms and for the difference between arms (Arm A minus Arm B).  Wilson 
score intervals will be used for within arm summaries and for any between arm summaries, unless 
otherwise specified.
Resistance:
For all subjects receiving ABT-493/ABT-530 and with available samples, the variants at signature 
resistance-associated amino acid positions at baseline identified by population or deep sequencing and 
comparison to the appropriate prototypic reference sequence will be tabulated and summarized.
The following resistance information will be analyzed for subjects receiving any study drugs who do not 
achieve SVR12 and who have an available post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the 
amino acid variants in available post-baseline samples identified by population or deep sequencing in 
comparison to the baseline sequence, 2) the amino acid variants in available post-baseline samples at 
signature resistance-associated positions identified by population or deep sequencing in comparison to 
the appropriate prototypic reference sequence, and 3) the persistence of viral variants by population or 
deep sequencing for subjects in Arm A.
Pharmacokinetic:
Plasma concentration of ABT-493, ABT-530, SOF, GS-331007, RBV and their possible metabolites will 
be tabulated for each subject and group.  Summary statistics will be computed for each time and visit.  
Population pharmacokinetic analyses will be performed using the actual sampling time relative to dosing.  
Pharmacokinetic models will be built using a non-linear mixed-effects modeling approach.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Statistical Methods (Continued):
Patient Reported Outcomes (PROs):
The mean change from baseline to Final Treatment Visit and from baseline to Post-Treatment Week 12 in 
the FSS total score, EQ-5D-3L health index score and VAS score will be compared between treatment 
arms using an analysis of covariance (ANCOVA) model with treatment arm as a factor and baseline 
score as a covariate.
Safety:
All subjects who receive at least one dose of study drugs will be included in the safety analyses.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  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 study arms, grade and relationship to study drug.  Change from baseline 
in laboratory tests and vital signs measurements to each time point of collection will be summarized, and 
values that are potentially clinically significant, according to predefined criteria, will be summarized.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
ANCOVA
Analysis of covariance
APRI
Aminotransferase/platelet ratio index
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
AUC
Area Under the Concentration Curve
BMI
Body Mass Index
BUN
Blood urea nitrogen
CRF
Case report form
DAA
Direct-acting antiviral agent
D/C
Discontinuation
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
FSS
Fatigue Severity Scale
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
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


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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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
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NONMEM
Non-linear mixed-effect modeling
NS5A
Nonstructural viral protein 5A
PI
Protease Inhibitor
PK
Pharmacokinetic
POR
Proof of Receipt
PRO
Patient Reported Outcome
PR
pegIFN/RBV
PT
Post-Treatment
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
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
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


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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ULN
Upper limit of normal
VAS
Visual Analog Scale
V/F
Apparent Volume of distribution
WBC
White blood cells
Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
Definition of Terms
Study Drug
ABT-493, ABT-530, SOF, RBV
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
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................3
1.3
List of Abbreviations and Definition of Terms........................................10
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................22
3.2
Benefits and Risks....................................................................................23
4.0
Study Objective......................................................................24
4.1
Primary Objective ....................................................................................24
4.2
Secondary Objective ................................................................................24
5.0
Investigational Plan...............................................................25
5.1
Overall Study Design and Plan:  Description ..........................................25
5.1.1
Screening..................................................................................................26
5.1.1.1
Rescreening..............................................................................................27
5.1.2
Treatment Period......................................................................................27
5.1.3
Post-Treatment Period .............................................................................28
5.2
Selection of Study Population..................................................................28
5.2.1
Inclusion Criteria .....................................................................................29
5.2.2
Exclusion Criteria ....................................................................................31
5.2.3
Prior and Concomitant Therapy...............................................................33
5.2.3.1
Prior HCV Therapy..................................................................................34
5.2.3.2
Concomitant Therapy...............................................................................35
5.2.3.3
Prohibited Therapy...................................................................................36
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables.............................................................................37
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................37
5.3.1.1
Study Procedures .....................................................................................42
5.3.1.2
Meals and Dietary Requirements.............................................................52
5.3.1.3
Blood Samples for Pharmacogenetic Analysis ........................................52
5.3.2
Drug Concentration Measurements .........................................................52


ABT-493, ABT-530
M15-828 Protocol Amendment 2
14
5.3.2.1
Collection of Samples for Analysis .........................................................52
5.3.2.2
Handling/Processing of Samples .............................................................54
5.3.2.3
Disposition of Samples ............................................................................54
5.3.2.4
Measurement Methods.............................................................................54
5.3.3
Efficacy Variables....................................................................................54
5.3.3.1
Primary Variable......................................................................................54
5.3.3.2
Secondary Variable..................................................................................55
5.3.4
Resistance Variables ................................................................................55
5.3.5
Safety Variables .......................................................................................55
5.3.6
Pharmacokinetic Variables ......................................................................55
5.3.7
Pharmacogenetic Variables......................................................................55
5.4
Removal of Subjects from Therapy or Assessment .................................56
5.4.1
Discontinuation of Individual Subjects....................................................56
5.4.1.1
Virologic Stopping Criteria......................................................................57
5.4.2
Discontinuation of Entire Study...............................................................58
5.5
Treatments................................................................................................58
5.5.1
Treatments Administered.........................................................................58
5.5.2
Identity of Investigational Products.........................................................59
5.5.2.1
Packaging and Labeling...........................................................................60
5.5.2.2
Storage and Disposition of Study Drugs..................................................60
5.5.3
Method of Assigning Subjects to Treatment Groups...............................60
5.5.4
Selection and Timing of Dose for Each Subject ......................................61
5.5.5
Blinding....................................................................................................61
5.5.6
Treatment Compliance.............................................................................61
5.5.7
Drug Accountability.................................................................................62
5.6
Discussion and Justification of Study Design..........................................63
5.6.1
Discussion of Study Design and Choice of Control Groups....................63
5.6.2
Appropriateness of Measurements...........................................................64
5.6.3
Suitability of Subject Population .............................................................64
5.6.4
Selection of Doses in the Study ...............................................................64
5.6.4.1
ABT-493, ABT-530, SOF and RBV Doses.............................................64
5.6.4.2
Rationale for Duration Selections............................................................66


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5.6.4.3
Risk of Development of Resistance Mutations During 
Combination DAA Trials.........................................................................66
6.0
Complaints .............................................................................67
6.1
Medical Complaints.................................................................................68
6.1.1
Definitions................................................................................................68
6.1.1.1
Adverse Event..........................................................................................68
6.1.1.2
Serious Adverse Events ...........................................................................69
6.1.2
Adverse Event Severity............................................................................70
6.1.3
Relationship to Study Drug......................................................................71
6.1.4
Adverse Event Collection Period.............................................................72
6.1.5
Adverse Event Reporting.........................................................................73
6.1.6
Pregnancy.................................................................................................75
6.1.7
Toxicity Management ..............................................................................76
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities or Adverse Events .....................76
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities ...................................................77
6.1.7.3
Grade 3 or 4 Adverse Event or Serious Adverse Event............................78
6.1.7.4
Management of Decreases in Hemoglobin ..............................................79
6.1.7.5
Management of Increases in ALT............................................................80
6.1.7.6
Creatinine Clearance................................................................................81
6.1.7.7
Management of Grade 3 or Greater Elevations of Total Bilirubin ..........82
6.2
Product Complaint ...................................................................................82
6.2.1
Definition .................................................................................................82
6.2.2
Reporting..................................................................................................83
7.0
Protocol Deviations................................................................83
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................84
8.1
Statistical and Analytical Plans................................................................84
8.1.1
Demographics ..........................................................................................85
8.1.2
Efficacy....................................................................................................86
8.1.2.1
Primary Efficacy Endpoints.....................................................................86
8.1.2.2
Secondary Efficacy Endpoints.................................................................87
8.1.2.3
Sensitivity Analysis .................................................................................88
8.1.2.4
Subgroup Analysis ...................................................................................89


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8.1.2.5
Additional Efficacy Endpoints.................................................................90
8.1.3
Patient Reported Outcomes......................................................................91
8.1.4
Resistance Analyses.................................................................................91
8.1.5
Safety .......................................................................................................94
8.1.5.1
Adverse Events ........................................................................................94
8.1.5.2
Clinical Laboratory Data..........................................................................95
8.1.5.3
Vital Signs Data .......................................................................................95
8.1.6
Pharmacokinetic and Exposure-Response Analyses ...............................95
8.1.7
Justification of Non-Inferiority Margin for SVR12 ..................................98
8.2
Determination of Sample Size .................................................................98
8.3
Randomization Methods ..........................................................................98
9.0
Ethics.......................................................................................99
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................99
9.2
Ethical Conduct of the Study ...................................................................99
9.3
Subject Information and Consent...........................................................100
9.3.1
Informed Consent Form and Explanatory Material ...............................100
9.3.2
Revision of the Consent Form and Explanatory Material .....................101
10.0
Source Documents and Case Report Form 
Completion ...........................................................................101
10.1
Source Documents .................................................................................101
10.2
Case Report Forms.................................................................................101
11.0
Data Quality Assurance......................................................102
12.0
Use of Information...............................................................103
13.0
Completion of the Study .....................................................103
14.0
Investigator's Agreement....................................................105
15.0
Reference List ......................................................................106
List of Tables
Table 1.
SVR12 Rates in GT2-Infected Non-Cirrhotic Subjects ............................19
Table 2.
SVR4 and SVR12 in GT2 Subjects in Study M14-868.............................21
Table 3.
Prohibited Medications and Supplements................................................36


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Table 4.
Treatment Period......................................................................................38
Table 5.
Post Treatment Period..............................................................................41
Table 6.
Clinical Laboratory Tests.........................................................................45
Table 7.
Identity of Investigational Products .........................................................59
Table 8.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases ............................................................................80
List of Figures
Figure 1.
Study Schematic.......................................................................................25
Figure 2.
Adverse Event Collection ........................................................................72
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................108
Appendix B.
List of Protocol Signatories....................................................................110
Appendix C.
Clinical Toxicity Grades ........................................................................111
Appendix D.
Protocol Amendment:  List of Changes.................................................114


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with over 170 million 
individuals infected worldwide.1  There are 7 identified HCV genotypes,2 with genotype 1 
(GT1) being most prevalent worldwide.  Depending on various risk factors, between 10% 
and 40% of patients with chronic HCV infection will develop cirrhosis.3  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.3  Patients diagnosed with hepatocellular carcinoma have a 33% probability of 
death during the first year.3  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.4,5
In Japan, it is estimated that 1.5 million individuals are HCV antibody positive and 
approximately 1 million of these are viremic.  An estimated 70% of HCV patients in 
Japan are infected with HCV genotype 1 (mainly 1b), approximately 30% with 
genotype 2 and approximately 2% with other genotypes (3, 4, 5, or 6).6-10  Due to an aging 
Japanese patient population and the associated disease progression, the health burden of 
chronic HCV infection in Japan is predicted to increase over the next several years.
The currently available HCV interferon-free treatment regimen in Japan for GT2 is 
sofosbuvir + RBV,11 which was approved in March 2015.  Evaluation of the 12-week 
SOF plus RBV regimen across multiple clinical trials (Table 1) resulted in an estimated 
SVR rate of 95% in GT2-infected non-cirrhotic subjects.


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Table 1.
SVR12 Rates in GT2-Infected Non-Cirrhotic Subjects
Trial
SVR (n/N)
SVR (%)
FISSION14
59/61
97%
POSITRON14
85/92
92%
FUSION14
26/29
90%
VALENCE14
59/63
94%
Japanese Study11
132/136
97%
Total
361/381
95%
There are currently no IFN-free regimens indicated for genotypes other than 1 and 2 in 
Japan, and no regimens that are indicated in both GT1 and GT2.  The available IFN-free 
regimen for GT2 requires coadministration with RBV and is not indicated for those with 
renal impairment.11  Despite recent treatment advances, unmet needs of HCV treatment in 
Japan remain and there is further opportunity to improve treatment options with 
pan-genotypic regimens that can treat all the HCV GTs in Japan with high SVR rates and 
highly tolerable regimens.
A next-generation 2-DAA regimen including ABT-493, an HCV NS3/4A protease 
inhibitor, and ABT-530, an NS5A inhibitor, are under development by AbbVie to further 
improve HCV treatment.  These compounds are denoted as "next generation" because 
each has demonstrated potent antiviral activity against all major HCV GTs in vitro while 
maintaining potent antiviral activity against known common single-position resistant 
variants.  Both compounds further demonstrated high barrier to resistance development in 
vitro.
ABT-493
ABT-493 is an NS-3/4A PI with potent and pangenotypic activity.  It demonstrates a high 
genetic barrier to resistance with 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.12


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ABT-530
ABT-530 is an NS5A inhibitor with pangenotypic activity and a high genetic barrier to 
resistance maintaining activity against all common single nucleotide change resistance 
associated variants in NS5A in all GTs.  ABT-530 is > 100-fold more active than the 
first generation NS5A inhibitors (ombitasvir, daclatasvir, and ledipasvir) against key 
single-position resistance-associated variants.
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. 13
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.
ABT-493 and ABT-530 combination has been well tolerated when administered to over 
590 healthy volunteers (including Japanese and Han Chinese).  Over 580 subjects have 
been dosed to-date with the combination of ABT-493 and ABT-530 in Phase 2 studies. 
The combination of ABT-493 and ABT-530 has also been evaluated in Japanese and 
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.
For a detailed discussion of drug-drug interaction and other Phase 1 studies please refer to 
the Investigator's Brochures for respective compounds.
Study M14-868 is an ongoing Phase 2b study assessing the efficacy, safety and 
pharmacokinetics of the combination of ABT-493 and ABT-530 in HCV GT2 and 
GT3-infected treatment-naïve (TN) and PR-experienced non-cirrhotic subjects.  The study 
arms including the GT2 population, doses, duration, and preliminary SVR4 and SVR12
results where available are presented in Table 2: 


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Table 2.
SVR4 and SVR12 in GT2 Subjects in Study M14-868
Study-Arm
Duration 
(Weeks)
493 Dose 
(mg QD)
530 Dose 
(mg QD)
RBV
N
SVR4
n/N 
(ITT%)
SVR12
n/N 
(ITT%)
Virologic 
Failure*
Other
Non-cirrhotic GT2 (PegRBV exp or naïve)
Part 1:
M14-868-A
12
300
120
no
24
24/25 
(96%)
24/25 
(96%)
0
1 lost to 
follow-up
M14-868-B
12
200
120
no
24
24/24 
(100%)
24/24 
(100%)
0
M14-868-C
12
200
120
yes
25
25/25 
(100%)
25/25 
(100%)
0
Part 2:
M14-868-J
8
300
120
no
54
53/54 
(98%)
na**
0
1 lost to 
follow-up
*
Virologic failure, includes failure to suppress, breakthrough on treatment or post-treatment relapse.
**
Few subjects have reached Post Treatment Week 12.
High rates of SVR4 and SVR12 and no virologic failures were observed across all GT2 
non-cirrhotics in Study M14-868.  The preliminary efficacy data for 8 weeks of treatment 
was similar to 12 weeks in GT2 non-cirrhotics, including treatment-naïve or pegIFN + 
RBV experienced subjects.  Coadministration of ribavirin (Arm C) was not needed to 
improve efficacy.
Preliminary assessment of safety was performed in Part 1 of Studies M14-867 and 
M14-868.  Study M14-867 is an ongoing Phase 2b study evaluating the efficacy, safety 
and pharmacokinetics of ABT-493 and ABT-530 in HCV GT1- through GT6-infected 
treatment naïve (TN) and PR-experienced non-cirrhotic subjects, and GT1-infected 
subjects with compensated cirrhosis.  Safety data from 274 subjects in Studies M14-867 
and M14-868 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) show that the most frequently 
reported adverse events were fatigue, nausea, and headache (occurring in > 5% and < 15% 
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.


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Of the 274 subjects in Part 1 of Studies M14-867 and M14-868, 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 in Arm F (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.
All subjects with baseline ALT elevations showed a trend toward ALT normalization or 
ALT became normal with DAA treatment, and there have been no on-treatment ALT 
elevations above baseline.  Other laboratory abnormalities were infrequent and were 
primarily associated with well-described hemolytic effect of RBV, manifesting as Grade 1 
anemia in a total of 4 subjects in the RBV-containing arms.  Occasional Grade 1 or 2 total 
bilirubin elevations that were predominantly indirect, were mostly isolated occurrences, 
and normalized or stabilized with continued DAA therapy.  The majority of these 
bilirubin elevations were observed in the RBV-containing arms.
Study M15-828 is a multi-center, randomized, active comparator, open label Phase 3 
study intended to evaluate the safety and efficacy of 8 weeks of treatment with the 
combination regimen of ABT-493 and ABT-530 compared to the currently approved 
12-week regimen of SOF plus RBV in DAA-naïve HCV GT2-infected patients without 
cirrhosis.  For more information on the pharmacokinetics, drug-drug interactions, clinical 
efficacy and safety of the active comparator regimen, please refer to the package inserts 
for sofosbuvir11,14 and ribavirin.15
Additional discussion and justification of study design may be found in Section 5.6.
3.1
Differences Statement
The current study (Study M15-828) is a Phase 3 study evaluating the efficacy, safety and 
pharmacokinetics of the ABT-493/ABT-530 combination regimen in the Japanese 


ABT-493, ABT-530
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population with chronic HCV GT2 infection.  An on-going global Phase 2b study 
(Study M14-868) is assessing the efficacy, safety and pharmacokinetics of the 
combination regimen of ABT-493 and ABT-530 in HCV GT2-infected subjects without 
cirrhosis for treatment durations of 12 weeks (Part 1) and 8 weeks (Part 2).
In healthy volunteer studies (Studies M14-066 and M15-432) the pharmacokinetics of 
ABT-493 and ABT-530 were found to be similar between Caucasians and Japanese 
subjects.  This, combined with preliminary efficacy and safety of 8 weeks of ABT-493 
and ABT-530 in Study M14-868, provides supporting data and rationale for the 
advancement of the ABT-493 and ABT-530 combination regimen into this Phase 3 study, 
the first study of the regimen in HCV GT2-infected Japanese subjects.  Study M15-828 
will evaluate the selected dose and regimen of ABT-493/ABT-530 for 8 weeks using the 
co-formulated, fixed dose combination tablet intended for marketing and will include a 
Japanese subject population with chronic HCV GT2-infection which is DAA 
treatment-naïve, without cirrhosis.
3.2
Benefits and Risks
Preliminary efficacy data in Study M14-868 (Part 1) have demonstrated high efficacy 
with no virologic failure for ABT-493 300 mg QD in combination with ABT-530 120 mg 
QD in GT2-infected patients without cirrhosis treated for 8 and 12 weeks; Post-Treatment 
Week 4 results to date show that 98% (53/54) of subjects treated for 8 weeks achieved 
SVR4 and 96% (24/25) of the subjects treated for 12 weeks achieved SVR12.  
Two subjects lost to follow-up and were considered non-responders.
In terms of safety, preliminary data across all arms in Study M14-868 (Part 1) using a 
regimen containing ABT-493 at a 300 mg dose (n = 55) demonstrate, no differences in the 
safety profile (including adverse events and LFT abnormalities) compared to arms using 
200 mg ABT-493.  No subjects in the study have experienced treatment-emergent ALT 
elevations. 


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Adverse events that are known, and those not previously described, may occur with the 
combination of the two DAAs, as detailed in the informed consent for this study.  In 
addition, subjects may experience inconvenience or discomfort related to the study visits 
or study procedures.  Additional safety data for each DAA alone and the combination of 
ABT-530 and ABT-493 are detailed in Section 3.0 and in the Investigator's Brochures for 
the respective compounds.
Risks associated with ABT-530 and ABT-493 co-administered 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 high 
SVR rate in these populations of HCV-infected subjects, the risk-benefit ratio is 
favorable. 
An approved regimen, sofosbuvir plus ribavirin, will be used in the study as an active 
comparator and has been shown to be safe and efficacious (Table 2) in subjects with HCV 
GT2 infection.
4.0
Study Objective
4.1
Primary Objective
The primary objectives of this study are to assess the efficacy (SVR 12) and safety of 
8 weeks of treatment with the ABT-493/ABT-530 combination regimen in comparison to 
SOF plus RBV for 12 weeks in DAA treatment-naïve, non-cirrhotic Japanese adults with 
chronic HCV GT2-infection.
4.2
Secondary Objective
The secondary objectives are to assess:
●
The percentage of subjects achieving SVR12 for Arm A;
●
The percentages of subjects with on-treatment virologic failure;
●
The percentages of subjects with post-treatment relapse.


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Additional objectives are to assess pharmacokinetics and emergence and persistence of 
viral variants in these treatment regimens.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, randomized, open-label, active-control, multicenter study to evaluate 
efficacy, safety and pharmacokinetics of ABT-493/ABT-530 in chronic HCV 
GT2-infected DAA treatment-naïve Japanese adult subjects without cirrhosis.  Subjects 
(including IFN treatment experienced with or without RBV) will be randomized in a 
2:1 ratio to ABT-493/ABT-530 for 8 weeks (Arm A) or SOF plus RBV for 12 weeks 
(Arm B).
This study will consist of:
Treatment Period:  Subjects will receive 8 weeks of ABT-493/ABT-530 or 12 weeks 
of SOF plus RBV.
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, HCV RNA levels, and to evaluate 
efficacy and the emergence and persistence of viral resistance-associate variants.
Figure 1.
Study Schematic


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HCV GT2-infected DAA treatment-naïve subjects (including subjects who are IFN 
treatment experienced with or without RBV) without cirrhosis will be enrolled into one of 
two treatment arms (80 subjects into Arm A and 40 subjects into Arm B):
●
Arm A:  ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks;
●
Arm B:  SOF 400 mg QD plus RBV (600 – 1000 mg based on weight divided 
BID) for 12 weeks.
Subjects meeting all eligibility criteria will be randomized in a 2:1 ratio to Arms A or B.  
The randomization will be stratified by prior IFN-experience (naive versus experienced) 
and Screening HCV RNA (< or ≥ 6 million IU/mL).
The study was designed to enroll 120 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target number of subjects has been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.
The primary analysis will occur after all subjects have completed the Post-Treatment 
Week 12 Visit or prematurely discontinue from the study.
5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study-specific procedures will receive a unique subject number via the 
Interactive Response Technology (IRT) system.  The investigator will evaluate whether 
the subject meets all of the eligibility criteria specified in Section 5.2.1 and Section 5.2.2
during the period from the Screening Visit through Study Day 1 prior to dosing, and will 
record the results of this assessment and the details of the informed consent process in the 
subject's medical records.  Eligible subjects have up to 35 days following the Screening 
Visit to enroll into the study.


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5.1.1.1
Rescreening
Subjects may be retested or rescreened only once.
Subjects who have exclusionary laboratory parameter(s) per Exclusionary Criteria 13, 
Section 5.2.2, are allowed to retest on the related panel(s) (e.g., exclusionary ALT 
requires a repeat chemistry panel) within the same screening period and must meet all 
eligibility laboratory criteria on any panel that is repeated.  If the retest result(s) are also 
exclusionary, the subject may not be rescreened or retested again.  
Subjects 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 upon 
retest/rescreen, 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 into a treatment 
arm.  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 Table 4.  Safety 
and tolerability will be assessed throughout the study.  Laboratory testing will include 
chemistry, hematology, and urinalysis as specified in Table 6.  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.  Blood 
samples for optional pharmacogenetic analysis will be collected as detailed in Table 4.
All subjects will continue to return to the site on an outpatient basis as outlined in Table 4.  
Sites should ensure that subjects adhere to all study visits.  Should a subject have an 
extraordinary circumstance which would preclude them from adhering to their originally 
scheduled visit date, visits in the Treatment Period will have an allowable visit window of 


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± 3 days.  It should be noted and reinforced to subjects that SOF is supplied with the exact 
amount of tablets (28) needed between the study drug dispensation visits in Table 4.  
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.
Virologic stopping criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in Table 4
and as described in Section 5.4.1.1.
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 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 Table 5.  Should 
a subject have an extraordinary circumstance which would preclude them from adhering 
to their originally scheduled visit date, visits in the Post-Treatment Period will have an 
allowable visit window of ± 3 days.
Subjects who prematurely discontinue the Post-Treatment Period should return to the site 
for a Post-Treatment discontinuation visit as outlined in Table 5.  
5.2
Selection of Study Population
The study population consists of chronic HCV GT2-infected Japanese male and females 
adults, without cirrhosis, who are HCV DAA treatment-naïve.  Subjects who meet all the


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inclusion criteria and none of the exclusion criteria will be eligible for enrollment into the 
study.
5.2.1
Inclusion Criteria
1.
Japanese male or female subjects at least 18 years of age at time of screening.
2.
Female who is:
●
not of childbearing potential, defined as:
○
postmenopausal for at least 2 years prior to screening (defined as 
amenorrheic for longer than 2 years, age appropriate and confirmed by a 
follicle-stimulating hormone [FSH] level indicating a postmenopausal 
state), or
○
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy 
or hysterectomy) or has a vasectomized partner(s);
●
of childbearing potential and sexually active with male partner(s):
○
currently using at least one effective method of birth control at the time of 
screening and agrees to practice one effective method of birth control for 
subjects randomized to Arm A and two effective methods of birth control 
for subjects randomized to Arm B while receiving study drugs 
(non-hormonal intrauterine device [IUD], subject or partner[s] using 
condoms, contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or creams), starting with Screening and for 30 days after 
stopping study drug for Arm A subjects and 6 months after stopping study 
drug for Arm B subjects.  (Note that both contraceptive sponge and vaginal 
ring with spermicidal jellies or creams are unapproved in Japan.)
3.
Sexually active males must be surgically sterile, or if sexually active with female 
partner(s) of childbearing potential must agree to practice one effective form of 
birth control (partner[s] using IUD [including those containing hormonal 
contraceptives], subject or partner[s] using condoms, contraceptive sponge,
diaphragm, or vaginal ring with spermicidal jellies or creams), starting with 
Screening and through 30 days after stopping study drug for Arm A subjects and 
6 months after stopping study drug for Arm B subjects.  (Note that both 


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contraceptive sponge and vaginal ring with spermicidal jellies or creams are 
unapproved in Japan.)
4.
Screening central laboratory result indicating HCV GT2-infection without 
co-infection of any other genotype.
5.
Subject has positive anti-HCV Ab and plasma HCV RNA viral load ≥ 1000 IU/mL 
at Screening Visit.
6.
Chronic HCV infection defined as one of the following:
●
Positive for anti-HCV antibody (Ab) and/or HCV RNA at least 6 months 
before Screening; or
●
A liver biopsy consistent with chronic HCV infection.
7.
Subject must be HCV DAA treatment-naïve (i.e., patient has not received a single 
dose of any approved or investigational DAA).  Prior HCV treatment using IFNs 
with or without ribavirin is acceptable.  Previous HCV IFN based treatment must 
have been completed ≥ 2 months prior to screening.
8.
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.
9.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
10.
Subject must be documented as non-cirrhotic, defined as meeting one of the 
following criteria:
●
A liver biopsy within 24 months prior to or during screening demonstrating the 
absence of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, 
Scheuer, New Inuyama or Laennec fibrosis score of ≤ 3, Ishak fibrosis score of 
≤ 4; 
●
A FibroScan® score of < 12.5 kPa within 6 months of Screening or during the 
Screening Period; 


ABT-493, ABT-530
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○
Subjects with indeterminate FibroScan® score (12.5 ≤ score < 14.6), must 
have a qualifying liver biopsy.
●
A screening FibroTest score of ≤ 0.72 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) ≤ 2;
○
Subjects with indeterminate FibroTest, or conflicting FibroTest and APRI 
results (e.g., FibroTest ≤ 0.72, but APRI > 2 or FibroTest ≥ 0.73, but APRI 
≤ 2) must have a qualifying FibroScan® or liver biopsy.
●
A screening Discriminant Score (z) less than zero, according to the following 
formula:  z = 0.124 × [gamma-globulin (%)] + 0.001 × [hyaluronate (µg×l–1)] 
–0.075 × [platelet (× 104 cells/mm3)] – 0.413 × gender (male, 1; female, 2) –
2.005.
○
Subjects with indeterminate Discriminant Score (score = 0), must have a 
qualifying FibroScan® or liver biopsy.
Rationale for Inclusion Criteria
1, 4 – 7, 10 
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, 9
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Female who is pregnant, planning to become pregnant during the study, or 
breastfeeding; or male whose partner is pregnant or planning to become pregnant 
during the study.
2.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
3.
Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti 
human immunodeficiency virus antibody (HIV Ab).


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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4.
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.
5.
Clinically significant abnormalities, other than HCV-infection, based upon the 
results of a medical history, physical examination, vital signs, laboratory profile, 
and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable 
candidate for this study in the opinion of the investigator, including, but not limited 
to: 
●
Uncontrolled diabetes as defined by a glycated hemoglobin (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, or any history of 
HCC.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, 
psychiatric, or other medical disease or disorder, which is unrelated to the 
existing HCV infection.
6.
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, or steatohepatitis considered to 
be the primary cause of the liver disease rather than concomitant/incidental 
with HCV infection.
7.
History of solid organ transplantation.
8.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks (whichever is longer) prior to 
study drug administration.
9.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-493/ABT-530.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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10.
History of severe, life-threatening or other significant sensitivity to any excipients 
of the study drug.
11.
Patients who can't participate in study per local law.
12.
Any current or past clinical evidence of Child-Pugh B or C classification or clinical 
history of decompensated liver disease such as ascites noted on physical exam, 
hepatic encephalopathy or variceal bleeding.
13.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Creatine Clearance (CrCL) ≤50 mL/min
●
Albumin:  < LLN 
●
International normalized ratio (INR):  ≥ 1.2 (Subjects with a known inherited 
blood disorder and INR ≥ 1.2 may be enrolled with permission of the AbbVie 
TA MD.)
●
Hemoglobin:  < 12 g/dL
●
Platelets:  < 90,000 cells per mm3
Rationale for Exclusion Criteria
1, 5, 7, 9 – 13 
In order to ensure safety of the subjects throughout the study
2, 4, 8
In order to avoid bias for the evaluation of efficacy and safety, 
including concomitant use of other medications
3, 6
To exclude subjects with HIV or liver diseases other than chronic 
HCV GT2 infection
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, traditional medicines 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 


ABT-493, ABT-530
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information including dose, route and frequency.  The investigator should review all 
concomitant medications for any potential interactions.
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 assessed as 
related to the study drugs and treatment of HCV will be recorded thereafter.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior HCV Therapy
Subjects must be HCV DAA treatment-naïve (i.e., subject has never received a single 
dose of such agents).  Prior treatment, such as interferons, with or without RBV, is 
acceptable.  Previous HCV IFN based treatment must have been completed ≥ 2 months 
prior to the Screening Visit.
Subjects will be categorized as:
●
Treatment-naïve:  subject has never received any treatment for HCV infection.
●
Subjects with prior Interferon-based treatment will be categorized as:
○
Non-responder:  HCV RNA detected (or quantifiable) 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 (or unquantifiable) at the end of treatment;
●
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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○
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 (or unquantifiable) at the end 
of a prior treatment course but HCV RNA was detectable (or quantifiable) 
following cessation of therapy.
○
Other:  subject received a prior treatment course and reason for not 
achieving SVR is other than above.
○
Unknown:  subject received a prior treatment course and reason for not 
achieving SVR is unknown.
Subjects must have discontinued prior IFN-based therapy at least 2 months prior to the 
Screening Visit in order to be eligible for the study.
5.2.3.2
Concomitant Therapy
Subjects should be on a stable dose of concomitant medications for at least 2 weeks prior 
to initiation of study drugs.  The investigator should confirm that a concomitant 
medication/supplement can be safely administered with study drugs.  Some medications 
may require dose adjustments due to the potential for drug-drug interactions. 
The use of hepatoprotective 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.  While the subject is using hepatoprotective medication, the 
dose should be kept stable.  When Investigators need to adjust hepatoprotective 
medications based on the Investigator's medical assessment, investigator must first consult 
with the AbbVie TA MD before making any adjustment of hepatoprotective medications.
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, 30 days following discontinuation 
of study drugs, if applicable.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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5.2.3.3
Prohibited Therapy
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 3 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.   
Table 3.
Prohibited Medications and Supplements
Medication or Supplement Name*
Any herbal medicines or supplements (excluding hepatoprotective agents), red yeast rice (monacolin K), 
St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, pitavastatin, simvastatin**
Astemizole, cisapride, terfenadine, bosentan, oxcarbazepine, silodosin, efavirenz, atazanavir, ethinyl 
estradiol-containing contraceptives
*
The use of SOF plus RBV is prohibited with the following drugs:  rifampicin, carbamazepine, phenytoin, St. John's 
Wort-containing food; and should be administered with care with:  rifabutin, phenobarbital, didanosine, and 
zathioprine.
**
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, pitavastatin, 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.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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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).
Anti-HCV medications other than those specified in the protocol will not be allowed 
during the Treatment Period of the study.
The investigator must refer to the current SOF and RBV package inserts or product labels 
for a complete list of prohibited medications for subjects randomized to the SOF plus 
RBV treatment arm (Arm B).
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Table 4 and Table 5.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Table 4.
Treatment Period
Activity
Screening
Day 1a
Week 1
Week 2
Week 4
Week 8*
Wk 8 EOT*, Week 12 EOT*, 
or Premature 
Discontinuation 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
ECG 
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])f
X (s)
X (u)
X (u)
X (u)
X (u)
HBsAg, anti-HCV Ab, anti-HIV Ab Tests
X
FSH (all females)
X
Drug/Alcohol Screen
X
HgbA1cg
X
HCV Genotype and Sub-genotype
X
Discriminant Score or FibroTest and APRI, or 
FibroScan®h or Liver Biopsyh
X
IL28B Samplei
X
Pharmacogenetic Sample (optional)i
X
Total Insulin
X
X


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Table 4.
Treatment Period (Continued)
Activity
Screening
Day 1a
Week 1
Week 2
Week 4
Week 8*
Wk 8 EOT*, Week 12 EOT*, 
or Premature 
Discontinuation from 
Treatmentb
Concomitant Medication Assessment
X
X
X
X
X
X
X
Adverse Event Assessmentj
X
X
X
X
X
X
X
Patient Reported Outcomes Instruments (PROs)k
X
X
Study Drug Dispensed
X
X
Xo
Study Drug Accountability, Review Study Drug Diary 
and Review of Study Drug Adherencel
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
Pharmacokinetic Samplesm
Xn
X
X
Xn
X
X
EOT = End of treatment
*
The EOT visit can be at Weeks 8 or 12 depending on treatment assignment.
a.
All procedures to be performed prior to first dose, with the 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 
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.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Table 4.
Treatment Period (Continued)
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.
Pregnancy testing is not required for females of non-childbearing potential as defined in Inclusion Criterion 2.
g.
For those with history of diabetes mellitus.
h.
For subjects who have not had a qualifying liver biopsy within the previous 24 months or a qualifying FibroScan® within the previous 6 months.
i.
If the IL28B sample or the optional Pharmacogenetic sample is not collected at Study Day 1, it may be collected at any other visit during the study.
j.
See specific information regarding adverse event collection in Section 6.1.1.1.
k.
PROs should be administered before any study procedures.  EOT PROs are at Weeks 8 or 12, as applicable.
l.
Subjects should bring all study drugs to every visit for the site to review adherence.  However, the site will record the number of tablets returned only at the Study Drug 
Accountability Visits at Weeks 4, 8 or Premature Discontinuation.
m.
Details regarding timing of PK samples are provided in Section 5.3.2.1.
n.
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.  Refer to specific details provided in Section 5.3.2.1.
o.
For subjects enrolled into Arm B with 12 weeks of treatment.


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Table 5.
Post Treatment Period
Activity
PT Week 2
PT Week 4
PT Week 8
PT Week 12
PT Week 24 or PT 
Discontinuationa
Vital Signs and Weight
X
X
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
Xb
Pregnancy Test (urine)c
X (u)
Xd
Xd
X (u)b,c,d
Concomitant Medication Assessmente
X
X
X
X
X
PRO Instrumentsf
X
Adverse Event Assessmentg
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
Archive Plasma Sample
X
X
X
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.
Urine pregnancy testing is not required in the PT Period for women that are not of childbearing potential.
d.
For subjects in the RBV-inclusive regimen (Arm B), subjects must have a urine pregnancy test performed every month and may have an unscheduled office visit for 
pregnancy testing or elect to perform the tests at home with test kits provided by the site at PT Weeks 16 and 20.  Additional testing may be required per local RBV label.
e.
Only medications taken for SAEs and treatment of HCV will be collected after 30 days post-dosing.
f.
PROs should be administered before any study procedures.
g.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  Only SAEs will be collected thereafter (see Section 6.1.4).
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
M15-828 Protocol Amendment 2
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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 illicit/illegal drug 
use, will be taken at Screening.  The subject's medical history will be updated on Study 
Day 1 Visit.  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 Table 4, 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 not measured at Screening, it may be measured on Study Day 1.
Vital Signs and Weight
Body temperature, blood pressure, pulse and weight will be measured at each study visit 
as specified in Table 4 and Table 5 or upon subject discontinuation.  Blood pressure and 
pulse rate should be measured after the subject has been sitting for at least 3 minutes.  The 
subject will wear lightweight clothing and no shoes during weighing.


ABT-493, ABT-530
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12-Lead Electrocardiogram (ECG)
A 12-lead resting ECG will be obtained at the visit indicated in Table 4.  The ECG should 
be performed prior to blood collection.
The ECG will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 6
at the visits indicated in Table 4 and Table 5.
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 after 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 


ABT-493, ABT-530
M15-828 Protocol Amendment 2
44
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 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Samples will be sent to the following addresses:
Covance Central Laboratory Services
c/o BML General Laboratory
1361-1, Matoba, Kawagoe City
Saitama, Japan 350-1101


ABT-493, ABT-530
M15-828 Protocol Amendment 2
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Table 6.
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 transaminase (SGPT/ALT) 
Aspartate transaminase (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)
Creatinine clearance 
(Cockcroft-Gault calculation)
eGFRJ (MDRD modified)c
HBsAgd
Anti-HCV Abd
Anti-HIV Abd
Opiatesd
Barbituratesd
Amphetaminesd
Cocained
Benzodiazepinesd
Alcohold
Phencyclidined
Propoxyphened
Methadoned
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG) for femalese
Follicle-Stimulating 
Hormone (FSH) (females)d
HCV RNA
Hepatitis B Panelf
Hemoglobin A1C
IL28B
HCV genotype and subtyped
Pharmacogenetic sample 
(optional)
Alpha2-macroglobuling
Haptoglobing
Apolipoprotein A1g
Hyaluronatei
Protein electrophoresis 
(includes Gamma-globulin 
and total protein)h
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Directly measured.
b.
Performed only at Baseline.
c.
eGFR calculated by the MDRD formula, modified for the Japanese population. 
d.
Performed only at Screening. 
e.
Pregnancy testing is not required for females of non-childbearing potential. 
f.
Performed for management of transaminase elevation (Section 6.1.7.4). 
g.
Component of FibroTest and collected only if needed during the Screening Period.
h.
Component of Discriminant Score and collected only if needed during the Screening Period.
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:


ABT-493, ABT-530
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●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or study drug or requires a subject to receive treatment will be recorded 
as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.1.7.
Pregnancy Test
A serum pregnancy test will be performed for all female subjects of childbearing potential 
at Screening.  Additional urine pregnancy tests will be performed at all the visits indicated 
in Table 6 and Table 7.  Arm B subjects will also have monthly urine pregnancy tests 
performed for a minimum of 6 months after the discontinuation or RBV, or according to 
the local RBV label and/or consistent with the local treatment guidelines for RBV.  
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 Table 4 (Treatment Period).  Thereafter, only medications taken 
for SAEs and treatment of HCV will be recorded in the eCRF at each study visit indicated 
in Table 5 (Post-Treatment Period).


ABT-493, ABT-530
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Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCV Ab and anti-HIV Ab tests will be 
performed at Screening.  The HIV Ab results will not be reported by the central laboratory 
to the clinical database.
Urine Screens for Drugs of Abuse
Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse.  
The panel for drugs of abuse will minimally include the drugs listed in Table 6.  Any 
positive result must be assessed for clinical significance, i.e., positive result is associated 
with documented short-term use or chronic stable use of a prescribed medication in that 
class.
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 (Discriminant Score, 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, New Inuyama 
or Laennec gradings with fibrosis score of ≤ 3, or Ishak grading with fibrosis score of ≤ 4 
are acceptable for ascertaining absence of cirrhosis.  Subjects with historical FibroScan®
or liver 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 
indeterminate FibroTest result (0.48 < result < 0.75), or conflicting FibroTest and APRI 
results (e.g., FibroTest ≤ 0.72, but APRI > 2 or FibroTest ≥ 0.73, but APRI ≤ 2) at 
Screening, a FibroScan® or liver biopsy can be performed during Screening to ascertain 
the presence or absence of cirrhosis.  Subjects with indeterminate FibroScan® score 


ABT-493, ABT-530
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(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.  Subjects with indeterminate 
Discriminant Score (score = 0) at Screening, a FibroScan or liver biopsy can be performed 
during Screening to ascertain the presence or absence of cirrhosis.
Study Drug Diary
Subjects will be provided self-administration instructions and study drug diaries to record 
the exact date, time and number of tablets of study drug administration.  On Study Day 1 
the time of dosing will be recorded to the nearest minute by the site staff.  The exact date, 
time and number of tablets of study drug taken will be recorded daily by the subjects 
between study visits.  The exact date, time and number of tablets of the last 2 doses of 
study drug will be recorded to the nearest minute on the 2 days prior to the scheduled 
pharmacokinetic (PK) sample collection starting with the Week 1 Visit, as specified in 
Table 4.  The site staff will record the information from the study drug diary for the last 
2 doses of study drug into the eCRF.  In the event the study drug diary is not available, the 
site may obtain dosing information via patient interview and record this information in the 
source notes. 
To facilitate proper dosing of study drug before PK evaluation blood samples are taken 
the following procedures should be performed:
●
The study coordinator should make sure the subject is given the dosing diary 
on the visit before the PK blood samples are taken.
●
The investigator or designee will contact the subject by telephone 
approximately 2 days prior to the scheduled PK blood collection date to review 
the importance of proper study drug administration relative to the PK blood 
collection and documentation of dosing times on the study drug diary.  
Documentation of the date and time of the phone contact will be entered into 
source documentation.
●
The subject should document on the study drug diary the exact date, time and 
number of tablets taken of the last 2 doses of study drug prior to the scheduled 
PK sampling.  The completed study drug diary will be collected by the 


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investigator or designee on the day of the PK sampling and be kept as a record 
of dosage administration times in the eCRF.
Subjects will be required to bring back all study drug kits (even if empty) and the study 
drug diary cards to the study site at the study visits indicated in Table 4.  Study drug 
compliance per the number of study drug tablets remaining in each kit will be recorded in 
the source and entered into the IRT system.  Additional information regarding treatment 
compliance can be found in Section 5.5.6.
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 Table 4 and Table 5.  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, 


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interfering with work, family, or social life).  The survey consists of 9 questions using a 
7-point Likert scale.  A total score is calculated as the average of the individual item 
responses.  The scale's psychometric properties have been confirmed in chronic 
hepatitis C and other diseases.  The FSS should require approximately 5 minutes to 
complete.
PRO instruments should be completed prior to drug administration on Study Day 1 and 
prior to any procedures or discussion of adverse events or any review of laboratory 
findings, including HCV RNA levels, at all other visits.
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 5-digit numbers and will begin with 20101 with the 
first three digits representing the investigative site, and the last two digits representing the 
subjects at that site.  Enrolled subjects will keep their screening number as their subject 
number throughout the study.  Subjects will be enrolled on Study Day 1 as described in 
Section 5.5.4 and will receive a separate unique 4-digit randomization number that will be 
recorded automatically in the eCRF through the IRT system.  This randomization number 
will be used only by AbbVie for loading the treatment schedule into the database.
Study Drug Compliance for Kits
Individual kits of ABT-493/ABT-530 and SOF and RBV will be provided for subject 
dosing to the site.  Each subject will have compliance documented by the site in the 
subject's source notes for ABT-493/ABT-530 and SOF and RBV.  At each Study Drug 
Accountability Visit in Table 4, the overall number of tablets of ABT-493/ABT-530 or 
SOF and RBV remaining in each kit will be recorded in the source and entered in the IRT 
system along with the date of reconciliation.


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HCV Genotype and Subgenotype
Plasma samples for HCV genotype and sub-genotype determination will be collected at 
Screening.  Genotype and sub-genotype will be assessed using the Versant® Inno-LiPA 
Assay, version 2.0 or higher, used by the central lab.  If the LiPA assay is unable to
genotype a sample, its genotype will be determined by a Sanger sequencing assay by the 
central lab.  Phylogenetic analysis of sequences will be performed by AbbVie to ascertain 
the HCV subtype.
HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Table 4 and 
Table 5.  Plasma HCV RNA levels will be determined for each sample collected by the 
central laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Quantitative Test, v2.0.  The lower limit of detection (LLOD) and lower limit of 
quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.  
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Study 
Day 1 and at the study visits indicated in Table 4 and Table 5.  Specific instructions for 
preparation and storage of HCV RNA and HCV resistance samples will be provided by 
the central laboratory, AbbVie, or its designee.
Archive Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Table 4 and 
Table 5.  Archive plasma samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, HCV RNA levels, 
safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and other 
possible predictors of response, as determined by AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.


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5.3.1.2
Meals and Dietary Requirements
Study drug (i.e., ABT-493/ABT-530 and SOF plus RBV) tablets/capsules should be taken 
after 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 (Required, JPMA Category A)
One (required) 2 mL whole blood sample for Deoxyribonucleic acid (DNA) isolation will 
be collected from each subject on Study Day 1 for Interleukin 28B (IL28B) 
pharmacogenetic analysis.  This sample will not be used for any testing other than IL28B 
genotypes.  IL28B genotyping will be performed by the central laboratory.  Any 
remaining DNA will be destroyed at the completion of the study.
Pharmacogenetic Sample (Optional, JPMA Category B)
A separate (optional) 4 mL whole blood sample for DNA isolation will be collected on 
Study Day 1 from each subject who consents to provide samples for pharmacogenetic 
analysis.  The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
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 20 years.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of ABT-493, ABT-530, SOF and RBV and 
their possible metabolites will be collected by venipuncture at each study visit indicated 
below and in Table 4.


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Subjects who do not participate in Optional Intensive PK sampling:
●
At all Treatment Period visits, except for Study Day 1, a single (3 mL) blood 
sample will be collected without regard to the time of dosing.
●
The date and time of blood sample collection and the two previous doses of the 
study drug from the study drug diary (see Section 5.3.1.1) 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 after food.  Blood samples will be 
collected on Study Day 1 at 2, 4 and 6 hours post-dose and at the Week 4 Visit 
immediately prior to dose (0 hour) and 2 and 4 hours post-dose.
○
The date and time of site-administered dose, blood sample collection and 
the two previous doses of study drug (for Week 4 Visit only) will be 
recorded to the nearest minute in the source documents.  Additionally, the 
date and time of the site-administered dose and two previous doses (for 
Week 4 Visit only) from the study drug diary (see Section 5.3.1.1) will be 
recorded to the nearest minute on the eCRF.
●
At all other Treatment Period visits, a single blood sample will be collected 
without regard to the time of dosing.
○
The date and time of blood sample collection and the two previous doses
of the study drug will be recorded to the nearest minute in the source 
documents.  Additionally, the date and time of the two previous doses of 
the study drug will be recorded to the nearest minute on the eCRF from the 
study drug diary (see Section 5.3.1.1).
A single (3 mL) blood sample will be collected from each subject at each time point (as 
applicable) for PK analysis in Arm A.  Two separate (3mL) blood samples will be 
collected from each subject at each time point (as applicable) for PK analysis in Arm B.


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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, ABT-530, 
SOF and RBV (and their possible metabolites) 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, ABT-530, SOF 
and RBV (and their possible metabolites) and archive plasma samples will be packed in 
dry ice sufficient to last during transport, and transferred from the study site to the central 
laboratory.
The central laboratory will then ship the ABT-493, ABT-530, SOF and RBV samples to 
the reference laboratories following separately provided instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of ABT-493, ABT-530, SOF, GS-331007 and RBV when 
applicable, will be determined using validated assay methods under the supervision of the 
Drug Analysis Department at AbbVie.  Plasma concentrations of possible metabolites of 
any analytes listed above may also be determined using either validated or non-validated 
methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Study Day 1 through 24 weeks after completion 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).


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5.3.3.2
Secondary Variable
The secondary efficacy variables are on-treatment virologic failure and post-treatment 
relapse.
5.3.4
Resistance Variables
For all subjects receiving ABT-493/ABT-530, the variants at signature 
resistance-associated amino acid positions at baseline identified by population or deep 
sequencing and comparison to the appropriate prototypic reference sequence will be 
analyzed.
The following resistance information will be analyzed for subjects receiving 
ABT-493/ABT-530 who do not achieve SVR12 and who have a post-baseline sample with 
HCV RNA ≥ 1000 IU/mL:  1) the amino acid variants in available post-baseline samples 
identified by population or deep sequencing in comparison to the baseline sequence, 
2) the amino acid variants in available post-baseline samples at signature 
resistance-associated positions identified by population or deep sequencing in comparison 
to the appropriate prototypic reference sequence, and 3) the persistence of viral variants 
by population or deep sequencing.
5.3.5
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, ECG, and laboratory tests assessments.
5.3.6
Pharmacokinetic Variables
Individual plasma concentrations of ABT-493, ABT-530, SOF, GS-331007 and RBV will 
be tabulated and summarized.
5.3.7
Pharmacogenetic Variables
IL28B status will be determined for each subject and analyzed as a possible factor 
contributing to the subject's response to study treatment.  These IL28B GT results may be 


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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 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 possibly contributing 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 the disease or drug response (including IL28B).  Some genes currently 
insufficiently characterized or unknown may be understood to be important at the time of 
analysis.  Pharmacogenetic analyses will be limited to studying response to the HCV 
therapy; no other analyses will be performed.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If, during the course of study drug administration, the subject prematurely discontinues, 
the procedures outlined for the applicable Premature D/C Visit should be completed as 
defined in Table 4 and Table 5.  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 


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judgment.  The last dose of any study drug and reason for discontinuation will be recorded 
in the EDC (electronic data capture) system.  The subject should then begin the 
Post-Treatment Period where the subject will be monitored for 24 weeks for HCV RNA, 
the emergence and persistence of resistant viral variants.
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 
ABT-493/ABT-530 to that subject may be continued after discussion with the AbbVie TA 
MD and the subject, if the benefit of continuing ABT-493/ABT-530 is felt to outweigh 
the potential risk.  However, those subjects receiving the SOF plus RBV regimen (Arm B) 
who have a positive result on a pregnancy test or report becoming pregnant during the 
Treatment Period, must be notified to stop SOF plus RBV immediately.  Specific 
instructions regarding subject pregnancy can be found in Section 6.1.6.  If a subject is 
discontinued, the subject will be monitored for SVR in the Post-Treatment Period as 
described in Section 5.1.3.  The investigator is also encouraged to report the pregnancy 
information to the voluntary RBV Pregnancy Registry.
5.4.1.1
Virologic Stopping Criteria
Virologic stopping criteria are defined as follows: 
●
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.


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When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic stopping criterion has been 
confirmed.  Subjects meeting virologic stopping criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistant viral variants until 24 weeks post-treatment.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Study drug (ABT-493/ABT-530) will be dispensed in the form of co-formulated tablets at 
the visits listed in Table 4.  SOF and RBV will be dispensed in the form of tablets and 
capsules, respectively, at the visits listed in Table 4.  Subjects will be instructed to take 
study drugs at the same time every day after 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 at these visits after food and having blood samples 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.


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ABT-493/ABT-530 will be provided by AbbVie as 100 mg/40 mg co-formulated tablets.  
ABT-493/ABT-530 will be taken orally as 3 tablets once daily, which corresponds to 
ABT-493 300 mg/ABT-530 120 mg QD.
SOF will be provided by AbbVie as 400 mg tablets.  SOF will be taken orally as 1 tablet 
once daily, which corresponds to 400 mg QD. 
RBV will also be provided by the AbbVie for use in this study as 200 mg capsules.  RBV 
should be dosed based on consideration of the subject's weight from the Study Day 1 Visit 
and their hemoglobin test results from the Screening Visit, according to the current 
approved local RBV label.
All study drugs should be taken after 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 virologic stopping 
criteria defined in Section 5.4.1.1 will be discontinued from treatment.
5.5.2
Identity of Investigational Products
Information about the study drugs to be used in this study is presented in Table 7.
Table 7.
Identity of Investigational Products
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
ABT-493/ABT-530
AbbVie
Oral
Tablet
100 mg/40 mg
SOF
Gilead
Oral
Tablet
400 mg
RBV
MSD
Oral
Capsule
200 mg


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5.5.2.1
Packaging and Labeling
ABT-493/ABT-530 will be supplied in bottles containing 30 tablets.  SOF will be 
supplied in bottles containing 28 tablets.  RBV will be supplied in blister/carton boxes 
containing 140 capsules.
Each kit will be labeled as required per country requirements.
The labels must remain affixed to the kits.  All blank spaces should be completed by site 
staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drugs
Study Drug
Storage Conditions
ABT-493/ABT-530 bottles
15° to 25°C (59° to 77°F)
SOF bottles
1° to 30°C (33.8° to 86°F)
RBV kits
1° to 30°C (33.8° to 86°F)
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use 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 randomization numbers.  The 
randomization number will be used only by AbbVie for loading the treatment assignments 
into the database.  The randomization numbers will be assigned according to schedules 
computer-generated before the start of the study by the AbbVie Statistics Department.  


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The randomization will be stratified by prior IFN-experience (naïve versus experienced) 
and Screening HCV RNA (< or ≥ 6 million IU/mL).
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 5.3.1.1.
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.  SOF will be dosed 
QD.  RBV should be dosed BID, e.g., 1 or 2 capsules taken in the morning, and 2 or 
3 RBV capsules should be taken in the evening.  All subjects should take all doses of 
study medications after 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 visit during the Treatment Period, subjects will be instructed to bring all 
bottles of study drug (full, partial or empty) for assessment of treatment compliance.  At 
post-baseline dispensing visits denoted in Table 4, study site personnel will assess subject 


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compliance by inspecting the contents of the bottles and record the status of each one, as 
well as the exact number of remaining tablets of study drug 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.  This will be documented by signing 
and dating the Proof of Receipt (POR) or similar document and via recording in the IRT 
system.  A current (running) and accurate inventory of study drug will be kept by the 
investigator and will include lot number, kit number, number of tablets dispensed, subject 
number, initials of 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 kit of 
ABT-493/ABT-530, SOF or RBV the IRT system must be contacted and informed of the 
misplaced or damaged study drug.  If the kit 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 kit, 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.


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Upon completion of or discontinuation from the Treatment Period, all original study drug 
kits (containing unused study drugs) will be returned to AbbVie (or designee).  All 
destruction procedures will be according to instructions from AbbVie and according to 
local regulations following completion of drug accountability procedures.  The number of 
tablets of each type of study drug returned in each kit 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
This is a multicenter, randomized, active-control, open label Phase 3 study in DAA 
treatment-naïve HCV GT2-infected Japanese subjects without cirrhosis, evaluating the 
safety and efficacy of the ABT-493/ABT-530 300/120 mg QD combination for 8 weeks 
of treatment.
Evaluation of an 8-week treatment duration in the current study is supported by efficacy 
data from Arm J in Part 2 of the ongoing Study M14-868 evaluating ABT-493 300 mg in 
combination with ABT-530 120 mg in GT2-infected patients without cirrhosis for 
8 weeks, where preliminary data show that 53/54 (98%) of subjects achieved SVR4.  Also 
GT2-infected patients in Part 1 of Study M14-868 receiving ABT-493 300 mg and 
ABT-530 120 mg for 12 weeks demonstrate 96% SVR12 rate in subjects 
(i.e., 24/25 patients achieved SVR12 with no subjects experiencing virologic failure and 
one patient was lost-to-follow-up).
The primary objective of this study is to assess the efficacy and safety of 8 weeks of 
treatment with the combination regimen ABT-493/ABT-530 compared to SOF plus RBV 
in HCV GT2-infected subjects without cirrhosis.  A comparative study utilizing an active 
control design provides an adequate assessment of the efficacy and safety of the 
combination of ABT-493 and ABT-530 compared to a standard of care regimen, while 
also providing a potentially efficacious or approved regimen to all participating subjects.


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5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays for the primary and secondary efficacy endpoints are 
standard and validated.
5.6.3
Suitability of Subject Population
This study will enroll subjects with HCV GT2 infection who are naïve or IFN experienced 
(with or without RBV) to HCV treatment, without cirrhosis.  The sample size of 
120 subjects is sufficient to power the non-inferiority efficacy comparison while limiting 
the number of subjects as only approximately 30% of the Japanese HCV-infected 
population has GT2 infection.  
5.6.4
Selection of Doses in the Study
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.  The dose of SOF plus 
RBV was selected based on its approval for use in Japan.
5.6.4.1
ABT-493, ABT-530, SOF and RBV Doses
The 300 mg ABT-493 and 120 mg ABT-530 doses were selected to provide one regimen 
for all HCV genotypes that is safe and achieves drug exposure coverage that maximizes 
the chance to prevent the selection of resistant virus and achieves the highest possible 
SVR rates.  Further detailed rationale is provided below:
●
ABT-493/ABT-530 doses lower than 300 mg/120 mg showed suboptimal SVR 
rate in Phase 2 GT1 and GT3-infected subjects:  in Part 1 of Study M14-867 in 
all 40 GT1-infected subjects who received ABT-493 200 mg and ABT-530 
120 mg (including 15 PR-null responders) achieved SVR12.  One subject 
(treatment-naive) in the ABT-493 200 mg and ABT-530 40 mg arm had 
virological relapse at Post-Treatment Week 4.  In Part 1 of Study M14-868 in 
GT3-infected subjects, both ABT-530 doses of 40 mg and 120 mg were 
evaluated in combination with ABT-493:  2 subjects experienced virologic 


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failure in the ABT-530 40 mg arm and 3 subjects experienced virologic failure 
in the ABT-530 120 mg arm.  For ABT-493, in the GT3 arms of Part 1 of 
Study M14-868, 2 subjects (1 treatment-naïve and 1 PR-experienced) had 
virologic breakthrough before the completion of treatment in the 200 mg 
ABT-493 groups.  No subjects receiving 300 mg ABT-493 have had 
breakthroughs before completion of treatment.  The results suggested that the 
300 mg ABT-493 dose reduces the incidence of breakthroughs and increases 
the chance of achieving SVR.  For GT2, ABT-493 300 mg and ABT-530 
120 mg have been administered to 54 subjects and no subject had virologic 
failure.  Across different HCV genotypes 1 to 6, ABT-493 300 mg + ABT-530 
120 mg dose demonstrated potent in vitro efficacy with high SVR rates of 
96% – 100%.  Since the objective is to develop one dose across all genotypes, 
the proposed dose for treatment of GT-2 infection is the fixed-dose 
combination of ABT-493/ABT-530 (300/120 mg).
●
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 
have been no on treatment ALT elevations above baseline grade.
●
In Phase 1 studies, no ethnic difference was observed in ABT-493 and 
ABT-530 exposures for Japanese, Han Chinese and Caucasian subjects which 
supports using the same doses in the Japanese subjects as those in the Western 
studies.
For Phase 3 studies, s film-coated co-formulated bilayer tablet of ABT-493 and ABT-530 
will be used.  Preliminary pharmacokinetic results of the Phase 3 bilayer tablet 
administered under fasting conditions showed approximately 35% to 56% lower 
bioavailability compared to the Phase 2 formulation at the ABT-493 300 mg and 
ABT-530 120 mg.  When the Phase 3 bilayer tablet was administered under non-fasting 


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conditions, exposures became comparable to the Phase 2 formulations.  Hence, in Phase 3 
studies, the ABT-493/ABT-530 bilayer tablet should be administered after food.  
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for 
8 weeks.
The dose of SOF plus RBV (SOF 400 mg per day, RBV 600 to 1000 mg per day based on 
body weight) to be administered in the study is the approved dose for HCV GT2-infected 
subjects in Japan.
The maximum dose of SOF will not exceed 400 mg per day for 12 weeks and the 
maximum dose of RBV will not exceed 1000 mg per day for 12 weeks.
5.6.4.2
Rationale for Duration Selections
Evaluation of an 8-week treatment duration for ABT-493/ABT-530 in the current study is 
supported by preliminary data from the ongoing Phase 2b Study M14-868 Part 2.  In 
Arm J of Part 2 evaluating ABT-493 300 mg + ABT-530 120 mg for 8 weeks in 
GT2-infected subjects without cirrhosis, 53 out of 54 (98%) subjects achieved SVR4
(1 subject lost to follow up) and to date, 23 out of 23 (100%) achieved SVR12.  The 
one subject that did not achieve SVR4 was lost to follow-up and did not experience 
virologic failure.  
For the active control arm, SOF plus RBV is approved for 12-week treatment duration in 
HCV GT2-infected subjects.
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 
resistance to paritaprevir or ombitasvir were detected in patients experiencing virologic 


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failure.  While data from patients treated with the combination of ABT-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 variants in NS3 that confer resistance 
to ABT-493, because there should not be any cross-resistance in variants resistant to 
DAAs targeting different proteins.  The converse is expected to be true as well –
ABT-493 should be able to suppress the appearance of virus containing NS5A variants 
conferring resistance to ABT-530.  In addition, in vitro resistant colony selection studies 
in HCV replicon cells containing GT1 – 6 NS5A demonstrated that ABT-530 had a high 
genetic barrier to resistance – very few colonies were selected, and those that were 
selected contained NS5A variants that conferred only modest levels of resistance to 
ABT-530.  It remains to be seen whether the development of resistance in subjects treated 
with ABT-530 resembles that seen in vitro.  Based on accumulated clinical and in vitro 
data to date, the risk of development of resistant variants during ABT-493 and ABT-530 
combination trials is reduced when compared to treatment with first generation protease 
and NS5A inhibitors.  For example, in Phase 2b Study M14-867 Part 1 evaluating the 
combination of ABT-493 and ABT-530 in GT1-infected subjects without cirrhosis for a 
12-week duration, 79 subjects have reached post-treatment Week 12 as of 22 May 2015.  
Among these 79 subjects, 1 subject experienced virologic failure, and preliminary 
sequencing results indicated that treatment-emergent NS5A RAVs were detected at the 
time of failure in this subject.  These results support the prediction that the risk of 
development of resistance-associated variants with ABT-493 and ABT-530 combination 
treatment is low.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.


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Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1.  
For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 


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event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, [meets protocol specific criteria (see Section 6.1.7 regarding toxicity 
management)] and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
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.


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Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency 
or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4).
The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 


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


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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.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related non-serious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study 
drug administration until 30 days following discontinuation of study treatment has 
elapsed, all adverse events will be collected, whether solicited or spontaneously reported 
by the subject.  After 30 days following completion of study treatment and throughout the 
Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection


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6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  
FAX to:
For safety concerns, contact the Japan Medical Science Group at:
Medical Science Group
Tokyo, 108-6302


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


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In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
6.1.6
Pregnancy
Subjects and their partners should avoid pregnancy starting with Screening and through 
30 days after stopping study drugs for Arm A and 6 months after stopping study drugs for 
Arm B.
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  The investigator should discuss the potential risks 
versus benefits with the subject and contact the AbbVie TA MD to determine if the 
subject should continue or discontinue ABT-493/ABT-530.  Administration of 
ABT-493/ABT-530 may be continued after approval by the AbbVie TA MD, if the 
benefit of continuing therapy is felt to outweigh the risk (Section 5.4.1).  However, in the 
event of pregnancy, administration of SOF plus RBV must be discontinued immediately.  
If study drug 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 with ABT-493/ABT-530 or through the duration of the study (or per local RBV 
label) for treatment with SOF plus RBV.  The investigator is encouraged to report the 
pregnancy information to the voluntary RBV Pregnancy Registry, if RBV is included 
within the regimen.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.


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6.1.7
Toxicity Management
The Toxicity Management guidance applies to all subjects enrolled in both arms of the 
study with additional guidance provided in sections addressing hemoglobin 
(Section 6.1.7.4) and creatinine clearance (Section 6.1.7.6) for subjects in Arm B.  For the 
purpose of medical management, all adverse events and laboratory abnormalities that 
occur during the study must be evaluated by the investigator.  The table of clinical toxicity 
grades for evaluating laboratory abnormalities is provided in Appendix C.  This table 
should be used in determination of the appropriate toxicity management as discussed in 
Section 6.1.7.1 and Section 6.1.7.2.  The toxicity management guidelines outlined below 
(Sections 6.1.7.1 through 6.1.7.5) should be followed throughout the Treatment Period of 
the study.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or the Sponsor as having a "reasonable possibility" 
of being related to the study drugs (Section 6.1.7.4).  A toxicity is deemed "clinically 
significant" based on the medical judgment of the investigator.  Laboratory abnormalities 
will be managed as deemed clinically appropriate by the investigator until resolved.
Study drugs should not be interrupted for toxicity management for more than 
7 consecutive days.  If study drugs needs to be interrupted for more than 7 consecutive 
days, consideration should be given to discontinue the subject and the AbbVie TA MD 
should be contacted.  The appropriate study drug interruption for toxicity management 
eCRF should be completed.
The toxicity management guidelines below should be followed. 
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities or Adverse Events
Subjects who develop a study drug-related (reasonable possibility) Grade 1 or 2 adverse 
event or Grade 1 or 2 laboratory abnormality [other than those discussed separately in the
Toxicity Management Section for ALT elevations and bilirubin elevations 
(Section 6.1.7.5 and Section 6.1.7.7) and hemoglobin and creatinine clearance decreases 


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(Section 6.1.7.4 and Section 6.1.7.6), may continue study drugs with appropriate medical 
management and follow-up per study protocol.
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities
If a subject experiences a Grade 3 or greater laboratory parameter during the study (other 
than those discussed separately in the Toxicity Management Section for ALT and 
bilirubin elevations [Section 6.1.7.5 and Section 6.1.7.7] and hemoglobin and creatinine 
clearance decreases for subjects in Arm B [Section 6.1.7.4 and Section 6.1.7.6]), the 
abnormal laboratory test should be repeated.  If the Grade 3 or greater abnormality is 
confirmed, the study drugs should be interrupted until the laboratory parameter has 
returned to its baseline level or stabilized.  The study drugs can be restarted if the 
laboratory parameter reaches baseline grade or Grade 1 (whichever is higher) within 
7 days of study drug interruption.  If study drugs are interrupted and restarted and the 
laboratory value rises to Grade 2+ or a grade higher than baseline, then study drugs should 
be permanently discontinued, unless approval for continuing study drugs is obtained from 
the AbbVie TA MD.  If the abnormality does not reach Grade 1 or the baseline grade 
within 7 days of interruption, the study drugs should be permanently discontinued.
If the investigator considers that the confirmed Grade 3 or greater laboratory parameter is 
not clinically significant or is not related to study drug and therefore study drug 
interruption or discontinuation is not warranted, study drugs can be continued with 
approval of the AbbVie TA MD.
Grade 3 or higher elevations in uric acid, phosphorous, total cholesterol, triglycerides, or 
glucose (in subjects with a history of diabetes) should be managed medically as 
appropriate and do not require confirmation or study drug interruption.  However, study 
drug may be interrupted if deemed necessary by the investigator.


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6.1.7.3
Grade 3 or 4 Adverse Event or Serious Adverse Event
If a subject experiences a Grade 3 or 4 adverse event or a serious adverse event that the 
investigator considers to have a reasonable possibility of relationship to study drug, the 
following should occur:
●
Study drugs should be discontinued,
●
The AbbVie TA MD should be contacted to discuss the event,
●
The subject should be monitored until event resolution.
If the investigator believes that the drug-related (reasonable possibility) Grade 3 or 4 
adverse event or serious adverse event can be managed medically without permanent 
discontinuation, then the AbbVie TA MD should be contacted to discuss continued study 
drug administration with medical management.
If a subject experiences a Grade 3 or 4 adverse event or serious adverse event that is 
considered unrelated (no reasonable possibility) to the study drugs, then study drugs may 
be continued.
If study drug interruption is deemed necessary for clinical management, the interruption 
should not exceed 7 days.  If study drug interruption is required for longer than 7 days, 
then study drugs should be permanently discontinued.
The investigator should ensure that all serious adverse events are reported to AbbVie 
within 24 hours of awareness.  Serious adverse event follow-up information, including 
associated dose interruptions (or discontinuations), must be reported to the AbbVie within 
24 hours of awareness by entering updated SAE information into the appropriate eCRFs.  
Grade 3 or 4 adverse events and any associated dose interruptions (or discontinuations) 
should be entered into the appropriate eCRFs.


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6.1.7.4
Management of Decreases in Hemoglobin
For subjects in Arm A (not receiving RBV), hemoglobin decreases should be managed 
according to Toxicity Grade based on the guidance in Section 6.1.7.1 and Section 6.1.7.2. 
For subjects in Arm B (receiving SOF and RBV), hemoglobin decreases should be 
managed according to Table 8.
Decreases in hemoglobin are a well characterized side effect of ribavirin exposure. If a 
subject receiving the standard dose of ribavirin experiences a hemoglobin decrease 
meeting one of the criteria outlined in Table 8, a confirmatory test should be performed.  
If the hemoglobin decrease is confirmed, the management guidelines in Table 8 should be 
followed.  Management will be different for subjects without a history of known cardiac 
disease and subjects with known cardiac disease.  Subjects experiencing decreases in 
hemoglobin that do not meet the criteria outlined in Table 8 may need hemoglobin 
evaluations at more frequent intervals at the discretion of the investigator.
Use of hematologic growth factors (such as erythropoietin or filgrastim) or blood 
transfusions are permitted at the discretion of the investigator.  Management of 
hematologic growth factor therapy is the responsibility of the Investigator, and growth 
factors will not be provided by AbbVie.
Alternate management of hemoglobin decreases outside of these criteria is permitted with 
approval of the AbbVie TA MD.


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Table 8.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases
Laboratory Parameter
Value
Ribavirin
Hemoglobin level (patients 
without current or a history of 
heart disorder
< 10 g/dL
Reduce dosage 
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1000 mg/day → 600 mg/day
< 8.5 g/dL
Discontinuea
Hemoglobin level (patients with 
current or a history of heart 
disorderb
< 10 g/dL, or a decrease of 
≥2 g/dL from baseline 
persisting for 4 weeks during 
treatment with a reduced dose
Reduce dosage 
600 mg/day → 400 mg/day
800 mg/day → 600 mg/day
1000 mg/day → 600 mg/day
< 8.5 g/dL or < 12g/dL after 
4 weeks of treatment with a 
reduced dose
Discontinuea
a.
If ribavirin is discontinued, sofosbuvir also must be discontinued to avoid sofosbuvir monotherapy.
b.
When REBETOL is administered to patients with current or a history of heart disorder, the treating physician 
should consider reducing the dose of REBETOL if a decrease of ≥ 2 g/dL from baseline persists for 4 weeks 
despite a current Hb level of ≥ 10 g/dL and should consider discontinuing REBETOL if the Hb level is less than 
12 g/dL (albeit 8.5 g/dL or higher) after 4 weeks of treatment with a reduced dose (see "Careful administration").
Notes:
Reduce RBV daily dose in accordance with local RBV prescribing information/product label.
Monitor neutrophil and platelet counts in accordance with the local RBV prescribing information/product 
label.
If the abnormality is reversed, RBV may be restarted at the discretion of the investigator and in accordance 
with local RBV prescribing information/product label.
6.1.7.5
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:
●
Evaluate for alternate etiology of ALT elevation; document in the source and 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain additional testing as appropriate (e.g., hepatitis B panel).*
●
Manage the subject as medically appropriate.


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●
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.
○
Onset of symptoms/signs of hepatitis.
○
At the discretion of the investigator.
*  If another cause is identified based on additional testing, study drugs may be 
continued and subject should be managed as medically appropriate.
Alternate management of ALT increases is permitted with approval of the AbbVie TA 
MD.
6.1.7.6
Creatinine Clearance
If calculated creatinine clearance (by Cockcroft-Gault formula) is confirmed to have 
decreased to < 50 mL/minute, medical evaluation should include a full review of current 
medications, including those taken on an as needed basis, those which are sold over the 
counter and any dietary and herbal supplements, and appropriate dose reduction or 
discontinuation based on impaired renal function should be done (if applicable).  For 
subjects in Arm B, if the investigator considers ribavirin to be the cause of decreased 
creatinine clearance < 50 mL/minute, then consideration should be given to discontinue 
both ribavirin and sofosbuvir.  However, the decision to discontinue ribavirin and 
sofosbuvir should be made only after discussion of the risks versus benefits of 
discontinuation with the AbbVie TA MD.  The investigator should also consider whether 
concomitant medications may have contributed to the decrease in creatinine clearance, 
and whether discontinuation or substitution of the concomitant drug might be needed.  
Alternative management of RBV continuation (including dose reduction of ribavirin) in 
the setting of reduced renal function will require approval of the AbbVie TA MD.


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In addition, the following should occur:
●
For subjects in Arm B, SOF and RBV local labels must be checked for any 
SOF and/or RBV dose adjustments.
●
Additional work-up (e.g., CPK, urine albumin) should be done as clinically 
indicated.
The Investigator should ensure that any concomitant medication changes, RBV dose 
reductions, and study drug discontinuations, as well as consequent related adverse events 
are entered into the appropriate eCRFs.
6.1.7.7
Management of Grade 3 or Greater Elevations of Total 
Bilirubin
All grade 3 or greater results for total bilirubin should be fractionated for direct and 
indirect bilirubin and repeated.  If there is a confirmed Grade 3 total bilirubin, these 
results should be discussed with the AbbVie TA MD and consideration given to 
discontinuation of study drugs in the subject.  The decision to discontinue study drugs 
should take into consideration the clinical status of the subject, including any clinical 
signs/symptoms reported by the subject as well as laboratory results, and will be at the 
clinical discretion of the investigator.
Alternate management of bilirubin increases is permitted with approval of the AbbVie 
TA MD.
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 


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


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authorities (as applicable), their assigned Site Monitor along with the following AbbVie 
Clinical Monitors:
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.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
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 
appropriate data cleaning.  Data after PT Week 12 will be added to a new version of the 
database which will be cleaned and locked at the end of the study.
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 αlevel of 
0.05.  


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Analyses will be performed on the intent-to-treat (ITT) population defined as all 
randomized subjects who receive at least one dose of study drug, unless otherwise 
specified.  Sensitivity analyses of the primary endpoint, will be performed on the modified 
ITT (mITT) population to exclude subjects not of GT2 according to the central laboratory 
or according to phylogenetic analyses (mITT-GT), and on the mITT-GT population 
further modified to exclude subjects who did not achieve SVR12 for reasons other than 
virologic failure (mITT-GT-VF).
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data) and the 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 and baseline characteristics will be summarized for all subjects in the ITT 
population for each treatment arm.  Demographics include age, weight, height, BMI, 
gender, race, and ethnicity.  Baseline characteristics will be summarized as continuous 
variables (where appropriate) and as categorical variables, including all subgroup 
variables defined in Section 8.1.2.4, and include HCV genotype and subtype, IL28B 
genotype, prior HCV treatment history, baseline HCV RNA level, fibrosis stage (F0 – F1, 
F2, F3]), baseline homeostasis model of assessment – insulin resistance (HOMA-IR), 
tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) 
status, former injection drug user (yes, within last 12 months; yes, more than 12 months 
ago; or no), use of stable opiate substitution, history of diabetes, history of bleeding 
disorders, history of depression or bipolar disorder, and history of cardiovascular disease.
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).  Treatment arms will be compared 


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using a chi-square test for categorical variables and using a one-way analysis of variance 
(ANOVA) with treatment arm as the factor for continuous variables.
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.  Compliance will be calculated for each subject for each tablet type, 
and summarized with the mean, median, standard deviation, minimum, and maximum.  A 
subject is considered to be compliant if the percentage is between 80% and 120%.  The 
percentage of compliant subjects will be summarized for each treatment arm and 
tablet/capsule type.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0 which has lower limit of quantification (LLOQ) and lower limit of detection 
(LLOD) of 15 IU/mL.  The notation "HCV RNA < LLOQ" is used to represent all HCV 
RNA values < 15 IU/mL that are HCV RNA detected or HCV RNA not detected.  HCV 
RNA ≥ LLOQ are all quantifiable values.
IL28B rs12979860 will be resulted as C/C, C/T, or T/T by the central laboratory.
8.1.2.1
Primary Efficacy Endpoints
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  
The primary efficacy endpoint is:
●
Non-inferiority of the ABT-493/ABT-530 8-week regimen (Arm A) to the 
SOF/RBV 12 week regimen (Arm B) in SVR12 using a non-inferiority margin 
of 10% in the ITT population.


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For the primary efficacy endpoint, to show non-inferiority of the SVR12 rate of the 
ABT-493/ABT-530 8-week regimen (Arm A) to that of the SOF/RBV 12-week regimen 
(Arm B), the percentage of subjects achieving SVR12 will be calculated for each arm and 
a two-sided 95% confidence interval for the difference in SVR12 rates (Arm A minus 
Arm B) will be calculated using the normal approximation to the binomial distribution.  
All subjects in the ITT population will be used when calculating SVR12.  If the lower 
bound of the confidence interval for the difference is above the non-inferiority margin of 
–10%, then the ABT-493/ABT-530 8-week regimen will be considered non-inferior to 
SOF/RBV 12 week regimen. 
8.1.2.2
Secondary Efficacy Endpoints
The following secondary endpoints will be summarized:
●
the percentage of subjects achieving SVR12 for Arm A (the 
ABT-493/ABT-530 8-week regimen)
●
the percentage of subjects with on-treatment virologic failure (defined as 
confirmed increase of > 1 log10 IU/mL above nadir during treatment, 
confirmed HCV RNA ≥ 100 IU/mL  after HCV RNA < LLOQ during 
treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks 
of treatment), and 
●
the percentage of subjects with post-treatment relapse (defined as confirmed 
HCV RNA ≥ LLOQ between end of treatment and 12 weeks after the last dose 
of study drug among subjects who completed treatment as planned with HCV 
RNA < LLOQ at the end of treatment, excluding subjects who have been 
shown to be reinfected).
For the first secondary efficacy endpoint, the percentage of achieving SVR12 in Arm A 
and a two-sided 95% confidence interval will be calculated using the normal 
approximation to the binomial distribution, unless the rate is 100% and then the Wilson's 
score method will be used.  


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For the analysis of relapse and reinfection, completion of treatment is defined as any 
subject assigned to the12-week treatment with study drug duration of 77 days or greater; 
or any subject assigned to the 8-week treatment with study drug duration of 52 days or 
greater.  Subjects with probable reinfection based on HCV sequencing or differing 
post-treatment HCV genotype or subtype will be summarized separately from relapse.
The percentage of subjects with on-treatment virologic failure and post-treatment relapse 
will be summarized for each treatment arm.  Two-sided 95% confidence intervals will be 
provided for rates within treatment arms and for the difference between arms (Arm A 
minus Arm B) using Wilson's score confidence intervals.
In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection, other) will be provided for each treatment arm.
8.1.2.3
Sensitivity Analysis
The following analysis approaches will be used as sensitivity analyses for evaluating 
SVR12 rates within and between treatment arms for the primary efficacy endpoint: 
●
A two-sided 95% confidence interval for the SVR12 rates within each arm will 
be calculated using a Wilson score interval.
●
The percentage of subjects achieving SVR12 will be compared using a logistic 
regression model with treatment arm as a factor, and baseline log10 HCV RNA 
level, HCV genotype 2 subtype, and prior HCV treatment history as 
coviariates.
●
The difference in SVR12 rates (Arm A minus Arm B) will be analyzed using a 
stratum-adjusted Mantel-Haenszel (MH) proportion with a continuity 
correction for variance, adjusting for both of the randomization stratum 
(described in Section 8.3).
●
A two-sided 95% confidence interval for the difference in SVR12 rates (Arm A 
minus Arm B) will be calculated using a Wilson score interval.


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The above analyses will be performed on the ITT, mITT-GT, and mITT-GT-VF 
populations, as applicable.
8.1.2.4
Subgroup Analysis
To evaluate the impact of various characteristics on treatment effect, subgroup analyses 
will be performed for the primary efficacy endpoint. Within each subgroup, the 
percentage of subjects with SVR12 within each arm and the difference between treatment 
arms in the percentage of subjects with SVR12 will be calculated, as will the 
corresponding two-sided 95% Wilson score confidence intervals.  A test of homogeneity 
will be conducted (Zelen's exact test) to evaluate whether differences between treatment 
arms are consistent across subgroups (i.e., confidence intervals for the difference in SVR12
rates will not be compared to the non-inferiority margin due to the decreased sample size 
in each subgroup).  The following subgroups will be analyzed:
●
HCV genotype 2 subtype;
●
Prior HCV treatment history;
○
For treatment experienced subjects, type of non-response to previous 
treatment;
●
IL28B genotype;
●
Sex;
●
Age;
●
Race;
●
Ethnicity;
●
BMI;
●
Baseline HCV RNA level;
●
Baseline HOMA-IR;
●
Baseline fibrosis stage;
●
Baseline platelet count;
●
Baseline albumin;
●
Baseline GGT; 


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●
Baseline LDL;
●
Baseline APRI;
●
Baseline FIB-4;
●
AST/ALT ratio;
●
History of diabetes;
●
History of bleeding disorders;
●
History of depression or bipolar disorder;
●
History of cardiovascular disease;
●
Former injection drug user;
●
Subject on stable opiate substitution;
●
Compliant to study drug.
Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized and analyzed for each 
treatment arm:
●
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;
●
The reasons for not achieving SVR12 and the reasons for not achieving SVR24
In the above analyses for SVR and reasons for not achieving SVR, the percentage of 
subjects in each treatment arm with a two-sided 95% Wilson score confidence interval 
will be summarized.


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8.1.3
Patient Reported Outcomes
For EQ-5D-3L index and VAS scores, no imputation will be performed for missing items.  
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.
The mean and mean change from baseline to each applicable post-baseline timepoint in 
the FSS total score, EQ-5D-3L health index score and VAS score will be summarized 
descriptively by treatment arm.  For each of these scores, mean change from baseline to 
Final Treatment Visit and from baseline to Post-Treatment Week 12 will be compared 
between treatment arms using an analysis of covariance (ANCOVA) model with 
treatment arm as a factor and baseline score as a covariate.
8.1.4
Resistance Analyses
The DNA encoding NS3 amino acids 1 – 181 and NS5A amino acids 1 – 215 will be 
sequenced by population or deep sequencing for analysis of available baseline samples 
from the SVR-achieving subjects in Arm A.  For subjects in Arm A who do not achieve 
SVR12, full length NS3/4A and NS5A genes from their available baseline and virologic 
failure (VF)/discontinuation 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.  For subjects who experience VF in Arm B 
(on-treatment VF or post-treatment relapse), the full length NS5B gene from their 
available baseline and VF samples will be sequenced by population or deep sequencing.  
An appropriate prototypic reference sequence will be used for comparison with sequences 
from subject 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 VF or treatment discontinuation is < 1000 IU/mL, the sample 
closest in time after VF/discontinuation with an HCV RNA level ≥ 1000 IU/mL will be 
used.  Included time points for analyses on available samples from subjects in Arm A who 
do not achieve SVR12 are 1) the sample closest in time after VF/discontinuation with an 


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HCV RNA level of ≥ 1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that 
resistance-associated variants were detected by either population or deep sequencing at 
the time of VF/discontinuation.  The included time point for analyses on available 
samples from subjects in Arm B who experience VF is the sample closest in time after VF 
with an HCV RNA level of ≥ 1000 IU/mL.
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:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline in the subject.
●
Enriched variant:  a post-baseline variant that is enriched by at least 20% 
relative to its prevalence in the corresponding baseline sequence 
(post-baseline % – baseline % ≥ 20) by deep sequencing. 
●
Treatment-emergent variant:  A post-baseline variant or an enriched variant.
●
Emerged variant:  a treatment-emergent variant that is observed in 2 or more 
subjects of the same HCV subtype.
The following baseline analyses will be performed:
The HCV amino acid sequence as determined by population or deep sequencing of 
available baseline samples from subjects in Arm A 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 impact of baseline variants on treatment outcome for subjects in Arm A will be 
assessed as follows:  for each variant, the SVR12 rate will be calculated for subjects 
with and for subjects without the variant, and the 2 rates will be compared using 


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Fisher's exact test.  The analyses will be grouped by baseline variant and prevalence of 
each variant within a subject's viral population, HCV subtype, and DAA target (NS3 
or NS5A).
For subjects in Arm B who experience VF, a listing by subject of all baseline variants 
relative to prototypic reference sequence at signature resistance-associated amino acid 
positions will be provided for NS5B.
The following analyses will be performed for subjects in Arm A who do not achieve 
SVR12 and have post-baseline resistance data available:
The HCV amino acid sequence as determined by population or deep sequencing on 
the sample closest in time after VF or treatment discontinuation with an HCV RNA 
level of ≥1000 IU/mL will be compared to the baseline and appropriate prototypic 
reference amino acid sequence.  Listings by subject of all treatment-emergent variants 
detected by population or deep sequencing relative to the baseline amino acid 
sequences will be provided for each DAA target (NS3 and NS5A).  In addition, 
listings by subject of all variants (by population or deep sequencing) at signature 
resistance-associated amino acid positions relative to the appropriate prototypic 
reference amino acid sequences will be provided for each DAA target (NS3 and 
NS5A).
The persistence of post-baseline variants at signature resistance-associated amino acid 
positions for each target (NS3 and NS5A) will be assessed by population or deep 
sequencing at Post-Treatment Week 24.  Listings by subject and time point of all post 
baseline variants relative to the baseline amino acid sequence will be provided for 
each DAA target (NS3 and NS5A).
If resistance-associated variants are not detected by either population or deep 
sequencing in a given target for a subject at the time of failure/discontinuation, then 
that target may not be sequenced in subsequent samples from that subject.


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The following will be provided for subjects in Arm B who experience VF and have 
post-baseline resistance data available:
A listing by subject of all treatment-emergent variants at signature 
resistance-associated amino acid positions in NS5B relative to the baseline amino acid 
sequence.
Phylogenetic analysis will be conducted on HCV sequence from available baseline 
samples from all subjects in order to accurately determine their subtype.  The resulting 
subtype information will be presented in summaries of baseline characteristics and 
efficacy subgroup analyses.
8.1.5
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.  
8.1.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects in each arm with treatment-emergent 
adverse events (i.e., any event that begins or worsens in severity after initiation of study 
drug through 30 days post-study drug dosing) will be tabulated by primary MedDRA 
System Organ Class (SOC) and preferred term (PT) and compared between arms using 
Fisher's exact test.  The tabulation of the number of subjects with treatment-emergent 
adverse events by severity grade and relationship to study drug also will be provided.  
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term using the most severe grade for the severity grade table 
and the most related for the relationship to study drug tables.  Subjects reporting more 
than one type of event within a SOC will be counted only once for that SOC.


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8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized by arm 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 and the between-arm comparison will be performed using contrasts within an 
ANOVA model with treatment arm as the factor.
Laboratory data values will be categorized as low, normal, or high based on reference 
ranges of the laboratory used in this study.  The number and percent of subjects who 
experience post-baseline shifts in clinical laboratory values from low/normal to high and 
high/normal to low based on the normal range will be summarized by arm.
In addition, the number and percentage of subjects with post-baseline values meeting 
pre-specified criteria for Potentially Clinically Significant (PCS) laboratory values or 
toxicity grades will be summarized by arm.  The between-arm comparison will be 
performed on the percentage of subjects with laboratory abnormalities (PCS or by toxicity 
grade) for each parameter using Fisher's exact tests.
8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each post-baseline visit, including Final Treatment Visit, will be 
summarized descriptively by arm and the between arm comparison will be performed 
using contrasts within an ANOVA model with treatment arm as the factor.  Frequencies 
and percentages of subjects with post-baseline values meeting pre-defined criteria for PCS 
vital signs values will be summarized.  The between-arm comparison of the percentage of 
subjects experiencing a value meeting the criteria will be performed using Fisher's exact 
tests.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual plasma concentrations of ABT-493, ABT-530, SOF, RBV and GS-331007 will 
be tabulated for each subject and each arm.  Values for pharmacokinetic parameters of 


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ABT-493, ABT-530, SOF, RBV and GS-331007 will be tabulated for each subject who 
participates in Optional Intensive PK sampling.  Individual plasma concentrations and 
pharmacokinetic parameters of possible metabolites of ABT-493, ABT-530, SOF (other 
than GS-331007) and RBV may be tabulated and summarized if measured and sufficient 
levels of metabolites are observed.  Summary statistics will be computed for each time 
and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of 
major interest in the NONMEM analyses.  If necessary, other parameters, including the 
parameters describing absorption characteristics, may be fixed if useful in the analysis.  
The evaluation criteria described below will be used to examine the performance of 
different models.
●
The objective function of the best model is significantly smaller than the 
alternative model(s).
●
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 


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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.
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.


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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.
8.1.7
Justification of Non-Inferiority Margin for SVR12
To establish a threshold for demonstrating non-inferiority to the current standard of care, 
SOF plus RBV, a margin of 10% is used.  The 10% margin is similar to the margin of 
10.5% used in previous clinical trials of first-generation interferon-free regimens, based 
on the higher SVR rates provided by the current standard of care.  The 10% margin is 
considered to be an appropriate potential loss of efficacy given that the current regimen 
reduces the duration of treatment to 8 weeks and eliminates the need for RBV.
8.2
Determination of Sample Size
It is planned to enroll a total of 120 subjects in this study.  The primary efficacy endpoint 
of SVR12 will be assessed between treatment Arms A and B.
With 80 subjects in the ABT-493/ABT-530 8-week arm (Arm A) and 40 subjects in the 
SOF plus RBV 12 week arm (Arm B) and assuming that 96% of the subjects in Arm A 
achieve SVR12 and 95% of subjects in Arm B (Table 1) achieve SVR12, this study has 
> 80% power to demonstrate non-inferiority of the ABT-493/ABT-530 8-week treatment 
arm compared to the active control in SVR12 rate (i.e., a two-sided 95% lower confidence 
bound for the difference above the non-inferiority margin of –10%).
8.3
Randomization Methods
Approximately 120 subjects meeting all eligibility criteria will be randomized in a 
2:1 ratio into Arms A and B and randomization will be stratified by prior IFN-experience 
(naive versus experienced) and Screening HCV RNA (< or ≥ 6 million IU/mL).


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.


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9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
The optional samples for intensive PK analyses and sample for optional pharmacogenetic 
analysis will only be collected if the subject has voluntarily signed and dated the a 
intensive PK section of the main ICF and a separate pharmacogenetic informed consent, 
respectively, 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 
informed consent must be signed before the optional pharmacogenetic sample is collected 
and testing is performed.  If the subject does not consent to the optional intensive PK 
analyses and/or optional pharmacogenetic testing, it will not impact the subject's 
participation in the study.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.


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9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded 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 


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


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12.0
Use of Information
Any research that may be done using optional pharmacogenetics 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 subject nor the investigator will be 
informed of individual optional pharmacogenetic 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 information will be published or 
presented only in a way that does not identify any individual subject.
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 Director of the Site in 
Japan and AbbVie.  Continuation of this study beyond this date must be mutually agreed 
upon in writing by both the Director of the Site in Japan and AbbVie.  The investigator 
will provide a final report to the Director of the Site following conclusion of the study.  
Upon being provided the report, the Director of the Site will notify AbbVie or their 
representative and the IEC/IRB of the conclusion of the study in Japan.
The Director of the Site in Japan must retain any records related to the study according to 
local requirements.  If the Director of the Site in Japan 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 


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accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-493 and 
ABT-530 and the product inserts for sofosbuvir and ribavirin.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:  
A Randomized, Open-Label, Active Comparator, Multicenter Study 
to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in 
Japanese Adults with Genotype 2 Chronic Hepatitis C Virus 
Infection (CERTAIN-2)
Protocol Date:
17 June 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
World Health Organization.  Worldwide Statistics for HCV.  Weekly 
Epidemiological Record No. 49.  10 December 1999.
2.
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.
3.
European Association for Study of Liver.  EASL Clinical Practice Guidelines:  
management of hepatitis C virus infection.  J Hepatol.  2014;60(2):392-420.
4.
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.
5.
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.
6.
Kobayashi M, Kumada H, Chayama K, et al.  Prevalence of HCV genotype among 
patients with chronic liver diseases in the Tokyo metropolitan area.  
J Gastroenterol.  1994;29(5):583-7.
7.
Hayashi K, Fukuda Y, Nakano I, et al.  Prevalence and characterization of hepatitis 
C virus genotype 4 in Japanese hepatitis C carriers.  Hepatol Res.  
2003;25(4):409-14.
8.
Toyoda H, Kumada T, Takaguchi K, et al.  Changes in hepatitis C virus genotype 
distribution in Japan.  Epidemiol Infect.  2014;142(12):2624-8.
9.
Kobayashi M, Chayama K, Arase Y, et al.  Enzyme-linked immunosorbent assay to 
detect hepatitis C virus serological groups 1 to 6.  J Gastroenterol.  
1999;34(4):505-9.
10.
Ikeda K, Chayama K, Saitoh S, et al.  Hepatitis C virus subtype 3b infection in a 
hospital in Japan:  epidemiological study.  J Gastroenterol.  1996;31(6):801-5.
11.
Sofosbuvir tablets [Japan package insert].  Tokyo, Japan; AbbVie Ltd, 2015.


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12.
AbbVie.  ABT-493 Investigator's Brochure Edition 4.  14 September 2015.
13.
AbbVie.  ABT-530 Investigator's Brochure Edition 4.  16 September 2015.
14.
Sofosbuvir tablets [US package insert].  Tokyo, Japan; AbbVie Ltd, 2015.
15.
Rebetol capsules [package insert]. Tokyo, Japan; AbbVie Ltd, 2015.
16.
Gottwein JM, Scheel TK, Jensen TB, et al.  Differential efficacy of protease 
inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant 
viruses.  Gastroenterology.  2011;141(3):1067-79.


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


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
CMC Group
Clinical
Pharmacokinetics
Clinical
Clinical
Statistics
Bioanalysis


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Appendix C.
Clinical Toxicity Grades


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Appendix D.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
  Contact:
Urgent contact during business 
hours:
Urgent contact after 
business hours (at night 
or on holidays):
Has been changed to read:
Sponsor/Emergency 
  Contact:
Urgent contact during business 
hours:
Urgent contact after 
business hours (at night 
or on holidays):
Section 1.2  Synopsis
Subsection AbbVie Inc.
Previously read:
AbbVie Inc.
Has been changed to read:
AbbVie GK


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Section 1.2  Synopsis
Subsection Phase of Development:
Add:  new subsection text
3
Section 1.2  Synopsis
Subsection Methodology:
Heading "Treatment Period"
Second paragraph previously read:
The randomization will be stratified by prior IFN-experience (naïve versus experienced) 
and baseline HCV RNA (< or ≥ 6 million IU/mL).
Has been changed to read:
The randomization will be stratified by prior IFN-experience (naïve versus experienced) 
and Screening HCV RNA (< or ≥ 6 million IU/mL).
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph, last sentence previously read:
The randomization will be stratified by prior IFN-experience (naive versus experienced) 
and baseline HCV RNA (< or ≥ 6 million IU/mL).
Has been changed to read:
The randomization will be stratified by prior IFN-experience (naive versus experienced) 
and Screening HCV RNA (< or ≥ 6 million IU/mL).
Section 5.2.3.1  Prior HCV Therapy
Add:  new last sub-bullet
Unknown:  subject received a prior treatment course and reason for not achieving SVR is 
unknown.


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Table 4.  Treatment Period
Activity "Vital Signs, Weight, Waist Circumference, Heighte" previously read:
Vital Signs, Weight, Waist Circumference, Heighte
Has been changed to read:
Vital Signs, Weight, Waist Circumference,e Heighte
Section 5.3.1.1  Study Procedures
Subsection Medical History
First sentence previously read:
A complete medical history, including history of alcohol, tobacco and nicotine-containing 
product use, will be taken at Screening.  
Has been changed to read:
A complete medical history, including history of alcohol, tobacco and illicit/illegal drug 
use, will be taken at Screening.  
Section 5.3.1.1  Study Procedures
Subsection Hepatitis and HIV Screen
Delete:  second and third sentence
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.  
Section 5.3.2.1  Collection of Samples for Analysis
Third paragraph
First bullet, first sentence previously read:
On Study Day 1 and the Week 4 visit, subjects will have their dose administered by study 
site personnel with food.  


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Has been changed to read:
On Study Day 1 and the Week 4 visit, subjects will have their dose administered by study 
site personnel after food.  
Section 5.3.7  Pharmacogenetic Variables
Last paragraph previously read:
DNA samples from subjects who separately consent for additional pharmacogenetic 
analysis may be sequenced and data analyzed for genetic factors possibly contributing to
the disease or to the subject's response to study treatment, in terms of pharmacokinetics, 
pharmacodynamics, 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 (including IL28B).  Some 
genes currently insufficiently characterized or unknown may be understood to be 
important at the time of analysis.  Pharmacogenetic analyses will be limited to studying 
response to HCV therapy; no other analyses will be performed.
Has been changed to read:
DNA samples from subjects who separately consent for additional pharmacogenetic 
analysis may be sequenced and data analyzed for genetic factors possibly contributing 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 the disease or drug response (including IL28B).  Some genes currently 
insufficiently characterized or unknown may be understood to be important at the time of 
analysis.  Pharmacogenetic analyses will be limited to studying response to the HCV 
therapy; no other analyses will be performed.


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Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Third paragraph previously read:
The randomization will be stratified by prior IFN-experience (naïve versus experienced) 
and baseline HCV RNA (< or ≥ 6 million IU/mL).
Has been changed to read:
The randomization will be stratified by prior IFN-experience (naïve versus experienced) 
and Screening HCV RNA (< or ≥ 6 million IU/mL).
Section 6.1.5  Adverse Event Reporting
"Primary TA MD:"
"Title" previously read:
Assistant Medical Director
Has been changed to read:
Japan Project Head/Associate Medical Director
Section 6.1.7.5  Management of Increases in ALT
First paragraph previously read:
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:
Has been changed to read:
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:


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Section 7.0  Protocol Deviations
"Alternate Contact:" previously read:
Alternate Contact:
Has been changed to read:
Alternate Contact:
Section 8.1.2.2  Secondary Efficacy Endpoints
Last paragraph previously read:
In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, other) will be provided for each treatment arm.
Has been changed to read:
In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection, other) will be provided for each treatment arm.


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Section 8.3  Randomization Methods
Previously read:
Approximately 120 subjects meeting all eligibility criteria will be randomized in a 
2:1 ratio into Arms A and B and randomization will be stratified by prior IFN-experience 
(naive versus experienced) and baseline HCV RNA (< or ≥ 6 million IU/mL).
Has been changed to read:
Approximately 120 subjects meeting all eligibility criteria will be randomized in a 
2:1 ratio into Arms A and B and randomization will be stratified by prior IFN-experience 
(naive versus experienced) and Screening HCV RNA (< or ≥ 6 million IU/mL).
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
CMC Group
Clinical
Pharmacokinetics
Clinical
Clinical
Statistics
Bioanalysis


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Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
CMC Group
Clinical
Pharmacokinetics
Clinical
Clinical
Statistics
Bioanalysis



SAP_000.pdf: 
ABT-493/ABT-530
M15-828 – Statistical Analysis Plan
Version 1.0 – 31 October 2016
1
1.0
Title Page
Statistical Analysis Plan
Study M15-828
A Randomized, Open-Label, Active Comparator, 
Multicenter Study to Evaluate the Efficacy and 
Safety of ABT-493/ABT-530 in Japanese Adults with 
Genotype 2 Chronic Hepatitis C Virus Infection 
(CERTAIN-2)
31 October 2016


ABT-493/ABT-530
M15-828 – Statistical Analysis Plan
Version 1.0 – 31 October 2016
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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
Primary Analysis........................................................................................7
4.5
Interim Analysis.........................................................................................8
5.0
Analysis Populations ...............................................................8
5.1
Definition for Analysis Populations...........................................................8
5.1.1
Intention-to-Treat Population.....................................................................8
5.1.2
Modified Intent-to-Treat (mITT) Populations ...........................................9
5.1.3
Safety Population.......................................................................................9
5.2
Variables Used for Stratification of Randomization..................................9
6.0
Analysis Conventions ............................................................10
6.1
Definition of Baseline and End of Treatment Assessment ......................10
6.1.1
Baseline....................................................................................................10
6.1.2
Study Days...............................................................................................10
6.2
Definition of Analysis Windows .............................................................11
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 .......................................................................................20
7.3
Prior, Concomitant and Post-Treatment Medications..............................21
8.0
Patient Disposition.................................................................21
8.1
Disposition of Safety Population .............................................................21
9.0
Study Drug Exposure and Compliance...............................22
9.1
Exposure ..................................................................................................22
9.2
Compliance ..............................................................................................23


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10.0
Efficacy Analysis....................................................................24
10.1
General Considerations............................................................................24
10.2
Handling of Multiplicity ..........................................................................29
10.3
Primary Efficacy Analysis .......................................................................29
10.4
Interim Analysis.......................................................................................30
10.5
Secondary Efficacy Analyses...................................................................30
10.6
Sensitivity Analyses for SVR ..................................................................31
10.6.1
Imputation Approaches............................................................................32
10.6.2
Assessment of Homogeneity Across Stratification Variables .................32
10.7
Efficacy Subgroup Analysis ....................................................................34
10.8
Additional Efficacy Analyses ..................................................................36
10.9
Resistance Analyses.................................................................................38
10.9.1
Presence of Baseline Resistance-Associated Variants.............................43
10.10
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..............................45
11.2.3
Listing of Adverse Events........................................................................50
11.3
Analysis of Laboratory Data....................................................................50
11.3.1
Variables and Criteria Defining Abnormality..........................................51
11.3.2
Statistical Methods...................................................................................52
11.4
Analysis of Vital Signs and Weight.........................................................55
11.4.1
Variables and Criteria Defining Abnormality..........................................55
11.4.2
Statistical Methods...................................................................................56
12.0
Summary of Changes ............................................................57
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ...................................................................................................57
13.0
References...............................................................................57


ABT-493/ABT-530
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List of Tables
Table 1.
SVR12 Rates in GT2-Infected Non-Cirrhotic Subjects ..............................7
Table 2.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, and PRO Instruments 
(Treatment Period)...................................................................................12
Table 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)...........................................................................13
Table 4.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period)...........................................................................13
Table 5.
Baseline Fibrosis Stage............................................................................18
Table 6.
Clinical Identification of Metabolic Syndrome .......................................19
Table 7.
Medical History eCRF .............................................................................20
Table 8.
List of Genotype-Specific Signature Amino Acid Positions and 
Associated Specific Variants ...................................................................39
Table 9.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................53
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Values.............56
List of Figures
Figure 1.
Study Schematic.........................................................................................6


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Statistics and Statistical Programming Departments for Study M15-828. 
Study M15-828 assesses the efficacy and safety of 8 weeks of treatment with the 
combination regimen ABT-493/ABT-530 in chronic HCV genotype 2 (GT2) infected 
DAA treatment-naïve Japanese adult subjects.
This SAP provides details to further elaborate the statistical methods outlined in the 
Clinical Study Protocol M15-828 Amendments 1 and 2 including Administrative 
Change 1 dated 17 June 2016, and describes analysis conventions to guide the statistical 
programming.  Analyses will be performed using SAS® Version 9.3 (SAS Institute, Inc., 
Cary, NC) or later under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the efficacy and safety of 8 weeks of 
treatment with the combination regimen ABT-493/ABT-530 compared to 12 weeks of 
treatment with SOF and RBV in HCV GT2-infected Japanese adults without cirrhosis.
The secondary objectives are to assess:
●
The percentage of subjects achieving SVR12 for Arm A;
●
The percentages of subjects with on-treatment virologic failure;
●
The percentages of subjects with post-treatment relapse.
Additional objectives are to assess pharmacokinetics and emergence and persistence of 
viral variants in these treatment regimens.


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4.2
Design Diagram
This is a Phase 3, randomized, open-label, active-control, multicenter study to evaluate 
the efficacy, safety and pharmacokinetics of ABT-493/ABT-530 in chronic HCV 
GT2-infected HCV DAA treatment-naïve Japanese adult subjects without cirrhosis.  This 
study consists of a Treatment Period (TP) and a Post-Treatment (PT) Period. 
Figure 1.
Study Schematic
Approximately 120 HCV GT2-infected DAA treatment-naïve subjects (including subjects 
who are IFN treatment experienced with or without RBV) without cirrhosis will be 
enrolled into one of two treatment arms (80 subjects into Arm A and 40 subjects into 
Arm B)
●
Arm A:  ABT-493/ABT-530 300 mg/120 mg QD for 8 weeks;
●
Arm B:  SOF 400 mg QD plus RBV (600 – 1000 mg based on weight divided 
BID) for 12 weeks.
Subjects meeting all eligibility criteria will be randomized to Arms A or B.  The 
randomization will be stratified by prior IFN-experience (naïve versus experienced) and 
screening HCV RNA viral load (< or ≥6 million IU/mL).  Subjects will be randomized in 
a 2:1 ratio to Arms A (80 subjects) or B (40 subjects).


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4.3
Sample Size
It is planned to enroll a total of 120 subjects in this study.  The primary efficacy endpoint 
of SVR12 will be assessed between treatment Arms A and B.
For the primary endpoint, with 80 subjects in the ABT-493/ABT-530 8-week arm 
(Arm A) and 40 subjects in the SOF plus RBV 12 week arm (Arm B) and assuming that 
96% of the subjects in Arm A achieve SVR12 and 95% of subjects in Arm B (Table 1) 
achieve SVR12, this study has > 80% power to demonstrate non-inferiority of the 
ABT-493/ABT-530 8-week treatment arm compared to the active control in SVR12 rate 
(i.e., a two-sided 95% lower confidence bound for the difference above the non-inferiority 
margin of –10%).  The 10% margin is considered to be an appropriate potential loss of 
efficacy given the possibility that the current regimen may provide additional clinical 
advantage over the comparator regimen by shortening the duration of treatment to 
8 weeks and eliminating the need for RBV. 
Table 1.
SVR12 Rates in GT2-Infected Non-Cirrhotic Subjects
Trial
SVR (n/N)
SVR (%)
FISSION1
59/61
97%
POSITRON1
85/92
92%
FUSION1
26/29
90%
VALENCE1
59/63
94%
Japanese Study2
132/136
97%
Total
361/381
95%a
a.
The SVR rate is an unweighted average across the studies.
Note:
Data included in the table is for 12-week SOF plus RBV regimen across multiple clinical trials in 
GT2-infected non-cirrhotic subjects.
4.4
Primary Analysis
The primary analysis will occur after all subjects have completed the PT Week 12 Visit or 
prematurely discontinued the study.  The data for the primary analysis will be locked after 
data cleaning.  Results from the primary analysis (e.g., SVR12 data) will be described in 


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the primary clinical study report (CSR) and submitted to regulatory agencies as part of an 
NDA submission. 
The final analysis will be conducted when all subjects enrolled in the study have 
completed the 24 week post-treatment visit or prematurely discontinued from the study.  
Data after the primary analysis will be added to a new version of the database which will 
be cleaned and locked at the end of the study.
4.5
Interim Analysis
An interim analysis that was not specified in the protocol will occur after all subjects have 
completed the Post-Treatment Week 4 Visit or prematurely discontinued from the study.  
This interim analysis will include sustained virologic response 4 weeks after end of 
treatment (SVR4).  The primary endpoint of the study remains unchanged as SVR12.  No 
decision to stop or adjust treatment will be based on this interim analysis and no inference 
will be performed at the SVR4 interim analysis so no adjustment of multiplicity will be 
implemented.  The intention is to follow all subjects who receive study drug for 24 weeks 
following treatment as specified in the protocol.  The interim analysis will include 
analyses of the endpoints specified in the protocol and this SAP for data collected through 
this time point, except pharmacokinetic and exposure-response analyses, and resistance 
analyses.  This interim analysis will support regulatory submission activities for 
ABT-493/ABT-530 in Japan. 
5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat Population
The intent-to-treat (ITT) population is defined as all randomized subjects who receive at 
least one dose of study drug.  Efficacy analyses will be performed on the ITT population, 
unless otherwise specified.  The data from the ITT population will be presented in 
efficacy analyses by the treatment arm assigned at the time of randomization. 


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5.1.2
Modified Intent-to-Treat (mITT) Populations
Sensitivity analyses of the primary efficacy endpoint, when applicable, will be performed 
on two modified ITT populations below:
Modified ITT Genotype (mITT-GT) Population
mITT-GT population includes subjects in the ITT population excluding subjects with 
genotype other than HCV GT2 infection as determined in Section 10.9.
Modified ITT Genotype and Virologic Failure (mITT-GT-VF) Population
mITT-GT-VF includes all subjects in the ITT-GT population defined above, excluding 
subjects who did not achieve SVR12 for reasons other than virologic failure.
Demographic analyses will also be performed on the mITT population(s), if needed.
5.1.3
Safety Population
All subjects who receive at least one dose (≥ 1 tablet) of study drug will be included in the 
safety population.  Safety and demographic analyses will be performed on the safety 
population and presented by the treatment arm assigned.
5.2
Variables Used for Stratification of Randomization
Subjects meeting all eligibility criteria will be randomized to Arm A or B.  The 
randomization will be stratified prior IFN-experience (naïve versus experienced) and 
screening HCV RNA viral load (< or ≥6 million IU/mL).  Subjects will be randomized in 
a 2:1 ratio to Arm A or B.


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6.0
Analysis Conventions
6.1
Definition of Baseline and End of Treatment Assessment
6.1.1
Baseline
The baseline value refers to the last available 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 available 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 
available measurement collected before the date and time of the first dose of study drug 
will be considered the baseline value.  If multiple measurements that are prior to dosing 
are recorded on the same date and with the same time or if time is not available, then the 
average of these measurements will be considered the baseline value.  The same baseline 
value will be used for analyses of the Treatment and Post-Treatment Periods.
Safety laboratory assessments that are related to a serious adverse event that occurred on 
the first dose day will not be used as baseline values.
6.1.2
Study Days
Study days are calculated for each time point relative to the first dose of study drug.  
Study days are negative values when the time point of interest is prior to the date the 
first study drug is taken.  Study days are positive values when the time point of interest is 
after the date the first study drug dose is taken.  There is no Study Day 0.  Study Day 1 is 
the day the first dose of study drug is taken.
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 date the last dose of 
study drug is taken.  The last day of study drug dosing is defined as Study Drug End 


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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 available measurement collected after 
Study Day 1 and on or before Study Drug End Day 2.
Final Post-Treatment Value
The final post-treatment value for each subject is the last available measurement collected 
after Study Drug End Day 2 and on or before Study Drug End Day 999.
6.2
Definition of Analysis Windows
For analyses of HCV RNA and resistance, the time windows specified in Table 2 and 
Table 3 describe how efficacy data are assigned to protocol-specified time points during 
the Treatment and PT Periods, respectively.  All time points and corresponding time 
windows are defined based on the date/time of blood sample collection.
For laboratory data and vital signs, the time windows specified in Table 2 and Table 4
describe how data are assigned to protocol specified time points during the Treatment and 
Post-Treatment periods respectively.
If more than one assessment is available for a time window, the assessment closest 
(except in analyses of SVR) to the nominal time will be used.  If there are 
two observations equally distant to the nominal time, the latest one will be used in 
analyses.  For analyses of SVR (e.g., SVR12), the last value in the window will be used. 
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used to calculate descriptive 
statistics and in analyses of the mean change from baseline. 


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Table 2.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory, Vital Sign Measurements, and PRO Instruments 
(Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window
(Study Day Range)
Day 1/Baselinea
1
≤ 1a
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 12b
84
71 to 98
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For 12-week treatment only.
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  PRO instruments are collected at Day 1 and End of Treatment Visit, which can be at Weeks 8 or 
12 depending on treatment assignment.


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Table 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day 
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 2
14
3 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24
168
127 to 999
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.
Table 4.
Laboratory Data, Vital Sign and PRO Instruments Visit Windows 
(Post-Treatment Period)
Scheduled Time
Nominal Day 
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 2
14
3 to 21
Post-Treatment Week 4
28
22 to 42
Post-Treatment Week 8
56
43 to 70
Post-Treatment Week 12
84
71 to 126
Post-Treatment Week 24
168
127 to 999
Final Post-Treatment Visita
> 2 days after last dose of study drug
a.
The last value within the Post-Treatment Period window will be used to define the final post-treatment value.  The 
lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
Vital signs are collected at every PT visit; hematology, chemistry, urinalysis, and coagulation panels are 
collected only at PTW4 or PTDC (if subject discontinued prior to PTW4).  PRO instruments are collected at 
PTW12 only.


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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.  HCV RNA values from central laboratory will be used as described in 
Section 10.1, unless otherwise specified. 
For analyses of SVR, subjects missing a visit HCV RNA value 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 continues to be missing an HCV RNA 
value within the appropriate SVR window after performing backward imputation, then 
this value will be imputed using an HCV RNA value from a local laboratory if available; 
otherwise, the HCV RNA value for that window will be considered missing.  Subjects 
with missing HCV RNA data in the analysis window, after applying these imputations, 
will be imputed as a failure of viral response.
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 
failure for summaries of viral response at all time points after the start of the new HCV 
treatment. 
Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
available in the appropriate time period, then the local laboratory data will be used to 
assess post-treatment relapse and on-treatment virologic failure. 


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Missing Data Imputation for PRO Questionnaires
For EQ-5D-3L index and VAS scores, no imputation will be performed for missing items.  
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.
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.
No imputation will be performed for missing data in other than specified above.
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 post-treatment 
medications for each treatment arm. 
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 and proportions will be compared 
across treatment arms with a chi-square test.  Continuous variables will be summarized 
with descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum and minimum), and means will be compared across the treatment arms 
with a one-way analysis of variance (ANOVA).
Continuous demographic variables include age, weight, height, waist circumference, and 
body mass index (BMI).  Categorical demographic variables include sex, race, ethnicity, 
age category (< 65 years, ≥ 65 – < 75 years, ≥ 75 years), and BMI category (< 25 or 
≥25 kg/m2).


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Continuous baseline characteristics include baseline log10 HCV RNA level, homeostasis 
model of assessment – insulin resistance (HOMA-IR), creatinine clearance, eGFR, 
platelet count, albumin, GGT, LDL, HDL, APRI, FIB-4, AST, ALT, total, direct, and 
indirect bilirubin for all subjects.
Categorical baseline characteristics include:
●
HCV genotype 2 subtype (as determined by the central laboratory);
●
HCV genotype 2 subtype (as determined by phylogenetic analysis);
●
Prior HCV treatment history (naïve or experienced);
●
For treatment experienced subjects, type of non-response to previous treatment 
(non-responder, breakthrough, relapse, or unknown/other);
●
IL28B genotype (CC, CT, or TT; CC or non-CC);
●
Baseline HCV RNA level (< 100,000 IU/mL or ≥ 100,000 IU/mL; 
< 800,000 IU/mL or ≥ 800,000 IU/mL; < 6,000,000 or ≥ 6,000,000 IU/mL; 
< 10,000,000 IU/mL, or ≥ 10,000,000 IU/mL);
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, F4 (if 
applicable));
●
Baseline platelet count (< 100 or ≥ 100 × 109/L; < 150 or ≥ 150 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 30, ≥ 30 to < 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2);
●
Baseline HOMA-IR (< 2 or ≥ 2 mU × mmol/L2) and (< 3 or 
≥3 mU × mmol/L2);
●
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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●
Tobacco use (user, ex-user, or non-user);
●
Alcohol use (drinker, ex-drinker, or non-drinker); 
●
Concomitant use of Proton Pump Inhibitors (PPIs);
●
Concomitant treatment with liver protectants (yes/no);
●
Concomitant use of Calcium Channel Blockers (CCBs) (yes/no)
●
Subject with high risk of carcinogenesis (Yes/No) per JSH guidance;3
●
Subject with advanced fibrosis (Yes/No) per JSH guidance.3
Summaries of baseline resistance analyses are described in Section 10.9.
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 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 available 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 5.


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A subject is categorized as high risk of carcinogenesis if fibrosis stage score ≥ F3 or 
platelet count < 120 × 109/L with age ≥ 66 years.  A subject is categorized as advanced 
fibrosis if fibrosis stage score ≥ F2 or platelet count < 150 × 109/L with age ≥ 66 years.
All subjects will be categorized as not having cirrhosis (cirrhosis = no) since this study 
excludes subjects with cirrhosis.
Table 5.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, 
Batts Ludwig, 
Knodell, IASL, 
Scheuer, Laennec 
Score, or New 
Inuyama 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
*
APRI will not be used to derive Baseline Fibrosis Stage.  However, per inclusion/exclusion criteria, subjects need 
to have concordant FibroTest and APRI scores in order to determine eligibility. 
Baseline APRI and FIB-4 are defined as the equations below.  Subjects who do not have 
concurrent AST and platelet values at baseline will be excluded from the summary of 
baseline APRI.  Age is defined in years at baseline.  Subjects who do not have concurrent 
values of AST, ALT, and platelet count at baseline, or subjects who are missing age will 
be excluded from the summary of FIB-4.  
APRI =
	
  (/)
	
 (   )(/)
 !!  "#$%  (&'(/))
× 100
FIB-4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10B/L) × CALT (U/L)


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Subjects will be classified as having metabolic syndrome if at least 3 of the 
5 characteristics in Table 6 are present.
Table 6.
Clinical Identification of Metabolic Syndrome
Risk Factor
Defining Level
Abdominal obesity, given as waist circumference
Men
> 102 cm (> 40 in)
Women
> 88 cm (> 35 in)
Triglycerides
≥ 150 mg/dL
HDL cholesterol
Men
< 40 mg/dL
Women
< 50 mg/dL
Blood pressurea
≥ 130/≥ 85 mmHg
Fasting glucose
≥ 100 mg/dL
a.
Raised blood pressure defined as either systolic blood pressure ≥ 130 mmHg or diastolic blood pressure 
≥85 mmHg.
Reference:  Grundy 2004.4
Histories of diabetes, bleeding disorders, depression or bipolar disorder, and 
cardiovascular disease will be based on the Medical History (MH) eCRF, as defined in 
Table 7.


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Table 7.
Medical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Diabetes
Metabolic
Diabetes mellitus
Bleeding disorders
Blood
Clotting/bleeding problems
Factor deficiency
Hemophilia
Von Willebrand disease
Depression or bipolar disorder
Neurologic and Psychiatric 
System
Bipolar disorder
Depression
Cardiovascular disease
Cardiovascular
Angina
Cardiac arrhythmia
Cardiovascular disease
Congenital heart disease
Congestive heart failure
Coronary artery disease
Hypertension
Myocardial infarction
Myocarditis
Peripheral vascular 
disease-arterial
Peripheral vascular 
disease-venous
Valvular heart disease
Vasculitis
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized for each treatment arm.  Subjects reporting more 


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than one condition/diagnosis within a body system will be counted only once for that 
body system.
7.3
Prior, Concomitant and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug (ABT-493/ABT-530 or SOF + RBV).  A concomitant medication is defined as 
any medication that started prior to the date of the first dose of study drug and continued 
to be taken on or after the first dose of study drug or any medication that started on or 
after the date of the first dose of study drug, but not after the date of the last dose of study 
drug.  A post-treatment medication for the treatment of HCV is defined as any medication 
taken on or after the last dose of study drug and entered as "Post-treatment HCV 
medications" on the eCRF.
The number and percentage of subjects taking prior medications, concomitant medications, 
and post-treatment HCV medications will be summarized for each treatment arm by 
generic drug name based on the WHO Drug Dictionary.  Prior medications will be divided 
by the following categories:
●
The prior anti-HCV medications taken by treatment experienced subjects;
●
All other prior medications for all treated subjects.
8.0
Patient Disposition
The number and percentage of subjects who screen failed for any reason, and for each 
screen failure reason, will be summarized for all subjects who screen failed.
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized by 
investigator for each treatment arm and overall.  
●
Randomized subjects;
●
Subjects who took at least one dose of study drug;


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Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug; 
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
●
Subjects ongoing in the Post-Treatment Period at the time of the primary 
analysis. 
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF) for each treatment arm and 
overall.  Similar summaries will be provided for discontinuations from the study.
The number and percentage of subjects with reported study drug interruptions will be 
summarized by treatment arm.
Reasons for study drug interruptions will be presented in the CSR listings. 
9.0
Study Drug Exposure and Compliance
9.1
Exposure
The duration of exposure to study drug will be summarized for the safety population.  
Duration of exposure is defined for each subject as the last study drug dose date minus the 
first study drug dose date plus 1 day.
The safety population will be used to summarize the duration of exposure for each 
treatment arm and for the study total. 
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


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●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days
●
> 90 days
In addition, the number and percentage of subjects with a study drug duration of ≥ 52 days 
for Arm A and ≥ 77 days for Arm B will be summarized.
9.2
Compliance
At each visit (starting with the Week 4 visit) during the Treatment Period, the total 
number of tablets dispensed and returned is recorded.  The compliance for study drug 
(ABT-493/ABT-530, SOF, and RBV) 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.  
For compliance to RBV, RBV dose modifications due to adverse events, toxicity 
management, or weight changes as recorded on the RBV Dose Modifications eCRF will 
be used to modify the total number of tablets that should have been taken.
A subject is considered to be compliant to each study drug if the percentage of compliance 
for that type is between 80% and 120%.  Compliance will be calculated for each subject 
and each tablet type by treatment arm and summarized with the mean, median, standard 
deviation, minimum, and maximum.  The percentage of compliant subjects will be 
summarized for each study drug and each treatment arm, based on data as observed.  An 
additional summary of the percentage of compliant subjects will be provided where 
subjects who are missing study drug accountability records will be imputed as 
non-compliant.


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10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
Treatment effects will be evaluated based on a 2-sided significance level of 0.050 (when 
rounded to three decimal places), and all efficacy analyses will be performed on the ITT 
population, unless otherwise specified. 
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.  
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database. 
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values < 15 IU/mL,  
including values reported as "HCV RNA NOT DETECTED" or "< 15 IU/ML HCV RNA 
DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values.
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.


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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).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-treatment virologic failure = Breakthrough or EOT failure.
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window. 
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
Relapse4 = confirmed HCV RNA ≥ LLOQ between end of treatment and 4 weeks after 
last actual dose of study drug (up to and including the SVR4 assessment time point) for a 
subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment 
(defined as study drug duration ≥ 52 days for Arm A and ≥ 77 days for Arm B), excluding 
reinfection as described below.
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 


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subject with HCV RNA < LLOQ at Final Treatment Visit who completed treatment 
(defined as study drug duration ≥ 52 days for Arm A and ≥ 77 days for Arm B), 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 (defined as study 
drug duration ≥ 52 days for Arm A and ≥ 77 days for Arm B), excluding reinfection.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as any 
subject with study drug duration of 52 days or greater for Arm A and 77 days or greater 
for Arm B.  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 


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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 SVR4 Non-Response
Subjects who do not achieve SVR4 (SVR4 non-responders) will be categorized as having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
Relapse by Post-Treatment Week 4 (defined according to the Relapse4 definition 
for subjects who complete treatment); 
3.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects in Arm A, and < 77 days for subjects in 
Arm B] and did not meet the On-treatment virologic failure definition);
4.
HCV reinfection (see definition described earlier);
5.
Missing follow-up data in the SVR4 window (defined as any subject who 
completed study drug without data in the SVR4 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR4 non-responder not meeting the definitions of 
[1] – [5]). 
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);


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2.
Relapse (defined according to the Relapse12 definition for subjects who complete 
treatment);
3.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects in Arm A, and < 77 days for subjects in 
Arm B] and did not meet the On-treatment virologic failure definition);
4.
HCV reinfection (see definition described earlier);
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR12 non-responder not meeting the definitions of 
[1] – [5]). 
Reasons for SVR24 Non-Response
Subjects who do not achieve SVR24 (SVR24 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
Relapse (defined according to the Relapse12 definition for subjects who complete 
treatment);
3.
Relapsed after achieving SVR12 (see Relapse24 definition);
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
[study drug duration < 52 days for subjects in Arm A, and < 77 days for subjects in 
Arm B] and did not meet the On-treatment virologic failure, Relapse12, or 
Relapse24 definitions);
5.
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6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], [4], or [5]);
7.
Other (defined as any SVR24 non-responder not meeting the definitions of 
[1] – [6]).
10.2
Handling of Multiplicity
No adjustment for multiple comparisons is used.
10.3
Primary Efficacy Analysis
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  
The primary efficacy endpoint is:
●
Non-inferiority of the ABT-493/ABT-530 8-week regimen (Arm A) to the 
SOF and RBV 12 week regimen (Arm B) in SVR12 using a non-inferiority 
margin of 10% in the ITT population.
For the primary efficacy endpoint, to show non-inferiority of the SVR12 rate of the 
ABT-493/ABT-530 8-week regimen (Arm A) to that of the SOF and RBV 12-week 
regimen (Arm B), the percentage of subjects achieving SVR12 will be calculated for each 
arm and a two-sided 95% confidence interval for the difference in SVR12 rates (Arm A 
minus Arm B) will be calculated using the normal approximation to the binomial 
distribution, unless the SVR12 rates are 100% for both Arm A and Arm B, then the 
Wilson's score method will be used for the confidence interval instead.  All subjects in the 
ITT population will be used when calculating SVR12.  If the lower bound of the 
confidence interval for the difference is above the non-inferiority margin of –10%, then 
the ABT-493/ABT-530 8-week regimen will be considered non-inferior to SOF and RBV 
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10.4
Interim Analysis
The efficacy variable for the interim analysis is SVR4 (HCV RNA < LLOQ 4 weeks after 
the last actual dose of study drug).  
The interim efficacy endpoint analysis is:
●
The difference between the ABT-493/ABT-530 8-week regimen (Arm A) to 
the SOF and RBV 12 week regimen (Arm B) in SVR4.
For the interim analysis, the difference between the SVR4 rate of Arm A and that of the 
Arm B will be calculated along with a two-sided 95% confidence interval for the 
difference in SVR4 rates (Arm A minus Arm B) using the normal approximation to the 
binomial distribution, unless the SVR4 rates are 100% for both Arm A and Arm B, then 
the Wilson's score method will be used for the confidence interval instead.  All subjects in 
the ITT population will be used when calculating SVR4 rates. 
10.5
Secondary Efficacy Analyses
The following secondary endpoints will be summarized:
●
the percentage of subjects achieving SVR12 for Arm A (the 
ABT-493/ABT-530 8-week regimen)
●
the percentage of subjects in each treatment arm with on-treatment virologic 
failure (defined as confirmed increase of > 1 log10 IU/mL above nadir during 
treatment, confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ 
during treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 
6 weeks of treatment), and 
●
the percentage of subjects in each treatment arm with post-treatment relapse 
(defined as confirmed HCV RNA ≥ LLOQ between end of treatment and 
12 weeks after the last dose of study drug among subjects who completed 
treatment as planned with HCV RNA < LLOQ at the end of treatment, 
excluding subjects who have been shown to be reinfected).


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For the first secondary efficacy endpoint, the percentage of achieving SVR12 in Arm A 
and a two-sided 95% confidence interval will be calculated using the normal 
approximation to the binomial distribution, unless the rate is 100% and then the Wilson's 
score method will be used.  
The percentage of subjects with on-treatment virologic failure and post-treatment relapse 
will be summarized for each treatment arm.  Two-sided 95% confidence intervals will be 
provided for rates within treatment arms and for the difference between arms (Arm A 
minus Arm B) using Wilson's score confidence intervals.  For the analysis of relapse and 
reinfection, completion of treatment is defined as any subject assigned to the12-week 
treatment with study drug duration of 77 days or greater; or any subject assigned to the 
8-week treatment with study drug duration of 52 days or greater.  Subjects with probable 
reinfection based on HCV sequencing or differing post-treatment HCV genotype or 
subtype will be summarized separately from relapse.
In addition, a summary of reason for SVR12 non-response (e.g., on-treatment virologic 
failure, relapse, re-infection, other) will be provided for each treatment arm.
Similar secondary endpoint analyses (SVR4 in Arm A, on-treatment virologic failure in 
each arm, and relapse through PT Week 4) will be performed for the interim analysis.
10.6
Sensitivity Analyses for SVR
The following analysis approaches will be used as sensitivity analyses for evaluating 
SVR12 rates within and between treatment arms for the primary efficacy endpoint: 
●
A two-sided 95% confidence interval for the SVR12 rates within each arm will 
be calculated using a Wilson score interval.
●
The percentage of subjects achieving SVR12 will be compared using a logistic 
regression model with treatment arm as a factor, and baseline log10 HCV RNA 
level, HCV genotype 2 subtype, and prior HCV treatment history as 
coviariates.


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●
The difference in SVR12 rates (Arm A minus Arm B) will be analyzed using a 
stratum-adjusted Mantel-Haenszel (MH) proportion with a continuity 
correction for variance, adjusting for both of the randomization stratum 
(described in Section 5.2).
●
A two-sided 95% confidence interval for the difference in SVR12 rates (Arm A 
minus Arm B) will be calculated using a Wilson score interval.
The above analyses will be performed on the ITT, and mITT-GT-VF populations, as 
applicable.  The same sensitivity analyses will be performed for SVR4 in the interim 
analysis.
10.6.1
Imputation Approaches
In addition to imputing SVR12 as described in Section 6.3, SVR12 rates will be calculated 
using the following other methods to impute missing HCV RNA values:
●
imputing any missing HCV RNA values in the SVR12 window by carrying 
forward the last non-missing (post-baseline) HCV RNA value prior to the 
SVR12 window; 
●
impute as described in Section 6.3 but treat SVR12 non-responders who were 
categorized as "prematurely discontinued study drug with no on-treatment 
virologic failure" or "missing follow-up data in the SVR12 window" as 
successes.
For each of these, the percentage of subjects with SVR12 in each arm and the difference 
between arms will be presented along with two-sided 95% confidence intervals.  The 
same sensitivity analyses will be performed for SVR4 in the interim analysis.
10.6.2
Assessment of Homogeneity Across Stratification Variables
Heterogeneity across the randomization stratification variable will be examined for the 
primary efficacy endpoint of SVR12 using the chi-square test of homogeneity.  The 
four strata for the ITT population are:


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1.
IFN-Naïve, Screening HCV RNA < 6 million IU/mL;
2.
IFN-Naïve, Screening HCV RNA ≥ 6 million IU/mL;
3.
IFN-Exp, Screening HCV RNA < 6 million IU/mL;
4.
IFN-Exp, Screening HCV RNA ≥ 6 million IU/mL.
The proportion of subjects in each treatment arm with SVR12 will be calculated across 
strata using stratum weighted proportions.
ps = the proportion of subjects with SVR12 among N subjects, which can be defined as:
  
,
where N represents the number of subjects in each arm within the ITT population, ph = the 
proportion of subjects achieving SVR12 in stratum h, Nh represents the number of subjects 
in stratum h, Wh = Nh/N, and  D = ∑
DF
G
FH&
.. 
Accompanying confidence intervals based on stratum-weighted variances will be 
calculated using the equations below.  The variance of ps will be estimated by:
  
and the 2-sided 95% confidence interval will be calculated as ps ± z, 
where z is 
the 1-α/2 point of the standard normal distribution.  
In addition, the number and percentage (ph) of subjects achieving SVR12 within each of 
the four strata will be presented.
The difference in SVR12 rates between Arm A and Arm B in hth stratum will be 
calculated as IF = J&F −JLF.  The variances for the difference in proportions, dh, within 
the hth stratum will be calculated using the simple asymptotic methods, MNO(IF) =



H
h
h
h
s
p
W
p
1





H
h
h
h
h
h
s
N
p
p
W
p
Var
1
2
1
)
1(
)
(


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JF
∗QF
∗(1/R&F + 1/RLF) where JF
∗= (R&FJ&F + RLFJLF)/(R&F + RLF) and QF
∗= 1 −JF
∗, 
and the 2-sided 95% confidence interval will be calculated as IF ± UCMNO(IF), where 
z is the 1 – α /2 point of the standard normal distribution.  The differences in SVR12 rates 
and accompanying CI will be presented for each strata.
Differences in proportions between Arm A and Arm B across strata will be calculated 
based on stratum-adjusted Mantel-Haenszel (MH) proportions, where the difference in the 
proportions is calculated as I = ∑
VFIF/ ∑
VF
G
FH&
G
FH&
where IF = J&F −JLF is the 
difference in the proportions between Arm A and Arm B in hth stratum and VF =
(R&FRLF)/(R&F + RLF) is the weight for hth stratum.  Its continuity corrected variance 
will be estimated by:
MNO(I) =
∑
VF
L(J&F
∗(1 −J&F
∗)
R&F −1
+ JLF
∗(1 −JLF
∗)
RLF −1
G
FH&
)
(∑
VF)L
G
FH&
Where J&F
∗= (W&F + 0.5) (R&F + 1)
⁄
and JLF
∗= (WLF + 0.5) (RLF + 1)
⁄
with W&F =
R&FJ&F and WLF = RLFJLF.  So the 2-sided 95% confidence interval will be calculated as 
I ± UCMNO(I) where z is the 1 – α/2 point of the standard normal distribution.
The same assessment of heterogeneity across strata will be performed for SVR4 in the 
interim analysis.
10.7
Efficacy Subgroup Analysis
Subgroup analyses will be performed for the primary efficacy endpoint of SVR12.
Within each subgroup, the percentage of subjects with SVR12 within each arm and the 
difference between treatment arms in the percentage of subjects with SVR12 will be 
calculated, as will the corresponding two-sided 95% Wilson score intervals.  A test of 
homogeneity will be conducted (Zelen's exact test) to evaluate whether differences 
between treatment arms are consistent across subgroups (i.e., confidence intervals for the 
difference in SVR12 rates will not be compared to the non-inferiority margin).


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Tests will be conducted at the nominal 0.05 level.  The 2-sided 95% Wilson score 
confidence interval will be produced if there are at least 10 subjects in the subgroup.
The following subgroups will be analyzed:
●
HCV genotype 2 subtype (final subtype as defined in Section 10.9);
●
Prior HCV treatment history (naïve or IFN-experienced);
●
IL28B genotype (CC or non-CC);
●
Sex (male or female);
●
Age (< 65 years, ≥ 65 – < 75 years, ≥ 75 years);
●
BMI (< 25, or ≥ 25 kg/m2);
●
Baseline HCV RNA level (< 100,000 IU/mL or ≥ 100,000 IU/mL; 
< 800,000 IU/mL or ≥ 800,000 IU/mL; < 6,000,000 or ≥ 6,000,000 IU/mL; 
< 10,000,000 IU/mL, or ≥ 10,000,000 IU/mL);
●
Baseline fibrosis stage (F0 – F1, F2, F3, F4 (if applicable));
●
Baseline platelet count (< 100 or ≥ 100 × 109/L; < 150 or ≥ 150 × 109/L);
●
Baseline HOMA-IR (< 2 or ≥ 2 mU × mmol/L2) and (< 3 or 
≥3 mU × mmol/L2);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Baseline creatinine clearance (< 60, ≥ 60 to < 90, ≥ 90 mL/min);
●
Baseline eGFR (< 30, ≥ 30 to < 60, ≥ 60 to < 90, ≥ 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);
●
Presence of baseline resistance-associated variants (any NS3 variant [yes/no]; 
any NS5A variant [yes/no]; any NS3 and any NS5A [yes/no], any NS3 or any 
NS5A [yes/no]) and (NS3 only, NS5A only, both NS3 and NS5A, or none);


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●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no);
●
DAA compliance (yes/no);
●
Concomitant treatment with liver protectants (yes/no);
●
Subject with high risk of carcinogenesis (Yes/No); 
●
Subject with advanced fibrosis (Yes/No).
Subgroup analysis will also be performed on relevant combinations of subgroup variables 
if deemed clinically meaningful.
For the subgroup analyses, the presence of baseline resistance-associated variants as listed 
above are defined in Section 10.9.1.
All subgroup analyses will be performed for SVR4 in the interim analysis except 
●
Presence of baseline resistance-associated variants (any NS3 variant [yes/no]; 
any NS5A variant [yes/no]; any NS3 and any NS5A [yes/no], any NS3 or any 
NS5A [yes/no]) and (NS3 only, NS5A only, both NS3 and NS5A, or none).
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) in the logistic 
regression model.  For the variables on presence of baseline resistance-associated variants, 
only one unique variable (NS3 only vs. NS5A only vs. both NS3 and NS5A vs. none) will 
be used in the logistic regression model.  A stepwise logistic regression approach will be 
used to assess the strength of each subgroup variable in predicting SVR12, with a 
significance level of 0.10 to enter and remain in the model.
10.8
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized and analyzed for each 
treatment arm:


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●
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 SVR24;
●
The percentage of subjects with SVR4 in Arm B;
●
The reasons for not achieving SVR12 and the reasons for not achieving SVR24
●
The percentage of subjects with virologic failure through Post-Treatment 
Week 4 (i.e., the SVR4 non-responders due to on-treatment virologic failure or 
Relapse4).
●
The percentage of subjects with virologic failure through Post-Treatment 
Week 12 (i.e., the SVR12 non-responders due to on-treatment virologic failure 
or Relapse12).
In the above analyses for SVR and relapse, the percentage of subjects in each treatment 
arm with a two-sided 95% Wilson score interval and the (unadjusted) difference in rates 
(Arm A minus Arm B) with a two-sided 95% Wilson score interval will be summarized.  
Imputations for missing data will be performed as described in Section 6.3 for analyses of 
SVR and virologic failure, where a missing response will be imputed as a failure after 
performing the described imputation.  All other endpoints will be presented using data as 
observed.
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject numbers and the SVR visit window corresponding to the 
first occurrence of relapse.  A similar summary and listing will be prepared for subjects 
who prematurely discontinued treatment and relapsed after having HCV RNA < LLOQ at 
their Final Treatment Visit.
The number and percentage of subjects who do not achieve SVR12 will be summarized by 
reason for non-response (as defined in Section 10.1).  A listing of subject numbers and 
reason for non-response will be prepared.  A similar summary and listing will be prepared 
for subjects who do not achieve SVR4 and SVR24.


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The concordance between SVR12 and SVR24 will be assessed for each treatment arm 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 SVR12 out of all subjects who did not achieve SVR12.  Similarly, the concordance 
between SVR4 and SVR12 will be summarized. 
10.9
Resistance Analyses
For all subjects in Arm A, full length NS3/4A or NS5A from baseline samples will be 
sequenced by next generation sequencing (NGS).  Subjects in Arm B will have full length 
NS5B NGS performed on baseline samples only if they do not achieve SVR12.
Subjects who do not achieve SVR12 will have post-baseline resistance testing conducted if 
(1) they have on-treatment breakthrough; (2) if they have post-treatment relapse, with a 
study drug duration ≥ 77 days for subjects assigned to 12 weeks of treatment (Arm B) or 
study drug duration ≥ 52 days for subjects assigned to 8 weeks of treatment (Arm A); or 
(3) if they have HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks of 
treatment.  Subjects meeting one of these criteria will be referred to as subjects in the 
primary virologic failure (PVF) population, and a listing by subject that includes 
treatment arm, HCV subtype, prior HCV treatment experience, reason for SVR12
non-response, time point(s) sequenced as closest to time of VF, and HCV RNA value at 
the VF time point(s) will be produced for these subjects.  All listings described below will 
also display treatment arm, HCV subtype, prior HCV treatment experience, 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).


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Subjects treated with study drug who do not achieve SVR12 and who do not meet the 
above criteria for the PVF population (e.g., those with less than 6 weeks of therapy who 
failed to suppress), but have a time point with HCV RNA ≥ 1000 IU/mL after treatment 
discontinuation, will have the sample at that time point and the corresponding baseline 
sample 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 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 available.
For all subjects in Arm A, the region encoding full length NS3/4A and NS5A from their 
available baseline samples will be sequenced by next generation sequencing (NGS).  For 
subjects in Arm A who do not achieve SVR12, the region encoding full length NS3/4A 
and NS5A from their virologic failure/early discontinuation samples will be sequenced by 
NGS.  For subjects in Arm B who do not achieve SVR12, the region encoding full length 
NS5B from their baseline sample and the sample closest in time after VF with an HCV 
RNA level of ≥ 1000 IU/mL will be sequenced by NGS. 
For each DAA target, signature amino acid positions in genotype 2 are listed in Table 8.
Table 8.
List of Genotype-Specific Signature Amino Acid Positions and 
Associated Specific Variants
GT2 Target
Signature Amino
Acid Positions
Amino Acid Positions for Subgroup 
Variant Analysis
NS3/4A
36, 43, 54, 55, 56, 80, 155, 156, 168
155, 156, 168
NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
24, 28, 30, 92, 93
NS5B
159, 282
An appropriate subtype specific prototypic reference sequence will be used for 
comparison with sequences from samples.


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The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant present by NGS in a baseline sample (≥ 2% or 
≥15% prevalence within a subject's viral population depending on variant 
frequency threshold utilized) that was not present in the appropriate prototypic 
reference amino acid sequence for a given DAA target.
●
Variant at signature amino acid position:  variant (relative to reference) present 
in a baseline or a post-baseline sample at a signature amino acid position. 
●
Post-baseline variant:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline (< 2%) in the subject and is detectable 
in ≥ 2% of the sequences from the sample.
●
Enriched variant:  a variant 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 variant:  A post-baseline variant or an enriched variant. 
●
Variants emerging at an amino acid position:  amino acid position where 2 or 
more subjects of the same HCV subtype have treatment emergent variants 
(with all variants at that position listed after the position).
Emerged variant:  a treatment-emergent variant that is observed in 2 or more 
subjects of the same HCV subtype.
The following (Analyses 1, 2, and 3) will be available in the primary CSR: 
Analysis 1:  The following analyses will be performed for the arm described: 
●
The number and percentage of subjects in Arm A with baseline variants at 
detection-thresholds of 2% and 15% for variants at signature amino acid 
positions, and 15% for variants at non-signature positions.  For analysis by 
signature amino acid positions, the number of subjects with variants at 
signature amino acid positions in NS3 only, NS5A only, NS3 + NS5A, any in 
NS3, any in NS5A, or any in [NS3 or NS5A] will also be provided.


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●
A listing of all baseline variants (2% detection threshold) at signature amino 
acid positions for each DAA target (NS3/4A and NS5A) for the ITT 
population of subjects in Arm A. 
●
A listing of all baseline variants (15% detection threshold) at non-signature 
amino acid positions for each DAA target (NS3/4A and NS5A) for the PVF 
population of subjects in Arm A.
●
For subjects in Arm B who experience VF, a listing by subject of all baseline 
variants relative to prototypic reference sequence will be provided for NS5B.
Analysis 2:  The impact of baseline variants on treatment outcome will be assessed for 
subjects in Arm A in the mITT-GT_VF population as follows:  for each variant, the 
SVR12 rate will be calculated for subjects with and without the variant and the 2 rates will 
be compared using Fisher's exact test.  Analyses will be grouped by subject's HCV 
subtype and DAA target (NS3 or NS5A).  Subjects not achieving SVR12 due to non-
virologic reasons will be excluded.  These analyses will be performed for the following 
subgroups based on variants in NS3/4A and NS5A separately:
●
Variants at signature amino acid positions (vs. no variant at that position), 
using detection thresholds of both 2% and 15%.  The analysis will also 
summarize the number of subjects with variants in NS3 only, in NS5A only, 
any in NS3, any in NS5A, any in NS3 or NS5A, any in NS3 + NS5A.
●
Variants at each non-signature amino acid position (vs. no variant at that 
position), at a detection threshold of 15%.
●
Each variant at a signature amino acid position (vs. not that variant) using 
detection thresholds of 2% and 15%.  The analysis will also summarize the 
number of subjects with variants in NS3 only, in NS5A only, any in NS3, any 
in NS5A, any in NS3 or NS5A, any in NS3 + NS5A.
Analysis 3:  The following will be provided for subjects who do not achieve SVR12 who 
have post-baseline resistance data available.


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●
Listings by subject of all treatment-emergent variants relative to the baseline 
amino acid sequence will be provided for each DAA target (NS3 and NS5A), 
separate listings for the PVF and non-PVF populations for subjects in Arm A.
●
Listings by subject of all variants at signature amino acid positions in a 
post-baseline time point for each DAA target (NS3 and NS5A); with separate 
listings for those in the PVF and non-PVF populations for subjects in Arm A.
●
Number and percentage of subjects in Arm A (with listing of subject numbers) 
with variants emerging at an amino acid position, with separate summaries for 
those in the PVF and non-PVF populations. 
●
Number and percentage of subjects in Arm A (with listing of subject numbers) 
with emerged variants, with separate summaries for those in the PVF and non-
PVF populations.
●
For subjects in Arm B who experience virologic failure who have post-baseline 
resistance data available, a listing by subject of all treatment-emergent variants 
relative to the baseline amino acid sequence will be provided for NS5B.  
The following data will be available in the final CSR:
●
Analysis 3 will be updated to include subjects who experience VF after Post-
Treatment Week 12.
●
The persistence of post-baseline variants at signature amino acid positions for 
each target (NS3 and NS5A) from subjects in Arm A who fail to achieve 
SVR12 will be assessed at Post-Treatment Week 24.  Listings by subject and 
time point of all treatment-emergent variants will be provided for each DAA 
target (NS3 and NS5A), separate listings for the PVF and non-PVF 
populations.
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequences from baseline samples from 
all subjects in order to accurately determine subtype.  
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 


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sequencing of 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 are 
available, then the Inno-LIPA assay results will be used to categorize the subject.
The above algorithm will be used to derive the final subtype used in summaries of 
efficacy subgroup analyses and resistance 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 genotype and subtype as provided by the central laboratory (Sanger 
sequencing or Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) versus 
phylogenetic analysis also will be provided. 
10.9.1
Presence of Baseline Resistance-Associated Variants
For the efficacy subgroup analyses defined in Section 10.6, any NS3/4A variant and any 
NS5A variant are defined as follows, where baseline amino acid variants with ≥ 15% 
prevalence at certain important signature amino acid positions are considered.  Amino 
acid positions in NS3/4A and NS5A in genotype 2 subjects to be used in subgroup 
analyses are 155, 156, 168 in NS3 and 24, 28, 30, 92, 93 in NS5A (see Table 8).  HCV 
GT2 subjects with any baseline variant at positions 155, 156, or 168 will be counted as 
having any NS3/4A variant at baseline.  Similarly, HCV GT2 subjects with any baseline 
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10.10
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  the 
EuroQol-5 Dimensions-3 Level (EQ-5D-3L)5 including the Visual Analog Scale (VAS) 
and the Fatigue Severity Scale (FSS). 
The change from baseline to each applicable post-baseline timepoint in the FSS total score, 
EQ-5D-3L health index score and VAS score will be summarized descriptively at each 
visit and for change from baseline to each visit by treatment arm.  For each of these scores, 
mean change from Baseline to Final Treatment Visit and from Baseline to Post-Treatment 
Week 12 will be compared between treatment arms using an analysis of covariance 
(ANCOVA) model with treatment arm as a factor and baseline score as a covariate.
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 
Japan-specific weights, if applicable.  The VAS score will be analyzed separately. 
The FSS consists of 9 questions using a 7-point Likert scale.  A total score is calculated as 
the average of the individual item responses, with lower scores indicating less impact of 
fatigue.
Summary statistics (n, mean, SD, median, minimum and maximum) at each visit and for 
change from baseline to each visit will be provided for the EQ-5D-3L health index score, 
VAS score and FSS total score.  In addition, the number and percentage of subjects who 
have ever experienced an increase from baseline up through each applicable time point of 
greater than or equal to 0.7 in the FSS total score will be computed by treatment arm, 
along with two-sided 95% CI calculated using the normal approximation to the binomial 
distribution. 
For EQ-5D-3L index and VAS scores, no imputation will be performed for missing items.  
The missing items of the FSS questionnaire will be imputed with the average score of the 
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If a subject starts another treatment for HCV, then all PRO values for this subject 
measured on or after the start date of the new HCV treatment will be excluded from 
analyses.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized for each treatment arm using the safety population.  For 
safety analyses specified below, comparisons between the treatment arms will be 
performed.
11.2
Analysis of Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
clinical study report.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events are defined as any adverse event (AE) with an onset 
date that is after the first dose of study drug and no more than 30 days after the last dose 
of study drug.  Events where the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent, unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
The number and percentage of subjects in each arm with treatment-emergent adverse 
events will be tabulated by primary MedDRA System Organ Class (SOC) and preferred 
term.  The system organ classes will be presented in alphabetical order, and the preferred 
terms will be presented in alphabetical order within each system organ class. 


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Adverse Event Overview
An overview of AEs will be presented for each treatment arm consisting of the number 
and percentage of subjects experiencing at least one event for each of the following AE 
categories:
●
Any treatment-emergent adverse event;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Treatment-emergent adverse events of grade 3 or higher;
●
Serious treatment-emergent adverse events;
●
Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to discontinuation of study drug 
with a "reasonable possibility" of being related to study drug 
(ABT-493/ABT-530, SOF or RBV);
●
Serious treatment-emergent adverse events leading to discontinuation of study 
drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Treatment-emergent adverse events leading to RBV dose modification 
(Arm B);
●
Treatment-emergent adverse events leading to death;
●
Deaths.
The percentage of subjects experiencing treatment-emergent adverse events and 
treatment-emergent adverse events with a "reasonable possibility" of being related to 
study drug, and grade 3 or higher treatment-emergent adverse events will be compared 
between the two arms using Fisher's exact tests.  Only p-values ≤ 0.100 when rounded to 
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Adverse Events by SOC and Preferred Term
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 an SOC 
will be counted only once for that SOC.  Subjects reporting more than one AE will be 
counted only once in the overall total.
The following summaries of AEs by SOC and preferred term will be generated by 
treatment arm:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Serious treatment-emergent adverse events;
●
Serious treatment-emergent adverse events with a "reasonable possibility" of 
being related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Grade 3 or higher treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to discontinuation of study drug 
with a "reasonable possibility" of being related to study drug 
(ABT-493/ABT-530, SOF or RBV);
●
Serious treatment-emergent adverse events leading to discontinuation of study 
drug;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to study drug (ABT-493/ABT-530, SOF or RBV);
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modification (Arm B 
only);
●
Treatment-emergent adverse events leading to death.


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The percentage of subjects experiencing treatment-emergent adverse events and 
treatment-emergent adverse events with a "reasonable possibility" of being related to 
study drug, and grade 3 or higher treatment-emergent adverse events will be compared 
between the two arms using Fisher's exact tests.  Only p-values ≤ 0.100 when rounded to 
three digits will be presented.  In addition, the number and percentage of subjects 
experiencing treatment-emergent adverse events and study drug related 
treatment-emergent adverse event (≥ 2% and ≥ 2 subjects in either Arm A or Arm B) will 
be tabulated according to SOC and preferred term.
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be created for each treatment arm.
Adverse Events by Preferred Term
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be tabulated according to preferred term and sorted by overall frequency for the total 
number of subjects in Arm A.  Similar summaries will be provided for Grade 3 or higher 
treatment-emergent adverse events, treatment-emergent adverse events and 
treatment-emergent serious adverse event related to study drug (ABT-493/ABT-530, SOF 
or RBV), and treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to study drug (ABT-493/ABT-530, SOF or RBV).  In 
addition, the number and percentage of subjects experiencing treatment-emergent adverse 
events and study drug related treatment-emergent adverse event (≥ 2% and ≥ 2 subjects in 
either Arm A or Arm B) will be tabulated according to PT and sorted by overall frequency 
for the total number of subjects in Arm A.
Adverse Events by Maximum Severity Grade Level
Treatment-emergent adverse events and study drug-related treatment emergent adverse 
events will be summarized by maximum severity grade level of each preferred term.  Each 
adverse event will be assigned a grade level (grade 1, 2, 3, 4, or 5) by the investigator.  If 
a subject has an AE with unknown severity, then the subject will be counted in the 
severity grade level category of "unknown," even if the subject has another occurrence of 


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the same event with a severity present.  The only exception is if the subject has another 
occurrence of the same AE with the highest grade level (grade 5).  In this case, the subject 
will be counted under the "Grade 5" category.
Adverse Event by Maximum Relationship
Treatment-emergent adverse events also will be summarized by maximum relationship of 
each preferred term to study drug (ABT-493/ABT-530, SOF or RBV), as assessed by the 
investigator.  If a subject has an adverse event with unknown relationship, then the subject 
will be counted in the relationship category of "unknown," even if the subject has another 
occurrence of the same event with a relationship present.  The only exception is if the 
subject has another occurrence of the same adverse event with a relationship assessment 
of "Reasonable Possibility."  In this case, the subject will be counted under the 
"Reasonable Possibility" category.
Adverse Events by Subgroups
Subgroup analyses will be performed for the safety population.  To evaluate the impact of 
various characteristics, treatment-emergent adverse events will be summarized by 
treatment arm for each of the following subgroups:
●
Sex (male, female)
●
Age (< 65 years, ≥ 65 – < 75 years, ≥ 75 years)
●
BMI (< 25, ≥ 25 kg/m2)
●
Baseline fibrosis stage (F0 – F1, F2, F3)  
●
History of cardiovascular disease (yes/no)
●
History of diabetes (yes/no)
●
Concomitant treatment with liver protectants (yes/no)
●
Concomitant use of Proton Pump Inhibitors (PPIs) (yes/no)
●
Concomitant use of Calcium Channel Blockers (CCBs) (yes/no)


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For each subgroup, the adverse event overview will be prepared and the number and 
percentage of subjects experiencing treatment-emergent adverse events will be 
summarized by primary MedDRA SOC and preferred term in each treatment arm. 
The Breslow-Day test will be used to examine the homogeneity of treatment effect across 
subgroups for each event type in the AE overview table.  The Breslow-Day test will only 
be performed if there are at least 10 subjects per arm with an event within the subgroup.
Other Adverse Events
The number and percentage of subjects experiencing at least one treatment-emergent 
adverse event in the search defined below by Product MedDRA Query (PMQ) will be 
presented overall and by SOC and PT.  In addition, a listing of treatment-emergent 
adverse events for subjects meeting the search criterion will be provided.
"Hepatic Decompensation and Hepatic Failure" (PMQ).
11.2.3
Listing of Adverse Events
The following listings of adverse events will be prepared:
●
All serious adverse events (from the time the subject signed the study-specific 
informed consent through the end of the study),
●
Treatment-emergent serious adverse events,
●
Treatment-emergent adverse events leading to death,
●
Treatment-emergent adverse events leading to discontinuation of study drug,
●
Treatment-emergent adverse events leading to study drug interruption,
●
Treatment-emergent adverse events leading to RBV dose modification (Arm B 
only).
11.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.


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11.3.1
Variables and Criteria Defining Abnormality
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, reticulocyte count, prothrombin time (PT), international 
normalized ratio (INR), and activated partial thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, sodium, potassium, calcium, inorganic phosphorus, uric acid, 
cholesterol, total protein, glucose, triglycerides, LDL, HDL, albumin, chloride, 
bicarbonate, magnesium, total insulin, gamma-glutamyl transferase (GGT), creatinine 
clearance (calculated using Cockcroft-Gault), and  estimated glomerular filtration rate 
(eGFR) calculated using the modification of diet in renal disease (MDRD) equation 
defined below.
Urinalysis variables include:  specific gravity, ketones, pH, protein, blood, glucose,
urobilinogen, bilirubin, leukocyte esterase, and microscopic (reflex performed if other 
variables are abnormal).
Some of the above laboratory variables are calculated by the laboratory vendor including 
indirect bilirubin, creatinine clearance, and eGFR by MDRD.  The central lab calculates 
eGFR by MDRD modified for Japanese population using the following equation, where 
serum creatinine is measured in mg/dL and age is measured in years:
eGFRj (mL/min/1.73 m2) = 194 × (Serum Creatinine)–1.094 × (Age)–0.287 × 0.739 (if 
Female).
The central lab calculates the estimated creatinine clearance (CrCl) based on the following 
Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum creatinine 
(mg/dL) × 72].


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11.3.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last available measurement on 
or before the day of the first dose of study drug.  Values on Day 1 must also be before the 
time of first dose if time is available.  The same baseline value will be used for change to 
Treatment Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable 
post-treatment visits, will be summarized for each treatment arm.  Each protocol-specified 
laboratory parameter will be summarized with the sample size, baseline mean, visit mean, 
change from baseline mean, standard deviation, minimum, median, and maximum.
Scatterplots of baseline versus final treatment visit for each hematology and chemistry 
parameter (specified in Table 9) and plots of the mean change in bilirubin (total, direct 
and indirect) from baseline to each treatment visit by treatment arm will be produced.
The laboratory parameters defined in Table 9 will be assigned a toxicity grade of 1, 2, 3, 
or 4.  The number and percentage of subjects with a maximum toxicity post-baseline 
grade of 1, 2, 3 or 4 will be summarized for each treatment arm.  The maximum 
post-baseline value must be in a toxicity grade that is more extreme than the toxicity grade 
corresponding to the baseline value to be counted.  The summary will also include the 
number and percentage of subjects with a maximum of at least Grade 3 for all laboratory 
parameters in Table 9.  Comparisons of the percentage of subjects experiencing a value 
meeting at least Grade 2 between treatment arms will be performed using Fisher's exact 
tests.  Only P values ≤0.100 when rounded to three digits will be presented.  A listing of 
all relevant laboratory parameters will be provided for each subject who had an increase 
to Grade 2 or higher value for any laboratory variable in Table 9.
For ALT and total bilirubin, shift tables from baseline to maximum value in toxicity grade 
(Table 9) during the treatment period will be created.  The shift tables will cross tabulate 
the frequency of subjects with baseline grade (0, 1, 2, 3, or 4) versus post-baseline 


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maximum grade (0, 1, 2, 3, or 4).  Laboratory values of ALT and total bilirubin within 
normal ranges are defined as Grade 0.
Table 9.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase 
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin 
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
White blood 
cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Absolute 
Neutrophil 
Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 –
50.0 × 109/L
< 50.0 –
25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Glucose 
(increased)
> ULN – 8.9 mmol/L
> 8.9 –
13.9 mmol/L
> 13.9 –
27.8 mmol/L
> 27.8 mmol/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 
mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Cholesterol
> ULN – 7.75 mmol/L
> 7.75 –
10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Assessment of Liver Safety
The number and percentage of subjects in each treatment arm with maximum 
on-treatment lab values meeting the following criteria will be summarized:


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●
ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN;
●
ALT ≥ 3 × ULN and total bilirubin < 2 × ULN;
●
ALT > 5 × ULN and total bilirubin < 2 × ULN;
●
ALT < 3 × ULN and total bilirubin ≥ 2 × ULN.
The maximum post baseline ratio relative to the ULN will be used to determine if subjects 
meet the criteria listed above.  The ALT and total bilirubin values do not need to be 
concurrent in order to meet the defined criteria.  For ALT and total bilirubin, a subject 
will be counted if the post-baseline laboratory value meets the above criteria regardless of 
the baseline laboratory value (i.e., the post-baseline laboratory value does not need to be 
worse than the baseline laboratory value).
A listing of all ALT, AST, total, indirect and direct bilirubin, ratio of direct to total 
bilirubin, and alkaline phosphatase values will be provided for each subject who met any 
of the criteria defined above.  The listings will be reviewed to assess bilirubin (e.g., mixed 
or direct predominance) and temporal relationships for subjects with ALT ≥ 3 × ULN and 
total bilirubin ≥ 2 × ULN.
The number and percentage of subjects with post-baseline values during the Treatment 
Period meeting the following criteria will be summarized:
●
ALT > 5 × ULN and ≥ 2 × baseline;
●
AST > 5 × ULN and ≥ 2 × baseline;
●
Total bilirubin ≥ 2.0 × ULN and > baseline.
As noted above, a post-baseline value must be more extreme than the baseline value to be 
considered.  A separate listing will be provided that presents all lab values for the subjects 
meeting any of these criteria during treatment.
Laboratory Variables by Subgroups 
Laboratory abnormalities of special interest will be assessed for the subgroups defined 
below:


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●
Sex (male, female)
●
Age (< 65 years, ≥ 65 – < 75 years, ≥ 75 years)
●
BMI (< 25, ≥ 25 kg/m2)
●
Baseline fibrosis stage (F0 – F1, F2, F3, F4 (if applicable))
●
Concomitant use of Calcium Channel Blockers (CCBs) (yes/no)
These subgroup analyses will be presented for the summary of ALT, AST, alkaline 
phosphatase, total bilirubin, and hemoglobin by maximum CTCAE grade.
Subgroup analyses will be presented by treatment arm and the Breslow-Day test will be 
used to examine the homogeneity of treatment effect across subgroups for the percentage 
of subjects with at least a Grade 2 abnormality and the percentage of subjects with at least 
a Grade 3 abnormality. 
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.
The criteria for potentially clinically significant vital sign findings are presented in 
Table 10.


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56
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic Blood Pressure
≤ 90 mmHg AND A decrease of 
≥20 mmHg from baseline
≥ 180 mmHg AND An increase of 
≥ 20 mmHg from baseline
Diastolic Blood Pressure
≤ 50 mmHg AND A decrease of 
≥15 mmHg from baseline
≥ 105 mmHg AND An increase of 
≥ 15 mmHg from baseline
Pulse Rate
≤ 50 bpm AND A decrease of 
≥15 bpm from baseline
≥ 120 bpm AND An increase of 
≥15 bpm from baseline
Weight
A decrease of ≥ 15% from baseline
An increase of ≥ 15% from 
baseline
Body Temperature
> 38.3°C AND An increase of 
≥1.1°C from baseline
11.4.2
Statistical Methods
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for change to Treatment 
Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable 
post-treatment visits, will be summarized for each treatment arm.  Each vital sign 
parameter will be summarized with the baseline mean, visit mean, change from baseline 
mean, standard deviation, minimum, median, and maximum.  
The number and percentage of subjects with on-treatment values meeting the specified 
criteria for Potentially Clinically Significant (PCS) vital sign values (Table 10) will be 
summarized for each treatment arm.  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.


ABT-493/ABT-530
M15-828 – Statistical Analysis Plan
Version 1.0 – 31 October 2016
57
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP
●
Added unplanned interim analysis when all subjects reach PT Week 4 or 
prematurely discontinue from the study to allow for the submission to the 
PMDA at the time of SVR4 analysis.
●
Added secondary analyses, sensitivity analyses, subgroup analyses, and 
additional analyses for the submission to the PMDA at the time of SVR4
analysis.
●
Updates were made to the resistance analysis plan to be consistent across the 
HCV ABT-493/ABT-530 program;
●
Updated safety analyses to align across the HCV ABT-493/ABT-530 program;
●
Added additional summaries of demographics, baseline characteristics to 
provide geographic region-specific information (Section 7.1).
13.0
References
1.
Sofosbuvir tablets [US package insert].  Tokyo, Japan; AbbVie Ltd, 2015.
2.
Sofosbuvir tablets [Japan package insert].  Tokyo, Japan; AbbVie Ltd, 2015.
3.
Asahina Y, Izumi N, Hiromitsu K, et al.  JSH Guidelines for the management of 
hepatitis C virus infection:  a 2016 update for genotype 1 and 2.  Hepatol Res.  
2016;46(2):129-65.
4.
Grundy SM, Brewer HB, 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.
5.
Reenen MV, Oppe M.  EQ-5D-3L user guide:  basic information on how to use the 
EQ-5D-3L instrument, Version 5.1.  April 2015.