Clinical trial NCT02292719
Conditions: Chronic Hepatitis C Virus Infection
Keywords: Hepatitis C Virus Genotype 2 Chronic Hepatitis C Genotype 3 Non-cirrhotic Cirrhotic
Sponsor: AbbVie
Start date: 2014-12-19; Completion date: 2017-07-14
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of Ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with sofosbuvir (SOF) with or without ribavirin (RBV) in adults with Genotype 2 Chronic Hepatitis C Virus (HCV) infection or Genotype 3 HCV infection with or without Cirrhosis.

Detailed description:

Arms: arm 1: Ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) 25/150/100 mg once daily (QD) and sofosbuvir (SOF) 400 mg QD for 12 weeks. arm 2: OBV/PTV/r (25/150/100) mg QD with SOF (400 mg QD) and ribavirin (RBV; weight-based 1,000 mg or 1,200 mg daily divided twice daily \[BID\]) for 12 weeks. arm 3: OBV/PTV/r (25/150/100) mg QD with SOF (400 mg QD) and RBV (weight- based 1,000 mg or 1,200 mg daily divided BID) for 8 weeks. arm 4: OBV/PTV/r (25/150/100) mg QD with SOF (400 mg QD) and RBV (weight-based 1,000 mg or 1,200 mg daily divided BID) for 6 weeks. arm 5: OBV/PTV/r (25/150/100) mg QD with SOF (400 mg QD) and RBV (weight-based 1,000 mg or 1,200 mg daily divided BID) for 12 weeks. arm 6: OBV/PTV/r (25/150/100) mg QD and SOF (400 mg QD) for 12 weeks.
Interventions: intervention 1: OBV/PTV/r intervention 2: Sofosbuvir intervention 3: Ribavirin (RBV)
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Tablet

Protocol documents:
Prot_000.pdf: 


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
EudraCT 2014-003147-35
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1.1
Synopsis
AbbVie Inc.
Protocol Number:  M14-567
Name of Study Drug:  Ombitasvir, ABT-450, 
ritonavir, sofosbuvir, ribavirin
Phase of Development:  2
Name of Active Ingredient:
ombitasvir:  Dimethyl ([(2S,5S)-1-(4-tert-
butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-
methyl-1-oxobutane-1,2-diyl]})biscarbamate 
hydrate
ABT-450:  (2R,6S,12Z,13aS,14aR,16aS)-N-
(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-
yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-
yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-
tetradecahydrocyclopropa[e]pyrrolo[1,2-
a][1,4]diazacyclopentadecine-14a(5H)-carboxamide
hydrate
ritonavir:  10-Hydroxy-2-methyl-5-(1-
methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-
dioxo-8,11-bis(phenylmethyl)-2,4,7,12-
tetraazatridecan-13-oic acid, 5-thiazolylmethyl 
ester, [5S-(5R*,8R*,10R*,11R*)]
sofosbuvir:  (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-
5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-
fluoro-3-hydroxy-4-methyltetrahydrofuran-2-
yl)methoxy)-
(phenoxy)phosphorylamino)propanoate
ribavirin:  1-β-D-ribofuranosyl-1H-1,2,4-triazole-
3-carboxamide
Date of Protocol Synopsis: 31 July 2014
Protocol Title:
A Randomized, Open-Label Study to Evaluate the Safety and Efficacy of the Co-Administration of 
Ombitasvir/ABT-450/Ritonavir (Ombitasvir/ABT-450/r) With Sofosbuvir (SOF) With or Without 
Ribavirin (RBV) in Subjects With Genotype 3 Chronic Hepatitis C Virus (HCV) Infection


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
EudraCT 2014-003147-35
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Objectives:
The primary objectives of this study are to assess the safety and efficacy (the percentage of subjects 
achieving a 12-week sustained virologic response ([SVR12] [HCV ribonucleic acid (RNA) < lower limit 
of quantification (LLOQ) 12 weeks following treatment]) of co-formulated ombitasvir with ABT-450 
and ritonavir (r) (ombitasvir/ABT-450/r) co-administered with sofosbuvir (SOF) with or without 
ribavirin (RBV) in treatment-naïve and prior (pegIFN, RBV, and/or SOF) treatment-experienced adults 
with genotype 3 HCV infection without cirrhosis.
The secondary objectives of this study are to assess the percentage of subjects with virologic failure 
during treatment, the percentage of subjects with post-treatment relapse, and to characterize the 
pharmacokinetics of direct-acting antiviral agents (DAAs) including ritonavir, SOF, GS-331007 
(predominant circulating metabolite of SOF), and RBV (if applicable) in adults with genotype 3 HCV 
infection.
Investigators:  Multicenter, investigator information on file at AbbVie
Study Sites:  Approximately 8 sites
Study Population:  Adult males and females at least 18 years of age with HCV genotype 3 infection 
without cirrhosis, who are treatment-naïve or previously treated with pegIFN, RBV, and/or SOF.
Number of Subjects to be Enrolled:  Approximately 20 subjects.
Methodology:
This is a Phase 2, randomized, open-label, multicenter study evaluating the safety and efficacy of 
co-formulated ombitasvir/ABT-450/r co-administered with SOF with or without RBV in treatment naïve 
and prior (pegIFN, RBV, and/or SOF) treatment-experienced adults with genotype 3 HCV infection 
without cirrhosis.  Approximately 20 subjects will be enrolled across approximately 8 sites globally into 
one of two arms.
The study consists of:
!
Treatment Period:  Approximately 20 subjects with genotype 3 HCV infection will be randomized 
1:1 into the following treatment arms (approximately 10 subjects each):
o
Arm A:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg once daily (QD) + SOF 400 mg QD for 
12 weeks
o
Arm B:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg QD + SOF 400 mg QD + RBV 
1000 – 1200 mg divided twice daily (BID) for 12 weeks.  
Randomization to Arms A and B will be stratified by IL28B genotype (CC versus non-CC) and 
prior treatment status (treatment-naïve versus treatment-experienced).  Study drugs should be 
administered with food.  Subject safety laboratory results and virologic failure criteria will be 
evaluated during the Treatment Period.  Upon completion of the Treatment Period or premature 
discontinuation, subjects will enter the Post-Treatment (PT) Period.
o
PT Period:  Subjects who complete or prematurely discontinue study drugs in the Treatment 
Period will be followed for 48 weeks to monitor safety, HCV RNA, the emergence and 
persistence of resistant viral variants, and assessments of Patient Report Outcomes (PROs).


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
EudraCT 2014-003147-35
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Methodology (Continued):
Virologic Failure Criteria for Subject Management:
The following criteria will be considered evidence of virologic failure.  Subjects demonstrating any of 
the following will be discontinued from study drug:
!
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
!
Failure to achieve HCV RNA < LLOQ by Week 8; or
!
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements ≥ LLOQ) 
at any point during treatment after HCV RNA < LLOQ.
Confirmatory testing, where required, should be completed as soon as possible.  Also, when 
confirmation is required, the subject should remain on study treatment until the virologic failure has been 
confirmed.
If any of the above criteria are met on therapy, the subject will discontinue study treatment as described 
above.
All subjects who receive at least one dose of study drug in the Treatment Period will be monitored in the 
Post-Treatment Period for up to 48 weeks following the last dose of study drug.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female at least 18 years of age at time of screening.
2.
Chronic HCV infection prior to study enrollment.  Chronic HCV infection is defined as one of the 
following:
!
Positive for anti-HCV Antibody (Ab) or HCV RNA at least 6 months before Screening, and 
positive for HCV RNA and anti-HCV Ab at the time of Screening; or
!
HCV RNA > 10,000 IU/mL at the time of Screening with a liver biopsy consistent with 
chronic HCV infection (or a liver biopsy performed prior to enrollment with evidence of 
chronic hepatitis C disease).
3.
Screening laboratory results from the central clinical laboratory indicating HCV 
genotype 3 infection only.
4.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements and must voluntarily sign and date an informed consent.
5.
Absence of cirrhosis, as documented by meeting one of the following criteria (per local standard 
practice):
!
Liver biopsy within 24 months prior to screening or during screening demonstrating the absence 
of cirrhosis.
!
Only in the absence of a biopsy within the 24 months prior to screening or during screening:
o
a screening FibroTest score of ≤ 0.72 and Aspartate Aminotransferase to Platelet Ratio 
Index (APRI) ≤ 2; or
o
a screening transient elastography (e.g., FibroScan®) result of < 12.5 kPa.


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion(Continued):
Subjects with a FibroScan® result that is ≥ 12.5 kPa and < 14.6 kPa, or a FibroTest result that is 
≤0.72 and an APRI ≥ 2, or a FibroTest result that is > 0.73 and an APRI ≤ 2, must have a liver 
biopsy performed within 24 months prior to screening showing no evidence of cirrhosis, or in the 
absence of an available biopsy results within 24 months prior to screening, may undergo a liver 
biopsy during screening to rule out cirrhosis.
Main Exclusion:
1.
Females who are pregnant or plan to become pregnant or breastfeeding, or males whose partners are 
pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last 
dose of study drug.
2.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol. 
3.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti-HIV Ab positive.
4.
Current enrollment in another clinical study, previous enrolment in this study, or previous use of 
any investigational or commercially available anti-HCV therapy (other than interferon, pegIFN, 
RBV, and or SOF) including previous exposure to telaprevir, boceprevir, ABT-450, or ombitasvir 
(ABT-267).  Subjects who previously participated in trials of investigational anti-HCV agents may 
be enrolled with approval of the AbbVie Study Designated Physician if they can produce 
documentation that they received only placebo.  Concurrent participation in a non-interventional, 
epidemiologic, or registry trial may be permitted with approval by the AbbVie Study Designated 
Physician.
5.
Any current or past clinical evidence of cirrhosis such as ascites or esophageal varices, or prior 
biopsy showing cirrhosis, e.g., a Metavir score > 3 or an Ishak score > 4.
6.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Calculated creatinine clearance (using Cockcroft-Gault method) < 30 mL/min.
!
Albumin < Lower limit of normal (LLN).
!
Prothrombin time/International normalized ratio (INR) > 1.5.  Subjects with a known inherited 
blood disorder and INR > 1.5 may be enrolled with permission of the AbbVie Study 
Designated Physician.
!
Hemoglobin < LLN.
!
Platelets < 120,000 cells per mm3.
!
Absolute neutrophil count (ANC) < 1500 cells/μL (< 1200 cells/μL for subjects of African 
descent who are black).
!
Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN.
Investigational Product:
ombitasvir/ABT-450/ritonavir:  12.5 mg/75 mg/50 mg tablet
sofosbuvir:  400 mg tablet
ribavirin:  200 mg tablet
Dose:
ombitasvir/ABT-450/ritonavir:  25 mg/150 mg/100 mg QD
sofosbuvir:  400 mg QD
ribavirin weight-based dosing 1000 to 1200 mg BID


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
EudraCT 2014-003147-35
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Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:
Subject will receive multiple QD doses of ombitasvir/ABT-450/r co-administered with SOF with or 
without RBV BID for 12 weeks.  
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA in IU/mL will be assessed at all Treatment Period visits and at all PT visits.
Criteria for Evaluation (Continued):
Patient Reported Outcomes (PROs):
Health State Utility will be assessed using the EuroQol-5 Dimensions-5 Level (EQ-5D-5L) including its 
Visual Analog Scale (VAS) component.  Fatigue severity will be assessed using the Fatigue Severity 
Scale (FSS) including its Visual Analog Fatigue Scale (VAFS) component.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects, the variants at baseline 
at signature resistance-associated amino acid positions relative to the reference sequence, and 2) for 
subjects who do not achieve SVR12, all post-baseline variants relative to baseline.
Pharmacokinetic:
Intensive pharmacokinetic samples will be collected on Day 1 at 2, 4, and 6 hours post DAA dosing and 
at the 2-week visit at pre-dose and approximately 2, 4, and 6 hours post DAA dose for measurement of 
concentrations of ombitasvir, ABT-450, ritonavir, SOF, GS-331007 (predominant circulating metabolite 
of SOF), and RBV (if applicable).  In addition, pharmacokinetic samples will be collected at each study 
visit during treatment.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-lead ECGs, and vital signs.
Statistical Methods:
Efficacy:
The primary endpoint is the percentage of subjects with SVR12 (HCV RNA < LLOQ 12 weeks after the 
last actual dose of study drugs).  The secondary endpoints are the percentage of subjects with virologic 
failure during treatment and the percentage of subjects with relapse post-treatment.  For the primary and 
secondary endpoints, the simple percentage of subjects meeting the endpoint will be calculated, and a 
2-sided 95% Wilson score confidence interval for a binomial proportion will be computed.


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
EudraCT 2014-003147-35
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Statistical Methods (Continued):
PROs:
Changes from baseline in the EQ-5D-5L health index score, the visual analogue scale (VAS) response 
component of the EQ-5D-5L, FSS score, and visual analogue fatigue scale (VAFS) component of the 
FSS will be summarized for each applicable post-baseline visit by overall and by treatment arm, 
respectively.
Resistance:
The following resistance information will be provided for all subjects:  the amino acid variants at 
baseline at signature resistance-associated positions identified by population nucleotide sequencing and 
comparison to the appropriate prototypic reference sequence.
The following resistance information will be analyzed for subjects 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 and/or clonal nucleotide sequencing and comparison to 
the baseline sequence, 2) the amino acid variants in available post-baseline samples at signature 
resistance-associated positions identified by population nucleotide sequencing and comparison to the 
appropriate prototypic reference sequence, and 3) the persistence of resistance-associated amino acid 
variants by population and/or clonal nucleotide sequencing during the post-treatment period.
Pharmacokinetic:
Individual plasma concentrations of ABT-450, ritonavir, ombitasvir, SOF, GS-331007, and ribavirin will 
be tabulated and summarized.  Individual plasma concentrations of possible metabolites of ABT-450, 
ombitasvir, and SOF (other than GS-331007) may be tabulated and summarized if measured and 
sufficient levels of metabolites are observed.
Values for the pharmacokinetic parameters of ombitasvir, ABT-450, ritonavir, SOF, GS-331007, and 
RBV (if applicable) including the Cmax, Tmax, Ctrough, and AUC will be determined by noncompartmental 
methods using intensive pharmacokinetic blood sampling data in the study.  Additional parameters or 
summaries may be determined if useful in the interpretation of the data.
Safety:
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term for each 
treatment arm and overall.  Tabulations by treatment arm will also be provided in which the number of 
subjects reporting a treatment emergent adverse event (MedDRA preferred term) is presented by severity 
(mild, moderate, or severe) and relationship to study drugs.
Change from baseline in laboratory tests and vital sign measurements to each time point of collection 
will be summarized descriptively for each treatment arm.  Laboratory test and vital sign values that are 
potentially clinically significant, according to predefined criteria, will be identified and the number and 
percentage of subjects with potentially clinically significant values during treatment will be calculated 
for each treatment arm.


Ombitasvir/ABT-450/Ritonavir
M14-567 Protocol
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1.2
List of Abbreviations and Definition of Terms
Abbreviations
Ab
Antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APRI
Aspartate aminotransferase-to-Platelet Ratio Index
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BMI
Body Mass Index
BUN
Blood urea nitrogen
CRF
Case report form
CT
Computed Tomography
CYP3A
Cytochrome P450 3A
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EP
European Pharmacopoeia
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Health State Instrument
EU
European Union
FDA
US Food and Drug Administration
FSH
Follicle stimulating hormone
FSS
Fatigue Severity Scale
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLP
Good laboratory Practice
GS-331007
Predominant circulating metabolite of sofosbuvir
GT
Genotype


Ombitasvir/ABT-450/Ritonavir
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HAV-IgM
Hepatitis A virus immunoglobulin M
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
Hemoglobin A1c
Glycated hemoglobin
HEOR
Heath Economics and Outcomes Research
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
HRQoL
Health Related Quality of Life
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IL28B
Interleukin 28B
INR
International normalized ratio
IP-10
Interferon gamma-induced protein 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to Treat
IU
International units
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
Messenger Ribonucleic acid
MRI
Magnetic Resonance Imaging
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
OATP1B1
Organic anion transporting polypeptide 1B1
OL
Open-label


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Ombitasvir/ABT-450/r
Ombitasvir co-formulated with ABT-450 and ritonavir
PCR
Polymerase Chain Reaction
pegIFN
Pegylated-interferon alfa-2b or alfa-2b
PG
Pharmacogenetic
PK
Pharmacokinetic
POR
Proof of Receipt
PRO
Patient Reported Outcomes
PT
Post-Treatment
QD
Once daily
QTc
QT interval corrected for heart rate
QTcF
QTc using Fridericia's correction formula
r
Ritonavir
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase PCR
SAE
Serious adverse event
sAFP
Serum Alpha-Fetoprotein
SAS
Statistical Analysis System
SD
Standard Deviation
SDP
Study Designated Physician
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SOF
Sofosbuvir
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
SVR4
Sustained virologic response 4 weeks post dosing
SVR12
Sustained virologic response 12 weeks post dosing
SVR24
Sustained virologic response 24 weeks post dosing
TP
Treatment Period
ULN
Upper limit of normal
USP
United States Pharmacopoeia
VAFS
Visual analogue fatigue scale


Ombitasvir/ABT-450/Ritonavir
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VAS
Visual analogue scale
WBC
White blood cells
Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
Cmax
Maximum observed plasma concentration
Ctrough
Trough plasma concentration
Tmax
Time to maximum observed plasma concentration
Definition of Terms
Study Drug
Ombitasvir/ABT-450/r, sofosbuvir, ribavirin
Screening Period
Up to 35 days prior to Study Day 1
Study Day 1
First day of study drug dosing
Treatment Period
Baseline/Day 1 through last dose of study drug
Post-Treatment Period
Day after last dose of study drug through Post-Treatment Week 48 or 
Post-Treatment Discontinuation


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Synopsis .....................................................................................................2
1.2
List of Abbreviations and Definition of Terms..........................................8
2.0
Table of Contents...................................................................12
3.0
Introduction ...........................................................................17
3.1
Differences Statement..............................................................................24
3.2
Benefits and Risks....................................................................................25
4.0
Study Objective......................................................................27
4.1
Primary Objectives...................................................................................27
4.2
Secondary Objectives...............................................................................27
5.0
Investigational Plan...............................................................27
5.1
Overall Study Design and Plan:  Description ..........................................27
5.1.1
Screening..................................................................................................30
5.1.1.1
Rescreening..............................................................................................31
5.1.2
Treatment Period......................................................................................31
5.1.3
Post-Treatment (PT) Period .....................................................................33
5.2
Selection of Study Population..................................................................33
5.2.1
Inclusion Criteria .....................................................................................33
5.2.2
Exclusion Criteria ....................................................................................36
5.2.3
Prior and Concomitant Therapy...............................................................40
5.2.3.1
Prior HCV Therapy..................................................................................41
5.2.3.2
Concomitant Therapy...............................................................................41
5.2.3.3
Prohibited Therapy...................................................................................42
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables.............................................................................43
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................43
5.3.1.1
Study Procedures .....................................................................................49
5.3.1.2
Meal and Dietary Requirements ..............................................................58
5.3.1.3
Blood Samples for Pharmacogenetic Analysis........................................59
5.3.2
Drug Concentration Measurements .........................................................60
5.3.2.1
Collection of Samples for Analysis .........................................................60


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5.3.2.2
Handling/Processing of Samples .............................................................61
5.3.2.3
Disposition of Samples ............................................................................61
5.3.2.4
Measurement Methods.............................................................................62
5.3.3
Efficacy Variables....................................................................................62
5.3.3.1
Primary Variable......................................................................................63
5.3.3.2
Secondary Variable..................................................................................63
5.3.4
HCV Resistance Variables.......................................................................63
5.3.5
Safety Variables.......................................................................................63
5.3.6
Pharmacokinetic Variables ......................................................................64
5.3.7
Pharmacogenetic Variables......................................................................64
5.4
Removal of Subjects from Therapy or Assessment.................................65
5.4.1
Discontinuation of Individual Subjects....................................................65
5.4.1.1
Virologic Failure Criteria for Subject Management ................................66
5.4.1.2
Safety Stopping Criteria...........................................................................67
5.4.2
Discontinuation of Entire Study...............................................................67
5.5
Treatments................................................................................................68
5.5.1
Treatments Administered.........................................................................68
5.5.2
Identity of Investigational Product...........................................................69
5.5.2.1
Packaging and Labeling...........................................................................69
5.5.2.2
Storage and Disposition of Study Drug ...................................................70
5.5.3
Method of Assigning Subjects to Treatment Arms..................................70
5.5.4
Selection and Timing of Dose for Each Subject......................................71
5.5.5
Blinding....................................................................................................71
5.5.6
Treatment Compliance.............................................................................71
5.5.7
Drug Accountability.................................................................................72
5.6
Discussion and Justification of Study Design..........................................73
5.6.1
Discussion of Study Design and Choice of Control Arms ......................73
5.6.2
Appropriateness of Measurements...........................................................75
5.6.3
Suitability of Subject Population .............................................................75
5.6.4
Selection of Doses in the Study ...............................................................75
6.0
Adverse Events.......................................................................78
6.1
Definitions................................................................................................79
6.1.1
Adverse Event..........................................................................................79


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6.1.2
Serious Adverse Events ...........................................................................79
6.2
Adverse Event Severity............................................................................81
6.3
Relationship to Study Drug......................................................................81
6.4
Adverse Event Collection Period.............................................................82
6.5
Adverse Event Reporting.........................................................................82
6.6
Pregnancy.................................................................................................84
6.7
Toxicity Management ..............................................................................84
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events ........................................................................................85
6.7.2
Grades 3 or 4 Laboratory Abnormalities .................................................85
6.7.3
Severe Adverse Events or Serious Adverse Events.................................86
6.7.4
Management of Decreases in Hemoglobin..............................................87
6.7.5
Management of ALT Elevations..............................................................88
6.7.6
Creatinine Clearance................................................................................89
7.0
Protocol Deviations................................................................90
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................91
8.1
Statistical and Analytical Plans................................................................91
8.1.1
Demographics ..........................................................................................92
8.1.2
Efficacy....................................................................................................93
8.1.2.1
Primary Efficacy Endpoint ......................................................................93
8.1.2.2
Secondary Efficacy Endpoints.................................................................93
8.1.2.3
Additional Efficacy Endpoints.................................................................94
8.1.3
Patient Reported Outcomes......................................................................94
8.1.4
Resistance Analyses.................................................................................95
8.1.5
Safety .......................................................................................................98
8.1.5.1
Adverse Events ........................................................................................98
8.1.5.2
Clinical Laboratory Data..........................................................................99
8.1.5.3
Vital Signs Data .......................................................................................99
8.1.6
Pharmacokinetic and Exposure-Response Analyses ...............................99
8.2
Determination of Sample Size ...............................................................102
8.3
Randomization Methods ........................................................................102
9.0
Ethics.....................................................................................103


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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................103
9.2
Ethical Conduct of the Study.................................................................104
9.3
Subject Information and Consent...........................................................104
10.0
Source Documents and Case Report Form 
Completion ...........................................................................105
10.1
Source Documents .................................................................................105
10.2
Case Report Forms.................................................................................105
11.0
Data Quality Assurance ......................................................106
12.0
Use of Information...............................................................106
13.0
Completion of the Study .....................................................107
14.0
Investigator's Agreement....................................................108
15.0
Reference List ......................................................................109
List of Tables
Table 1.
Overview of Treatment-Emergent Adverse Events (AE)........................20
Table 2.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline 
Lab Abnormalities ...................................................................................21
Table 3.
Medications Contraindicated for Use with the Study Drug 
Regimen ...................................................................................................38
Table 4.
Study Activities – Treatment Period........................................................44
Table 5.
Study Activities – Post-Treatment (PT) Period .......................................47
Table 6.
Clinical Laboratory Tests.........................................................................53
Table 7.
Identity of Investigational Products.........................................................69
Table 8.
Recommended Ribavirin Dosing in Chronically HCV-Infected 
Patients with Chronic Kidney Disease.....................................................71
Table 9.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases ............................................................................88
Table 10.
Dosing of RBV in Subjects with Renal Impairment................................90
Table 11.
Probability of Not Observing an Adverse Event or Lab 
Abnormality for Various True Incidence Rates.....................................102


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List of Figures
Figure 1.
Study Design............................................................................................28
Figure 2.
Adverse Event Collection ........................................................................82
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................112
Appendix B.
List of Protocol Signatories....................................................................114
Appendix C.
Clinical Toxicity Grades........................................................................115


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with 170 million individuals 
chronically infected worldwide and at risk of developing liver cirrhosis, hepatocellular 
carcinoma, or both.1  Cirrhosis develops after prolonged HCV infection.2  Complications 
of cirrhosis include hepatic decompensation (ascites, encephalopathy, variceal 
hemorrhage, hepatorenal syndrome, or hepatic synthetic dysfunction) and hepatocellular 
carcinoma, which ensues at a rate of about 3% per year.3-6  Without liver transplantation, 
decompensated cirrhosis leads to death in 50% to 72% of patients after 5 years.7  As a 
result of the high prevalence of HCV infection and resultant complications, HCV is the 
leading indication for liver transplantation in the United States and the world as a whole.8
While the advent of new direct-acting antiviral agents (DAAs) has improved efficacy and 
reduced the need for interferon in the treatment of HCV, treatment of genotype 3 infection 
still remains problematic.  While genotype 3 accounts for only approximately 7% of 
infections in the US, it is especially prevalent in India and Pakistan, as well as in many 
countries in Europe.9  In many regions of Europe and North America, prevalence of 
genotype 3 appears to be increasing among younger patients who are active injecting drug 
users.10,11  Pegylated interferon and ribavirin for up to 24 weeks is an approved treatment, 
and is associated with a sustained virologic response (SVR) rate of approximately 66%.12
Sofosbuvir, a nucleoside nonstructural protein 5B (NS5B) RNA-dependent RNA 
polymerase inhibitor, is one of the newest DAAs approved by the Food and Drug 
Administration (FDA), and in clinical studies, sofosbuvir 400 mg daily in combination 
with ribavirin (RBV) achieved sustained virological response (SVR) rates of 85% in 
patients with chronic HCV genotype 3 infection when given for 24 weeks, though 
responses were lower in previously treated patients and those with cirrhosis.13
AbbVie currently has a number of DAAs in clinical development for the treatment of 
HCV infection, two of which have in vitro activity against HCV genotype 3.  ABT-450 is 
a nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease inhibitor 
co-administered with the pharmacokinetic enhancer, ritonavir (ABT-450/r), and 


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ombitasvir is a NS5A inhibitor.  These agents have the potential for co-administration 
with sofosbuvir in the treatment of genotype 3 HCV infection.  An additional AbbVie 
DAA in development, dasabuvir, is a non-nucleoside NS5B polymerase inhibitor; 
however, dasabuvir is not active against genotype 3 HCV, and is therefore not included in 
this trial.  Additional information on ABT-450 and ombitasvir is provided below.
ABT-450
ABT-450, (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-
2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14, 
15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-
14a(5H)-carboxamide hydrate, is an NS3/4A protease inhibitor with EC50 values in 
subgenomic replicon stable cell lines of 1.0, 0.21, 5.3, 19 and 0.085 nM against 
genotypes 1a, 1b, 2a, 3a and 4a, respectively.  ABT-450 is metabolized primarily by 
cytochrome P450 3A4 (CYP3A4) and thus is dosed with ritonavir, a potent CYP3A4 
inhibitor, in order to enhance exposures (ABT-450/r).  ABT-450/r has been well tolerated 
in single- and multiple-dose studies in healthy volunteers.
ABT-450/r has a favorable safety, tolerability, and pharmacokinetic profile at doses 
administered to date and has shown potent antiviral activity at doses of 50/100 mg QD 
and greater in HCV genotype 1-infected subjects.  Additional detailed information about 
preclinical toxicology, metabolism, pharmacology, and clinical data can be found in the 
Investigator's Brochure for ABT-450.14
Ombitasvir (ABT-267)
Ombitasvir, dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis 
{benzene4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-
diyl]}) biscarbamate hydrate, is an NS5A inhibitor, with EC50 values in subgenomic 
replicon stable cell lines of 0.014, 0.005, 0.012, 0.004, 0.019 and 0.002 nM against 
genotypes 1a, 1b, 2a, 2b, 3a, and 4a, respectively.


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Ombitasvir has a favorable safety, tolerability, and pharmacokinetic profile at all doses 
administered to date, and has shown potent antiviral activity at doses of 5 mg QD and 
greater in HCV genotype 1-infected subjects.  Additional detailed information about 
preclinical toxicology, metabolism, pharmacology and clinical data can be found in the 
Investigator's Brochure for ombitasvir.15
Phase 2 Results with ABT-450 and Ombitasvir in Genotype 3 Infection
The combination of ombitasvir and ABT-450/r has been studied in genotype 1 infection in 
several Phase 2 trials.  However, only one Phase 2a trial (Study M12-998) enrolled 
subjects infected with genotype 3.  In this study, which included subjects with 
genotypes 1, 2 and 3, 21 genotype 3-infected subjects were enrolled, 11 of whom received 
ABT-450/r and ombitasvir and 10 of whom received ABT-450/r, ombitasvir, and 
weight-based RBV 1000 – 1200 mg daily.  Antiviral activity was seen in both treatment 
groups; however, 7 of 10 subjects had suppressed HCV RNA levels (< 25 IU/mL) at the 
end of 12 weeks of dosing with RBV, compared to 2 of 11 who received treatment for 
12 weeks without RBV.  SVR was achieved for 5 of 10 subjects who received ombitasvir 
+ ABT-450/r + RBV, compared to 1 of 11 who received ombitasvir + ABT-450/r alone.
Integrated Safety Results
The interferon (IFN)-free regimen of ABT-450/r, ombitasvir, and the non-nucleoside 
NS5B polymerase inhibitor, dasabuvir, has been studied with and without RBV in over 
2,300 genotype 1-infected patients in Phase 3 trials across a variety of patient populations, 
including patients with compensated cirrhosis.  Based on these data, this 3-DAA regimen 
with or without RBV is safe and well tolerated in treatment-naïve and 
treatment-experienced HCV genotype 1-infected subjects including those with 
compensated cirrhosis.  In a Phase 2 trial, Study M12-998, 61 subjects were treated with 
ombitasvir/ABT-450/r with or without RBV for 12 weeks.  Based on findings from this 
study, the safety profile of ombitasvir/ABT-450/ritonavir with or without RBV appears
comparable to that of ombitasvir/ABT-450/ritonavir plus dasabuvir with or without RBV, 
respectively.


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A summary of treatment-emergent adverse events from pooled analyses of data from the 
Phase 3 studies in genotype 1-infected subjects is presented in Table 1.  A majority of 
subjects experienced at least one event, but most subjects experienced events that were 
mild in severity.  Rates of severe adverse events and adverse events leading to 
discontinuation were low across studies, but numerically higher in the study of subjects 
with cirrhosis.
Table 1.
Overview of Treatment-Emergent Adverse Events (AE)
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-wk
3-DAA + RBV
12-wk 
PBO
12-wk
3-DAA + RBV
12-wk
3-DAA
12-wk
3-DAA + RBV
24-wk
3-DAA + RBV
Events, %
N = 770
N = 255
N = 401
N = 509
N = 208
N = 172
Subjects ≥ 1 AE
89.0
76.9
82.8
75.0
91.8
90.7
Severe AE
3.5
0.4
1.0
1.2
6.7
7.6
Grade 3 or 4 AE
3.9
0.8
3.0
2.0
7.7
8.1
Serious AE
2.1
0.4
2.2
1.4
6.3
4.7
AE leading to 
discontinuation
0.8
0.4
0.5
0.4
1.9
2.3
Deaths
0.1a
0
0
0
0
0
wk = week, PBO = placebo
a.
Lung cancer.
The most common adverse events regardless of causality are listed in Table 2.  Adverse 
events that occurred with an incidence at least 5% greater in the 3-DAA + RBV regimen 
compared to placebo were considered to be adverse drug reactions related to the study 
treatment.  These include fatigue, nausea, pruritus, insomnia, asthenia, and anemia.  The 
frequency of these events was generally lower in the arm treated without RBV.  In 
general, rates of adverse events were similar in patients with cirrhosis versus patients 
without cirrhosis.


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Table 2.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline Lab 
Abnormalities
Treatment-Emergent 
Adverse Events, %
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-wk
3-DAA + 
RBV
12-wk 
PBO
12-wk
3-DAA + 
RBV
12-wk
3-DAA
12-wk
3-DAA + 
RBV
24-wk
3-DAA + 
RBV
N = 770
N = 255
N = 401
N = 509
N = 208
N = 172
Headache
34.3
29.8
24.4
25.1
27.9
30.8
Fatigue
34.2
26.3
29.9
26.5
32.7
46.5
Nausea
22.3
14.9
15.7
8.4
17.8
20.3
Pruritus
15.7
4.3
12.0
6.1
18.3
19.2
Insomnia
14.0
7.5
12.2
5.1
15.4
18.0
Diarrhea
13.5
9.0
8.7
11.4
14.4
16.9
Asthenia
13.5
6.7
9.0
3.9
13.9
12.8
Rash
10.0
5.9
6.2
3.7
11.1
14.5
Cough
8.7
5.1
6.7
4.7
11.5
11.0
Irritability
5.3
4.7
3.2
3.1
7.2
12.2
Anemia
5.3
0
7.5
0.2
7.7
10.5
Dyspnea
9.7
5.5
4.7
2.2
5.8
12.2
Laboratory Events, %
N = 765
N = 254
N = 401
N = 509
N = 208
N = 172
Hemoglobin
< 10 g/dL (Gr 2)
5.5
0
6.2
0
7.2
11.0
< 8.0 g/dL (Gr 3)
0.1
0
0.5
0
1.4
0.6
ALT
> 5 × ULN (Gr 3)
1.2
3.9
0.7
0.2
2.9
0
Bilirubin
> 3 × ULN (Gr 3)
2.6
0
5.7
0.4
13.5
5.2
wk = week, PBO = placebo
Note:
Percentages of laboratory events are based on the number of subjects with at least one post-baseline value.
Transient elevations in total (predominantly indirect) bilirubin have been observed, due to 
ABT-450 inhibition of the bilirubin transporters OATP1B1 and OATP1B3 and 
RBV-induced hemolysis.  The elevations generally peaked by Weeks 1 and 2, declined 
through the end of treatment and returned to within the normal range by 4 weeks 


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post-treatment.  Hyperbilirubinemia occurred less frequently in subjects treated with 
3 DAAs without RBV compared to 3 DAAs with RBV.  The frequency and degree of 
hyperbilirubinemia were higher in subjects with cirrhosis, but the temporal pattern of 
elevation followed by resolution was similar and few episodes were symptomatic.  
Grade 2 + hemoglobin reductions occurred in 6% of subjects without cirrhosis who 
received the 3-DAA + RBV regimen for 12 weeks, and 7% and 11% of subjects with 
cirrhosis who received the 3-DAA + RBV regimen for 12 and 24 weeks, respectively.  
Grade 3 hemoglobin values were rare.  The decline in hemoglobin was largely managed 
with RBV dose reductions.  Anemia observed during the clinical trials was largely 
attributable to the presence of RBV as it was not observed when the 3-DAA regimen was 
administered without RBV.
Transient asymptomatic post-baseline serum ALT elevations of > 5 × ULN occurred at a 
frequency of 1% across active treatment arms and were evaluated by an external panel of 
expert hepatologists.  The ALT elevations were asymptomatic, usually occurred within 
the first 4 weeks of treatment and typically declined with ongoing treatment.  A 
disproportionate number of the cases were in women on concurrent systemic 
estrogen-containing therapy (i.e., contraceptives or hormone replacement) and 
discontinuation of the hormonal therapy with continuation or brief interruption of the 
DAA regimen led to resolution in serum ALT elevation.  Concomitant use of systemic 
estrogen-containing medications is a risk factor for these post-baseline elevations in serum 
ALT.  No ALT elevations > 5 × ULN were observed in subjects receiving progestins only 
or in subject receiving topical vaginal estrogen preparations.  Among the cases of serum 
ALT elevation thought to be related to the DAA regimen, none resulted in hepatic 
dysfunction and they generally resolved or improved with ongoing treatment.  All cases 
had resolved completely in the post-treatment follow-up.
ABT-450/ritonavir and ombitasvir (and its major inactive human metabolites) had no 
effects on embryo-fetal development in rodent and/or nonrodent species at maximal 
feasible exposures that provided AUC multiples at least 4-fold higher than exposure at the 


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recommended clinical doses.  Clinical studies in women who are pregnant have not been 
conducted.
Sofosbuvir
Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor indicated for the treatment 
of chronic hepatitis C infection as a component of a combination antiviral treatment 
regimen.  The approved dose is 400 mg orally once daily, without regard to food.16  
Sofosbuvir has demonstrated potent activity when administered to HCV 
genotype 3-infected subjects in combination with RBV.
After oral administration, sofosbuvir is rapidly converted to the predominant circulating 
metabolite GS-331007 that accounts for greater than 90% of drug related material system 
exposure, while sofosbuvir accounts for approximately 4% of drug related material.  
Sofosbuvir peak plasma concentrations occurred 0.5 to 2 hours post-dose and GS-331007 
peak plasma concentrations were reached 2 to 4 hours post dose.16
Sofosbuvir is a substrate of drug transporters P-gp and breast cancer resistance protein 
(BCRP), while GS-331007 is not.  Co-administration of sofosbuvir with drugs that are 
P-gp inducers in the intestines may decrease sofosbuvir plasma concentrations leading to 
reduced effect and are not recommended for co-administration with sofosbuvir.  Drugs 
that inhibit P-gp and BCRP may increase sofosbuvir plasma concentrations without 
increasing GS-331007 plasma concentrations; thus, no precautions in co-administration 
are warranted.  Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP.16
Sofosbuvir is a prodrug extensively metabolized in the liver to the pharmacologically 
active nucleoside analog triphosphate, GS-461203.  Dephosphorylation results in the 
formation of nucleoside metabolite GS-331007 that cannot be efficiently 
rephosphorylated and lacks anti-HCV activity in vitro.16
The majority of the sofosbuvir dose recovered in urine was GS-331007 while 3.5% was 
recovered as sofosbuvir, suggesting that renal clearance is the major elimination pathway 


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for GS-331007.  The median terminal half-lives of sofosbuvir and GS-331007 were 
0.4 and 27 hours, respectively.16
Sofosbuvir was well tolerated in clinical trials, with ≤ 1.5% of subjects discontinuing 
therapy with SOF + RBV or SOF + pegIFN + RBV for 12 weeks.  The most frequently 
reported adverse events were typically mild to moderate and included fatigue, nausea, and 
headache.
Sofosbuvir has in vitro activity against genotype 3a in the replicon system.19  Sofosbuvir 
in combination with RBV resulted in SVR rates of 56% and 92% – 94% in 
treatment-naïve genotype 3-infected subjects when given for 12 and 24 weeks, 
respectively.13,17  Response rates were lower in treatment-experienced subjects, especially 
those with cirrhosis, who had an SVR rate of 60% with 24 weeks of treatment.13  
Sofosbuvir was also studied in a smaller trial in combination with the NS5A inhibitor 
daclatasvir.  No clinically relevant interactions were observed, and significant antiviral 
activity was observed, with 89% of 18 treatment-naïve subjects with genotype 3 infection 
achieving SVR with 24 weeks of treatment.23  No clinically meaningful drug interactions 
have been observed when sofosbuvir was combined with NS5A inhibitors (daclatasvir,19
ledipasvir21) or the protease inhibitor simeprevir.
An ongoing Phase 1 trial, Study M14-527, is assessing the safety and pharmacokinetics of 
the combination of ombitasvir/ABT-450/r with or without dasabuvir plus sofosbuvir 
(SOF) in healthy volunteers for up to 14 days.  No significant pharmacokinetic 
interactions are expected, and no safety signals of concern have been reported from that 
trial.  The current study is intended to examine the safety and antiviral activity of 
ombitasvir/ABT-450/r in combination with SOF with or without RBV in treatment-naïve 
and treatment-experienced subjects with chronic genotype 3 HCV infection.
3.1
Differences Statement
A previous trial evaluated ABT-450/r and ombitasvir with or without RBV in 
genotype 3 infection (Study M12-998), and the combination of ombitasvir/ABT-450/r 


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with SOF is being assessed in healthy volunteers in an ongoing drug interaction study 
(Study M14-527).  In addition, Phase 3 studies have evaluated SOF plus RBV for 
genotype 3 infection.  This is the first study to evaluate the combination of the 
co-formulated ombitasvir/ABT-450/r tablet co-administered with SOF with or without 
RBV in HCV genotype 3-infected subjects.
3.2
Benefits and Risks
Based on results of the Phase 2 Study M12-998 and the known activity of SOF, it is 
expected that the combination of ombitasvir/ABT-450/r and SOF with or without RBV 
may lead to SVR for a significant proportion of subjects.  However, the likelihood of 
achieving SVR in this study is unknown.  Risks of the study regimen include drug toxicity 
and virologic failure, which may result in selection of drug resistance.
Risk of Toxicity
Combination dosing of ABT-450/r with ombitasvir, with or without dasabuvir, has 
generally been well tolerated in healthy volunteers and HCV-infected subjects.  Both 
groups have been dosed with and without RBV, for lengths up to 24 weeks in HCV 
genotype 1-infected subjects in Phase 3 studies.  Preclinical toxicology studies have 
assessed the toxicity of ombitasvir for up to 6 months, and ABT-450 for up to 9 months.  
No dose-limiting toxicities have thus far been observed in animal studies, or in humans 
receiving the doses of ABT-450/r and/or ombitasvir used in this study.  SOF has likewise 
been well tolerated in clinical trials when given for up to 24 weeks with or without RBV.  
Preclinical toxicology studies showed heart inflammation and degeneration in rats at 
(GS-331007) exposures approximately 29-fold higher than those seen in humans at the 
recommended clinical dose.  These findings were not observed in dogs or mice at similar 
or higher exposures, when treated for 9 and 3 months, respectively.  ABT-450/r and 
ombitasvir have not previously been dosed together in combination with SOF in 
HCV-infected subjects, so there is a risk of toxicity associated with the combination, but 
given the benign safety profile of both ombitasvir/ABT-450/r and SOF, the likelihood is 
low.  A drug interaction study in healthy volunteers, Study M14-527, is ongoing.  No 


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safety findings of concern have been reported in healthy volunteers receiving 
ombitasvir/ABT-450/r, dasabuvir and SOF for up to 14 days.  Study drug dosing in the 
current study will not begin until preliminary pharmacokinetic results from 
Study M14-527 confirm absence of clinically meaningful drug-drug-interactions.  Study 
drug dosing in the current study will not begin until preliminary pharmacokinetic results 
from Study M14-527 confirm absence of clinically meaningful drug-drug interactions.
Risk of Treatment Failure
The likelihood of successfully curing genotype 3-infected subjects with a regimen 
containing ombitasvir/ABT-450/r and SOF is unknown. However, ABT-450/r plus 
ombitasvir showed modest efficacy against genotype 3 when administered for 12 weeks in 
a previous study (Study M12-998), which was improved with the addition of RBV,18 and 
the combination of SOF plus RBV is also active against genotype 3.13  Furthermore, in a 
small trial, the combination of SOF and the NS5A inhibitor daclatasvir achieved SVR in 
89% of 18 treatment-naïve subjects with genotype 3 HCV infection.23  Hence, it is 
reasonable to predict that the combination (with or without RBV) will be efficacious in a 
significant proportion of subjects in this study.
It is not known what impact prior treatment experience will have on the risk of treatment 
failure in this study.
In summary, the risks associated with the individual study drugs to be administered in 
Study M14-567 have been well characterized and appear limited and manageable.  
Subjects will be closely monitored for any potential risks which may occur when the 
DAAs are dosed in combination, including risks of toxicity and of virologic failure.  
Given the potential benefit of achieving cure in a population of HCV-infected subjects 
with limited available treatment options, as well as the manageable risks associated with 
the planned therapy, the risk-benefit comparison is considered favorable.


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4.0
Study Objective
4.1
Primary Objectives
The primary objectives of this study are to assess the safety and efficacy (the percentage 
of subjects achieving a 12-week sustained virologic response ([SVR12] [HCV ribonucleic 
acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following treatment]) of 
co-formulated ombitasvir with ABT-450 and ritonavir (ombitasvir/ABT-450/r) 
co-administered with SOF with or without RBV in treatment-naïve and prior (pegIFN, 
RBV, and/or SOF) treatment-experienced adults with genotype 3 HCV infection without 
cirrhosis.
4.2
Secondary Objectives
The secondary objectives of this study are to assess the percentage of subjects with 
virologic failure during treatment, to assess the percentage of subjects with post-treatment 
relapse, and to characterize the pharmacokinetics of DAAs including ritonavir, sofosbuvir, 
GS-331007 (predominant circulating metabolite of SOF), and RBV (if applicable) in 
adults with genotype 3 HCV infection.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, randomized, open-label, multicenter study evaluating the safety and 
efficacy of co-formulated ombitasvir/ABT-450/r co-administered with SOF with or 
without RBV in treatment-naïve and prior (pegIFN, RBV, and/or SOF) 
treatment-experienced adults with genotype 3 HCV infection without cirrhosis.  
Approximately 20 subjects will be enrolled across approximately 8 sites globally into 
one of two treatment arms (Figure 1).  


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Figure 1.
Study Design
These subjects will be randomized to Arms A and B in a 1:1 ratio (approximately 
10 subjects each).  Randomization to Arms A and B will be stratified by IL28B genotype 
(CC versus non-CC) and prior treatment status (treatment-naïve versus 
treatment-experienced).
●
Arm A:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg and SOF 400 mg QD 
for 12 weeks
●
Arm B:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg and SOF 400 mg QD 
with RBV 1000 – 1200 mg BID for 12 weeks
RBV dosing will be weight-based, either 1000 mg or 1200 mg daily divided BID per local 
label (e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg daily divided 
BID).
The duration of the study will be up to 60 weeks long (not including a screening period of 
up to 35 days) consisting of two periods:  the Treatment Period and the Post-Treatment 
(PT) Period.  All subjects who complete or prematurely discontinue the Treatment Period 
will be followed for 48 weeks to monitor safety, HCV RNA, the persistence of resistant 
viral mutants, and assessment of Patient Reported Outcomes (PROs).


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Subjects will be either HCV treatment-naïve or previously treated with interferon, 
pegIFN, RBV, and/or SOF.  Categorization of prior HCV treatment experience will be 
based on the last prior HCV treatment course.  This prior HCV therapy must have been 
completed no less than 2 months prior to the Screening Visit.  
Subjects whose only prior treatment experience included standard (non-pegylated) 
interferon will not be eligible.  However, subjects with a prior history of non-pegylated 
interferon therapy who were subsequently treated with pegIFN/RBV, pegIFN/RBV plus 
SOF, or SOF plus RBV may be enrolled.
Subjects with previous HCV RNA measurements that provide complete documentation of 
the type of response to prior treatment with pegIFN/RBV without sofosbuvir, 
pegIFN/RBV plus sofosbuvir, or sofosbuvir plus RBV therapy will be categorized as one 
of the following:
●
Prior pegIFN/RBV 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 pegIFN/RBV treatment course;
●
Prior pegIFN/RBV partial responder:  achieved at least a 2 log10 IU/mL 
reduction in HCV RNA by Week 12 during a prior pegIFN/RBV treatment 
course, but failed to achieve HCV RNA undetectable at the end of treatment;
●
Prior SOF breakthrough/non-responder:  HCV RNA quantifiable at the end of 
treatment with SOF plus pegIFN/RBV, or SOF plus RBV;
●
Prior HCV therapy relapser:  achieved HCV RNA unquantifiable (detected or 
undetected) at end of a prior treatment course of pegIFN/RBV, SOF plus 
pegIFN/RBV, or SOF plus RBV, but HCV RNA was quantifiable following 
cessation of therapy.
Subjects treated with pegIFN/RBV without SOF, pegIFN/RBV plus SOF, or SOF plus 
RBV therapy with a less well-characterized treatment experience, including those subjects 
with incomplete HCV RNA and treatment date documentation, will require approval by 


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the AbbVie Study Designated Physician for the determination of study eligibility.  These 
subjects will be categorized as one of the following:
●
Prior HCV therapy relapse/breakthrough:  Achieved at least one documented 
result of HCV RNA unquantifiable (detected or undetected) during a prior 
treatment course of pegIFN/RBV, SOF plus pegIFN/RBV, or SOF plus RBV;
●
Prior HCV therapy non-responder:  No documented result of HCV RNA 
unquantifiable (detected or undetected) during a previous treatment with 
pegIFN/RBV, SOF plus pegIFN/RBV, or SOF plus RBV treatment with 
insufficient data available to distinguish between breakthrough, partial, and 
null responder;
●
pegIFN intolerant (Category does not apply to subjects previously treated with 
SOF plus RBV):  Did not meet any definitions of treatment-failure and 
discontinued pegIFN-containing therapy prior to a full course of treatment due 
to pegIFN intolerability.
●
pegIFN experienced – other (Category does not apply to subjects previously 
treated with SOF plus RBV):  Includes pegIFN/RBV or SOF plus 
pegIFN/RBV experienced subjects who do not have adequate documentation 
of response to be included in any of the above categories.
5.1.1
Screening
At the Screening Visit, subjects who provided written (signed and dated) informed 
consent prior to any study specific procedures, will receive a unique subject number via 
an Interactive Response Technology (IRT) system and will undergo the study procedures 
indicated within the Study Activities table and detailed in Section 5.3.1.1 associated with 
the Screening Visit.  The investigator will evaluate whether the subject meets eligibility 
criteria, as specified in Section 5.2.1 and Section 5.2.2.  The informed consent process and 
all screening procedures performed will be recorded and documented.  Eligible subjects 
have up to 35 days following the Screening Visit to enroll into the study.  Subjects who 
require a liver biopsy to determine eligibility should meet all of the other inclusion and 
none of the exclusion criteria before undergoing a liver biopsy.


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The study was designed to enroll approximately 20 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.
5.1.1.1
Rescreening
Subjects who meet all eligibility criteria with the exception of up to three exclusionary 
laboratory parameters may rescreen once within the 35-day screening period without prior 
AbbVie approval.  However, subjects with any of the following exclusionary values will 
not be allowed to rescreen:  exclusionary HCV genotype, a positive hepatitis B surface 
antigen (HBsAg), positive human immunodeficiency virus (HIV) antibody, or confirmed 
pregnancy.  Subjects with more than three exclusionary laboratory results will require 
approval from the AbbVie Study Designated Physician prior to rescreening.  Subjects 
being rescreened because of exclusionary laboratory parameter(s) must have the related 
panel(s) repeated (e.g., exclusionary hemoglobin requires a repeat hematology panel) 
within the same screening period.
For subjects who do not meet the study eligibility criteria, the site personnel must register 
the subject as a screen failure in both IRT and electronic data capture (EDC) systems.
5.1.2
Treatment Period
Non-cirrhotic subjects with HCV genotype 3 infection who meet the eligibility criteria 
will be randomized via IRT in a 1:1 ratio to either ombitasvir/ABT-450/r co-administered 
with SOF (Arm A) or ombitasvir/ABT-450/r co-administered with SOF and RBV 
(Arm B).  The Treatment Period of the study consists of 12 weeks of open-label treatment.  
All DAAs will be administered once daily (QD) as detailed below.
●
ombitasvir/ABT-450/r 25 mg/150 mg/100 mg QD
●
SOF 400 mg QD


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RBV dosing, if applicable, will be weight based, either 1000 mg or 1200 mg daily divided 
BID per local label (e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg 
daily divided BID).
Subjects will receive instructions regarding study drug administration and dosing and will 
be administered the first doses of study drugs at the site on Study Day 1.  All subjects will 
continue to return to the site on an outpatient basis through the end of their Treatment 
Period for study procedures as identified in Table 4; site personnel should make every 
reasonable effort to ensure visit schedule adherence.  It should be noted and reinforced to 
subjects that SOF is supplied with the exact amount of tablets needed between the study 
drug dispensation visits in Table 4.  Subjects who cannot complete study visits according 
to schedule will need assistance in managing their study drug supply between visits to 
ensure they do not run out of study drugs prior to their next study visit.
Safety and efficacy evaluations will occur through the study.  As this is an open-label 
study, the safety data will be reviewed by AbbVie during the Treatment Period of the 
study.  Virologic failure criteria for subject management, as detailed in Section 5.4.1.1, 
will be evaluated and applied by the investigator.
Plasma samples for pharmacokinetic analysis will be collected as detailed in 
Section 5.3.2.1.
Safety and tolerability of the treatments will be assessed throughout the study.  Laboratory 
testing will include chemistry, hematology, and urinalysis (Table 6).  Ongoing review of 
the data is planned in order to determine if subjects meet the virologic failure criteria 
(Section 5.4.1.1).  Virologic failure criteria will be evaluated and applied by the 
Investigator as detailed in Section 5.4.1.1.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as defined in Table 4
and as described in Section 5.4.1.  Ideally, this should occur on the day of the study drug 
discontinuation, but is recommended to be no later than 2 days after their final dose of 


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study drugs and prior to initiation of any other anti-HCV therapy.  Subjects who complete 
or prematurely discontinue study drug will immediately start the PT Period and be 
monitored for safety, virologic failure, and resistance as detailed in Section 5.4.1.1.
5.1.3
Post-Treatment (PT) Period
All subjects who receive at least one dose of study drugs will be monitored for safety, 
HCV RNA, the emergence and/or persistence of resistance viral variants, and assessment 
of PROs for an additional 48 weeks following the last dose of study drugs.  Subjects will 
return to the study site as outlined in Table 5 for PT procedures.  The PT Period will begin 
the day after the last dose of study drugs.  Subjects who prematurely discontinue the PT 
Period should return to the site for a PT Discontinuation Visit as outlined in Table 5.
5.2
Selection of Study Population
The subject population consists of HCV genotype 3-infected treatment-naïve and prior 
(pegIFN, RBV, and/or SOF) treatment-experienced adult subjects without cirrhosis.  
Subjects who meet all the following inclusion criteria and who do not meet any of the 
following exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
1.
Male or female at least 18 years of age at time of screening.
2.
Female who is:
●
practicing total abstinence from sexual intercourse (minimum 1 complete 
menstrual cycle); or
●
sexually active with female partners only; or
●
not of childbearing potential, as 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


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○
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy 
or hysterectomy) or has a vasectomized partner(s); or
●
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 two effective methods of birth control 
while receiving study drugs (as outlined in the subject information and 
consent form or other subject information documents),
For subjects whose study drug regimen will not include RBV, 
contraceptive practices must start on Study Day 1 and must continue 
for 30 days after stopping study drugs.
For subjects whose study drug regimen will include RBV, the 
contraceptive practices must start on Study Day 1 and must continue 
for 7 months after stopping study drug, or as directed by the local 
ribavirin label.  
(Note:  Estrogen-containing hormonal contraceptives, including oral, 
injectable, implantable, patch and ring varieties, may not be used 
during study drug treatment).
3.
Females must have negative results (unless otherwise noted below) for pregnancy 
tests performed:
●
at Screening by serum specimen within 35 days prior to initial study drug 
administration, and
●
at Baseline (prior to dosing) by urine specimen
Female subjects with a borderline human chorionic gonadotropin (hCG) result at 
Screening and/or Day 1 may enroll into the study if they either:
●
have a documented history of bilateral tubal ligation, hysterectomy, bilateral 
oophorectomy; or
●
are confirmed to be postmenopausal defined as amenorrheic for longer than 
2 years, age appropriate, and confirmed by a FSH level indicating a 
postmenopausal state at Screening.


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4.
Males who are not surgically sterile who are sexually active with female partner(s) 
of childbearing potential, must agree to practice two effective forms of birth control 
(as outlined in the subject information and consent form or other subject 
information documents).
For subjects whose study regimen includes RBV, the contraceptive practices must 
be observed from Study Day 1 and must continue for 7 months after stopping study 
drug, or as directed by the local RBV label.
For subjects whose study regimen does not include RBV, these contraceptive 
practices must start on Study Day 1 and must continue until 30 days after stopping 
study drugs.
5.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements and must voluntarily sign and date an informed 
consent.
6.
Body Mass Index (BMI) is from ≥ 18 to < 38 kg/m2 at the time of screening.  BMI 
is calculated as weight measured in kilograms (kg) divided by the square of height 
measured in meters (m).
7.
Chronic HCV infection prior to study enrollment.  Chronic HCV infection is 
defined as one of the following:
●
Positive for anti-HCV Antibody (Ab) or HCV RNA at least 6 months before 
Screening, and positive for HCV RNA and anti-HCV Ab at the time of 
Screening; or
●
HCV RNA > 10,000 IU/mL at the time of Screening with a liver biopsy 
consistent with chronic HCV infection (or a liver biopsy performed prior to 
enrollment with evidence of chronic hepatitis C disease).
8.
Screening laboratory results from the central laboratory indicating HCV genotype 3 
infection only.
9.
Absence of cirrhosis, as documented by meeting one of the following criteria (per 
local standard practice):


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●
A liver biopsy within 24 months prior to or during screening demonstrating the 
absence of cirrhosis;
●
Only in the absence of a biopsy within the 24 months prior to screening or 
during screening:
○
a Screening FibroTest score of ≤ 0.72 and Aspartate Aminotransferase to 
Platelet Ratio Index (APRI) ≤ 2; or
○
a Screening transient elastography (e.g., FibroScan®) results of < 12.5 kPa.
Subjects with a FibroScan result that is ≥ 12.5 kPa and < 14.6 KPa, or a FibroTest 
result that is ≤ 0.72 and an APRI > 2, or a FibroTest result that is > 0.73 and an 
APRI ≤ 2 must have a liver biopsy performed within 24 months prior to screening 
showing no evidence of cirrhosis, or in the absence of an available biopsy result 
within 24 months prior to screening, may undergo a liver biopsy during screening 
to rule out cirrhosis.  The result of the liver biopsy will be considered the decisive 
result for study eligibility and subjects may be enrolled as non-cirrhotic only if the 
biopsy performed within the previous 24 months or during the Screening period 
shows no evidence of cirrhosis.
Rationale for Inclusion Criteria
1, 7 – 9
To select the appropriate subject population with sufficient disease 
severity for evaluation
6
For the safety of study subjects
2 – 4
RBV has known teratogenic effects
5
In accordance with Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Use of any herbal supplements (including milk thistle) within 2 weeks or 
10 half-lives (if known) of the respective supplement, whichever is longer, prior to 
the first dosing of study drug.


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2.
Females who are pregnant or plan to become pregnant, or breastfeeding, or males 
whose partners are pregnant or planning to become pregnant within 7 months (or 
per local RBV label) after their last dose of study drug.
3.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol.
4.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti HIV Ab 
positive.
5.
HCV genotype performed during screening indicates co infection with any 
genotype other that genotype 3.
6.
Use of known strong inducers of cytochrome P450 3A (CYP3A) or any strong 
inducers of P-glycoprotein (e.g., phenobarbital, rifampin, carbamazepine, St. John's 
Wort) and any medications listed below, as well as those that are contraindicated 
for SOF, ritonavir or RBV, if applicable, within 2 weeks prior or 10 half-lives of 
the medication whichever is longer, to study drug administration including but not 
limited to:


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Table 3.
Medications Contraindicated for Use with the Study Drug Regimen
Alfuzosin
Ergot Derivatives 
Quinidine
Alprazolam
Estazolam
Rifabutin
Amiodarone 
Estrogen-containing medications for 
systemic use 
Rifampin
Ampiroxicam
Flecainide
Rifapentine
Astemizole
Flurazepam
Rivaroxaban
Azelnidipine
Fusidic Acid
Salmeterol
Bepridil
Lovastatin
Sildenafil*
Blonanserin
Midazolam 
Simvastatin
Carbamazepine
Oxcarbazepine
St. John's Wort
Cisapride
Phenobarbital
Tadalafil
Clorazepate
Phenytoin
Terfenadine
Diazepam
Pimozide
Triazolam
Efavirenz
Piroxicam
Vardenafil 
Eletriptan
Propafenone 
Voriconazole
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with SOF, ritonavir and ribavirin are listed above.  Refer to the most 
current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated 
medications.
7.
Clinically significant abnormalities or co-morbidities, other than HCV infection 
that make the subject an unsuitable candidate for this study in the opinion of the 
investigator.
8.
History of uncontrolled seizures, 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.
9.
Any cause of liver disease other than chronic HCV infection, including but not 
limited to the following:
●
Hemochromatosis
●
Alpha-1 antitrypsin deficiency


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●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Drug-related liver disease
10.
Receipt of any investigational product within a time period equal to 10 half-lives of 
the product, if known, or a minimum of 6 weeks prior to study drug administration.
11.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive ombitasvir, ABT-450, ritonavir, SOF, or RBV (if applicable).
12.
Current enrollment in another clinical study, previous enrollment in this study, or 
previous use of any investigational or commercially available anti-HCV therapy 
(other than interferon, pegIFN, RBV, and/or SOF) including previous exposure to 
telaprevir, boceprevir, ABT-450,  or ombitasvir (ABT-267).  Subjects who 
previously participated in trials of investigational anti-HCV agents may be enrolled 
with the approval of the AbbVie Study Designated Physician if they can produce 
documentation that they received only placebo.  Concurrent participation in a 
non-interventional, epidemiologic, or registry trial may be permitted with approval 
by the AbbVie Study Designated Physician.
13.
Uncontrolled clinically significant cardiac, respiratory (except mild asthma), 
hepatic (except HCV-related disease), gastrointestinal, hematologic, or psychiatric 
disease or disorder, or any uncontrolled medical illness, which is unrelated to the 
hepatic disease.
14.
History of solid organ transplant.
15.
Any current or past clinical evidence of cirrhosis such as ascites or esophageal 
varices, or prior biopsy showing cirrhosis, e.g., a Metavir score > 3 or an Ishak 
score > 4.
16.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Calculated creatinine clearance (using Cockcroft-Gault method) < 30 mL/min.


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●
Albumin < Lower limit of normal (LLN).
●
Prothrombin time/International normalized ratio (INR) > 1.5.  Subjects with a 
known inherited blood disorder and INR > 1.5 may be enrolled with 
permission of the AbbVie Study Designated Physician.
●
Hemoglobin < LLN.
●
Platelets < 120,000 cells per mm3.
●
Absolute neutrophil count (ANC) < 1500 cells/μL (< 1200 cells/μL for 
subjects of African descent who are black).
●
Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN.
Rationale for Exclusion Criteria
1, 3, 5, 10, 12
To avoid bias for the evaluation of efficacy and safety by concomitant 
use of other medication
2, 6 – 8, 11, 
13 – 16
To ensure safety of the subjects throughout the study
4, 9
To exclude subjects with liver diseases other than HCV
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.  The Investigator should review all concomitant medications for any 
potential interactions.
During the PT Period, all medications will be recorded until 30 days following the last 
dose of study drugs.  Only medications associated with HCV treatment will be collected 
thereafter.
The AbbVie Study Designated Physician should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).


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5.2.3.1
Prior HCV Therapy
Subjects may have previously received prior interferon, pegIFN, RBV, and/or SOF 
treatment and failed treatment (either on treatment or via relapse post-treatment).  All 
available documentation of prior treatment history, including start and stop dates and 
HCV RNA levels, should be collected in the source to document the type of non-response.
Subjects must have discontinued prior therapy at least 2 months prior to the Screening 
Visit in order to be eligible for the study.
Prior or current use of any other investigational or commercially available anti-HCV 
agents other than interferon, pegIFN, RBV, and/or SOF, excludes a subject from this 
study.  Subjects who previously participated in trials of investigational anti-HCV agents 
may be enrolled if they can provide documentation that they received only placebo.
5.2.3.2
Concomitant Therapy
Subjects must be able to safely discontinue any prohibited medications or herbal 
supplements within 2 weeks or within 10 half-lives of the respective 
medication/supplement (if known), whichever is longer, prior to initial study drug 
administration and through 2 weeks following discontinuation of study drugs.  Subjects 
must be consented prior to discontinuing any prohibited medications or herbal 
supplements for the purpose of meeting study inclusion criteria.
The investigator should confirm that concomitant medication can be safely administered 
with DAAs (including ritonavir) and RBV, if applicable.  Some medications may require 
dose adjustments due to potential for drug-drug interactions.  Subjects should be on a 
stable dose of concomitant medications for at least 2 weeks prior to initiation of study 
drug.  The investigator can also review the label(s) for the concomitant medication(s) for 
additional information.


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During the PT Period, investigators should reassess concomitant medications and subjects 
may resume previously prohibited medications, or revert to pre-study doses, 2 weeks 
following discontinuation of study drugs, if applicable.
Influenza vaccinations and all essential vaccinations in this subject population are allowed 
during Screening through the PT Period.
5.2.3.3
Prohibited Therapy
Subjects must be able to safely discontinue any prohibited medications within 2 weeks or 
within 10 half-lives of the respective medication/supplement (if known), whichever is 
longer, prior to initial study drug administration through 2 weeks following 
discontinuation of study drugs.  Subjects must be consented prior to discontinuing any 
prohibited medications for the purpose of meeting study inclusion criteria.
In addition to the medications listed in Table 3, use of known strong inducers of CYP3A 
or strong inhibitors or inducers of P-glycoprotein is prohibited within 2 weeks of the 
respective medication/supplement prior to the initial dose of study drug through the 
first 2 weeks after the subject has completed study drugs.
Refer to the current local labels for ritonavir, RBV, and SOF for a list of prohibited 
medications.  Anti-HCV medications other than those specified in the protocol will not be 
allowed during the treatment period of the study.
Contraceptives
Prior to enrollment, subjects should agree to practice two effective methods of birth 
control while receiving study drugs starting with Study Day 1 and for 7 months after 
stopping study drug or as directed by the local ribavirin label.  Subjects using systemic 
estrogen-containing contraceptive therapy (including estrogen-containing oral 
contraceptives) have a higher risk for elevated ALT levels.  Subjects using these 
medications must discontinue them at least 2 weeks prior to study drug administration or 
10 half-lives (if known), whichever is longer.  Subjects may replace the systemic 


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estrogen-containing contraceptive with a progestin-only hormonal contraceptive method.  
Estrogen-containing contraceptives may be resumed 2 weeks after the last dose of DAAs.
Use of hematopoietic growth factors is not permitted during this study without the 
approval of the AbbVie Study Designated Physician.  Management of hematologic 
growth factor therapy is the responsibility of the investigator; growth factors will not be 
provided by AbbVie, and AbbVie will not reimburse for the expense of growth factors or 
their use.
Investigators should refer to the package inserts for erythropoiesis stimulating agents for 
additional information regarding their use.
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described in this protocol are summarized in Table 4 and Table 5.


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Table 4.
Study Activities – Treatment Period
Activity
Screeninga
Day 1/
Baselineb
Wk 1
Wk 2
Wk 4
Wk 8
Wk 10
Wk 12 
(EOT)
Premature D/C 
Treatmentc
Informed Consent
X
Provide RBV Medication Guided
X
Medical History
X
Xe
Physical Exam
X
X
X
X
Vital Signs, Weight, Heightf
X
X
X
X
X
X
X
X
X
ECGg
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation 
Panel
X
X
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])h
X (s)
X (u, s)
X (u)
X (u)
X (u)
X (u)
FSH (all females)
X
HBsAg, Anti-HCV Ab, Anti HIV Ab
X
HgbA1c
X
HCV Genotype and Subtype
X
Liver Biopsy or FibroTest or FibroScan®i
X
IL28B Sample
X
Pharmacogenetic Sample (Optional)j
X
Messenger RNA (mRNA) Sample (Optional)
X
X
X
X
Total Insulin
X
X
X


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Table 4.
Study Activities – Treatment Period (Continued)
Activity
Screeninga
Day 1/
Baselineb
Wk 1
Wk 2
Wk 4
Wk 8
Wk 10
Wk 12 
(EOT)
Premature D/C 
Treatmentc
Concomitant Medication Assessment
X
X
X
X
X
X
X
X
X
Adverse Event Assessment
Xk
X
X
X
X
X
X
X
X
Patient Report Outcomes Instruments (PROs)l
X
X
X
X
X
Study Drugs Dispensed
X
X
X
Study Drugs Collected and Compliance 
Reconciled in IRT
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
Archive Serum Sample
X
X
X
X
X
X
X
X
X
Pharmacokinetic Samplesm
X
X
X
X
X
X
X
X
Interferon Gamma-Induced Protein 10 (IP-10) 
Sample 
X
X
X
X
X
EOT = End of treatment; D/C = Discontinuation
a.
A signed study-specific informed consent will be obtained from the subject (with proper source documentation reflecting this process) beforeany study procedures are 
performed at the Screening Visit.
b.
All procedures will be performed prior to first dose.
c.
All subjects should begin PT Period after the subject prematurely discontinues study drugs treatment in this period.
d.
Where applicable/locally available.
e.
The medical history will be updated at the Day 1 Visit.  This updated medical history will serve as the Baseline for clinical assessment.
f.
Height will be measured at the Screening Visit only.


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Table 4. 
Study Activities – Treatment Period (Continued)
g.
Evaluate the Screening ECG prior to dosing to determine eligibility.
h.
Urine pregnancy test is not required after the Day 1 Visit for female subjects with a documented history of bilateral tubal ligation, bilateral oophorectomy or hysterectomy or 
who are confirmed to be post-menopausal.  A positive urine pregnancy test requires a confirmatory serum test.
i.
For subjects who have not had a qualifying liver biopsy within the previous 24 months.
j.
If the optional pharmacogenetic sample is not collected at Study Day 1, it may be collected at any other visit during the study. Verify subject has given consent to 
pharmacogenetic testing.
k.
Protocol-related nonserious adverse events will be collected from the time the subject signed the study-specific informed consent until study drug administration.
l.
EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L) and Fatigue Severity Scale (FSS) should be administered before any study procedures and in the order 
listed.
m.
PK samples will be collected at 2, 4, and 6 hours post-DAA dose at Day 1.  Additional intensive PK samples will be collected at the Week 2 study visit where samples will be 
collected at pre-dose and approximately 2, 4, and 6 hours post-DAA dose.  On the day of intensive blood sampling, subjects will take their morning dose of DAAs and 
ribavirin onsite in the presence of study site personnel and the time of administration will be recorded to the nearest minute.


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Table 5.
Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48 
or PT D/C
Vital Signs and Weight
X
X
X
X
X
X
X
Hematology/Chemistry/Urinalysis/Coagulation 
Panel
X
X
Monthly Pregnancy Test (females)a
X
X
(Weeks 12, 16, 20, 24, 28)
PRO Instrumentsb
X
X
X
X
Concomitant Medication Assessmentc
X
X
X
X
X
X
X
Adverse Event Assessmentd
X
X
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
Archive Serum Sample
X
X
X
X
X
X
X
IP-10 Sample
X
X
mRNA Sample (Optional)
X
X
Wk = Week; PT D/C = Post-Treatment Discontinuation
a.
Urine pregnancy testing is not required after the Day 1 Visit for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or 
who are confirmed post-menopausal.  For subjects on a RBV-inclusive regimen, subjects 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, 20 and 28.  Additional testing may be required per local RBV label.
b.
EuroQol5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L) and Fatigue Severity Scale (FSS) should be administered before any study procedures and in the order 
listed.


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Table 5. 
Study Activities – Post-Treatment (PT) Period (Continued)
c.
Only medications related to the treatment of HCV will be collected after 30 days post-dosing.
d.
Adverse events and serious adverse events will be collected until 30 days post-dosing.
Note:
Day 1 of the PT Period will be defined as the day after the last dose of active study drug treatment.


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5.3.1.1
Study Procedures
The study procedures outline in Table 4 and Table 5 are discussed in detail in this section, 
with the exception of the assessment of concomitant medications (Section 5.2.3.2), the 
monitoring of treatment compliance (Section 5.5.6), the collection of adverse event 
information (Section 6.4), the collection of the IL28B sample (Section 5.3.1.3), the 
collection of blood samples for the optional pharmacogenetic analysis (Section 5.3.1.3), 
and the collection of blood samples for pharmacokinetic analysis (Section 5.3.2).  All 
study data will be recorded in the subject's source documentation and then on the 
appropriate eCRFs, with the exception of central laboratory data which will be provided 
to AbbVie electronically from the individual laboratory(ies).
Informed Consent and RBV Information
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Subjects on a RBV-inclusive regimen will be given the RBV 
Medication Guide (where applicable/locally available).  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 tobacco and alcohol, will be taken from 
each subject during the Screening Visit.  The subject's medical history will be updated at 
the Study Day 1 Visit.  This updated medical history will serve as the baseline for clinical 
assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Table 4 or upon 
subject discontinuation.  A symptom-directed physical examination may be performed at 
any other visit, when necessary.


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The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Vital Signs, Weight, Height
Body temperature (oral or tympanic), blood pressure, pulse, and body weight will be 
measured at the visits indicated in Table 4 and Table 5.  Blood pressure and pulse rate will 
be measured after the subject has been sitting for at least 3 minutes.  The subject should 
wear lightweight clothing and no shoes during weighing.  Height will only be measured at 
Screening; the subject will not wear shoes.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at visits specified in Table 4 (or as clinically 
needed).  The ECG will be obtained prior to the blood collection.
ECGs will be recorded after the subject has been supine for at least 5 minutes.  Subjects 
should be instructed to remain completely stationary during the ECG recording 
(approximately 10 seconds), with no talking, laughing, deep breathing, sleeping, or 
swallowing.
The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will interpret, sign, and date all ECG tracings and 
will provide his/her global interpretation as a written commitment 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 


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and interpretation that are automatically printed on the ECG tracing) will not be collected.  
The QT interval measurement (corrected by Fridericia's formula, QTcF) will be 
documented in the eCRF only if the local reader selects "prolonged QT" on the eCRF.
The original ECG tracing will be retained in the subject's record at the study site.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 6
at the visits specified in Table 4 and Table 5.  Blood samples for serum chemistry tests 
should ideally be collected following a minimum 8-hour fast (with the exception of the 
Screening Visit, which may be done non-fasting).  Subjects whose visits occur prior to the 
morning dose of study drugs should be instructed to fast after midnight.  Subjects whose 
visits occur following the morning dose of study drugs should be instructed to fast after 
breakfast until the study visit occurs.  Blood samples should still be drawn if the subject 
did not fast for at least 8 hours.  Fasting status will be recorded in the source documents 
and on the laboratory requisition.  The baseline laboratory test results for clinical 
assessment for a particular test will be defined as the last measurement prior to the initial 
dose of study drugs.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Sites should refer to the laboratory manual provided by the central laboratory, AbbVie, or 
its designee for instructions regarding the collection, processing, and shipping of all 
laboratory samples.
The certified laboratory chosen for this study is Covance.  Depending on the location of 
the study site, samples will be sent to one of the following addresses:


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For sites in the Canada and USA:
Covance
8211 SciCor Drive
Indianapolis, IN  46214 USA
For sites in the United Kingdom:
Covance
7 rue Marcinhes
1217 Geneva
Meyrin Switzerland
For sites in Australia and New Zealand:
Covance (Asia) Pte Ltd.
1 International Business Park
#01-01 The Synergy
Singapore 609917


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Table 6.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count 
White Blood Cell (WBC) count 
Neutrophils
Bands Lymphocytes Monocytes 
Basophils 
Eosinophils
Platelet count (estimate not 
acceptable) 
ANC
Prothrombin Time/INR
Activated partial thromboplastin 
time (aPTT)
Reticulocyte count
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubina
Direct and indirect bilirubin
Serum glutamic-pyruvic transaminase 
(SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium Potassium Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase (GGT)a
Creatinine clearance 
(Cockcroft-Gault calculation) 
Alpha2-macroglobulina,b
Haptoglobina,b
Apolipoprotein A1a,b
Specific gravity
Ketones 
pH 
Protein 
Blood Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
Albumin
Additional Tests
HBsAg
Anti-HCV Abc
Anti-HIV Abc
FSH (females)c
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG) (females)d
Total insulin
HCV RNA Hemoglobin A1Cc
IP-10
IL28Bc
HCV genotype and subtypec
Pharmacogenetic sample (optional)
mRNA sample (optional)
a.
Component of FibroTest.
b.
Performed only during Screening Period for FibroTest, if needed.
c.
Performed only at Screening.
d.
Urine pregnancy testing is not required after Day 1 for female subjects who are confirmed to be post-menopausal 
or who have a documented history of prior bilateral tubal ligation, bilateral oophorectomy or hysterectomy. 
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.


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●
A laboratory test value that requires a subject to be discontinued from the 
study or study drugs or requires a subject to receive treatment that will be 
recorded as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.7.
Pregnancy Test
A urine pregnancy test will be performed for all female subjects at all visits specified in 
Table 4 and Table 5.  In addition, a serum pregnancy test will be performed at Screening 
and Study Day 1 Visits and analyzed by the central laboratory.  All urine pregnancy tests 
will be performed on-site during the study visit if there is a scheduled visit, as specified in 
Table 4 and Table 5.  A positive urine pregnancy test requires a confirmatory serum test.  
Urine pregnancy tests are not required after Day 1 for female subjects with a documented 
history of bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or for subjects 
who are confirmed to be postmenopausal.  Confirmation of postmenopausal status will be 
determined during the Screening period, based on the subject's history, and measured by 
FSH.
For subjects on a RBV-inclusive regimen where there is not a scheduled study visit, 
female subjects of childbearing potential may either have PT Period pregnancy testing 
performed at the site as an unscheduled visit using an unscheduled visit test kit or a urine 
pregnancy test may be conducted by the subject at home with a pregnancy test kit 
provided by the site; site personnel should contact these female subjects to capture the 
results of any study-related pregnancy tests performed at home.  The pregnancy test 
results will only be recorded in the subject's source records.
If the subject elects to return to the study site for an unscheduled visit for pregnancy 
testing, the results of the urine pregnancy test will be recorded on the eCRF, unless serum 
pregnancy test is elected.  Serum pregnancy testing will be completed by the central 
laboratory and loaded into the clinical database.


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Hepatitis and HIV Screen
HBsAg, anti-HCV Ab, and anti-HIV Ab will be performed at Screening.  The investigator 
must discuss any local reporting requirements to local health agencies with the subject.  
The site will report these results per local regulations, if necessary.  The HBV HBsAg 
results will be reported by the central laboratory to the clinical database.
HCV Genotype and Subtype 
Plasma samples for HCV genotype and subtype will be collected at Screening.  Genotype 
will be assessed using the Versant® HCV Genotype Inno-LiPA Assay, version 2.0 or 
higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY).
Liver Diagnostic Testing
FibroTest/APRI and FibroScan are non-invasive measurements of liver fibrosis that have 
shown good correlation with liver biopsy on predicting the presence of significant fibrosis 
or cirrhosis.
The identification of cirrhosis on an appropriately performed and reported liver biopsy at 
any prior time point is considered sufficient and definitive evidence to establish the 
presence of cirrhosis.
Subjects who have not had a liver biopsy within previous 24 months and who have not a 
biopsy establishing cirrhosis at any time prior to 24 months but who otherwise meet all of 
the inclusion criteria and none of exclusion criteria will undergo liver biopsy or 
one non-invasive test (FibroTest/APRI or FibroScan) prior to enrollment.  Selection of 
whether liver biopsy or one of the non-invasive tests should be performed will be based 
on local standard practice.
For subjects with a FibroScan result that is ≥ 12.5 kPa and < 14.6 kPa; or a FibroTest 
result that is ≤ 0.72 and an APRI > 2; or a FibroTest result that is ≥ 0.73 and an APRI ≤ 2, 
the subject must have a liver biopsy performed within 24 months prior to screening, or in 


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the absence of an available biopsy result within 24 months of Screening, may undergo a 
liver biopsy during Screening to rule out cirrhosis.
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 will 
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 will encourage completion of each instrument at 
all visits and will ensure that a response is entered for all items.
In this study, PRO instruments should be consistently presented so that subjects complete 
the EQ-5D-5L first and then the FSS.  PRO instruments should be completed prior to drug 
administration on Day 1 and prior to any discussion of adverse events or any review of 
laboratory findings, including HCV RNA levels.
EuroQol-5Dimensions-5 Level (EQ-5D-5L)
The EQ-5D-5L is a health state utility instrument that evaluates preference for health 
status (utility).  The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 
5 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-5L should require approximately 5 minutes to complete.
Fatigue Severity Scale (FSS) Instrument
The FSS measures the impact of fatigue over the past week on specific types of 
functioning (e.g., motivation, exercise, physical functioning, carrying out duties, 
interfering with work, family, or social life).  The survey consists of 9 questions using a 


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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.  Subjects also rate their perception of their fatigue on a 
separate visual analogue fatigue scale (VAFS).  The FSS should require approximately 
5 minutes to complete.
Randomization and Assignment of Subject Numbers
All screening activities must be completed and reviewed prior to subject randomization.  
Screening numbers will be unique 4-digit numbers and will begin with 1001, with the 
first two digits representing the investigative site and the last two digits representing the 
subjects at the site.  Enrolled subjects will keep their screening number as their subject 
number.  Subjects who meet the eligibility criteria may proceed to randomization via the 
IRT system at the Study Day 1 Visit.
Randomized subjects will keep their screening number as their subject number.  Subjects 
will be randomized on Day 1 as described in Section 5.5.3 and will receive a separate 
unique randomization number that will be recorded automatically in the eCRF through the 
IRT system.  The randomization number will be used only by the Sponsor for loading the 
treatment schedule into the database.
HCV RNA Samples
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 TaqMan® real-time reverse transcriptase-PCR 
(RT-PCR) assay v. 2.0.  The lower limit of detection (LLOD) is 20 IU/mL and results 
below LLOD are reported as "HCV RNA not detected;" the LLOQ for this assay is 
25 IU/mL and results below LLOQ, but detectable are reported as "< 25 IU/mL HCV 
RNA detected."


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HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected at the study visits indicated 
in Table 4 and Table 5.
Specific instructions for preparation and storage of these samples will be provided by the 
central laboratory, AbbVie, or its designee.
Archive Plasma and Serum Sample
Archive plasma and serum samples will be collected at the study visits indicated in 
Table 4 and Table 5.  Archive plasma and serum samples are being collected for possible 
additional analyses, including but not limited to, study drug or metabolite measurements, 
viral load, safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, 
and other possible predictors of response, as determined by AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.
Interferon Gamma-Induced Protein 10 (IP-10) Levels
A plasma sample for IP-10 testing will be collected at the study visits indicated in Table 4
and Table 5.  The IP-10 testing is exploratory and may not be provided to the investigator.
5.3.1.2
Meal and Dietary Requirements
All study drugs should be dosed together and administered with food, i.e., the AM dose of 
ombitasvir/ABT-450/r and SOF and, if applicable, RBV should be taken together with 
food and, if applicable, the PM dose of RBV should be taken together with food.
It is recommended that subjects avoid consumption of alcohol within the 72-hour period 
prior to any study drug administration and throughout the duration of the study.


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5.3.1.3
Blood Samples for Pharmacogenetic Analysis
IL28B Samples
One (required) 2 mL whole blood sample for Deoxyribonucleic acid (DNA) isolation will 
be collected from each subject at Screening for Interleukin 28B (IL28B) pharmacogenetic 
analysis.  The sample will not be used for any testing other than IL28B genotypes.  IL28B 
genotyping will be performed by the central laboratory.
Blood Samples for Pharmacogenetic Analysis (Optional)
One 4 mL whole blood sample for DNA isolation will be collected on Day 1 from each 
subject who consents to provide a sample for pharmacogenetic analysis.  The procedure 
for obtaining and documenting informed consent is discussed in Section 9.3.  If the 
sample is not collected on Day 1, it may be collected at any time throughout the study.
The sample collection tubes will minimally be labeled with "PG-DNA," protocol number, 
and subject number.  Samples will be shipped frozen to AbbVie or a designated laboratory 
for DNA extraction and long-term storage.  Instructions for the preparation and shipment 
of pharmacogenetic samples will be provided in the lab manual.
AbbVie will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on 
ABT-450/ombitasvir (or drugs of this class) continues but no longer than 20 years.
Blood Samples for Messenger RNA (mRNA) Analysis (Optional)
Separate optional whole blood samples will be collected from those subjects who choose 
to participate and consent to additional mRNA analysis.  The procedure for obtaining and 
documenting informed consent for this optional sample is discussed in Section 9.3.
Subjects who consent to participate in the mRNA substudy will have blood samples taken 
as indicated in Table 4 and Table 5.


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Messenger RNA levels related to HCV disease or response to drug therapy will be 
measured in peripheral whole blood.  For biomarker analysis, mRNA expression may be 
analyzed using microarray and polymerase chain reaction (PCR) technique in peripheral 
blood samples.  This analysis will measure the levels of essentially all mRNAs present in 
the collected peripheral blood samples.
Results of mRNA testing are considered exploratory and may not be included in the 
Clinical Study Report.
The optional blood samples for mRNA must be collected at visits specified in Table 4 and 
Table 5.  Samples will be shipped frozen to AbbVie or a designated laboratory for RNA 
extraction and long-term storage.
Samples will be stored in a secure storage space with adequate measures to protect 
confidentiality.  These samples will be retained while research on ombitasvir and 
ABT-450 or drugs of these classes 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 assay of ombitasvir, possible ombitasvir metabolites, ABT-450, 
possible ABT-450 metabolites, ritonavir, SOF, GS-331007 (predominant circulating 
metabolite of SOF), and RBV (if applicable) will be collected by venipuncture at each 
study visit specified in Table 4 (irrespective of study drug dosing time).  Actual times of 
dosing for the last dose and second to the last dose will be recorded on the applicable 
requisition forms and in the eCFR, and accordingly, time after dose for pharmacokinetic 
sample collection will be determined.
Intensive pharmacokinetic samples will be collected on Day 1 at 2, 4, and 6 hours 
post-DAA dose and at the 2-week visit at predose and approximately 2, 4, and 6 hours 
post-DAA dose.  The time that each blood sample is collected will be recorded to the 
nearest minute on the subject dosing card and in the eCRF.


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At each planned collection time, two blood samples will be collected (one 4 mL sample 
intended for DAA/RBV analysis and one 4 mL sample intended for SOF/GS-331007 
analysis).
Approximately 12 DAA/RBV and 12 SOF/GS-331007 blood samples are planned to be 
collected per subject during 12 weeks of treatment for pharmacokinetic analysis.  At 
minimum, the total number of samples planned for pharmacokinetic analysis is 480 for 
the entire study.
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 pharmacokinetic assays of ombitasvir, possible 
ombitasvir metabolites, ABT-450, possible ABT-450 metabolites, SOF, GS-331007, 
ritonavir, and RBV (if applicable) 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 ombitasvir, possible 
ombitasvir metabolites, ABT-450, possible ABT-450 metabolites, ritonavir, SOF, 
GS-331007, RBV (if applicable), 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 samples for the pharmacokinetic assays of 
ombitasvir, possible ombitasvir metabolites, ABT-450, possible ABT 450 metabolites, 
and RBV to:


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Sample Receiving
c/o:  Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
An inventory of the samples included will accompany the package and an electronic copy 
of the Manifests (including subject number, study day, the time of sample collection, and 
barcode) will be sent to the contact person at sample.receiving@abbvie.com.
The central laboratory will then ship samples for the pharmacokinetic assays of SOF, 
GS-331007, and other possible metabolites of SOF to reference laboratories following 
separately provided instructions.
An inventory of the SOF samples included will accompany the package and an electronic 
copy of the Manifests (including subject number, study day, and the time of sample 
collection) will be sent to 
.
5.3.2.4
Measurement Methods
The plasma concentration of ombitasvir, ABT-450, ritonavir, SOF, GS-331007 
(predominant circulating metabolite of SOF), and RBV (if applicable), will be analyzed 
using validated assay methods under the supervision of the Drug Analysis Department at 
AbbVie.  Plasma concentrations of possible metabolites of ombitasvir, ABT-450, and 
SOF (other than GS-331007) may also be determined using either validated or 
non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by HCV RNA in IU/mL at various time points from 
Day 1 through 48 weeks after completion of treatment.


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5.3.3.1
Primary Variable
The primary endpoint is the percentage of subjects with SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug).
5.3.3.2
Secondary Variable
The secondary endpoints are:
●
The percentage of subjects with virologic failure during treatment;
●
The percentage of subjects with post-treatment relapse.
5.3.4
HCV Resistance Variables
The following resistance information will be provided for all subjects:  the amino acid 
variants at baseline at signature resistance-associated positions identified by population 
nucleotide sequencing and comparison to the appropriate prototypic reference sequence.
The following resistance information will be analyzed for subjects 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 and/or 
clonal nucleotide sequencing and comparison to the baseline sequence, 2) the amino acid 
variants in available post-baseline samples at signature resistance-associated positions 
identified by population nucleotide sequencing and comparison to the appropriate 
prototypic reference sequence, and 3) the persistence of resistance-associated amino acid 
variants by population and/or clonal nucleotide sequencing during the post-treatment 
period.
5.3.5
Safety Variables
The following safety evaluations will be analyzed during the study:  adverse event 
monitoring and vital signs, physical examination, and laboratory test assessments.


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5.3.6
Pharmacokinetic Variables
Plasma samples for ombitasvir, ABT-450, ritonavir, SOF, GS-331007 (predominant 
circulating metabolite of SOF), and RBV (if applicable) will be collected at each study 
visit up to 12 weeks.  Individual plasma concentrations of possible metabolites of 
ombitasvir and ABT-450 may be measured and summarized if they are needed for 
additional safety or efficacy evaluation.
Values for the pharmacokinetic parameters of ombitasvir, ABT-450, ritonavir, SOF, 
GS-331007 (predominant circulating metabolite of SOF), and RBV (if applicable) 
including the Cmax, Tmax, Ctrough, and AUC will be determined by noncompartmental 
methods using intensive pharmacokinetic blood sampling data in the study.  Additional 
parameters or summaries may be determined if useful in the interpretation of the data.
5.3.7
Pharmacogenetic Variables
IL28B genotypes are associated with response to pegIFN and RBV and to some 
pegIFN-free regimens.  IL28B status will be determined for each subject and analyzed as 
a factor contributing to the subject's response to study treatment.  These IL28B genotype 
results may be analyzed as part of a multi-study assessment of IL28B and response to 
ombitasvir, ABT-450, and SOF.
DNA samples from subjects who separately consent for additional pharmacogenetic 
analysis may be sequenced and data analyzed for genetic factors contributing to the 
disease or subject's response to ombitasvir/ABT-450, or other 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, other genes believed to be related to the disease or to drug response (including 
IL28B).  Some genes currently insufficiently characterized or unknown may be 
understood to be important at the time of analysis.  The samples may be analyzed as part 
of a multi-study assessment of genetic factors involved in the response to 
ombitasvir/ABT-450, drugs of this class, or the disease state.  The samples may also be 
used for the development of diagnostic tests related to ombitasvir/ABT-450 and SOF, 


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drugs of these classes, or the disease state.  The results of pharmacogenetic analyses may 
not be reported with the study summary.
Messenger RNA samples from subjects who separately consent for the mRNA substudy 
may be analyzed for RNA expression levels contributing to the subject's response to study 
treatment in terms of pharmacokinetics, pharmacodynamics, efficacy, tolerability and 
safety.  Analysis may include quantifying RNA levels from interferon-stimulated 
pathways or other families believed to be related to drug response.  Messenger RNA 
analysis will be limited to studying response to 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 treatment or the study at any time.  In 
addition, the investigator may discontinue a subject from treatment or 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 
treatment, the procedures outlined for the applicable Premature D/C Visit should be 
completed as defined in Table 4.  It is recommended that this visit occur on the day of 
study drug discontinuation; however, this visit should occur within 2 days following their 
final dose of study drugs 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 
conditions.  Following discontinuation of study drugs, the subject will be treated in 
accordance with the investigator's best clinical judgment.  The date of the last dose of 
study drug and reason for discontinuation will be recorded in the eCRF.  The subject 
should then begin the PT Period where the subject will be monitored for 48 weeks for 
safety, HCV RNA, the emergence and persistence of resistant viral variants, and 
assessments of PROs.


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If a subject discontinues from the PT Period, the subject should return for post-treatment 
discontinuation procedures defined in Table 5.  The reason for discontinuation will also be 
recorded in the eCRF.
If a subject is discontinued from study drug (Treatment Period) or the PT Period with an 
ongoing adverse event or an unresolved laboratory result that is significantly outside 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 (Section 6.7).  
Subjects receiving a RBV-inclusive regimen who report a positive result is obtained on a 
pregnancy test during the Treatment Period must be notified to stop RBV immediately.  
Administration of DAAs may be continued at the investigator's discretion, if the benefit of 
continuing therapy is felt to outweigh the risk.  Specific instructions regarding subject 
pregnancy can be found in Section 6.6.  Subjects will continue to be monitored for SVR in 
the PT Period as described in Section 5.1.3.  If the subject is receiving a RBV-containing 
regimen, the investigator is also encouraged to report the pregnancy information to the 
voluntary RBV Pregnancy Registry.
5.4.1.1
Virologic Failure Criteria for Subject Management
The following criteria will be considered evidence of virologic failure leading to 
discontinuation of study drug while receiving study drug and will be discontinued from 
study drug:
●
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
●
Failure to achieve HCV RNA < LLOQ by Week 8; or
●
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA 
measurements ≥ LLOQ) at any point during treatment after HCV RNA 
≤LLOQ.


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Confirmatory testing should be completed as soon as possible.  Subjects should remain on 
study drug treatment until the virologic failure has been confirmed.  If any of the above 
criteria are met, the subject will discontinue study drug treatment (Section 5.4.1).
Subjects with HCV RNA < LLOQ at the end of treatment and who have a confirmed 
HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements ≥ LLOQ) at any 
point in the PT Period will be considered to have relapsed.  Confirmation of an HCV 
RNA ≥ LLOQ in the PT Period should be completed as soon as possible per Section 5.1.3.
5.4.1.2
Safety Stopping Criteria 
Enrollment in any treatment arm may be discontinued at any time by the AbbVie Study 
Designated Physician if ongoing data review reveals a potential risk to subject safety.  
Treatment arms may also be dropped prior to initiation of the study based on available 
safety data from ongoing studies.
Depending on the nature and severity of the triggering safety event(s), subjects already 
enrolled in the affected arm(s) might continue to receive study treatment, or subjects 
might discontinue all study drug dosing.  In the latter case, subjects may be offered 
another off-study (non-AbbVie) treatment regimen, as determined appropriate by the 
investigator.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.


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5.5
Treatments
5.5.1
Treatments Administered
Each dose of DAA study drugs (ombitasvir/ABT-450/r and SOF) and RBV (if applicable) 
will be dispensed in the form of tablets.  Study drugs will be dispensed at the visits listed 
in Table 4.
Ombitasvir/ABT-450/r will be provided by AbbVie as 12.5 mg/75 mg/50 mg tablets.  
Ombitasvir/ABT-450/r will be taken orally as 2 tablets every morning which corresponds 
to a 25 mg ombitasvir/150 mg ABT-450/100 mg ritonavir dose QD.
SOF will be provided by AbbVie as 400 mg tablets.  SOF will be taken orally as 1 tablet 
every morning, which corresponds to a 400 mg dose QD.
For subjects randomized to a RBV-inclusive regimen, RBV will be provided as 200 mg 
tablets during the Treatment Period.  RBV should be dosed based on consideration of the 
subject's weight from Study Day 1, either 1000 mg or 1200 mg daily divided BID per 
local label (e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg daily 
divided BID) and his/her hemoglobin test results from the Screening Visit, according to 
the current approved local RBV label.
For subjects with calculated creatinine clearance ≥ 30 to < 50 mL/min, RBV should be 
given as alternating daily doses of 200 mg and 400 mg as described in Section 6.7.6; 
Table 9.  Subjects will be instructed to take study medication at the same time(s) every 
day.  All study drugs should be administered with food.  Subjects will be instructed to 
bring in all bottles at each visit.
Following enrollment, the site will use the IRT system to obtain the study drug container 
numbers to dispense at the study visits specified in Table 4.  Study drugs must not be 
dispensed without contacting the IRT system, and only for subjects enrolled in the study 
through the IRT system.  The site will also contact the IRT system to provide study drug 
return information for each container at the visits specified in Table 4 (Section 5.5.7).


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At Study Day 1, subjects will be administered study drugs by the study site personnel and 
receive instructions for self-administration of all study drugs from Study Day 2 through 
the end of the Treatment Period.
All subjects who receive at least one dose of DAA who meet virologic failure criteria 
during treatment (Section 5.4.1.1) will be discontinued from treatment.  Resistance 
monitoring will continue in the PT Period regardless of whether subjects opt for 
alternative post-study treatment.
5.5.2
Identity of Investigational Product
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
ombitasvir/ABT-450/ 
ritonavir
AbbVie
Oral
Tablet
12.5 mg/75 mg/ 
50 mg
sofosbuvir
Gilead Sciences Inc.
Oral
Tablet
400 mg
ribavirin
Roche or generic 
manufacturer
Oral
Tablet
200 mg
5.5.2.1
Packaging and Labeling
Ombitasvir/ABT-450/ritonavir will be supplied in bottles containing 64 tablets.  
Sofosbuvir will be supplied in bottles containing 28 tablets.  Ribavirin, if applicable, will 
be supplied in bottles containing 168 tablets each.
Each bottle will be labeled as required per country requirements.
The labels must remain affixed to the bottles.  All blank spaces should be completed by 
site staff prior to dispensing to subject.


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5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions
ombitasvir/ABT-450/ritonavir bottles
15° to 25°C (59° to 77°F)
Australia and New Zealand:  Store below 25°C
ribavirin bottles
15° to 25°C (59° to 77°F)
Australia and New Zealand:  Store below 25°C
sofosbuvir bottles
15° to 25°C (59° to 77°F) and protect from moisture
Australia and New Zealand:  Store below 25°C and protect 
from moisture
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.  Upon receipt of study drugs, the 
site will acknowledge receipt within the IRT system.
5.5.3
Method of Assigning Subjects to Treatment Arms
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  For enrollment of eligible subjects into the study, the site will 
utilize the IRT system in order to receive unique study drug container numbers and a 
randomization number.  The randomization number will be used only by the Sponsor for 
loading the treatment assignments into the database.  The study drug container numbers 
and randomization numbers will be assigned according to schedules computer-generated 
before the start of the study by the AbbVie Statistics Department.  Upon receipt of study 
drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided for each site.


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5.5.4
Selection and Timing of Dose for Each Subject
Study drug dosing will be initiated at the Study Day 1 Visit.  Ombitasvir/ABT-450/r and 
SOF will be dosed QD.  Thus with normal dosing, 2 ombitasvir/ABT-450/r tablets and 
1 SOF tablet should be taken in the morning.
RBV (if applicable) should be dosed BID, e.g., 2 or 3 tablets taken in the morning, and 
3 RBV tablets should be taken in the evening.  Subjects with renal impairment should 
receive a reduced dose of RBV, as described below (Table 8).
Table 8.
Recommended Ribavirin Dosing in Chronically HCV-Infected 
Patients with Chronic Kidney Disease
Renal Impairment and Creatinine 
Clearance, mL/min
Renal Severity
RBV Dose (mg/day)
Normal (> 80 mL/min)
None
1000/1200
CKD Stage 3 (30 – 50 mL/min)
Moderate
200 alternating with 400
CKD Stage 4 (< 30 mL/min)
Severe
200
Note:
Brennan et al.25
All study drugs should be dosed together and administered with food.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.  All study drugs will be dispensed to study subjects by study-site personnel 
under the direction of the investigator.
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 


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potential development of resistance.  Subjects will be administered study drugs at the site 
at the Day 1 Visit.  The start and stop dates of all study drugs will be recorded in the 
source documents and eCRFs.
Subjects will be instructed to bring all study drug containers of ombitasvir/ABT-450/r and 
SOF and, when relevant, RBV (full, partial or empty) to the study site at each visit 
indicated in Table 4.  Study site personnel will inspect the contents of the containers and 
record the exact number of remaining tablets of ombitasvir/ABT-450/r and SOF and, 
when relevant, tablets of RBV.  Reconciliation in IRT should occur only when the 
container is returned to the site at the reconciliation visits indicated in Table 4.  If poor 
adherence is noted, the subject should be counseled and this should be documented in the 
subject's source.
At the Day 1 visit, the date and time of the first dose of all drugs (i.e., first dose of first 
drug) will be recorded in the source documents and the eCRF.  The date of last dose of all 
study drugs (i.e., last dose of last drug) will be recorded in the source documents and the 
appropriate eCRF.  Subjects will be given dosing cards to record the last 2 doses of all 
study drugs prior to each study visit during the treatment period.
Study drugs should not be interrupted for toxicity management or any other reason for 
more than 7 days consecutively.  If study drugs need to be interrupted for more than 
7 days consecutively, the AbbVie Study Designated Physician should be contacted and 
consideration should be given to discontinue the subject.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drugs will be kept by the investigator 
and will include shipping invoices and date dispensed for each subject.  An overall 
accountability of the study drugs will be performed and verified by the AbbVie monitor 


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throughout the Treatment Period.  Final accountability will be performed 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 container, 
the IRT system must be contacted and informed of the misplaced or damaged study drug.  
If the containers are damaged, the subject will be requested to return the remaining study 
drugs to the site.  Replacement study drugs may only be dispensed to the subject by 
contacting the IRT system.  Study drug replacement and an explanation of the reason for 
the misplaced or damaged study drug container will be documented within the IRT 
system.  Study drug start/end dates will be documented in the subject's source documents 
and recorded on the appropriate eCRF.  The status of each container, 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 periodically throughout 
the study.
Upon completion of or discontinuation from the Treatment Period, all original containers 
(containing unused study drugs) will be destroyed on site where possible or returned to 
AbbVie (or designee).  All empty bottles should be destroyed on site.  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 container will be noted in the IRT 
system.  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 Arms
This study is an open-label pilot study designed to evaluate the safety, tolerability, 
pharmacokinetics, and antiviral activity of ombitasvir/ABT-450/r dosed in combination 
with SOF with or without RBV.  The study will also provide information on the role of 
RBV with this regimen, the pharmacokinetics of ombitasvir/ABT-450/r and SOF with or 
without RBV in HCV-infected subject, the proportion of subjects achieving SVR12, and 
the development and persistence of viral resistance with this treatment regimen.


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High SVR rates have been reported in subjects with HCV genotype 3 infection treated 
with the combination of SOF and daclatasvir, another NS5A inhibitor, for 24 weeks.23  
Due to the presence of a third active agent, ABT-450, the treatment regimen in the current 
study is expected to have greater activity than that seen with SOF and daclatasvir; thus a 
greater treatment response is anticipated.  The treatment duration for this study was 
selected based upon viral load modeling and simulations.  Data for ABT-450/r + 
ombitasvir ± RBV in HCV genotype 3-infected subjects enrolled into Study 
 
were modeled, as well as data for 
.  
Since 
 in vitro potency is similar between genotypes 1 and 3, genotype 1 parameters 
were used to simulate the response in subjects infected with HCV genotype 3 infection.  
SVR for the combination of ABT-450/r + ombitasvir + SOF ± RBV was simulated using 
model parameters from the
 analyses.  Based upon these 
simulations, > 
% of subjects receiving 2DAA + SOF ± RBV for 12 weeks are predicted 
to achieve SVR12 while treatment durations less than 12 weeks are predicted to result in a 
greater number of relapses.  Hence, 12 weeks of dosing is planned.
The total daily dose of ombitasvir/ABT-450/r administered in this study has been 
administered to over 2000 HCV genotype 1-infected subjects, most often in combination 
with the non-nucleoside NS5B inhibitor dasabuvir for up to 24 weeks, and has been 
shown to be safe and well tolerated.  Doses of both ABT-450/r and ombitasvir used in this 
study have both shown significant antiviral activity against genotype 1 HCV, and similar 
doses have shown activity against genotype 3 HCV (Study M12-998).  Preliminary 
findings when ombitasvir/ABT-450/r and SOF were co-administered to healthy 
volunteers (Study M14-527) suggest that the combination is well tolerated, and based on 
the known metabolic and excretion pathways of the individual agents, no significant 
drug-drug interaction is anticipated; therefore, no dose adjustment for either component is 
expected to achieve exposures predicted to have optimal antiviral activity when compared 
to the individual compounds dosed singly.  Ombitasvir/ABT-450/r and SOF dosing will 
not begin in this study until preliminary pharmacokinetic results from Study M14-527 are 
available to confirm absence of clinically meaningful drug-drug interactions.


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The primary endpoint of this study is to assess the rate of SVR12.  The SVR rate for 
genotype 3-infected subjects treated with pegIFN and RBV and with SOF and RBV have 
been described previously;13,22 hence, no control group is needed for this open-label 
exploratory study.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.  Clonal sequencing and 
population sequencing methods are experimental.  EQ-5D-5L and FSS PRO instruments 
are standards in the literature and thoroughly validated.
5.6.3
Suitability of Subject Population
The selection of subjects infected with HCV genotype 3 virus will allow for the 
assessment of safety, pharmacokinetics, and antiviral activity of ombitasvir/ABT-450/r 
and SOF, and if applicable RBV, dosed in combination.  Patients chronically (rather than 
acutely) infected with HCV comprise the target population for DAA-based regimens.  
This study will enroll subjects who are naïve to treatment and subjects who have 
previously been treated with pegIFN, RBV, and/or SOF, to assess the impact of prior 
treatment failure.  Previous SOF exposure is not expected to impact the response to SOF 
in this trial, since SOF exposure does not select persistent resistant variants.
5.6.4
Selection of Doses in the Study
Doses of the DAAs (ombitasvir/ABT-450/r and SOF) to be used in this study have been 
studied in Phase 3 trials in HCV-infected subjects without cirrhosis and those with 
compensated cirrhosis.  Doses of ABT-450/r and ombitasvir comparable to and higher 
than the doses to be administered in this study have been studied in single- and 
multiple-dose healthy volunteer studies and administered to HCV-infected subjects 
without cirrhosis as monotherapy or in combination with pegIFN/RBV and found to be 
generally safe and well tolerated.  The components of this study regimen and the doses 
used in this study were administered to more than 2,700 subjects as part of a 3-DAA 


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treatment regimen.  SOF is currently marketed in the US and EU at a dose of 400 mg once 
daily.
ABT-450/r
The 25/150/100 mg doses of the co-formulated ombitasvir/ABT-450/r tablets will be used 
in this study.  In Study
, ABT-450 200 mg and ritonavir 100 mg dosed with 
ombitasvir 25 mg and weight-based RBV achieved an SVR rate of 
% in HCV 
genotype  infected subjects.  However, different formulations of ABT-450 
 
 ritonavir (soft gelatin capsule) and ombitasvir 
 
 were used in that study.  The ombitasvir/ABT-450/r co-formulated tablet dosed at 
25/150/100 mg has lower ABT-450 exposures 
 compared to the 
ABT-450 200 mg 
 tablet used in Study 
.  
Since ABT-450 has a 
 exposure-response relationship, the 
% decrease in 
exposure is not expected to impact response.  
Based on the 
 response rate seen in genotype -infected subjects in Study 
 
 
higher ABT-450 doses could result in better efficacy.  However, because of the 
 
 relationship seen with ABT-450,
 than those 
achieved in Phase 3 clinical trials for genotype  infection would be required, and the 
doses necessary to achieve 
 would increase the risk of ALT 
elevations.  Furthermore, when combined with SOF and ombitasvir, 2 agents that are 
highly active against genotype 3, the 150 mg dose is expected to provide maximal SVR 
rates.  
The maximum dose of ombitasvir/ABT-450/ritonavir 12.5 mg/75 mg/50 mg tablets will 
not exceed 25 mg/150 mg/100 mg per day for 12 weeks.


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Ombitasvir
Based on 
 in vitro potencies between HCV genotype 
 and HCV genotype , 
the same ombitasvir doses were chosen for HCV genotype 3-infected subjects.  In vitro 
activity of ABT-450 against HCV genotype 
 is comparable to that against HCV 
genotype 
 using subgenomic replicon cell line.
Ombitasvir exposures from the ombitasvir/ABT-450/r co-formulated tablet are 
comparable to those from the ombitasvir HME tablet used in Study M12-998.  Therefore, 
the ombitasvir/ABT-450/r co-formulated tablet at the 25/150/100 mg dose is the 
recommended formulation and dose to be administered with weight-based ribavirin for 
HCV genotype 3-infected subjects.
The maximum dose of ombitasvir/ABT-450/ritonavir 12.5 mg/75 mg/50 mg tablets will 
not exceed 25 mg/150 mg/100 mg per day for 12 weeks.
Sofosbuvir
Sofosbuvir is an HCV nucleotide analog NS5B polymerase inhibitor with in vitro activity 
against genotype 3a,19 which is approved for use at a dose of 400 mg per day.  At this 
dose, sofosbuvir has been variously studied in genotype 3-infected subjects in 
combination with RBV, pegIFN, RBV, and the NS5A inhibitor daclatasvir.  This dose has 
been shown to demonstrate significant antiviral activity with minimal treatment limiting 
toxicities and a safety profile that is similar to that of the AbbVie DAA regimen.  
Therefore this dose will be used in this study.
The maximum total daily dose of SOF 400 mg tablets administered in this study will not 
exceed 400 mg per day for 12 weeks.
RBV
In subjects selected to receive RBV-inclusive treatment regimens, the daily dose of RBV 
in this study is 1000 mg or 1200 mg daily divided BID per local label 
(e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg daily divided BID).  


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This dose is approved for treatment of adult patients with chronic HCV infection in 
combination with pegIFN.  The same dose is selected for this study because its safety 
profile has been well characterized when administered with pegIFN, including incidence 
of hemolytic anemia, and there are well-defined dose reduction criteria in the event of 
RBV-induced anemia as noted in Section 6.7.4.  In addition, this dose was studied in the 
absence of pegIFN in Studies M12-267, M12-746, M12-998, M11-652, M11-646, 
M13-098, M13-389, M13-961, M14-002, M13-099, and M14-004 and was found to be 
generally safe and well tolerated, and resulted in high SVR rates in genotype 1 infection.
The maximum RBV dose administered in this study will not exceed 1200 mg, divided 
twice daily for 12 weeks.  RBV dosage will be reduced in subjects with a calculated 
creatinine clearance < 50 mL/min (Section 6.7.6).
6.0
Adverse Events
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.


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6.1
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.7 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.
6.1.2
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 SAE.
Death of Subject
An event that results in the death of a subject.


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Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.


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6.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.3
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.  Assessment of relatedness will be made with respect to the 
DAAs (ombitasvir/ABT-450/r and SOF) and with respect to RBV:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the SAE.


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6.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 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 and serious adverse 
events will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, serious adverse events will be collected from the time the subject signed the 
study-specific informed consent until 30 days after the last dose of study drug.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.5
Adverse Event Reporting
In the event of a SAE, whether associated with study drug or not, the Investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the electronic data capture (EDC) system.  SAEs that 
occur prior to the site having access to the RAVE® system or if RAVE is not operable 
should be faxed to Clinical Pharmacovigilance within 24 hours of being made aware of 
the SAE.


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FAX to:  
Email to:
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
1 North Waukegan Road
North Chicago, IL  60064
For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.


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6.6
Pregnancy
Subjects and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the study, starting with Study Day 1 and for 30 days 
after the end of treatment with DAAs only, or for 7 months after the last dose of RBV (or 
per local RBV label) and/or consistent with local treatment guidelines for RBV.
Pregnancy in a study subject must be reported to the AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  Subjects receiving a RBV-inclusive regimen who 
report a positive pregnancy test during the Treatment Period must be notified to stop RBV 
immediately.  Administration of DAAs may be continued at the investigator's discretion, 
if the benefit of continuing therapy is felt to outweigh the risk (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment with DAAs only, or 7 months (or per local RBV label) after the last dose of 
RBV for treatment with DAAs plus RBV.  The investigator is encouraged to report the 
pregnancy information to the voluntary RBV Pregnancy Registry, if RBV is included 
within the regimen.
Subjects who discontinue study medications due to pregnancy will be monitored for SVR 
in the Post-Treatment Period as described in Section 5.1.3.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  A table of Clinical 
Toxicity Grades for evaluating laboratory abnormalities is provided in Appendix C.  This 


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table should be used in determination of the appropriate toxicity management as 
discussed in Section 6.7.1, Section 6.7.2, Section 6.7.3, Section 6.7.4, Section 6.7.5, and 
Section 6.7.6.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or AbbVie as having a "reasonable possibility" of 
being related to the study drug (Section 6.3).  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.
Investigators should avoid interrupting study drugs for more than 7 consecutive days.  The 
Investigator should ensure that any study drug interruptions or RBV dose modifications 
and associated adverse events are promptly entered into the appropriate eCRFs.
The toxicity management guidelines below should be followed throughout the Treatment 
Period of the study.
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or 
Moderate Adverse Events
Subjects who develop a mild or moderate adverse event or Grade 1 or 2 laboratory 
abnormality, other than those discussed separately in Section 6.7.4 (Management of 
Decreases in Hemoglobin), Section 6.7.5 (Management of ALT Elevations), and 
Section 6.7.6 (Management of Creatinine Clearance), may continue study drugs with 
follow-up per study protocol and in accordance with local standard of care.
6.7.2
Grades 3 or 4 Laboratory Abnormalities 
With the exception of Grade 3 or higher abnormalities of total bilirubin, uric acid, 
phosphorus, total cholesterol, triglycerides, or glucose (in subjects with a history of 
diabetes), if a subject experiences a Grade 3 or greater abnormal laboratory parameter 
during the Treatment Period, the abnormal laboratory test should be repeated.  If the 
Grade 3 or greater abnormality is confirmed, the investigator should assess whether the 
abnormality can be managed medically without interruption of study drug, or whether 


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study drugs should be interrupted and the laboratory parameter followed until it improves.  
If study drugs are interrupted and restarted and the abnormality recurs, then study drugs 
should be permanently discontinued.
Decreases in serum hemoglobin or in calculated creatinine clearance, or elevations of 
serum ALT should be managed according to the guidance in Section 6.7.4, Section 6.7.5, 
and Section 6.7.6 below.  Grade 3 or greater abnormalities of total bilirubin, uric acid, 
phosphorus, 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 unless deemed necessary by the investigator.
6.7.3
Severe Adverse Events or Serious Adverse Events 
If a subject experiences a severe adverse event or a serious adverse event that the 
investigator considers to have a reasonable possibility of relationship to study drug, the 
investigator should assess whether the adverse event can be managed medically without 
interruption of study drug, or whether study drugs should be interrupted until it improves.  
If study drugs are interrupted and restarted and the adverse event recurs, then study drugs 
should be permanently discontinued.
If a subject experiences a severe adverse event or serious adverse event that is considered 
unrelated (no reasonable possibility) to the study drugs, it is not necessary to interrupt 
study drugs unless an interruption is required because of the nature of the event 
(e.g., unable to take oral medications).  The investigator should ensure that all serious 
adverse events are reported to AbbVie within 24 hours of awareness.  Serious adverse 
event follow-up information, including associated dose interruptions (or discontinuations), 
must be reported to AbbVie within 24 hours of awareness by entering updated SAE 
information into the appropriate eCRFs.
Severe adverse events and any associated dose interruptions (or discontinuations) should 
be promptly entered into the appropriate eCRFs.


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6.7.4
Management of Decreases in Hemoglobin
For Subjects Not Receiving Ribavirin:
Hemoglobin decreases should be managed according to grade, based on the guidance in 
Section 6.7.1 and Section 6.7.2 above.
For Subjects Receiving Ribavirin:
Reductions 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 9, a confirmatory test should be performed.  
If the hemoglobin decrease is confirmed, the management guidelines in Table 9 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 9 may need hemoglobin 
evaluations at more frequent intervals at the discretion of the investigator.
The dose of RBV should not be further modified in subjects with creatinine clearance 
< 50 mL/min who are receiving a reduced dose of RBV.  Reductions in hemoglobin in 
these subjects should be managed as medically appropriate and as outline in Table 9.
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 Study Designated Physician.


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Table 9.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases
Hemoglobin Value
Intervention
Subjects with Creatinine Clearance ≥ 50 mL/min
< 10 g/L and ≥ 8.5 g/dL
Reduce RBV dose.*  Study drugs may be continued.  If hemoglobin 
increases to ≥ 10 g/dL, may increase RBV; with gradual dose increases 
in 200 mg increments towards original dose.
< 8.5 g/dL
Interrupt ribavirin.  Manage the subject as medically appropriate.
If hemoglobin increases to ≥ 8.5 g/dL, RBV may be restarted.
Additional Guidance for Subjects with History of Stable Cardiac Disease and Creatinine 
Clearance ≥ 50 mL/min
Hemoglobin decrease of 
≥2 g/dL during any 4-week 
treatment period
Reduce RBV dose.*  If a subsequent hemoglobin result is greater than 
the level that triggered the dose reduction, RBV dose may be increased; 
with gradual dose increases in 200 mg increments.
< 12 g/dL after a 4-week RBV 
dose reduction
Interrupt ribavirin.  Manage the subject as medically appropriate.
If subsequent hemoglobin increases to ≥ 12 g/dL, RBV may be 
restarted.
For Subjects with Creatinine Clearance < 50 mL/min
< 10 g/L
Interrupt RBV.  Manage the subject as medically appropriate.  If 
hemoglobin increases ≥ 10 g/dL, RBV may be restarted.  If creatinine 
clearance increases to ≥ 50 mL/min, refer to guidance above.
*
First dose reduction of ribavirin is by 200 mg/day.  If needed, second dose reduction of ribavirin is by an additional 
200 mg/day.  Subjects whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the 
morning and two 200 mg capsules in the evening.
6.7.5
Management of ALT Elevations
Transient asymptomatic Grade 3 – 4 ALT elevations have been observed in 
approximately 1% of subjects receiving ABT-450/r-containing regimens.  If a subject 
experiences a post-baseline increase in ALT to > 5 × ULN that is increased from a 
previous measurement, the subject should have a confirmatory ALT measurement 
performed.
If the ALT increase is confirmed to be > 5 × ULN and increased from the previous 
measurement, the recommendations below should be followed:


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●
Evaluate for alternative etiology of ALT elevation:  update medical history and 
concomitant medications eCRF (if applicable), and obtain additional testing as 
appropriate.
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase, and 
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Discontinue study drugs if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN.
○
Increasing direct bilirubin, increasing INR, or onset of symptoms/signs of 
hepatitis.
Alternate management of ALT increases is permitted with approval of the AbbVie Study 
Designated Physician. 
6.7.6
Creatinine Clearance
If calculated creatinine clearance (by Cockcroft-Gault formula) is confirmed to have 
decreased to < 50 mL/minute (in a subject with a baseline creatinine clearance of 
≥50 mL/min), or to below 30 mL/min (in a subject with baseline creatinine clearance 
< 50 mL/min), 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).  Ribavirin dose should be 
adjusted as in Table 10.  Alternative management of RBV dose in the setting of reduced 
renal function will require approval of the AbbVie Study Designated Physician.
The investigator should also consider whether drug-drug interactions with concomitant 
medications may have contributed to the decrease in creatinine clearance, and whether 
discontinuation or substitution of the possible interacting drug might be considered.  For 
example, drug interactions between DAAs and some antihypertensive medications could 
potentially increase exposures of the antihypertensive, which may lead to reduction in 
renal function.  If anti-hypertensive medications are adjusted, vital signs should be 


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monitored to ensure appropriate blood pressure control.  Refer to Section 5.2.3 for 
additional information regarding drug-drug interactions.
Table 10.
Dosing of RBV in Subjects with Renal Impairment
CrCl Value
RBV Dose
30 – 50 mL/min
Alternating doses, 200 mg and 400 mg every other day
< 30 mL/min
200 mg daily
Hemodialysis
200 mg daily
Note:
For RBV dosing in subjects with concurrent creatinine clearance < 50 mL/min and Hb < 10 (Table 8).
If creatinine clearance improves, the site should perform all necessary readjustments of 
any dose modifications that have been made.  If creatinine clearance improves to above 
the level that triggered the RBV dose reduction, the RBV dose may be increased 
accordingly.
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.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol, except when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Contacts:


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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorizes, as applicable, prior to 
implementation.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
An interim analysis will occur after all enrolled subjects have completed through 
Post-Treatment Week 12 or prematurely discontinued from the study.  The database will 
be versioned after performing appropriate data cleaning.  Final data through 
Post-Treatment Week 48 will be locked in a later version of the database after appropriate 
data cleaning is performed.
SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  The intent-to-treat (ITT) population will consist of all enrolled subjects who 
received at least one dose of study drug.  Efficacy, safety, and demographic analyses will 
be performed on all subjects in the ITT population.
Detailed statistical methods for all endpoints will be provided in the Statistical Analysis 
Plan (SAP).


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No data will be imputed for any efficacy or safety analyses except for analyses of the 
HCV RNA endpoints. 
HCV RNA values will be selected for the SVR12 analysis based on defined visit windows.  
When there is no HCV RNA value in a visit window based on defined visit windows, the 
closest values before and after the window, regardless of the value chosen for the 
subsequent and preceding window, will be used for the flanking imputation described 
below.
If a subject has a missing HCV RNA value at a post-Day 1 visit, but with undetectable or 
unquantifiable HCV RNA levels at both the preceding value and succeeding value, the 
HCV RNA level will be considered undetectable or unquantifiable, respectively, at this 
visit for this subject.  For SVR12 analysis, if there is no value in the appropriate window 
but there is an HCV RNA value after the window, then it will be imputed into the SVR12
window.  Subsequent to this imputation, if a subject is missing a value for the visit 
window associated with the analysis, the subject will be imputed as a visit failure (i.e., not 
undetectable or unquantifiable).
8.1.1
Demographics
Demographics and baseline characteristics will be summarized by treatment arm for all 
subjects in the ITT population.  Demographics include age, weight, height, and BMI as 
continuous variables, and sex, race, age category ([< 55 years or ≥ 55 years] and [< 65 or 
≥ 65 years]), and BMI category (< 30 kg/m2 or ≥ 30 kg/m2).  Baseline characteristics will 
include:  IL28B genotype ([CC, CT, or TT] and [CC or non-CC]), prior treatment history 
(treatment naïve, pegIFN/RBV null-responder, pegIFN/RBV partial responder, SOF 
breakthrough/nonresponder, HCV therapy relapser, HCV relapse/breakthrough, HCV 
therapy nonresponder, pegIFN intolerant, and pegIFN experienced), baseline HCV RNA 
levels ([continuous] and [< 800,000 IU/mL or ≥ 800,000 IU/mL]), and HCV subgenotype 
(3, 3a, 3b, or 3c).  Summary statistics (N, mean, median, standard deviation [SD], and 
range) will be generated for continuous variables (e.g., age and BMI).  The number and 
percentage of subjects will be presented for categorical variables (e.g., sex and race).


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8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population.  Plasma HCV RNA levels 
will be determined for each sample collected by the central laboratory using the Roche 
COBAS TaqMan® real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0.  The lower 
limit of detection (LLOD) is 20 IU/mL and results below LLOD are reported as "HCV 
RNA not detected;" the LLOQ for this assay is 25 IU/mL and results below LLOQ but 
detectable are reported as" < 25 IU/mL HCV RNA detected."
8.1.2.1
Primary Efficacy Endpoint
The primary endpoint is the percentage of subjects with SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drugs).  The number and percentage of 
subjects achieving SVR12 will be calculated for each treatment arm and 2-sided 95% 
Wilson score confidence intervals for a binomial proportion will be computed.
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The percentage of subjects in each treatment arm and across all treatment arms 
with on-treatment virologic failure (rebound defined as confirmed HCV RNA 
≥ LLOQ after HCV RNA < LLOQ during treatment, or confirmed increase 
from nadir in HCV RNA at any time point during treatment, or failure to 
suppress during treatment (all on-treatment values of HCV RNA ≥ LLOQ) 
with at least 6 weeks (defined as active study drug duration ≥ 36 days) of 
treatment.
●
The percentage of subjects with post-treatment relapse (relapse12 defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of active study drug (up to and including the SVR12 assessment 
time point) for a subject with HCV RNA < LLOQ at Final Treatment Visit 
who completes treatment.  Completion of treatment is defined as study drug 
duration ≥ 77 days.


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The numbers and percentages of the subjects with virologic failure during treatment and 
with post-treatment relapse will be calculated for each arm.  The corresponding 2-sided 
95% Wilson score confidence intervals for a binomial proportion will be calculated.
8.1.2.3
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized and analyzed for each 
treatment arm:
●
All reasons for not achieving SVR12 for subjects who do not achieve SVR12;
●
Number and percentage with unquantifiable HCV RNA at each post-baseline 
visit throughout the Treatment Period (using data from the central laboratory 
as observed, i.e., no imputation for missing data);
●
The percentage of subjects with HCV RNA < LLOQ 24 weeks after the last 
actual dose of study drug (SVR24);
●
All reasons for not achieving SVR24 for subjects who do not achieve SVR24.
●
Time to suppression of HCV RNA (defined as the study day of the first of 
two successive HCV RNA < LLOQ) during the Treatment Period.
In the above analyses that use the number and percentage of responders, the rates and 
2-sided 95% Wilson score confidence interval for a binomial proportion will be 
calculated.  For HCV RNA levels, the time to suppression during treatment will be 
calculated for each subject, and the median time will be estimated using Kaplan-Meier 
methodology for right censored observations.
8.1.3
Patient Reported Outcomes
The following exploratory analyses of patient reported outcomes (PROs) will be 
performed:
●
mean change from baseline in EQ-5D-5L health index score and its VAS score 
to each applicable post-baseline time point
●
mean change from baseline in the FSS score and its VAFS score to each 
applicable post-baseline time point


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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-5L health index and its 
VAS scores, and the FSS and its VAFS scores.
Additional analyses of PROs will be performed as useful and appropriate.
8.1.4
Resistance Analyses
The genes of interest for population sequencing in this study are those encoding full 
length NS3/4A, NS5A, and NS5B.  For clonal sequencing, the DNA encoding NS3 amino 
acids 1 – 181, NS5A amino acids 1 – 215, and NS5B amino acids 280 – 591 will be 
sequenced.  Amino acid positions where resistance-associated variants have been 
identified in vitro and/or in vivo in genotype 3 are 56, 80, 155, 156, 166, and 168 in NS3 
for ABT-450; 28, 30, 31, 32, 58, and 93 in NS5A for ombitasvir; and 282 in NS5B for 
sofosbuvir.
Only samples with an HCV RNA level of ≥ 1,000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore if the HCV 
RNA level at the time of virologic failure or treatment discontinuation is < 1,000 IU/mL, 
the sample closest in time after the failure/discontinuation with an HCV RNA level 
≥1,000 IU/mL will be used.  Included time points for analyses on samples from subjects 
who do not achieve SVR12 are:  1) time of virologic failure/treatment discontinuation or 
sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1,000 IU/mL, 2) 24 weeks post-DAA treatment, provided that resistance-associated 
variants were detected by either population or clonal sequencing at the time of 
failure/discontinuation, and 3) 48 weeks post-DAA treatment, provided that 
resistance-associated variants were detected by either population or clonal sequencing at 
24 weeks post-DAA treatment.  For these samples, clonal sequencing of a given target 
will be performed only if no variants are detected at signature resistance-associated amino 
acid positions by population sequencing.  In addition, clonal sequencing may be 
performed if there is a complex mixture of amino acids at a signature 
resistance-associated position that cannot be resolved by population sequencing.


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The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant (by population sequencing) in a baseline sample 
determined by comparison of the amino acid sequence of the baseline sample 
to the appropriate prototypic reference amino acid sequence for a given DAA 
target.
●
Post-baseline variant by population sequencing:  an amino acid variant 
detected by population sequencing in a post-baseline time point sample that 
was not detected by population sequencing at baseline in the subject.
●
Post-baseline variant by clonal sequencing:  a variant at a signature 
resistance-associated amino acid position that was not present in a subject by 
population sequencing at baseline, but that is detected in a post-baseline 
sample from that subject by clonal sequencing in at least 2 clones from that 
sample (among the subset of subjects for whom clonal sequencing is 
performed).
●
Emerged variant by population sequencing:  a post-baseline variant that is 
observed in samples from 2 or more subjects of the same HCV subgenotype by 
population sequencing.
●
Linked variant by population sequencing:  2 or more signature 
resistance-associated or emerged amino acid variants identified within a target 
by population sequencing, and no mixture of amino acids is detected at either 
position.
●
Linked variant by clonal sequencing:  at least 2 clones from a given sample 
containing the same 2 or more signature resistance-associated amino acid 
variants by clonal sequencing.
Baseline samples will be sequenced by population sequencing for all subjects for whom 
samples are available.  A listing by subject of all baseline variants relative to the 
appropriate prototypic reference sequence at signature resistance-associated amino acid 
positions will be provided for each DAA target (NS3, NS5A, and NS5B).  In addition, a 
summary of the number and percentage of subjects with each baseline variant at a 
signature resistance-associated amino acid position within each target by HCV 
subgenotype out of the total number of baseline samples sequenced will also be provided.


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The following analyses will be performed for subjects who do not achieve SVR12 and 
have post-baseline resistance data available.
The HCV amino acid sequence as determined by population sequencing on the sample 
closest in time after virologic failure or treatment discontinuation with an HCV RNA level 
of ≥ 1,000 IU/mL will be compared to the baseline and appropriate prototypic reference 
amino acid sequences.  Listings by subject of all post-baseline variants detected by 
population sequencing relative to the baseline amino acid sequences will be provided for 
each DAA target (NS3, NS5A, and NS5B).  Listings by subject of all emerged variants by 
population sequencing, by amino acid position and variants within a DAA target in a 
post-baseline sample relative to the baseline amino acid sequence will be provided for 
each DAA target.  In addition, listings by subject of all post-baseline variants (by 
population sequencing) at signature resistance-associated amino acid positions relative to 
the appropriate prototypic reference amino acid sequence will be provided for each DAA 
target (NS3, NS5A, and NS5B).
The number and percentage of subjects with emerged variants by population sequencing 
by amino acid position and variant within a DAA target at the time of VF compared to 
baseline will be summarized.  The analyses will be grouped by HCV subgenotype and 
DAA target (NS3, NS5A, or NS5B).
Linkage between emerged or signature variants by population sequencing will also be 
evaluated.  A listing by subject and time point of the linked variants by population 
sequencing for each target will be provided.
For the subset of samples for which clonal sequencing is performed, a listing of 
post-baseline variants by clonal sequencing at signature resistance-associated amino acid 
positions by subject, amino acid position and variant, as well as time point will be 
provided for each DAA target.  Furthermore, listings of the linked variants by clonal 
sequencing by subject, DAA target, and time point will be provided.


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The persistence of post-baseline variants at signature resistance-associated amino acid 
positions for each target (NS3, NS5A, and NS5B) will be assessed by population and/or 
clonal sequencing at Post-Treatment Weeks 24 and 48.  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, NS5A, and NS5B).  Additionally, the number and percent of 
subjects in whom an emerged variant persists at Post-Treatment Weeks 24 or 48 out of the 
total number of subjects with that emerged variant at the failure/discontinuation time point 
and at Post-Treatment Week 24 and/or Post-Treatment Week 48 will be summarized by 
HCV subgenotype, DAA target, and variant.
Replicon EC50 values may not be obtainable for all samples, but for samples where 
phenotype data is obtained, the fold change in EC50 level at each post-baseline time point 
where phenotypic analysis was performed will be determined relative to the EC50 level of  
baseline and of prototypic standard.
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).24  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT) for each treatment arm and overall.  The 
tabulation of the number of subjects with treatment-emergent adverse events by severity 
rating and relationship to study drug will also 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 incident for the severity rating table and the most related for 
the relationship to study drug table.  Subjects reporting more than one type of event within 
a SOC will be counted only once for that SOC.


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Additional analyses will be performed if useful and appropriate.
8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last measurement prior to the initial dose of study drug.  Mean changes from baseline to 
each Post-Baseline Visit will be summarized descriptively for each treatment arm.
Laboratory data values collected during the Treatment Period 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 during treatment in 
clinical laboratory values from low/normal to high and high/normal to low based on the 
normal range will be summarized for each treatment arm.
In addition, the number and percentage of subjects with post-baseline values meeting 
pre-specified criteria for Potentially Clinically Significant laboratory values during 
treatment will be summarized for each arm.  Additional analyses will be performed if 
useful and appropriate.
8.1.5.3
Vital Signs Data
Vital sign measurements will be summarized at each visit during the treatment period.  
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each Post-Baseline Visit will be summarized descriptively for each 
treatment arm.  The baseline value will be the last measurement prior to the initial dose of 
study drugs.  Frequencies and percentages of subjects with post-baseline values meeting 
pre-defined criteria for Potentially Clinically Significant vital signs values during 
treatment will be summarized for each treatment arm.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual plasma concentrations of ABT-450, ritonavir, ombitasvir, SOF, GS-581007, 
and RBV will be tabulated and summarized.  Individual plasma concentrations of possible 


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metabolites of ABT-450, ombitasvir, and SOF (other than GS-331007) may be tabulated 
and summarized if measured and sufficient levels of metabolites are observed.
Values for the pharmacokinetic parameters of ABT-450, ombitasvir, ritonavir, SOF, 
GS-331007, and RBV including the Cmax, Tmax, Ctrough, and AUC will be summarized and 
tabulated. 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 a nonlinear mixed-effects modeling 
(NONMEM) software (Version VI or higher).  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 interest in the 
analysis.  If the estimation of the parameters describing absorption characteristics is not 
possible then they will be fixed to the values obtained from previous analysis.  The 
evaluation criteria described below will be used to examine the performance of different 
models.
●
Model discrimination will be assessed by a likelihood ratio test comparing 
objective function values (OFVs) when two competing models are compared.  
An OFV difference (ΔOFV) of 3.84 will be considered to be significant (χ2, 
p < 0.05) when two nested models with a difference of one parameter (df = 1) 
are compared.  The Akaike's information criterion (AIC) will be used to 
compare non-nested models.
●
Various goodness-of-fit criteria, including diagnostic scatter plots and 
individual plots of model fits.
●
Visual predictive checks or standardized visual predictive checks.
●
Plausibility of parameter estimates and precision of parameter estimates.
Covariate-parameter relationships will be tested based on scientific principles or prior 
knowledge i.e., only 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.  Covariate modeling will also be guided by plots of 


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posterior Bayesian estimates of pharmacokinetic parameters versus covariates (delta plots) 
or plots of η versus covariates (eta plots).  If needed, a generalized additive method 
(GAM) or another suitable regression/smoothing method may be employed for covariate 
selection.  Several covariate models (linear or nonlinear mathematical functions) will be 
explored to adequately describe the pharmacokinetic data.  A likelihood ratio test will be 
employed for covariate selection by comparing OFVs obtained from NONMEM.  A 
decrease in the OFV of at least 3.84 (χ2, p < 0.05, df = 1) is considered significant in the 
univariate analysis.  A full model will be developed with all significant covariates from 
the univariate analysis.  Finally, backward elimination will be performed to develop a 
final model.  An increase in the OFV of at least 7.88 (χ2, p < 0.005, df = 1) will be 
considered significant in the backward elimination.  The AIC will be used to compare 
non-nested models.
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.  Exposure response 
relationships will be explored using a semi-mechanistic viral dynamic model and/or 
logistic regression analyses.
The viral dynamic model will account for target cell growth and death, infection of target 
cells, infected cell infection and death rate, production of virus by infected cells, and 
inhibition of production of virus by the various DAAs.  Effect of RBV will be explored on 
infection of target cells by virus.  Models will explore mutation of the wild type to single 
and/or double mutant species depending on the available clinical resistance data.
Additional adjustments to the structural and error models will be made during model 
development as appropriate.


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Logistic regression analyses will explore the relationship between exposure and one or 
more virologic endpoints (e.g., RVR, EVR, SVR4, SVR12, relapse following end of 
treatment and breakthrough on treatment).
Additionally, relationships between exposure and safety endpoints of interest may be 
explored.
8.2
Determination of Sample Size
It is planned to enroll approximately 20 subjects into this study.  With a sample size of 
10 subjects per arm and an observed SVR12 rate of 90%, the 2-sided 95% confidence 
interval, using Wilson's score confidence interval, will be (59.6%, 98.2%).  Subjects who 
do not have data at PT Week 12 (after performing the described imputation) count as 
failures for SVR12 so no adjustment for dropout is applicable.
From the perspective of safety assessment, the probability that a given adverse event 
would not be observed among 20 subjects is shown in the second column of Table 11 for 
various true population incidence rates.  With 20 subjects, the probability is at least 97.8% 
to observe an adverse event with an incidence rate of 10% or higher.
Table 11.
Probability of Not Observing an Adverse Event or Lab 
Abnormality for Various True Incidence Rates 
True Incidence Rate
Probability of Not Observing
0.10
0.122
0.20
0.012
0.30
< 0.001
0.40
< 0.001
0.50
< 0.001
8.3
Randomization Methods
Approximately 20 subjects will be randomized to ombitasvir/ABT-450/r 
25 mg/150 mg/100 mg QD + sofosbuvir 400 mg QD for 12 weeks (Arm A) or 


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ombitasvir/ABT-450/r 25 mg/150 mg/100 mg QD + sofosbuvir 400 mg QD + 
weight-based RBV for 12 weeks (Arm B) in a 1:1 ratio.  Randomization will be stratified 
by IL28B genotype (CC versus non-CC) and prior treatment status (treatment-naïve 
versus treatment-experienced).
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.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed, 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.
IL28B genotypes will be determined for each subject.  Consent for determination of 
IL28B status will be included in the study informed consent.  Additional pharmacogenetic 
analysis, other than IL28B analysis and mRNA analysis will only be performed if the 
subject has voluntarily signed and dated the IEC/IRB approved pharmacogenetic and 
mRNA informed consents, after the nature of the testing has been explained and the 
subject has had the opportunity to ask questions.  The subject must provide consent 
specific to pharmacogenetic and mRNA testing before the pharmacogenetic and mRNA 
testing is performed.  If the subject does not consent to the additional pharmacogenetic or 
mRNA testing it will not impact the subject's participation in the study.
The optional pharmacogenetic analysis will only be performed if the subject has 
voluntarily signed and dated a separate pharmacogenetic informed consent form, 
approved by an IRB/IEV, after the nature of the testing has been explained and the subject 
has had the opportunity to ask questions.  The separate pharmacogenetic informed consent 


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must be signed before the pharmacogenetic testing is performed.  If the subject does not 
consent to the pharmacogenetic testing, it will not impact the subject's participation 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 
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 


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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.
12.0
Use of Information
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 


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subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  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 investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug, and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ombitasvir and 
ABT-450, and the product inserts for SOF and RBV.
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 Study to Evaluate the Safety and 
Efficacy of the Co-Administration of 
Ombitasvir/ABT-450/Ritonavir (Ombitasvir/ABT-450/r) With 
Sofosbuvir (SOF) With or Without Ribavirin (RBV) in Subjects 
With Genotype 3 Chronic Hepatitis C Virus (HCV) Infection 
Protocol Date: 
31 July 2014
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Weekly Epidemiological Record.  No. 41, 7 October 2011, WHO.
2.
Freeman AJ, Dore GJ, Law MG, et al.  Estimating progression to cirrhosis in 
chronic hepatitis C virus infection.  Hepatology.  2011;34(4 Pt 1):809-16.
3.
Sangiovanni A., Prati GM, Fasani P, et al.  The natural history of compensated 
cirrhosis due to hepatitis C virus:  a 17-year cohort study of 214 patients.  
Hepatology.  2006;43(6):1303-10.
4.
El-Serag HB.  Hepatocellular carcinoma:  recent trends in the United States.  
Gastroenterology.  2004;127(5 Suppl 1):S27-34.
5.
Serfaty L, Aumaitre H, Chazouilleres O, et al.  Determinants of outcome of 
compensated hepatitis C virus-related cirrhosis.  Hepatology.  1998;27(5):1435-40.
6.
Fattovich G, Giustina G, Degos F, et al.  Morbidity and mortality in compensated 
cirrhosis type C:  a retrospective follow-up study of 384 patients.  
Gastroenterology.  1997;112(2):463-72.
7.
Fattovich G, Pantalena M, Zagni I, et al.  Effect of hepatitis B and C virus 
infections on the natural history of compensated cirrhosis:  a cohort study of 
297 patients.  Am J Gastroenterol.  2002;97(11):2886-95.
8.
Wasley A, Alter MJ.  Epidemiology of hepatitis C:  geographic differences and 
temporal trends.  Semin Liver Dis.  2000;20(1):1-16.
9.
Sy T, Jamal MM.  Epidemiology of hepatitis C virus (HCV) infection.  Int J Med 
Sci.  2006;3(2):41-6.
10.
Cornberg M, Razavi HA, Alberti A, et al.  A systematic review of hepatitis C virus 
epidemiology in Europe, Canada and Israel.  Liver Int.  2011;31(Suppl 2):30-60.
11.
Esteban JI, Sauleda S, Quer J.  The changing epidemiology of hepatitis C virus 
infection in Europe.  J Hepatol.  2008;48:148-62.
12.
Shiffman ML, Suter F, Bacon BR, et al.  Peginterferon alfa-2a and ribavirin for 
16 or 24 weeks in HCV genotype 2 or 4.  N Engl J Med.  2008;357:124-34.


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13.
Zeuzem S, Dusheiko GM, Salupere R, et al.  Sofosbuvir and ribavirin in HCV 
genotypes 2 and 3.  N Engl J Med.  2014;370(21):1993-2001.
14.
AbbVie.  ABT-450 Investigator Brochure Edition 6.  26 March 2013.
15.
AbbVie.  ABT-267 Investigator Brochure Edition 4.  26 March 2013.
16.
Gilead Sciences.  Solvadi US Package Insert.  Dec 2013.
17.
Lawitz E, Mangia A, Wyles D, et al.  Sofosbuvir for previously untreated chronic 
hepatitis C infection.  N Engl J Med.  2013;368:1878-87.
18.
Lawitz E, Sullivan G, Rodriguez-Torres M, et al.  A 12-week trial of 
interferon-free regimens containing ABT-450/r and ABT-267 ± ribavirin in 
treatment-naïve patients with HCV genotypes 1 – 3.  APASL 2013.  
June 6-10 2013; Suntec City, Singapore.
19.
Lam AM, Espiritu C, Bansal S, et al.  Genotype and subtype profiling of PSI-7977 
as a nucleotide inhibitor of hepatitis C virus.  Antimicrob Agents Chemother.  
2012;56:3359-68.
20.
Eley T, You X, Huang S, et al.  Evaluation of drug interaction potential between 
daclatasvir and sofosbuvir.  8th International Workshop on Clinical Pharmacology 
of Hepatitis Therapy, June 26-27, 2013; Cambridge, MA.  Abstract O 14.
21.
German P, Mathias A, Pang PS, et al.  Lack of a clinically significant 
pharmacokinetic drug-drug interaction between sofosbuvir (GS-7977) and 
GS-5885 or GS-9669 in healthy volunteers.  63rd Annual Meeting of the American 
Association for the Study of Liver Diseases (AASLD).  November 9-13 2012; 
Boston, MA.  Abstract 1888. 
22.
Fried MW, Shiffman ML, Reddy KR, et al.  Peginterferon alfa-2a plus ribavirin for 
chronic hepatitis C virus infection.  N Engl J Med.  2002;347:975-82.
23.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.  Daclatasvir plus 
sofosbuvir for previously treated or untreated chronic HCV infection.  N Engl J 
Med.  2014;370(3):211-21.
24.
Medical Dictionary for Regulatory Activities (MedDRA), Version 14.1.


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25.
Brennan BJ, Wang K, Blotner S, et al.  Safety, tolerability, and pharmacokinetics 
of ribavirin in hepatitis C virus-infected patients with various degrees of renal 
impairment.  Antimicrob Agents Chemother.  2013;57(12):6097-105.  


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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
Project Director
CPD
Sr. Manager
Statistics
Director
PK
Sr. Medical Director
CPD
Clinical Supply Project Manager
GDSM
CRMA
CPD


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Appendix C.
Clinical Toxicity Grades


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SAP_001.pdf: 


Ombitasvir/ABT-450/Ritonavir
M14-567 – Statistical Analysis Plan
Version 2.0 – 12 Jul 2017
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 8
4.4
Planned Analysis.................................................................................... 9
4.4.1
Interim Analysis..................................................................................... 9
5.0
Analysis Populations ........................................................... 10
5.1
Definition for Analysis Populations ...................................................... 10
5.1.1
Intent-to-Treat (ITT) Population........................................................... 10
5.1.2
Safety Population ................................................................................. 10
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions .......................................................... 11
6.1
Baseline and Final Value...................................................................... 11
6.1.1
Baseline................................................................................................ 11
6.1.2
Study Days........................................................................................... 11
6.2
Analysis Windows................................................................................ 12
6.3
Missing Data Imputation ...................................................................... 16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............18
7.1
Demographic and Baseline Characteristics ........................................... 18
7.2
Medical History.................................................................................... 20
7.3
Previous Treatment and Concomitant Medications ............................... 20
8.0
Patient Disposition............................................................... 21
9.0
Study Drug Exposure and Compliance.............................. 22
9.1
Exposure .............................................................................................. 22
9.2
Compliance .......................................................................................... 23
10.0
Efficacy Analysis .................................................................23
10.1
General Considerations......................................................................... 23


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10.2
Handling of Multiplicity....................................................................... 28
10.3
Primary Efficacy Analysis.................................................................... 28
10.4
Secondary Efficacy Analyses ............................................................... 28
10.5
Sensitivity Analysis.............................................................................. 29
10.6
Additional Efficacy Analyses ............................................................... 29
10.7
Resistance Analyses ............................................................................. 30
10.8
Patient Reported Outcomes .................................................................. 34
11.0
Safety Analysis.....................................................................35
11.1
General Considerations......................................................................... 35
11.2
Analysis of Adverse Events.................................................................. 35
11.2.1
Treatment-Emergent Adverse Events.................................................... 35
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events ............................ 35
11.2.2
Listing of Adverse Event...................................................................... 39
11.3
Analysis of Laboratory Data................................................................. 40
11.3.1
Variables and Criteria Defining Abnormality........................................ 40
11.3.2
Statistical Methods ............................................................................... 44
11.4
Analysis of Vital Signs and Weight ...................................................... 46
11.4.1
Variables and Criteria Defining Abnormality (if Applicable)................ 46
11.4.2
Statistical Methods ............................................................................... 47
12.0
Summary of Changes .......................................................... 48
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ............................................................................................... 48
12.2
Summary of Changes from SAP Version 1.0 ........................................ 48
13.0
References............................................................................48
List of Tables
Table 1.
Probability of Not Observing an Adverse Event or Lab 
Abnormality with 70 Subjects for Various True Incidence Rates ............ 9
Table 2.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 12-Week 
of Treatment......................................................................................... 13


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Table 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 8-Week 
of Treatment......................................................................................... 13
Table 4.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 6-Week 
of Treatment......................................................................................... 14
Table 5.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
(Post-Treatment Period) ....................................................................... 14
Table 6.
Analysis Time Windows for PRO Instruments...................................... 15
Table 7.
Laboratory Data and Vital Sign Visit Windows (Post-Treatment 
Period) ................................................................................................. 16
Table 8.
Child-Pugh Classification of Severity of Cirrhosis................................ 19
Table 9.
Baseline Fibrosis Stage......................................................................... 20
Table 10.
Criteria for Potentially Clinically Significant Hematology Values ........ 42
Table 11.
Criteria for Potentially Clinically Significant Chemistry Values ........... 43
Table 12.
Definitions of CTCAE Grades 1, 2, 3, and 4......................................... 46
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Values............ 47
List of Figures
Figure 1.
Study Schematic..................................................................................... 7


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
AbbVie Statistics and Statistical Programming for Study Protocol M14-567.  
Study M14-567 examines the safety and efficacy of co-administration of 
ombitasvir/ABT-450/ritonavir (r) with sofosbuvir (SOF) with and without ribavirin 
(RBV) in adults with genotype 3 chronic hepatitis C virus (HCV) infection with and 
without cirrhosis for 12 weeks, and genotype 2 HCV infection without cirrhosis for 8 and 
6 weeks.
This SAP provides details to further elaborate statistical methods as outlined in the
protocol and describes analysis conventions to guide the statistical programming work for 
both the interim analyses (after all subjects in Arm A and Arm B reach Post-Treatment 
[PT] Week 12 or permanently discontinue the study, after all subjects in Arm C, D, E and 
F reach PT Week 12 or permanently discontinue the study) and the final analysis (at the 
end of study).  Analyses will be performed using SAS® (SAS Institute, Inc., Cary, NC) for 
the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the safety and efficacy (the percentage 
of subjects achieving a 12-week sustained virologic response, SVR12 [HCV ribonucleic 
acid {RNA} < lower limit of quantification {LLOQ} 12 weeks following treatment]) of 
co-formulated ombitasvir with ABT-450/r (ombitasvir/ABT-450/r) co-administered with 
sofosbuvir (SOF) with or without ribavirin (RBV) for 12 weeks in HCV 
genotype 3-infected adult subjects with and without cirrhosis, and 8 and 6 weeks in HCV 
genotype 2-infected adult subjects without cirrhosis.
The secondary objectives of this study are to assess the percentage of subjects with on 
treatment virologic failure and the percentage of subjects with relapse post-treatment 
(PT), and characterize the pharmacokinetics of direct-acting antiviral agents (DAAs) 


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including ombitasvir/ABT-450/r, SOF, GS-331007 (predominant circulating metabolite of 
SOF), and RBV (if applicable).
4.2
Design Diagram
This is a Phase 2, randomized, open-label, multicenter study evaluating the efficacy and 
safety of co-administration of ombitasvir/ABT-450/r with SOF with or without RBV 
administered for 12 weeks in HCV GT3 (with and without cirrhosis) and 8 and 6 weeks 
for GT2 (without cirrhosis) infected, treatment-naïve and treatment-experienced (previous 
pegIFN/RBV and/or SOF) adults.  Approximately 70 subjects will be enrolled at 
approximately 8 sites globally.
Treatment Period and Post-Treatment Period
Approximately 20 GT3 subjects without cirrhosis meeting the eligibility criteria will be 
randomized 1:1 into Arm A and Arm B and treated as below:
●
Arm A:  ombitasvir/ABT-450/ritonavir 25/150/100 mg once daily (QD) and 
SOF 400 mg (QD) for 12 weeks;
●
Arm B:  ombitasvir/ABT-450/ritonavir 25/150/100 mg once daily (QD) and 
SOF 400 mg (QD) with RBV 1000 – 1200 mg divided twice daily (BID) per 
local label for 12 weeks.
Randomization to Arms A and B will be stratified by IL28B genotype (CC versus non-
CC) and prior treatment status (treatment-naïve versus treatment-experienced).
Approximately 10 GT2 subjects meeting the eligibility criteria will be enrolled in to each 
of Arm C and Arm D and treated as described below.  Arm D would be launched if no 
more than one subject who completes treatment in Arm C experiences relapse through PT 
Week 4.


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Figure 1.
Study Schematic
●
Arm C:  ombitasvir/ABT-450/ritonavir 25/150/100 mg once daily (QD) and 
SOF 400 mg (QD) with weight based RBV 1000 – 1200 mg BID per local 
label for 8 weeks;


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●
Arm D:  ombitasvir/ABT-450/ritonavir 25/150/100 mg once daily (QD) and 
SOF 400 mg (QD) with weight based RBV 1000 – 1200 mg BID per local 
label for 6 weeks;
Approximately 20 subjects with genotype 3 HCV infection with compensated cirrhosis 
(aminimum of approximately 20% will be treatment-experienced) will be enrolled into 
Arm E:
●
Arm E:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg and SOF 400 mg QD 
with RBV 1000 – 1200 mg BID for 12 weeks
An additional 10 subjects with genotype 3 HCV infection without cirrhosis will be 
enrolled in open-label fashion into Arm F:
●
Arm F:  ombitasvir/ABT-450/r 25 mg/150 mg/100 mg and SOF 400 mg QD 
for 12 weeks
RBV dosing will be weight-based, either 1000 mg or 1200 mg daily divided BID per local 
label (e.g., < 75 kg = 1000 mg daily divided BID or ≥ 75 kg = 1200 mg daily divided 
BID).
Upon completing the Treatment Period (TP) or premature discontinuation of the TP, 
subjects will enter the PT Period.  All subjects who receive at least one dose of study 
drugs in the TP and either complete treatment or prematurely discontinue study drug will 
be monitored for an additional 48 weeks in the Post-Treatment Period for safety, HCV 
RNA, the emergence and/or persistence of resistant viral variants and assessment of 
patient reported outcomes (PROs).  A study schematic is shown in Figure 1.  The PT 
Period will begin the day following the last dose of study drug treatment.
4.3
Sample Size
It is planned to enroll approximately 70 subjects into this study.  With a sample size of 
10 subjects per arm and an observed SVR12 rate of 90%, the 2-sided 95% confidence 


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interval, using Wilson's score confidence interval, will be (59.6%, 98.2%); With a sample 
size of 20 subjects per arm and an observed SVR12 rate of 90%, the 2-sided 95% 
confidence interval, using Wilson's score confidence interval, will be (69.9%, 97.2%).  
Subjects who do not have data at PT Week 12 (after performing the described imputation) 
count as failures for SVR12 so no adjustment for dropout is applicable.
From the perspective of safety assessment, the probability that a given adverse event 
would not be observed among 70 subjects is shown in the second column of Table 1 for 
various true population incidence rates.  With 70 subjects, the probability is at least 99.9% 
to observe an adverse event with an incidence rate of 10% or higher.
Table 1.
Probability of Not Observing an Adverse Event or Lab 
Abnormality with 70 Subjects for Various True Incidence Rates 
True Incidence Rate
Probability of Not Observing
0.10
< 0.001
0.20
< 0.001
0.30
< 0.001
0.40
< 0.001
0.50
< 0.001
4.4
Planned Analysis
All analyses will be conducted by statisticians and programmers at AbbVie or designee 
according to the methodologies specified in this SAP.  There is no intention of stopping 
the study early based on efficacy findings from the interim analysis.  The intention is to 
follow all subjects who receive active drugs for defined durations in each arm.
4.4.1
Interim Analysis
There will be an interim analysis after all enrolled subjects in Arms A and B have 
completed through Post-Treatment Week 12 or prematurely discontinued from the study,
and another interim analysis after all enrolled subjects in Arms C, D, E and F have 


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completed through Post-Treatment Week 12 or prematurely discontinued from the study.  
For interim analyses, data will be locked after performing appropriate data cleaning.
Data collected after each interim analysis will be added to a new version of the database.  
At the end of the study, all data will be cleaned and locked and included in the final CSR.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intent-to-Treat (ITT) Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
ITT population.  Efficacy analyses will be performed on the ITT population. 
Modified Intent-to-Treat Population
Sensitivity analyses of the primary endpoint, when applicable, will be performed on the 
modified ITT (mITT) population to exclude subjects not of genotype as specified in each 
arm or not of genotype specified in each arm 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).
5.1.2
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population.  Safety and demographic analyses will be performed on the safety population.
5.2
Variables Used for Stratification of Randomization
Approximately 20 HCV genotype 3-infected subjects will be randomized to Arm A or 
Arm B in a 1:1 ratio.  Randomization will be stratified by IL28B genotype (CC versus 
non-CC) and prior treatment status (treatment-naïve versus treatment-experienced).
There is no randomization for HCV subjects enrolled into Arms C to F.


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6.0
Analysis Conventions
6.1
Baseline and Final Value
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug.  All assessments on Study Day 1 should be performed prior to 
administering the first dose of study drug, in accordance with the protocol.  The baseline 
value is therefore determined by the last non-missing measurement collected on or before 
the first day of study drug administration. 
If multiple measurements are recorded on the same day, the last measurement recorded 
prior to dosing will be used as the baseline value.  If these multiple measurements occur at 
the same time or time is not available, then the average of these measurements (for 
continuous data) or the worst among these measurements (for categorical data) will be 
considered as the baseline value.  This same baseline value will be used for Treatment and 
PT Periods.
6.1.2
Study Days
Study days (days relative to the first dose of study drug) are calculated for each time point 
relative to the first dose of study drug.  Study Days are negative values when the time 
point of interest is prior to the first study drug dose day.  Study Days are positive values 
when the time point of interest is after the first study drug dose day.  There is no Study 
Day 0.  Study Day 1 is the day of the first dose of study drug.
Study Drug End Days
For all subjects who receive at least one dose of study drug, study drug end days (days 
relative to the last dose of study drug) are calculated relative to the last dose of study drug.  
The last day of study drug is defined as Study Drug End Day 0.  Days before it have 
negative study drug end days and days after it have positive study drug end days.


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Final Treatment Value
The final treatment value for each subject is the last non-missing measurement collected 
after Study Day 1 and on or before Study Drug End Day 2.
Final Post-Treatment Value
The final post-treatment value for each subject is the last non-missing measurement 
collected after Study Drug End Day 2, and on or before Study Drug End Day 999.
6.2
Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 2, 
Table 3, Table 4, and Table 5 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 blood sample collection date.
For visit windows of analyses of health-related quality of life (QoL) patient reported 
outcomes (PROs) collected throughout the study, Table 6 will be used.
For laboratory data and vital signs, the time windows specified in Table 2, Table 3, 
Table 4, and Table 7 describe how data are assigned to protocol specified time points 
during the Treatment and PT Periods.
If more than one assessment is included in a time window, the assessment closest 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.  The only exception to this is for the SVR 
windows (e.g., SVR4, SVR12, and SVR24); for these windows, 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 in analyses.  For summaries of 
shifts from baseline and potentially significant values, multiple values on the same day 
will not be averaged; all values will be considered for these analyses.


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Table 2.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 12-Week 
of Treatment
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 42
Week 8
56
43 to 63
Week 10
70
64 to 77
Week 12
84
78 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  Child-Pugh classification (for cirrhotic subjects only), FibroTest are collected at Screening and
Week 12 (or upon study discontinuation) and will use those visit windows as defined above.  FibroTest is also 
collected at baseline, only if not performed at the time of screening.
Table 3.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 8-Week of 
Treatment
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.


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Table 4.
Analysis Time Windows for HCV RNA, Resistance Endpoints, 
Laboratory Data, and Vital Sign (Treatment Period) for 6-Week of 
Treatment
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 1
7
2 to 10
Week 2
14
11 to 21
Week 4
28
22 to 35
Week 6
42
36 to 49
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.
Table 5.
Analysis Time Windows for HCV RNA, 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 77
Post-Treatment Week 12
84
78 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 378
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.


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Table 6.
Analysis Time Windows for PRO Instruments
Scheduled Visit
Nominal Day
(Study Day)
Time Window
(Study Days Range)
12-Week Treatment
Day 1/Baseline
1a
≤ 1a
Week 4
28
2 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
8-Week Treatment
Day 1/Baseline
1a
≤ 1a
Week 4
28
2 to 42
Week 8
56
43 to 70
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
6-Week Treatment
Day 1/Baseline
1a
≤ 1a
Week 4
28
2 to 35
Week 6
42
36 to 49
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 252
Post-Treatment Week 48
336
253 to 378
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
The last value within the window will be used to define the Final Treatment visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
c.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment visit 
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.  For visits during treatment, data must also be 
within 2 days of the last dose of study drug.  For post-treatment visits, data must also have Study Drug End 
Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug.


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Table 7.
Laboratory Data and Vital Sign 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 77
Post-Treatment Week 12
84
78 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 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 Post-Treatment Period visit.  Hematology, chemistry, urinalysis, and 
coagulation panels are collected at Post-Treatment Week 4 and 12 and will use visit windows defined above.  
Child-Pugh classification, fibro test are collected at Post-Treatment Week 12 and 48 (or upon study 
discontinuation) and will use those visit windows as defined above.
6.3
Missing Data Imputation
No data will be imputed for any efficacy or safety analyses except for analyses of the 
HCV RNA endpoints.  
HCV RNA values will be selected for the SVR12 analysis based on defined visit windows.  
When there is no HCV RNA value in a visit window based on defined visit windows, the 
closest values before and after the window, regardless of the value chosen for the 
subsequent and preceding window, will be used for the flanking imputation described 
below.
If a subject has a missing HCV RNA value at a post-Day 1 visit, but with undetectable or 
unquantifiable HCV RNA levels at both the preceding value and succeeding value, the 
HCV RNA level will be considered undetectable or unquantifiable, respectively, at this 
visit for this subject.  For SVR12 analysis, if there is no value in the appropriate window 


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after flanking imputation but there is an HCV RNA value after the window, then it will be 
imputed into the SVR12 window.  Similarly, for SVR24 analysis, if there is no value in the 
appropriate window after flanking imputation but there is HCV RNA value after the 
window, then it will be imputed into the SVR24 window.
If a subject starts another treatment for HCV, then all HCV RNA and PRO 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.
HCV RNA < LLOQ Analyses for SVR
If a subject is missing an HCV RNA value for the visit window associated with the 
analysis of SVR after performing the imputations described above, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value for this visit will be missing.  Subjects with missing HCV RNA data in the 
analysis window, after imputations, will be imputed as a failure.
HCV RNA Analyses for Relapse and Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure.
Missing Data Imputation for PRO Questionnaires
The handling of missing data for patient reported outcomes (PROs) will be as follows.  
The missing items of the FSS questionnaire will be imputed with the average score of the 
answered items as long as more than 50% of the items on the FSS are answered.  For EQ-
5D-5L index and VAS scores, no imputation will be performed for missing items.


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
Demographics, baseline characteristics, medical history, and previous/concomitant 
medications will be summarized for the safety population.
7.1
Demographic and Baseline Characteristics
Demographics include age, weight, and BMI as continuous variables, and sex, race, 
ethnicity, age category ([< 55 years or ≥ 55 years] and [< 65 or ≥ 65 years]), birth year 
(< 1945, 1945 to 1965, > 1965), country (Canada, New Zealand, Australia, and United 
Kingdom), and BMI category (< 30 kg/m2 or ≥ 30 kg/m2).
Baseline characteristics will include:  IL28B genotype ([CC, CT, or TT] and [CC or non-
CC]), prior treatment history (treatment naïve, pegIFN/RBV null-responder, pegIFN/RBV 
partial responder, SOF breakthrough/nonresponder, HCV therapy relapser, HCV 
relapse/breakthrough, HCV therapy nonresponder, pegIFN intolerant, and pegIFN 
experienced), baseline HCV RNA levels ([continuous (use log10 HCV RNA)] and 
[< 800,000 IU/mL or ≥ 800,000 IU/mL]), baseline HOMA-IR
(< 3 or ≥ 3 mU × mmol/L2), baseline IP-10 category (< 600 or ≥ 600 ng/L), baseline 
albumin (continuous), baseline albumin (< 35, ≥ 35 g/L), baseline platelet count 
(continuous, and < 90 × 109/L, ≥ 90 × 109/L), baseline alpha fetoprotein (continuous, and 
< 20 ng/mL, ≥ 20 ng/mL), baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, 
or F4), Child Pugh score (5, 6, or > 6), FibroTest Score, tobacco (user, ex-user, or non-
user) and alcohol (drinker, ex-drinker, or non-drinker) use status, history of diabetes, 
history of depression or bipolar disorder, history of hypertension, and history of 
cardiovascular disease other than hypertension. 
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.  


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Baseline Child-Pugh score is determined by the Day 1 assessment of ascites and hepatic 
encephalopathy along with the baseline values of total bilirubin, serum albumin, and 
international normalized ratio (INR).  The Child-Pugh score is the sum of the point 
assigned for each of the five observed findings as defined in Table 8.
Table 8.
Child-Pugh Classification of Severity of Cirrhosis
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2 (< 2)
34.2 – 51.3 (2 – 3)
> 51.3 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 – 35 (2.8 – 3.5)
< 28 (< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2 (or suppressed 
with medication)
Grade 3 or 4 (or 
refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores, 
FibroScan scores, or FibroTest scores.  Only one score will be used to categorize each 
subject even if a subject has more than one score recorded.  If a biopsy score is present, 
then it will be used to categorize the subject, regardless of the FibroScan/FibroTest score.  
Similarly, if a FibroScan score is present along with a FibroTest score, then the FibroScan 
score will be used to categorize the subject.  If biopsy and FibroScan scores are not 
present and more than one FibroTest result is available, then the Baseline FibroTest result 
(i.e., last non-missing FibroTest result on or before Day 1) will be used to categorize the 
subject.  Subjects will be categorized as F0 – F1, F2, F3, or F4 according to Table 9.


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Table 9.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, 
Batts-Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan 
(kPa)
FibroTest
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥ 8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 14.6
0.59 to 0.72
F4
4
≥ 5
≥ 14.6
≥ 0.73
Summary statistics (N, mean, median, standard deviation (SD), and range) will be 
generated for continuous variables (e.g., age and BMI).  The number and percentage of 
subjects will be presented for categorical variables (e.g., sex and race).
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF.  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 
than one condition/diagnosis within a body system will be counted only once for that 
body system.
7.3
Previous Treatment and Concomitant Medications
Prior and concomitant medications will be summarized.  A prior medication is defined as 
any medication taken prior to the date of the first dose of study drug 
(Ombitasvir/ABT-450/r or SOF).  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 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 (maximum) dose of study drug.  
Concomitant medications will be summarized for all subjects in the Safety population.  
The number and percentage of subjects taking prior or concomitant medications will be 


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summarized by generic drug name based on the WHO Drug Dictionary.  Note that prior 
HCV medications (pegIFN and RBV, SOF) will be summarized separately from other 
prior medications.
Medications for the treatment of HCV will be collected in the PT Period and will be 
summarized for each treatment arm by generic drug name.  A post-treatment medication 
for the treatment of HCV is defined as any medication taken on or after the last 
(maximum) dose of study drug and entered as "Post treatment HCV medications" on the 
eCRF.
8.0
Patient Disposition
The number of subjects for 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;
●
Subjects who completed study drug;
●
Subjects who discontinued from study drug; 
●
Subjects who completed the study;
●
Subjects who discontinued from the study.
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.  Similar 
summaries will be provided for discontinuations from the study.
The number and percentage of all subjects as applicable will be summarized by treatment 
arm for:
●
Subjects with interruptions of all study drugs for toxicity management;
●
Subjects with any RBV dose modifications;
○
Subjects with RBV dose modification due to decrease in hemoglobin;


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○
Subjects with RBV dose modification due to decrease in creatinine 
clearance;
○
Subjects with RBV dose modification due to other reasons;
○
Subjects with any RBV dose modifications to 0 mg (i.e., RBV 
interruptions).
Reasons for study drug interruptions and RBV dose modifications 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 in 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. 
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will 
be presented.  Study drug duration also will be summarized with frequencies and 
percentages using the following categories:
●
1 to 15 days
●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days
●
> 90 days


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In addition, the number and percentage of subjects with a study drug duration of ≥ 77 days 
for Arm A, B, E and F, ≥ 49 days for Arm C, and ≥ 38 days for Arm D will be 
summarized.
9.2
Compliance
At each protocol-specified visit, the total number of tablets dispensed and returned is 
recorded for each type of study drug.  The compliance for each study drug 
(Ombitasvir/ABT-450/r, SOF, and RBV, if applicable) within the Treatment Period will 
be calculated as the percentage of tablets taken relative to the total tablets, respectively, 
expected to be taken.  The total number of tablets prescribed 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 – date of first dose + 1 day).  Study 
drug interruptions due to an adverse event or other planned interruptions recorded on the 
eCRF will be subtracted from the duration.  A subject is considered to be compliant if the 
percentage is between 80% and 120%.  Compliance will be calculated for each subject 
and summarized with the mean, median, standard deviation, minimum, and maximum.  In 
addition, the percentage of compliant subjects will be calculated for each study drug and 
each treatment arm.
10.0
Efficacy Analysis
10.1
General Considerations
Analyses will be performed on the intent-to-treat (ITT) population.  Sensitivity analyses 
of the primary endpoint, when applicable, will be performed on the mITT-GT-VF 
population specified in Section 5.1.1.
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 TaqMan® real-time reverse transcriptase-PCR (RT-


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PCR) assay v.2.0.  For this assay, the lower limit of quantitation (LLOQ) is 25 IU/mL 
regardless of genotype, and the lower limit of detection (LLOD) varies by genotype.  For 
GT3, the lower limit of detection (LLOD) is 20 IU/mL; for GT2, LLOD is 20 IU/mL.  
HCV RNA results that are detectable but not quantifiable are reported as "< 25 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 
< 25 IU/mL, including values reported as "HCV RNA not detected" or "< 25 IU/mL HCV 
RNA detected."  HCV RNA ≥ LLOQ are all quantifiable values of 25 IU/mL or greater.
IL28B rs12979860 will be resulted as C/C, C/T, or T/T by the central laboratory.
Definitions for Efficacy Endpoints
Note that a confirmed quantifiable post-treatment value is defined as two consecutive 
post-treatment HCV RNA measurements ≥ LLOQ.  During treatment, a confirmed 
quantifiable value is defined as any two consecutive HCV RNA values ≥ LLOQ, either 
both during treatment or at the final treatment measurement and the next consecutive post-
treatment measurement.
Breakthrough = confirmed HCV RNA ≥ LLOQ after HCV RNA < LLOQ during 
treatment, or confirmed increase from nadir in HCV RNA (two consecutive HCV RNA 
measurements > 1 log10 IU/mL above nadir) at any time point during treatment.  A single 
breakthrough value (≥ LLOQ or > 1 log10 IU/mL above nadir) followed by lost to follow-
up will be considered a breakthrough (i.e., will not require confirmation).
On-treatment virologic failure = breakthrough or failure to suppress during treatment 
(all on-treatment values of HCV RNA ≥ LLOQ) with at least 6 weeks (defined as study 
drug duration ≥ 36 days) of treatment for 12-week and 8-week treatment or at least 
26 days of treatment for 6-week treatment.
RVR (rapid virologic response) = HCV RNA < LLOQ in the Week 4 window.


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EOTR (end of treatment response) = HCV RNA < LLOQ in the Week 12 window for 
12-week regimen, Week 8 window for 8-week regimen, and Week 6 for 6-week regimen.
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window. 
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of active study drug (up to and including the SVR12 assessment time 
point) for a subject with HCV RNA < LLOQ at Final Treatment Visit who completes 
treatment, excluding re-infection as described below.
Relapse24 = confirmed HCV RNA ≥ LLOQ during SVR24 window among subjects who 
achieved SVR12 and have data available during the SVR24 window, excluding re-
infection.
Relapselate = confirmed HCV RNA ≥ LLOQ at any time after the SVR24 assessment time 
point for a subject who achieved SVR24 and has post-SVR24 HCV RNA data available, 
excluding re-infection.
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 completes treatment.  Completion of 
treatment is defined as a study drug duration ≥ 37 days, ≥ 49 days and ≥ 77 days for 
planned treatment duration of 6 week, 8 weeks and 12 week, respectively.  Also, include a 


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summary of Relapseoverall for subjects who prematurely discontinued treatment, excluding 
re-infection.
For relapse analyses, the completion of treatment is defined as above.  If the last available 
post-treatment value is ≥ LLOQ, then the subject will be considered a relapse (i.e., will 
not require confirmation).  Relapse analyses will exclude subjects who do not have any 
post-treatment HCV RNA values. 
HCV re-infection 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.  Re-infection in the case of the same HCV subtype is defined as a clade 
switch, as indicated by the lack of clustering between the baseline and post-treatment 
sequences by phylogenetic analysis.  If phylogenetic analysis is not possible due to 
technical difficulties, HCV re-infection may be determined with a confirmed HCV 
genotype or subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
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 
(duration < 77 days, < 49 days, and < 38 days for 12 week, 8 week, and 6 week 
treatment regimens) and did not meet the On-treatment virologic failure 
definition);


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4.
HCV re-infection (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 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], 
such as a subject with a single quantifiable value within the SVR12 window 
followed by an undetectable value beyond the SVR12 window).
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);
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 
[duration < 154 days] and did not meet the On-treatment virologic failure, 
Relapse12, or Relapse24 definitions);
5.
HCV re-infection;
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window, 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]).


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10.2
Handling of Multiplicity
No multiplicity issue applicable in this study.
10.3
Primary Efficacy Analysis
The primary endpoint is the percentage of subjects with SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drugs).  The number and percentage of 
subjects achieving SVR12 will be calculated for each treatment arm and 2-sided 95% 
Wilson score confidence intervals for a binomial proportion will be computed by 
treatment arm.
10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
The percentage of subjects in each treatment arm and across all treatment arms 
with on-treatment virologic failure (breakthrough defined as confirmed HCV 
RNA ≥ LLOQ after HCV RNA < LLOQ during treatment, or confirmed 
increase from nadir in HCV RNA at any time point during treatment, or failure 
to suppress during treatment (all on-treatment values of HCV RNA ≥ LLOQ) 
with at least 6 weeks (defined as active study drug duration ≥ 36 days) of 
treatment for 12-week and 8-week treatment or at least 26 days of treatment 
for 6-week treatment.
●
The percentage of subjects with post-treatment relapse (relapse12 defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of active study drug (up to and including the SVR12 assessment 
time point) for a subject with HCV RNA < LLOQ at Final Treatment Visit 
who completes treatment.  Completion of treatment is defined as study drug 
duration ≥ 77 days, 49 days and 38 days for 12-week, 8-week, and 6-week of 
treatment, respectively.
The numbers and percentages of the subjects with virologic failure during treatment and 
with post-treatment relapse will be calculated for each arm.  The corresponding 2-sided 
95% Wilson score confidence intervals for a binomial proportion will be calculated.


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10.5
Sensitivity Analysis
A sensitivity analysis for the primary efficacy endpoint as described in Section 10.3 will 
be conducted using mITT-GT-VF population defined in Section 5.1.1.
10.6
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized and analyzed for each 
treatment arm:
●
All reasons for not achieving SVR12 for subjects who do not achieve SVR12;
●
Number and percentage with unquantifiable HCV RNA at each post-baseline 
visit throughout the Treatment Period (using data from the central laboratory 
as observed, i.e., no imputation for missing data);
●
The percentage of subjects with HCV RNA < LLOQ 24 weeks after the last 
actual dose of study drug (SVR24);
●
All reasons for not achieving SVR24 for subjects who do not achieve SVR24.
●
Time to suppression of HCV RNA (defined as the study day of the first of 
two successive HCV RNA < LLOQ) during the Treatment Period.
In the above analyses that use the number and percentage of responders, the rates and 
2-sided 95% Wilson score confidence interval for a binomial proportion will be 
calculated.
For HCV RNA levels, the time to suppression during treatment will be calculated for each 
subject, and the median time will be estimated using Kaplan-Meier methodology for right 
censored observations.
Imputations for missing data will be performed as described in Section 6.3 for analyses of 
SVR, RVR, and EOTR 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.


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The number and percent of subjects who fail to suppress HCV RNA and received at least 
6 weeks of treatment (active study drug duration ≥ 38 days) will be tabulated along with 
the subject numbers corresponding to the subjects who failed to suppress.
The number of subjects who breakthrough at any time during treatment and within each 
protocol-specified visit (defined in Table 2, Table 3, and Table 4) will be summarized
along with a corresponding listing displaying the subject numbers at the first occurrence 
of breakthrough.
The number of completers (defined as study drug duration ≥ 77 days, ≥ 49 days, ≥ 38 days 
for 12-week, 8-week, 6-week of treatment, respectively) with final on treatment HCV 
RNA < LLOQ who relapse within the SVR4 window, within the SVR12 window, within 
the SVR24 window (defined in Table 5), and anytime post-treatment (study drug end day 
≥3) will be summarized along with a corresponding listing displaying the first occurrence 
of relapse.  A similar table and listing will be provided of Preterm Relapses for subjects 
who do not complete treatment (defined as study drug duration < 77 days, < 49 days, 
< 38 days for 12-week, 8-week, 6-week of treatment, respectively) with HCV RNA 
< LLOQ at the Final Treatment visit.
The concordance between SVR12 and SVR24 will be assessed by agreement between 
SVR12 and SVR24 and by the positive predictive value (PPV) and the negative predictive 
value (NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is defined as 
the number of subjects achieving both SVR12 and SVR24 and the number of subjects not 
achieving both SVR12 and SVR24 out of all subjects in the ITT population.  The PPV of 
SVR12 on SVR24 is the proportion of subjects who achieve SVR24 out of all subjects who 
achieved SVR12.  The NPV of SVR12 on SVR24 is the proportion of subjects who do not 
achieve SVR24 out of all subjects who do not achieve SVR12.
10.7
Resistance Analyses
If possible, subjects treated with study drug during the Treatment Period who experience 
virologic failure will have resistance testing conducted if 1) they have on-treatment 


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breakthrough; 2) if they have post-treatment relapse (irrespective of the time of relapse), 
with a study drug duration ≥ 77 days, 49 days and 38 days for 12-week, 8-week, and 
6-week of treatment, respectively; or 3) if they have at least 6 weeks of treatment and fail 
to suppress by Week 6 (i.e., meet virologic stopping criteria).  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 HCV subtype, IL28B genotype, reason 
for non-response, time point(s) sequenced as closest to time of VF, and HCV RNA value 
at the VF time point(s) will be produced for these subjects.  In addition, all listings 
described below will display HCV subtype and reason for non-response in the subject 
identifier for each subject.  A separate listing will delineate all subjects in the PVF 
population for whom no sequencing was performed (e.g., lost to follow-up while HCV 
RNA ≤ 1000 IU/mL).  Subjects treated with study drugs who do not achieve SVR12 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 sequenced.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore if the HCV 
RNA level at the time of virologic failure (VF) or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after the failure/discontinuation with an HCV 
RNA level ≥ 1000 IU/mL will be used if available.  Next generation sequencing (NGS) of 
a given target will be performed only if no variants are detected at signature amino acid 
positions by population sequencing in that sample.  Included time points for analyses on 
subjects in the PVF and non-PVF population are:  1) time of virologic failure/treatment 
discontinuation or sample closest in time after failure/discontinuation with an HCV RNA 
level of ≥ 1,000 IU/mL, 2) 24 weeks post-DAA treatment, provided that resistance-
associated variants were detected by either population sequencing or NGS at the time of 
failure/discontinuation, and 3) 48 weeks post-DAA treatment, provided that resistance-
associated variants were detected by either population sequencing or NGS at 24 weeks 
post-DAA treatment.  For these samples, NGS will be performed on a given target only if 
no variants are detected at signature amino acid positions by population sequencing.


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The regions of interest for population sequencing and NGS for all samples from subjects 
who do not achieve SVR12 are those encoding complete NS3/4A, NS5A, and NS5B.  The 
regions encoding NS3 amino acids 1 – 181, NS5A amino acids 1 – 215, and NS5B amino 
acids 1 – 591 will be sequenced for analysis of baseline samples from the SVR-achieving 
subjects.  An appropriate prototypic reference sequence will be used for comparison with 
sequences from samples.
The following are considered signature amino acid positions in genotypes 2 and 3:  36, 
43, 54, 55, 56, 80, 155, 156, 166 (GT3 only), 168 in NS3; 24, 28, 29, 30, 31, 32, 58, 92, 
93 in NS5A; and 142, 159, 237, 282, 289, 320, 321 in NS5B.
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant (by population 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 (NS3, NS5A, or NS5B).
●
Post-baseline variant by population sequencing:  an amino acid variant in a 
post baseline time point sample that was not detected at baseline in the subject.
●
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 (for 
NGS, detectable at 2% detection threshold).
●
Emerged variant:  a post-baseline variant that is observed in 2 or more subjects 
of the same subtype by population sequencing or NGS.
●
Linked variant by population sequencing:  2 or more signature or emerged 
amino acid variants identified within a target by population sequencing, and no 
mixture of amino acids is detected at either position.
Analysis will be performed separately for each HCV subtype and study arms within each 
listing.
Analysis 1:  The following analyses will be performed for all subjects:


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●
A listing of all baseline variants at signature amino acid positions for each 
DAA target (NS3, NS5A and NS5B) (ITT population).
●
Listing of all baseline variants at non-signature amino acid positions for 
subjects in PVF population.
●
The number and percentage of subjects with each baseline variant at a 
signature amino acid position within each target out of the total number of 
baseline samples that were sequenced will be provided (ITT population). This 
table includes prevalence of each baseline variant, and a summary of number 
of subjects with variants in NS3 only, in NS5A only, in NS5B only, any in 
NS3, any in NS5A, any in NS5B, any in NS3 or NS5A or NS5B, any in NS3 
+ NS5A, any in NS3 + NS5B, any in NS5A + NS5B, any in NS3 + NS5A 
+ NS5B.
Analysis 2:  The impact of baseline variants on treatment outcome will be assessed 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.  Subjects in the non-
PVF population will be excluded from this analysis.  Analysis will be grouped by 
(1) study Arm, (2) HCV subtype, (3) DAA target (NS3, NS5A or NS5B).
●
Variants at signature amino acid positions (vs no variant at that position).
●
Each variant at signature amino acid position (vs not that variant).
●
Variants at non-signature amino acid positions (vs no variant at that positions).
Analysis 3:  The following analyses will be performed for subjects in the PVF and non-
PVF populations who have post-baseline resistance data available.
For analysis by population sequencing, the following tables will be provided:
●
Listings by subject of all post baseline variants relative to the baseline amino 
acid sequence will be provided for each DAA target (NS3, NS5A and NS5B).  
●
Listings by subject of all emerged variants, by amino acid position and 
variants within a DAA target in a post-baseline sample relative to the baseline 
amino acid sequence will be provided for each DAA target.  


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●
Listings by subject of all post-baseline variants at signature amino acid 
positions relative to the appropriate prototypic reference amino acid sequences 
will be provided for each DAA target (NS3, NS5A and NS5B).
●
A listing by subject and time point of the linked variants by population 
sequencing for each target will be provided.
For analysis by NGS, the following tables will be provided:
●
Listings by subject of all variants at signature amino acid positions in a post-
baseline time point for each DAA target (NS3, NS5A and NS5B).
10.8
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  
EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L) and Fatigue 
Severity Scale (FSS).  Missing data for each measurement will be handled as described in 
Section 6.3.
The following exploratory analyses of PROs will be performed:
●
mean change from baseline in EQ-5D-5L health index score and its VAS score 
to each applicable post-baseline time point;
●
mean change from baseline in the FSS score and its VAFS score to each 
applicable post-baseline time point.
Subject's responses to the EQ-5D-5L 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-5L states will be 
converted into a single preference-weighted health utility index score by applying 
country-specific weights (if available) or US weights (if not available).  The VAS score 
will be measured separately.
The FSS measures the impact of fatigue over the past week on specific types of 
functioning.  The survey consists of 9 questions using a 7-point Likert scale.  A total score 


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is calculated as the average of the individual item responses (adding up all the answers 
and dividing by nine).  Subjects also rate their perception of their fatigue on a separate 
visual analogue fatigue scale (VAFS).  Higher FSS scores indicate a higher degree of 
impact of fatigue.
Summary statistics (n, mean, SD, median, minimum and maximum) for the mean change 
from baseline to each applicable visit will be provided for the EQ-5D-5L index and its 
VAS scores, the FSS score and its VAFS scores.
11.0
Safety Analysis
11.1
General Considerations
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.  Safety data will be summarized for each treatment arm using the safety 
population. 
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent adverse events are defined as any event that begins or 
worsens in severity after initiation of study drug through 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).
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events
Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) by treatment arm according to the version 
of the MedDRA coding dictionary used for the study at the time of database lock.  The 


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actual version of the MedDRA coding dictionary used will be noted in the clinical study 
report.  The system organ classes will be presented in alphabetical order and the preferred 
terms will be presented in alphabetical order within each system organ class. 
Adverse Event Overview
An overview of adverse events will be presented consisting of the number and percentage 
of subjects experiencing at least one event for the following adverse event categories:
●
Any treatment-emergent adverse event;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs (Ombitasvir/ABT-450/r);
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV (applicable for RBV-containing arms);
●
Severe treatment-emergent adverse events;
●
Serious treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modification 
(applicable for RBV-containing arms);
●
Treatment-emergent adverse events leading to death;
●
Deaths.
The adverse event overview summary will be provided for each treatment arm.
Adverse Event by SOC and PT
The following summaries of adverse events will be generated by treatment arm:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs (Ombitasvir/ABT-450/r);


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●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV;
●
Serious treatment-emergent adverse events;
●
Moderate or severe treatment-emergent adverse events;
●
Severe treatment-emergent adverse events;
●
Grade 3 or 4 (see definition below) treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug; 
Treatment-emergent adverse events leading to RBV dose modification;
●
Treatment-emergent adverse events leading to death;
●
Treatment-emergent adverse events leading to concomitant medication use 
(events with other action taken of "concomitant medication prescribed").
For all adverse event summaries, the number and percentage of subjects experiencing 
treatment-emergent adverse events will be tabulated according to SOC and PT.  Subjects 
reporting more than one adverse event for a given PT will be counted only once for that 
term (most severe incident for the severity tables and most related incident for the 
relationship tables).  Subjects reporting more than one adverse event within a SOC will be 
counted only once for that SOC.  Subjects reporting more than one adverse event will be 
counted only once in the overall total.
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 Event by PT
The number and percentage of subject experiencing treatment-emergent adverse events 
will be tabulated according to preferred term and sorted by overall frequency for the total 
number of subjects in each treatment arm.  Similar summaries will be provided for 
moderate to severe treatment-emergent adverse events and treatment-emergent adverse 
events with a "reasonable possibility" of being related to DAAs.  These summaries will 
display for each treatment group and be sorted by overall total.


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Adverse Event of Special Interest
Specific treatment-emergent adverse events of special interest, which may be searched 
using Standardized or Company MedDRA Queries, will be summarized and include 
severe cutaneous reactions and anemia.  The search criteria for the adverse event of 
interest are as follows:
●
Severe Cutaneous Reactions
SMQ "Severe cutaneous adverse reactions" (narrow search)
●
Anemia
SMQ "Haematopoietic erythropenia" (broad search) plus the following 
preferred terms:
Haemolytic anaemia,
Coombs negative haemolytic anaemia,
Coombs positive haemolytic anaemia.
For each adverse event of interest (severe cutaneous reactions and anemia), the number 
and percentage of subjects experiencing at least one treatment-emergent adverse event in 
the search for the event of interest will be presented for each treatment arm and overall 
and by SOC and PT.
A listing of treatment-emergent adverse events for subjects meeting the search criterion 
will be provided for the adverse event of special interest.
Adverse Event by Maximum Severity
Treatment-emergent adverse events and treatment-emergent adverse events with a 
"reasonable possibility" of being related to DAAs will be summarized by maximum 
severity of each preferred term.  If a subject has an adverse event with unknown severity, 
then the subject will be counted in the severity category of "unknown," even if the subject 
has another occurrence of the same event with a severity present.  The only exception is if 
the subject has another occurrence of the same adverse event with the most extreme 
severity – "Severe."  In this case, the subject will be counted under the "Severe" category.


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Adverse Events by Maximum Severity Grade Level
Treatment-emergent adverse events will be summarized by maximum severity grade level 
of each preferred term.  Each preferred term will be assigned to a grade level based on 
severity and seriousness, adapted from the Division of AIDS (DAIDS) table for grading 
severity of adverse events.  All serious adverse events will be categorized as Grade 4.  
Nonserious adverse events categorized by the investigators as mild, moderate, or severe 
will be categorized as Grade 1, Grade 2, or Grade 3, respectively.  If a subject has a 
nonserious adverse event with unknown severity, then the subject will be counted in the 
severity grade level category of "unknown," even if the subject has another occurrence of 
the same event with a severity present.  The only exception is if the subject has another 
occurrence of the same adverse event with the most extreme severity – "Severe."  In this 
case, the subject will be counted under the "Grade 3" category.  Similarly, if a subject has 
an adverse event with unknown seriousness, then the subject will be counted in the 
severity grade level category of "unknown" unless the subject has another occurrence of 
the same adverse event that is marked serious.  In this case, the subject will be counted 
under the "Grade 4" category.
Adverse Event by Maximum Relationship
Treatment-emergent adverse events also will be summarized by maximum relationship of 
each preferred term to study drug (DAA), as assessed by the investigator.  If a subject has 
an adverse event with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same adverse event with a relationship assessment of "Reasonable 
Possibility."  In this case, the subject will be counted under the "Reasonable Possibility" 
category.
11.2.2
Listing of Adverse Event
Listings of all serious adverse events (from the time the subject signed the study-specific 
informed consent through end of study), treatment-emergent serious adverse events, 


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treatment-emergent adverse events leading to death, treatment-emergent adverse events 
leading to discontinuation of study drug, treatment-emergent adverse events leading to 
RBV dose modifications, treatment-emergent adverse events leading to study drug 
interruptions, and treatment-emergent adverse events of special interest will be provided.
11.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional lab testing due to 
all SAEs will be used in all analysis.
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, absolute neutrophil count (ANC), reticulocyte count, PT/INR, 
and activated partial thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, serum glutamic pyruvic transaminase (SGPT/ALT), serum glutamic 
oxaloacetic transaminase (SGOT/AST), alkaline phosphatase, sodium, potassium, 
calcium, inorganic phosphorus, uric acid, cholesterol, total protein, glucose, triglycerides, 
albumin, chloride, bicarbonate, magnesium, gamma glutamyl transferase (GGT), and 
creatinine clearance (Cockcroft-Gault calculation), calculation of estimated glomerular 
filtration rate (eGFR) using the modification of diet in renal disease (MDRD) equation as 
defined below, alpha2-macroglobulin, haptoglobin, and apolipoprotein A1.
Urinalysis variables include:  specific gravity, ketones, pH, protein, blood, glucose, 
urobilinogen, bilirubin, leukocyte esterase, albumin, and microscopic (reflexly performed 
if other variables are abnormal).
Additional variables are total insulin and IP-10.
The following calculation is used by the central lab for eGFR by MDRD, where serum 
creatinine is measured in mg/dL and age is measured in years: 


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GFR (mL/min/1.73 m2) = 175 × Serum Creatinine (–1.154) × Age (–0.203) × 1.212 (if Black) 
× 0.742 (if Female).
The central lab calculates the estimated creatinine clearance (CrCl) based on the following 
Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum 
creatinine (mg/dL) × 72].
The Criteria for Potentially Clinically Significant (PCS) Laboratory Findings are 
described in Table 10 and Table 11.  Note that a post-baseline value must be more 
extreme than the baseline value to be considered a PCS finding.


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Table 10.
Criteria for Potentially Clinically Significant Hematology Values
Test/Units
Very Low (VL)
Very High (VH)
Hemoglobin
(mmol/L)
< 4.9
(g/dL)
< 8.0
(g/L)
< 80
Platelets Count
(cells/mm3)
< 50,000
(cells/L)
< 50 × 109
White Blood Cell Count
(cells/mm3)
< 2000
> 20,000
(cells/L)
< 2.0 × 109
> 20 × 109
Absolute Neutrophil Count
(cells/mm3)
< 1000
(cells/L)
< 1 × 109
Lymphocyte Count
(cells/mm3)
< 500
(cells/L)
< 0.5 × 109
Eosinophil Count 
(cells/mm3)
> 5000
(cells/L)
> 5 × 109
aPTT
> 2 × ULN
International Normalized Ratio
> 2 × ULN
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.


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Table 11.
Criteria for Potentially Clinically Significant Chemistry Values
Test/Units
Very Low (VL)
Very High (VH)
ALT/SGPT
> 5 × ULN and ≥ 2 × baseline
AST/SGOT
> 5 × ULN and ≥ 2 × baseline
Alkaline Phosphatase
> 1.5 × ULN
Total Bilirubin (mg/dL)
≥ 2.0 × ULN
Creatinine
(mcmol/L)
≥ 132.605
(mg/dL)
≥ 1.5
Creatinine Clearance (mL/min)
< 50
BUN
> 5 × ULN
Uric Acid
(mcmol/L)
> 713.817
(mg/dL)
> 12.0
Phosphate
(mmol/L)
< 0.6
(mg/dL)
< 2.0
Calcium, Serum
(mmol/L)
< 1.75
> 3.1
(mg/dL)
< 7.0
> 12.5
Sodium (mmol/L)
< 130
> 155
Potassium (mmol/L)
< 3.0
> 6.0
Magnesium
(mmol/L)
< 0.4
> 1.23
(mg/dL)
< 0.9
> 3.0
Glucose
(mmol/L)
< 2.2
> 13.9
(mg/dL)
< 40
> 250
Albumin
(g/L)
< 20
(g/dL)
< 2


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Table 11.
Criteria for Potentially Clinically Significant Chemistry Values 
(Continued)
Test/Units
Very Low (VL)
Very High (VH)
Protein
(g/L)
< 50
(g/dL)
< 5.0
Cholesterol
(mmol/L)
> 10.34
(mg/dL)
> 400
Triglycerides
(mmol/L)
> 5.7
(mg/dL)
> 500
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.
11.3.2
Statistical Methods
Clinical laboratory tests will be summarized at each visit during the Treatment Period.  
The baseline value will be the last measurement on or before the day of the first dose of 
study drug.  This same baseline value will be used for all change from baseline tables in 
the Treatment Period and Post-Treatment Periods.
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 with the baseline mean, visit mean, change from baseline mean, 
standard deviation, and median.
Laboratory data values will be categorized as low, normal, or high based on normal 
ranges of the laboratory used in this study.  Shift tables from baseline to minimum value, 
maximum value, and final values during the Treatment Period (Study Drug End Day ≤ 2) 
will be created for each treatment arm.  The shift tables will cross tabulate the frequency 
of subjects with baseline values below/within/above the normal range versus 
minimum/maximum/final values below/within/above the normal range.


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The number and percentage of subjects with post-baseline values during the Treatment 
Periods meeting the specified criteria for Potentially Clinically Significant (PCS) 
laboratory values (defined in Table 10 and Table 11) 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 lab values 
for the subjects meeting PCS criteria during treatment.
For hemoglobin and the liver function tests (LFTs) of alkaline phosphatase, and total 
bilirubin, the number and percentage of subjects with a maximum Common Terminology 
Criteria for Adverse Events (CTCAE) Grade of 1, 2, 3, or 4 (see definitions in Table 12) 
at any post-baseline visit (regardless of the baseline value) through the end of treatment 
(i.e., Final Treatment Value) will be summarized for each treatment arm.  All LFT tables 
will include summary rows for the number and percentage of subjects with at least 
Grade 2 and at least Grade 3 laboratory abnormalities.  The hemoglobin table will include 
a summary row for the number and percentage of subjects with at least a Grade 2 
laboratory abnormality.
For the liver function tests (LFTs) of ALT and AST, the number and percentage of 
subjects in with a maximum CTCAE Grade of 1, 2, 3, or 4 (see definitions in Table 12) at 
any post-nadir visit (regardless of the baseline value) through the end of treatment 
(i.e., Final Treatment Value) will be summarized for each treatment arm.  Note, for these 
analyses, the nadir is used for reference instead of baseline.  Both ALT and AST tables 
will include summary rows for the number and percentage of subjects with at least 
Grade 2 and at least Grade 3 laboratory abnormalities.
Accompanying listings of all ALT, AST, total, indirect and direct bilirubin, and alkaline 
phosphatase will be created for any subject who had at least a Grade 3 ALT, AST, 
alkaline phosphatase, or total bilirubin.  A listing of the hematology results will be 
provided for subjects with at least Grade 2 hemoglobin abnormalities.


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Table 12.
Definitions of CTCAE Grades 1, 2, 3, and 4
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin Decreased
< LLN – 100 g/L
< 100 – 80 g/L
< 80 – 65 g/L
< 65 g/L
The number and percentage of subjects in each treatment arm with maximum on treatment 
lab values meeting the following criteria will be summarized:
●
Post nadir ALT ≥ 3 × ULN and  post baseline total bilirubin value ≥ 2 × ULN;
●
Post nadir ALT > 5 × ULN (equivalent to Grade 3 or higher) and post baseline
total bilirubin value < 2 × ULN.
A subject or event will be counted if the post-nadir ALT or AST laboratory values meet 
the above criteria regardless of the baseline laboratory value (i.e., the post nadir laboratory 
value does not need to be worse than the baseline laboratory value).  The maximum ratio 
relative to the ULN will be used to determine if subjects meet the criteria listed above. 
For subjects meeting the ALT ≥ 3 × ULN and total bilirubin value ≥ 2 × ULN criterion 
during the Treatment Period, a corresponding listing of all ALT, AST, alkaline 
phosphatase, and total, direct, and indirect bilirubin values will be provided.
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality (if Applicable)
Vital sign variables are body temperature (oral), 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 13.


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Table 13.
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
Heart 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
Temperature
> 38.3°C AND
An increase of ≥ 1.1°C from baseline
11.4.2
Statistical Methods
Vital signs will be summarized at each visit during the Treatment and Post-Treatment 
Periods.  The baseline value will be the last measurement on or before the day of the first 
dose of study drug.  This same baseline value will be used for all change from baseline 
tables in the Treatment and Post-Treatment Periods.
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 post baseline values during the Treatment 
Period meeting Criteria for Potentially Clinically Significant Vital Sign Values (Table 13) 
will be summarized for each treatment arm.  A post-baseline value must be more extreme 
than the baseline value to be considered as a PCS finding.  A separate listing will be 
provided that presents all of the vital sign values for the subjects meeting the PCS vital 
sign criteria during treatment.


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12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP
1.
Updates were made to the resistance analysis plan to be consistent across the HCV 
program.
12.2
Summary of Changes from SAP Version 1.0
1.
Resistance analyses were updated to incorporate the following changes:
a.
Added signature amino acid positions in genotypes 2 – 3.
b. Resistance analysis will be conducted at 2% instead of 1% detection 
threshold to reduce reporting of variants considered as "noise."
c.
Updated analyses for each HCV subtype and study arms within each 
listing. 
2.
Updated analysis interval of exposure and the definition of EOTR to fit all arms 
with different treatment duration.
3.
Corrected the title of Table 5.
4.
Added re-infection to be consistent across the HCV program. 
13.0
References
1.
Szende A, Williams A, editors.  Measuring self-reported population health:  an 
international perspective based on EQ-5D-5L.  EuroQol Group Monographs 
Volume 1.  SpringMed, 2004.
2.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L User Guide:  Basic Information on 
How to Use the EQ-5D-5L Instrument, Version 1.0.  April 2011.