Clinical trial NCT02219490
Conditions: Chronic Hepatitis C Virus (HCV) Infection Genotype 1
Keywords: Hepatitis C Genotype 1 Compensated Cirrhosis Cirrhosis Naive Hepatitis C Hepatitis C Virus Treatment-Experienced Relapser Null responder Non responder
Sponsor: AbbVie
Start date: 2014-10-30; Completion date: 2021-05-13
Enrollment: 1596 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the effect of treatment with ABT-450 co-formulated with ritonavir and ABT-267 (ABT-450/r/ABT-267) and ABT-333; 3-DAA regimen, with or without ribavirin (RBV) in adults with chronic hepatitis C virus genotype 1 (HCV GT1) infection.

Detailed description:
This study (TOPAZ-I; M14-423), was a Phase 3b, open-label, multicenter study conducted outside of the United States which, together with its companion study TOPAZ-II (M14-222; NCT 02167945) conducted in the United States, was designed with the primary objective of assessing the effect of treatment response on long-term clinical outcomes in adults with chronic HCV GT1 infection with or without compensated cirrhosis, who were either treatment-naïve or interferon/ribavirin (IFN/RBV) treatment- experienced. In both studies, participants were treated with the 3-DAA regimen with or without RBV. This study consisted of a screening period of up to 42 days, a treatment period of either 12 weeks for HCV GT1a-infected subjects without cirrhosis and for HCV GT1b-infected subjects without cirrhosis or with compensated cirrhosis or 24 weeks for GT1a-infected participants with compensated cirrhosis, and a 260-week post-treatment period.

Arms: arm 1: Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.
Interventions: intervention 1: ABT-450/r/ABT-267 intervention 2: ABT-333 intervention 3: Ribavirin (RBV)
Intervention descriptions: intervention 1: Tablet for oral use intervention 2: Tablet for oral use intervention 3: Ribavirin was provided as 200 mg tablets, and dosed based on weight,1000 to 1200 mg divided twice daily per local label. For example, for participants weighing \< 75 kg, RBV may have been taken orally as 2 tablets in the morning and 3 tablets in the evening which corresponds to a 1000 mg total daily dose. For participants weighing ≥ 75 kg, RBV may have been taken orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 1200 mg total daily dose.

Protocol documents:
Prot_000.pdf: 
NCT02219490


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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1.1
Protocol Amendment:  Summary of Changes
The purpose of this amendment is to:
●
Update the treatment duration for subjects with GT1a infection and 
compensated cirrhosis (F4 fibrosis stage) from 12 to 24 weeks, with 12 weeks 
considered for some patients where consistent with the local label.
Rationale:  To align the treatment duration for these subjects with that 
recommended in the prescribing information of section of the approved local 
product labels in countries where the AbbVie product containing the regimen 
for this study (i.e., ABT-450/r/ABT-267 and ABT-333) has received marketing 
authorization.
●
Update Introduction to remove language detailing effects of 
ABT-450/ritonavir, ABT-267 (and it major, inactive human metabolites) and 
ABT-333 on embryo-fetal development.
Rationale:  Results of embryo-fetal toxicity studies are described in the locally 
approved labels and in the investigator brochures.
●
Update Introduction to refer investigators to locally approved labels for 
preclinical toxicology (including reproductive and development toxicity), 
metabolism, pharmacokinetics and drug-drug interactions in countries that 
have received marketing approval.
●
Clarify elevated ALT risk associated with ethinyl estradiol therapy in 
Section 3.0 Introduction; Integrated Safety Results.
Rationale:  AbbVie re-evaluated data on grade 3 or higher post-baseline 
serum ALT values in subjects and identified concurrent use of ethinyl estradiol 
as a risk factor for ALT elevations.  Concurrent use of estrogens other than 
ethinyl estradiol was not associated with an increased risk of grade 3+ ALT 
values, and therefore, there are no contraindications for these estrogen 
products that are commonly used in hormone replacement.
●
Clarify enrollment caps for cirrhotic subjects.
●
Update Contraindicated Medication list in Synopsis and Exclusion 3 (Table 6) 
to refer investigators to locally approved labels were AbbVie product 
containing the regimen for this study has been approved. 


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M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Rationale:  To align the contraindicated medication list with that 
recommended in the prescribing information section of the approved local 
product labels in countries where the AbbVie product containing the regimen 
for this study has received marketing authorization.
●
Update Schedule of Activities (Table 7) removing duplicate "Study Drug 
Returned for IRT Reconciliation" entry.
●
Update Schedule of Activities (Table 7, footnote "j.") and Section 5.3.1.1 to 
clarify urine pregnancy testing requirements for subjects on DAA regimen 
only.
●
Add AFP to the list of Clinical Laboratory Tests collected at the Screening 
Visit.
Rationale: To more fully characterize the subject's baseline laboratory status.
●
Update Table 12 to allow for RBV dose modifications in management of 
hemoglobin decreases per local label.
●
Update Section 9.1 to include submission of amendments to Regulatory 
Authority(ies) as applicable.
●
Update Table 4 (Baseline Fibrosis Stage) to correct administrative error for F4 
FibroScan range.
●
Add back-up Sponsor contact phone number to Title Page and Section 6.5.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix D.


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-423
Name of Study Drug:  
ABT-450, ritonavir, ABT-267 and ABT-333 with or 
without ribavirin (RBV)
Phase of Development:  3b
Name of Active Ingredient:  
ABT-450
Ritonavir
ABT-267
ABT-333
Ribavirin 
Date of Protocol Synopsis:  19 January 2015
Protocol Title:  
An Open-Label, Multicenter Study to Evaluate Long-Term Outcomes With ABT-450/Ritonavir/
ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With 
Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (TOPAZ-I)
Objectives:  
The primary objective of this study is to evaluate the effect of response to treatment (assessed by SVR12
status) on the long-term progression of liver disease in adults with chronic HCV GT1 infection who 
received treatment with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin, as measured by 
all-cause death, liver-related death, liver decompensation, liver transplantation, and hepatocellular 
carcinoma.
Secondary Objectives:
!
To evaluate the long-term progression of fibrosis by baseline fibrosis stage and sustained 
virologic response, as measured by change from baseline in liver stiffness measured by transient 
elastography (FibroScan®) when available, in adults with genotype 1 (GT1) chronic HCV 
infection who received treatment with ABT-450/r/ABT-267 and ABT-333 with or without 
ribavirin.
!
To evaluate the percentage of subjects achieving SVR12 with ABT-450/r/ABT-267 and 
ABT-333 with or without ribavirin in adults with GT1 chronic HCV infection.
Investigators:  
Multicenter, investigator information on file at AbbVie
Study Sites:  
Approximately 200 sites
Study Population:  
Adults at least 18 years of age, with GT1 chronic HCV infection, with or without compensated cirrhosis, 
who are treatment-naïve or IFN-based therapy treatment-experienced.
Number of Subjects to be Enrolled:  
Approximately 1650 subjects


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Methodology:  
The TOPAZ studies are composed of 2 studies (TOPAZ-I [M14-423; to be conducted in non-US regions] 
and TOPAZ-II [Study M14-222; to be conducted in the US]) due to administrative reasons.  This study 
(TOPAZ-I) is a Phase 3b, open-label, multi-center study designed together with companion study 
TOPAZ-II, which shares the primary objective of evaluating the effect of SVR12 status on the long-term 
clinical outcomes in adults with GT1 chronic HCV infection with or without compensated cirrhosis, who 
are either treatment-naïve or IFN-based therapy (IFN or pegIFN monotherapy, IFN/RBV, or 
pegIFN/RBV) treatment-experienced.  In both studies, subjects will be treated with ABT-450/r/ABT-267 
and ABT-333 with or without ribavirin (RBV). 
Subjects meeting the eligibility criteria will be enrolled until approximately 1650 subjects have been 
enrolled at approximately 200 sites. 
The study will consist of a Screening Period, Treatment Period and a Post-Treatment Period. 
Treatment Period:  HCV GT1-infected subjects who are either treatment-naïve or IFN-based therapy 
treatment experienced will receive ABT-450/r/ABT-267 and ABT-333.  Subjects with HCV GT1a 
infection and all GT1-infected subjects with compensated cirrhosis will also receive RBV. 
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected subjects with 
compensated cirrhosis; these subjects will receive treatment for 24 weeks.  Treatment duration of 
12 weeks for HCV GT1a-infected subjects with compensated cirrhosis may be selected by the 
investigator where consistent with the local approved label, in countries where marketing authorization 
has been granted for the regimen included in this study.
HCV GT1a-infected subjects with compensated cirrhosis who were originally assigned to 12 weeks of 
treatment under a previous version of this protocol will be assigned to 24 weeks of treatment unless 1) the 
investigator determines that a 12-week duration of therapy is appropriate based on the approved local 
label; or 2) the subject has already completed the original study drug treatment and additional treatment 
cannot be initiated within 15 days of the date that the original treatment was completed.
Post-Treatment Period:  subjects who receive at least one dose of study drug will be followed for up to 
260 weeks.  At these visits subjects will be assessed for antiviral response, progression of liver fibrosis, 
and clinical outcomes, including all-cause death, liver-related death, occurrence of hepatocellular 
carcinoma, liver decompensation and liver transplantation.
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to less than or 
approximately equal to 400 subjects; the number of subjects enrolled without fibrosis or with portal 
fibrosis without septa (an equivalent Metavir score of F0 or F1 respectively) will be limited to 
1000 subjects.  In the absence of a qualifying liver biopsy, the equivalent Metavir score corresponding to 
the results of a screening FibroScan or FibroTest will be used to determine the fibrosis stage.


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M14-423 Protocol Amendment 2
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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
Main Inclusion:  
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) 
!
sexually active with female partners only
!
not of childbearing potential, defined as:
o
postmenopausal for at least 2 years prior to screening (defined as amenorrheic for longer 
than 2 years, age appropriate, and confirmed by a follicle-stimulating hormone (FSH) level 
indicating a postmenopausal state), or
o
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy) or has a vasectomized partner(s);
!
of childbearing potential and sexually active with male partner(s):
o
currently using at least one effective method of birth control at the time of screening and 
o
agree 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),  starting with Study Day 1 and for 30 days after stopping study drug, or for 
7 months after stopping study drug if receiving RBV (or as directed by local RBV label).
(Note:  Ethinyl estradiol-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug treatment).
3.
Males who are not surgically sterile and 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) throughout the course of the 
study, starting with starting with Study Day 1 and for 30 days after stopping study drug, or for 
7 months after stopping study drug if receiving RBV (or as directed by local RBV label).
4.
Chronic HCV infection prior to study enrollment.  Chronic HCV infection is defined as one of the 
following:
!
Positive for anti-HCV Ab or HCV RNA > 1,000 IU/mL at least 6 months before Screening, and 
positive for HCV RNA and anti-HCV Ab at the time of Screening; or 
!
HCV RNA > 1,000 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).
5.
Screening laboratory result indicating HCV genotype 1 infection.


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
1.
Use of medications listed below, or medications contraindicated for ritonavir or RBV (for those that 
receive RBV), within 2 weeks or 10 half-lives whichever is longer, prior to study drug administration 
including but not limited to:
For additional medications contraindicated with AbbVie's 3 DAA regimen, refer to the recommended 
prescribing information section of the approved local product labels in countries where the regimen 
contained in this study (i.e., ABT-450/r/ABT-267 and ABT-333) has received marketing authorization. 
If locally approved labels are not available, refer to the following Contraindicated Medication list:
Alfuzosin
Astemizole 
Carbamazepine
Cisapride
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Ethinyl estradiol-containing medications
Fusidic Acid
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Salmeterol
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with ritonavir, ribavirin, and 3DAA regimen are listed above.  Refer to 
the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of 
contraindicated medications.
2.
History of solid organ transplant.
3.
Screening laboratory analyses showing any of the following abnormal laboratory results:
!
Creatinine Clearance (CrCl) < 30 mL/min as estimated by the Cockcroft-Gault equation:  
CrCl = [(140 – Age) × Mass (in kg) × (0.85 if female)] / [72 × Serum creatinine (in mg/dL)]
!
Albumin < 2.8 g/dL
!
Hemoglobin < LLN
!
Platelets < 25,000 cells per mm3
!
Total bilirubin > 3.0 mg/dL
4.
Any current or past clinical evidence of Child-Pugh B or C Classification (Child-Pugh Score ≥ 7) or 
clinical history of liver decompensation such as ascites (noted on physical exam), variceal bleeding 
or hepatic encephalopathy.
5.
Confirmed presence of hepatocellular carcinoma indicated on imaging techniques such as computed 
tomography (CT) scan or magnetic resonance imaging (MRI) within 3 months prior to Screening or 
on an ultrasound performed at Screening (a positive ultrasound result will be confirmed with CT scan 
or MRI).
Investigational Products:
ABT-450/r/ABT-267:  75 mg/50 mg/12.5 mg tablet
ABT-333:  250 mg tablet
Ribavirin:  200 mg tablet


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Doses:
ABT-450/r/ABT-267:  150/100/25 mg QD
ABT-333:  250 mg BID 
Ribavirin:  weight-based dosing 1000 or 1200 mg divided twice daily or 
adjusted for renal impairment subjects
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  
Subjects will receive ABT-450/r/ABT-267 and ABT-333 with or without RBV for 12 or 24 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit.  Clinical 
outcomes related to death and the liver will be assessed during treatment and post-treatment.
Patient Reported Outcomes (PROs):
During treatment and post-treatment, fatigue and general health related quality of life will be assessed 
using the short form 36 version 2 (SF-36v2) and Functional Assessment of Chronic Illness 
Therapy – Fatigue (FACIT–F) questionnaires.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests and vital signs.
Statistical Methods:
Efficacy:
Primary efficacy endpoint is the effect of response to treatment (assessed by SVR12) on clinical 
outcomes, based on subjects in this study and companion study TOPAZ II.  The endpoint will be assessed 
by comparing the incidence of the following events between subjects who achieve SVR12 and those who 
do not using the Cox regression model:
!
All-cause death
!
Liver-related death
!
Liver decompensation
!
Liver transplantation
!
Hepatocellular carcinoma
!
Composite of any of the above outcomes
Secondary endpoint analyses:
!
The long-term change from baseline in liver stiffness (as assessed by transient elastography 
[Fibroscan®]), when available, will be assessed by baseline fibrosis stage and sustained virologic 
response. 
!
The percentage of subjects achieving SVR12 and 2-sided 95% confidence interval will be 
presented by baseline fibrosis score (F0-F1, F2, F3 and F4).


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Statistical Methods (Continued):
Resistance:
The following resistance information will be provided for a subset of the subjects who experience 
virologic failure:  1) the amino acid variants at signature resistance-associated positions at baseline 
identified by population nucleotide sequencing and comparison to the appropriate prototypic reference 
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 baseline sequence, and
3) 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.  
In addition, the persistence of viral resistance-associated amino acid variants will be evaluated in selected 
samples during the 5-year (through PT Week 260) post-treatment period.
Safety:
The overall 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.  Tabulations will also be provided in which the number of subjects reporting an 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.  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 will be calculated.


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABT-450/r
ABT-450 administered with ritonavir
ABT-450/r/ABT-267
ABT-450 co-formulated with ritonavir and ABT-267
AE
Adverse event
AFP
Alpha-fetoprotein
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
BID
Twice Daily
BMI
Body mass index
BUN
Blood urea nitrogen
CrCl
Creatinine Clearance
CRF
Case report form
CYP2C8
Cytochrome P450 2C8
CYP3A
Cytochrome P450 3A
DAA
Direct-acting antiviral agent
DDI
Drug-Drug Interaction
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
EOT
End of treatment
FACIT–F
The Functional Assessment of Chronic Illness Therapy – Fatigue 
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HBsAg
Hepatitis B surface antigen
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus


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EudraCT 2014-001022-14
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HCV Ab
Hepatitis C virus antibody
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
IL28B
Interleukin 28B
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to Treat
IU
International units
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NS3
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
PCR
Polymerase chain reaction
PegIFN
Pegylated-interferon alfa-2a or 2b
POR
Proof of Receipt
PRO
Patient Reported Outcomes
PT
Post-Treatment
QD
Once daily
r
Ritonavir
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase PCR
SAE
Serious adverse event
SAS
Statistical Analysis System
SF-36v2
Short-Form 36 Version 2 health survey


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
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SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks post-treatment
ULN
Upper limit of normal
WBC
White blood cells
Definition of Terms
Study Drug
ABT-450/ritonavir/ABT-267, ABT-333, Ribavirin
Day 1
First day a subject took study drug
Treatment Period
Baseline/Day 1 through the last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 260 or Post-
Treatment Discontinuation


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................10
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................27
3.2
Benefits and Risks....................................................................................28
4.0
Study Objectives....................................................................30
5.0
Investigational Plan...............................................................30
5.1
Overall Study Design and Plan:  Description ..........................................30
5.1.1
Screening..................................................................................................34
5.1.1.1
Rescreening..............................................................................................34
5.1.2
Treatment Period (TP) .............................................................................35
5.1.3
Post-Treatment Period (PT) .....................................................................37
5.2
Selection of Study Population..................................................................38
5.2.1
Inclusion Criteria .....................................................................................38
5.2.2
Exclusion Criteria ....................................................................................40
5.2.3
Prior and Concomitant Therapy...............................................................42
5.2.3.1
Prior HCV Therapy..................................................................................43
5.2.3.2
Concomitant Therapy...............................................................................43
5.2.3.3
Prohibited Therapy...................................................................................44
5.3
Efficacy:  Pharmacokinetic and Safety Assessments/Variables ..............45
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................45
5.3.1.1
Study Procedures .....................................................................................51
5.3.1.2
Blood Samples for Pharmacogenetic Analysis........................................62
5.3.1.3
Meals and Dietary Requirements.............................................................63
5.3.2
Efficacy Variables....................................................................................63
5.3.2.1
Primary Variable......................................................................................63
5.3.2.2
Secondary Variables ................................................................................64
5.3.3
Safety Variables.......................................................................................64


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5.3.4
Pharmacogenetic Variable .......................................................................64
5.4
Removal of Subjects from Therapy or Assessment.................................65
5.4.1
Discontinuation of Individual Subjects....................................................65
5.4.2
Discontinuation of Entire Study...............................................................66
5.4.3
Discontinuation of Subjects that Meet Virologic Failure Criteria...........66
5.5
Treatments................................................................................................67
5.5.1
Treatments Administered.........................................................................67
5.5.2
Identity of Investigational Products.........................................................68
5.5.2.1
Packaging and Labeling...........................................................................68
5.5.2.2
Storage and Disposition of Study Drug(s)...............................................69
5.5.3
Method of Assigning Subjects to Treatment Groups...............................69
5.5.4
Selection and Timing of Dose for Each Subject......................................69
5.5.5
Blinding....................................................................................................70
5.5.6
Treatment Compliance.............................................................................70
5.5.7
Drug Accountability.................................................................................71
5.6
Discussion and Justification of Study Design..........................................71
5.6.1
Discussion of Study Design and Choice of Control Groups....................71
5.6.2
Appropriateness of Measurements...........................................................72
5.6.3
Suitability of Subject Population .............................................................72
5.6.4
Selection of Doses in the Study ...............................................................73
6.0
Adverse Events.......................................................................74
6.1
Definitions................................................................................................74
6.1.1
Adverse Event..........................................................................................74
6.1.2
Serious Adverse Events ...........................................................................76
6.2
Adverse Event Severity............................................................................77
6.3
Relationship to Study Drug......................................................................77
6.4
Adverse Event Collection Period.............................................................78
6.5
Adverse Event Reporting.........................................................................79
6.6
Pregnancy.................................................................................................80
6.7
Toxicity Management ..............................................................................81
6.7.1
Grade 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events ........................................................................................82
6.7.2
Grade 3 or 4 Laboratory Abnormalities...................................................82


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6.7.3
Severe Adverse Events or Serious Adverse Events.................................83
6.7.4
Management of Decreases in Hemoglobin..............................................83
6.7.5
Management of ALT Elevations..............................................................85
6.7.6
Creatinine Clearance................................................................................86
7.0
Protocol Deviations................................................................87
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................88
8.1
Statistical and Analytical Plans................................................................88
8.1.1
Demographics ..........................................................................................90
8.1.2
Efficacy....................................................................................................90
8.1.2.1
Primary Efficacy Endpoint ......................................................................91
8.1.2.2
Secondary Efficacy Endpoints.................................................................91
8.1.2.3
Subgroup Analyses ..................................................................................92
8.1.2.4
Additional Efficacy Endpoints.................................................................92
8.1.3
Resistance ................................................................................................93
8.1.4
Safety .......................................................................................................94
8.1.5
Adverse Events ........................................................................................94
8.1.6
Clinical Laboratory Data..........................................................................95
8.1.7
Vital Signs Data .......................................................................................95
8.2
Determination of Sample Size .................................................................96
8.3
Randomization Methods ..........................................................................96
9.0
Ethics.......................................................................................96
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................96
9.2
Ethical Conduct of the Study...................................................................97
9.3
Subject Information and Consent.............................................................97
10.0
Source Documents and Case Report Form 
Completion .............................................................................98
10.1
Source Documents ...................................................................................98
10.2
Case Report Forms...................................................................................98
11.0
Data Quality Assurance ........................................................99
12.0
Use of Information.................................................................99
13.0
Completion of the Study .....................................................100


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EudraCT 2014-001022-14
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14.0
Investigator's Agreement....................................................101
15.0
Reference List ......................................................................102
List of Tables
Table 1.
Pooled SVR12 Rates (Intent-to-treat, missing = failure) from 
Phase 3 Studies by Subpopulation of Subtype, Prior Treatment 
History, and Presence or Absence of Cirrhosis........................................20
Table 2.
Overview of Treatment-Emergent Adverse Events (AE)........................24
Table 3.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline 
Lab Abnormalities ...................................................................................25
Table 4.
Baseline Fibrosis Stage............................................................................33
Table 5.
Treatment Regimen and Duration............................................................36
Table 6.
Medications Contraindicated for Use with the Study Drug 
Regimen ...................................................................................................40
Table 7.
Study Activities........................................................................................46
Table 8.
Clinical Laboratory Tests.........................................................................55
Table 9.
Child-Pugh Classification of Severity of Cirrhosis .................................57
Table 10.
Identity of Investigational Products.........................................................68
Table 11.
Study Drug Storage Conditions ...............................................................69
Table 12.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases ............................................................................85
Table 13.
Dosing of RBV in Subjects with Renal Impairment................................87
List of Figures
Figure 1.
Study Design............................................................................................34
Figure 2.
Adverse Event Collection ........................................................................79


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................105
Appendix B.
List of Protocol Signatories....................................................................107
Appendix C.
Clinical Toxicity Grades........................................................................108
Appendix D.
Protocol Amendment:  List of Changes.................................................111


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
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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
Treatment of HCV-infected patients could reduce the risk of cirrhosis, decompensation, 
cancer and liver-related deaths.  Among patients treated with pegylated interferon 
(pegIFN) and ribavirin (RBV) therapy, achieving a sustained virologic response (SVR) 
was associated with significant reduction in all-cause death compared to subjects who did 
not achieve SVR (5-year mortality rate in HCV genotype 1-infected patients:  6.7% versus 
14.4%, respectively).9  In addition, the 5-year occurrence of the composite clinical events 
of death, liver failure, and hepatocellular carcinoma were significantly lower in 
HCV-infected patients with advanced fibrosis or cirrhosis who achieved SVR versus 
those without SVR (9.2% versus 28.2%, respectively).10  Patients with SVR following 
treatment with pegIFN with or without RBV have also shown improvement in liver 
histology and a reduction in liver-related death in several studies.11-13  Moreover, patients 
with compensated cirrhosis who achieve SVR essentially eliminate their subsequent risk 
of decompensation, may achieve histologic regression, and decrease their risk of 
hepatocellular carcinoma by two-thirds.14-16  In patients with advanced fibrosis and 
cirrhosis, viral suppression by more than 4 logs10 with pegIFN and RBV was associated 
with marked reduction in death/liver transplantation, and in liver-related morbidity and 
death.17


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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In patients with HCV infection, liver histology is a key determinant of clinical 
complications such as decompensation and hepatocellular carcinoma as the risk is greatest 
in patients with advanced fibrosis.  Treatment with IFN-based therapy with or without 
RBV has demonstrated a delay in fibrosis progression in patients who relapse and 
regression of fibrosis in patients with SVR.  While liver biopsy remains the reference 
standard, noninvasive tests such as transient elastography (FibroScan) have emerged as 
validated methods to evaluate degree of liver fibrosis and to monitor progression and 
regression of fibrosis.18  Whereas liver stiffness increased or did not change over time in 
untreated patients, patients treated with pegIFN/RBV therapy exhibited decreases in liver 
stiffness during and after treatment with the greatest improvements observed in patients 
with more advanced fibrosis at baseline.19-21
Combinations of direct-acting antiviral agents (DAAs) targeting different steps of viral 
replication have the potential to significantly improve HCV treatment compared to the 
current interferon-containing regimens for HCV genotype 1 infection by increasing SVR 
rates, eliminating IFN as a component of therapy, increasing the safety and tolerability of 
treatment, shortening duration of therapy and simplifying the treatment algorithm.  In 
addition, wider application of DAA therapy and better responses with combination DAA 
regimens could significantly reduce the public health burden of this disease.
AbbVie's IFN-free regimen for the treatment of chronic HCV genotype 1 infection 
includes 3 DAAs targeting different steps in HCV replication.  ABT-450 is a 
nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease inhibitor 
co-administered with the pharmacokinetic enhancer, ritonavir (ABT-450/r); ABT-267 
(ombitasvir) is a NS5A inhibitor, and ABT-333 (dasabuvir) is a NS5B non-nucleoside 
polymerase inhibitor.  
The 3-DAA regimen has been studied with and without ribavirin in over 2,300 patients in 
Phase 3 trials across a variety of patient populations including those with compensated 
cirrhosis.  Based on Phase 3 data, the regimen with or without RBV appears to be safe, 
well tolerated and efficacious in treatment-naïve and treatment-experienced HCV 


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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genotype 1-infected subjects including those with compensated cirrhosis.  The overall 
efficacy results (intent-to-treat) from the Phase 3 studies are listed in Table 1.
Table 1.
Pooled SVR12 Rates (Intent-to-treat, missing = failure) from Phase 3 
Studies by Subpopulation of Subtype, Prior Treatment History, and 
Presence or Absence of Cirrhosis
Subpopulation
3-DAA
12 Weeks
SVR12
3-DAA + RBV
12 Weeks
SVR12
3-DAA + RBV
24 Weeks
SVR12
Genotype 1b non-cirrhotics
     Naïve
     Null
     Partial
     Relapser
99.0
100
100
100
98.9
94.4
98.1
98.5
--
--
--
--
Genotype 1a non-cirrhotics
     Naïve
     Null
     Partial
     Relapser
90.2
--
--
--
95.7
95.4 
100
94.0
--
--
--
--
Genotype 1b cirrhotics
     Naïve
     Null
     Partial
     Relapser
--
--
--
--
100
100
85.7*
100
100
100
100
100
Genotype 1a cirrhotics
     Naïve
     Null
     Partial
     Relapser
--
--
--
--
92.4
80.0
100
93.3
92.9
92.9
100
100
*
Based on N = 7; 6/7 achieved SVR.
Phase 3 Placebo-Controlled Studies:  Studies M11-646 and M13-098
Study M11-646 and Study M13-098 are randomized, placebo-controlled studies that 
assessed the safety and efficacy of 12 weeks of therapy with 3 DAA + RBV in HCV 
genotype 1-infected treatment-naïve subjects (Study M11-646) and prior pegIFN/RBV 


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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non-responders (Study M13-098) without cirrhosis.  Subjects received 3-DAA + RBV for 
12 weeks of treatment.  Subjects randomized to the placebo arm received placebo for 
12 weeks, after which they received open-label 3-DAA + RBV for 12 weeks. 
In Study M11-646, a total of 631 subjects were randomized and received at least one dose 
of study drug, of which 67.7% had HCV genotype 1a and 32.3% had HCV genotype 1b.  
The SVR12 rate for treatment-naïve subjects receiving 3-DAA + RBV for 12 weeks was 
96.2%.  Virologic failure was noted in 7/322 (2.2%) genotype 1a subjects (on treatment 
virologic failure:  n = 1; relapse:  n = 6) and 1/151 (0.7%) genotype 1b subjects (relapse). 
In Study M13-098, a total of 394 subjects were randomized and received at least one dose 
of study drug, of which 58.4% had HCV genotype 1a, 41.4% had HCV genotype 1b, 
49.0% were prior pegIFN/RBV null responders, 21.9/% were prior pegIFN/RBV partial 
responders, and 29.2% were prior pegIFN/RBV relapsers.  The SVR12 rate for 
treatment-experienced subjects receiving 3-DAA + RBV for 12 weeks was 96.3%.  
Virologic failure (all relapse) was noted in 5/173 (2.9%) genotype 1a subjects and 2/123 
(1.6%) genotype 1b subjects. 
Phase 3 Regimen-Controlled Studies:  Studies M13-389, M13-961 and M14-002
Studies M13-389, M13-961, and M14-002 are randomized, regimen-controlled trials that 
assessed the safety and efficacy of 12 weeks of treatment with 3 DAAs with or without 
RBV.  Studies M13-961 and M14-002 are ribavirin placebo-controlled studies, while 
Study M13-389 is an open-label study.  The patient population was different in each of 
the 3 studies.  Study M13-389 enrolled genotype 1b-infected subjects with prior 
non-response to pegIFN/RBV, Study M13-961 enrolled genotype 1b-infected subjects 
who were treatment-naïve, and Study M14-002 enrolled genotype 1a-infected subjects 
who were treatment-naïve.  All three studies excluded subjects with cirrhosis.
In Study M13-389, a total of 186 subjects were randomized and received at least one dose 
of study drug, of which 34.9% were prior pegIFN/RBV null responders, 28.5% were prior 
pegIFN/RBV partial responders, and 36.6% were prior pegIFN/RBV relapsers.  The 


ABT-450/r/ABT-267, ABT-333
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SVR12 rates were 96.6% in the 3-DAA + RBV arm and 100% in the 3-DAA without RBV 
arm.  The difference in SVR12 rates between the 2 regimens met the protocol-specified 
criteria for noninferiority; hence, the 3-DAA regimen without RBV demonstrated 
noninferiority compared to 3-DAA + RBV.  No subject in either arm experienced on-
treatment virologic failure or post-treatment relapse. 
In Study M13-961, a total of 419 subjects were randomized and received at least one dose 
of study drug.  The SVR12 rates for treatment-naïve subjects with HCV genotype 1b 
infection who received either 3 DAAs with or without RBV for 12 weeks were 99.5% and 
99.0%, respectively.  The difference in SVR12 rates between the 2 regimens in this study 
also met the protocol-specified criteria for noninferiority.  One of the 419 treated subjects 
(3-DAA + RBV arm) experienced on-treatment virologic failure.
In Study M14-002, 305 subjects were randomized and received at least one dose of study 
drug.  The SVR12 rates for treatment-naïve subjects with HCV genotype 1a infection who 
received either 3 DAAs with or without RBV for 12 weeks in Study M14-002 were 97.0% 
and 90.2%, respectively.  The SVR12 rate in the 3-DAA arm did not achieve noninferiority 
to the 3-DAA + RBV arm.  Virologic failure was noted in 2/100 (2.0%) subjects (on 
treatment virologic failure:  n = 1; relapse:  n = 1) in the RBV-containing regimen and 
16/205 (7.8%) subjects (on treatment virologic failure:  n = 6; relapse:  n = 10) in the 
RBV-free regimen.  The difference between arms demonstrates that RBV contributes to 
the efficacy in genotype 1a-infected patients and suggests that 3-DAA + RBV is the 
optimal regimen for these patients.
Phase 3 Study in Cirrhotics:  Study M13-099
Study M13-099 is a randomized, multicenter, open-label trial in treatment-naïve subjects 
or subjects previously treated with pegIFN/RBV with chronic HCV genotype 1infection 
with compensated (Child-Pugh A, score ≤ 6) cirrhosis. The 3 DAAs + RBV were 
administered for either 12 or 24 weeks of treatment.


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A total of 380 subjects were randomized and received at least one dose of study drug, of 
which 68.7% had HCV genotype 1a, 31.3% had HCV genotype 1b, 42.1% were 
treatment-naïve, 36.1% were prior pegIFN/RBV null responders, 8.2% were prior 
pegIFN/RBV partial responders, and 13.7% were prior pegIFN/RBV relapsers. 
The SVR12 rates for subjects with compensated cirrhosis treated with 3-DAA + RBV for 
12 or 24 weeks were 91.8% and 95.9%, respectively.  Virologic failure was noted in 
13/208 (6.3%) subjects (on treatment virologic failure:  n = 1; relapse:  n = 12) receiving 
the 12-week regimen and 4/172 (2.3%) subjects (on treatment virologic failure:  n = 3; 
relapse:  n = 1) receiving the 24-week regimen.
Analyses of subgroups suggest that the overall difference in SVR12 rates was driven 
largely by a lower SVR12 rate among genotype 1a prior null responders who received 
12 weeks of treatment, while other subgroups had comparable response rates when treated 
for 12 or 24 weeks.  Thus, a 12-week treatment regimen is recommended for all patients 
with cirrhosis with the exception of genotype 1a prior null responders, for whom 
24 weeks of treatment provides a higher SVR.
Integrated Safety Results
A summary of treatment-emergent adverse events from the pooled analyses of data from 
the Phase 3 studies is presented in Table 2.  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.


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
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Table 2.
Overview of Treatment-Emergent Adverse Events (AE)
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-Week 
3-DAA + 
RBV
12-Week 
PBO
12-Week 
3-DAA + 
RBV
12-Week 
3-DAA
12-Week 
3-DAA + 
RBV
24-Week 
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
PBO = Placebo
a.
Lung cancer.
The most common adverse events regardless of causality are listed in Table 3.  Adverse 
events that occurred at a ≥ 5% incidence in the 3-DAA + RBV regimen versus the 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. 


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Table 3.
Treatment-Emergent Adverse Events with ≥ 10% Frequency in at 
Least One Arm of the Analysis and Rates of Key Post-Baseline Lab 
Abnormalities
Placebo-Controlled
Regimen-Controlled
Cirrhotics
12-Week 
3-DAA + 
RBV
12-Week 
PBO
12-Week 
3-DAA + 
RBV
12-Week 
3-DAA
12-Week 
3-DAA + 
RBV
24-Week 
3-DAA + 
RBV
Treatment-emergent 
Adverse Events, %
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
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 may occur due to ABT-450 
inhibition of the bilirubin transporters OATP1B1 and OATP1B3, and RBV-induced 
hemolysis.  The elevations generally peaked by Weeks 1 – 2, declined through the end of 


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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treatment and returned to within the normal range by 4 weeks post-treatment.  Rates of 
hyperbilirubinemia were lower in subjects treated with 3-DAA without RBV compared to 
3-DAA with RBV.  The rates and degree of hyperbilirubinemia were higher in patients 
with cirrhosis, but the temporal pattern of elevation followed by resolution was similar 
and few were symptomatic (jaundice).  Rates of ≥ Grade 2 hemoglobin reductions were 
6% among subjects without cirrhosis who received the 3-DAA + RBV regimen for 
12 weeks, and 7% and 11% among 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; use of 
hematologic growth factors and blood transfusion were rare.  The anemia reported in the 
clinical trials was primarily observed when the 3-DAA regimen was administered with 
RBV.
Transient asymptomatic postbaseline serum ALT elevations of > 5× ULN occurred at a 
frequency of 1% across active treatment arms and were evaluated by an external hepatic 
panel.  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 ethinyl estradiol-containing therapy 
(i.e., combination contraceptives) 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 ethinyl estadiol-containing medications is a risk 
factor for these postbaseline elevations in serum ALT.  There was no increase in the risk 
of ALT elevations greater than 5 × ULN in subjects on estrogens other than ethinyl 
estradiol (i.e., estradiol, conjugated estrogens) or in subjects on only progestins. 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.
In summary, the 3-DAA regimen, with or without RBV, was well tolerated with a low 
discontinuation rate.  Adverse events were typically mild, and many of the adverse events 
and laboratory abnormalities observed were attributable to the presence of RBV.  


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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Transient, asymptomatic serum ALT elevations were observed at a low rate, were not 
associated with hepatic dysfunction and generally resolved with ongoing treatment.
A detailed discussion of the preclinical toxicology (including reproductive and 
development toxicity), metabolism, pharmacokinetics and drug-drug interactions can be 
found in the Investigator's Brochure for ABT-267, ABT-450, ABT-333 or prescribing 
information for ombitasvir/paritaprevir/r and dasabuvir in countries with marketing 
authorization, and product label for ritonavir and ribavirin.22-26
The current study is intended to evaluate the long-term outcomes with ABT-450/r/ 
ABT-267 and ABT-333 with or without RBV for treatment-naïve and IFN/RBV 
treatment-experienced adults with chronic HCV GT1 infection, with or without 
compensated cirrhosis.
3.1
Differences Statement
The 3-DAA regimen with or without RBV was explored in treatment-naïve and 
treatment-experienced HCV GT1-infected subjects with or without compensated cirrhosis, 
in several Phase 3 studies.  These studies were conducted in a randomized, controlled, 
double-blind or open-label fashion.  This study is a Phase 3b, single arm, open-label study 
in approximately 1650 treatment-naïve and IFN-based therapy treatment-experienced 
subjects. 
This is the first study to evaluate long term outcomes with ABT-450/r/ABT-267 and 
ABT-333 with or without RBV for 12 or 24 weeks in subjects with chronic HCV GT1 
infection outside of the US.  The study population comprises HCV GT1 infected subjects 
who are treatment-naïve or treatment-experienced, including subjects with and without 
cirrhosis.  The study will include up to 25% of subjects with compensated cirrhosis which 
approximates the projected prevalence among chronic HCV-infected subjects.27


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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3.2
Benefits and Risks
This Phase 3b study is a single arm study in which eligible HCV genotype 1-infected 
subjects will receive ABT-450/r/ABT-267 and ABT-333 with or without RBV for either 
12 or 24 weeks.  The combination of ABT-450/r/ABT-267 and ABT-333 with or without 
RBV have been evaluated in six Phase 3 studies.  Treatment with ABT-450/r/ABT-267 
and ABT-333 with RBV for 12 weeks resulted in SVR12 in 96.2% of HCV GT1-infected, 
treatment-naïve subjects without cirrhosis in Study M11-646, and in 96.3% of 
HCV GT1-infected, pegIFN/RBV treatment-experienced subjects without cirrhosis in 
Study M13-098.  In Study M13-961, 99.5% and 99.0% of HCV GT1b-infected 
treatment-naïve subjects without cirrhosis achieved SVR12 following treatment with 
ABT-450/r/ABT-267 and ABT-333, with or without RBV for 12 weeks, respectively.  
Similarly, in Study M13-389, 96.6% and 100% of HCV GT1b-infected pegIFN/RBV 
treatment-experienced subjects without cirrhosis achieved SVR12 following treatment 
with ABT-450/r/ABT-267 and ABT-333, with or without RBV for 12 weeks, 
respectively.  ABT-450/r/ABT-267 and ABT-333 with or without RBV was also 
evaluated in Study M14-002.  In Study M14-002, 97.0% and 90.2% of HCV 
GT1a-infected treatment-naïve subjects achieved SVR12 following treatment with and 
without RBV, respectively, suggesting that ABT-450/r/ABT-267 and ABT-333 with RBV 
is the optimal regimen for HCV GT1a-infected subjects.  In this study, HCV 
GT1a-infected subjects will receive 3-DAA with RBV.
The likelihood of successfully curing HCV in compensated cirrhotics following treatment 
with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV was evaluated in 
Study M13-099.  In Study M13-099, 91.8% and 95.9% of HCV GT1-infected 
treatment-naïve and pegIFN/RBV treatment-experienced subjects achieved SVR12
following treatment for 12 and 24 weeks, respectively.  Analysis of subgroups 
demonstrated that the difference in SVR12 rates between treatment arms was due to the 
lower SVR12 rate in GT1a-infected pegIFN/RBV treatment-experienced prior null 
responders treated for 12 weeks.  Among HCV GT1a-infected subjects, partial responders 
and relapsers had higher SVR rates than null responders in the 12-week treatment group, 


ABT-450/r/ABT-267, ABT-333
M14-423 Protocol Amendment 2
EudraCT 2014-001022-14
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while similar SVR rates were seen among the null responders, partial responders and 
relapsers treated for 24 weeks, suggesting that the longer duration of 24 weeks is required 
only for HCV GT1a null responders.  SVR rates were high across all subgroups in HCV 
GT1b-infected subjects treated for 12 and 24 weeks.  For this reason, in previous versions 
of this protocol HCV GT1a-infected subjects with compensated cirrhosis and who were 
prior null responders or non-responders to pegIFN/RBV were assigned to receive 3-DAA 
with RBV for 24 weeks, while HCV GT1a-infected subjects with compensated cirrhosis 
who were not prior null responders or non-responders to IFN/RBV were assigned to 
received 3-DAA with RBV for 12 weeks.  In order to align the treatment duration for 
subjects with GT1a infection and compensated cirrhosis with the recommended treatment 
duration that is found in the prescribing information of some approved local labels for the 
AbbVie product containing the regimen included in this study (i.e., ABT-450/r/ABT-267 
and ABT-333), the protocol now specifies that all HCV GT1a-infected subjects with 
compensated cirrhosis will be assigned to receive 3-DAA with RBV for 24 weeks.  
Treatment duration of 12 weeks for HCV GT1a-infected subjects with compensated 
cirrhosis may be selected by the investigator where consistent with the approved local 
label.
HCV GT1a-infected subjects with compensated cirrhosis who were assigned to 12 weeks 
of treatment under a previous version of this protocol will be assigned to 24 weeks of 
treatment unless 1) the investigator determines that a 12-week duration of therapy is 
appropriate based on the approved local label; or 2) the subject has already completed the 
original study drug treatment and additional treatment cannot be initiated within 15 days 
of the date that the original treatment was completed.
ABT-450/r, ABT-267 and ABT-333 with or without RBV have been well tolerated in the 
Phase 3 studies.  Adverse events that are known, and those not previously described, may 
occur with the DAAs or RBV as detailed in the informed consent for this study.  In 
addition, subjects may experience inconvenience or discomfort related to the study visits 
or study procedures.  


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Risks associated with ABT-450/r/ABT-267 and ABT-333 coadministered with or without 
RBV, including the risks of toxicity and virologic failure, appear limited and manageable 
based on the results from the Phase 3 studies.  Given the potential high rate of cure in 
HCV GT1-infected subjects, the risk-benefit comparison is favorable.
4.0
Study Objectives 
Primary Objective
The primary objective of this study is to evaluate the effect of response to treatment 
(assessed by SVR12 status) on the long-term progression of liver disease in adults with 
chronic HCV GT1 infection who received treatment with ABT-450/r/ABT-267 and 
ABT-333 with or without ribavirin, as measured by all-cause death, liver-related death, 
liver decompensation, liver transplantation, and hepatocellular carcinoma.
Secondary Objectives
●
To evaluate the long-term progression of fibrosis by baseline fibrosis stage and 
sustained virologic response, as measured by change from baseline in liver 
stiffness measured by transient elastography (FibroScan®) when available, in 
adults with genotype 1 (GT1) chronic HCV infection who received treatment 
with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin.
●
To evaluate the percentage of subjects achieving SVR12, with 
ABT-450/r/ABT-267 and ABT-333 with or without RBV in adults with 
GT1chronic HCV infection.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, multi-center study designed together with companion study 
TOPAZ-II (M14-222), which shares the primary objective of assessing the effect of 
treatment response on long-term clinical outcomes in adults with GT-1 chronic HCV 
infection with or without compensated cirrhosis, who are either treatment-naïve or 


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IFN-based therapy (IFN or pegIFN monotherapy, IFN/RBV or pegIFN/RBV) 
treatment-experienced.  In both studies, subjects will be treated with ABT-450/r/ABT-267 
and ABT-333 with or without RBV.
In the TOPAZ-I and TOPAZ-II studies, the primary objective is to assess the effect of 
treatment response (SVR12) on long-term clinical outcomes, based on the data from both 
studies combined.  The studies differ based on geographic region (this study will be 
conducted outside the US while the TOPAZ-II study will be conducted in the US) and 
based on certain procedures that are not related to the primary outcome.  For example, this 
study will assess the long-term change from baseline in liver elastography, and the 
TOPAZ-II study will utilize a Subject Care Plan Model to facilitate subjects' adherence to 
the study drug.   
The study is designed to enroll 1650 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. 
Subjects will be considered treatment-naïve if they have never received any antiviral 
treatment for hepatitis C infection.
Subjects will be considered treatment-experienced if they have received prior IFN-based 
therapy excluding DAAs (including IFN or pegIFN monotherapy, IFN/RBV or 
pegIFN/RBV).  Subjects with documentation required to classify prior response to 
IFN/RBV or pegIFN/RBV treatment will be categorized as one of the following:
●
Prior IFN/RBV or 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 IFN/RBV or pegIFN/RBV 
treatment course;
●
Prior IFN/RBV or pegIFN/RBV partial responder:  achieved at least a 2 log10
IU/mL reduction in HCV RNA by Week 12 during a prior IFN/RBV or 


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pegIFN/RBV treatment course but failed to achieve HCV RNA undetectable at 
the end of treatment;
●
Prior IFN/RBV or pegIFN/RBV Relapser:  achieved HCV RNA undetectable 
at end of a prior IFN/RBV or pegIFN/RBV treatment course but HCV RNA 
was detectable following cessation of therapy.
Subjects with a less well-characterized IFN-based treatment experience, including those 
subjects with incomplete HCV RNA and treatment date documentation, will be 
categorized as one of the following:
●
Prior IFN/RBV or pegIFN/RBV relapse/breakthrough:  achieved at least one 
documented result of HCV RNA undetectable during a prior IFN/RBV or 
pegIFN/RBV treatment course;
●
Prior IFN/RBV or pegIFN/RBV nonresponder:  did not achieve a documented 
result of HCV RNA undetectable or HCV RNA was detected at the end of 
treatment during a prior IFN/RBV or pegIFN/RBV treatment course, with 
insufficient data available to categorize as a breakthrough, partial or null 
responder;
●
Interferon intolerant:  did not meet any of the above definitions of 
treatment-failure and discontinued IFN/RBV or pegIFN/RBV therapy due to 
IFN intolerability.  
●
Interferon experienced-other:  Includes IFN or pegIFN monotherapy, 
IFN/RBV, or pegIFN/RBV experienced subjects.  Includes subjects who do 
not have adequate documentation of response.
Note:  subjects receiving IFN or pegIFN monotherapy must be categorized as 
'Interferon experienced-other'.
Subjects will be considered to be non-cirrhotic based on a liver biopsy within 24 months 
prior to or during screening demonstrating the absence of cirrhosis (e.g., a METAVIR 
Score of 3 or less, Ishak score of 4 or less) or, if a liver biopsy is unavailable, a screening 
FibroScan result of < 12.5 kPa or a screening FibroTest score of ≤ 0.72 and Aspartate 
Aminotransferase to Platelet Ratio Index (APRI) ≤ 2.


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Subjects will be considered to have cirrhosis based on previous histologic diagnosis of 
cirrhosis on a liver biopsy (e.g., Metavir Score of > 3 [including 3 – 4 or 3/4], Ishak score 
of > 4) or, if a liver biopsy is unavailable, a screening FibroScan score ≥ 14.6 kPa or a 
screening FibroTest ≥ 0.73 and APRI > 2. 
In the absence of a qualifying liver biopsy, subjects with a screening FibroScan result that 
is ≥ 12.5 kPa and < 14.6 kPa, a FibroTest result that is ≤ 0.72 and an APRI > 2, or a 
FibroTest result that is ≥ 0.73 and an APRI ≤ 2, should be evaluated based on the 
investigator's clinical judgment to determine the presence or absence of cirrhosis.  The 
investigator will then determine and assign a fibrosis score (either F3 or F4), as shown in 
Table 4, which will be documented in the subject's source and recorded in the IRT system.
Table 4.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy 
Metavir, Batts-
Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2 
2
3
≥ 8.8 to < 9.6
0.49 to 0.58
F3
3
4
≥ 9.6 to < 12.5
0.59 to 0.72
F3 or F4*
NA
NA
≥ 12.5 to < 14.6
NA
F4 
4
5 or 6
≥ 14.6
≥ 0.73
*
In the absence of a qualifying liver biopsy, subjects with a screening FibroScan result that is ≥ 12.5 kPa and 
< 14.6 kPa, a screening Fibrotest result that is ≤0.72 and an APRI > 2, or a FibroTest result that is ≥ 0.73 and an 
APRI ≤ 2, should be evaluated based on the investigator's clinical judgment to determine the fibrosis stage (either 
F3 or F4).
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to 
less than or approximately equal to 400 subjects; the number of subjects enrolled without 
fibrosis or with portal fibrosis without septa (an equivalent Metavir score of F0 or F1 
respectively) will be limited to 1000 subjects.


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After meeting the eligibility criteria, subjects will be enrolled to either 12 or 24 weeks of 
treatment.
Figure 1.
Study Design
5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures, will receive a unique subject number via the 
Interactive Response Technology (IRT) system and will undergo the study procedures
identified in Section 5.3.1 associated with the Screening Visit.  The investigator or 
designee will evaluate whether the subject meets all of the eligibility criteria specified in 
Section 5.2.1 and Section 5.2.2 during the period from the Screening Visit through Study 
Day 1 prior to dosing and record the results of this assessment and the details of the 
informed consent process in the subject's medical records. 
Eligible subjects have up to 42 days following the Screening Visit to enroll into the study.
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 42-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, positive human immunodeficiency virus (HIV) antibody, or confirmed 


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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 ALT requires a repeat chemistry panel) within the 
same screening period and must meet all eligibility laboratory criteria on any panel that is 
repeated.
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 (TP)
Subjects who meet the eligibility criteria will be enrolled to either 12 or 24 weeks of 
combination therapy with or without RBV as described below and Table 5.
HCV GT1-infected subjects who are either treatment-naïve or treatment-experienced will 
receive ABT-450/r/ABT-267 and ABT-333.  Subjects with HCV GT1a infection and all 
GT1-infected subjects with compensated cirrhosis will receive RBV.
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with compensated cirrhosis who will receive treatment for 24 weeks.  Treatment 
duration of 12 weeks for HCV GT1a-infected subjects with compensated cirrhosis may be 
selected by the investigator where consistent with the approved local label.  Subjects will 
receive study drug regimens according to criteria listed in Table 5.


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Table 5.
Treatment Regimen and Duration
Subject Population
Treatment Regimen*
Treatment Duration
Genotype 1a, without cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
12 weeks
Genotype 1a, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
24 weeks**
Genotype 1b, without cirrhosis
ABT-450/r/ABT-267 + ABT-333
12 weeks
Genotype 1b, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed 
genotype 1 infection.
**
Treatment for 12 weeks may be considered in some patients where consistent with the approved local label.
The site will enter subject's genotype (1b/Non-1b), fibrosis stage and prior IFN-based 
treatment information in the IRT system in order to assign subject's treatment regimen as 
described in Table 5.
ABT-450/r/ABT-267, ABT-333 and RBV (if applicable) will be administered as 
described in Section 5.5.1.  Subjects will receive instructions about the study drugs and 
the dosing schedule at the Day 1 Visit.  The study drugs will be dispensed at the visits 
indicated in Table 7.
All subjects will continue to return to the site on an outpatient basis through Week 12 or 
Week 24 depending on treatment assignment, following the study procedures identified in 
Table 7.  Subjects could also return to the site as an unscheduled study visit for additional 
safety visits if the investigator feels it is necessary.  Sites should ensure that subjects 
adhere to the study visits.  Sites should provide additional study drug for subjects who 
cannot complete their study visit per the visit schedule to ensure they do not run out of 
study drug prior to their next study visit.  Compliance is critical to ensure adequate drug 
exposure.
Some of the Treatment Period study visits and visit activities (including but not limited to 
vital signs, clinical laboratory tests, and concomitant medication assessment) may be 
conducted in the home or non-hospital/clinic environment by qualified individuals at the 


ABT-450/r/ABT-267, ABT-333
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request of the Investigator, with approval from the Sponsor, and with the agreement of the 
subject.
Virologic failure criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.3. 
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as listed in Table 7 and 
as described in Section 5.4.1. Ideally, this should occur on the day of study drug 
discontinuation, but is recommended to be no later than 2 days after their final dose of 
study drugs and prior to the initiation of any other anti-HCV therapy.
Following completion or premature discontinuation of study drug treatment, all subjects 
will enter the 260-week Post-Treatment Period.  The Treatment Period will assess safety, 
antiviral response, progression of liver fibrosis, patient reported outcomes and clinical 
outcomes, including all-cause death, liver-related death, liver decompensation, occurrence 
of hepatocellular carcinoma, and liver transplantation.
5.1.3
Post-Treatment Period (PT)
All subjects who receive at least one dose of study drugs will be monitored for an 
additional 260 weeks following the last dose of study drugs.  Subjects will return to the 
study site as outlined in Table 7 for Post-Treatment procedures.  The Post-Treatment 
Period will begin the day after the last dose of study drugs.  Subjects could also return to 
the site as an unscheduled study visit for additional safety visits if the investigator feels it 
is necessary.  Subjects who prematurely discontinue the Post-Treatment Period should 
return to the site for a Post-Treatment Discontinuation Visit as outlined in Table 7.
The post-treatment period will assess safety, antiviral response, progression of liver 
fibrosis, patient reported outcomes, and clinical outcomes, including all-cause death, 
liver-related death, hepatocellular carcinoma, liver decompensation and need for liver 
transplantation.


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Some of the Post-Treatment Period study visits and visit activities (including but not 
limited to vital signs, clinical laboratory tests, and concomitant medication assessment) 
may be conducted in the home or non-hospital/clinic environment by qualified individuals 
at the request of the Investigator, with approval from the Sponsor, and with the agreement 
of the subject.
5.2
Selection of Study Population
The study population consists of HCV genotype 1-infected adult subjects with or without 
compensated cirrhosis, who are treatment naïve or IFN-based treatment experienced. 
Subjects who meet the inclusion criteria and who do not meet any of the 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) 
●
sexually active with female partners only
●
not of childbearing potential, defined as:
○
postmenopausal for at least 2 years prior to screening (defined as 
amenorrheic for longer than 2 years, age appropriate, and confirmed by a 
follicle-stimulating hormone (FSH) level indicating a postmenopausal 
state), or
○
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy 
or hysterectomy) or has a vasectomized partner(s); 
●
of childbearing potential and sexually active with male partner(s):
○
currently using at least one effective method of birth control at the time of 
screening and 
○
agree to practice two effective methods of birth control while receiving 
study drugs (as outlined in the subject information and consent form or 


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other subject information documents), starting with Study Day 1 and for 
30 days after stopping study drug, or 7 months after stopping drug if 
receiving RBV (or as directed by the local RBV label).  (Note:  Ethinyl 
estradiol-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug 
treatment).
3.
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) throughout the course of the study, starting with Study 
Day 1 and for 30 days after stopping study drug, or for 7 months after stopping 
study drug if receiving RBV (or as directed by the local RBV label).
4.
Chronic HCV-infection prior to study enrollment.  Chronic HCV-infection is 
defined as one of the following:
●
Positive for anti-HCV Ab or HCV RNA > 1,000 IU/mL at least 6 months 
before Screening, and positive for HCV RNA and anti-HCV Ab at the time of 
Screening; or 
●
HCV RNA > 1,000 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).
5.
Screening laboratory result indicating HCV genotype 1-infection.
6.
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 form, approved by an Institutional Review Board (IRB), prior to the 
initiation of any screening or study specific procedures.
Rationale for Inclusion Criteria
(1, 4, 5)  To select the appropriate subject population with sufficient disease severity for 
evaluation.


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(2, 3,)  RBV has known teratogenic effects.  The impact of AbbVie DAAs on pregnancies 
is unknown.
(6)  In accordance with harmonized Good Clinical Practice (GCP).
5.2.2
Exclusion Criteria
1.
Women who are pregnant or breastfeeding.
2.
Positive test result for Hepatitis B surface antigen (HbsAg) or confirmed positive 
anti-HIV antibody (HIV Ab) (test).
3.
Use of medications listed below, or medications contraindicated for ritonavir or 
RBV (for those that receive RBV), within 2 weeks or 10 half-lives whichever is 
longer, prior to study drug administration including but not limited to: 
Table 6.
Medications Contraindicated for Use with the Study Drug Regimen
For medications contraindicated with AbbVie's 3 DAA regimen, refer to the 
recommended prescribing information section of the approved local product labels in 
countries where the regimen contained in this study (i.e., ABT-450/r/ABT-267 and 
ABT-333) has received marketing authorization. If locally approved labels are not 
available, refer to the following Contraindicated Medication list:
Alfuzosin
Astemizole 
Carbamazepine
Cisparide
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Ethinyl estradiol-containing medications 
Fusidic Acid 
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Salmeterol
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with ritonavir, ribavirin, and 3DAA regimen are listed above.  Refer to the 
most current package inserts or product labeling of ritonavir and ribavirin for a complete list of 
contraindicated medications.


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4.
Use of known moderate or strong inducers of cytochrome P450 3A (CYP3A) or 
strong inducers of cytochrome P450 2C8 (CYP2C8) or strong inhibitors of 
CYP2C8 within 2 weeks of the respective medication/supplement, prior to initial 
dose of study drug.
5.
Clinically significant abnormalities or co-morbitities, other than HCV infection that 
in the opinion of the investigator make the subject an unsuitable candidate for this 
study or drug regimen. 
6.
Current enrollment in another interventional clinical study, previous enrollment in 
this study, prior or current use of any investigational or commercially available 
anti-HCV agents other than IFNs or RBV  (including previous exposure to 
ABT-450, ABT-267 or ABT-333), or receipt of any investigational product within 
6 weeks prior to study drug administration.
7.
History of solid organ transplant.
8.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Creatinine Clearance (CrCl) < 30 mL/min as estimated by the Cockcroft-Gault 
equation:  
CrCl = [(140-Age) × Mass (in kg) × (0.85 if female)] /
[72 × Serum creatinine (in mg/dL)]
●
Albumin < 2.8 g/dL
●
Hemoglobin < LLN
●
Platelets < 25,000 cells per mm3
●
Total bilirubin > 3.0 mg/dL
9.
Any current or past clinical evidence of Child-Pugh B or C Classification 
(Child-Pugh Score ≥ 7)  or clinical history of liver decompensation such as ascites 
(e.g., as noted on a physical exam or imaging test), variceal bleeding or hepatic 
encephalopathy.


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10.
Confirmed presence of hepatocellular carcinoma indicated on imaging techniques 
such as computed tomography (CT) scan or magnetic resonance imaging (MRI) 
within 3 months prior to Screening or on an ultrasound performed at Screening (a 
positive ultrasound result will be confirmed with CT scan or MRI.)
11.
HCV genotype performed during screening indicating infection with any genotype 
other than genotype 1.
Rationale for the Exclusion Criteria 
(1)  The impact of AbbVie DAAs on pregnancies is unknown.
(5, 7 – 10)  To ensure safety of the subjects throughout the study.
(3, 4, 6)  To avoid bias for the evaluation of efficacy and safety by concomitant use of 
other medications.
(2, 11)  To exclude subjects with viral infection other than HCV genotype 1.
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.
All medications will be recorded until 30 days following the last dose of study drugs.  
Only anti-HCV medications and concomitant medications relevant to SAE of death will 
be collected thereafter.
The AbbVie study-designated physician should be contacted if there are any questions 
regarding concomitant or prior therapies.


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5.2.3.1
Prior HCV Therapy
Subjects may be either treatment-naïve or IFN-based therapy (IFN or pegIFN 
monotherapy, IFN/RBV or pegIFN/RBV) treatment-experienced.  Prior or current use of 
any investigational or commercially available anti-HCV agents other than IFN or RBV, 
including telaprevir, boceprevir, sofosbuvir, simeprevir or an investigational agent, 
excludes a subject from this study.  Subjects who previously participated in trials of 
investigational anti-HCV agents may be enrolled if they can produce documentation that 
they received only placebo.
5.2.3.2
Concomitant Therapy
Subjects must be able to safely discontinue any prohibited medications within 2 weeks or 
10 half-lives of the medication whichever is longer, prior to initial study drug 
administration.  Subjects must be consented prior to discontinuing any prohibited 
medications for the purpose of meeting study inclusion criteria.
The investigator or a qualified designee should confirm that concomitant medication can 
be safely administered with DAAs (including ritonavir) and RBV.  Some medications 
may require dose adjustments due to potential for drug-drug interactions.  The investigator 
or qualified designee should review the locally approved labels for concomitant 
medication(s), ribavirin and ritonavir and, where available, ABT-450, ABT-267, and 
ABT-333 and utilize the drug-drug interactions (DDI) tool that will be provided by the 
sponsor to screen concomitant medications at each visit for potential DDIs with study 
drugs.  The investigator or qualified designee should document their DDI review in the 
subject's source or print report and place in subject's source documents.
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.


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Prior to enrollment, subjects should agree to practice two effective methods of birth 
control while receiving study drugs starting with Study Day 1 for 30 days after stopping 
study drug or for 7 months after stopping study drug if receiving RBV.  Subjects using 
ethinyl estradiol-containing medications (including combination 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 ethinyl estradiol-containing contraceptive 
with a progestin-only hormonal contraceptive method.
During the Post-Treatment Period, investigators should reassess concomitant medications.  
Subjects may resume revert to pre-study doses, at a minimum of 2 weeks following 
discontinuation of study drugs.
5.2.3.3
Prohibited Therapy
In addition to the medications listed above in Table 6, use of known moderate or strong 
inducers of CYP3A or strong inhibitors or inducers of CYP2C8 is prohibited within 
2 weeks or 10 half-lives of the medication, whichever is longer, prior to the initial dose of 
study drugs and through the first 2 weeks after the subject has completed study drugs in 
the Treatment Period.
The investigator or qualified designee should refer to the RBV labeling and DDI tool for a 
list of prohibited medications.  The investigator or qualified designee should document 
their DDI review in the subject's source or print report and place in subject's source 
documents.  Anti-HCV medications other than those specified in the protocol will not be 
allowed during the Treatment Period of the study.  Some medications may require dose 
adjustments due to potential for drug-drug interactions.
During the Post-Treatment Period, investigators should reassess concomitant medications.  
Subjects may resume revert to pre-study doses, at a minimum of 2 weeks following 
discontinuation of study drugs, if applicable.


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5.3
Efficacy: Pharmacokinetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart


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Table 7.
Study Activities
Activity
Treatment Period (TP)
Post-Treatment (PT) Period
Screening
Day 
1a
Week 
2
Week 
4
Week 
12b
End of Treatment 
(EOT) (Week 12 or 
24) or Treatment 
D/Cb,c
PT Weeks 4d, 12, 24, 52, 104, 
156,  208, 260 or PT D/Cc
Informed Consente
X
Provide RBV Medication Guidef
X
Medical History
X
Xg
Physical Examh
X
X
ECG
X
Vital Signs, Weight and Height
Xi
X
X
X
X
X
X
Pregnancy Test
   [serum (s) urine (u)]j
X
(s)
X
(u)
X 
(u)
X 
(u)
X 
(u)
X 
(u)
Hematology/Chemistry/Urinalysis/ 
Coagulation Panel
X
X
X
X
X
X
Xk
FSH (all females)
X
HBsAg, Anti-HCV Ab, Anti-HIV Ab
X
HCV Genotype and Subtype
X
IL28B Sample
X
Child-Pugh Scorel
X
Pharmacogenetic DNA (optional)m
X


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Table 7.
Study Activities (Continued)
Activity
Treatment Period (TP)
Post-Treatment (PT) Period
Screening
Day 
1a
Week 
2
Week 
4
Week 
12b
End of Treatment 
(EOT) (Week 12 or 
24) or Treatment 
D/Cb,c
PT Weeks 4d, 12, 24, 52, 104, 
156,  208, 260 or PT D/Cc
Liver Ultrasoundn
X
X
Xn
Concomitant Medication Assessmento
X
X
X
X
X
X
Xp
Patient Reported Outcomes (SF-36v2 and 
FACIT-F)q
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
Xp
Study Drugs Dispensedr
X
X
X
Study Drug Returned for IRT Reconciliation
X
X
Xb
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
Liver Biopsy, FibroScan or FibroTest for 
liver fibrosis assessments
X
X
X
X
X
Archive Samples (Plasma and Serum)
X
X
X
X
X
X
Assignment of Subject Number via IRT
X
Enrollment
X
Assessment of Clinical Outcomest
X
X
X
X
X


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Table 7.
Study Activities (Continued)
Activity
Treatment Period (TP)
Post-Treatment (PT) Period
Screening
Day 
1a
Week 
2
Week 
4
Week 
12b
End of Treatment 
(EOT) (Week 12 or 
24) or Treatment 
D/Cb,c
PT Weeks 4d, 12, 24, 52, 104, 
156,  208, 260 or PT D/Cc
Clinical Assessment of Liver 
Decompensation
X
Total Insulin
X
X
X
Xu
Wk = Week; D/C = Discontinuation 
a.
All procedures to be performed prior to first dose. 
b.
Treatment Duration Study Visits:
!
Subjects assigned to 12 weeks of treatment will complete the procedures and return drug from the screening visit through the End of Treatment Week 12/ D/C visit 
procedures.  Subjects will complete EOT Week 12 visit procedures instead of completing a TP Week 12 visit.
!
Subjects assigned to 24 weeks of treatment will complete the procedures and return drug from the screening visit through the EOT Week 24/D/C visit procedures at 
Week 24.  Subjects will complete a TP Week 12 Study Visit as an interim visit.
!
Study drug returned for IRT Reconciliation at TP Week 24 is only applicable to subjects who will receive treatment for 24 weeks.
c. 
Subjects that prematurely discontinue from the Treatment Period should return to the site to complete the Treatment D/C visitprocedures.  Subjects that prematurely 
discontinue from the Post-Treatment Period should return to the site to complete the PT D/C visit procedures.
d.
Study procedures at PT Week 4 are the same as for the remaining PT visits with the exception that FibroScan and Liver ultrasound should not be conducted.
e.
Subjects will need to sign an informed consent for the study (prior to performing any screening or study-specific procedures).
f.
RBV Medication Guide where applicable/locally available.
g.
Medical history will be updated at the Day 1 Visit.  This updated medical history will serve as the baseline for clinical assessment.
h.
A symptom-directed physical examination may be performed at any other visit, when necessary.
i.
Height will be measured at Screening only.


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Table 7.
Study Activities (Continued)
j.
Female subjects with a documented history of bilateral tubal ligation, bilateral oophorectomy or hysterectomy or who are confirmed to be post-menopausal do not require 
pregnancy testing throughout the trial.  A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.) 
Monthly urine pregnancy testing is required for women of childbearing potential who receive RBV for seven months (or per local RBV label) after end of treatment.  Females 
of childbearing potential that were treated with DAAs only in the Treatment Period should have urine pregnancy testing done through Post-Treatment Week 4.
k.
Urinalysis will not be conducted after the PT Week 4 Visit.
l.
Applies only to subjects with cirrhosis or suspected cirrhosis.  The Child-Pugh score will be calculated in the EDC RAVE system.  Subjects who were considered to be non-
cirrhotic at the Screening Visit but identified as cirrhotic (according to definitions listed in Section 5.1) during the screening period will return to the site prior to the baseline 
visit for Child-Pugh assessment.
m.
Verify the subject has given consent for the pharmacogenetic sample. If the optional pharmacogenetic sample is not collected on Study Day 1, it may be collected at any other 
visit during the study.
n. 
For subjects with compensated cirrhosis:  
!
Subjects receiving 12 weeks of treatment will have a liver ultrasound performed at the screening visit and all PT visits except PT Week 4.
!
Subjects receiving 24 weeks of treatment will have a liver ultrasound performed at the screening visit, Week 24 Visit, and all PT visits except the PT Week 4 and PT 
Week 12.  
For subjects without cirrhosis:  
!
Liver ultrasound will be performed at the screening visit, PT Week 52, PT Week 156 and PT Week 260.  
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to screening) are not required to undergo a screening ultrasound.
o.
The DDI tool provided by the sponsor should be utilized to evaluate the concomitant medications.
p.
AE and concomitant medications will not be collected after the PT Week 4 Visit.  Only anti-HCV medications and concomitant medications relevant to SAE of death will be 
collected after the PT Week 4 Visit.
q.
SF-36v2 and FACIT-F should be administered as the first study procedure at each visit and in the order listed.
r.
Study drugs dispensed at Week 12 only for subjects in the 24-week arm.
s.
Historical or screening liver biopsy, FibroScan or FibroTest results will be used to determine the presence or absence of cirrhosis for the purpose of treatment assignment.  
FibroTest will be performed at Day 1, PT Week 12 during the post-treatment period.  At sites where FibroScan is available, subjects will have FibroScan performed at 
Screening, End-of-Treatment Visit, and at all Post-Treatment Visits with the exception of PT Week 4. 


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Table 7.
Study Activities (Continued)
t.
Clinical Outcome events that occur during the Treatment Period through PT Week 4 are to be recorded and documented in the eCRF as an AE/SAE in addition to being 
captured in the Clinical Outcome eCRF(s).  Clinical outcome events that occur after the PT Week 4 are to be recorded in the Clinical Outcome eCRFs only, except when the 
clinical outcome is death, in which case the SAE eCRF would also need to be completed.
u.
Total Insulin will not be obtained at PT Week 4, 12, and 24.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 7 are discussed in detail in this section with the 
exception of the assessment of concomitant medications (Section 5.2.3), and the 
collection of adverse event information (Section 6.4).  All study data will be recorded in 
the subject's source documentation and then on the appropriate eCRFs, with the exception 
of laboratory data which will be provided to the Sponsor 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.  All subjects 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 use, will be taken at 
Screening.  The subject's medical history will be updated at the Study Day 1 Visit.  This 
updated medical history will serve as the baseline for clinical assessment.
Physical Examination
A complete physical examination will be performed at the Screening Visit and at Study 
Day 1.  A symptom-directed physical examination may be performed at any other visit, 
when necessary.
The physical examination performed at the Study Day 1 Visit 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.


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Vital Signs, Weight and Height
Body temperature, blood pressure, pulse and body weight will be measured at each study 
visit as specified in Table 7 or upon subject discontinuation.  Blood pressure and pulse 
rate will be measured after the subject has been sitting for at least 3 minutes.  The vital 
signs performed on Study Day 1 will serve as the baseline for clinical assessment.  The 
subject will wear lightweight clothing and no shoes during weighing.
Height will be measured only at Screening; the subject will not wear shoes.
12-lead Electrocardiogram
A 12-lead resting ECG will be obtained at the Screening Visit and when clinically needed.
The ECG should be obtained prior to the blood collection.
The ECG will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will interpret, sign, and date ECG tracings and 
will provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's assessment of the ECG tracing will be collected on case report 
forms, entered into the database and summarized.  The automatic machine reading 
(i.e., machine-generated measurements and interpretation that are automatically printed on 
the ECG tracing) will not be collected.  
Pregnancy Test
Pregnancy tests are not required for female subjects with documented prior bilateral tubal 
ligation, bilateral oophorectomy or hysterectomy or for subjects who are confirmed to be 


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postmenopausal.  Confirmation of postmenopausal status measured by FSH will be 
obtained at the Screening Visit only for all female subjects.
For females of childbearing potential:
●
A serum pregnancy test will be performed at the Screening Visit only and sent 
to the central laboratory for analysis.
●
Pregnancy testing will be performed as specified in Table 7 regardless of 
treatment regimen.
●
Females of childbearing potential that were treated with DAAs only in the 
Treatment Period should have urine pregnancy testing done through 
Post-Treatment Week 4.
●
Subjects that receive a RBV containing regimen will have pregnancy tests 
performed monthly throughout the Treatment Period and for a minimum of 
7 months after the discontinuation of RBV, or according to the local RBV 
label and/or local treatment guidelines for RBV. 
●
Urine pregnancy testing will be performed on-site during the study visit if 
there is a scheduled visit.  If there is not a scheduled study visit, subjects may 
either have pregnancy testing performed at the site as an unscheduled study 
visit using an unscheduled test kit or a urine pregnancy test may be conducted 
by the subject at home with a pregnancy test kit provided by the site.  If a urine 
pregnancy test is performed at home, site personnel should contact these 
female study subjects to capture the results of any study-related pregnancy 
tests in the source records only.
●
If a urine pregnancy result is positive a confirmatory hCG serum test should be 
collected and sent to the central lab.
Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCVAb and anti-HIV Ab will be performed at 
Screening.  A positive anti-HIV Ab test must be confirmed.  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.


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Clinical Laboratory Samples
Clinical Laboratory Samples will be obtained at a minimum for the clinical laboratory 
tests outlined in Table 8 at the visits specified in Table 7.  Blood samples for serum 
chemistry tests should be collected following a minimum 8-hour at fast on the following 
visits:  Day 1, End of Treatment Visit, and PT Week 52, 104, 156, 208, and 260.  The 
remaining visits may be non-fasting.  Subjects whose visits occur prior to the morning 
dose of study drug should be instructed to fast after midnight.  Subjects whose visits occur 
following the morning dose of study drug should be instructed to fast after breakfast until 
the study visit occurs.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is ICON.  Depending on the location of the study site, samples may be sent 
to one of the following addresses:
ICON Central Laboratories, Inc.
123 Smith Street
Farmingdale, NY  11735
USA
ICON Central Laboratories, Inc.
South County Business Park
Leopardstown, Dublin 18
Ireland
ICON Central Laboratories, Inc.
30 Loyang Way
#02-13 Loyang Industrial Estate
Singapore 508769


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Table 8.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Additional Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
ANC
Prothrombin Time/INRa
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
Albumina
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase 
(GGT)d
Creatinine clearance (Cockcroft 
Gault calculation)
Alpha2-macroglobulind
Haptoglobind
Apolipoprotein A1d
Alpha-Fetoprotein (AFP)b
HBsAgb
Anti-HCV Abb
Anti-HIV Abb
FSH (all females)b
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG) females)c
HCV RNA
Total Insulin
IL28Bb
HCV genotype and subtypeb
Pharmacogenetic DNA 
(optional)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Also a component of the Child-Pugh Assessment.
b.
Performed only at Screening.
c.
Urine pregnancy testing is not required 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.
d.
Also a component of FibroTest.
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.


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●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study, discontinued from study drug or requires a subject to receive treatment 
will be recorded as an adverse event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.7.
Liver Biopsy, FibroScan or FibroTest
At screening, subjects who have not had a liver biopsy within 24 months prior to 
screening, but who otherwise meet all of the inclusion criteria and none of the exclusion 
criteria will undergo either a liver biopsy or non-invasive test (FibroScan or 
FibroTest/APRI prior to enrollment) to determine presence or absence of cirrhosis.  APRI 
should be calculated from samples drawn on the same day.  Selection of liver biopsy or 
non-invasive testing should be based on local standard practice.
FibroScan (if available) and FibroTest will be performed as indicated in Table 7.
Child-Pugh Score and Category
The Child-Pugh score will be calculated prior to the Day 1 Visit and documented on the 
Screening Visit eCRFs for cirrhotic subjects only.  Subjects who were considered to be 
non-cirrhotic at the Screening Visit but identified as cirrhotic (according to definitions 
listed in Section 5.1) during the screening period will return to the site prior to the Study 
Day 1 Visit for Child-Pugh assessment.
The Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters 
and 2 clinical assessments) and is applicable only to subjects with cirrhosis.  Child-Pugh 
score will be determined at the Screening Visit as indicated in Table 7.  The Child-Pugh 
score will be automatically calculated prior to Day 1 by EDC RAVE once the investigator 
or designated site personnel enters the subject's parameters (as listed in Table 9).  A total 


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score of 5 – 6 is considered Class A (compensated disease); 7 – 9 is Class B (significant 
functional compromise); and 10 – 15 is Class C (decompensated disease).
Table 9.
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
Clinical Assessment of Liver Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed at Study 
Day 1 prior to dosing to confirm the subject has not progressed to hepatic decompensation 
since screening for all subjects who have compensated cirrhosis.  Grading system 
guidelines for ascites are listed above in Table 9.


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Liver Ultrasound 
In order to monitor for the presence of hepatocellular carcinoma (HCC) an ultrasound of 
the liver will be performed as indicated in Table 7.
For subjects with compensated cirrhosis: 
●
Subjects receiving 12 weeks of treatment will have a liver ultrasound 
performed at the Screening Visit and all post-treatment visits except PT 
Week 4
●
Subjects receiving 24 weeks of treatment will have a liver ultrasound 
performed at the screening visit, Week 24 visit, and all post-treatment visits 
except the PT Week 4 and PT Week 12.
For subjects without cirrhosis:  Liver ultrasound will be performed at the screening visit, 
PT Week 52, PT Week 156 and PT Week 260.
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to 
screening) are not required to undergo a screening ultrasound.
A positive ultrasound result suspicious for HCC at screening will be confirmed with CT 
scan or MRI during the screening period.  Suspicious ultrasound lesions confirmed by CT 
or MRI are exclusionary.
A positive Ultrasound result suspicious for HCC during the treatment or post-treatment 
period will be confirmed with CT scan or MRI. 
Assessment of Clinical Outcomes
The following clinical outcomes will be assessed during the study:
●
All-cause death:  death due to any cause
●
Liver-related death:  death as the result of a liver-related cause
●
Liver decompensation:  development of any of the following conditions:  
ascites, hepatic encephalopathy or variceal bleeding


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●
Liver transplantation:  any subject who had a liver transplantation
●
Hepatocellular carcinoma (HCC):  development of HCC in any subject at any 
time during the study.  HCC is defined by histologic confirmation or a > 1 cm 
mass lesion on cross-sectional imaging that meets the diagnostic criteria for 
HCC according to EASL guidelines.
●
Composite of any of the above outcomes
Clinical Outcome events that occur during the Treatment Period through Post-Treatment 
Week 4 are to be recorded and documented in the eCRF as an AE/SAE (Section 6.0) in 
addition to being captured in the Clinical Outcome eCRF(s).  Clinical Outcome events 
that occur after Post-Treatment Week 4 are considered a progression of the subject's 
existing liver disease and are to be recorded in the Clinical Outcome eCRFs only, except 
when the clinical outcome is death, in which case the AE/SAE eCRF would also need to 
be completed.  This information may be collected over the telephone in the event the 
subject is unable to return to the investigative site.
An independent outcome committee will review and adjudicate the validity of each 
clinical outcome.
Concomitant Medication Assessment
Use of medications (prescription or over-the-counter, including vitamins and herbal 
supplements) from the time of signing the consent through 30 days after last dose of study 
drug will be recorded in the eCRF at each study visit indicated in Table 7.  The 
investigator or qualified designee should review the locally approved labels for 
concomitant medication(s), ribavirin and ritonavir and, where applicable, ABT-450, 
ABT-267, and ABT-333 and should also utilize the DDI tool that will be provided by the 
sponsor for potential drug interactions.  The investigator or qualified designee should 
document their DDI review in the subject's source or print report and place in subject's 
source documents.


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During the Post-Treatment Period, all medications will be collected until 30 days 
following the last dose of study drugs.  Only anti-HCV medications and concomitant 
medications relevant to SAE of death will be collected thereafter.
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 7.  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 or understand any of the instruments may have site personnel read the 
questionnaires to them.  Site personnel will encourage completion of each instrument at 
all applicable visits and will ensure that a response is entered for all items.
PRO instruments will be consistently presented so that subjects will complete the 
Short-Form 36 Version 2 health survey (SF-36v2) instrument first and the FACIT–F 
instrument second.  PRO instruments should be completed as of the first study procedure 
at each visit and prior to any discussion of adverse events or any review of laboratory 
findings, including HCV RNA levels.
Short Form 36 – Version 2 Health Survey (SF-36v2)
The SF-36v2 is a non-disease specific Health Related Quality of Life (HRQoL) 
instrument with extensive use in multiple disease states.  The SF-36v2 instrument 
comprises 36 total items (questions) targeting a subject's functional health and well-being 
in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, 
social functioning, role emotional and mental health) with a recall period of 4 weeks.  
Domain scores are aggregated into a Physical Component Summary score and a Mental 
Component Summary score.  Higher SF-36v2 scores indicate a better state of health.  
Completion of the SF-36v2 should require approximately 10 minutes.


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The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT–F)
The FACIT–F is a symptom specific instrument with a focus on measuring fatigue in a 
variety of chronic diseases or health conditions.  It was originally developed from 
interviews with oncology patients and clinical experts to assess anemia-associated fatigue.  
Its 13-item version assesses peripheral, central, or mixed fatigue with a recall period of 
7 days and yields a summed total score ranging between 0 and 52.  Higher FACIT–F 
scores indicate a lesser degree of fatigue.  Completion of the FACIT–F (version 4) should 
require approximately 5 – 10 minutes.
Assignment of Subject Numbers 
A subject number is assigned at screening via IRT.  Subjects enrolled in the study will 
continue with the same subject number assigned at screening.  Subject numbers will be 
unique 5-digit numbers and will begin with 10001. 
Study Drug Dispensation:
Study drugs will be dispensed at the visits as indicated in Table 7.
Study Drug Returned for IRT Reconciliation
At each visit noted in Table 7, study drug compliance per the number of tablets of 
ABT-450/r/ABT-267, ABT-333, and RBV (if applicable) remaining in each kit (blister 
card for DAAs or bottle for RBV) will be recorded in the IRT system.  Additional 
information regarding treatment compliance can be found in Section 5.5.7.
HCV Genotype and Subtype
Plasma samples for HCV genotype and subtype will be collected at Screening.  Genotype 
and subtype will be assessed using the Versant® HCV genotype Inno-LiPA Assay, 
version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY).  Only 
subjects with HCV genotype 1 infection will be allowed to enroll.


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Table 7.  Plasma 
HCV RNA levels will be determined for each sample collected by the central laboratory 
using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0.  For this assay the 
lower limit of quantification (LLOQ) is 15 IU/mL.
HCV Resistance Testing Sample 
A plasma sample for HCV resistance testing will be collected at the study visits as 
indicated in Table 7.  Specific instructions for preparation and storage of HCV RNA and 
HCV resistance samples will be provided by the central laboratory, the Sponsor, or its 
designee.
Archive Samples
Archive plasma and serum samples will be collected at the study visits, indicated in 
Table 7.  Archive samples are being collected for possible additional analyses, including 
but not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, biomarkers of inflammation, HCV gene sequencing, HCV resistance testing, 
and other possible predictors of response, as determined by the Sponsor.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, the Sponsor, or its designee.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
IL28B Sample
One (required) 4mLwhole blood sample for deoxyribonucleic acid (DNA) isolation will 
be collected from each subject at screening for Interleukin 28B (IL28B) pharmacogenetic 
analysis and related markers.  If the sample is not collected at this visit, it may be 
collected at any time throughout the study.  This sample will not be used for any testing 
other than IL28B genotypes. 


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Specific instructions for sample collection, preparation and storage will be provided by 
the central laboratory, the Sponsor, or its designee.  Samples will be used only for IL28B 
testing and then destroyed.
Optional Pharmacogenetic Sample
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/r/ 
ABT-267, ABT-333 (or drugs of this class) continues but no longer than 20 years.
5.3.1.3
Meals and Dietary Requirements
All study drugs should be dosed together and administered with food, i.e., the AM dose of 
ABT-450/r/ABT-267, ABT-333 and RBV (if applicable) should be taken together with 
food and the PM dose of ABT-333 and RBV (if applicable) should be taken with food.
5.3.2
Efficacy Variables
5.3.2.1
Primary Variable
The primary endpoint is the incidence of all-cause death, liver-related death, liver 
decompensation, liver transplantation, hepatocellular carcinoma, and the composite of any 
of the above outcomes observed during the post-treatment period.


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5.3.2.2
Secondary Variables
The secondary endpoints are:
●
The mean change from baseline in FibroScan score, when available, during 
treatment period and post-treatment period. 
●
The percentage of subjects achieving SVR12 and corresponding 2-sided
95% confidence interval.
5.3.3
Safety Variables
The following safety evaluations will be analyzed during the study: adverse event 
monitoring and vital signs, physical examination, and laboratory tests assessments.
5.3.4
Pharmacogenetic Variable
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 ABT-450, ABT-267, 
ABT-333, or drugs of these classes.  The results may also be used for the development of 
diagnostic tests related to IL28B and study treatment, or drugs of these classes.
The optional DNA samples may be sequenced and data analyzed for genetic factors 
contributing to the disease or to the subject's response to ABT-450, ABT-267, ABT-333, 
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 ABT-450, ABT-267, ABT-333, or to drugs of these classes, or the disease state.  The 
samples may also be used for the development of diagnostic tests related to ABT-450, 


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ABT-267, ABT-333, drugs of these classes, or the disease state.  The results of 
pharmacogenetic analyses may not be reported with the study summary.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
Subjects that discontinue study regardless of cause should be contacted (minimally as a 
telephone assessment) at each yearly scheduled visit to collect the survival status only if 
they provide consent.
If the subject prematurely discontinues during the Treatment Period or the Post-Treatment 
Period, the procedures outlined for the applicable Premature D/C Visit should be 
completed as defined in Table 7.  Ideally for study drug discontinuation, this should occur 
on the day of study drug discontinuation, but no later than 2 days after their final dose of 
study drug and prior to the initiation of any other anti-HCV therapy.  However, these 
procedures should not interfere with the initiation of any new treatments or therapeutic 
modalities that the investigator feels are necessary to treat the subject's condition.  
Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment.  The last dose of any study drug and reason for 
discontinuation from the Treatment Period will be recorded in the EDC.  
If a subject has an ongoing adverse event or an unresolved laboratory result that is 
significantly outside of the reference range at the time of study drug discontinuation, the 
investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.


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In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of RBV (if 
applicable) to that subject must be discontinued immediately and DAAs may be continued 
at the principal investigator's discretion after discussion with the subject, if the benefit of 
continuing DAAs is felt to outweigh the potential risk.  Specific instructions regarding 
subject pregnancy can be found in Section 6.6.  Subjects will be monitored for SVR in the 
Post-Treatment Period as described in Section 5.1.2.  The investigator is also encouraged 
to report the pregnancy information to the voluntary RBV Pregnancy Registry, if 
applicable.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.4.3
Discontinuation of Subjects that Meet Virologic Failure 
Criteria
The following criteria will be considered evidence of virologic failure:  
●
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;
●
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA 
measurements ≥ LLOQ) at any point after HCV RNA < LLOQ


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Confirmatory testing for the above criteria should be completed as soon as possible.  
Subjects receiving study drug treatment should remain on treatment until the virologic 
failure has been confirmed.
If any of the above criteria are confirmed for subjects during study drug treatment, the 
subject will discontinue treatment.  If the investigator believes the virologic failure is due 
to study drug interruption and/or is compliance related, the AbbVie Study Designated 
Physician should be contacted to discuss alternative management.
5.5
Treatments
5.5.1
Treatments Administered
ABT-450/r/ABT-267 will be provided by the Sponsor as 75 mg/50 mg/12.5 mg tablets.  
ABT-450/r/ABT-267 will be taken orally as 2 tablets once daily which corresponds to a 
ABT-450 150 mg/ ritonavir 100 mg/ ABT-267 25 mg dose.  
ABT-333 will be provided by the Sponsor as 250 mg tablets.  ABT-333 will be taken 
orally as 1 tablet twice daily, which corresponds to a 250 mg dose BID.
RBV will also be provided by the sponsor to the Investigator for use in this study.  RBV 
will be provided as 200 mg tablets.  RBV is dosed based on weight, for subjects with CrCl 
≥ 50 mL/min 1000 to 1200 mg divided twice daily per local label.  (For example, for 
subjects weighing less than 75 kg, RBV may be taken orally as 2 tablets in the morning 
and 3 tablets in the evening which corresponds to a 1000 mg total daily dose.  For subjects 
weighing 75 kg or more, RBV may be taken orally as 3 tablets in the morning and 
3 tablets in the evening which corresponds to a 1200 mg total daily dose.)
For subjects with CrCl ≥ 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 13.


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5.5.2
Identity of Investigational Products
Table 10.
Identity of Investigational Products
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
ABT-450/ritonavir/ 
ABT-267
AbbVie
Oral
Tablet
75 mg/ 
50 mg/ 
12.5 mg
ABT-333
AbbVie
Oral
Tablet
250 mg
Ribavirin 
Roche or Generic 
Manufacturer
Oral
Tablet
200 mg
5.5.2.1
Packaging and Labeling
ABT-450/r/ABT-267 and ABT-333 tablets will be supplied in weekly kits.  Each kit will 
consist of a blister card containing 1 week of study medication plus one additional day of 
drug.  There will be 16 ABT-333 250 mg tablets and 16 ABT-450/r/ABT-267 
75 mg/50 mg/12.5 mg tablets for a total of 32 tablets per blister card.
The blister cards indicate which drugs on the card should be taken in the morning (both 
ABT-450/r/ABT-267 tablets and one ABT-333 tablet) with a picture of a sun and which 
should be taken in the evening (one ABT-333 tablet) with a picture of a moon. 
Ribavirin tablets will be supplied to the site in bottles containing 168 tablets.
All study drugs will be labeled as required per country requirements.  
The labels must remain affixed to the primary and potential secondary packaging material.  
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(s)
Table 11.
Study Drug Storage Conditions
Study Drug
Storage Conditions
ABT-450/r/ABT-267 and ABT-333 blister cards
15° to 25°C (59° to 77°F)
Australia:  Store below 25°C
Ribavirin bottles
15° to 25°C (59° to 77°F)
Australia:  Store below 25°C
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drugs 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 the Sponsor.  Upon receipt of study drugs, 
the site will acknowledge receipt within the IRT system.
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT 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 
contact IRT in order to receive unique study drug kit numbers.  The study drug kit 
numbers will be assigned according to schedules computer-generated before the start of 
the study by the AbbVie Statistics Department.
Contact information and user guidelines for IRT will be provided to each site.  Upon 
receipt of study drug, the site will acknowledge receipt in IRT.
5.5.4
Selection and Timing of Dose for Each Subject
Study drug dosing will be initiated at the Day 1 Visit.  ABT-450/r/ABT-267 will be dosed 
QD, ABT-333 and RBV (if applicable) will be dosed BID.  Thus with normal dosing, 


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2 ABT-450/r/ABT-267 tablets and 1 ABT-333 tablet should be taken in the morning, and 
1 ABT-333 tablet should be taken in the evening.
RBV (if applicable) should be dosed BID, e.g., with 2 to 3 tablets taken in the morning, 
and 3 tablets taken in the evening based on weight.
All study drugs should be dosed together and administered with food; i.e., the AM dose of 
ABT-450/r/ABT-267, ABT-333 and RBV (if applicable) should be taken together with 
food and the PM dose of RBV and ABT-333 should be taken 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 those described in 
the protocol.
All study drugs will be dispensed to 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 potential development of resistance.  The start and stop dates of all 
study drugs will be recorded in the source documents and eCRFs.
During the Treatment Period, subjects will be instructed to bring all study drug kits (full, 
partial or empty) to the study site at each study visit.  The study site personnel will inspect 
the contents of the bottles and blister cards at study visits defined as Study Drug Returned 
for IRT Reconciliation in Table 7 and record the status of each one as well as the exact 
number of remaining tablets of ABT-450/r/ABT-267 and ABT-333 or tablets of RBV and 
the date of reconciliation in the IRT system.  If poor adherence is noted, the subject 
should be counseled and this should be documented in the subject's source.


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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 in the IRT system.  A current 
(running) and accurate inventory of study drug will be kept by the investigator and will 
include lot number, POR number, number of tablets dispensed, subject number, and date 
dispensed for each subject.  
During the study, should an enrolled subject misplace or damage a study drug bottle, the 
IRT system must be contacted and informed of the misplaced or damaged study drug.  If 
the bottle is damaged, the subject will be requested to return the remaining study drug to 
the site.  Replacement study drug may only be dispensed to the subject by contacting the 
IRT system.  Study drug replacement(s) and an explanation of the reason for the 
misplaced or damaged study drug(s) will be documented within the IRT system at study 
visits defined as Study Drug Returned for IRT Reconciliation as specified in Table 7.  
Study drug start dates for each drug and the last dose of the regimen will be documented 
on the appropriate eCRF.  The status of each bottle, number of tablets remaining in each 
one returned, and the date of reconciliation will be documented in the IRT system.
Upon completion of or discontinuation from the Treatment Period, all original study drug 
bottles (containing unused study drugs) will be returned to the Sponsor (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  The number of tablets of each type of study drug returned in each bottle will 
be noted in the IRT.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The combination regimen of ABT-450/r/ABT-267 and ABT-333 with or without RBV for 
12 and 24 weeks has been evaluated in treatment-naïve and pegIFN/RBV 
treatment-experienced HCV GT1-infected subjects, with or without compensated 


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cirrhosis, in the Phase 3 studies.  Based upon the results from Studies M11-646, M13-098, 
M13-961, M13-389, M14-002 and M13-099 (discussed in detail in Section 3.0), AbbVie 
plans to evaluate the same combination regimen used in the Phase 3 studies in a study 
population of treatment-naïve and IFN-based therapy treatment-experienced HCV 
GT1-infected subjects, with or without compensated cirrhosis. 
The intention of this study is to assess the effect of treatment response on long-term 
clinical outcomes and evaluate the SVR12 following treatment with ABT-450/r/ABT-267 
and ABT-333, with or without RBV.  As such, the absence of randomization, blinding or 
control groups is appropriate.  
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  HCV 
RNA assays are standard and validated.  FibroScan® is a validated non-invasive 
diagnostic test to evaluate liver disease.  The SF-36v2 and FACIT–F instruments are 
standard in the literature and thoroughly validated in the general population and in 
subjects who have chronic health conditions.  The SF-36v2 health survey is the standard 
Health-related Quality of Life instrument in hepatitis C subjects worldwide and FACIT–F 
has been used in hepatitis C registration clinical trials as an assessment tool for fatigue.
5.6.3
Suitability of Subject Population
This study plans to enroll both HCV treatment-naïve and IFN-based therapy treatment-
experienced subjects with genotype 1 chronic HCV, with or without compensated 
cirrhosis.  The subject population to be studied is reflective of the current demographics of 
chronic HCV infection.  Moreover, this study population has been evaluated in the 
Phase 3 studies where more than 2,300 subjects received the 3-DAA combination regimen 
that is planned to be administered in this study.  In the Phase 3 studies, treatment with 
ABT-450/r/ABT-267 and ABT-333 with RBV for 12 weeks resulted in SVR12 in 96% to 
99% of HCV GT1-infected, treatment-naïve subjects without cirrhosis, and 96% to 100% 
of HCV GT1-infected, pegIFN/RBV treatment-experienced subjects without cirrhosis.  
Similarly, high SVR12 rates (99-100%) were seen in HCV GT1b-infected treatment-naïve 


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and pegIFN/RBV treatment-experienced subjects without cirrhosis following treatment 
with ABT-450/r/ABT-267 and ABT-333, without RBV for 12 weeks.  Among subjects 
with compensated cirrhosis, 92% and 96% of HCV GT1-infected treatment-naïve and 
pegIFN/RBV treatment-experienced subjects achieved SVR12 following treatment with 
ABT-450/r/ABT-267 and ABT-333 with RBV for 12 and 24 weeks, respectively.  The 
DAA regimen ABT-450/r, ABT-267 and ABT-333 with or without RBV has been well 
tolerated in the Phase 3 studies, as evidenced by the low rate of treatment discontinuation 
and serious adverse events. 
5.6.4
Selection of Doses in the Study
ABT-450/r/ABT-267 and ABT-333
Doses of the three DAAs to be used in this study have been administered in the Phase 3 
Studies M11-646, M13-098, M13-389, M13-961, M14-002 and M13-099, and have 
shown high SVR12 rates in combination with each other, with or without RBV, with a 
favorable safety profile.  The maximum dose of ABT-450/r/ABT-267 
75 mg/50 mg/12.5 mg tablets will not exceed 150 mg/100 mg/25 mg per day for 
24 weeks.  The maximum dose of ABT-333 250 mg tablets administered in this study will 
not exceed 500 mg per day for 24 weeks.  
RBV (if applicable)
The daily dose of RBV in this study is 1000 or 1200 mg, divided twice daily, and based 
on subject weight.  This dose is approved for treatment of adult patients with chronic 
hepatitis C infection in combination with pegIFN.  The same dose was studied in the 
Phase 3 Studies M11-646, M13-098, M13-389, M13-961, M14-002 and M13-099 and 
was found to be generally safe and well tolerated and resulted in high SVR rates. 
The maximum RBV dose administered in this study will not exceed 1200 mg, divided 
twice daily for 24 weeks.


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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 related to study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
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, and/or if the investigator considers them to be adverse events.


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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 or 
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.
Protocol defined clinical outcomes consist of:
●
All-cause death:  death due to any cause.
●
Liver-related death:  death as the result of a liver-related cause.
●
Liver transplantation:  Any subject who had a liver transplantation.
●
Liver decompensation:  development of any of the following conditions:  
ascites, hepatic encephalopathy, or variceal bleeding.
●
Hepatocellular carcinoma (HCC):  development of HCC in any subject at any 
time during the study.  HCC is defined by histologic confirmation or a > 1 cm 
mass lesion on cross-sectional imaging that meets the diagnostic criteria for 
HCC according to EASL guidelines.
Clinical Outcome events that occur during the Treatment Period through Post Treatment 
Week 4 are to be recorded and documented in eCRF as an AE/SAE in addition to being 
captured in the Clinical Outcome eCRF(s).  Clinical Outcome events that occur after 
Post-Treatment Week 4 are considered a progression of the subject's existing liver disease 
and are to be recorded in the Clinical Outcome eCRFs only, except when the clinical 
outcome is death, in which case the AE/SAE eCRFs would also need to be completed.
These outcomes will form part of the study endpoints and will be reported in the clinical 
study report at the end of the study, or earlier as locally required.


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


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). 
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
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:


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Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.4
Adverse Event Collection Period
All serious adverse events, as well as protocol related non-serious 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 drug treatment has elapsed, all adverse events and serious 
adverse events will be collected, whether solicited or spontaneously reported by the 
subject.  After PT Week 4 until the end of the study only SAE of death will be collected.
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
SAEs and 
protocol-
related non-
serious AEs
SAEs and Non-Serious AEs
Elicited and/or Spontaneously Reported
SAE of Death
∀
∀
∀
∀
∀
Consent 
Signed
Study 
Drug Start
Study 
Drug 
Stopped
30 Days 
After Study 
Drug Stopped
End of 
Study
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.  For SAEs 
that occur prior to the site having access to the RAVE® system, or if RAVE is not 
operable, the forms should be faxed to Clinical Pharmacovigilance within 24 hours of the 
site being made aware of the SAE.
FAX to:  +1 (847)-938-0660
Email:  PPDINDPharmacovigilance@AbbVie.com
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
Dept. R48S, Bldg. AP30-3
1 North Waukegan Road
North Chicago, IL  60064
Office:
+1 (847) 938-1870
Email:
SafetyManagement_Virology@abbvie.com




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Pregnancy in a study subject must be reported to the AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  Subjects who report a positive pregnancy test 
during the Treatment Period must be notified to stop RBV (if applicable) immediately.  
Administration of DAAs may be continued at the investigator's discretion after discussion 
with the subject, if the benefit of continuing therapy is felt to outweigh the risk 
(Section 5.4.1).
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.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to the Sponsor within 24 hours of 
the site becoming aware of the event.
6.7
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 
table should be used in determination of the appropriate toxicity management as discussed 
in Sections 6.7.1 through 6.7.5.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or the Sponsor as having a "reasonable possibility"
of being related to the study drug (Section 6.3).  A toxicity is deemed "clinically 


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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
Grade 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) for subjects receiving RBV, Section 6.7.5 (Management of 
ALT Elevations) and Section 6.7.6 (Creatinine Clearance), may continue study drugs with 
follow-up per study protocol and in accordance with local standard of care.
6.7.2
Grade 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 
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 for subjects 
receiving RBV 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 


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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 entered into the appropriate eCRFs.
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 – Section 6.7.2 above.


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For subjects receiving ribavirin:  
Reductions in hemoglobin are a well characterized side effect of RBV exposure.  If a 
subject receiving the standard dose of RBV experiences a hemoglobin decrease meeting 
one of the criteria outlined in Table 12, a confirmatory test should be performed.  If the 
hemoglobin decrease is confirmed, the management guidelines in Table 12 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 12 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 outlined in Table 12.
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 12.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases
Hemoglobin Value
Intervention
Subjects with creatinine clearance ≥ 50 mL/min
< 10 g/dL 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 RBV.  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 RBV.  Manage the subject as medically appropriate.
If hemoglobin increases to ≥ 12 g/dL RBV may be restarted.
For subjects with creatinine clearance < 50 mL/min
< 10 g/dL
Interrupt RBV.  Manage the subject as medically appropriate.
If hemoglobin increases to ≥ 10 g/dL, RBV may be restarted. If 
creatinine clearance increases to ≥ 50 mL/min, refer to guidance above.
*
1st dose reduction of RBV is by 200 mg/day or per local label.  If needed, 2nd dose reduction of RBV is by an 
additional 200 mg/day.  Subjects whose dose of RBV is reduced to 600 mg daily receive one 200 mg tablet in the 
morning and two 200 mg tablets 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 the 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 
≥50 mL/min), or to below 30 mL/minute (in a subject with a 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).  RBV dose should be adjusted 
as in Table 13.  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 needed.  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 13.
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
If creatinine clearance improves, the site should perform all necessary readjustment of any 
dose modifications that have been made.  If creatinine clearance improves to above the 
level that triggered the RBV dose reduction, 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.
Clinical Toxicity Table will be appended to protocol in Appendix C.  
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  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 their assigned Monitor or the 
following AbbVie personnel:




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primary efficacy analysis on clinical outcomes will be performed on all subjects in the 
ITT population. 
The ITT-I population will consist of all subjects enrolled in this study only who receive at 
least one dose of study drug.  All other efficacy, safety, and demographic analyses will be 
performed on all subjects in the ITT-I population. 
No data will be imputed for any efficacy or safety analyses except for the PRO 
questionnaires and for analyses of the HCV RNA endpoints.  If a respondent answers at 
least 50% of the items in a multi-item scale of the SF-36v2, the missing items will be 
imputed with the average score of the answered items in the same scale.  In cases where 
the respondent did not answer at least 50% of the items, the score for that domain will be 
considered missing.  Similarly, the missing items of the FACIT-F questionnaire will be 
imputed with the average score of the answered items in the same scale as long as at least 
50% of the items in the scale were answered.  The SF-36v2 Mental and Physical 
Component Summary measures will not be computed if any domain is missing.  
HCV RNA values will be selected for the SVR12 analysis based on the 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.  In addition, if a subject has an unquantifiable HCV RNA level at the 
preceding value and an undetectable HCV RNA level at the succeeding value, or vice 
versa, the HCV RNA level will be imputed as unquantifiable at this visit for this subject.  
Subsequent to this flanking 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).  For SVR12 analysis, if there is no value in the appropriate 


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window but there is an HCV RNA value after the window, then it will be imputed into the 
SVR12 window.
8.1.1
Demographics
Demographics and baseline characteristics will be summarized for all subjects in the ITT 
population.  Demographics include age, weight, height, and BMI, and the frequency of 
gender, race and ethnicity.  Baseline characteristics will include HCV genotype 1 subtype 
(1a, 1b, other), IL28B genotype ([CC, CT, or TT] and [CC or non-CC]), IFN treatment 
history (treatment-naïve [IFN-eligible, IFN-ineligible] or IFN-based treatment-
experienced [null responder, partial responder, relapse, prior relapse/breakthrough, prior 
nonresponder, interferon intolerant and interferon experienced-other]), baseline HCV 
RNA levels [(continuous) and (≤800,000 IU/mL or > 800,000 IU/mL)], baseline 
HOMA-IR (< 3 mU × mmol/L2 or ≥ 3 mU × mmol/L2), baseline fibrosis stage (F0-1, F2, 
F3, F4), tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or 
non-drinker) status.  Summary statistics (N, mean, median, 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., gender and race).
8.1.2
Efficacy
The primary efficacy analysis on clinical outcomes will be performed on all subjects in 
the ITT population.  All other efficacy analyses will be performed on the ITT-I population
At sites where FibroScan is available, subjects will have FibroScan® performed at 
Screening, End-of-Treatment Visit and throughout the Treatment and Post-Treatment 
Period as indicated in Table 7 for the purpose of assessing changes in liver fibrosis over 
time.
Incidence of all-cause death, liver-related death, liver decompensation, liver 
transplantation, and hepatocellular carcinoma as defined in protocol Section 5.3.1.1 will 
be collected during the 5-Year Post-Treatment Period.


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Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0.  For this 
assay, the lower limit of quantification (LLOQ) is 15 IU/mL.  HCV RNA results that are 
detectable but not quantifiable are reported as "HCV RNA is detected, less than 15 IU/mL 
HCV RNA".
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is to assess the effect of response to treatment on clinical 
outcomes by comparing the time to incidence of the following events between subjects 
who achieve SVR12 and those who do not using a Cox regression model:
●
All-cause death
●
Liver-related death
●
Liver decompensation
●
Liver transplantation
●
Hepatocellular carcinoma
●
Composite of any of the above outcomes
8.1.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
The effect of sustained virologic response and baseline fibrosis stage on 
longitudinal change from baseline in Fibroscan score (assessed at the end of 
treatment and/or post-treatment visits) will be evaluated by comparing mean 
change between subjects who achieve SVR12 and those who do not.  Point 
estimates and 95% confidence intervals will be provided.
●
The percentage of subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks after 
the last actual dose of study drug).  The simple percentage of subjects achieving 
SVR12 will be calculated and a two-sided 95% confidence interval of the 
percentage will be computed based on Wilson's score method.  


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8.1.2.3
Subgroup Analyses
Subgroup efficacy analyses on clinical outcomes, liver stiffness and the percentage of 
subjects achieving SVR12 will be performed as appropriate and useful.
8.1.2.4
Additional Efficacy Endpoints
The following additional efficacy endpoints will be analyzed and summarized:
●
The number and percentage of subjects meeting each and any of the following 
SVR12 non-response categories:
○
On-treatment virologic failure (rebound or fail to suppress)
○
Relapse 
○
Premature study drug discontinuation with no on-treatment virologic 
failure
○
Missing SVR12 data 
○
Other
The following analyses of patient reported outcomes (PROs) will be performed.  For PRO 
analysis, summary statistics (n, mean, SD, minimum and maximum) will be provided at 
Day 1 and each applicable visit.  The mean change from baseline in quality of life and 
fatigueto Post Treatment Week 12 and to Post-Treatment Week 24 (assessed by the 
Short-Form 36 Version 2 health survey (SF-36v2) questionnaires) and (The Functional 
Assessment of Chronic Illness Therapy – Fatigue (FACIT–F) and will be compared by 
appropriate baseline fibrosis stages.  In particular, the comparison of the mean change 
from baseline to Post-Treatment Week 12 and to Post Treatment Week 24 in the SF-36 
V2 Vitality scale, Mental Component Summary score, Physical Component Summary 
score and FACIT–F score, will be performed using ANCOVA analyses with appropriate 
baseline fibrosis stage as factor, and baseline PRO score and SVR12 status as covariates.  
Additional analysis on the PRO data will be performed as useful and appropriate.


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8.1.3
Resistance
For subjects who do not achieve or maintain SVR12, and who are included in the analyses 
described below, the sample closest in time after virologic failure with an HCV RNA 
level ≥ 1000 IU/mL will be used if the HCV RNA level at the time of failure is 
< 1000 IU/mL.  The prototypic reference strains with their associated GenBank Accession 
IDs for sequence analyses are genotype 1a-H77 (NC_004102) and 1b-Con1 (AJ238799).
For each DAA target, resistance-associated signature amino acid variants will be 
identified by AbbVie Clinical Virology.  Amino acid positions where resistance-
associated variants have been identified in vitro and/or in vivo are 1) for ABT-450:  36, 
43, 56, 155, 156, and 168 in NS3 for genotype 1a; 56, 155, 156, and 168 in NS3 for 
genotype 1b; 2) for ABT-267:  28, 30, 31, 32, 58, and 93 in NS5A for genotype 1a; 28, 
29, 30, 31, 32, 58, and 93 in NS5A for genotype 1b; and 3) for ABT-333:  316, 414, 446, 
448, 451 553, 554, 555, 556, 558, 559, and 561 in NS5B for genotype 1a; 316, 368, 411, 
414, 445, 448, 553, 556, 558, and 559 in NS5B for genotype 1b.
The following definitions will be used in the resistance analyses:
●
Baseline sample:  sample collected before the first dose of DAA study drug.
●
Baseline variant:  a variant in the 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:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline.
●
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 any of 
these positions.
For those samples evaluated, a listing by subject of all baseline variants relative to 
prototypic reference sequence at signature resistance-associated amino acid positions will 


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be provided for each DAA target (NS3, NS5A, and/or 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 subtype out of the 
total number of baseline samples sequenced will also be provided.
The HCV amino acid sequence at post-baseline time points with an HCV RNA level of 
≥1000 IU/mL that are analyzed will be compared to the baseline and appropriate 
prototypic reference amino acid sequences.  Listings by subject and time point of all 
post-baseline variants at signature resistance-associated amino acid positions relative to 
the baseline and to the appropriate prototypic reference amino acid sequences will be 
provided.  
Linkage between variants at signature resistance-associated amino acid positions by 
population sequencing will also be evaluated.  A listing by subject and time point of the 
linked variants by population sequencing will be provided.  In addition, a summary of the 
number and percentage of subjects with linked variants within each target by HCV 
subtype out of the total number of baseline samples sequenced will be provided.
The persistence of resistance-associated substitutions that emerged for each target (NS3, 
NS5A, and NS5B) will be assessed by population sequencing at selected post-treatment 
time points in a subset of subjects.  Listings by subject and time point of all post-baseline 
variants at signature resistance-associated amino acid positions relative to the baseline 
amino acid sequence will be provided for each DAA target (NS3, NS5A, and NS5B).
8.1.4
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.
8.1.5
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subject treatment-emergent adverse events 


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(i.e., any event that begins or worsens in severity after initiation of study drug through 
30 days post-study drug dosing) will be tabulated by primary MedDRA System Organ 
Class (SOC) and preferred term (PT).  The tabulation of the number of subjects with 
treatment-emergent adverse events by severity 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.
Additional analyses will be performed if useful and appropriate.
8.1.6
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.
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.
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.  Additional analyses will be performed if useful and 
appropriate.
8.1.7
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from Day 1 to each Post Baseline Visit will be summarized descriptively.  Number and 


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percentage of subjects with post-baseline values meeting pre-defined criteria for 
Potentially Clinically Significant vital signs values during treatment will be summarized.  
8.2
Determination of Sample Size
Assuming 4% of subjects do not achieve SVR12 and assuming the 5-year event rate of the 
composite clinical outcome is 20% in the non-SVR12 subjects, with a 75% reduction in  
SVR12 subjects (Hazard Ratio of 0.25), then based on two-sample log rank test (using 
EAST 6.0), a sample size of at least 2000subjects enrolled in TOPAZ-I and TOPAZ-II 
provides greater than 80% power to reject the null hypothesis of no difference between 
SVR12 and non-SVR12 subjects in the rate of clinical outcome events.  Power calculations 
were based on a dropout rate of up to 20%. 
8.3
Randomization Methods
There is no randomization in this study
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, and approved by 
Regulatory Authority (ies), if required by local regulations, prior to implementation of any 


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changes made to the study design.  The investigator will be required to submit, maintain 
and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  The subject 
will sign for acceptance of the optional pharmacogenetic sample on the informed consent.  
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.
The decision to allow pharmacogenetic analysis will be determined by local regulations.  
A blood sample for optional pharmacogenetic analysis will only be collected if the subject 


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has voluntarily signed and dated the optional IRB/IEC portion of the informed consent, 
after the nature of the testing has been explained and the subject has had the opportunity 
to ask questions.  The optional pharmacogenetic informed consent section must be signed 
before the pharmacogenetic analysis is performed.  If the subject does not consent to the 
pharmacogenetic analysis 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.


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The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any optional pharmacogenetic research that may be done using DNA samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision-making or patient management.  Hence, the investigator, the subject, nor the 
subject's physician (if different than the investigator) will be informed of individual 


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subject pharmacogenetic results, should analyses be performed, nor will anyone not 
directly involved in this research.  Correspondingly, genetic researchers will have no 
access to subject identifiers.  Individual results will not be reported to anyone not directly 
involved in this research other than for regulatory purposes.  Aggregate 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 Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-450, ABT-267, 
ABT-333 and the product labeling for ribavirin.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-Label, Multicenter Study to Evaluate Long-Term 
Outcomes With ABT-450/Ritonavir/ABT-267 (ABT-450/r/
ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults 
With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection 
(TOPAZ-I)
Protocol Date:
19 January 2015
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.  2001;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.
Backus LI, Boothroyd DB, Phillips BR, et al.  A sustained virologic response 
reduces risk of all-cause mortality in patients with hepatitis C.  Clin Gastroenterol 
Hepatol.  2011;9(6):509-516.e1.
10.
Veldt BJ, Heathcote EJ, Wedemeyer H, et al.  Sustained virologic response and 
clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.  Ann 
Intern Med.  2007;147(10):677-84.
11.
Everson GT, Balart L, Lee SS, et al.  Histological benefits of virological response 
to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced 
fibrosis or compensated cirrhosis.  Aliment Pharmacol Ther.  2008;27(7):542-51.


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12.
Poynard T, McHutchison J, Manns M, et al.  Impact of pegylated interferon alfa-2b 
and ribavirin on liver fibrosis in patients with chronic hepatitis C.  
Gastroenterology.  2002;122(5):1303-13.
13.
Shiffman ML, Hofmann CM, Thompson EB, et al.  Relationship between 
biochemical, virologic and histologic response during interferon treatment of 
chronic hepatitis C.  Hepatology.  1997;26:780-5.
14.
Bruno S, Stroffolini T, Colombo M, et al.  Sustained virological response to 
interferon-alpha is associated with improved outcome in HCV-related cirrhosis:  a 
retrospective study.  Hepatology.  2007;45(3):579-87.
15.
Di Bisceglie AM, Everson GT, Linsay KL, et al.  Prolonged antiviral therapy with 
peginterferon to prevent complications of advanced liver disease associated with 
hepatitis C:  results of the hepatitis C antiviral long-term treatment against cirrhosis 
(HALT-C) trial.  Hepatology.  2007;46:ALB1-ALB1.
16.
Camma C, Di Bona D, Schepis F, et al.  Effect of peginterferon alfa-2a on liver 
histology in chronic hepatitis C:  a meta-analysis of individual patient data.  
Hepatology.  2004;39:333-42
17.
Shiffman ML, Morishima C, Dienstag JL, et al; HALT-C Trial Group.  Effect of 
HCV RNA suppression during peginterferon alfa-2a maintenance therapy on 
clinical outcomes in the HALT-C trial.  Gastroenterology.  2009;137(6):1986-94.
18.
Backus LI, Boothroyd DB, Phillips BR, et al.  A sustained virologic response 
reduces risk of all-cause mortality in patients with hepatitis C.  Clin Gastroenterol 
Hepatol.  2011;9(6):509-16.
19.
Martinez SM, Foucher J, Combis JM, et al.  Longitudinal liver stiffness assessment 
in patients with chronic hepatitis C undergoing antiviral therapy.  PLoS One.  
2012;7(10):e47715.
20.
Vergniol J, Foucher J, Castéra L, et al.  Changes of non-invasive markers and 
FibroScan values during HCV treatment.  J Viral Hepat.  2009;16(2):132-40.


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21.
Ogawa E, Furusyo N, Toyoda K, et al.  The longitudinal quantitative assessment by 
transient elastography of chronic hepatitis C patients treated with pegylated 
interferon alpha-2b and ribavirin.  Antiviral Res.  2009;83(2):127-34.
22.
AbbVie.  ABT-450/r Investigator's Brochure Edition 7.  2014.
23.
AbbVie.  ABT-267 Investigator's Brochure Edition 5.  2014.
24.
AbbVie.  ABT-333 Investigator's Brochure Edition 7.  2014.
25.
Norvir® (ritonavir) [package insert].  North Chicago, IL; AbbVie Inc., 2013. 
26.
Ribasphere® (ribavirin tablets) [package insert].  Warrendale, PA; Kadmon 
Pharmaceuticals, LLC, 2012.
27.
Davis GL, Alter MJ, El-Serag H, et al.  Aging of hepatitis C virus (HCV)-infected 
persons in the United States:  a multiple cohort model of HCV prevalence and 
disease progression.  Gastroenterology.  2010;138:513-21.


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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
Statistics
Clinical
Clinical
Clinical
Global Drug Supply Management
Clinical


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Appendix C.
Clinical Toxicity Grades


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Appendix D.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:"
Add:  central back-up phone number
Central Back-Up Phone:
+1 (973) 784-6402
Section 1.2  Synopsis
Subsection Methodology:
Fifth paragraph previously read:
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with compensated cirrhosis who are prior IFN/RBV or pegIFN/RBV null 
responders or nonresponders; these subjects will receive treatment for 24 weeks.
Has been changed to read:
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with compensated cirrhosis; these subjects will receive treatment for 24 weeks.  
Treatment duration of 12 weeks for HCV GT1a-infected subjects with compensated 
cirrhosis may be selected by the investigator where consistent with the local approved 
label, in countries where marketing authorization has been granted for the regimen 
included in this study.
Section 1.2  Synopsis
Subsection Methodology:
Add:  new sixth paragraph
HCV GT1a-infected subjects with compensated cirrhosis who were originally assigned to 
12 weeks of treatment under a previous version of this protocol will be assigned to 
24 weeks of treatment unless 1) the investigator determines that a 12-week duration of 


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therapy is appropriate based on the approved local label; or 2) the subject has already 
completed the original study drug treatment and additional treatment cannot be initiated 
within 15 days of the date that the original treatment was completed.
Section 1.2  Synopsis
Subsection Methodology:
Eighth paragraph, first sentence previously read:
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to 
less than or equal to 400 subjects; the number of subjects enrolled without fibrosis or with 
portal fibrosis without septa (an equivalent Metavir score of F0 or F1 respectively) will be 
less than or equal to 1000 subjects
Has been changed to read:
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to 
less than or approximately equal to 400 subjects; the number of subjects enrolled without 
fibrosis or with portal fibrosis without septa (an equivalent Metavir score of F0 or F1 
respectively) will be limited to 1000 subjects.  
Section 1.2  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Inclusion:"
Criterion 2
Fourth bullet, second sub-bullet, second paragraph previously read:
(Note:  Estrogen-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug treatment).
Has been changed to read:
(Note:  Ethinyl estradiol-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug treatment).


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Section 1.2  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Exclusion:"
Criterion 1 previously read:
1.
Use of medications listed below, or medications contraindicated for ritonavir or RBV (for those that 
receive RBV), within 2 weeks or 10 half-lives whichever is longer, prior to study drug administration 
including but not limited to:
Alfuzosin
Astemizole 
Carbamazepine
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Estrogen-containing Medications for 
Systemic Use
Fusidic Acid
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Not all medications contraindicated with 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.
Has been changed to read:
1.
Use of medications listed below, or medications contraindicated for ritonavir or RBV (for those that 
receive RBV), within 2 weeks or 10 half-lives whichever is longer, prior to study drug administration 
including but not limited to:
For additional medications contraindicated with AbbVie's 3 DAA regimen, refer to the recommended 
prescribing information section of the approved local product labels in countries where the regimen 
contained in this study (i.e., ABT-450/r/ABT-267 and ABT-333) has received marketing authorization. If 
locally approved labels are not available, refer to the following Contraindicated Medication list:
Alfuzosin
Astemizole 
Carbamazepine
Cisapride
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Ethinyl estradiol-containing medications
Fusidic Acid
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Salmeterol
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with ritonavir, ribavirin, and 3DAA regimen are listed above.  Refer to the 
most current package inserts or product labeling of ritonavir and ribavirin for a complete list of 
contraindicated medications.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
AFP
Alpha-fetoprotein
Section 3.0  Introduction
Subsection Integrated Safety Results
Fourth paragraph previously read:
Transient asymptomatic postbaseline serum ALT elevations of > 5× ULN occurred at a 
frequency of 1% across active treatment arms and were evaluated by an external hepatic 
panel.  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 postbaseline elevations in serum ALT.  No ALT elevations greater than 
5 times ULN were observed in subjects receiving progestins only or in subjects 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.
Has been changed to read:
Transient asymptomatic postbaseline serum ALT elevations of > 5× ULN occurred at a 
frequency of 1% across active treatment arms and were evaluated by an external hepatic 
panel.  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 ethinyl estradiol-containing therapy 
(i.e., combination contraceptives) and discontinuation of the hormonal therapy with 
continuation or brief interruption of the DAA regimen led to resolution in serum ALT 


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elevation.  Concomitant use of systemic ethinyl estadiol-containing medications is a risk 
factor for these postbaseline elevations in serum ALT.  There was no increase in the risk 
of ALT elevations greater than 5 × ULN in subjects on estrogens other than ethinyl 
estradiol (i.e., estradiol, conjugated estrogens) or in subjects on only progestins. 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.
Section 3.0  Introduction
Subsection Integrated Safety Results
Delete:  fifth paragraph
ABT-450/ritonavir, ABT-267 (and its major, inactive human metabolites) and ABT-333 
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 
exposures at the recommended clinical doses.  Clinical studies in women who are 
pregnant have not been conducted.
Section 3.0  Introduction
Subsection Integrated Safety Results
Seventh paragraph previously read:
A detailed discussion of the preclinical toxicology, metabolism, pharmacokinetics and 
drug-drug interactions can be found in the Investigator's Brochure for ABT-267, 
ABT-450, ABT-333 and product label for ritonavir and ribavirin.22-26
Has been changed to read:
A detailed discussion of the preclinical toxicology (including reproductive and 
development toxicity), metabolism, pharmacokinetics and drug-drug interactions can be 
found in the Investigator's Brochure for ABT-267, ABT-450, ABT-333 or prescribing 
information for ombitasvir/paritaprevir/r and dasabuvir in countries with marketing 
authorization, and product label for ritonavir and ribavirin.22-26


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Section 3.2  Benefits and Risks
Second paragraph previously read:
The likelihood of successfully curing HCV in compensated cirrhotics following treatment 
with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV was evaluated in 
Study M13-099.  In Study M13-099, 91.8% and 95.9% of HCV GT1-infected 
treatment-naïve and pegIFN/RBV treatment-experienced subjects achieved SVR12
following treatment for 12 and 24 weeks, respectively.  Analysis of subgroups 
demonstrated that the difference in SVR12 rates between treatment arms was due to the 
lower SVR12 rate in GT1a-infected pegIFN/RBV treatment-experienced prior null 
responders treated for 12 weeks.  Among HCV GT1a-infected subjects, partial responders 
and relapsers had higher SVR rates than null responders in the 12 week treatment group, 
while similar SVR rates were seen among the null responders, partial responders and 
relapsers treated for 24 weeks, suggesting that the longer duration of 24 weeks is required 
only for HCV GT1a null responders.  SVR rates were high across all subgroups in HCV 
GT1b-infected subjects treated for 12 and 24 weeks.  For this reason, HCV GT1a-infected 
subjects with compensated cirrhosis and were prior null responders to pegIFN/RBV will 
receive 3-DAA with RBV for 24 weeks.
Has been changed to read:
The likelihood of successfully curing HCV in compensated cirrhotics following treatment 
with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV was evaluated in 
Study M13-099.  In Study M13-099, 91.8% and 95.9% of HCV GT1-infected 
treatment-naïve and pegIFN/RBV treatment-experienced subjects achieved SVR12
following treatment for 12 and 24 weeks, respectively.  Analysis of subgroups 
demonstrated that the difference in SVR12 rates between treatment arms was due to the 
lower SVR12 rate in GT1a-infected pegIFN/RBV treatment-experienced prior null 
responders treated for 12 weeks.  Among HCV GT1a-infected subjects, partial responders 
and relapsers had higher SVR rates than null responders in the 12-week treatment group, 
while similar SVR rates were seen among the null responders, partial responders and 
relapsers treated for 24 weeks, suggesting that the longer duration of 24 weeks is required 


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only for HCV GT1a null responders.  SVR rates were high across all subgroups in HCV 
GT1b-infected subjects treated for 12 and 24 weeks.  For this reason, in previous versions 
of this protocol HCV GT1a-infected subjects with compensated cirrhosis and who were 
prior null responders or non-responders to pegIFN/RBV were assigned to receive 3-DAA 
with RBV for 24 weeks, while HCV GT1a-infected subjects with compensated cirrhosis 
who were not prior null responders or non-responders to IFN/RBV were assigned to 
received 3-DAA with RBV for 12 weeks.  In order to align the treatment duration for 
subjects with GT1a infection and compensated cirrhosis with the recommended treatment 
duration that is found in the prescribing information of some approved local labels for the 
AbbVie product containing the regimen included in this study (i.e., ABT-450/r/ABT-267 
and ABT-333), the protocol now specifies that all HCV GT1a-infected subjects with 
compensated cirrhosis will be assigned to receive 3-DAA with RBV for 24 weeks.  
Treatment duration of 12 weeks for HCV GT1a-infected subjects with compensated 
cirrhosis may be selected by the investigator where consistent with the approved local 
label.
Section 3.2  Benefits and Risks
Add:  new third paragraph 
HCV GT1a-infected subjects with compensated cirrhosis who were assigned to 12 weeks 
of treatment under a previous version of this protocol will be assigned to 24 weeks of 
treatment unless 1) the investigator determines that a 12-week duration of therapy is 
appropriate based on the approved local label; or 2) the subject has already completed the 
original study drug treatment and additional treatment cannot be initiated within 15 days 
of the date that the original treatment was completed.


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Table 4.  Baseline Fibrosis Stage
Last table row previously read:
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy 
Metavir, Batts-
Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest
F4 
4
5 or 6
≥ 12.5 to ≥ 14.6
≥ 0.73
Has been changed to read:
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy 
Metavir, Batts-
Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest
F4 
4
5 or 6
≥ 14.6
≥ 0.73
Section 5.1  Overall Study Design and Plan:  Description
Tenth paragraph previously read:
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to 
less than or equal to 400 subjects; the number of subjects enrolled without fibrosis or with 
portal fibrosis without septa (an equivalent Metavir score of F0 or F1 respectively) will be 
less than or equal to 1000 subjects.
Has been changed to read:
The number of cirrhotic subjects (an equivalent Metavir score of F4) will be limited to 
less than or approximately equal to 400 subjects; the number of subjects enrolled without 
fibrosis or with portal fibrosis without septa (an equivalent Metavir score of F0 or F1 
respectively) will be limited to 1000 subjects.


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Section 5.1.2  Treatment Period (TP)
Third paragraph, first sentence previously read:
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected prior 
IFN/RBV or pegIFN/RBV null responder or nonresponder subjects with compensated 
cirrhosis who will receive treatment for 24 weeks.  
Has been changed to read:
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with compensated cirrhosis who will receive treatment for 24 weeks.  Treatment 
duration of 12 weeks for HCV GT1a-infected subjects with compensated cirrhosis may be 
selected by the investigator where consistent with the approved local label.
Table 5.  Treatment Regimen and Duration
Previously read:
Subjects
Treatment Regimen
Treatment 
Duration
HCV 
GT1a-infected 
subjects*
without cirrhosis
ABT-450/r/ABT-267 
+ ABT-333 + RBV
12 weeks
with compensated cirrhosis who are:
!
treatment-naïve 
!
prior IFN/RBV or pegIFN/RBV partial 
responder 
!
prior IFN/RBV or pegIFN/RBV relapser 
!
prior IFN/RBV or pegIFN/RBV 
relapse/breakthrough
!
interferon intolerant
!
interferon experienced-other
with compensated cirrhosis who are:
!
prior IFN/RBV or pegIFN/RBV null 
responders 
!
prior IFN/RBV or pegIFN/RBV 
nonresponder
ABT-450/r/ABT-267 
+ ABT-333 + RBV
24 weeks
HCV 
GT1b-infected 
subjects
without cirrhosis
ABT-450/r/ABT-267 
+ ABT-333
12 weeks
with compensated cirrhosis
ABT-450/r/ABT-267 
+ ABT-333 + RBV
12 weeks
*
Includes subjects that are unable to be subtyped or with mixed subtypes.


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Has been changed to read:
Subject Population
Treatment Regimen*
Treatment Duration
Genotype 1a, without cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
12 weeks
Genotype 1a, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
24 weeks**
Genotype 1b, without cirrhosis
ABT-450/r/ABT-267 + ABT-333
12 weeks
Genotype 1b, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 
+ ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed 
genotype 1 infection.
**
Treatment for 12 weeks may be considered in some patients where consistent with the approved local label.
Section 5.2.1  Inclusion Criteria
Criterion 2
Fourth bullet, second sub-bullet, second sentence previously read:
(Note:  Estrogen-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug treatment).
Has been changed to read:
(Note:  Ethinyl estradiol-containing hormonal contraceptives, including oral, injectable, 
implantable, patch and ring varieties, may not be used during study drug treatment).


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Table 6.  Medications Contraindicated for Use with the Study Drug Regimen
Previously read:
Alfuzosin
Astemizole 
Carbamazepine
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Estrogen-containing Medications 
for Systemic Use
Fusidic Acid 
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Not all medications contraindicated with 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.
Has been changed to read:
For medications contraindicated with AbbVie's 3 DAA regimen, refer to the 
recommended prescribing information section of the approved local product labels in 
countries where the regimen contained in this study (i.e., ABT-450/r/ABT-267 and 
ABT-333) has received marketing authorization. If locally approved labels are not 
available, refer to the following Contraindicated Medication list:
Alfuzosin
Astemizole 
Carbamazepine
Cisparide
Dihydroergotamine
Efavirenz 
Ergotamine
Ergonovine
Ethinyl estradiol-containing medications 
Fusidic Acid 
Gemfibrozil
Lovastatin
Methylergonovine 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide 
Rifampin
Salmeterol
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
*
When used for the treatment of pulmonary arterial hypertension.
Note:
Not all medications contraindicated with ritonavir, ribavirin, and 3DAA regimen are listed above.  Refer to the 
most current package inserts or product labeling of ritonavir and ribavirin for a complete list of 
contraindicated medications.


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Section 5.2.2  Exclusion Criteria
Criterion 4 previously read:
Use of known strong inducers of cytochrome P450 3A (CYP3A) or strong inducers of 
cytochrome P450 2C8 (CYP2C8) or strong inhibitors of CYP2C8 within 2 weeks of the 
respective medication/supplement, prior to initial dose of study drug.
Has been changed to read:
Use of known moderate or strong inducers of cytochrome P450 3A (CYP3A) or strong 
inducers of cytochrome P450 2C8 (CYP2C8) or strong inhibitors of CYP2C8 within 
2 weeks of the respective medication/supplement, prior to initial dose of study drug.
Section 5.2.2  Exclusion Criteria
Criterion 6 previously read:
Current enrollment in another interventional clinical study, previous enrollment in this 
study, prior or current use of any investigational or commercially available anti-HCV 
agents other than IFN or RBV  (including previous exposure to ABT-450, ABT-267 or 
ABT-333), or receipt of any investigational product within 6 weeks prior to study drug 
administration.
Has been changed to read:
Current enrollment in another interventional clinical study, previous enrollment in this 
study, prior or current use of any investigational or commercially available anti-HCV 
agents other than IFNs or RBV  (including previous exposure to ABT-450, ABT-267 or 
ABT-333), or receipt of any investigational product within 6 weeks prior to study drug 
administration.


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Section 5.2.3.2  Concomitant Therapy
Second paragraph, third sentence previously read:
The investigator or qualified designee should review the concomitant medication(s) labels 
and utilize the drug-drug interactions (DDI) tool that will be provided by the sponsor to 
screen concomitant medications at each visit for potential DDIs with study drugs.  
Has been changed to read:
The investigator or qualified designee should review the locally approved labels for 
concomitant medication(s), ribavirin and ritonavir and, where available, ABT-450, 
ABT-267, and ABT-333 and utilize the drug-drug interactions (DDI) tool that will be 
provided by the sponsor to screen concomitant medications at each visit for potential 
DDIs with study drugs.
Section 5.2.3.2  Concomitant Therapy
Fifth paragraph previously read:
Prior to enrollment, subjects should agree to practice two effective methods of birth 
control while receiving study drugs starting with Study Day 1 for 30 days after stopping 
study drug or for 7 months after stopping study drug if receiving RBV.  Subjects using 
systemic estrogen-containing medications (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 
estrogen-containing contraceptive with a progestin-only hormonal contraceptive method.
Has been changed to read:
Prior to enrollment, subjects should agree to practice two effective methods of birth 
control while receiving study drugs starting with Study Day 1 for 30 days after stopping 
study drug or for 7 months after stopping study drug if receiving RBV.  Subjects using 
ethinyl estradiol-containing medications (including combination oral contraceptives) have 
a higher risk for elevated ALT levels.  Subjects using these medications must discontinue 


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them at least 2 weeks prior to study drug administration or 10 half-lives (if known), 
whichever is longer.  Subjects may replace the ethinyl estradiol-containing contraceptive 
with a progestin-only hormonal contraceptive method.
Section 5.2.3.3  Prohibited Therapy
First paragraph previously read:
In addition to the medications listed above in Table 6, use of known strong inducers of 
CYP3A or strong inhibitors or inducers of CYP2C8 is prohibited within 2 weeks or 
10 half-lives of the medication, whichever is longer, prior to the initial dose of study 
drugs and through the first 2 weeks after the subject has completed study drugs in the 
Treatment Period.
Has been changed to read:
In addition to the medications listed above in Table 6, use of known moderate or strong 
inducers of CYP3A or strong inhibitors or inducers of CYP2C8 is prohibited within 
2 weeks or 10 half-lives of the medication, whichever is longer, prior to the initial dose of 
study drugs and through the first 2 weeks after the subject has completed study drugs in 
the Treatment Period.
Table 7.  Study Activities
Delete:  row "Study Drug Returned for IRT Reconciliation"
Activity
Treatment Period (TP)
Post-Treatment 
(PT) Period
Screening
Day
1a
Week 
2
Week 
4
Week 
12b
End of 
Treatment 
(EOT) (Week 12 
or 24) or 
Treatment D/Cb,c
PT Weeks 4d, 12, 
24, 52, 104, 156,  
208, 260 or PT 
D/Cc
Study Drug 
Returned for IRT 
Reconciliation
X
X
X
Xb


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Table 7.  Study Activities
Table note "j."
Add new last sentence to second paragraph
Females of childbearing potential that were treated with DAAs only in the Treatment 
Period should have urine pregnancy testing done through Post-Treatment Week 4.
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Test
Add:  new third bullet
Females of childbearing potential that were treated with DAAs only in the Treatment 
Period should have urine pregnancy testing done through Post-Treatment Week 4.
Table 8.  Clinical Laboratory Tests
"Clinical Chemistry" column
Add:  
Alpha-Fetoprotein (AFP)b
Section 5.3.1.1  Study Procedures
Subsection Concomitant Medication Assessment
First paragraph, second sentence previously read:
The investigator or qualified designee should review concomitant medication(s) label(s) 
and should also utilize the DDI tool that will be provided by the sponsor for potential drug 
interactions.
Has been changed to read:
The investigator or qualified designee should review the locally approved labels for 
concomitant medication(s), ribavirin and ritonavir and, where applicable, ABT-450, 
ABT-267, and ABT-333 and should also utilize the DDI tool that will be provided by the 
sponsor for potential drug interactions.  




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Table 12.  Ribavirin Dose Modification Guidelines in Management of Hemoglobin 
Decreases
Table note previously read:
*
1st dose reduction of RBV is by 200 mg/day.  If needed, 2nd dose reduction of RBV is by an additional 200 mg/day.  
Subjects whose dose of RBV is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg 
tablets in the evening
Has been changed to read:
*
1st dose reduction of RBV is by 200 mg/day or per local label.  If needed, 2nd dose reduction of RBV is by an 
additional 200 mg/day.  Subjects whose dose of RBV is reduced to 600 mg daily receive one 200 mg tablet in the 
morning and two 200 mg tablets in the evening.
Section 9.1  Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB)
Second paragraph, first sentence previously read:
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.
Has been changed to read:
Any amendments to the protocol will require IEC/IRB approval, and approved by 
Regulatory Authority (ies), if required by local regulations, prior to implementation of any 
changes made to the study design.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Statistics
Clinical
Clinical
Clinical
Global Drug Supply Management
HEOR
Clinical


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Has been changed to read:
Name
Title
Functional Area
Statistics
Clinical
Clinical
Clinical
Global Drug Supply Management
Clinical

SAP_001.pdf: 
ABT-450/r/ABT-267 and ABT-333
M14-423 – Statistical Analysis Plan
Version 1.0 – 22 March 2017
1
1.0
Title Page
Statistical Analysis Plan
Study M14-423
An Open-Label, Multicenter Study to Evaluate
Long-Term Outcomes With
ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and 
ABT-333 With or Without Ribavirin (RBV) in Adults 
With Genotype 1 Chronic Hepatitis C Virus (HCV) 
Infection
(TOPAZ-I)
Date:  22 March 2017
NCT02219490


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................6
4.1
Objectives .............................................................................................. 6
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 8
4.4
Planned Analysis.................................................................................... 9
5.0
Analysis Populations .............................................................9
5.1
Definition for Analysis Populations ........................................................ 9
5.1.1
Intention-to-Treat (ITT) Population ........................................................ 9
5.1.2
Intention-to-Treat-I (ITT-I) Population................................................. 10
5.1.3
Safety Population ................................................................................. 10
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions .......................................................... 10
6.1
Baseline and Final Value...................................................................... 11
6.1.1
Baseline................................................................................................ 11
6.1.2
Study Days........................................................................................... 11
6.1.3
Study Drug End Days........................................................................... 12
6.1.4
Final Treatment Value.......................................................................... 12
6.1.5
Final Post-Treatment Value .................................................................. 12
6.2
Analysis Windows................................................................................ 12
6.3
Missing Data Imputation ...................................................................... 17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............19
7.1
Demographic and Baseline Characteristics ........................................... 19
7.2
Medical History.................................................................................... 22
7.3
Previous Treatment and Concomitant Medications ............................... 22
8.0
Patient Disposition............................................................... 23
9.0
Study Drug Exposure and Compliance.............................. 24
9.1
Exposure .............................................................................................. 24


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9.2
Compliance .......................................................................................... 24
10.0
Efficacy Analysis .................................................................25
10.1
General Considerations......................................................................... 25
10.2
Handling of Multiplicity....................................................................... 29
10.3
Primary Efficacy Analysis.................................................................... 29
10.4
Secondary Efficacy Analyses ............................................................... 31
10.5
Efficacy Subgroup Analysis ................................................................. 32
10.6
Sensitivity Analysis for the Efficacy Endpoint of SVR12....................... 34
10.7
Additional Efficacy Analyses ............................................................... 34
10.8
Resistance Analyses ............................................................................. 37
10.9
Patient Reported Outcomes .................................................................. 40
11.0
Safety Analysis.....................................................................42
11.1
General Considerations......................................................................... 42
11.2
Analysis of Adverse Events.................................................................. 42
11.2.1
Treatment-Emergent Adverse Events.................................................... 42
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events ............................ 42
11.2.2
Listing of Adverse Event...................................................................... 46
11.3
Analysis of Laboratory Data................................................................. 46
11.3.1
Variables and Criteria Defining Abnormality........................................ 46
11.3.2
Statistical Methods ............................................................................... 50
11.4
Analysis of Vital Signs and Weight ...................................................... 52
11.4.1
Variables and Criteria Defining Abnormality (if Applicable)................ 52
11.4.2
Statistical Methods ............................................................................... 53
12.0
References............................................................................54
List of Tables
Table 1.
Treatment Regimen and Duration........................................................... 8
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period) ............................................................................... 13
Table 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 14
Table 4.
Analysis Time Windows for PRO Instruments...................................... 15


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Table 5.
Laboratory Data and Vital Sign Visit Windows (Treatment 
Period) ................................................................................................. 16
Table 6.
Laboratory Data and Vital Sign Visit Windows (Post-Treatment 
Period) ................................................................................................. 17
Table 7.
Child-Pugh Classification of Severity of Cirrhosis................................ 21
Table 8.
Criteria for Potentially Clinically Significant Hematology Values ........ 48
Table 9.
Criteria for Potentially Clinically Significant Chemistry Values ........... 49
Table 10.
Definitions of CTCAE Grades 1, 2, 3, and 4......................................... 52
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values............ 53


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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 M14-423.  TOPAZ-I 
(Study M14-423) and companion study TOPAZ-II (Study M14-222) are designed 
together and share the primary objective of assessing the effect of treatment response 
(assessed by SVR12 status, i.e., HCV ribonucleic acid (RNA) < lower limit of 
quantification (LLOQ) 12 weeks following treatment) on long-term clinical outcomes in 
adults with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection who received 
treatment with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin, as measured 
by all-cause death, liver-related death, liver decompensation, liver transplantation, and 
hepatocellular carcinoma. 
In the TOPAZ-I and TOPAZ-II studies, the primary objective is to assess the effect of 
treatment response on long-term clinical outcomes, based on the data from both studies 
combined.  The studies differ based on geographic region (this study will be conducted 
outside the US while the TOPAZ-II study will be conducted in the US) and based on 
certain procedures that are not related to the primary outcome.  For example, this study 
will assess the long-term change from baseline in liver elastography, and the TOPAZ-II 
study will utilize a Subject Care Plan Model to facilitate subjects' adherence to the study 
drug.
The SAP provides details to guide the analyses for baseline, efficacy, and safety variables 
and describes the populations and variables that will be analyzed and the statistical 
methods that will be utilized.  An interim analysis (after all subjects reach Post-Treatment 
[PT] Week 12 or prematurely discontinue the study) and an end of study analysis will be 
conducted for Study M14-423.  Analyses will be performed using SAS® Version 9.3 
(SAS Institute, Inc., Cary, NC) or later under the UNIX operating system.


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4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to evaluate the effect of virologic response to 
treatment (assessed by SVR12 status) on the long-term progression of liver disease in 
adults with chronic HCV GT1 infection who receive treatment with ABT-450/r/ABT-267 
and ABT-333 with or without ribavirin, as measured by all-cause death, liver-related 
death, liver decompensation, liver transplantation, and hepatocellular carcinoma.
The secondary objectives are to evaluate the long-term progression of fibrosis and 
sustained virologic response in adults with GT1 chronic HCV infection who received 
treatment with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin.  Progression 
of fibrosis is measured by change from baseline in liver stiffness using transient 
elastography (FibroScan®), when available.  Sustained virologic response is evaluated by 
the percentage of subjects achieving SVR12.
4.2
Design Diagram
Study M14-423 is a Phase 3b, open-label, multi-center study, which is designed together 
with companion Study M14-222 (TOPAZ-II) to share the primary objective of assessing 
the effect of treatment response on long-term clinical outcomes in adults with GT1 
chronic HCV infection with or without compensated cirrhosis, who are either 
treatment-naïve or IFN/RBV (IFN or peg IFN/RBV) treatment-experienced.  
Approximately 1650 subjects will be enrolled in Study M14-423 at approximately 
200 sites outside the US.  The number of cirrhotic subjects (fibrosis stage of F4) will be 
limited to approximately 400 subjects; the number of subjects enrolled without fibrosis or 
with portal fibrosis without septa (fibrosis stage of F0 or F1) will be limited to 
approximately 1000 subjects.
As shown in Figure 1, subjects meeting eligibility criteria will be enrolled to either 12 or 
24 weeks of treatment according to HCV subgenotype and presence of cirrhosis.  Subjects 


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who receive at least one dose of study drug will be followed in the Post-Treatment Period 
for up to 5 years (PT Week 260).
Figure 1.
Study Schematic
The duration of the study will be 272 weeks (for subjects receiving a 12-week treatment) 
or 284 weeks (for subjects receiving a 24-week treatment), not including a screening 
period of up to 42 days, consisting of a 12-week or 24-week Treatment Period and a 
260-week Post-Treatment (PT) Period for all subjects who receive at least one dose of 
study drug.
Treatment Period
Subjects who meet the eligibility criteria will be enrolled to either 12 or 24 weeks of 
combination therapy with or without RBV as described below and in Table 1.
All HCV GT1-infected subjects who are either treatment-naïve or treatment-experienced 
will receive ABT-450/r/ABT-267 150/100/25 mg once daily (QD) and ABT-333 250 mg 
twice daily (BID).  Subjects with HCV GT1a infection and all GT1-infected subjects with 
compensated cirrhosis will also receive RBV with weight-based dosing 1000 or 1200 mg 
BID.
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with compensated cirrhosis, who will receive treatment for 24 weeks, unless a
treatment duration of 12 weeks is selected by the investigator based on the subject's prior 


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treatment history.  Subjects will receive a study drug regimen according to criteria listed 
in Table 1.  Upon completing the Treatment Period or premature discontinuation of the 
Treatment Period, subjects will enter the Post Treatment (PT) Period.
Table 1.
Treatment Regimen and Duration
Subject Population
Treatment Regimen*
Treatment 
Duration
Genotype 1a, without cirrhosis
ABT-450/r/ABT-267 + ABT-333 + ribavirin
12 weeks
Genotype 1a, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 + ribavirin
24 weeks**
Genotype 1b, without cirrhosis
ABT-450/r/ABT-267 + ABT-333
12 weeks
Genotype 1b, with cirrhosis
ABT-450/r/ABT-267 + ABT-333 + ribavirin
12 weeks
*
Note:  Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with 
mixed genotype 1 infection.
**
Treatment for 12 weeks may be considered in some patients where consistent with the approved local label.
Post-Treatment Period
Subjects who receive at least one dose of study drug in the Treatment Period and either 
complete treatment or prematurely discontinue study drug will be followed in the Post-
Treatment Period for up to 260 weeks.  At the Post-Treatment visits, subjects will be 
assessed for antiviral response, progression of liver fibrosis, patient reported outcomes 
(PROs) and clinical outcomes, including all-cause death, liver-related death, and 
occurrence of hepatocellular carcinoma, liver decompensation and liver transplantation. 
The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.
4.3
Sample Size
Assuming 4% of subjects do not achieve SVR12 and assuming the 5-year event rate of the 
composite clinical outcome is 20% in the non-SVR12 subjects, with a 75% reduction in 
SVR12 subjects (Hazard Ratio of 0.25),1,2 then based on two-sample log rank test (using 
EAST 6.0), a sample size of at least 2000 subjects enrolled in TOPAZ-I (planned to enroll 
1650 subjects) and TOPAZ II (planned to enroll 600 subjects) provides greater than 80% 


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power to reject the null hypothesis of no difference between SVR12 and non-SVR12
subjects in the rate of clinical outcome events.  Power calculations were based on a 
dropout rate of up to 20% for the hazard ratio.
4.4
Planned Analysis
The primary analysis to evaluate the effect of response to treatment on clinical outcomes, 
will occur at the final analysis after all subjects have completed the study or prematurely 
discontinued the study.  An interim analysis to assess the percentage of subjects achieving 
SVR12 will occur after all subjects have completed the Post-Treatment Week 12 Visit or 
prematurely discontinued the study.  For both final and interim analyses, data will be 
locked after performing appropriate data cleaning.  Data after the interim analysis will be 
added to a subsequent version of the database.  SAS® (SAS Institute, Inc., Cary, NC) for 
the UNIX operating system will be used for all analyses.  All statistical tests and all 
confidence intervals will be two-sided with an α level of 0.05.
All analyses will be conducted by statisticians and statistical programmers at AbbVie or 
the designee according to the methodologies specified in this SAP.  
There is no intention of shortening the follow-up time of subjects based on efficacy 
findings from the interim analysis.  The intention is to follow all subjects who receive 
study drug for 260 weeks following treatment.  There will be no statistical adjustment 
employed due to this interim analysis.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
The Intention-to-treat (ITT) population will consist of all enrolled subjects in this study 
(ITT-I) and the companion study TOPAZ-II (ITT-II) who receive at least one dose of 
study drug.


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The primary efficacy analysis on clinical outcomes will be performed on the ITT 
population.
5.1.2
Intention-to-Treat-I (ITT-I) Population
The ITT-I population will consist of all enrolled subjects in this study who receive at least 
one dose of study drug.  The data from the ITT-I population will be presented for all 
subjects regardless of treatment duration and ribavirin use in one column.
All efficacy, patient reported outcomes and resistance analyses, except for the primary 
efficacy analysis, will be performed on the ITT-I population.  In addition, sensitivity 
analyses of SVR12 will be performed on the Modified Intention-to-Treat-I Genotype 
(mITT-I-GT) population and Modified Intention-to-Treat-I Genotype and Virologic 
Failure (mITT-I-GT+VF) population, respectively, as specified in Section 10.6.
5.1.3
Safety Population
All subjects in this study who receive at least one dose of study drug will be included in 
the safety population.  Safety analyses will be performed on the safety population and be 
presented also for all subjects together.  In other words, the safety population will be the 
same as the ITT-I population.
Demographic and safety analyses will be performed on the safety population.
5.2
Variables Used for Stratification of Randomization
Approximately 1650 subjects will be enrolled to receive ABT-450/r/ABT-267 and 
ABT-333 with or without RBV depending on their HCV genotype and cirrhotic status.  
No stratification of randomization will be used for this study.  
6.0
Analysis Conventions
ICON Inc is the central laboratory used in this study.  The chemistry platform will be 
transitioned from the Roche Diagnostics Hitachi Modular System (old) to the Abbott 
Architecture (new) in January 2016 while the study is expected to be still on-going. The 


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chemistry data obtained from the old chemistry platform will be converted to the new 
chemistry platform and the converted data will be combined with the data obtained from 
the new system for all statistical analysis and the normal ranges associated with the new 
chemistry platform will be applied.  The analysis of mean changes from baseline, shifts 
above and below the normal ranges, the flagging of potentially clinically significant (PCS) 
laboratory data, and the CTCAE grading of chemistry labs will be performed as if all the 
chemistry data were generated by one platform – the new chemistry platform.
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.
Safety assessments that are related to a serious adverse event that occurs on the first dose 
day are excluded when applying this algorithm.
6.1.2
Study Days
Study days (days relative to the first dose of study drug) are calculated for each time point 
relative to the first dose of study drug.  Study Days are negative values when the time 
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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.
6.1.3
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.
6.1.4
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.
6.1.5
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.
6.2
Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 2
and Table 3 describe how efficacy data are assigned to protocol-specified time points 
during the Treatment and PT Periods, respectively.  All time points and corresponding 
time windows are defined based on the blood sample collection date.
For analyses of health-related quality of life (QoL) PROs collected throughout the study, 
the time windows specified in Table 4 will be used.
For laboratory data and vital signs, the time windows specified in Table 5 and Table 6
describe how data are assigned to protocol specified time points during the Treatment and 
PT Periods, respectively.


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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.
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 2
14
2 to 21
Week 4
28
22 to 56
Week 12
84
57 to 126
Week 24b
168
127 to 182
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
Week 24 Visit is only applicable to subjects assigned to 24 weeks of treatment.
c.
The last value within the window will be used to define the Final Treatment visit value.
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 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day 
(Study Drug End Day)
Time Window 
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 266
Post-Treatment Week 52
364
267 to 546
Post-Treatment Week 104
728
547 to 910
Post-Treatment Week 156
1092
911 to 1274
Post-Treatment Week 208
1456
1275 to 1638
Post-Treatment Week 260
1820
1639 to 2002
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 4.
Analysis Time Windows for PRO Instruments
Scheduled Visita
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baseline
1b
≤ 1b
Week 4
28
2 to 56
Week 12
84
57 to 126
Week 24c
168
127 to 182
Final Treatment Visitd
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 266
Post-Treatment Week 52
364
267 to 546
Post-Treatment Week 104
728
547 to 910
Post-Treatment Week 156
1092
911 to 1274
Post-Treatment Week 208
1456
1275 to 1638
Post-Treatment Week 260
1820
1639 to 2002
Final Post-Treatment Visite
> 2 days after last dose of study drug
a.
SF-36v2 and FACIT-F are collected at Baseline, Week 4, Week 12 and Week 24 (for subjects with 24 weeks of 
treatment), and Post-Treatment Weeks 4, 12, 24, 52, 104, 156, 208 and 260.
b.
Day of first dose of study drug.
c.
Applicable to subjects with 24 weeks of treatment.
d.
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.
e.
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 through Treatment Week 24, data must 
also be within 2 days after 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 5.
Laboratory Data and Vital Sign Visit Windows (Treatment Period)
Scheduled Time
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baselinea
1
≤ 1
Week 2
14
2 to 21
Week 4
28
22 to 56
Week 12
84
57 to 126
Week 24b
168
127 to 182
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
Applicable to subjects with 24 weeks of treatment.
c.
The last value within the window will be used to define the final on-treatment value.  The upper bound of this Final 
window is Study Drug End Day ≤ 2.
Note:
The result closest to the scheduled time point will be used.  Data must also be ≤ 2 days of the last dose of 
study drug.  Total Insulin is measured at baseline, Week 12, Week 24 (for subjects on 24-week treatment 
regimen only), or EOT, and will use those visit windows as defined above.


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Table 6.
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 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 266
Post-Treatment Week 52
364
267 to 546
Post-Treatment Week 104
728
547 to 910
Post-Treatment Week 156
1092
911 to 1274
Post-Treatment Week 208
1456
1275 to 1638
Post-Treatment Week 260
1820
1639 to 2002
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.
Note:
The result closest to the scheduled time point will be used.  Data must also have Study Drug End Day > 2.  
Vital signs and hematology, chemistry, urinalysis, and coagulation panels are collected at every 
Post-Treatment Period visit.  Urinalysis is not conducted after PT Week 4.  Total Insulin is collected at 
Post-Treatment Weeks 52, 104, 156, 208, and 260 and will use those visit windows as defined above.  
FibroTest samples are collected at Post-Treatment Weeks 12 (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 the PRO 
questionnaires, for analyses of the HCV RNA endpoints, and for analysis of the 
persistence of resistance.  If a respondent answers at least 50% of the items in a multi-item 
scale of the SF-36v2, the missing items will be imputed with the average score of the 
answered items in the same scale.  In cases where the respondent did not answer at least 
50% of the items, the score for that domain will be considered missing.  Similarly, the 
missing items of the FACIT-F questionnaire will be imputed with the average score of the 
answered items in the same scale as long as more than 50% (≥ 7 out of 13) of the items in 
the scale are answered.  The SF-36v2 Mental and Physical Component Summary 
measures will not be computed if any domain is missing.


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HCV RNA values will be selected for an SVR analysis based on visit windows as defined 
in Section 6.2.  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.  In addition, if a subject has an unquantifiable HCV RNA level at the 
preceding value and an undetectable HCV RNA level at the succeeding value, or vice 
versa, the HCV RNA level will be imputed as unquantifiable at this visit for this subject.  
For SVR analyses, if there is no value in the appropriate window after flanking imputation 
but there is an HCV RNA value after the window, then it will be imputed into the SVR 
window.  Subsequent to this flanking and backward 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).  
If a subject starts another treatment for HCV, then all HCV RNA and PRO assessment 
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.


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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.
Finally, missing sequence data will be imputed as follows in the analysis of the 
persistence of resistance from the sequences from PT Week 52 through PT Week 260 
(5 years).  If a signature variant is not detectable by population, clonal or deep sequencing 
at PT Week 24 (or later), the variant is imputed as not detectable at the PT Week 52 (or 
timepoints after the sequence with the variant not detectable) and time points thereafter if 
a sample from Post-Treatment Week 52 or later is not sequenced.  If a signature variant is 
detectable by population, clonal, or deep sequencing at Post-Treatment Week 52 or later, 
then the variant is imputed as being detectable at earlier time points if the sample at the 
earlier time point is not sequenced.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
Demographics, baseline characteristics, medical history, and previous/concomitant 
medications will be summarized overall and by presence of cirrhosis and genotype 1 
subtype on the safety population.
7.1
Demographic and Baseline Characteristics
Demographics include age, weight, height 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, and BMI category (< 30 kg/m2 or ≥ 30 kg/m2).
Baseline characteristics will include:  HCV genotype 1 subtype (1a, 1b, 1-other), IL28B 
genotype ([CC, CT, or TT] and [CC or non CC]), prior treatment history (treatment-naïve 
[IFN-eligible, IFN-ineligible] or IFN-based treatment-experienced [null responder, partial 
responder, relapser, prior relapse/breakthrough, prior nonresponder, IFN-intolerant and 
IFN experienced-other]), baseline HCV RNA levels ([continuous (use log10 HCV RNA)] 


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and [< 800,000 IU/mL or ≥ 800,000 IU/mL]), baseline HOMA-IR (< 3 or 
≥3 mU × mmol/L2), baseline fibrosis stage (F0 – F1, F2, F3, F4), baseline Child-Pugh 
score (non-cirrhotic, 5, 6, or > 6), baseline FibroTest score (continuous and [< 0.49, 0.49 –
0.58, 0.59 – 0.74, ≥ 0.75]), baseline albumin (continuous), baseline albumin (< 35, 
≥35 g/L), baseline creatinine clearance (continuous; < 30 mL/min, ≥ 30 – 49 mL/min, 
≥50 – 89 mL/min, ≥ 90 mL/min), baseline eGFR by MDRD (continuous; < 30, 30 – 59, 
60 – 89, ≥ 90 mL/min/1.73 m2; < 60 or ≥60 mL/min/1.73 m2), baseline platelet count 
(continuous; < 90 × 109/L, ≥ 90 × 109/L; < 50 × 109/L, ≥ 50 × 109/L; < 100 × 109/L, 
≥100 × 109/L; < 150 × 109/L, ≥ 150 × 109/L), baseline alpha fetoprotein (continuous, and 
< 20 ng/mL, ≥ 20 ng/mL), 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 bleeding disorders, AST to platelet ratio index (APRI) (continuous; 
≤2.0 or > 2.0), and Fibrosis-4 score (FIB-4) (continuous; ≤ 3.25, > 3.25). 
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab, the ARUP Assay for Hepatitis C High-Resolution Genotype by 
the Central lab and/or from phylogenetic analysis of the full length NS3/4A, NS5A, 
and/or NS5B sequences performed by AbbVie.  If the phylogenetic analysis is available it 
will be used to determine the subject's HCV genotype and subtype.  If it is not available, 
then the ARUP assay result will be used to determine the subject's HCV genotype and 
subtype, if available.  Finally, if neither the phylogenetic analysis result nor the ARUP 
assay results are available, then the Inno-LIPA assay results will be used to categorize the 
subject.
Subjects' baseline fibrosis stage will be assessed by investigator during the screening 
period and categorized as F0 – F1, F2, F3, or F4.
For subjects with baseline fibrosis stage of F4, the 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 7.


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Table 7.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2
(or suppressed with 
medication)
Grade 3 or 4
(or refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Baseline APRI and FIB-4 are defined as the equations below.  Subjects without baseline 
values of AST, platelet count or age will be excluded from the summary of APRI; 
subjects without baseline values of AST, ALT, platelet count, or age will be excluded 
from the summary of FIB-4.
APRI =
AST Level (IU/L)
AST (Upper Limit of Normal)(IU/L)
Platelet Count (10!/L)
× 100
FIB-4 =
Age (years) ×  AST Level (U/L)
Platelet Count (10!/L) × *ALT (U/L)
 


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Summary statistics (N, mean, median, standard deviation [SD], and range) will be 
generated for continuous variables (e.g., age and BMI) and the number and percentage of 
subjects will be presented for categorical variables (e.g., sex and race).
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.
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.  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 summarized by generic drug name based on the WHO 
Drug Dictionary.  Note that prior HCV medications (IFN, pegIFN and RBV) 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 by generic drug name.  A post-treatment medication for the treatment of 
HCV is defined as any medication taken on or after the last dose of study drug and entered 
as "Post treatment HCV medications" on the eCRF.


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8.0
Patient Disposition
The number of subjects for each of the following categories will be summarized overall 
and by each investigator on the safety population.
●
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 ongoing in the Post-Treatment Period at the time of the interim 
analysis;
●
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).  Similar summaries will be 
provided for discontinuations from the study.  
The number and percentage of subjects will be summarized for:
●
Subjects with interruptions of all study drugs for toxicity management;
●
Subjects with any RBV dose modification;
○
Subjects with RBV dose modification due to decrease in hemoglobin;
○
Subjects with RBV dose modification due to decrease in creatinine 
clearance;
○
Subjects with RBV dose modification due to weight change;
○
Subjects with RBV dose modification due to other reasons;
●
Subjects with any RBV dose modification to 0 mg (i.e., RBV interruptions).
Reasons for study drug interruptions and RBV dose modifications will be presented in the 
CSR listings.


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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.
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be presented.  
Study drug duration also will be summarized with frequencies and percentages using the 
following categories depending on the treatment duration:
●
12 weeks of treatment:  1 to 15 days, 16 to 30 days, 31 to 45 days, 46 to 
60 days, 61 to 76 days, and > 76 days.
●
24 weeks of treatment:  1 to 15 days, 16 to 30 days, 31 to 60 days, 61 to 
90 days, 91 to 120 days, 121 to 153 days, and > 153 days.
9.2
Compliance
At each protocol-specified visit, the total number of tablets dispensed and returned is 
recorded together for ABT-450/r/ABT-267 and ABT-333, and is recorded separately for 
RBV.  The compliance for ABT-450/r/ABT-267 and ABT-333 combined and the 
compliance for RBV 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.  For compliance to RBV, RBV dose modifications due to adverse events, 
toxicity management, or weight changes as recorded on the RBV Dose Modifications 
eCRF will be used to modify the total number of tablets that should have been taken.  A 
subject is considered to be compliant if the percentage is between 80% and 120%.  
Compliance will be calculated for each subject and summarized with the N, mean, SD, 


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median, minimum and maximum.  In addition, the percentage of compliant subjects will 
be calculated separately for ABT-450/r/ABT-267 + ABT-333, and RBV.
10.0
Efficacy Analysis
10.1
General Considerations
The primary efficacy analysis on clinical outcomes will be performed on all subjects in 
the ITT population as defined in Section 5.1.  All other efficacy analyses will be 
performed on the ITT-I population. 
Treatment effects will be evaluated based on a two-sided significance level of 0.05 (when 
rounded to three decimal places).  The data from the ITT-I population will be presented in 
one column/row as it represents the labelled treatment. 
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0.  For this 
assay, the lower limit of quantification (LLOQ) and the lower limit of detection (LLOD) 
is 15 IU/mL.  HCV RNA results that are detectable but not quantifiable are reported as 
"< 15 IU/mL" and results that are not detectable are reported as "NON-DETECTED."
Assessment of Clinical Outcomes
Incidence of the following clinical outcome events will be collected during the 
12/24 weeks of treatment and the 5-year (PT Week 260) Post-Treatment Period.  Data will 
be adjudicated by an independent outcome committee and results will be reported in the 
"Clinical Outcome" eCRFs:
●
All-cause death:  Death due to any cause.
●
Liver-related death:  Death as the result of a liver-related cause.
●
Liver decompensation:  Development of any of the following conditions:  
ascites, hepatic encephalopathy, or variceal bleeding.
●
Liver transplantation:  any subject who had a liver transplantation.


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●
Hepatocellular carcinoma (HCC):  development of HCC in any subject at any 
time during the study.  HCC is defined by histologic confirmation or a > 1 cm 
mass lesion on cross-sectional imaging that meets the diagnostic criteria for 
HCC according to EASL guidelines.
●
Composite of any of the above outcomes.
Definitions for HCV RNA 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.
RVR (rapid virologic response) = HCV RNA < LLOQ in the Week 4 window.
EOTR (end of treatment response) = HCV RNA < LLOQ in the Week 12 window for 
subjects receiving 12 weeks of treatment and in the Week 24 window for subjects 
receiving 24 weeks of treatment.
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 during 
that SVR window.


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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.  
Relapse24 = confirmed HCV RNA ≥ LLOQ during SVR24 window among subjects who 
achieved SVR12 and have data available during the SVR24 window.
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.
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.  For relapse 
analyses, the completion of treatment is defined as a study drug duration ≥77 days for 
subjects assigned to 12 weeks of treatment and ≥ 154 days for subjects assigned to 
24 weeks of treatment.  If the last available post treatment value is ≥ LLOQ, then the 
subject will be considered a relapse (i.e., will not require confirmation).  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 


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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.
Any subjects with documented re-infection will be excluded from relapse analyses and 
will be analyzed separately.
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 for subjects assigned to 12 weeks of treatment or duration 
< 154 days for subjects assigned to 24 weeks of treatment) and did not meet the 
On-treatment virologic failure definition);
4.
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), or (3)];
5.
Other (including subjects with documented re-infections and subjects defined as 
any SVR12 non-responder not meeting the definitions of [1] – [4], such as a subject 
with a single quantifiable value within the SVR12 window followed by an 
undetectable value beyond the SVR12 window).


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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 
and did not meet the On-treatment virologic failure, Relapse12, or Relapse24
definitions);
5.
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), or (4)];
6.
Other (including subjects with documented re-infections and subjects defined as 
any SVR24 non-responder not meeting the definitions of [1] – [5]).
10.2
Handling of Multiplicity
No adjustment for multiple comparisons is used in this open-label long-term outcome 
study.
10.3
Primary Efficacy Analysis
The primary efficacy analysis will be conducted among subjects in the ITT population as 
described in Section 5.1.  HCV RNA values and SVR12 will be imputed as described in 
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The primary efficacy endpoint is to assess the effect of response to treatment (as assessed 
by SVR12 status) on clinical outcomes by comparing the time to incidence of the 
following events between subjects who achieve SVR12 and those who do not.
●
All-cause death
●
Liver-related death
●
Liver decompensation
●
Liver transplantation
●
Hepatocellular carcinoma
●
Composite of any of the above outcomes
For each of the six event types as listed above, a subject's time to event will be defined as 
the number of days from the first day of study drug to the day the subject experiences an 
event of interest.  All events of interest will be included, regardless of whether the event 
occurred while the subject was still taking study drug or had previously discontinued 
study drug. However, events occurred after a subject started another treatment for HCV 
will be excluded and the subject will be censored at the time of starting the new HCV 
treatment. If the subject has not experienced an event of interest nor has the subject died 
(all-cause death), the subject's data will be censored at the date of the subject's last 
available assessment of clinical outcomes.  All-cause death is a censoring event for liver-
related death, liver decompensation, liver transplantation and hepatocellular carcinoma.  
For subjects with no post-baseline assessment, the subject's data will be censored on the 
first day of study drug.  Time to the composite of clinical outcomes is the time to the 
first occurrence of any clinical outcome.
For each of the six event types, the distribution of time to event will be estimated for 
subjects who have achieved SVR12 and those who haven't using Kaplan-Meier 
methodology and compared between the subjects who have achieved SVR12 and those 
who haven't using the log-rank test.


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For each of the six event types, the 1-, 2-, 3-, 4-, and 5-year event-free survival rate will 
be estimated using Kaplan-Meier methodology and a 95% confidence interval will be 
constructed separately for those who have achieved SVR12 and those who haven't.
For each of the six event types, a test statistic based on Kaplan-Meier estimates of the 
event-free survival probability at Year 5 and the estimated variance will be constructed to 
test the null hypothesis that the 5-year event-free survival rates for subjects who have 
achieved SVR12 and those who haven't are the same.
For each of the six event types, a Cox proportional hazards (PH) model will be 
constructed to include all the baseline characteristics as described in Section 7.1, SVR12
status, and other variables as appropriate to compare the risk of experiencing a clinical 
outcome between subjects who have achieved SVR12 and those who haven't.
10.4
Secondary Efficacy Analyses
The following analyses of secondary efficacy endpoints will be performed on the ITT-I 
population:
●
The effect of sustained virologic response on change and percentage change 
from baseline in FibroScan score (assessed at the end of treatment and all 
post-treatment visits except PT Week 4) will be evaluated by comparing mean 
change from baseline at each applicable visit between subjects who achieve 
SVR12 and those who do not using descriptive statistics and ANCOVA 
analyses.  SVR12 status will be included as a factor and baseline FibroScan 
score will be included as a covariate in the ANCOVA model.  From the 
ANCOVA analyses, point estimates of the mean difference and 95% 
confidence intervals will be provided.
●
Sustained virologic response will be evaluated using the percentage of subjects 
achieving SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose of 
study drug).  The simple percentage of subjects achieving SVR12 will be 
calculated and a two-sided 95% confidence interval of the percentage will be 
computed based on Wilson's score method.


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10.5
Efficacy Subgroup Analysis
The analysis on SVR12 rate as described in Section 10.4 will be performed on the ITT-I 
population for the following subgroups (assessed at baseline), as appropriate:
●
The presence of cirrhosis and subgenotype (GT1b without cirrhosis, GT1b 
with compensated cirrhosis, GT1 non-b without cirrhosis, and GT1 non-b with 
compensated cirrhosis);
●
Prior treatment history(treatment-naïve [IFN-eligible, IFN-ineligible] or 
IFN/RBV treatment-experienced [null responder, partial responder, relapser, 
prior relapse/breakthrough, prior nonresponder, IFN-intolerant and IFN 
experienced-other]);
●
IL28B ([CC, CT, TT] and [CC or non-CC]);
●
Sex (male or female);
●
Age (< 55 or ≥ 55 years) and (< 65 or ≥ 65 years);
●
Birth year (< 1945, 1945 to 1965, > 1965);
●
Race (Black or Non-Black; Black will include any subject who marks 'Black 
or African American' for race on the Demographics eCRF);
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
●
BMI (< 30 or ≥ 30 kg/m2);
●
Baseline HCV RNA levels (< 800,000 or ≥ 800,000 IU/mL; below median or 
above or equal to median);
●
Baseline creatinine clearance (< 50 mL/min, ≥ 50 mL/min); 
●
Baseline eGFR by MDRD (< 30, 30 – 59, 60 – 89, ≥ 90 mL/min/1.73 m2; 
< 60 or ≥ 60 mL/min/1.73 m2);
●
Baseline HOMA-IR (< 3 or ≥ 3 mU × mmol/L2);
●
History of Depression or Bipolar Disorder (yes/no);
●
History of Bleeding Disorders (yes/no);
●
Baseline Child-Pugh score (non-cirrhotic, 5, 6, or > 6);
●
Baseline fibrosis stage (F0 – F1, F2, F3, F4);
●
APRI (≤ 2.0 or > 2.0);


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●
FIB-4 (≤ 3.25 or > 3.25); Any of APRI > 2.0 and FIB-4 > 3.25, or neither.
For subjects with cirrhosis only:
●
Baseline platelets (< 50 × 109/L, ≥ 50 × 109/L; < 90 × 109/L, ≥ 90 × 109/L; 
< 100 × 109/L, ≥ 100 × 109/L; < 150 × 109/L and ≥ 150 × 109/L);
●
Baseline albumin (< 35, ≥ 35 g/L);
●
Baseline alpha fetoprotein (< 20, ≥ 20 ng/mL);
●
Any of platelets < 90 × 109/L, albumin < 35 g/L, or alpha fetoprotein 
≥20 ng/mL, or none of the three.
The 2-sided 95% Wilson score confidence interval for a binomial proportion (percentage 
of subjects achieving SVR12) will be produced for each subgroup with at least 10 subjects.  
In addition, stepwise logistic regression will be performed on both SVR12 and virologic 
failure (on-treatment virologic failure or relapse) using subgroup variables as described 
above.  Some variables may be treated as continuous to decrease the chance of separation 
or quasi-separation and some variables may be eliminated if missing for too many 
subjects.
For GT1 non-b subjects with cirrhosis only:
●
Treatment Duration (12 weeks, 24 weeks);
The analysis on liver stiffness (change and percentage change from baseline in FibroScan 
score) as described in Section 10.4 will be performed on the mITT-I-GT population for 
the following subgroup (assessed at baseline), as appropriate:
●
The presence of cirrhosis (subjects with cirrhosis vs subjects without 
cirrhosis);
Subgroup analyses will be performed if there are an adequate number of subjects.  


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The effect of subgroup status on change and percentage change from baseline in 
FibroScan score (assessed at the end of treatment and all post-treatment visits except PT 
Week 4) will be evaluated if there are at least 10 subjects in each subgroup using 
summary statistics and ANOVA analyses separately for each applicable visit.  The 
subgroup status, SVR12 status, and their interaction will be included in the model.  From 
the ANOVA analyses, point estimates of the mean difference from the reference subgroup 
(subjects without cirrhosis) and 95% confidence intervals will be provided.
10.6
Sensitivity Analysis for the Efficacy Endpoint of SVR12
In addition to presenting the secondary efficacy endpoint of SVR12 as described in 
Section 10.4, two sensitivity analyses of SVR12 will be presented using the following 
modified populations.  The first sensitivity analysis of SVR12 will be conducted using a 
Modified Intention-to-Treat Genotype (mITT-I-GT) population that includes subjects who 
receive at least 1 dose of study drug in Study M14-423 (with imputation as described in 
Section 6.3) but excludes the subjects who are not of HCV genotype 1 infection.  The 
mITT-I-GT population is used to reduce the risk of bias that could occur due to enrolled 
population deviating from the protocol selected study population. 
The other sensitivity analysis of SVR12 will be conducted using a Modified Intention-to-
Treat Genotype and Virologic Failure (mITT-I-GT+VF) population.  The mITT-I-GT+VF 
population is used to reduce the risk of bias that could occur due to either discordant HCV 
genotype or irrelevant failures unrelated to study drug.  The mITT-I-GT+VF population 
includes all subjects who receive at least 1 dose of study drug in Study M14-423 (with 
imputation as described in Section 6.3) but excludes the subjects who are not of HCV 
genotype 1 infection and the subjects who did not achieve SVR12 due to reasons other 
than on treatment virologic failure or relapse.
10.7
Additional Efficacy Analyses
The following additional HCV RNA efficacy endpoints will be summarized and analyzed 
on the ITT-I population, as specified:


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●
The number and percentage of subjects with on-treatment virologic failure;
●
The number and percentage of subjects with post-treatment relapse;
●
The number and percentage of subjects with documented re-infection;
●
The number and percentage of subjects with RVR;
●
The number and percentage of subject with EOTR;
●
The 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 number and percentage of subjects with HCV RNA < LLOQ 24 weeks 
after the last actual dose of study drug (SVR24);
●
Reasons for not achieving SVR24 for subjects who do not; 
●
Mean change from baseline in prothrombin time (PT), International 
normalized ratio (INR), FibroTest, and albumin to each applicable 
post-baseline time point;
●
The number of subjects who fail to suppress and accompanying listing;
●
The number of subjects who breakthrough any time during treatment and 
accompanying listing;
●
The number of completers with final on-treatment HCV RNA < LLOQ who 
relapse within the SVR4 window, SVR12 window, or SVR24 window and 
accompanying listing;
●
The concordance between SVR12 and SVR24 will be assessed.
In the above analyses that use the number and percentage of responders, 2-sided 95% 
Wilson score confidence interval for a binomial proportion will be calculated. 
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.  For the change from baseline to each post-baseline time point in PT/INR, 
Fibrotest, and albumin, descriptive statistics will be calculated.


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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 ≥ 36 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) will be summarized along with a 
corresponding listing displaying the subject numbers at the first occurrence of 
breakthrough.
The number of documented re-infected subjects who re-infected within the SVR4 window, 
within the SVR12 window, within the SVR24 window (defined in Table 3), after the SVR24
window and anytime post-treatment (study drug end day ≥ 3) will be summarized along 
with a corresponding listing of the subjects numbers displaying the window of the 
first occurrence/detection of re-infection.
The number of completers (defined as study drug duration ≥ 77 days for subjects assigned 
to 12 weeks of treatment and ≥ 154 days for subjects assigned to 24 weeks of treatment) 
with final on treatment HCV RNA < LLOQ who relapse within the SVR4 window, within 
the SVR12 window, within the SVR24 window (defined in Table 3), after the SVR24
window 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 for subjects assigned to 12 weeks of treatment 
and < 154 days for subjects assigned to 24 weeks of treatment) 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 


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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.
10.8
Resistance Analyses
If possible, subjects treated with study drug who experience virologic failure will have 
resistance testing conducted if 1) they have on-treatment breakthrough; 2) if they have 
post-treatment relapse, with a study drug duration ≥77 days for subjects assigned to 
12 weeks of treatment or with a study drug duration ≥154 days for subjects assigned to 
24 weeks of treatment; 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).
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) is < 1000 IU/mL, the sample closest in 
time after the failure with an HCV RNA level ≥ 1000 IU/mL will be used if available.  
The regions of interest for next generation sequencing (NGS) from all evaluated time 
points in this study are those encoding full length NS3/4A, NS5A, and NS5B.  The 
prototypic reference sequences used for analysis will be H77 for genotype 1a or Con1 for 
genotype 1b.
For each DAA target, resistance-associated amino acid variants will be identified by 
AbbVie Clinical Virology. Amino acid positions where resistance associated variants 
have been identified in vitro and/or in vivo are 1) for ABT-450:  36, 43, 55, 56, 80, 155, 


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156, and 168 in NS3 for genotype 1a; 56, 155, 156, and 168 in NS3 for genotype 1b; 
2) for ABT-267:  28, 30, 31, 32, 58, and 93 in NS5A for genotype 1a; 28, 29, 30, 31, 32, 
58, and 93 in NS5A for genotype 1b; and 3) for ABT-333:  316, 414, 446, 448, 451, 553, 
554, 555, 556, 558, 559, and 561 in NS5B for genotype 1a; 316, 368, 411, 414, 445, 448, 
553, 556, 558, and 559 in NS5B for genotype 1b.  The final list of amino acid positions 
where resistance-associated variants have been identified will be included in the CSR.
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant by NGS in a baseline sample (≥ 2% or ≥ 15% 
prevalence within a subject's viral population depending on variant frequency 
threshold utilized) that was not present in the appropriate prototypic reference 
amino acid sequence for a given DAA target (NS3, NS5A, or NS5B).
●
Post-baseline variant by NGS:  an amino acid variant in a post baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.
●
Enriched variant:  variant present in both the baseline and a post-baseline 
sample whose prevalence in the post-baseline sample is at least 20 percentage 
points greater than the prevalence in the baseline sample [(post-baseline % –
baseline %) ≥ 20].
●
Treatment-emergent variant:  A post-baseline variant or an enriched variant.
The following will be provided for subjects who are in the PVF population and have 
resistance data available. 
Listings by subject of all baseline variants (≥ 2% and > 15% detection thresholds) relative 
to prototypic reference sequence at signature resistance-associated amino acid positions 
will be provided for each DAA target (NS3, NS5A, and NS5B).
A listing by subject of all baseline variants (≥ 15% detection threshold) at non-signature 
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A listing by subject and time point of all treatment-emergent variants relative to the 
baseline amino acid sequences will be provided across all DAA targets (NS3, NS5A, and 
NS5B).
The number and percentage of subjects with post-baseline variants at signature amino acid 
positions or emerged variants at non-signature amino acid positions by, listed by amino 
acid position and variant within a DAA target at the time of VF compared to baseline will 
be summarized, along with the number of subjects within a DAA target and overall.  The 
analyses will be grouped by HCV subtype (1a or 1b) and DAA target (NS3, NS5A, or 
NS5B) and will list the subject numbers of subjects with each variant.  The number of 
subjects with resistance variants in 3 targets, 2 targets or 1 target will be provided.  
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). In 
addition, a listing by subject and time point of all post-baseline variants at signature 
resistance-associated amino acid positions relative to the appropriate prototypic reference 
amino acid sequences will be provided.
For all subjects who experience VF, the persistence of resistance-associated variants for 
each target (NS3, NS5A, and NS5B) will be assessed by NGS at Post-Treatment 
Weeks 24 and 52 and at time points up to Post-Treatment Week 260 (5 years).  The 
number and percentage of subjects with post-baseline variants at signature amino acid 
positions, listed by amino acid position and variant within a DAA target at each Post-
Treatment time point compared to baseline will be summarized, along with the number of 
subjects within a DAA target and overall.  Additionally, the number and percentage of 
subjects in whom a signature variant persisted at Post-Treatment Week 24 and 52 and 
time points up to Post-Treatment Week 260 (5 years) out of the total number of subjects 
with that emerged variant at the VF time point and at that time point will be summarized 
by DAA target, and variant.  The number and percentage of subjects who still have a 
variant at a given Post-Treatment time point will be calculated out of all subjects with that 
variant at VF who have sequencing at that time point.  The imputation described below 
will be used for PT Week 52 or time points up to Post-Treatment Week 260 (5 years).  If a 


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signature variant is not detectable at Post-Treatment Week 24, the variant is imputed as 
not detectable at the Post-Treatment Week 52 and time points thereafter even if a sample 
from Post-Treatment Week 52 or later is not sequenced.  If a signature variant is 
detectable at Post-Treatment Week 52 or later, then the variant is imputed as being 
detectable at earlier time points even if the sample at the earlier time point is not 
sequenced.
If resistance-associated variants are not detected by NGS in a given target for a subject 
either at the time of failure or in a post treatment sample, then that target will not be 
sequenced in subsequent samples from that subject.
10.9
Patient Reported Outcomes
The following instruments will be used to collect patient reported outcomes (PROs):  
SF-36 version 2 (SF-36v2) and FACIT-F.  Missing data for each measurement will be 
handled as described in Section 6.3.
The following exploratory analyses of PROs will be performed by baseline fibrosis stage:  
●
mean change from baseline to each applicable post-baseline time point in the 
SF-36v2 Mental Component Summary (MCS), Physical Component Summary 
(PCS) and eight individual domain measures;
●
mean change from baseline to each applicable time point in the FACIT-F total 
score;
●
percentage of subjects without a decrease from Baseline to Final Treatment 
Visit in the SF-36v2 PCS and MCS that is greater than or equal to the 
minimally important difference (MID) of five points.
The SF-36v2 measures dimensions of a patient's functional health and well-being in 
8 domains and also provides 2 summary scores that characterize a patient's mental (MCS) 
and physical (PCS) health status.  The score for each of the 8 domains ranges from 0 to 
100 and will be normalized according to the user manual.  The standardization of the 
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The two summary scores are based on the norm-based scores.  Per the SF-36v2 
instrument manual, score for any item with multiple responses will be set to "missing."  
Subject's responses to the SF-36v2 will be summarized for the PCS and MCS measures.
The FACIT-F is a symptom specific instrument with a focus on measuring fatigue in a 
variety of chronic diseases or health conditions.  Its 13-item-version assesses peripheral, 
central, or mixed fatigue and yields a summed total score ranging between 0 and 52.  
Higher FACIT-F scores indicate a lesser degree of fatigue.  Notice that item 7 (I have 
energy) and item 8 (I am able to do my usual activities) are reverse scored.
Summary statistics (n, mean, SD, median, minimum and maximum) for the mean change 
from baseline to each applicable visit will be provided for the FACIT-F score and the 
SF-36v2 PCS and MCS scores.
In particular, an analysis of the mean change from baseline to Post-Treatment Week 12 
and to Post Treatment Week 24 in the SF-36 V2 Vitality scale, Mental Component 
Summary score, Physical Component Summary score and FACIT-F score, will be 
performed using ANCOVA analyses with appropriate baseline fibrosis stage, SVR12
status, and their interaction as factors, and baseline PRO score as covariate.  A summary 
of the analysis results comparing subjects who have achieved SVR12 and subjects who 
have not will be provided. A similar summary of analysis results comparing subjects with 
different fibrosis stage will be provided also. Additional analysis on the PRO data will be 
performed as useful and appropriate.
An MID of –5 will be used for the change from Baseline to Final Treatment Visit in the 
SF-36v2 PCS and MCS.  The percentage of subjects with a change from Baseline to Final 
Treatment Visit > –5 will be presented along with 95% confidence intervals.


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11.0
Safety Analysis
11.1
General Considerations
All subjects who receive at least one dose of study drug in Study M14-423 will be 
included in the safety analyses.
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) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The 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;


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●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV;
●
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 modifications;
●
Treatment-emergent adverse events leading to death;
●
Deaths.
Adverse Event by SOC and PT
The following summaries of adverse events will be generated:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs;
●
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 modifications;
●
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").


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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.
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.  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.
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.  The search 
criterion for the adverse event of interest is as follows:
●
Hepatic Decompensation and Hepatic Failure
PMQ "Hepatic decompensation and hepatic failure"
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 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.


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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.
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 DAA study drug and RBV, as assessed by the investigator.  If a 
subject has an adverse event with unknown relationship, then the subject will be counted 


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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 until the end of the study), treatment-emergent serious adverse events, 
treatment-emergent adverse events leading to death, treatment-emergent adverse events 
leading to discontinuation of study drug, treatment-emergent adverse events leading to 
study drug interruptions, treatment-emergent adverse events leading to RBV dose 
modifications, 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 SAE 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), total 
insulin, creatinine clearance (Cockcroft-Gault calculation), calculation of estimated 
glomerular filtration rate (eGFR) using the modification of diet in renal disease (MDRD) 


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equation as defined below, alpha2-macroglobulin, haptoglobin, apolipoprotein A1, and 
alpha fetoprotein.
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 variable is total insulin.
The following equation will be used to calculate eGFR by MDRD, where serum
creatinine is measured in mg/dL and age is measured in years: 
GFR (mL/min/1.73 m2) = 175 × Serum Creatinine (–1.154) × Age (–0.203) × 1.212 (if Black) 
× 0.742 (if Female).
The Criteria for Potentially Clinically Significant (PCS) Laboratory Findings are 
described in Table 8 and Table 9.


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Table 8.
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 9.
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 9.
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 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.  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 8 and Table 9) will be summarized.  A post-baseline 
value must be more extreme than the baseline value to be considered a PCS finding.  A 
separate listing will be provided that presents all 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 10) 
at any post-baseline visit (regardless of the baseline value) through the end of treatment 
(i.e., Final Treatment Value) will be summarized.  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 with a maximum Common Terminology Criteria for Adverse Events (CTCAE) 
Grade of 1, 2, 3, or 4 (see definitions in Table 10) at any post-nadir visit (regardless of the 
baseline value) through the end of treatment (i.e., Final Treatment Value) will be 
summarized.  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 listing of hemoglobin results will be provided for any subjects with at 
least Grade 2 hemoglobin 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 hemoglobin abnormalities.


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Table 10.
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 meeting the following criteria will be 
summarized:
●
ALT ≥ 3 × ULN and total bilirubin value ≥ 2 × ULN;
●
ALT > 5 × ULN (equivalent to Grade 3 or higher) and total bilirubin value 
< 2 × ULN.
A subject or event will be counted if the post-nadir 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)
The criteria for potentially clinically significant vital sign findings are presented in 
Table 11.


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Table 11.
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 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 
and Post-Treatment Periods.
Mean changes from baseline to each post-baseline visit, including applicable post 
treatment visits, will be summarized for each vital sign parameter 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 11) 
will be summarized.  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
References
1.
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reduces risk of all-cause mortality in patients with hepatitis C.  Clin Gastroenterol 
Hepatol.  2011;9(6):509-16.e1.
2.
Veldt BJ, Heathcote EJ, Wedemeyer H, et al.  Sustained virologic response and 
clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.  Ann 
Intern Med.  2007;147(10):677-84.
3.
Julious SA.  Two-sided confidence intervals for the single proportion:  comparison 
of seven methods by Robert G. Newcombe, Statistics in Medicine.  
1998;17:857-72.  Stat Med.  2005;24(21):3383-4.
4.
Cella D, Webster K. Linking outcomes management to quality-of-life 
measurement.  Oncology (Williston Park).  1997;11(11A):232-5.
5.
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health 
Survey.  2nd ed.  Lincoln, RI:  QualityMetric Incorporated; 2007.