Conditions: Chronic Hepatitis C
Keywords: Hepatitis C Virus (HCV) Hepatitis C Genotype 1 Chronic Hepatitis C HCV
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
A study to evaluate the safety and effect of treatment with experimental antiviral drugs in combination with peginterferon alpha-2a and ribavirin in people with hepatitis C virus who did not respond to treatment in a previous AbbVie/Abbott combination study.

Detailed description:

Arms:
arm 1: 2-direct-acting antiviral (2-DAA: ABT-450 \[paritaprevir\] 200 mg once daily \[QD\], ritonavir 100 mg QD, ABT-267 \[ombitasvir\] 25 mg QD) plus pegylated interferon alpha-2a (pegIFN) 180 mcg once weekly and Ribavirin (RBV) weight-based dosing, 1000 to 1200 mg divided twice daily (BID) for 24 weeks (Substudy 1) and followed by pegIFN and RBV alone for an additional 24 weeks (Substudy 2).

Interventions: intervention 1: ABT-450/r intervention 2: ABT-267 intervention 3: pegylated interferon alpha-2a (pegIFN) intervention 4: Ribavirin (RBV)
Intervention descriptions: intervention 1: ABT-450 (tablets) dosed with ritonavir (capsules or tablets) intervention 2: ABT-267 (tablets) intervention 3: pegIFN alpha-2a (syringe) intervention 4: Ribavirin (tablets)

Protocol document:
Prot_000.pdf: 
ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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1.0
Title Page
Clinical Study Protocol M13-101
An Open-Label Study to Evaluate the Safety, 
Antiviral Activity and Pharmacokinetics of
Direct-Acting Antiviral Agent (DAA) Treatment in 
Combination with Peginterferon α-2a and Ribavirin 
(pegIFN/RBV) in Chronic Hepatitis C Virus (HCV) 
Infected Subjects Who Have Experienced Virologic 
Failure in a Previous AbbVie or Abbott DAA 
Combination Study
Incorporating Administrative Changes 1, 2, 3, 4 
and 5 and Amendments 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10
AbbVie Investigational 
  Product:
ABT-450, ritonavir, ABT-267
Date:
26 June 2015
Development Phase:
2
Study Design:
This is an open-label rollover study.
EudraCT Number:
2011-005393-32
Investigators:
Multicenter.  Investigator Information is on file at AbbVie.
Sponsor:
AbbVie Inc.*
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
/$5


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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1.1
Protocol Amendment:  Summary of Changes
The purpose of this amendment is to:
●
Update Section 1.2 and Section 5.5.1 to correct the number of subjects 
Rationale for change:  A smaller proportion of subjects experienced virologic 
failure in previous AbbVie or Abbott DAA combination studies than previously 
anticipated.
●
Update Section 1.0, Section 6.5 and Appendix B
Rationale for change:  Reflect the change of the Study Designated Physician.
●
Update Section 5.3.1 for study activities 
Rationale for change:  To reflect the correct collection time point for HCV 
RNA level at screening and to change the collection time for Archive Plasma 
Samples to reflect the updated archive plasma sample analysis strategy.  
●
Update Section 5.3.1 and Section 5.5.7 concerning Electronic Pill Monitors 
(MEMS Caps) 
Rationale for change:  The collection of MEMS caps data as a daily dosing 
monitoring tool has been removed as the drug compliance is reviewed and 
documented by the site, to minimize the workload for the subject and the site.  
The MEMS caps data collected so far will be analyzed and included in the 
Clinical Study Report.
●
Update Section 5.1.3 and Section 8.0 for Interim analysis
Rationale for change:  Due to the significantly decreased number of subjects 
expected to enroll in this study, the interim analyses have been removed.
●
Update Section 5.3.2.3, Disposition of Samples.
Rationale for change:  To clarify in the protocol how and when samples are to 
be disposed of.
●
Update Section 5.4.2 for Non Efficacy (Futility) Criteria
Rationale for change:  Due to the reduced number of subjects to be enrolled in 
this study (up to 35), the assessments at subsequent time points will not be 
relevant.


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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●
Update Section 5.5.6 for treatment compliance
Rationale for change:  To reflect that RBV bottles are no longer re-dispensed 
to patients according with the last updates to the drug supply strategy and 
supported by the IRT system.
●
Update Section 5.6.4 for Selection of the Doses in the Study
Rationale for change:  To update information about the dose selection and the 
information from other recent AbbVie studies.
●
Update Section 6.1.2 for Serious Adverse Events
Rationale for change:  To specify that elective or spontaneous abortion or 
stillbirth is considered an important medical event.
●
Update Section 6.5 for safety contact or medical emergencies information
Rationale for change:  Offering additional contact information for subject 
safety concerns or medical emergencies in case it is not possible to contact the 
Primary Study Designated Physician.
●
Update Section 6.6 for Pregnancy
Rationale for change:  To update how to instruct subjects who report a 
positive pregnancy test during the Treatment Period.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix D.


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-101
Name of Study Drug:  ABT-450, ritonavir, 
ABT-267, ribavirin, Pegylated interferon α-2a
Phase of Development:  Phase 2b
Name of Active Ingredient:  
ABT-267
ABT-450
ritonavir
Date of Protocol Synopsis:  26 June 2015
Protocol Title:  An Open-Label Study to Evaluate the Safety, Antiviral Activity and Pharmacokinetics of 
Direct-Acting Antiviral Agent (DAA) Treatment in Combination with Peginterferon α-2a and Ribavirin 
(pegIFN/RBV) in Chronic Hepatitis C Virus (HCV) Infected Subjects Who Have Experienced Virologic 
Failure in a Previous AbbVie or Abbott DAA Combination Study
Objectives:
The primary objective of this study is to evaluate the safety and antiviral efficacy, defined as the 
percentage of subjects with sustained virologic response 12 weeks post-dosing (SVR12; HCV RNA 
< LLOQ 12 weeks after the last dose of study drug).
The secondary objectives of this study are to evaluate the percentage of subjects with sustained virologic 
response 24 weeks post-dosing (SVR24; HCV RNA < LLOQ 24 weeks after the last dose of study drug) 
and the percentage of subjects with extended rapid virologic response (eRVR) (HCV RNA < LLOQ at TI 
Weeks 4 through 12).
Investigators:  Multicenter
Study Sites:  Up to 150 sites who participated in a previous AbbVie/Abbott DAA combination study.
Study Population:  Subjects who have experienced virologic failure in a previous AbbVie/Abbott DAA 
combination study.
Number of Subjects to be Enrolled:  Up to 35.  The enrollment number of this study depends on the 
treatment failure rate of subjects in previous AbbVie/Abbott DAA combination studies, therefore there 
will be no lower or upper limit of enrollment.


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M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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Methodology:
This is an open-label, multiple-dose, rollover study exploring the safety, antiviral activity and 
pharmacokinetics of ABT-450 with ritonavir (ABT-450/r) + ABT-267 in combination with pegIFN and 
RBV in HCV genotype 1-infected subjects (including subjects with compensated cirrhosis) who have 
experienced virologic failure in a previous AbbVie/Abbott DAA combination study.  Among subjects 
who previously experienced null or partial response to pegIFN/RBV treatment at any time prior to 
pre-screening for this study or any prior failure with pegIFN/RBV plus telaprevir in the previous 
AbbVie/Abbott study, enrollment will be limited to only those subjects in whom variants relative to 
appropriate prototypic reference sequence in HCV protease at positions 155, 156, or 168 or in HCV 
NS5A at positions 28, 29, 30, 31, 32, 58, or 93 are not present at the Pre-screening Visit.  All other 
subjects will be allowed to enroll in Study M13-101 at the discretion of the investigator, regardless of 
whether variants at any of these amino acid positions are detected.
This protocol consists of three substudies.  In Substudy 1, subjects who have experienced virologic 
failure in a previous AbbVie/Abbott DAA combination study may choose to enter this study and receive 
intensified treatment with ABT-450/r, ABT-267, pegIFN and RBV for 24 weeks.  Subjects who complete 
or discontinue DAA treatment in Substudy 1 will enter Substudy 2.  In Substudy 2, subjects receive 
pegIFN and RBV for an additional 24 weeks for a total treatment of up to 48 weeks across Substudies 1 
and 2.  In Substudy 3, subjects will be monitored for resistance and viral response for 48 weeks after 
discontinuation of study drug treatment.
Ongoing review of the data is planned in order to determine if a subject meets the virologic stopping 
criteria as defined in this protocol.  Subjects who meet virologic stopping criteria during DAA treatment 
will discontinue ABT-450/r and ABT-267, but at the investigator's discretion may continue to receive 
pegIFN and RBV therapy for a total of 48 weeks across Substudies 1 and 2.  Ongoing review of the data 
is also planned for non-efficacy (futility) assessment.  Data will be assessed separately for the population 
of subjects who were null or partial responders to prior pegIFN/RBV or who had any prior failure to 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study, and for the population of subjects who 
do not fall in the previous population at the time of enrollment into this study.
In Substudy 3, the study will monitor and evaluate subjects for 48 weeks after the last dose of study drug 
for HCV RNA and the evolution and persistence of viral resistance to DAAs.
Study Procedures:
Subjects will visit the site on an outpatient basis for testing of HCV RNA, pharmacokinetics sampling, 
safety and resistance.  Safety of the treatments will be evaluated throughout the study using assessments 
of adverse events (AEs), physical exam findings, electrocardiograms (ECGs), and laboratory parameters 
which will include chemistry, hematology and urinalysis.  Additional procedures will be done for 
cirrhotic subjects to evaluate hepatic compensation and to rule-out hepatocellular carcinoma.


ABT-450, ritonavir, ABT-267
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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
To be enrolled in this protocol, subjects must meet all of the following inclusion criteria:
1.
Subject must have experienced virologic failure as defined in a previous AbbVie/Abbott DAA 
combination trial.
2.
Female subjects of childbearing potential must be willing to use two effective forms of birth control 
(not including contraceptives containing ethinyl estradiol) while receiving study drug and for 
7 months (or per local ribavirin label) after stopping study drug (Note:  Estrogen-containing 
hormonal contraceptives, including oral, injectable, implantable, patch and ring varieties, may not be 
used during DAA treatment).  Females are considered of childbearing potential unless they are either:
!
Post-menopausal 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 history of bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy) or has a vasectomized partner(s), or
!
Practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle), or
!
Sexually active with female partner(s) only.
3.
Males must be surgically sterile, or have male partners only, or if sexually active with female 
partner(s) of childbearing potential must agree to practice two effective forms of birth control 
throughout the course of the study, starting with Study Day 1 and for 7 months (or per local ribavirin 
label) after the last dose of study drug, unless abstinent from sexual intercourse.  
(Note:  Contraceptives containing ethinyl estradiol may be considered effective if used by the female 
partners of male subjects.)
4.
For cirrhotic subjects, compensated cirrhosis defined as Child-Pugh score of ≤ 6 at Screening.
5.
Subject is infected with HCV genotype 1 at Screening Visit.
Main Exclusion:
To be enrolled in this protocol, subjects must not meet any of the following exclusion criteria:
1.
In subjects with a prior null or partial response to pegIFN/RBV treatment at any time prior to 
pre-screening for this study or any prior failure with pegIFN/RBV plus telaprevir, the presence of 
variants relative to the appropriate prototypic reference sequence (H77 for 1a or Con1 for 1b) at any 
of the following amino acid positions:  NS3 protease 155, 156, or 168; NS5A 28, 29, 30, 31, 32, 58, 
or 93.
2.
Females who are pregnant or plan to become pregnant, or breastfeeding, or males whose partners are 
pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last 
dose of RBV.
3.
Use of known strong inducers (e.g., phenobarbital, rifampin, carbamazepine, St. John's Wort) of 
CYP3A within 2 weeks prior to study drug administration.


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
4.
Use of any medications contraindicated for use with ABT-450, ABT-267, pegIFN, RBV or ritonavir 
within 2 weeks prior to study drug administration.
5.
Discontinuation of antiviral therapy due to intolerance or a DAA or RBV associated adverse event in 
a previous AbbVie/Abbott DAA combination study (excluding intolerance or AEs associated with 
telaprevir).
Investigational Products:
ABT-267 25 mg tablet
ABT-450 50 mg tablet
Ritonavir 100 mg capsule/tablet
Doses:
ABT-267 25 mg daily (QD)
ABT-450/r 200/100 mg QD
Mode of Administration:
Oral
PegIFN and RBV Therapy:
pegylated interferon α-2a (pegIFN) 180 ∀g per 0.5 mL syringe + 
ribavirin (RBV) 200 mg tablets
Doses:
pegIFN 180 ∀g once weekly + weight-based RBV 1000 to 1200 mg 
divided twice daily 
Mode of Administration:
pegIFN – SC injection; RBV – oral
Duration of Treatment:
Subjects will receive ABT-450/r and ABT-267 in combination with pegIFN and RBV from Study Day 1 
through Study Week 24 (Substudy 1).  Subjects will then proceed to Substudy 2 where they will receive 
additional pegIFN and RBV for 24 weeks.
Criteria for Evaluation:
Efficacy:
Virologic response (HCV RNA) in log10 IU/mL will be assessed at various time-points from Study Day 1 
through 24 weeks after pegIFN and RBV treatment.
Resistance:
The following resistance analyses will be performed for subjects who do not achieve SVR:  the variants 
at each amino acid position identified by population and/or clonal nucleotide sequencing (1) at baseline 
will be compared to the appropriate prototypic reference sequence, and (2) at available post-baseline time 
points will be compared to baseline and the appropriate prototypic reference sequences.
Pharmacokinetic:
Plasma concentrations for ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 
metabolites, ritonavir, RBV and serum concentrations for pegIFN will be tabulated and summarized, if 
measured.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, 12-lead ECGs and vital signs.


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects with sustained virologic response 12 weeks 
after the last actual dose of study drug (including DAA, pegIFN, and RBV) (SVR12actual).  The percentage 
of subjects with SVR12actual and the corresponding 95% exact binomial confidence interval will be 
calculated overall and by treatment group in the prior study.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are the percentage of subjects with sustained virologic response 
24 weeks after the last actual dose of study drug (including DAA, pegIFN, and RBV) (SVR24actual) and 
the percentage of subjects with eRVR (HCV RNA < LLOQ at Weeks 4 through 12 in Substudy 1).
The percentage of subjects with SVR24actual and eRVR and the corresponding 95% exact binomial
confidence intervals will be calculated overall and by treatment group in the prior study.
Pharmacokinetic:
Plasma concentrations for ABT-267, ABT-450, ritonavir, and RBV and serum concentrations of pegIFN 
will be summarized, if measured.  Plasma concentrations of metabolites if measured will also be 
summarized.
Safety:
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and preferred term.  
Tabulations will also be provided in which the number of subjects reporting an adverse event (MedDRA 
term) is additionally broken down by severity (mild, moderate, or severe) and relationship to study drug.  
Change from baseline in laboratory tests and vital sign measurements to each time-point of collection 
will be summarized, and values that are potentially clinically significant, according to predefined criteria, 
will be identified.


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
A1C
Apolipoprotein A1
ABT-450/r
ABT-450 administered with ritonavir
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
Anti-HIV Ab
Anti-HIV antibody
aPTT
Activated partial thromboplastin time
AARDEX
Advanced Analytical Research on Drug Exposure
AST
Aspartate aminotransferase
AUC
Area under the curve
BDI-II
Beck Depression Inventory-II
BID
Twice daily
BMI
Body mass index
BUN
Blood urea nitrogen
Cmax
Maximum observed plasma concentration
CRF
Case report form
CYP3A
Cytochrome P450 3A
CYP3A4
Cytochrome P450 3A4
DAA
Direct-acting antiviral agent
EC
Ethics Committee
EC50
Half maximal effective concentration
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EOTR
End of Treatment Response (Week 12)
eRVR
Extended rapid virologic response
EVR
Early virological response
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice


ABT-450, ritonavir, ABT-267
M13-101 Protocol Amendment 10
EudraCT 2011-005393-32
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HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IL28B
Interleukin 28B
IMP
Investigational medical product
INR
International normalized ratio
IRB
Institutional Review Board
IP-10
Interferon gamma-induced protein 10
IRT
Interactive response technology
IU
International units
IUD 
Intrauterine device
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MEMS
Medication Event Monitoring System
MDRD
Modification of diet in renal disease
NS3
Nonstructural protein 3
NS4A
Nonstructural protein 4A
NS5A
Nonstructural protein 5A
NS5B
Nonstructural protein 5B
OATP1B1
Organic anion transporting polypeptide 1B1
PCS
Potentially clinically significant
pegIFN
Peginterferon alfa-2a
PO
Oral
POR
Proof of Receipt
PT
Prothrombin time
QD
Once daily
QTcF
QTc using Fridericia's correction formula
RBC
Red blood cells


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RBV
Ribavirin
RNA
Ribonucleic acid
RVR
Rapid virologic response
SAE
Serious adverse event
SAS
Statistical Analysis System
SDP
Study Designated Physician
SDS
Sodium dodecyl sulfate
SC
Subcutaneous
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SOC
Standard of care
SUSAR
Suspected unexpected serious adverse reaction
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks post-dosing
SVR24
Sustained virologic response 24 weeks post-dosing
TI
Treatment intensification
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cells
Definition of Terms
Post-Treatment Period
48 weeks duration after the last dose of study drug in Substudy 1 or 2
Substudy 1 Study Drug
ABT-450/r, ABT-267, pegIFN, RBV
Substudy 2 Study Drug
pegIFN, RBV
Study Day 1
First day a subject took study drug in Substudy 1
Treatment Intensification 
Period
Substudy 1
Treatment Period
Day 1 through last treatment visit in Substudy 1 or 2


ABT-450, ritonavir, ABT-267
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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..........................................9
2.0
Table of Contents...................................................................12
3.0
Introduction ...........................................................................17
3.1
Differences Statement..............................................................................29
3.2
Benefits and Risks....................................................................................30
4.0
Study Objective......................................................................32
4.1
Primary Objective ....................................................................................32
4.2
Secondary Objectives...............................................................................32
5.0
Investigational Plan...............................................................32
5.1
Overall Study Design and Plan:  Description ..........................................32
5.1.1
Pre-screening............................................................................................34
5.1.2
Screening..................................................................................................36
5.1.3
Treatment Period (Substudy 1 and Substudy 2) ......................................38
5.1.4
Post-Treatment Follow-Up Period (Substudy 3) .....................................40
5.2
Selection of Study Population..................................................................42
5.2.1
Inclusion Criteria .....................................................................................43
5.2.2
Exclusion Criteria ....................................................................................45
5.2.3
Prior and Concomitant Therapy...............................................................48
5.2.3.1
Prior HCV Therapy..................................................................................49
5.2.3.2
Prohibited Therapy...................................................................................50
5.2.3.3
Post-Treatment Therapy...........................................................................51
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic, and Safety 
Assessments/Variables.............................................................................51
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................51
5.3.1.1
Study Procedures .....................................................................................59
5.3.1.1.1
Additional Procedures for Cirrhotic Subjects Only.................................69
5.3.1.2
Meals and Dietary Requirements.............................................................71
5.3.2
Drug Concentration Measurements .........................................................71


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5.3.2.1
Collection of Samples for Analysis .........................................................71
5.3.2.2
Handling/Processing of Samples .............................................................72
5.3.2.3
Disposition of Samples ............................................................................72
5.3.2.4
Measurement Methods.............................................................................73
5.3.3
Efficacy Variables....................................................................................73
5.3.3.1
Primary Variable......................................................................................74
5.3.3.2
Secondary Variable..................................................................................74
5.3.3.3
Resistance Variables ................................................................................74
5.3.4
Safety Variables.......................................................................................74
5.3.5
Pharmacokinetic Variables ......................................................................74
5.4
Removal of Subjects from Therapy or Assessment.................................75
5.4.1
Discontinuation of Individual Subjects....................................................75
5.4.1.1
Virologic Failure Criteria.........................................................................76
5.4.2
Non Efficacy (Futility) Criteria ...............................................................77
5.4.3
Discontinuation of Entire Study...............................................................78
5.5
Treatments................................................................................................79
5.5.1
Treatments Administered.........................................................................79
5.5.2
Identity of Investigational Products.........................................................80
5.5.2.1
Packaging and Labeling...........................................................................80
5.5.2.2
Storage and Disposition of Study Drugs..................................................81
5.5.3
Method of Assigning Subjects to Treatment Groups...............................81
5.5.4
Selection and Timing of Dose for Each Subject......................................82
5.5.5
Blinding....................................................................................................82
5.5.6
Treatment Compliance.............................................................................82
5.5.7
Electronic Pill Monitors (MEMS Caps) ..................................................83
5.5.8
Drug Accountability.................................................................................85
5.6
Discussion and Justification of Study Design..........................................86
5.6.1
Discussion of Study Design and Choice of Control Groups....................86
5.6.2
Appropriateness of Measurements...........................................................87
5.6.3
Suitability of Subject Population .............................................................87
5.6.4
Selection of Doses in the Study ...............................................................88
6.0
Adverse Events.......................................................................90
6.1
Definitions................................................................................................90


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6.1.1
Adverse Event..........................................................................................90
6.1.2
Serious Adverse Events ...........................................................................91
6.2
Adverse Event Severity............................................................................92
6.3
Relationship to Study Drug......................................................................93
6.4
Adverse Event Collection Period.............................................................93
6.5
Adverse Event Reporting.........................................................................94
6.6
Pregnancy.................................................................................................95
6.7
Toxicity Management ..............................................................................97
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events ........................................................................................97
6.7.2
Grades 3 or 4 Laboratory Abnormalities and Severe or Serious 
Adverse Events ........................................................................................98
6.7.3
Management of Decreases in Hemoglobin..............................................98
6.7.4
Management of ALT Elevations............................................................100
6.7.5
Management of Creatinine Clearance Decreases...................................101
6.7.6
Management of Neuropsychiatric Complications..................................102
6.7.7
Management During Peginterferon Therapy .........................................103
6.7.8
Management of Neutropenia and Thrombocytopenia ...........................103
7.0
Protocol Deviations..............................................................103
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................104
8.1
Statistical and Analytical Plans..............................................................105
8.1.1
Demographics ........................................................................................105
8.1.2
Pharmacokinetics ...................................................................................105
8.1.2.1
Pharmacokinetics Endpoints..................................................................106
8.1.3
Efficacy..................................................................................................106
8.1.3.1
Primary Efficacy Endpoints...................................................................106
8.1.3.2
Secondary Efficacy Endpoints...............................................................106
8.1.3.3
Additional Efficacy Endpoints...............................................................107
8.1.4
Exploratory Analyses.............................................................................108
8.1.5
Resistance Analyses...............................................................................108
8.1.6
Safety .....................................................................................................111
8.1.6.1
Adverse Events ......................................................................................111


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8.1.6.2
Clinical Laboratory Data........................................................................112
8.1.6.3
Vital Signs Data .....................................................................................112
8.2
Determination of Sample Size ...............................................................113
9.0
Ethics.....................................................................................113
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................113
9.2
Ethical Conduct of the Study.................................................................114
9.3
Subject Information and Consent...........................................................114
10.0
Source Documents and Case Report Form 
Completion ...........................................................................115
10.1
Source Documents .................................................................................115
10.2
Case Report Forms.................................................................................115
11.0
Data Quality Assurance ......................................................116
12.0
Use of Information...............................................................116
13.0
Completion of the Study .....................................................117
14.0
Investigator's Agreement....................................................119
15.0
Reference List ......................................................................120
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........................................22
Table 2.
Overview of Treatment-Emergent Adverse Events (AE)........................26
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 ...................................................................................27
Table 4.
Medications Contraindicated for Use with the Study Drug 
Regimen ...................................................................................................46
Table 5.
Study Activities........................................................................................52
Table 6.
Additional Study Activities for Cirrhotic Subjects Only.........................56
Table 7.
Study Activities – Substudy 3 Post-Treatment ........................................57
Table 8.
Additional Study Activities for Cirrhotic Subjects Only –
Substudy 3 Post-Treatment......................................................................58


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Table 9.
Clinical Laboratory Tests.........................................................................66
Table 10.
Dosing Schematic ....................................................................................80
Table 11.
Identity of Investigational Products.........................................................80
Table 12.
Hematologic Toxicities..........................................................................100
Table 13.
Dosing of RBV in Subjects with Renal Impairment..............................102
List of Figures
Figure 1.
Study Schematic.......................................................................................33
Figure 2.
Pre-screening Visit Flow Chart................................................................36
Figure 3.
Subject Flow Chart ..................................................................................42
Figure 4.
Adverse Event Collection ........................................................................94
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................121
Appendix B.
List of Protocol Signatories....................................................................123
Appendix C.
Clinical Toxicity Grades........................................................................124
Appendix D.
Protocol Amendment:  List of Changes.................................................127


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with over 170 million 
individuals infected worldwide.1  While therapy for this condition has improved 
considerably, the currently available treatment regimens are not optimal.  Until 2011 with 
the FDA approval of the protease inhibitors (PI) telaprevir and boceprevir, the standard of 
care (SOC) for treatment of HCV genotypes 1a and 1b (the most common genotypes in 
North America and Europe) consisted of weekly injections of pegylated interferon-alpha 
(pegIFN) and daily oral doses of ribavirin (RBV) for up to 48 weeks.2  Approximately 
50% of patients with genotype 1 HCV infection treated with pegIFN and RBV fail to 
achieve a sustained virologic response (SVR).  While the triple drug regimen of 
PI/pegIFN/RBV increased SVR rates to 70% – 80%, there were many treatment 
discontinuations due to drug toxicities like rash and anemia, and virologic failure rates 
were still unacceptably high.  These two, distinct eras of HCV therapy generated a large 
cohort of patients in need of more potent antiviral regimens.
To meet this need, a number of small molecules with direct antiviral activity (direct-acting 
antiviral agent [DAA]) against specific stages of the HCV life cycle have been 
developed.3  Clinical studies to date with these DAA HCV inhibitors, such as the NS3/4A 
protease inhibitors telaprevir and boceprevir, used in combination with pegIFN plus RBV, 
have demonstrated improved SVR rates in treatment-naïve and pegIFN-experienced 
patients, with shorter treatment durations for a subset of naïve subjects.  As a result, these 
regimens are now considered the standard of care for chronic genotype 1 HCV infection.4  
Combinations of multiple DAAs with pegIFN and RBV have also been studied and may 
further improve SVR rates or shorten duration of therapy.5,6
Data from studies on the retreatment of HCV-infected subjects who failed prior treatment 
with regimens containing one or more DAAs are limited.  In one study, an NS5A inhibitor 
(BMS 790052) and a PI (BMS 650032) combined with pegIFN and RBV for 24 weeks 
achieved SVR24 in over 90% of prior pegIFN/RBV null responders, suggesting that these 
patients may be successfully treated with a DAA combination added to pegIFN/RBV.  In 


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several exploratory studies, subjects who experienced viral breakthrough or non-response 
(with emergence of DAA-related associated resistance mutations) were managed by the 
addition of pegIFN, or pegIFN and RBV to the failing DAA combination regimen.  This 
treatment strategy resulted in suppression of HCV RNA to undetectable levels in a 
number of subjects despite the presence of resistant virus, including in prior pegIFN/RBV 
null responders.7  This response may be related to the impaired replicative capacity of the 
resistant viral variants, or to improved interferon responsiveness following a course of 
DAA therapy.  The replicative fitness of resistant variants plays a role not only in the 
likelihood and timing of the emergence of resistance, but also in the likelihood of a 
quasispecies population dominated by resistant variants reverting to predominantly wild 
type virus in the absence of drug selective pressure.  Continuation of the DAAs in these 
cases may therefore contribute to antiviral activity even in the presence of resistant 
variants, by providing selective pressure to maintain a population of poorly fit variants.
The antiviral response in patients whose HCV is re-exposed to a DAA has not yet been 
studied, but will be important in understanding future treatment options for patients who 
fail initial therapy.  Unlike HIV infection, in which resistant variants generated during 
unsuccessful antiretroviral therapy are archived as latently integrated proviruses in resting 
memory T cells, no such long-lived reservoir has been demonstrated for HCV.  Thus, it 
may be possible for patients who initially failed a DAA-containing regimen to achieve 
successful retreatment with a new regimen that includes DAAs that were components of 
the initial regimen.
AbbVie has three DAAs that were recently approved by North American and European 
regulatory agencies.  ABT-450 (paritaprevir) is an NS3/4A protease inhibitor, ABT-267 
(ombitasvir) is an NS5A inhibitor, and ABT-333 (dasabuvir) is a non-nucleoside NS5B 
polymerase inhibitor.  These 3 DAAs have been studied both with and without RBV in 
the absence of pegIFN in phase 3 trials in HCV-infected subjects, as summarized below.  
The current study will explore the utility of pegIFN and RBV, in combination with 
ABT-450/r and ABT-267, in HCV-infected subjects who have experienced virologic 


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failure in a previous AbbVie/Abbott trial of combination DAA therapy.  Additional 
information on ABT-450 and ABT-267 is provided below.
ABT-450
ABT-450, (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-
2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14, 
15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-
14a(5H)-carboxamide hydrate, is an NS3/4A protease inhibitor with nanomolar potency 
against genotype 1 HCV in vitro.  ABT-450 is metabolized primarily by cytochrome P450 
3A4 (CYP3A4) and thus is dosed with ritonavir, a potent CYP3A4 inhibitor, in order to 
enhance exposures (ABT-450/r).  ABT-450/r has been well tolerated in single- and 
multiple-dose studies in healthy volunteers, and when administered to HCV-infected 
subjects at doses of 50/100 mg QD, 100/100 mg QD and 200/100 mg QD for 12 weeks in 
combination with pegIFN and RBV in Study M11-602.  Repeated dosing of ABT-450/r in 
both healthy volunteers and HCV-infected subjects has been associated with transient 
asymptomatic increases in total and indirect bilirubin, occurring with greater frequency at 
total daily doses of 200/100 mg or greater.  These increases in bilirubin appear to be due 
to ABT-450-mediated inhibition of the bilirubin transporter organic anion transporting 
polypeptide 1B1 (OATP1B1).  
In Study M11-602, ABT-450/r monotherapy for 3 days resulted in a mean maximum 
4.01 log10 international units (IU)/mL HCV RNA decline, compared to 0.36 log10 IU/mL 
with placebo (n = 11), P < 0.001.  Twenty-two of 24 subjects receiving ABT-450/r plus 
pegIFN/RBV achieved an HCV RNA below the level of detection at Week 12, compared 
to 2 of 11 receiving pegIFN/RBV alone (P < 0.001).  Confirmed virologic failure 
subsequently occurred in 3 subjects receiving ABT-450/r 50/100 mg QD (2 relapses after 
discontinuing therapy and one failure to achieve undetectable HCV RNA), suggesting that 
this dose may have less antiviral activity than the higher doses.  In an analysis of clonal 
sequencing results from the monotherapy portion of ABT-450/r administration, variants 
associated with resistance were observed less commonly in the NS3 protease gene in 


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subjects receiving ABT-450/r 200/100 mg compared to the lower doses, likely 
representing suppression of pre-existing resistant variants at the 200/100 mg dose.
ABT-450/r has a favorable safety, tolerability, and pharmacokinetic profile at doses 
administered to date and has shown potent antiviral activity at doses of 50/100 mg QD 
and greater in HCV genotype 1-infected subjects.  Additional detailed information about 
preclinical toxicology, metabolism, pharmacology and clinical data can be found in the 
Investigator's Brochure for ABT-450.8
ABT-267
ABT-267, dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene4,1-
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}) 
biscarbamate hydrate, is an NS5A inhibitor, with inhibitory concentrations in the 
picomolar range against genotype 1 HCV in vitro.
ABT-267 has been well tolerated in single- and multiple-dose studies in healthy 
volunteers, and when administered to HCV-infected subjects at doses of 5 mg QD to 
200 mg QD for 12 weeks in combination with pegIFN and RBV in Study M12-114.  
Three days of ABT-267 monotherapy resulted in approximately a 2.9 log10 IU/mL mean 
maximal HCV RNA decrease from baseline across a range of doses from 5 mg QD to 
200 mg QD.
ABT-267 has a favorable safety, tolerability, and pharmacokinetic profile at all doses 
administered to date, and has shown potent antiviral activity at doses of 5 mg QD and 
greater in HCV genotype 1-infected subjects.  Additional detailed information about 
preclinical toxicology, metabolism, pharmacology and clinical data can be found in the 
Investigator's Brochure for ABT-267.9
Combination Antiviral Effect In Vitro 
ABT-450 plus ABT-267 has been studied in combination in the in vitro replicon system.  
This compound combination displayed additive to synergistic interactions at most 


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concentrations tested.  In longer term cell passage studies, the combination of ABT-450
plus ABT-267 reduced replicon RNA to below detectable levels.
Phase 3 studies with ABT-450, ABT-267 and ABT-333
The IFN-free regimen of ABT-450/r, ABT-267, and ABT-333 has been studied with and 
without RBV in over 2,300 patients in Phase 3 trials across a variety of patient 
populations, including patients with compensated cirrhosis.  Based on these data, the 
regimen with or without RBV is safe, well tolerated and efficacious in treatment-naïve 
and treatment-experienced HCV 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.


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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-cirrhotic
Naïve
99.0
98.9
--
Null
100
94.4
--
Partial
100
98.1
--
Relapser
100
98.5
--
Genotype 1a non-cirrhotic
Naïve
90.2
95.7
--
Null
--
95.4
--
Partial
--
100
--
Relapser
--
94.0
--
Genotype 1b cirrhotic
Naïve
--
100
100
Null
--
100
100
Partial
--
85.7*
100
Relapser
--
100
100
Genotype 1a cirrhotic
Naïve
--
9.4
92.9
Null
--
80.0
92.9
Partial
--
100
100
Relapser
--
93.3
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 DAAs + RBV in HCV 
genotype 1-infected treatment-naïve subjects (Study M11-646) and prior pegIFN/RBV 
non-responders (Study M13-098) without cirrhosis.  Subjects received 3 DAAs + RBV 


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for 12 weeks of treatment.  Subjects randomized to the placebo arm received placebo for 
12 weeks, after which they received 3 DAAs + RBV in open-label fashion 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 DAAs + RBV for 12 weeks was 
96.2%.  Virologic failure was noted in 7/322 (2.2%) genotype 1a-infected subjects 
(on-treatment virologic failure:  n = 1; relapse:  n = 6) and 1/151 (0.7%) 
genotype 1b-infected 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-infected subjects 
and 2/123 (1.6%) genotype 1b-infected 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 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 who did not achieve 
SVR with 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 


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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 DAAs + RBV is the 
optimal regimen for these patients.
Phase 3 Study in Cirrhosis:  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 1 infection 
with compensated (Child-Pugh A, Child-Pugh score 5 or 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-infected 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 with 3-DAA + RBV 
is recommended for all patients with cirrhosis with the exception of genotype 1a-infected 
prior null responders, for whom 24 weeks of treatment provides a higher SVR.
Integrated Safety Results
A summary of treatment-emergent adverse events from 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.


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


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


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post-treatment.  Hyperbilirubinemia occurred less frequently in subjects treated with 
3 DAAs without RBV compared to 3 DAAs with RBV.  The frequency and degree of 
hyperbilirubinemia were higher in subjects with cirrhosis, but the temporal pattern of 
elevation followed by resolution was similar and few episodes were symptomatic.  
Grade 2 + hemoglobin reductions occurred in 6% of subjects without cirrhosis who 
received the 3-DAA + RBV regimen for 12 weeks, and 7% and 11% of subjects with 
cirrhosis who received the 3-DAA + RBV regimen for 12 and 24 weeks, respectively.  
Grade 3 hemoglobin values were rare.  The decline in hemoglobin was largely managed 
with RBV dose reductions.  Anemia observed during the clinical trials was largely 
attributable to the presence of RBV as it was not observed when the 3-DAA regimen was 
administered without RBV.
Transient asymptomatic 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 > 5 × ULN 
were observed in subjects receiving progestins only or in subject receiving topical vaginal 
estrogen preparations.  Among the cases of serum ALT elevation thought to be related to 
the DAA regimen, none resulted in hepatic dysfunction and they generally resolved or 
improved with ongoing treatment.  All cases had resolved completely in the 
post-treatment follow-up.
ABT-450/ritonavir and ABT-267 (and its major inactive human metabolites) had no 
effects on embryo-fetal development in rodent and/or nonrodent species at maximal 
feasible exposures that provided AUC multiples at least 4-fold higher than exposure at the 


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recommended clinical doses.  Clinical studies in women who are pregnant have not been 
conducted.
The current study is intended to offer subjects with genotype 1 HCV infection who 
experience virologic failure in a previous AbbVie/Abbott DAA combination study an 
optional intensified treatment regimen.  This study will assess the safety, antiviral activity 
and resistance profile of ABT-450/r 200/100 mg QD and ABT-267 25 mg QD combined 
with pegIFN and RBV in subjects who met a virologic failure criterion in a previous 
study.  Among subjects who previously experienced null or partial response to 
pegIFN/RBV treatment (with or without approved DAAs) at any time prior to 
pre-screening for this study, or who experienced virologic failure with pegIFN/RBV plus 
telaprevir in the prior AbbVie/Abbott study, enrollment will be limited to only those 
subjects in whom variants in HCV NS3/4A protease and NS5A at amino acid residues 
known to be associated with resistance are not present at a pre-screening visit.  Subjects 
who never experienced prior null or partial response to pegIFN/RBV treatment, and who 
never experienced virologic failure with pegIFN/RBV plus telaprevir in the prior 
AbbVie/Abbott study, will be allowed to enroll in Study M13-101 at the discretion of the 
investigator, regardless of whether resistant variants are detected.
3.1
Differences Statement
The differences between previous DAA combination studies in HCV-infected subjects 
and this study are as follows:
The current study, Study M13-101, is a single arm study evaluating ABT-450/r in 
combination with ABT-267, pegIFN and RBV for 24 weeks followed by pegIFN and 
RBV alone for an additional 24 weeks in subjects who have experienced virologic failure 
in a previous AbbVie/Abbott DAA combination study.  None of the previous 
AbbVie/Abbott DAA combination studies included pegIFN with both ABT-450 and 
ABT-267 in the treatment regimen, or explored efficacy of a DAA, pegIFN and RBV 
containing regimen in subjects who previously failed a DAA-based therapy.


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3.2
Benefits and Risks
Risk of Toxicity
The toxicity profile of pegIFN and RBV has been well described and includes headache, 
myalgia, fatigue, pyrexia, injection site reactions, and cytopenias.  Previous studies of 
pegIFN and RBV in combination with ABT-450/r (Study M11-602) or ABT-267 
(Study M12-114) demonstrated that the safety profiles of the respective regimens were 
generally comparable to those of pegIFN and RBV alone.  In contrast, combination dosing 
of ABT-450/r with ABT-267 has generally been well tolerated both in healthy volunteers 
and both with and without RBV for up to 12 weeks in HCV-infected subjects (based on 
ongoing studies).  Preclinical toxicology studies have assessed the toxicity of ABT-267 
for up to 6 months, and ABT-450 for up to 9 months.  ABT-450 and ABT-267 have been 
administered in clinical trials for up to 24 weeks.  Subjects who enroll in Study M13-101 
after having completed > 12 weeks of prior combination therapy may ultimately receive 
ABT-450/r and ABT-267 cumulatively for more than 24 weeks; thus there is also a risk of 
toxicity due to administration longer than 24 weeks that has not previously been observed.  
However, no dose-limiting toxicities have thus far been observed in animal studies, or in 
humans receiving the doses of ABT-450/r and/or ABT-267 used in this study.  ABT-450/r 
and ABT-267 have not previously been dosed together in combination with pegIFN and 
RBV.
Risk of Treatment Failure
The likelihood of successfully curing HCV-infected subjects with a regimen containing 
2 DAAs + pegIFN + RBV after they have previously failed therapy with DAA 
combination therapy is not known.  A previous study by Bristol Myers-Squibb used the 
NS5A and protease inhibitors BMS-790052 and BMS-65003210 in combination with 
pegIFN and RBV in prior pegIFN/RBV null responders and achieved a high rate of 
virologic suppression.  Subjects who experience virologic failure in this study are at risk 
of selecting HCV variants with resistance to up to 3 classes of DAA (depending on their 
prior DAA combination therapy), which may compromise future treatment options if the 
variants persist off treatment.  However, it is assumed that many of these subjects will 


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already have selected resistance to one or more DAA class in the setting of their prior 
treatment failure.  Therefore, the risk of incurring a greater degree of viral drug resistance 
(and the resulting loss of additional treatment options) must be weighed against the 
possible benefit of an efficacious treatment regimen.  Since this balance may be different 
depending on multiple factors (including prior treatment experience, stage of liver disease, 
other available treatment options, IL28B host genotype and others), this study will be 
made available on a purely optional basis to all subjects who previously experienced 
virologic failure in an AbbVie/Abbott DAA combination trial.  It is expected that subjects 
will make a decision regarding participation in consultation with the investigator.  
However, since prior non-responders (null or partial response) to pegIFN/RBV may have 
a suboptimal response to a second course of pegIFN and RBV, this population will only 
be eligible if population sequencing of HCV NS3/4A protease and NS5A from a sample 
collected at the Pre-screening Visit does not detect variants at positions known to be 
associated with reduced susceptibility to ABT-450 and ABT-267.  Likewise, even 
subjects who had an initial response to pegIFN/RBV plus telaprevir or boceprevir and 
then failed (due to relapse or breakthrough) may, in fact, be poor responders to interferon, 
and the initial virologic response may have reflected suppression due to the protease 
inhibitor.  Hence, subjects who received pegIFN/RBV plus telaprevir in the previous 
AbbVie/Abbott study will only be eligible if population sequencing does not detect 
ABT-450 or ABT-267 resistance-associated variants.
In summary, the risks associated with the individual study drugs to be administered in 
Study M13-101 have been well characterized and appear limited and manageable.  
Subjects will be closely monitored for any potential risks which may occur when the 
DAAs are dosed in combination, including risks of toxicity and of virologic failure.  
Given the potential benefit of achieving cure in a population of HCV-infected subjects 
with limited available treatment options, as well as the manageable risks associated with 
the planned therapy, the risk-benefit comparison is considered favorable.


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4.0
Study Objective
4.1
Primary Objective
The primary objective of this study is to evaluate the safety and antiviral efficacy, defined 
as the percentage of subjects with sustained virologic response 12 weeks post-dosing 
(SVR12; HCV RNA < LLOQ 12 weeks after the last dose of study drug). 
4.2
Secondary Objectives
The secondary objectives of this study are:
●
to evaluate the percentage of subjects with sustained virologic response 
24 weeks post-dosing (SVR24; HCV RNA < LLOQ 24 weeks after the 
last dose of study drug) and
●
to evaluate the percentage of subjects with extended rapid virologic response 
(eRVR) (HCV RNA < LLOQ at Weeks 4 through 12 of therapy with 
ABT-450/r plus ABT-267 plus pegIFN plus RBV). 
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, open-label, single arm combination treatment study of ABT-450/r and 
ABT-267 in combination with pegIFN/RBV in HCV genotype 1-infected subjects 
(including subjects with compensated cirrhosis) who have experienced virologic failure 
while participating in a previous AbbVie/Abbott DAA combination study.  Among 
subjects who previously experienced null or partial response to pegIFN/RBV treatment at 
any time prior to pre-screening for this study, or who experienced any prior failure with 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study, enrollment in this 
study will be restricted to those in whom population sequencing at the Pre-screening Visit 
does not detect the presence of variants relative to the appropriate prototypic reference 
sequence (H77 for 1a or Con1 for 1b) at any of the following amino acid positions:  NS3 
155, 156, or 168; or NS5A 28, 29, 30, 31, 32, 58, or 93.  All other subjects will be 


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allowed to enroll in Study M13-101 at the discretion of the investigator, regardless of 
whether variants at any of these amino acid positions are detected.
This study consists of a pre-screening period, a screening period and three substudies:
●
Substudy 1 (Treatment Intensification [TI]):  24 weeks of therapy with 
ABT-450/r plus ABT-267 plus pegIFN plus RBV;  
●
Substudy 2 (PegIFN/RBV [PR] Treatment):  24 weeks of pegIFN and RBV 
therapy alone; 
●
Substudy 3 (Post-treatment [PT] Follow-up Period):  48 weeks after last dose 
of any study drug for resistance monitoring and HCV RNA viral load testing. 
Figure 1.
Study Schematic
This study is designed to assess the safety, antiviral activity and pharmacokinetics (PK) of 
the DAAs ABT-450/r plus ABT-267, dosed for 24 weeks in combination with pegIFN 
and RBV, followed by an additional 24 weeks of pegIFN and RBV alone.  All subjects 
who receive at least 1 dose of DAA therapy in this protocol, regardless of whether they 
prematurely discontinue or complete the study drug as planned, will be monitored for 
viral response and viral resistance on an outpatient basis for an additional 48 weeks 
following the last dose of any study drug as described in Section 5.1.4.
ABT-450/r 200/100 mg+
ABT-267 25 mg +pegIFN/RBV
pegIFN + RBV
SS1: TI Period
SS2: PR Treatment  
Period
SS3: PT Period
Follow up for HCV RNA and resistance monitoring
24 weeks
24 weeks
48 weeks after last dose of Study Drug


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5.1.1
Pre-screening
Subjects who receive at least 1 dose of DAA and who experience virologic failure either 
during DAA therapy (rebound, breakthrough or failure to suppress) or after the end of 
therapy (relapse) in a previous AbbVie/Abbott DAA combination study, will be offered 
enrollment in this study if the subject meets all of the eligibility criteria specified in 
Section 5.2.1 and Section 5.2.2, and if study drug therapy is considered medically 
appropriate based on the opinion of the investigator.
The Pre-screening Visit may be conducted at any time after the subject is confirmed 
failure from the previous AbbVie/Abbott DAA combination study.  Once the subject is 
confirmed to meet all the eligibility criteria then the subject must discontinue from the 
previous AbbVie/Abbott DAA combination study.  Subjects must provide written (signed 
and dated) informed consent for Study M13-101 prior to any study-specific procedures, 
including the population sequencing analysis done at the Pre-screening Visit.  The 
investigator will record the details of the informed consent process in the subject's 
medical records.  A blood sample will be collected for all subjects at the Pre-screening 
Visit for population sequencing of the HCV NS3/4A protease and NS5A genes.  Another 
sample will be drawn at the same time at this visit to determine the HCV RNA level.  The 
HCV RNA level must be at least 2000 IU/mL in order to perform the population 
sequencing testing.  The Pre-screening Visit may be repeated at a later date per the 
investigator's discretion if the HCV RNA level is < 2000 IU/mL.  Subjects will retain their 
subject number from the previous DAA combination study.  This information will be 
entered into the Interactive Response Technology (IRT) system under the Pre-screening 
Visit flow.  This number will be written on the Pre-screening Visit blood collection tubes 
and on the lab requisition form prior to shipping the samples to the central laboratory.  
The results of the population sequencing will take approximately 3 weeks to complete.
Among subjects who previously experienced null or partial response to pegIFN/RBV 
treatment at any time prior to pre-screening for this study, or who had any prior failure 
with pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study, enrollment will 
be limited to only those subjects in whom variants in HCV NS3/4A protease and NS5A at 


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amino acid residues known to be associated with resistance are not present at the 
Pre-screening Visit.  All other subjects will be allowed to enroll in Study M13-101 at the 
discretion of the investigator, regardless of whether resistant variants are detected.  If the 
results of population sequencing do not exclude the subject from participation, the subject 
should undergo a Screening Visit for this study as soon as possible.  However, subjects 
will have up to 12 weeks after the Pre-screening Visit to perform the Screening Visit. If it 
is longer than 12 weeks, the site must get approval from the Study Designated Physician 
prior to conducting the Screening Visit.  Refer to Figure 2 for the Pre-screening Visit flow 
chart.
Subjects who do not meet inclusion criteria for HCV RNA level or who meet the 
exclusion criteria for resistance at the Pre-screening Visit must be entered into the IRT 
system as a Pre-screen failure under the Discontinuation Visit flow.  Subjects with 
exclusionary resistance-associated variants detected at the Pre-screening Visit will not be 
allowed to repeat the Pre-Screening Visit.


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Figure 2.
Pre-screening Visit Flow Chart
5.1.2
Screening
Once the Investigator has established that the subject does not meet exclusion criteria 
No. 1 (by review of results of the Pre-screening resistance testing, if applicable), the 
Screening Visit can be performed.  The subject will be entered into the Interactive 
Response Technology (IRT) system under the Screening Visit flow.  The subjects will 
undergo the study procedures identified in Table 5 and Table 6 (for cirrhotic subjects).
The investigator will evaluate whether the subject meets all of the eligibility criteria 
specified in Section 5.2.1 and Section 5.2.2 during the period from the Screening Visit 
through TI Day 1 prior to dosing, capture the concomitant medication and record the 
results of all assessments in the subject's medical records.  Eligible subjects have up to 


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42 days following the Screening Visit to enroll into the study.  Prior to enrollment, 
subjects should agree to practice two effective methods of birth control while receiving 
study drugs starting with Study Day 1 and for 7 months after stopping study drug or as 
directed by the local ribavirin label.  Subjects using systemic estrogen-containing 
contraceptive therapy (including estrogen-containing oral contraceptives) have a higher 
risk for elevated ALT levels.  Subjects using these medications must discontinue them at 
least 2 weeks prior to study drug administration or 10 half-lives (if known), whichever is 
longer.  Subjects may replace the systemic estrogen-containing contraceptive with a 
progestin-only hormonal contraceptive method.
Once the subject is confirmed to meet all the eligibility criteria then the subject must 
discontinue from the Post-Treatment Period of the previous AbbVie/Abbott DAA 
combination study.
Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol 
screen, may have only the urine drug screen repeated.  If the repeat urine drug screen is 
qualifying (does not meet Exclusion Criterion No. 4), the subject may be considered 
eligible.
Subjects who meet all inclusion criteria and none of the exclusion criteria with the 
exception of one exclusionary lab parameter may rescreen once without prior AbbVie 
approval.  AbbVie Study Designated Physician approval is required to rescreen a subject 
who has multiple exclusionary laboratory results.  Subjects undergoing rescreening must 
repeat all laboratory tests that were initially out-of-range.  Subjects who fail to enroll 
within 42 days of the Screening Visit may be allowed to rescreen only once without 
approval of the AbbVie Study Designated Physician and must be rescreened for all 
laboratory and eligibility criteria (with the exception of HCV genotype, Anti-HCV Ab, 
FSH, BDI-II Scale and fundoscopic exam).  Liver ultrasound and alpha-fetoprotein testing 
for subjects with cirrhosis do not need to be repeated unless 6 months or more have 
elapsed since the initial screening.


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Subjects with an exclusionary HCV genotype, exclusionary drug screen (other than a 
positive urine alcohol), positive anti-HIV antibodies or hepatitis B surface antigen, a 
Becks Depression Inventory II (BDI–II) score > 21 or positive pregnancy test will be 
excluded and may not rescreen.
Subjects who are not eligible to enroll per the inclusion/exclusion criteria after the 
Screening Visit must be entered into the IRT system as a screen failure under the 
Discontinuation flow.
5.1.3
Treatment Period (Substudy 1 and Substudy 2)
Substudy 1 – Treatment Intensification (TI) Period
There is one treatment group for this study.  After meeting entry criteria, subjects will 
receive ABT-450/r 200/100 mg, ABT-267 25 mg, pegIFN and RBV.  ABT-450/r and 
ABT-267 will be administered once daily; pegIFN will be dosed once weekly and RBV 
will be dosed twice daily.  See Section 5.5.1 for details.
At the TI Day 1 Visit, subjects will undergo the study procedures identified in Table 5
(and Table 6 for cirrhotic subjects).
Subjects will be administered study drugs at the site on TI Day 1.  Plasma and serum 
samples for pharmacokinetic analysis will be collected at TI Week 1 through TI Week 24 
(Substudy 1).  All subjects will continue to return to the site on an outpatient basis 
through TI Week 24 for the study procedures identified in Table 5 (and Table 6 for 
cirrhotic subjects).  Sites should ensure that subjects adhere to the study visits listed in 
Table 5 (and Table 6 for cirrhotic subjects).  Subjects who cannot complete their study 
visit per the visit schedule through TI Week 24 should 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 request of the investigator and with the agreement of the subject.


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Subjects who prematurely discontinue from the DAA study drug treatment in Substudy 1 
should return for a TI Week 24/TI Discontinuation Visit and undergo study procedures as 
defined in Table 5 (and Table 6 for cirrhotic subjects) and as described in Section 5.4.1.  
The subject should either proceed to Substudy 2 if the investigator feels it is appropriate 
or proceed to Substudy 3 if it is not appropriate to continue on Substudy 2.  Refer to 
Figure 3, Subject Flow Chart.
Substudy 2 – PegIFN/RBV (PR) Treatment Period
Subjects who complete TI treatment will continue on to Substudy 2, the PR Treatment 
Period, for continued dosing of pegIFN and RBV.  Subjects who prematurely discontinue 
TI treatment may also continue on to Substudy 2, unless the investigator feels it is not 
appropriate to continue pegIFN and RBV either due to toxicity or to lack of virologic 
response.  Substudy 2 will begin the day after the last dose of DAA.  Substudy 2 is 
designed to allow completion of pegIFN + RBV treatment for a total duration of 48 weeks 
across Substudies 1 and 2 and to monitor HCV RNA levels and emergence of any 
ABT-450 and ABT-267 resistance-associated variants.
For subjects who complete Substudy 1, an additional 24 weeks of pegIFN and RBV will 
be administered in Substudy 2.  Subjects who complete 24 weeks of treatment in 
Substudy 2 should undergo the procedures listed in the PR Final/PR Discontinuation Visit 
in Table 5 (and Table 6 for cirrhotic subjects), not the PR Week 24 visit and then continue 
on to Substudy 3.
Subjects who receive less than 24 weeks of TI treatment in Substudy 1 may receive 
pegIFN and RBV in Substudy 2 at the discretion of the investigator, up to a total of 
48 weeks across Substudies 1 and 2.  All subjects will continue to return to the site on an 
outpatient basis for the PR Treatment study procedures identified in Table 5 (and Table 6
for cirrhotic subjects).  For those subjects who do not complete 24 weeks of TI treatment 
in Substudy 1, additional study visits as indicated in Table 5 (and Table 6 for cirrhotic 
subjects) should be performed if required to complete a total of 48 weeks across 
Substudies 1 and 2.  These additional visits are PR Week 24, PR Week 36 and PR 


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Final/PR Discontinuation Visit (which may be out to 48 weeks or earlier).  All subjects 
should complete the PR Final/PR Discontinuation Visit procedures at that subject's final 
visit in Substudy 2.  In some cases this final visit may fall in between study visits listed in 
Table 5.  Sites should ensure that subjects adhere to the study visits listed in Table 5 (and 
Table 6 for cirrhotic subjects).  Subjects who cannot complete their study visit per the 
visit schedule should ensure they do not run out of study drug prior to their next study 
visit.  Compliance is critical to ensure adequate drug exposure.
Subjects who prematurely discontinue Substudy 2 should return to the site for a PR 
Final/PR Discontinuation Visit as outlined in Table 5 (and Table 6 for cirrhotic subjects).
Safety and tolerability of the treatments will be assessed throughout the study.  Laboratory 
testing will include chemistry, hematology, and urinalysis (refer to Table 9).  Ongoing 
review of the data is planned in order to determine if subjects meet the virologic stopping 
criteria.
Ongoing review of the data is also planned for non-efficacy (futility) assessment.  Data 
will be assessed separately for the population of subjects who were null or partial 
responders to prior pegIFN/RBV treatment or experienced any prior failure with 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study, and for the population 
of subjects who do not fall in the previous population at the time of enrollment into this 
study.  Refer to Section 5.4.2 for further details regarding these ongoing reviews.
5.1.4
Post-Treatment Follow-Up Period (Substudy 3)
In Substudy 3, the Post-treatment (PT) Period, subjects will be followed for 48 weeks 
after the last dose of study drugs for evaluation of the emergence, evolution and 
persistence of viral resistance to ABT-450/r and ABT-267 and for viral response.  
All subjects who receive at least 1 dose of DAA will be monitored for viral resistance on 
an outpatient basis for an additional 48 weeks following the last dose of study drugs, 
regardless of whether they prematurely discontinue study drug treatment or complete 
treatment as planned in Substudies 1 and 2.  Refer to Figure 3, Subject Flow Chart.


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Subjects will return to the study site as outlined in Table 7 (and Table 8 for cirrhotic 
subjects) for post-treatment visit procedures including resistance monitoring, HCV RNA 
testing, and assessment of adverse events (for 30 days post-treatment only) and serious 
adverse events.  Substudy 3 will begin the day after the last dose of study drug treatment.  
Subjects who prematurely discontinue Substudy 3 should return to the site for a 
PT Week 48/PT Discontinuation Visit as outlined in Table 7 (and Table 8 for cirrhotic 
subjects).
Some of the Post-Treatment Period study visits and visit activities (including but not 
limited to vital signs, clinical laboratory tests and concomitant medication assessment) 
may be conducted in the home or non-hospital/clinic environment at the request of the 
Investigator and with the agreement of the subject.
All subjects who receive at least one dose of DAA may be offered participation in a 
separate AbbVie-sponsored observational study to evaluate the durability of virologic 
response for subjects who achieve SVR or to study the emergence and persistence of 
resistant variants in subjects who fail treatment.


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Figure 3.
Subject Flow Chart
5.2
Selection of Study Population
Subjects who have experienced virologic failure in a previous AbbVie/Abbott DAA 
combination study and who meet the inclusion criteria, and who do not meet any of the 
exclusion criteria, will be eligible for enrollment into the study.  In addition, no more than 
ten (10) subjects who received pegIFN/RBV plus telaprevir in a previous AbbVie/Abbott 
study will be enrolled.


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5.2.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria: 
1.
Must voluntarily sign and date an informed consent, approved by an Institutional 
Review Board/Ethics Committee (IRB/EC), prior to the initiation of any study 
specific procedure.
2.
Subject must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
3.
Subject must have experienced virologic failure as defined in a previous 
AbbVie/Abbott DAA combination study.
4.
Female who is:
●
not of childbearing potential, defined as:
○
postmenopausal for at least 2 years prior to screening (defined as 
amenorrheic for longer than 2 years, age appropriate, and confirmed by a 
follicle-stimulating hormone [FSH] level indicating a postmenopausal 
state), or
○
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy 
or hysterectomy) or has a vasectomized partner(s), or
○
practicing total abstinence from sexual intercourse (minimum 1 complete 
menstrual cycle), or
○
sexually active with female partners only
●
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 other subject information documents), starting with Study 
Day 1 and for 7 months after stopping study drug or as directed by the 
local ribavirin label (Estrogen-containing hormonal contraceptives, 
including oral, injectable, implantable, patch and ring varieties, may not be 
used during DAA treatment).


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5.
Females must have negative results for pregnancy tests performed:
●
at Screening by urine specimen within 42 days prior to initial study drug 
administration, and
●
at Baseline (prior to dosing) by urine specimen.
Female subjects with a borderline hCG result at Day 1 may enroll into the study if 
they either:
●
have a documented history of bilateral tubal ligation, hysterectomy, bilateral 
oophorectomy; or
●
are confirmed to be postmenopausal defined as amenorrheic for longer than 
2 years, age appropriate, and confirmed by a follicle-stimulating hormone 
(FSH) level indicating a postmenopausal state at Screening.
6.
Sexually active males must be surgically sterile or have male partners only or if 
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 7 months after stopping study drug or 
as directed by the local ribavirin label.  (Note:  Contraceptives containing ethinyl 
estradiol are considered effective if used by the female partners of male subjects.)
7.
Subject must be considered an appropriate candidate for pegIFN, RBV, ABT-450/r 
and ABT-267 therapy in the opinion of the investigator.
8.
Subject is infected with HCV genotype 1 at the Screening Visit.
9.
Subject has a plasma HCV RNA level ≥ 2,000 International Units (IU)/mL at the 
Pre-screening Visit.
In addition to Inclusion Criteria 1 through 9, subjects diagnosed with cirrhosis must also 
meet the following criteria:
10.
Compensated cirrhosis defined as Child-Pugh score of ≤ 6 at Screening.


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11.
Absence of hepatocellular carcinoma (HCC) based on a negative ultrasound, 
computed tomography (CT) scan or magnetic resonance imaging (MRI) performed 
within 3 months prior to Screening or during the Screening period.
Rationale for Inclusion Criteria
(1, 2)  In accordance with harmonized Good Clinical Practice (GCP).
(3 – 7)  For safety of the subjects.
(8 – 11)  To select the appropriate subject population.
5.2.2
Exclusion Criteria
Subjects must not meet any of the following exclusion criteria:
1.
In subjects with a prior null or partial response to pegIFN/RBV treatment at any 
time prior to pre-screening for this study or any prior failure with pegIFN/RBV 
plus telaprevir, the presence of variants relative to the appropriate prototypic 
reference sequence (H77 for 1a or Con1 for 1b) at any of the following positions:  
NS3 155, 156, or 168; or NS5A 28, 29, 30, 31, 32, 58, or 93.
2.
Prior use of an investigational HCV therapy or approved DAA not included in this 
protocol or the previous AbbVie/Abbott DAA combination study.
3.
Females who are pregnant or plan to become pregnant, or breastfeeding, or males 
whose partners are pregnant or planning to become pregnant within 7 months (or as 
per local RBV label) after their last dose of RBV.
4.
Positive result of a urine drug screen at the Screening Visit for opiates, barbiturates, 
amphetamines, cocaine, benzodiazepines, phencyclidine, and propoxyphene with 
the exception of a positive result (including methadone), associated with 
documented short-term use or chronic stable use of a prescribed medication in that 
class. 


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5.
Positive test for hepatitis B surface antigen (HBsAg) or anti-HIV antibodies 
(anti-HIV Ab).
6.
Use of known strong inducers (e.g., phenobarbital, rifampin, carbamazepine, 
St. John's Wort) of CYP3A within 2 weeks prior to study drug administration.
7.
Use of any medications listed in Table 4 within 2 weeks or 10 half-lives, of the 
medication, whichever is longer, prior to study drug administration, including but 
not limited to:
Table 4.
Medications Contraindicated for Use with the Study Drug Regimen
Alfuzosin
Astemizole 
Carbamazepine
Cisapride
Efavirenz
Ergot derivatives (ergotamine, 
dihydroergotamine, ergonovine, 
methylergometrine)
Fusidic Acid 
Lovastatin 
Midazolam (oral)
Phenobarbital
Phenytoin
Pimozide
Rifampin
Salmeterol
Sildenafil*
Simvastatin
St. John's Wort
Terfenadine
Triazolam
Estrogen-containing medications 
for systemic use
*
When used for the treatment of pulmonary arterial hypertension.
Not all medications contraindicated with ritonavir, ribavirin and pegIFN are listed in 
Table 4.  Refer to the most current product labeling for each drug for a complete list.
8.
Discontinuation of antiviral therapy due to intolerance or a DAA- or 
RBV-associated adverse event in the previous AbbVie/Abbott DAA combination 
study (excluding intolerance or AEs associated with telaprevir).
9.
Beck's Depression Inventory-II (BDI-II) score of > 21 at Screening.  Subjects with 
BDI-II score > 21 will not be allowed to rescreen. 
10.
Clinically significant abnormal ECG, ECG with QT interval corrected for heart rate 
using Fridericia's correction formula (QTcF) > 470 msec at Screening or TI Day 1 
visits.


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11.
Screening laboratory analyses show any of the following abnormal laboratory 
results: 
●
Alanine aminotransferase (ALT) > 7 × upper limit of normal (ULN);
●
Aspartate aminotransferase (AST) > 7 × ULN;
●
Calculated creatinine clearance (using Cockcroft-Gault method) < 60 mL/min; 
●
Albumin < LLN;
●
International normalized ratio (INR) > 1.7; (Subjects with a known inherited 
blood disorder and INR > 1.7 may be enrolled with permission of the AbbVie 
Study Designated Physician.)
●
Hemoglobin < LLN;
●
Platelets < 90,000 cells per mm3;
●
Absolute neutrophil count < 1,500 cells/μL (< 1200 cells/μL for subjects of 
black/African descent);
●
Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN;
●
Thyroid stimulating hormone (TSH) values outside the normal range.
12.
The use of colony stimulating factors, such as granulocyte colony stimulating 
factor (GCSF) or erythropoietin within 2 months of the Screening Period.
13.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that, in the opinion of the investigator, could preclude adherence to 
the protocol.
14.
Clinically significant abnormalities, other than HCV infection, based upon the 
results of a medical history, physical examination, vital signs, laboratory profile 
and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable 
candidate for this study in the opinion of the investigator.
15.
Evidence of infection with other HCV genotypes other than genotype 1 at the 
Screening Visit.


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16.
Current enrollment in another clinical study or previous enrollment in this study.  
Concurrent participation in a non-interventional, epidemiologic or registry trials 
may be permitted with approval by the AbbVie Study Designated Physician.
17.
History of solid organ transplantation. 
In addition to Exclusion criteria 1 through 18, subjects with compensated cirrhosis must 
not meet the following criteria:
18.
Any current or past clinical evidence of Child-Pugh B or C Classification or 
clinical history of liver decompensation such as ascites (noted on physical exam), 
variceal bleeding or hepatic encephalopathy.
19.
Serum Alpha-Fetoprotein (sAFP) > 100 ng/mL at Screening.
20.
A screening ultrasound suspicious for hepatocellular carcinoma (HCC) and 
confirmed with a subsequent CT scan or MRI during the screening period.
Rationale for Exclusion Criteria
(1)  To exclude subjects with a high likelihood of virologic failure.
(2 – 5, 10 – 12, 14, 15)  To ensure safety of the subjects throughout the study.
(6 – 9, 13)  To avoid medication interactions which could complicate evaluation of 
efficacy and safety.
(16 – 21)  To select the appropriate subject population.
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 time periods defined below, must be recorded along with the reason 
for use, date(s) of administration including start and end dates, and dosage information 


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including dose, route and frequency.  The investigator should review all concomitant 
medications for any potential interactions.  The investigator should confirm that 
concomitant medication can be safely administered with DAAs as well as ritonavir, 
pegIFN and RBV.  Some medications may require dose adjustments due to potential for 
drug-drug interactions.  Subjects should be on a stable dose of concomitant medications 
for at least 2 weeks prior to initiation of study drug.
Use of all medications at the time of enrollment and through 30 days after the last dose of 
DAAs in Substudy 1 will be recorded in the electronic case report form (eCRF).  During 
Substudy 2 and Substudy 3, only antiviral therapies related to the treatment of HCV and 
medications prescribed in association with a serious adverse event (SAE) will be recorded 
in the eCRF.
During Substudy 3, investigators should reassess concomitant medications and subjects 
may resume previously prohibited medications, or revert to pre-study doses, 2 weeks 
following discontinuation of DAAs, if applicable.
The AbbVie Study Designated Physician should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).
5.2.3.1
Prior HCV Therapy
Any HCV therapy the subject received after terminating from the previous 
AbbVie/Abbott DAA combination study and prior to enrollment in this study must be 
recorded.  Use of any investigational anti-HCV agents or approved DAAs during this 
period excludes a subject from this study.  Subjects who received pegIFN and RBV 
during this period may be enrolled in the study.  These subjects should have complete 
documentation of pegIFN and RBV treatment history, including start and stop dates, type 
of response (if known), and reason for discontinuation.  Categories on the eCRF will 
include the following:


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●
Null responder:  Subject has documentation that they previously received 
PegIFN/RBV for at least 10 weeks and failed to achieve a 2 log10 IU/mL HCV 
RNA decrease at Week 12 (Week 10 to Week 16)
●
Partial responder:  Received at least 20 weeks of PegIFN/RBV for the 
treatment of HCV and achieved ≥2 log10 reduction in HCV RNA at Week 12 
(Weeks 10 – 16), but failed to achieve HCV RNA undetectable at the end of 
treatment
●
Relapser: Received at least 36 weeks of PegIFN/RBV for the treatment of 
HCV and was undetectable at the end of treatment, but HCV RNA was 
detectable within 52 weeks of treatment follow-up
●
Not documented/Other
5.2.3.2
Prohibited Therapy
In addition to the medications listed above in Table 4, use of known strong inducers of 
CYP3A is prohibited within 2 weeks or 10 half-lives, whichever is longer, prior to the 
initial dose of study through the first 2 weeks after the subject has completed DAA 
therapy.
Use of any medications contraindicated with pegIFN or RBV is prohibited within 2 weeks 
prior to the initial dose of study drug through the first 2 weeks after the subject has 
completed Substudy 2.
Prior to enrollment, subjects should agree to practice two effective methods of birth 
control while receiving study drugs starting with Study Day 1 and for 7 months after 
stopping study drug or as directed by the local ribavirin label.  Subjects using systemic 
estrogen-containing contraceptive therapy (including estrogen-containing oral 
contraceptives) have a higher risk for elevated ALT levels. Subjects using these 
medications must discontinue them at least 2 weeks prior to study drug administration or 
10 half-lives (if known), whichever is longer.  Subjects may replace the systemic 
estrogen-containing contraceptive with a progestin-only hormonal contraceptive method.  
Estrogen-containing contraceptives may be resumed 2 weeks after the last dose of DAAs.


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Refer to the pegIFN, RBV and ritonavir labeling for a list of prohibited medications.  
HCV medications other than those specified in the protocol will not be allowed during the 
Treatment Period of the study.
Use of hematopoietic growth factors is not permitted during this study without the 
approval of the AbbVie Study Designated Physician.  Management of hematologic 
growth factor therapy is the responsibility of the investigator; growth factors will not be 
provided by the Sponsor, and the Sponsor will not reimburse for the expense of growth 
factors or their use.
Investigators should refer to the package inserts for erythropoiesis stimulating agents for 
additional information regarding their use.
5.2.3.3
Post-Treatment Therapy
No further treatment is planned after subjects have ended their participation in the study.  
This study is intended to offer intensified therapy with two investigational drugs plus 
pegIFN and RBV for subjects who have failed treatment for HCV infection in a previous 
AbbVie/Abbott study.  Some safety assessments, measurements of HCV RNA (HCV viral 
levels) and monitoring for viral resistance are performed for 48 weeks following the last 
dose of study treatment. 
If a subject meets virologic failure criteria in this study or relapses in the post-treatment 
follow-up period (Substudy 3), the investigator should treat the subject according to 
his/her best clinical judgment.
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic, and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures are summarized in Table 5 and Table 6 (for cirrhotic subjects).


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Table 5.
Study Activities
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
Informed Consenta
X
Population Sequencing 
Assessment
X
Provide pegIFN/RBV 
Information and 
Medication Guidesf
X
Medical Historyg
X
X
Adverse Event 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Physical Examination
Xi
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Pregnancy Testj (Females) 
Serum (s) Urine (u)
X(u)
X(u) 
(s)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
X(u)
FSH (all females) 
X


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Table 5.
Study Activities (Continued)
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
HBsAg, Anti HIV Ab 
X
Drug/Alcohol Screen
X
HCV Genotype
X
Clinical Laboratory Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total Insulin
X
TSH
X
X
X
X
X
X
X
X
BDI-II Depression Scale
X
Study Drugs Dispensed/ 
Drug Accountabilityk
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense MEMS Capl
(X)
Download MEMSl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Collect MEMS Capl,m
(X)


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Table 5.
Study Activities (Continued)
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
HCV RNA Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV Resistance Testing 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DAA/ritonavir, 
PegIFN/RBV Assay (PK) 
Samplen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP-10 Testing
X
X
X
X
SCR = Screening; D/C = Premature discontinuation; Wk = Week
a.
Prior to performing any study-specific procedures.
b.
Activities to be performed prior to first dose of any study drug.
c.
Subjects who prematurely discontinue from the DAA study drug treatment in Substudy 1 should return for a TI Week 24/TI Discontinuation Visit.  These subjects will 
continue on to Substudy 2 if the investigator feels it is appropriate or proceed to Substudy 3 if it is not appropriate to continue on Substudy 2.
d.
These visits are only needed for subjects who did not complete 24 weeks of pegIFN/RBV in Substudy 1 such that the subject completes a total of 48 weeks of pegIFN/RBV 
across Substudy 1 and Substudy 2.
e.
Subjects who prematurely discontinue from the pegIFN/RBV study drug treatment in Substudy 2 should return for a PR Final/PR Discontinuation Visit.  These subjects will 
continue on to Substudy 3.


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Table 5.
Study Activities (Continued)
f.
Where applicable/locally available.
g.
The subject's medical history will be updated at the Screening Visit with any relevant information that was not collected in the previous AbbVie/Abbott DAA combination 
study and any new medical history that occurred between the end of the previous AbbVie/Abbott DAA combination study and this study.  The subject's medical history will 
also be updated if needed for the period between the Screening Visit and the TI Day 1 Visit.
h.
Only concomitant medications related to HCV treatment and/or medications prescribed in association with a serious adverse event will be collected during Substudy 2.
i.
Height will be measured at Screening only.  Will include a thorough eye exam to confirm that the subject is an appropriate candidate for pegIFN therapy.
j.
Urine pregnancy testing is not required after the TI Day 1 Visit for female subjects with a documented prior hysterectomy or bilateral oophorectomy or bilateral tubal ligation 
or those confirmed to be postmenopausal.  Urine pregnancy tests must be conducted monthly during treatment in Substudy 1 and Substudy 2 (per local RBV label) for women 
of childbearing potential.  Subjects may come to the clinic for an unscheduled visit for pregnancy testing atPR Study Weeks 16 and 20 and PR Weeks 28, 32, 40 and 44 if 
needed or perform the tests at home with test kits provided by the site.  Sites may substitute serum pregnancy testing for urine pregnancy testing only if required per local 
regulations.
k.
Refer to Section 5.5.1 for additional information on treatments administered and Section 5.5.8 for additional information on drug accountability.  Drug Accountability is not 
assessed at TI Day 1.
l.
Collected from subjects participating in study under original protocol and Amendments 1 – 9.
m.
MEMS cap is collected at any point upon completion of Substudy 1.
n.
A total of two pharmacokinetic samples will be drawn at each time-point, one plasma and one serum.  The site will contact the subject approximately 2 days prior to the 
scheduled PK blood collection date to review the importance of proper study drug administration.


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Table 6.
Additional Study Activities for Cirrhotic Subjects Only
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/C
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
Child-Pugh Score
X
X
X
X
X
Clinical Assessment of 
Hepatic Decompensation
Xa
HCC Screening:  Liver 
Ultrasound and Alpha 
Fetoproteinc
Xb
X
X
X
a.
Clinical assessment of hepatic decompensation based on physical exam on TI Day 1 prior to dosing.
b.
Subjects with a historical negative Liver Ultrasound, CT or MRI (within 3 months prior to screening) are not required to have a Screening Ultrasound performed.
c.
If additional liver ultrasound testing is required it should be completed as an unscheduled visit.  A positive ultrasound result suspicious for HCC will be confirmed with 
CT scan or MRI.
d.
These visits are only needed for subjects who did not complete 24 weeks of pegIFN/RBV in Substudy 1 such that the subject completes a total of 48 weeks of pegIFN/RBV 
across Substudy 1 and Substudy 2.
e.
Subjects who prematurely discontinue from the pegIFN/RBV study drug treatment in Substudy 2 should return for a PR Final/PR Discontinuation Visit.  These subjects will 
continue on to Substudy 3.


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Table 7.
Study Activities – Substudy 3 Post-Treatment
Substudy 3 Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48/
PT D/C
Adverse Event Assessmenta
X
X
X
X
X
X
X
Concomitant Medication Assessmentb
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
Pregnancy Test (Females) Urine (u)c
X
X
X
X
Clinical Laboratory Tests
X
X
Xd
IP-10
X
Xd
HCV RNA Sample
X
X
X
X
X
X
X
HCV Resistance Testing
X
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
PT = Post-treatment; Wk = week; D/C = discontinuation
a.
AEs will be collected for only 30 days following last dose of study drugs.  SAE's will be collected during the entire Substudy 3 period.
b.
Only concomitant medications related to HCV treatment and/or medications prescribed in association with a serious adverse event will be collected during Substudy 3.
c.
Post-treatment pregnancy testing is to be completed at the visits outlined in Table 7.  Additional pregnancy testing (urine and/or serum) during the Post-treatment Period, 
e.g., at PT Week 16, PT Week 20, PT Week 28 or at other time points should be completed according to the local RBV label and/or local treatment guidelines for RBV or 
local legal requirements.  Additional pregnancy testing (urine and/or serum) done outside of the visits specified in Table 7 should be completed using the unscheduled test kit 
or the subject can perform the tests at home with test kits provided by the site.
d.
Sample to be drawn only if conducting a Discontinuation Visit.


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Table 8.
Additional Study Activities for Cirrhotic Subjects Only – Substudy 3 Post-Treatment
Substudy 3 Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48/
PT D/C
Clinical Laboratory Tests
X
X
X
X
Child-Pugh Score
X
HCC Screening:  Liver Ultrasound and 
Alpha Fetoproteina
X
X
a.
If additional liver ultrasound testing is required it should be completed as an unscheduled visit.  An ultrasound result suspicious for HCC will be confirmed with CT scan or 
MRI


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5.3.1.1
Study Procedures
Informed Consent 
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Population Sequencing Assessment
Population Sequencing will be performed for all subjects on blood samples drawn at the 
Pre-screening Visit (after signing the informed consent).  This testing will only be 
performed on samples with an HCV RNA level ≥ 2000 IU/mL, so another sample will 
also be drawn to measure the HCV RNA level.  If the HCV RNA level is < 2000 IU/mL, 
the Pre-Screening Visit may be repeated at a later date per the investigator's discretion.
A certified laboratory will be utilized to perform the testing and provide results for the 
population sequencing.  The sample will be sent to Covance central laboratory which will 
then ship them to the following address for testing:
Approximately 3 weeks should be allowed for the testing of the population sequencing to 
be completed.  For subjects who were null or partial responders to prior pegIFN/RBV 
treatment, or who experienced any prior failure with pegIFN/RBV plus telaprevir in the 
previous AbbVie/Abbott study, results from this sequencing will be assessed for 
exclusionary variants in NS3 or NS5A at any of the following positions:  NS3 155, 156, 
or 168; or NS5A 28, 29, 30, 31, 32, 58, or 93.  


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For all other subjects the results should be taken into account in the investigator's 
determination of the subject's appropriateness for enrollment in this study.  After this 
assessment, the subject may proceed with the Screening Visit procedures if appropriate.
PegIFN and Ribavirin Information
Subjects will be given copies of the Medication Guides for Peginterferon α-2a 
(PEGASYS®) and Ribavirin (RIBASPHERE® or Copegus®) where applicable and locally 
available prior to dosing.  Sexually active subjects must use two effective forms of birth 
control during the study and for 7 months (or as per local RBV labeling) after stopping 
study drugs unless surgically sterile.  Male subjects will be given the RBV Partner Risk 
Fact Sheet to share with their female partner(s).
Medical History
The subject's medical history will automatically be transferred from the previous 
AbbVie/Abbott DAA combination study to the Study M13-101 EDC system.  The 
subject's medical history will then be updated at the Screening Visit with any relevant 
information that was not collected in the previous AbbVie/Abbott DAA combination 
study and any new medical history that occurred between the end of the previous 
AbbVie/Abbott DAA combination study and this study.  The subject's medical history 
will also be updated, if needed, for the period between the Screening Visit and the TI 
Day 1 Visit.  The updated medical history as of TI Day 1 will serve as the baseline for 
clinical assessment.
Concomitant Medication Assessment
Use of medications (prescription or over-the-counter, including vitamins and herbal 
supplements) at the time of enrollment through 30 days after last dose of DAAs in 
Substudy 1 will be recorded in the electronic case report form (eCRF).
During Substudy 2 and Substudy 3, only antiviral therapies related to the treatment of 
HCV and medications prescribed in association with an SAE will be recorded in the 
electronic case report form (eCRF). 


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Physical Examination
A complete physical examination will be performed at visits specified in Table 5 or upon 
subject discontinuation.  A symptom-directed physical examination may be performed at 
any other visit, when necessary.
The physical examination at the Screening Visit will include a thorough eye exam to 
confirm that the subject is an appropriate candidate for pegIFN therapy.  The physical 
examination performed on TI Day 1 will serve as the baseline physical examination for 
clinical assessment.  Any significant physical examination findings after the first dose will 
be recorded as adverse events.
Height will be measured only at Screening; the subject will not wear shoes. 
Vital Signs and Weight
Body temperature (oral), blood pressure, pulse and body weight will be measured at each 
study visit as specified in Table 5 and Table 7 and upon subject discontinuation.  Blood 
pressure and pulse rate will be measured after the subject has been sitting for at least 
3 minutes.  The subject should wear light weight clothing and no shoes during weighing.
12-Lead ECG
A 12-lead resting ECG will be obtained at the visits specified in Table 5 and upon subject 
discontinuation (or as clinically needed).
When an ECG is scheduled on the same day as a blood collection, the ECG will be 
obtained prior to the blood collection.
ECGs will be recorded after the subject has been supine for at least 5 minutes.  Subjects 
should be instructed to remain completely stationary during the ECG recording 
(approximately 10 seconds), with no talking, laughing, deep breathing, sleeping, or 
swallowing.


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The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will interpret, sign, and date all ECG tracings and 
will provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
The local reader will capture the assessment of the ECG tracing in the subject's source 
notes.  Only the local reader's assessment of the ECG tracing will be collected on case 
report forms, entered into the database and summarized. 
Pregnancy Test
A serum pregnancy test will be performed at TI Day 1 for all female subjects and 
analyzed by the central laboratory.  In addition, a urine pregnancy test will be performed 
for female subjects at the visits specified in Table 5 and Table 7.  All urine pregnancy 
tests will be performed on-site during the study visit, if there is a scheduled visit.  Urine 
pregnancy tests are not required after TI Day 1 for female subjects with a documented 
prior hysterectomy or bilateral tubal ligation or bilateral oophorectomy or who are 
confirmed to be postmenopausal.  Confirmation of postmenopausal status will be 
determined based on the subject's history and the FSH level obtained at the Screening 
Visit.  Sites may substitute serum pregnancy testing for urine pregnancy testing only if 
required per local regulations.
Women of childbearing potential should have urine pregnancy testing completed monthly 
during treatment with RBV and monthly for 7 months after the discontinuation of RBV or 
according to the local RBV label and/or local treatment guidelines for RBV.  During the 
PR Treatment Period and the PT Period where there is not a scheduled study visit (i.e., PR 
Weeks 16 and 20, 28, 32, 40 and 44, and PT Week 16, 20 and 28), female subjects of 
childbearing potential may either have pregnancy testing performed at the site as an 


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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.  Site 
personnel should contact these female study subjects to capture the results of any 
study-related pregnancy tests performed at home; the pregnancy test results will only be 
recorded in the subject's source records.  
If the subject elects to return to the study site for an unscheduled visit for pregnancy 
testing, the results of the urine pregnancy test will be captured in the eCRF, unless serum 
pregnancy testing is elected.  Serum pregnancy testing will be completed by the central 
laboratory.
If urine pregnancy result is positive a confirmatory hCG serum test should be collected 
and sent to the central lab.
Hepatitis and HIV Screen
HBsAg and anti-HIV Ab, will be performed at Screening (Table 5).  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, and the HBsAg results 
will be reported by the central laboratory to the clinical database.  The anti-HIV Ab 
results will not be reported by the central laboratory to the clinical database.
Urine Screens for Drugs of Abuse
Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse.  
The panel for drugs of abuse will minimally include the drugs listed in Table 9.  A 
positive screen is exclusionary, with the exception of a positive screen associated with 
documented short-term use or chronic stable use of a prescribed medication in that class.
These analyses will be performed by the certified central laboratory chosen for the study.


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Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 9
at the visits specified in Table 5 and Table 7 for all subjects.  Additional clinical 
laboratory tests for cirrhotic subjects are outlined in Table 6 and Table 8.
Blood samples for serum chemistry tests, whenever possible, should be collected 
following a minimum 8-hour fast (with the exception of the Screening Visit, which may 
be non-fasting).  Subjects whose visits occur prior to the morning dose of study drug 
should be instructed to fast after midnight.  Subjects whose visits occur following the 
morning dose of study drug should be instructed to fast after breakfast until the study visit 
occurs.  Blood samples should still be drawn if the subject did not fast for at least 8 hours.  
Fasting status will be recorded in the source documents and on the laboratory requisition.  
The baseline laboratory test results for clinical assessment for a particular test will be 
defined as the last measurement prior to the initial dose of study drug.
In addition to the standard chemistry, hematology and urinalysis, coagulation panel and 
total insulin results will be reported.
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 shown below.
For sites in North America and South America:
Covance 
8211 SciCor Drive
Indianapolis, IN  46214 
USA


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For sites in Europe:
Covance 
7 rue Marcinhes
1217 Geneva
Meyrin Switzerland
For sites in Asia, Australia and New Zealand:
Covance (Asia) Pte Ltd
1 International Business Park
#01-01 The Synergy
Singapore 609917


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Table 9.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC)
count
White blood cell (WBC) 
count
Platelet count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Absolute neutrophil count 
(ANC)
Prothrombin time (PT)/ 
International 
Normalized Ratio (INR) 
Activated partial 
thromboplastin time 
(aPTT)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Chloride
Bicarbonate
Magnesium
Serum glutamic oxaloacetic 
transaminase/Aspartate 
aminotransferase 
(SGOT/AST)
Serum glutamic pyruvic
transaminase/Alanine
aminotransferase
(SGPT/ALT)
Gamma-glutamyl transferase 
(GGT)
Creatinine clearance
TSH
Free T4 (performed for any 
abnormal TSH after 
screening)
Uric acid
Alpha fetoproteind
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
Additional Tests
HBsAga
Anti-HIV-1 Aba
Anti-HIV-2 Aba
Opiatesa
Barbituratesa
Amphetaminesa
Cocainea
Benzodiazepinesa
Alcohola
Phencyclidinea
Propoxyphenea
Methadonea
Human chorionic gonadotropin (hCG) (females)b
Total insulinc
HCV RNA
IP-10
FSH (all females)a
HCV genotype and subgenotypea
a.
Performed only at Screening.
b.
Urine pregnancy testing is not required after TI Day 1 Visit for female subjects with a documented prior 
hysterectomy or bilateral oophorectomy or bilateral tubal ligation or confirmed postmenopausal.  Pregnancy testing 
post-treatment is to be completed per local label and/or local treatment guidelines and at a minimum at the visits 
detailed in Table 7.
c.
Performed at TI Day 1 only.
d.
Tested for cirrhotic subjects only as indicated on Table 6 and Table 8.


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For any laboratory test value after the subject has enrolled that is outside the reference 
range and the investigator considers clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to discontinue study drug or to 
be discontinued from the study, or that requires 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.
BDI-II Depression Inventory 
The Beck Depression Inventory will be completed by all subjects at Screening.  Subjects 
with a score > 21 at the Screening Visit will not be enrolled.  Subjects will not be allowed 
to retake the BDI-II unless rescreening is required due to more than 42 days elapsing since 
the initial screening procedures (due to reasons beyond the investigator's control).
Assignment of Subject Numbers 
Subjects will retain their subject number from the previous AbbVie/Abbott DAA 
combination study and will enter the previous study number and subject number into the 
IRT system at the Pre-Screening Visit.  
Subjects who meet the inclusion criteria and do not meet any of the exclusion criteria will 
proceed to enrollment via the IRT system on TI Day 1.
Study Drug Dosing Card
On TI Day 1, subjects will be provided with self-administration instructions for each 
study drug of the intensified treatment regimen.  


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MEMS Cap
Subjects participating in the study prior to approval of Amendment 10:
Subjects will be assigned a MEMS cap for the following ABT-450 and ABT-267 bottles.  
Subjects whose treatment includes ritonavir capsules will also receive a MEMS cap for 
that bottle.  Subjects who receive ritonavir tablets will not receive a MEMS cap for the 
ritonavir bottle.  To ensure that a dosing event is recorded for the first dose of study drug 
at the site on T1 Day 1, the site should place the MEMS cap on each bottle before 
dispensing the first dose.  Additionally, at each visit, site personnel should download the 
MEMS dosing history data from the MEMS caps.  The MEMS cap will be collected from 
the subject at the completion of study drug treatment during Substudy 1.  Additional 
information regarding treatment compliance and MEMS can be found in Section 5.5.6 and 
Section 5.5.8.
Following approval of Amendment 10, all MEMS caps assigned to subjects participating 
in Substudy 1 will be collected at the subject's next study visit.  Site personnel should 
download the MEMS dosing history data from the MEMS caps.  MEMs caps will not be 
used for the remaining Substudy 1 visits.
HCV Genotype and HCV RNA Levels
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).  Genotype 
will be tested again to rule out any additional infection by another HCV genotype which 
may not have been present or detected when the subject screened for the previous study.  
Subjects with evidence of non-genotype 1 infection will be excluded.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS TaqMan® real-time reverse transcriptase-PCR 
(RT-PCR) assay v2.0.  The lower limit of detection (LLOD) is 15 IU/mL and lower limit 
of quantitation (LLOQ) for this assay is 25 IU/mL.  


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Interferon Gamma-Induced Protein 10 (IP-10) Levels
A plasma sample for IP-10 testing will be collected at the study visits indicated in Table 5
and Table 7.  
Specific instructions for preparation and storage of IP-10 samples will be provided by the 
central laboratory, AbbVie, or its designee.  Results for IP-10 will not be released to the 
sites.  This testing is done for research purposes only, and has no role in subject 
management.  In the event the data are needed per local requirements, the data can be 
provided upon request.
HCV Resistance Testing Sample
A plasma sample for resistance testing will be collected at the study visits, indicated in 
Table 5 and Table 7.
Specific instructions for preparation and storage of HCV RNA and HCV resistance 
samples will be provided by the central laboratory, AbbVie, or its designee.
Archive Plasma Sample
An archive plasma sample will be collected at the study visits indicated in Table 7.  
Archive plasma samples are being collected for possible additional analyses including, but 
not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, and/or HCV resistance testing, and other possible 
predictors of response, such as IP10, as determined by AbbVie.
5.3.1.1.1
Additional Procedures for Cirrhotic Subjects Only
Child-Pugh Score and Category
The Child-Pugh score uses five clinical measures of liver disease 3 laboratory parameters 
(bilirubin, serum albumin, prothrombin time INR) and 2 clinical assessments (ascites and 
encephalopathy).  Child-Pugh score will be determined at the visits indicated in Table 6
and Table 8.


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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 Hepatic Decompensation
As a result of the physical exam findings, hepatic encephalopathy and ascites will be 
assessed at TI Day 1 prior to dosing to confirm the subject has not progressed to hepatic 
decompensation since screening.
Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
In order to monitor for the presence of hepatocellular carcinoma (HCC), alpha fetoprotein 
will be assayed and an ultrasound of the liver will be performed as indicated in Table 6 for 
the Screening and Treatment Period and in Table 8 during the Post-Treatment Period.  
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to 
screening) are not required to have a screening ultrasound performed.


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Ultrasound findings suspicious for HCC at screening must be confirmed with CT scan or 
MRI during the screening period.  Suspicious ultrasound lesions confirmed by CT or MRI 
are exclusionary.
Ultrasound findings suspicious for HCC during the treatment or post-treatment period will 
be confirmed with CT scan or MRI.  Confirmatory results should be discussed with the 
AbbVie Study Designated Physician as appropriate.
5.3.1.2
Meals and Dietary Requirements
ABT-450, ritonavir and ABT-267 should be dosed together and administered with food 
(for example, ABT-450, ritonavir, ABT-267 and RBV may be taken together in the 
morning with food and RBV taken in the evening with food).
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples will be collected by venipuncture for assay of ABT-450, possible 
ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ritonavir, RBV and 
pegIFN in Substudy 1 starting at TI Week 1 and at each specified study visit (irrespective 
of study drug dosing time) or upon subject discontinuation as indicated in Table 5.  Blood 
samples for assay of pegIFN and RBV will be collected in Substudy 2 at each specified 
study visit (irrespective of study drug dosing time) or upon subject discontinuation as 
indicated in Table 5.
The time that each blood sample is collected will be recorded to the nearest minute in the 
subject's records and eCRF.  Site personnel will record the last dose of PegIFN and RBV 
prior to each pharmacokinetic blood sample in the subject's records and eCRF based on 
subject interview.
A total of approximately 30 samples are planned for pharmacokinetic analysis per subject 
in the study.  The exact number of samples to be collected in this study is unknown and 
depends on the number of subjects who enroll.


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5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-450, possible 
ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ritonavir and RBV and 
for serum samples for pegIFN will be provided by the central laboratory, AbbVie, or its 
designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of ABT-450, possible 
ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ritonavir and RBV, 
frozen serum sample for pegIFN will be packed in dry ice sufficient to last during 
transport, and transferred from the study site to the central laboratory.  An inventory of the 
samples included will accompany the package.  
The central laboratory will then ship the samples according to a predetermined schedule to 
the appropriate location.  
ABT-450, ABT-267, ritonavir and RBV samples will be sent to AbbVie:
An inventory of the included samples will accompany the package and an electronic copy 
of the manifests (including subject number, study day, the time of sample collection and 
barcode) will be sent to the contact person at 


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The central laboratory will ship pegIFN samples to:
An inventory of the included pegIFN samples will accompany the package and an 
electronic copy of the manifests (including subject number, study day, the time of sample 
PK samples will be maintained by AbbVie at least until the analytical reports have been 
finalized but no longer than 6 months from completion of the Clinical Study Report.
5.3.2.4
Measurement Methods
Plasma concentrations of ABT-450, ritonavir, ABT-267 and RBV will be determined 
using validated assay methods under the supervision of the Drug Analysis Department at 
AbbVie.  Plasma concentrations of metabolites of ABT-267 and ABT-450 may also be 
determined using non-validated methods.  Serum concentrations of pegIFN will be 
determined using a validated assay method under the supervision of the Sponsor's Drug 
Analysis Department.
5.3.3
Efficacy Variables
Virologic response will be assessed by HCV RNA in log10 IU/mL at various time-points 
from Study Day 1 through 48 weeks after completion of pegIFN and RBV treatment.


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5.3.3.1
Primary Variable
The primary efficacy endpoint is the percentage of subjects with SVR12 (HCV RNA 
< LLOQ 12 weeks after the last dose of study drug), both overall and according to 
treatment in the previous study.
5.3.3.2
Secondary Variable
The secondary efficacy endpoints are the percentage of subjects with SVR24 (HCV RNA 
< LLOQ 24 weeks after the last dose of study drug) and the percentage of subjects with 
eRVR (HCV RNA < LLOQ at TI Weeks 4 through 12).  The endpoints will be examined 
for the overall treated group and according to the previous treatment as appropriate.
5.3.3.3
Resistance Variables
The following resistance analyses will be performed for subjects who do not achieve 
SVR:  the variants at each amino acid position identified by population and/or clonal 
nucleotide sequencing (1) at baseline will be compared to the appropriate prototypic 
reference sequence, and (2) at available post-baseline time points will be compared to 
baseline and the appropriate prototypic reference sequences.
5.3.4
Safety Variables 
The following safety evaluations will be performed during the study:  adverse event 
monitoring and vital signs, physical examination, ECG, and laboratory tests assessments.
5.3.5
Pharmacokinetic Variables
Plasma concentrations for ribavirin, ritonavir, ABT-450, ABT-267 and possible 
metabolites of ABT-450 or ABT-267, and serum concentrations for pegIFN will be 
summarized.


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If, during the course of study drug administration, the subject prematurely discontinues 
during the Substudy 1 Treatment Intensification Period, the procedures outlined for the 
Treatment Intensification Discontinuation (TI D/C) Visit should be completed as defined 
in Table 5.  Ideally, this should occur 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.  The 
dosing end dates for each DAA and ritonavir and reason for discontinuation from 
Substudy 1 will be recorded in the eCRF.
The subject should continue to Substudy 2, the pegIFN/RBV Treatment Period, unless the 
investigator considers continued pegIFN and RBV inappropriate due to either intolerance 
or inadequate virologic response.  If the subject prematurely discontinues during 
Substudy 2, the subject should return for PR D/C visit procedures as defined in Table 5
and proceed to Substudy 3.  If the investigator does not consider the subject appropriate to 
participate in Substudy 2, the subject should start Substudy 3, the Post-treatment Period 
for monitoring of HCV resistance and viral response.  Following discontinuation of study 
drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  The dosing end dates for RBV and pegIFN and reason for discontinuation 
from Substudy 2 will be recorded in the eCRF.
If a subject discontinues from the Post-treatment Period, the subject should return for 
post-treatment discontinuation procedures (PT D/C) as defined in Table 7.  The reason for 
discontinuation from Substudy 3 will be recorded in the Study Completion eCRF.


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If a subject is discontinued prematurely with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the treatment period of the study, the administration of 
study drug (including RBV) to that subject must be discontinued immediately.  Specific 
instructions regarding subject pregnancy can be found in Section 6.6.  Subjects will 
continue to be monitored for antiviral drug resistance in the Post-Treatment Period as 
described in Section 5.1.4.  The investigator is also encouraged to report the pregnancy 
information to the voluntary RBV Pregnancy Registry.
5.4.1.1
Virologic Failure Criteria
During the Treatment Period and Follow-up Period of the study, the virologic data will be 
reviewed by the investigator to evaluate if subjects have met virologic failure criteria.
The following criteria will be considered evidence of virologic failure:
●
Failure to achieve HCV RNA level < 1,000 IU/mL at TI Week 4.  Subject will 
stop all DAAs and continue pegIFN and RBV at the investigator's discretion.
●
Failure to achieve at least a 2 log10 IU/mL HCV RNA reduction from baseline 
at TI Week 12.  Subject will stop all study drugs. 
●
HCV RNA ≥25 IU/mL at TI Week 24.  Subject will stop all study drugs.
●
Confirmed HCV RNA increase of > 1 log10 from nadir (defined as 
2 consecutive HCV RNA measurements > 1 log10 IU/mL above nadir) in HCV 
RNA at any time-point.  Subject will stop all study drugs.
●
Confirmed breakthrough or relapse:  HCV RNA ≥ LLOQ (defined as 
2 consecutive HCV RNA measurements ≥ LLOQ) at any point after HCV 
RNA < LLOQ.  Subject will stop all study drugs (if applicable).


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For the latter 2 criteria, confirmatory testing should be completed as soon as possible.  If 
the investigator feels that a subject who meets one of these criteria should still remain on 
DAA + pegIFN + RBV or pegIFN + RBV treatment, the subject would only be allowed to 
remain on DAA + pegIFN + RBV or pegIFN + RBV treatment with approval of the 
AbbVie Study Designated Physician.
5.4.2
Non Efficacy (Futility) Criteria
In order to categorize subjects according to type of response to prior HCV therapy, for 
subjects who receive pegIFN and RBV during the period between the previous 
AbbVie/Abbott DAA combination study and enrollment in this study, the type of 
response to the PegIFN and RBV treatment will be recorded on the eCRF, if known.  
Categories on the eCRF will include the following:
●
Null responder: Subject has documentation that they previously received 
PegIFN/RBV for at least 10 weeks and failed to achieve a 2 log10 IU/mL HCV 
RNA decrease at Week 12 (Week 10 to Week 16)
●
Partial responder: Received at least 20 weeks of PegIFN/RBV for the 
treatment of HCV and achieved ≥2 log10 reduction in HCV RNA at Week 12 
(Weeks 10 – 16), but failed to achieve HCV RNA undetectable at the end of 
treatment
●
Relapser: Received at least 36 weeks of PegIFN/RBV for the treatment of 
HCV and was undetectable at the end of treatment, but HCV RNA was 
detectable within 52 weeks of treatment follow-up
●
Not documented/Other
Data will be assessed separately for the population of subjects who were null or partial 
responders to prior pegIFN/RBV treatment or who experienced any prior failure with 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study and for the population 
of subjects who do not fall in the previous population at the time of enrollment into this 
study.


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●
After the first 20 subjects who were not null or partial responders to prior 
pegIFN/RBV treatment (and who never received pegIFN/RBV plus telaprevir 
in the previous AbbVie study) have completed 24 weeks of ABT-450/r + 
ABT-267 + pegIFN/RBV treatment or prematurely discontinued, the 
percentage of these subjects meeting the protocol defined virologic stopping 
criteria will be calculated.
If greater than or equal to 50% of subjects have met virologic stopping criteria, 
enrollment in Study M13-101 will be stopped for all subjects.  All 
investigators will be notified that enrollment in the study has been suspended 
due to virologic stopping criteria having been met.
●
Similarly, after the first 20 subjects who were null or partial responders to 
prior pegIFN/RBV treatment or who experienced any prior failure with 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study have 
completed 24 weeks of ABT-450/r + ABT-267 + pegIFN/RBV treatment or 
prematurely discontinued, the percentage of these subjects meeting the 
protocol defined virologic stopping criteria will be calculated.
If greater than or equal to 50% of subjects have met virologic stopping criteria, 
enrollment in Study M13-101 will be stopped for all prior null or partial 
responder subjects, as well as for those who failed treatment with 
pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study.  Subjects 
who were not null or partial responders to prior pegIFN/RBV treatment and 
who never received pegIFN/RBV plus telaprevir in the previous 
AbbVie/Abbott study may continue to enroll.  All investigators will be notified 
that enrollment in this population has been suspended due to virologic 
stopping criteria having been met.  
If enrollment is stopped in a population, subjects who are already on study may remain on 
treatment if, in the opinion of their investigator, the potential benefits of continued 
treatment outweigh the risks.  
5.4.3
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 


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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 notify the 
investigator and subsequently provide written instructions for study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of study drug will be dispensed in the form of tablets (ABT-450, ABT-267, 
ritonavir and RBV), capsules (ritonavir) or pre-filled syringes (pegIFN) at the visits listed 
in Table 5.  Subjects will receive either ritonavir as capsules or tablets, but not both during 
Substudy 1.
At TI Day 1, subjects will be administered study medications by the study site personnel 
and receive instructions for self-administration of assigned study medications from TI 
Day 2 through 24 weeks in PR (Substudy 2) or later.  ABT-450, ritonavir, and ABT-267 
will be administered from TI Day 1 through TI Week 24 in Substudy 1.  PegIFN and RBV 
will be administered from TI Day 1 through TI Week 24 in Substudy 1 and PR Treatment 
Period Day 1 through 24 weeks or later in Substudy 2.
Following the screening period, the site will contact the IRT to obtain the study drug kit 
numbers to dispense at the study visits specified in Table 5.  Study drug must not be 
dispensed without contacting the IRT.  Study drug may only be dispensed to subjects 
enrolled in the study through the IRT.  After study drug accountability and compliance 
have been assessed at the study drug dispensation visits specified in Table 5, the site will 
contact the IRT to provide visit date information and study drug return information for 
each kit.
Subjects will be instructed to take study medication with food at the same time(s) every 
day.  


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Table 10.
Dosing Schematic
N
Treatment
Duration
Approximately 35
ABT-450/r 200/100 mg QD + 
ABT-267 25 mg QD + pegIFN + 
RBVa
24 weeks
pegIFN + RBVa
24 weeksb
a.
pegIFN 180 μg once weekly, RBV weight-based dosing 1,000 to 1,200 mg divided twice daily.
b.
Duration could be longer if the subject did not complete 24 weeks of treatment during Substudy 1.
5.5.2
Identity of Investigational Products
Information about the study medications to be used in this study is presented in Table 11.
Table 11.
Identity of Investigational Products
Investigational 
Product
ABT-450
Ritonavir
ABT-267
RBV
PegIFN
Manufacturer
AbbVie/Abbott
AbbVie/Abbott
AbbVie/Abbott
Roche or 
Generic 
Manufacturer
Roche
Mode of 
Administration
Oral
Oral
Oral
Oral
SC 
Injection
Dosage Form
Tablet
Soft Gelatin 
Capsule or 
Tablet
Tablet
Tablet
Syringe
Strength
50 mg
100 mg
25 mg
200 mg
180 mcg/
0.5 mL
5.5.2.1
Packaging and Labeling
ABT-450 will be packaged in bottles containing 36 tablets.  Ritonavir will be packaged in 
bottles containing 30 or 84 capsules, or in bottles containing 30 tablets.  ABT-267 will be 
packaged in bottles containing 30 tablets.  RBV tablets will be supplied to the site in 
bottles containing 168 tablets each.  PegIFN will be supplied in a carton containing 4 or 
1 pre-filled syringe(s).  Canadian sites will receive PegIFN co-packaged with Ribavirin in 
a carton containing 4 pre-filled syringes and 1 × 168-count bottle of Ribavirin, plus an 


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additional 28-ct bottle of Ribavirin supplied with each carton.  Each bottle or carton will 
be labeled as required per country requirements.
Labels must remain affixed to the bottle or carton.
5.5.2.2
Storage and Disposition of Study Drugs
ABT-450, ABT-267, RBV, and ritonavir tablets must be stored at 15° to 25°C (59° to 
77°F).  Ritonavir capsules must be stored at 2° to 8°C (36° to 46°F) and protected from 
light.  Do not freeze and avoid exposure to excessive heat  PegIFN α-2a must be stored at 
2° to 8°C (36° to 46°F), protected from light, not frozen and not shaken.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie. 
5.5.3
Method of Assigning Subjects to Treatment Groups
Contact information and user guidelines for the IRT system will be provided to each site.  
Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
The site will enter the previous study number that the subject participated in and the 
previous subject number into the IRT system at the Pre-screening visit.  If the subject is a 
failure at the Pre-screening Visit due to inclusion criterion No. 9 or exclusion criterion 
No. 1 they will be entered as a Pre-screen failure in the IRT system under the 
Discontinuation flow (refer to Section 5.1.1).  For subjects who are eligible after the 
Pre-screening Visit, the site will enter the Screening Visit into the IRT.  After the 
Screening Visit, for those subjects who do not meet the study selection criteria, the site 
personnel must identify the subject as a screen failure via IRT under the Discontinuation 
flow (refer to Section 5.1.2).  For enrollment of eligible subjects, at the TI Day 1 Visit, 
site personnel must receive unique study drug kit numbers via IRT.  All subjects will be 
assigned the same treatment regimen.


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5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated on the TI Day 1 Visit.  ABT-450, ritonavir and ABT-267 will be dosed QD 
and RBV will be dosed BID.  PegIFN will be dosed weekly.  Thus with normal dosing, 
4 ABT-450 tablets, 1 ritonavir capsule/tablet and 1 ABT-267 tablet should be taken in the 
morning.  RBV should be dosed BID, e.g., 2 to 3 tablets taken in the morning, and 3 RBV 
tablets should be taken in the evening.  All study drugs should be dosed together and 
administered with food.  All medications should be taken at the same time (for example, 
ABT-450, ritonavir, ABT-267 and RBV should be taken together in the morning with 
food and RBV should be taken in the evening with food).  PegIFN should be taken once 
every 7 days.
5.5.5
Blinding
There will be no blinding since this is a single arm, open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
All study drugs will be dispensed to 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.  Subjects will be administered 
study drugs at the site at the TI Day 1 Visit.  The start and stop dates of all study drugs 
will be recorded in the source documents and eCRFs.  
At each study drug dispensation visit specified in Table 5, study site personnel will 
inspect the contents of the bottles (full, partial or empty) subjects have brought back and 
record the status of each one as well as the exact number of remaining tablets of 


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ABT-450, ABT-267 and RBV or capsules/tablets of ritonavir and the date of 
reconciliation in the IRT system.  If poor compliance is noted, the subject should be 
counseled and this should be documented in the subject's source.
ABT-450, ritonavir, ABT-267 and RBV should be returned for destruction and 
reconciliation performed at the study drug dispensation visits and discontinuation visits 
indicated in Table 5.  ABT-450, ritonavir and ABT-267 and RBV should not be 
re-dispensed to the subject.  The date of reconciliation will be recorded in the IRT system. 
Subjects will be given a safe disposal needle container for the pegIFN syringes.  Once the 
container is full, subjects will be required to bring the container back to the site for proper 
disposal.  The number of used syringes returned in the disposal container will not be 
counted and should remain in the safe disposal container for destruction.
The subject will write on the pegIFN kit the date (s) and approximate time the injection 
(s) was/were taken.  The subject will return the empty pegIFN kit(s) at each study 
dispensation visit and discontinuation visit as indicated in Table 5.  Study site personnel 
will inspect the pegIFN kit(s) returned and transcribe the date each injection was taken in 
the subject's source as well as record the number of syringes used and the date of 
reconciliation in the IRT system.  (For Canadian sites, pegIFN and RBV are co-packaged 
into one kit so only the RBV drug return will be captured in the IRT and pegIFN 
accountability will be documented using paper accountability forms.)  In all cases, if poor 
compliance is noted, the subject should be counseled and this should be documented in 
the subject's source.
Dose modifications, interruptions or discontinuations of pegIFN or RBV should be 
undertaken in accordance with local prescribing information.
5.5.7
Electronic Pill Monitors (MEMS Caps)
All subjects participating under Protocol Amendment 10 will not utilize MEMS caps to 
obtain dosing histories.


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Subjects enrolled in the protocol prior to the implementation of the Protocol 
Amendment 10 will utilize a MEMS monitor (cap), manufactured by Advanced 
Analytical Research on Drug (AARDEX Group Ltd., Switzerland) on the bottles of 
ABT-450, ABT-267 during Substudy 1.  Subjects receiving ritonavir capsules will also 
receive a MEMS cap for use on the ritonavir bottle.  Subjects receiving ritonavir tablets 
will not receive a MEMS cap for that bottle.  The MEMS caps will be used to obtain daily 
dosing histories for ABT-450, ritonavir capsules and ABT-267 for all subjects. In 
addition, MEMS data may be used to assess PK time relative to dose.  In the event MEMS 
data are not available, site personnel will perform subject interviews to obtain the date and 
approximate dosing time, which will be entered into the eCRF prior to a scheduled 
pharmacokinetic sample collection.  MEMS data will not be provided to the investigator 
or included as part of source documentation as it will not be used to guide treatment 
compliance.  
The MEMS cap is a threaded cap containing an internal electronic clock, with an 
integrated electronically erasable programmable read-only memory, a special 
micro-switch and battery.  Once fastened onto the medication bottle, the MEMS cap 
silently records the date and time of all dosing events (event = opening + closing).  This 
electronic monitor provides a means of objectively measuring a subject's adherence with 
the study medication.
At the TI Day 1 Visit, subjects will be assigned the appropriate number of MEMS caps 
that will be placed on the ABT-450, ritonavir capsules and ABT-267 bottles in place of 
the original caps.  Subjects who receive ritonavir tablets will not receive a MEMS cap for 
the bottle.  For the study drugs that will use the MEMS cap, the original cap should be 
saved so it can be placed back on the bottle by the investigator or designee in order to 
store returned study drug.  Each drug will be assigned a specific color, identified by a 
color coded marking on the drug bottle.  The colored marking which corresponds to a 
particular drug will also be placed on the MEMS cap so that the same MEMS cap is used 
for only one drug throughout the study.  


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The MEMS caps must only be used by the subject to whom it was assigned.  Each MEMS 
cap has a unique serial number that must be recorded in the MedAmigo system.  It is 
suggested that the subject's subject number be written on his or her MEMS caps in 
permanent ink.
The subjects will be instructed to open the bottle when it is time to take the medicine, to 
remove the proper amount of medication and promptly close the bottle, then ingest the 
prescribed dose.  The subject should be instructed to transfer the MEMS cap to the next 
full bottle of study drug at the same time that they take their last dose from the current 
in-use bottle.  
At each study visit specified in Table 5, subjects should return to the clinic with all bottles 
of study medication (full, partial or empty) with the MEMS cap attached to the bottles.  
The site staff will download the data collected on the MEMS cap at each visit designated 
in Table 5 via the MEMS reader.  Instructions on how to transfer the MEMS data will be 
provided to the site by AbbVie.
The MEMS cap will be collected from the subject at the completion of study drug 
treatment during Substudy 1 or at the subject's first study visit following approval of 
Amendment 10 at the site.  The collected MEMS caps should be sent to AbbVie or its 
designee.  Additional instructions for the subject on how to use the MEMS caps will be 
provided by the Sponsor.
5.5.8
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include lot number, POR number, number of tablets/capsules/syringes dispensed, 
subject number and the date on which study drug is dispensed to the subject.  An overall 
accountability of the study drug will be performed and verified by the AbbVie monitor 


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throughout the study.  Final accountability will be performed by the monitor at the end of 
study drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug kit, the 
misplaced or damaged study drug kit must be registered in the IRT system.  If study drug 
kit is misplaced or damaged, the subject will be requested to return the remaining study 
drug to the site.  A new study drug kit may only be dispensed to the subject by contacting
the IRT system.  Study drug replacement and an explanation of the reason for misplaced 
or damaged study drug kit will be documented in the subject's source documents.  Study 
drug start/end dates will be documented in the subject's source documents and recorded 
on the appropriate eCRF.  The status of each bottle/kit of syringes, number of 
tablets/capsules/syringes returned and the date of reconciliation will be recorded in the 
IRT system (Note:  co-packaged kits of RBV/pegIFN dispensed in Canada will only track 
RBV in the IRT system.).  The drug accountability recorded in the IRT may be considered 
source documents if the site is not using their own accountability forms.  In this case, 
copies of reports from the IRT must be placed in the subject's source documents.
Upon completion of study drug or discontinuation from Substudies 1 or 2, all original 
containers with unused study drug will be returned to AbbVie (or designee) according to 
instructions from AbbVie and according to local regulations following completion of drug 
accountability procedures.  The number of capsules, tablets and syringes of each type of 
study drug returned will be noted in the IRT (if not previously recorded) and appropriate 
drug return forms.  Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study is specifically intended to provide an optional intensified treatment regimen for 
subjects who experienced virologic failure in a previous AbbVie/Abbott DAA 
combination study.  No control group is included in this study.  Safety and efficacy of the 
study regimen will be compared with historical data for pegIFN and RBV therapy. 


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5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical and laboratory procedures will be utilized in 
this study.  HCV RNA assays are standard and validated.  Population sequencing done by 
Monogram Biosciences at the Pre-screening Visit is validated for both NS3/4A and NS5A 
sequence.  Clonal sequencing, population sequencing methods and phenotype assays 
during the study after pre-screening are experimental.
5.6.3
Suitability of Subject Population
Because this study is specifically intended to provide an optional intensified treatment 
regimen for subjects who experienced virologic failure in a previous AbbVie/Abbott DAA 
combination study, the population consisting of subjects who experienced virologic 
failure in a previous study is appropriate.  The decision to enroll in this study will be made 
by the subject in consultation with the investigator, and will be based on review of 
multiple factors, such as the subject's HCV disease status, the previous study treatment 
regimen, HCV RNA responses and virologic failure category during the previous study, 
HCV genotype, IL28B genotype, treatment adherence history, any available resistance 
data and availability of alternative treatment options.  Discussion of the use of a DAA 
combination with pegIFN and RBV in subjects who have failed previous therapy with a 
DAA-based regimen is contained in Section 3.0.
Subjects who have previously experienced null or partial response to pegIFN/RBV 
treatment at any time prior to pre-screening for this study or who experienced any prior 
failure with pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study will not be 
enrolled in this study if population sequencing identifies the presence of variants relative 
to the prototypic reference sequence (H77 for 1a or Con1 for 1b) at any of the following 
positions:  NS3 155, 156, or 168; or NS5A 28, 29, 30, 31, 32, 58, or 93.  Because in vitro 
and in vivo studies have shown that exposure to ABT-450 or ABT-267 leads to the 
selection of variants at one or more of these positions, any variant at one or more of these 
positions may have the potential to decrease viral susceptibility to the corresponding 
DAA.  Until prospective data are available on the response to treatment of patients with 


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virus harboring these variants, variants at any one or more of these positions are therefore 
considered as potentially decreasing susceptibility to the study drug regimen.  Subjects 
with prior non-response to pegIFN/RBV are more likely to have a suboptimal response to 
a second course of pegIFN/RBV, and the presence of variants associated with decreased 
susceptibility to ABT-450 and/or ABT-267 could therefore lead to an unacceptable risk of 
treatment failure (with possible worsening of genotypic resistance).  Until further data are 
available on response to ABT-450/r and ABT-267 in subjects who previously failed 
pegIFN/RBV telaprevir in the previous AbbVie study, these subjects will conservatively 
be treated as pegIFN nonresponders.
5.6.4
Selection of Doses in the Study
Doses of the DAAs to be used in this study have shown significant antiviral activity both 
as monotherapy and in combination with pegIFN and RBV.  Doses comparable to, and 
higher than, the DAA doses to be administered in this study have been studied in 
single- and multiple-dose healthy volunteer studies and administered to HCV-infected 
subjects as monotherapy or in combination with pegIFN and RBV and found to have a 
good safety profile and well tolerated.  Of note, co-administration of ABT-450/r and 
ABT-267 at the doses planned for use in this study does not clinically significantly impact 
plasma exposures compared to administration as single agents.  Therefore doses selected 
based on data from monotherapy studies are considered appropriate for use when these 
agents are combined. 
ABT-450/r
The dose of ABT-450/r is 200/100 mg QD.  This is higher than the 150 mg dose used in 
Phase 3 studies and the approved dose of ABT-450 for HCV GT1 infection with the 
interferon free 3-DAA regimen.  The 200 mg dose has been evaluated in Phase 2a study 
(Study M11-602) with peg-IFN and ribavirin for 12 weeks; in the Phase 2a and 2b 
Studies M12-998 and M11-652, the 200 mg dose was administered for 12 to 24 weeks 
with 25 mg ABT-267 with and without ribavirin.  Doses higher than 200 mg have been 
evaluated in Phase 2 Study M12-746 with ABT-333 and ribavirin for 12 weeks as well as 


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in Phase 1 Study M12-187 and Study M12-221 for up to 14 days with ABT-267.  Studies 
in both healthy volunteers (Study M12-187) and HCV-infected subjects (Study M12-746) 
suggest that a higher dose of ABT-450/r (250/100 mg QD) may be associated with a risk 
of elevated ALT levels when co-administered with other DAAs (ABT-333 or ABT-267 + 
ABT-333).  Therefore, the maximum ABT-450 dose administered in this study will not 
exceed 200 mg daily for 24 weeks.
ABT-267
The 25 mg dose of ABT-267 is the dose evaluated in Phase 3 studies and the approved 
dose of ABT-267 for HCV GT1 infection with the interferon free 3-DAA regimen.  This 
was the same dose that has been evaluated in multiple Phase 2 studies (Studies M11-652, 
M12-998, M13-393).  The dose of ABT-267 in this study is 25 mg QD.  Following 3 days 
of ABT-267 monotherapy at doses of 1.5 mg, 5 mg QD, 25 mg QD, 50 mg QD and 
200 mg QD, in Study M12 116 and Study M13-386, mean viral load decreases were 2 to 
3 log10 IU/mL and comparable across doses.  In addition, data from Phase 2a study of 
ABT-267 with pegIFN and RBV (Study M12-114) suggest that the 3 doses used in that 
study (5 mg QD, 50 mg QD and 200 mg QD) are all well tolerated and show comparable 
short term antiviral activity.  Resistance analysis from a short-term monotherapy trial 
(Study M12-116) suggests that ABT-267 doses greater than 25 mg QD do not appear to 
confer an advantage in suppression of commonly selected resistant variants.  The 
maximum ABT-267 dose administered in this study will not exceed 25 mg daily for 
24 weeks.
RBV
The daily dose of RBV in this study is 1,000 mg to 1,200 mg, divided twice daily.  This 
dose is approved for treatment of adult patients with chronic hepatitis C in combination 
with pegIFN.  This dose is selected for this study because the safety profile has been well 
characterized when administered with pegIFN, including the incidence of hemolytic 
anemia, and there are well-defined dose reduction criteria in the event of RBV-induced 
anemia.


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pegIFN
PegIFN will be dosed per the package insert in this study.11  PegIFN will be dosed at 
180 μg/0.5 mL SC once a week for the duration of 48 weeks.  This dose is approved for 
treatment of adult patients with chronic hepatitis C in combination with RBV.  The same 
dose is selected for this study because the safety profile has been well characterized when 
administered with RBV, and there are well-defined dose reduction criteria in the event of 
hematologic adverse effects.
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, duration and outcome, relationship of the adverse 
event to study drug, and any action(s) taken.  For serious adverse events not considered 
"probably 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.


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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.  
Laboratory abnormalities and changes in vital signs are considered to be adverse events 
only if they result in discontinuation from the study, necessitate therapeutic medical 
intervention, (meets protocol specific criteria [see Section 6.7 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had 
not been taken. This does not include an event that would 
have been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to 
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.


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Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
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.


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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 DAA (ABT-450/r or ABT-267), RBV and pegIFN:
Probably Related
An adverse event has a strong temporal relationship to study 
drug or recurs on re-challenge and an Other cause of event 
is unlikely or significantly less likely.
Possibly Related
An adverse event has a strong temporal relationship to the 
study drug and an Other cause of event is equally or less 
likely compared to the potential relationship to study drug.
Probably Not Related
An adverse event has little or no temporal relationship to the 
study drug and/or a more likely Other cause of event exists.
Not Related
An adverse event is due to an underlying or concurrent 
illness or effect of another drug and is not related to the 
study drug (e.g., has no temporal relationship to study drug 
or has a much more likely Other cause of event).
For causality assessments, events meeting the categories of probably or possibly will be 
considered "associated."  Events that are probably not or not related 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 possibly, probably not, or not 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 adverse events reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration (including pegIFN and RBV) have 
elapsed will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, serious adverse events will be collected from the time the subject signed the 
study-specific informed consent through the end of Substudy 3 (End of Study).


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Adverse event information will be collected as shown in Figure 4.
Figure 4.
Adverse Event Collection
SAEs
SAEs and Non-Serious AEs
Elicited and/or Spontaneously Reported
SAEs
#
#
#
#
#
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days or 
After Study 
Drug Stopped
End of 
Study
6.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the EDC 
system.  Serious adverse events that occur prior to the site having access to the RAVE®
system or if RAVE is not operable should use the SAE non-CRF paper forms and send 
them to Clinical Pharmacovigilance within 24 hours of the site being aware of the serious 
adverse event.
For safety concerns, contact the Antiviral Safety Team at:


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For any subject safety concerns, please contact the physician listed below:
In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated AbbVie SDP.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.6
Pregnancy
Subjects and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the study, starting with Study Day 1 and for 7 months 
(or per local RBV label) after the last dose of RBV.
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who report a positive pregnancy test during 


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the Treatment Period must be notified to stop RBV immediately.  Administration of 
DAA's, including ritonavir, and Peginterferon may be continued at the investigator's 
discretion if the benefit of continuing therapy is felt to outweigh the risk (Section 5.4.1).  
Subjects will continue to be monitored for antiviral drug resistance in the Post-Treatment 
Period as described in Section 5.1.4.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 7 months (or per local RBV 
label) after the last dose of RBV.  The investigator is encouraged to report the pregnancy 
information to the voluntary RBV Pregnancy Registry as applicable.
Male subjects who are not surgically sterile must either abstain from sexual intercourse or 
agree to use a double barrier method of birth control (condom), including informing their 
partner(s) to use an effective method of birth control (e.g., contraceptive sponge, 
diaphragm, or vaginal ring with spermicidal jellies or creams) for 7 months (or per local 
RBV label) after the last dose of RBV.  In the event of pregnancy occurring in the partner 
of an enrolled subject, the investigator should contact the AbbVie Study Designated 
Physician to discuss the potential benefit of the male subject remaining on study drug 
treatment.  If considered appropriate, the subject may remain in the study and the 
investigator should counsel the subject on the pregnancy risks associated with RBV, and 
instruct him to use 2 effective forms of contraception (including at least one barrier 
method) for the remainder of the partner's pregnancy.  The investigator is encouraged to 
report the partner's pregnancy information to the voluntary RBV Pregnancy Registry.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.


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6.7
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 Section 6.7.1 through Section 6.7.5.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range reported as an adverse event that is judged by the investigator or AbbVie to be 
either "possibly related" or "probably related" to the study drug (Section 6.3).  A toxicity 
is deemed "clinically significant" based on the medical judgment of the investigator.  
During the study, timeliness of EDC data entry to reflect study drug dose interruptions 
and/or dose modifications and consequent required adverse events insures that the AbbVie 
Safety Team (Study Designated Physician, safety monitor) have the data necessary for 
signal detection at safety data review meetings.  The investigator should ensure that any 
interruptions or modifications and consequent required adverse events are entered into the 
appropriate eCRFs within 5 business days.
Lowering of the pegIFN and RBV dose for reasons not provided in the protocol is 
permitted.  The following guidelines should be used for study drug-related toxicity 
management.
6.7.1
Grades 1 or 2 Laboratory Abnormalities and Mild or 
Moderate Adverse Events
Subjects who develop a study drug-related mild or moderate adverse event or Grade 1 or 2 
laboratory abnormality, other than those discussed separately in Section 6.7.3, 
Section 6.7.4 and Section 6.7.5, may continue study drugs with follow-up per study 
protocol and in accordance with local standard of care.


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6.7.2
Grades 3 or 4 Laboratory Abnormalities and Severe or 
Serious Adverse Events
If a subject experiences a Grade 3 or greater laboratory abnormality during the study 
(other than those discussed in Section 6.7.3 and Section 6.7.4 below), the abnormal 
laboratory test should be repeated.  If the Grade 3 or greater abnormality is confirmed, 
then all study drugs should be interrupted and the subject monitored until the laboratory 
parameter has returned to its baseline level or stabilized.  Study drugs may be resumed 
only with approval of the AbbVie Study Designated Physician.  If the investigator 
believes that a Grade 3 or greater laboratory parameter is not clinically significant or is 
not related to study drug and that study drug discontinuation is not warranted, the study 
drug may be continued with approval of the AbbVie Study Designated Physician.
Study drug-related Grade 3 or higher elevations in uric acid, total cholesterol or 
triglycerides do not require study drug discontinuation, but study drug may be interrupted 
if deemed necessary by the investigator.
If a subject experiences a severe adverse event or a serious adverse event and that event is 
considered possibly or probably related to study drug by the investigator, the AbbVie 
Study Designated Physician should be notified and all study drugs should be interrupted.  
The investigator should ensure that the serious adverse event is report to AbbVie Safety 
within 24 hours of awareness of it; a severe event should be entered into EDC within 
5 business days.  Dose interruptions (or discontinuations) should be entered into the 
appropriate eCRFs within 5 business days.
6.7.3
Management of Decreases in Hemoglobin
Reductions in hemoglobin are a well characterized side effect of ribavirin exposure.  
Hematologic abnormalities which the investigator believes are due to RBV therapy may 
be managed according to Table 12.  Management will be different for subjects without a 
history of known cardiac disease and subjects with known cardiac disease.


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If a subject experiences a hemoglobin decrease (as 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.
Use of hematologic growth factors (e.g., epoetin, filgrastim) is permitted at the discretion 
of the investigator, only with approval of the AbbVie Study Designated Physician (see 
Section 5.2.3.2 for further details).  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 requires approval of the AbbVie Study 
Designated Physician.
Alternative management of the RBV dose in the setting of reduced renal function will also 
require approval of the AbbVie Study Designated Physician.


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Table 12.
Hematologic Toxicities
Hemoglobin in Patients with No History of Cardiac Disease
Hemoglobin < 10.0 g/dL, but 
≥8.5 g/dL
Study drugs may be continued
Reduce RBV dose to 600 mg/day  and continue to monitor 
hemoglobin per protocol
If hemoglobin increases to ≥ 10 g/dL, may increase RBV; with 
gradual dose increases in 200 mg increments towards original 
dose
If Hb decreases to < 8.5 g/dL see appropriate row below
Hemoglobin < 8.5 g/dL
Permanently discontinue all study drugs
Manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create 
corresponding adverse event
Hemoglobin in Patients with History of Stable Cardiac Disease
Hemoglobin decrease of ≥ 2 g/dL 
during a 4-week treatment period 
Study drugs may be continued
Reduce RBV dose to 600 mg/day and continue to monitor 
hemoglobin levels per protocol; manage subject as medically 
appropriate; AbbVie Study Designated Physician may be 
contacted
If a subsequent hemoglobin result is greater than the level that 
triggered the dose reduction, the investigator may gradually 
increase RBV in 200 mg increments towards original dose
Hemoglobin <12 g/dL despite 4 weeks 
at reduced dose
Permanently discontinue all study drugs; manage subject as 
medically appropriate
Enter discontinuation into appropriate eCRFs and create 
corresponding adverse event (AE)
6.7.4
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, 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.
6.7.5
Management of Creatinine Clearance Decreases
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).  Ribavirin 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 con sequent related adverse events 
are entered into the appropriate eCRFs.
6.7.6
Management of Neuropsychiatric Complications
Refer to the pegIFN label for management of depression.11
History of past or current severe psychiatric conditions should be taken into account when 
determining if enrollment in this study is warranted.  Such subjects should only be 
enrolled after appropriate individualized diagnostic and therapeutic management of the 
psychiatric condition has been undertaken.
All patients receiving pegIFN should be closely monitored for any signs or symptoms of 
psychiatric disorders.  If such symptoms appear while a subject is receiving study drug 
treatment, the severity of those symptoms and potential risk to the subject should be 
assessed, and the need for adequate therapeutic management should be determined.  If 
psychiatric symptoms persist or worsen, discontinuation of study drug treatment and/or 
psychiatric intervention should be considered, based on the risk of additional psychiatric 
adverse events compared to the potential benefit of continuing study drug treatment.  If 


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suicidal ideation is identified, study drug treatment must be discontinued and the subject 
should be referred for psychiatric intervention as appropriate.
6.7.7
Management During Peginterferon Therapy
An eye examination should be scheduled for any subject complaining of decrease or loss 
of vision.
Good dental hygiene and regular dental examinations should be encouraged while 
subjects are receiving pegIFN.
6.7.8
Management of Neutropenia and Thrombocytopenia
Refer to the pegIFN prescribing information for management of neutropenia and 
thrombocytopenia.
7.0
Protocol Deviations
The investigator should not implement any deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects.  When a deviation from the 
protocol is deemed necessary for an individual subject, the investigator must contact the 
following AbbVie study personnel:
Primary Contact:
Alternate Contact:


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Such contact must be made as soon as possible to permit a review by AbbVie to
determine the impact of the deviation on the subject and/or the study.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation.
8.0
Statistical Methods and Determination of Sample 
Size
There will be no interim analysis.  The final analysis will occur after all enrolled subjects 
have completed the Post-Treatment Period or prematurely discontinued from the study.  
Data will be locked after performing appropriate data cleaning.
In addition, ongoing review of the data is also planned for non-efficacy (futility) 
assessment.  Data will be assessed separately for the population of subjects who were null
or partial responders to prior pegIFN/RBV treatment or who experienced any prior failure 
with pegIFN/RBV plus telaprevir in the previous AbbVie/Abbott study, and for the 
population of subjects who do not fall in the previous population at the time of enrollment 
into this study.  Refer to Section 5.4.2 for further details regarding these ongoing reviews.
SAS for the UNIX operating system will be used for all analyses.  All confidence 
intervals will be two-sided with an α level of 0.05.
Efficacy, safety and demographic analyses will be performed on all subjects who receive 
at least one dose of study drug.
No data will be imputed for any efficacy or safety analysis except for analyses of the 
HCV RNA endpoints or RVR, eRVR, EOTR, and all SVR endpoints.  For the endpoints 
of RVR, eRVR, and EOTR, if an HCV RNA value is missing within the window, the 
closest values before and after the window, regardless of the value chosen for the 
subsequent and preceding window, will be used for flanking imputation.  If a subject has a 
missing HCV RNA value at a post-baseline visit but with undetectable or unquantifiable 
HCV RNA levels at both the preceding value and the succeeding value, the HCV RNA 


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level will be imputed as undetectable or unquantifiable, respectively, at this visit for this 
subject.  For SVR analyses, if there is no value in the appropriate window a backward 
imputation approach will be used such that if the nearest HCV RNA value after the SVR 
window is unquantifiable, then it will be used to impute the response in the SVR window.  
Subsequent to these imputations, if a subject is missing a value for the analysis time-point, 
the subject will be imputed as a failure.
8.1
Statistical and Analytical Plans
8.1.1
Demographics
Demographics and baseline characteristics will be summarized overall, and based on 
treatment in the previous study.  Demographics include age, weight, and body mass index 
(BMI), and the frequency of gender, race, ethnicity, age category (< 50 years and 
≥50 years; < 65 years and ≥ 65 years), birth year (< 1945, 1945 to 1965, > 1965), BMI 
category (< 30 kg/m2 and ≥ 30 kg/m2), and geographic region (North America, Europe, 
Australia/New Zealand, Latin America).  Baseline characteristics will include HCV 
genotype/subtype (1a, 1b, other 1 subtype), IL 28B genotype (CC, CT, and TT; CC and 
non-CC), RBV dose modifications (yes, no), history of diabetes, history of bleeding 
disorders, baseline fibrosis score (equivalent to Metavir F0–F1, F2, F3–F4), prior 
response to pegIFN/RBV, type of response to combination DAA treatment in prior study, 
treatment during the gap between the prior study and Study M13-101 (none, 
pegIFN/RBV), baseline log10 HCV RNA levels, baseline IP-10, baseline HOMA-IR, and 
tobacco and alcohol use 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
Pharmacokinetics
Plasma concentrations for ABT-267, ABT-450, ritonavir (where applicable) and possible 
metabolites of ABT-450 and ABT-267 will be determined at each study visit up to 
24 weeks.  Plasma concentrations for RBV and serum concentrations for pegIFN may be 
determined at each study visit up to 48 weeks.


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8.1.2.1
Pharmacokinetics Endpoints
Plasma concentrations for ABT-267, ABT-450, ritonavir and possible metabolites of 
ABT-450 and ABT-267 will be determined at each study visit up to 24 weeks.  Plasma 
concentrations for RBV and serum concentrations for pegIFN may be determined at each 
study visit up to 48 weeks.
8.1.3
Efficacy
Analyses of primary and secondary endpoints will be performed by the overall treatment 
cohort, and by previous treatment group.  No statistical comparisons will be made 
between groups according to previous treatment.  
8.1.3.1
Primary Efficacy Endpoints
The primary efficacy endpoint is the percentage of subjects with sustained virologic 
response 12 weeks after the last actual dose of study drug (including DAA, pegIFN, and 
RBV) (SVR12actual; HCV RNA < LLOQ 12 weeks after the last actual dose of study drug).  
The percentage of subjects with SVR12actual and the corresponding 95% exact binomial 
confidence interval will be calculated overall and by treatment group in the prior study.
8.1.3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are the percentage of subjects with sustained virologic 
response 24 weeks after the last actual dose of study drug (including DAA, pegIFN, and 
RBV) (SVR24actual; HCV RNA < LLOQ 24 weeks after the last actual dose of study drug) 
and the percentage of subjects with eRVR (HCV RNA < LLOQ at TI Weeks 4 through 
12).
The percentage of subjects with SVR24actual and eRVR and the corresponding 95% exact 
binomial confidence intervals will be calculated overall and by treatment group in the 
prior study. 


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8.1.3.3
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized for the overall treatment 
group as specified:
●
the percentage of subjects with rapid virologic response (RVR) (HCV RNA 
< LLOQ at TI Week 4),
●
the percentage of subjects with complete early virologic response (EVR) 
(HCV RNA < LLOQ at TI Week 12), 
●
the percentage of subjects with end of treatment response (EOTR:  HCV RNA 
< LLOQ at the end of treatment [DAAs, pegIFN, and RBV]), 
●
the percentage of subjects with unquantifiable HCV RNA at each post-baseline 
visit during treatment,
●
the percentage of subjects with SVR12planned (12 weeks after the last planned 
dose of pegIFN and RBV, i.e., 60 weeks after the first dose of study drug) and 
SVR24planned (24 weeks after the last planned dose pegIFN and RBV, 
i.e., 72 weeks after the first dose of study drug),
●
The percentage of subjects with sustained virologic response (HCV RNA 
< LLOQ) 4 weeks after the last dose of study drug (SVR4),
●
the percentage of subjects who fail to suppress (never achieving HCV RNA 
< LLOQ) during treatment and received at least 6 weeks of treatment 
(i.e., study drug duration ≥36 days), 
●
the number of subjects with virologic rebound (two consecutive HCV RNA 
measurements > 1 log10 IU/mL above nadir during treatment or 
two consecutive HCV RNA measurements ≥ LLOQ during treatment after 
HCV RNA < LLOQ) at each protocol-specified visit during treatment,
●
the percentage of subjects with on-treatment virologic failure during the 
Treatment Period (defined as rebound or failure to suppress during treatment, 
i.e., all on-treatment values of HCV RNA ≥ LLOQ, with at least 6 weeks of 
treatment),
●
the percentage of subjects with relapse through Post-Treatment Week 12 and 
any time post-treatment, among subjects completing treatment and with HCV 
RNA < LLOQ at the Final Treatment Visit,


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●
the percentage of subjects who achieved SVR24 and subsequently relapsed,
●
time to suppression in HCV RNA(defined as the study day of the 
first occurrence of HCV RNA < LLOQ),
●
time to relapse  at any time post-treatment, among subjects completing 
treatment and with HCV RNA < LLOQ at the Final Treatment Visit 
The percentages of subjects with RVR, ETR, SVR4, SVR12planned, and SVR24planned, and the 
corresponding 95% exact binomial confidence intervals will be calculated overall.  
Similarly, the percentage of subjects with on-treatment virologic failure and the 
percentage of subjects who relapse through Post-Treatment Week 12 and any time 
post-treatment, among subjects completing treatment and with HCV RNA < LLOQ at the 
Final Treatment Visit, will be calculated overall along with the corresponding 95% exact 
binomial confidence intervals.
From HCV RNA levels, the time to suppress, and the time to relapse, will be calculated 
for each subject, will be displayed graphically using a Kaplan-Meier curve.
8.1.4
Exploratory Analyses
Logistic regression will be used with SVR12actual as the dependent variable to explore 
potential predictors of response.  The following variables will be considered as possible 
independent variables:  baseline log10 HCV RNA level, HCV subgenotype (1a, 1b), 
geographic region, IL-28B genotype (CC, non-CC), IP10, GGT, sex, race, age, and 
baseline BMI.
8.1.5
Resistance Analyses
The genes of interest for population sequencing in this study are those encoding full 
length NS3/4A and NS5A, while for clonal sequencing they are those encoding NS3 
amino acids 1 to 181 and NS5A amino acids 1 to 215.  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:  155, 156, and 168 in NS3 for ABT-450; 28, 30, 31, 58, and 


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93 in NS5A for ABT-267.  This list may be expanded if treatment-emerged 
resistance-conferring variants are identified at additional amino acid positions in 
DAA-treated patients.  The prototypic reference sequences used for analysis will be H77 
for genotype 1a or Con1 for genotype 1b.
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 is < 1000 IU/mL, the sample closest in 
time after the failure with an HCV RNA level ≥ 1000 IU/mL will be used.  Clonal 
sequencing of a given target will be performed only if no variants are detected at signature 
resistance-associated amino acid positions by population sequencing in that sample.  In 
addition, clonal sequencing may be performed if there is a complex mixture of amino 
acids at one or more signature resistance-associated position that cannot be resolved by 
population sequencing.
Included time points for analyses on samples from subjects who experience virologic 
failure (as defined in Section 5.4.1.1) are (1) time of virologic failure or sample closest in 
time after failure with an HCV RNA level of ≥ 1000 IU/mL, (2) 24 weeks post-DAA 
treatment, provided that resistance-associated variants were detected by either population 
or clonal sequencing at the time of failure, and (3) 48 weeks post-DAA treatment, 
provided that resistance-associated variants were detected by either population or clonal 
sequencing at post-DAA treatment Week 24.
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant (by population sequencing) in a baseline sample 
determined by comparison of the amino acid sequence of the baseline sample 
to the appropriate prototypic reference amino acid sequence for a given DAA 
target (NS3 or NS5A).
●
Post-baseline variant by population sequencing:  an amino acid variant in a 
post-baseline time point sample that was not detected at baseline and is 
detectable by population sequencing.


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●
Post-baseline variant by clonal sequencing:  a variant at a signature 
resistance-associated amino acid position that was not present by population 
sequencing at baseline that is detected in a post-baseline sample by clonal 
sequencing in at least 2 clones from that sample (among the subset of subjects 
for whom clonal sequencing is performed).  
●
Emerged variant by population sequencing:  a post-baseline variant that is
observed in 2 or more subjects of the same HCV subgenotype by population 
sequencing.
●
Linked variant by population sequencing:  2 or more signature 
resistance-associated or emerged amino acid variants identified within a target 
by population sequencing, where at least one of the variants is at a signature 
position, and no mixture of amino acids is detected at either position.
●
Linked variant by clonal sequencing:  at least 2 clones from a given sample 
containing the same 2 or more signature resistance-associated amino acid 
variants by clonal sequencing.
For those subjects whose baseline sample has an HCV RNA level ≥ 1000 IU/mL, a listing 
by subject of all baseline variants relative to prototypic reference sequence at signature 
resistance-associated amino acid positions will be provided for each DAA target (NS3 and 
NS5A).
The following analyses will be performed on the samples from subjects who experienced 
virologic failure and have post-baseline resistance data available.
The HCV amino acid sequence as determined by population sequencing will be compared 
with the baseline and appropriate prototypic reference amino acid sequences.  Listings by 
subject of all post-baseline variants detected by population sequencing relative to the 
baseline amino acid sequences will be provided for each DAA target (NS3 and NS5A).  In 
addition, listings by subject of variants detected by population sequencing at signature 
resistance-associated amino acid positions relative to baseline and the appropriate 
prototypic reference amino acid sequences will be provided.


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For the subset of samples for which clonal sequencing is performed, the amino acid 
variants determined by clonal sequencing will be summarized by counting the number of 
clones whose amino acid sequence does not match that of the population baseline 
sequence by subject at each time point and amino acid position, out of the total number of 
clones analyzed.  Listings by subject of post-baseline variants at signature 
resistance-associated positions detected by clonal sequencing will be provided for each 
DAA target.
Linkage between emerged or signature variants by population sequencing will also be 
evaluated.  A listing by subject and time point of the linked variants by population 
sequencing for each target will be provided.  Furthermore, where clonal sequencing is 
performed and the sample has at least 2 clones with the same 2 or more signature 
resistance-associated amino acid variants within a DAA target, then a listing by subject 
and time point of the linked variants by clonal sequencing will be provided.
8.1.6
Safety
All subjects who receive at least 1 dose of study drug will be included in the safety 
analyses.  Safety data will be summarized for the overall treatment cohort but not by prior 
treatment. 
8.1.6.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).12  The number and percentage of subjects having DAA treatment-emergent 
adverse events (i.e., any event that begins or worsens in severity after initiation of study 
drug through 30 days post-DAA) will be tabulated by primary MedDRA System Organ 
Class and preferred term.  The tabulation of the number of subjects with 
treatment-emergent adverse events also will be provided with further breakdown by 
severity rating and relationship to DAA (ABT-450/r or ABT-267), pegIFN, and RBV.  
Subjects reporting more than 1 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 


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1 type of event within a System Organ Class will be counted only once for that System 
Organ Class.
The number and percentage of subjects experiencing adverse events with an onset date 
greater than 30 days post-DAA dosing through 30 days after the last dose of pegIFN/RBV 
will also be tabulated by primary MedDRA System Organ Class and preferred term.
Additional analyses will be performed if useful and appropriate.
8.1.6.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last measurement prior to the initial dose of study drug.  Mean changes from baseline to 
each post-baseline visit will be summarized. 
Laboratory data values will be categorized as low, normal, or high based on reference 
ranges of the laboratory used in this study.  The number and percent of subjects who 
experience post-baseline shifts in clinical laboratory values from low/normal to high and 
high/normal to low based on the normal range will be summarized.
In addition, the number and percentage of subjects with post-baseline values meeting 
pre-specified criteria for Potentially Clinically Significant (PCS) laboratory values will be 
summarized.  For hemoglobin and the liver function tests of ALT, AST, alkaline 
phosphatase, and total bilirubin, the frequency and percentage of subjects with a 
maximum CTCAE Grade of 1, 2, 3, or 4 will be summarized.
8.1.6.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each post-baseline visit will be summarized descriptively.  Frequencies 
and percentages of subjects with post-baseline values meeting pre-defined criteria for PCS 
Vital Signs values will be summarized.


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8.2
Determination of Sample Size
There is no predetermined sample size for this study.  Subjects who experience virologic 
failure in a previous AbbVie/Abbott DAA combination study and who meet the eligibility 
criteria will be treated 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 prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
A copy of the informed consent form medication guides for pegIFN and RBV will be 
given to the subject.
Male subjects will also be given instructions and copies of the RBV medication guide and 
RBV Partner Risk Fact Sheet to share with their female partner(s).
The original informed consent 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 of the consent and copies of the RBV medication guide and RBV Partner 
Risk Fact Sheet (for male subjects).  Refer to Section 6.6 for partner pregnancy 
information.


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


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performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic checks will be run to identify items such as inconsistent study dates.  Any 
necessary corrections will be made by the site to the eCRF.
12.0
Use of Information
All information concerning ABT-450/r, and ABT-267, and AbbVie operations, such as 
AbbVie patent applications, formulas, manufacturing processes, basic scientific data, or 
formulation information, supplied by AbbVie and not previously published is considered 
confidential information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
ABT-450/r and ABT-267.  This information may be disclosed as deemed necessary by 
AbbVie to other clinical investigators, other pharmaceutical companies and to 
governmental agencies.  To allow for the use of the information derived from this clinical 
study and to ensure complete and thorough analysis, the investigator is obligated to 


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provide AbbVie with complete test results and all data developed in this study and to 
provide direct access to source data/documents for study-related monitoring, audits, 
IEC/IRB and regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access and will not be 
retrieved by AbbVie.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.


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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, and 
ABT-267 and the product labeling for ritonavir, pegIFN and RBV.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
Protocol Title:
An Open-Label Study to Evaluate the Safety, Antiviral Activity and 
Pharmacokinetics of Direct-Acting Antiviral Agent (DAA) 
Treatment in Combination with Peginterferon α-2a and Ribavirin 
(pegIFN/RBV) in Chronic Hepatitis C Virus (HCV) Infected 
Subjects Who Have Experienced Virologic Failure in a Previous 
AbbVie/Abbott DAA Combination Study
Protocol Date:
26 June 2015
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
WHO.  Weekly Epidemiological Record.  No. 49.  10 December 1999.
2.
Strader D, Wright T, Thomas D, Seeff L.  Diagnosis, management, and treatment 
of hepatitis C.  Hepatology.  2004;39(4):1147-71.
3.
Pawlotsky JM, Chevaliez S, McHutchison J.  The hepatitis C virus life cycle as a 
target for new antiviral therapies.  Gastroenterology.  2007;132(5):1979-98.
4.
Ghany M, Nelson D, Stradler D, Thomas D, Seeff L.  An update on treatment of 
genotype 1 chronic hepatitis C virus infection:  2011 practice guideline by the 
American Association for the Study of Liver Diseases.  Hepatology.  
2011;54(4):1433-44.
5.
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, 
Kauffman R, et al.  Telaprevir with peginterferon and ribavirin for chronic HCV 
genotype 1 infection.  N Engl J Med.  2009;360(18):1827-38.
6.
Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al.  Telaprevir 
and peginterferon with or without ribavirin for chronic HCV infection.  N Engl J 
Med.  2009;360(18):1839-50.
7.
Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, et al.  Oral 
Presentation No. 193.  60th AASLD; 2009; Boston.
8.
AbbVie.  ABT-450 Investigator's Brochure Edition 6.  26 March 2013.
9.
AbbVie.  ABT-267 Investigator's Brochure Edition 4.  26 March 2013.
10.
Lok A, Gardiner D, Lawitz E, Martorell C, Everson G, Ghalib R, et al.  Preliminary 
study of two antiviral agents for hepatitis C genotype 1.  N Engl J Med.  
2012;366(3):216-24.
11.
Pegasys® [package insert].  Nutley, New Jersey; Hoffmann-La Roche Inc., 2010.
12.
Medical Dictionary for Regulatory Activities (MedDRA), Version 12.1.


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


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


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


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Appendix C.
Clinical Toxicity Grades


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Appendix D.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Has been changed to read:
Section 1.2  Synopsis
Subsection Number of Subjects to be Enrolled:
First sentence previously read:
Up to 150.
Has been changed to read:
Up to 35.
Section 3.0  Introduction
First paragraph, third sentence previously read:
Until recently, the standard of care (SOC) for treatment of HCV genotypes 1a and 1b (the 
most common genotypes in North America and Europe) consisted of weekly injections of 


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pegylated interferon-alpha (pegIFN) and daily oral doses of ribavirin (RBV) for up to 
48 weeks.2
Has been changed to read:
Until 2011 with the FDA approval of the protease inhibitors (PI) telaprevir and 
boceprevir, the standard of care (SOC) for treatment of HCV genotypes 1a and 1b (the 
most common genotypes in North America and Europe) consisted of weekly injections of 
pegylated interferon-alpha (pegIFN) and daily oral doses of ribavirin (RBV) for up to 
48 weeks.2
Section 3.0  Introduction
First paragraph, last sentence previously read:
Thus, there is a clear unmet need for effective anti-HCV compounds which can increase 
the likelihood of successful treatment for this population.
Has been changed to read:
While the triple drug regimen of PI/pegIFN/RBV increased SVR rates to 70% – 80%, 
there were many treatment discontinuations due to drug toxicities like rash and anemia, 
and virologic failure rates were still unacceptably high.  These two, distinct eras of HCV 
therapy generated a large cohort of patients in need of more potent antiviral regimens.
Section 3.0  Introduction
Delete:  third paragraph
Limited data suggest regimens containing pegIFN, RBV and DAAs may also represent a 
potential treatment option for subjects who previously failed HCV therapy.  In one study, 
an NS5A inhibitor (BMS-790052) and a protease inhibitor (BMS-650032) combined with 
pegIFN and RBV for 24 weeks achieved 24-week SVR (SVR24) in over 90% of prior 
pegIFN/RBV null responders.  While the study is still ongoing, these preliminary findings 
suggest that prior pegIFN/RBV null responders may be successfully treated with a DAA 
combination added to pegIFN/RBV.


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Section 3.0  Introduction
Fourth paragraph, first and second sentence previously read:
Data from studies on the retreatment of HCV-infected subjects who have failed prior 
treatment with regimens containing one or more DAAs are currently very limited.  In 
several of the exploratory studies, subjects who experienced viral breakthrough or 
non-response (with emergence of DAA-related associated resistance mutations) were 
managed by the addition of pegIFN, or pegIFN and RBV to the failing DAA combination 
regimen.
Has been changed to read:
Data from studies on the retreatment of HCV-infected subjects who failed prior treatment 
with regimens containing one or more DAAs are limited.  In one study, an NS5A inhibitor 
(BMS 790052) and a PI (BMS 650032) combined with pegIFN and RBV for 24 weeks 
achieved SVR24 in over 90% of prior pegIFN/RBV null responders, suggesting that these 
patients may be successfully treated with a DAA combination added to pegIFN/RBV.  In 
several exploratory studies, subjects who experienced viral breakthrough or non-response 
(with emergence of DAA-related associated resistance mutations) were managed by the 
addition of pegIFN, or pegIFN and RBV to the failing DAA combination regimen.
Section 3.0  Introduction
Sixth paragraph, first sentence previously read:
AbbVie currently has a number of DAA compounds in clinical development:  ABT-450 is 
an NS3/4A protease inhibitor, ABT-267 (ombitasvir) is an NS5A inhibitor, and ABT-333 
(dasabuvir) is a non-nucleoside NS5B polymerase inhibitor.
Has been changed to read:
AbbVie has three DAAs that were recently approved by North American and European 
regulatory agencies.  ABT-450 (paritaprevir) is an NS3/4A protease inhibitor, ABT-267 
(ombitasvir) is an NS5A inhibitor, and ABT-333 (dasabuvir) is a non-nucleoside NS5B 
polymerase inhibitor.


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Section 5.1.3  Treatment Period (Substudy 1 and Substudy 2)
Subsection Substudy 2 – PegIFN/RBV (PR) Treatment Period
Last paragraph, first, second and third sentence previously read:
There will be interim analyses of available data at time-points determined based on the 
rate of enrollment into this study.  Appropriate data base clean up procedures will be 
performed for each interim analysis.  In addition, ongoing review of the data is also 
planned for non-efficacy (futility) assessment.
Has been changed to read:
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Table 5.  Study Activities
Twentieth through twenty-fifth row previously read:
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
Dispense MEMS Cap
X
Download MEMS
X
X
X
X
X
X
X
X
Collect MEMS Capl
X
HCV RNA Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV Resistance Testing 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DAA/ritonavir, 
PegIFN/RBV Assay (PK) 
Samplem
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Has been changed to read:
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
Dispense MEMS Capl
(X)
Download MEMSl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Collect MEMS Capl,m
(X)
HCV RNA Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV Resistance Testing 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DAA/ritonavir, 
PegIFN/RBV Assay (PK) 
Samplen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 5.  Study Activities
Delete:  last row
Substudy 1 Treatment Intensification (TI) Period
Substudy 2-PegIFN/RBV Alone (PR) 
Treatment Period
Activity
Pre-
SCR
SCR
TI 
Day 
1b
TI 
Wk 
1
TI 
Wk 
2
TI 
Wk 
4
TI 
Wk 
8
TI 
Wk 
12
TI 
Wk 
16
TI 
Wk 
20
TI 
Wk 
24/
TI 
D/Cc
PR 
Wk 
2
PR 
Wk 
4
PR 
Wk 
8
PR 
Wk 
12
PR 
Wk 
24d
PR 
Wk 
36d
PR 
Final/
PR 
D/Cd,e
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 5.  Study Activities
Table note "l." and "m." previously read:
l.
MEMS cap is collected at any point upon completion of Substudy 1.
m. A total of two pharmacokinetic samples will be drawn at each time-point, one plasma 
and one serum.  The site will contact the subject approximately 2 days prior to the 
scheduled PK blood collection date to review the importance of proper study drug 
administration.
Has been changed to read:
l.
Collected from subjects participating in study under original protocol and 
Amendments 1 – 9.
m. MEMS cap is collected at any point upon completion of Substudy 1.
n. A total of two pharmacokinetic samples will be drawn at each time-point, one plasma 
and one serum. The site will contact the subject approximately 2 days prior to the 
scheduled PK blood collection date to review the importance of proper study drug 
administration.


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Table 7.  Study Activities – Substudy 3 Post-Treatment
Last row previously read:
Substudy 3 Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48/
PT D/C
Archive Plasma Sample
X
X
X
X
X
X
X
Has been changed to read:
Substudy 3 Post-Treatment (PT) Period
Activity
PT Wk 2
PT Wk 4
PT Wk 8
PT Wk 12
PT Wk 24
PT Wk 36
PT Wk 48/
PT D/C
Archive Plasma Sample
X
X
X


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Section 5.3.1.1  Study Procedures
Subsection MEMS Cap
Add:  new first paragraph
Subjects participating in the study prior to approval of Amendment 10:
Section 5.3.1.1  Study Procedures
Subsection MEMS Cap
Add:  second paragraph
Following approval of Amendment 10, all MEMS caps assigned to subjects participating 
in Substudy 1 will be collected at the subject's next study visit.  Site personnel should 
download the MEMS dosing history data from the MEMS caps.  MEMs caps will not be 
used for the remaining Substudy 1 visits.
Section 5.3.1.1  Study Procedures
Subsection Archive Plasma Sample
First sentence previously read:
An archive plasma sample will be collected at the study visits indicated in Table 5 and 
Table 7.
Has been changed to read:
An archive plasma sample will be collected at the study visits indicated in Table 7.
Section 5.3.2.3  Disposition of Samples
Add:  new last paragraph
PK samples will be maintained by AbbVie at least until the analytical reports have been 
finalized but no longer than 6 months from completion of the Clinical Study Report.


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Section 5.4.2  Non Efficacy (Futility) Criteria
Delete:  third and fourth bullet following second paragraph
●
Subsequently, for each population, after the next 20 subjects have completed 
24 weeks of ABT-450/r + ABT-267 + pegIFN/RBV treatment or prematurely 
discontinued, the percentage of subjects meeting virologic stopping criteria 
will be assessed relative to the same thresholds.  Again, study drug treatment 
will be stopped for all subjects or subjects within a population if the threshold 
is reached.  
●
Similar assessments will then continue to occur after each additional 
40 subjects within a population have completed 24 weeks of ABT-450/r + 
ABT-267 + pegIFN/RBV treatment or prematurely discontinued.
Table 10.  Dosing Schematic
Previously read:
N
Treatment
Duration
Approximately 150
ABT-450/r 200/100 mg QD + 
ABT-267 25 mg QD + pegIFN + 
RBVa
24 weeks
pegIFN + RBVa
24 weeksb
Has been changed to read:
N
Treatment
Duration
Approximately 35
ABT-450/r 200/100 mg QD + 
ABT-267 25 mg QD + pegIFN + 
RBVa
24 weeks
pegIFN + RBVa
24 weeksb
Section 5.5.6  Treatment Compliance
Fourth paragraph, second and third sentence previously read:
ABT 450, ritonavir and ABT-267 should not be re-dispensed to the subject.  RBV bottles 
may be re-dispensed to the subject.


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Has been changed to read:
ABT-450, ritonavir and ABT-267 and RBV should not be re-dispensed to the subject.
Section 5.5.7  Electronic Pill Monitors (MEMS Caps)
Add:  new first paragraph
All subjects participating under Protocol Amendment 10 will not utilize MEMS caps to 
obtain dosing histories.
Section 5.5.7  Electronic Pill Monitors (MEMS Caps)
First paragraph, first sentence previously read:
All subjects will utilize a MEMS monitor (cap), manufactured by Advanced Analytical 
Research on Drug (AARDEX Group Ltd., Switzerland) on the bottles of ABT-450, 
ABT-267 throughout Substudy 1.
Has been changed to read:
Subjects enrolled in the protocol prior to the implementation of the Protocol 
Amendment 10 will utilize a MEMS monitor (cap), manufactured by Advanced 
Analytical Research on Drug (AARDEX Group Ltd., Switzerland) on the bottles of 
ABT-450, ABT-267 during Substudy 1.
Section 5.5.7  Electronic Pill Monitors (MEMS Caps)
First paragraph, fifth sentence previously read:
In addition, MEMS data will be the primary data used to assess PK time relative to dose.
Has been changed to read:
In addition, MEMS data may be used to assess PK time relative to dose.


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Section 5.5.7  Electronic Pill Monitors (MEMS Caps)
Last paragraph, first sentence previously read:
The MEMS cap will be collected from the subject at the completion of study drug 
treatment during Substudy 1.
Has been changed to read:
The MEMS cap will be collected from the subject at the completion of study drug 
treatment during Substudy 1 or at the subject's first study visit following approval of 
Amendment 10 at the site.
Section 5.6.4  Selection of Doses in the Study
Subsection ABT-450/r
Second sentence previously read:
This dose is greater than or equal to the dose subjects will have received in a previous 
AbbVie/Abbott DAA combination study.
Has been changed to read:
This is higher than the 150 mg dose used in Phase 3 studies and the approved dose of 
ABT-450 for HCV GT1 infection with the interferon free 3-DAA regimen.  The 200 mg 
dose has been evaluated in Phase 2a study (Study M11-602) with peg-IFN and ribavirin 
for 12 weeks; in the Phase 2a and 2b Studies M12-998 and M11-652, the 200 mg dose 
was administered for 12 to 24 weeks with 25 mg ABT-267 with and without ribavirin.  
Doses higher than 200 mg have been evaluated in Phase 2 Study M12-746 with ABT-333 
and ribavirin for 12 weeks as well as in Phase 1 Study M12-187 and Study M12-221 for 
up to 14 days with ABT-267.
Section 5.6.4  Selection of Doses in the Study
Subsection ABT-267
Previously read:
The dose of ABT-267 in this study is 25 mg QD.  Following 3 days of ABT-267 
monotherapy at doses of 5 mg QD, 25 mg QD, 50 mg QD and 200 mg QD, in 


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Study M12-116, mean viral load decreases were 2 to 3 log10 IU/mL and comparable 
across doses.  In addition, preliminary data from subjects in an ongoing Phase 2a study of 
ABT-267 with pegIFN and RBV (Study M12-114) suggest that the 3 doses used in that 
study (5 mg QD, 50 mg QD and 200 mg QD) are all well tolerated and show comparable 
short term antiviral activity.  Preliminary resistance analysis from a short-term 
monotherapy trial (Study M12-116) suggests that ABT-267 doses greater than 25 mg QD 
do not appear to confer an advantage in suppression of commonly selected resistant 
variants.  Modeling and simulation to predict SVR rates suggest that ABT-267 25 mg is 
optimal when combined with ABT-450/r.  The maximum ABT-267 dose administered in 
this study will not exceed 25 mg daily for 24 weeks.
Has been changed to read:
The 25 mg dose of ABT-267 is the dose evaluated in Phase 3 studies and the approved 
dose of ABT-267 for HCV GT1 infection with the interferon free 3-DAA regimen.  This 
was the same dose that has been evaluated in multiple Phase 2 studies (Studies M11-652, 
M12-998, M13-393).  The dose of ABT-267 in this study is 25 mg QD.  Following 3 days 
of ABT-267 monotherapy at doses of 1.5 mg, 5 mg QD, 25 mg QD, 50 mg QD and 
200 mg QD, in Study M12 116 and Study M13-386, mean viral load decreases were 2 to 
3 log10 IU/mL and comparable across doses.  In addition, data from Phase 2a study of 
ABT-267 with pegIFN and RBV (Study M12-114) suggest that the 3 doses used in that 
study (5 mg QD, 50 mg QD and 200 mg QD) are all well tolerated and show comparable 
short term antiviral activity.  Resistance analysis from a short-term monotherapy trial 
(Study M12-116) suggests that ABT-267 doses greater than 25 mg QD do not appear to 
confer an advantage in suppression of commonly selected resistant variants.  The 
maximum ABT-267 dose administered in this study will not exceed 25 mg daily for 
24 weeks.


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Section 6.1.2  Serious Adverse Events
In-text table
Row "Important Medical Event Requiring Medical or Surgical Intervention to 
Prevent Serious Outcome"
Add:  new second sentence
Additionally, any elective or spontaneous abortion or stillbirth is considered an important 
medical event.
Section 6.1.2  Serious Adverse Events
In-text table
Delete:  row "Spontaneous Abortion" and "Elective Abortion"
Spontaneous Abortion
Miscarriage experienced by study subject.
Elective Abortion
Elective abortion performed on study subject.
Section 6.5  Adverse Event Reporting
Address following third paragraph previously read:


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Has been changed to read:
Section 6.5  Adverse Event Reporting
Last paragraph previously read:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the 
European Union (EU) countries will be the most current version of the Investigator's 
Brochure.
Has been changed to read:
In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated AbbVie SDP.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 


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Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
Section 6.6  Pregnancy
Second paragraph, second sentence previously read:
Subjects who report a positive pregnancy test during the treatment period must be notified 
to stop all study medication (Section 5.4.1).
Has been changed to read:
Subjects who report a positive pregnancy test during the Treatment Period must be 
notified to stop RBV immediately.  Administration of DAA's, including ritonavir, and 
Peginterferon may be continued at the investigator's discretion if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1).
Section 6.7  Toxicity Management
First paragraph, last sentence previously read:
This table should be used in determination of the appropriate toxicity management as 
discussed in Section 6.7.1 and Section 6.7.2.
Has been changed to read:
This table should be used in determination of the appropriate toxicity management as 
discussed in Section 6.7.1 through Section 6.7.5.


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Section 7.0  Protocol Deviations
"Alternate Contact:" previously read:
Alternate Contact:
Has been changed to read:
Alternate Contact:
Section 8.0  Statistical Methods and Determination of Sample Size
First paragraph previously read:
There will be interim analyses of cumulative data at appropriate intervals based on 
enrollment in this study.  For each interim analysis, appropriate data base clean up 
procedures will be performed.  There will be no statistical adjustment employed due to 
these analyses as this is a single-arm, open-label trial and no trial design changes will be 
made as a result of these analyses.


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Has been changed to read:
There will be no interim analysis.  The final analysis will occur after all enrolled subjects 
have completed the Post-Treatment Period or prematurely discontinued from the study.  
Data will be locked after performing appropriate data cleaning.
Appendix B.  List of Protocol Signatories
First row previously read:
Name
Title
Functional Area
Clinical
Has been changed to read:
Name
Title
Functional Area
Clinical



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