Clinical trial NCT02939989
Conditions: Hepatitis C Virus Infection
Keywords: Chronic Hepatitis C (HCV) HCV Genotype 1 (HCV GT1) HCV Genotype 2 (HCV GT2) HCV Genotype 3 (HCV GT3) HCV Genotype 4 (HCV GT4) HCV Genotype 5 (HCV GT5) HCV Genotype 6 (HCV GT6) Compensated Cirrhosis Non-cirrhotics Virologic failure
Sponsor: AbbVie
Start date: 2016-11-21; Completion date: 2021-07-30
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of co-administration of glecaprevir (ABT-493)/pibrentasvir (ABT 530) plus sofosbuvir (SOF) plus ribavirin (RBV) in hepatitis C virus (HCV) genotype (GT) 1 - 6-infected participants (including non-cirrhotic, or cirrhotic with compensated cirrhosis participants) who had experienced virologic failure in an AbbVie parent clinical study.

Detailed description:
This study enrolled HCV infected adults who had experienced virologic failure following treatment with glecaprevir/pibrentasvir or paritaprevir/ritonavir/ombitasvir + dasabuvir (DSV) (3D) or paritaprevir/ritonavir/ombitasvir (2D) regimens in one of the following AbbVie hepatitis C virus parent studies:

* M13-594 (NCT02640157)
* M13-596 (NCT02692703)
* M14-172 (NCT02642432)
* M14-242 (NCT02493855)
* M14-868 (NCT02243293)
* M15-410 (NCT02446717)
* M15-592 (NCT03222583)
* M16-126 (NCT02966795)
* M16-135 (NCT03089944)

Arms: arm 1: Participants without cirrhosis who had non-genotype 3 infection and were naïve to protease inhibitor (PI) and/or nonstructural viral protein 5A inhibitor (NS5Ai) prior to participation in AbbVie HCV parent study received daily treatment with glecaprevir/pibrentasvir (GLE/PIB) 300 mg/120 mg plus sofosbuvir (SOF) 400 mg plus twice-daily weight-based ribavirin (RBV) 600 mg - 1200 mg daily total for 12 weeks. arm 2: Participants with genotype 3, and/or compensated cirrhosis, and/or experience with PI and/or NS5Ai prior to participation in Abbvie HCV parent study received daily treatment with GLE/PIB 300 mg/120 mg plus SOF 400 mg plus twice-daily weight-based RBV 600 mg - 1200 mg daily total for 16 weeks.
Interventions: intervention 1: Sofosbuvir intervention 2: Glecaprevir/Pibrentasvir intervention 3: Ribavirin
Intervention descriptions: intervention 1: Tablet for oral administration intervention 2: Coformulated tablet for oral administration intervention 3: Tablet for oral administration

Protocol documents:
Prot_000.pdf: 
NCT02939989


ABT-493/ABT-530
M15-942 Protocol Amendment 2
EudraCT 2016-002491-26
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
15 July 2016
Amendment 1
31 August 2016
Administrative Change 1
09 February 2017
The purpose of this amendment is to:
●
Update Section 1.0, Title Page, and Section 6.1.5, Adverse Event Reporting
Rationale:  A 24-hour emergency number was added in the event emergency 
calls need to be re-directed to a designated backup AbbVie Therapeutic Area 
Medical Director (TA MD).  Language was updated, per the latest AbbVie 
protocol template.
●
Update Section 1.2 Synopsis and Section 1.3 List of Abbreviations and 
Definitions of Terms, and Appendix C, Study Activities – Treatment Period
Rationale:  Updated to be consistent with other updates made throughout the 
protocol.
●
Update Section 3.0, Introduction
Rationale:  Updated the section to reflect the recent approval of 
glecaprevir/pibrentasvir in some parts of the world and the number of patients 
that were enrolled in the registrational or Phase 2b studies.
●
Update Table 1, In Vitro Antiviral Activity of ABT-493 and Other Protease 
Inhibitors Against HCV Genotypes 1, 2, 3, 4, and 6, Section 3.0, Introduction, 
Section 14.0, Investigator's Agreement, and Section 15.0, Reference List.
Rationale:  Updated in-text citations, table, and text to refer to the updated 
Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's Brochure. 
●
Update Section 4.0, Study Objective, Figure 1, Study Schematic (Treatment 
Period), Section 5.2, Selection of Study Population, Section 5.2.1, Inclusion 
Criteria, Section 5.2.2, Exclusion Criteria, and Section 6.1.7.4, Management of 
Decreases in Hemoglobin for Subjects Receiving RBV.


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Rationale:  Updated study design and several entry criteria to broaden the 
study population in order to receive virologic failures from AbbVie's 
Phase 3b/4 glecaprevir/pibrentasvir studies.
●
Update Section 5.1, Overall Study Design and Plan:  Description, Table 7, 
Treatment Arm Allocation in Study M15-942, and Section 8.2, Determination 
of Sample Size.
Rationale:  Updated the study's sample size and the distribution of subjects in 
each treatment arm to allow for subjects experiencing virologic failure in 
AbbVie's Phase 3b/4 glecaprevir/pibrentasvir studies to also be enrolled in 
Study M15-942.
●
Update Section 5.1, Overall Study Design and Plan: Description, Section 5.5.4, 
Selection and Timing of Dose for Each Subject, and Table 8, Ribavirin Dosing 
Recommendations
Rationale:  Updated the section and added a table to include RBV dosing 
recommendations for adolescent subjects based on their baseline age and 
weight.  
●
Update Section 5.1, Overall Study Design and Plan: Description, Table 7.
Rationale:  Added a footnote to clarify in which arm subjects with mixed and 
unknown HCV genotypes will be enrolled in.
●
Update Section 5.1.1, Screening, Section 5.3.1.1, Study Procedures, Section 
5.3.2.1, Collection of Samples for Analysis, Section 5.3.2.2, 
Handling/Processing of Samples, Section 5.3.2.3, Disposition of Samples, 
Section 5.3.2.4, Measurement Methods, and Appendix C, Study Activities –
Treatment Period
Rationale:  Updated the sections to remove collection of dosing information 
for HIV ARV and collection/analysis of HIV ARV PK samples because 
sufficient data regarding the PK of these agents when co-administered with 
glecaprevir/pibrentasvir is now available.
●
Update Section 5.1.1.1, Rescreening, Section 5.6.4.2, Rationale for Duration 
Selections, Section 8.1, Statistical and Analytical Plans, and Section 8.1.2.3
Sensitivity Analysis
Rationale:  Given the demonstrated pan-genotypic activity of the 
glecaprevir/pibrentasvir combination, subjects infected with more than 


ABT-493/ABT-530
M15-942 Protocol Amendment 2
EudraCT 2016-002491-26
4
one HCV genotype are being allowed.  Statistical analyses have been updated 
to include these subjects.  Section was also updated to be consistent with other 
sections of the protocol.
●
Update Section 5.2.1, Inclusion Criteria, Section 5.2.2, Exclusion Criteria, 
Section 5.2.4, Contraception Recommendations, Section 5.3.1, Study 
Procedures, Section 6.1.6, Pregnancy, and Appendix C, Study Activities –
Post-Treatment (PT) Period
Rationale:  Updated the sections to clarify that the more restrictive approach 
to contraception between the local RBV label and the protocol language 
should be used.
●
Update Section 5.2.2, Exclusion Criteria, Section 6.1.8, Collection of Data 
Regarding Known AIDS-Defining Conditions, and Appendix D, List of AIDS-
Defining Conditions
●
Rationale:  Updated the abbreviation for AIDS-Defining Conditions 
throughout the protocol and the list of AIDS-Defining Conditions.
●
Update Section 5.2.2, Exclusion Criteria, Criterion 20.
Rationale:  Added a new exclusion criterion to clarify that subjects who have 
documented HCV reinfection after receiving glecaprevir/pibrentasvir in the 
parent AbbVie study are not eligible for this study, since they are essentially 
treatment-naïve for the new infection.
●
Update Section 5.2.3, Prior and Concomitant Therapy.
Rationale:  Updated guidance for medications taken during the treatment and 
post-treatment period.
●
Update Section 5.2.3.4, Prohibited Therapy, Table 9, Medications and 
Supplements Prohibited with ABT-493/ABT-530 Administration.
Rationale:  Updated the section text and Table 9 footnote to require the 
investigator to discontinue any medications or supplements based on the most 
recent drug interaction data.  Guidance for investigators for prohibited 
medications or supplements administered with ABT-493/ABT-530 was also 
provided.  Ethinyl estradiol was added to the table.  Added progestogen in the 
section to be consistent with the language in the AbbVie protocol template.


ABT-493/ABT-530
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EudraCT 2016-002491-26
5
●
Update Section 5.3.1.1, Study Procedures, Hepatocellular Carcinoma 
Screening:  Liver Ultrasound.
Rationale:  Updated language to ensure all cirrhotic subjects will have a 
protocol required liver ultrasound result for the last post-treatment visit, in 
order to determine more accurately if the subject was HCC-free during the 
course of the observation period.
●
Update Section 5.3.2.1, Collection of Samples for Analysis.
Rationale:  To clarify pharmacokinetic samples are not to be collected on 
Day 1 and dosing on Week 4 is not required to occur at the site. 
●
Update Section 5.4.1.1, HCV Virologic Failure Criteria.
Rationale:  The section was re-written to clarify the HCV virologic failure 
criteria and that cases of confirmed HCV reinfection, for which a definition 
was provided, are excluded from the definition of relapse. 
●
Update Section 5.5.1, Treatments Administered.
Rationale:  Updated the section for clarity and to rectify when dosing is to be 
administered at site.  In addition, text was added to guide the exceptional use 
of commercial supplies in the study. 
●
Update Section 5.6.4.1, Rationale for Dose Selections.
Rationale:  Deleted the fourth paragraph as the information is not relevant to 
this protocol. 
●
Update Section 5.2.4, Contraception Recommendations, Section 6.0, 
Complaints, Section 6.1.3, Relationship to Study Drug, Section 6.1.5, Adverse 
Event Reporting, Section 6.2.2, Reporting, Section 7.0, Protocol Deviations, 
Section 9.1, Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB), Section 9.3, Subject Information and Consent, Section 10.1, 
Source Documents, and Section 13.0, Completion of the Study
Rationale:  Language was updated, per the latest AbbVie protocol template. 
●
Update Section 6.1.7.5, Management of Increases in ALT.
Rationale:  Updates were made to specify the minimum requirements for 
laboratory assessment of ALT elevations and the criteria for study drug 
discontinuation.  Updated the section by deleting anti-hepatitis A virus 


ABT-493/ABT-530
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immunoglobulin test and replacing it with anti-hepatitis A virus total test as a 
result of an error in the original list of tests.  
●
Update Section 8.1, Statistical and Analytical Plans.
Rationale:  To specify that an interim analysis may be conducted as part of 
regulatory authority interactions. 
●
Update Section 8.1.2.1, Primary Efficacy Endpoints.
Rationale:  The text was updated to comply with Regulatory Authority 
feedback, which requested that, for high SVR12 rates that are less than 100%, 
the Wilson score test be used for calculating the 95% confidence interval in 
the primary efficacy analysis, rather than using the normal approximation to 
the binomial distribution.  
●
Update Appendix B, List of Protocol Signatories
Rationale:  Updated to reflect changes in signatories.
●
Update Appendix C, Study Activities.
Rationale:  Updated the tables and footnotes to be consistent with the changes 
made in the body of the protocol text.
●
Incorporated Protocol Administrative Change 1.
Rationale:  In accordance with AbbVie's protocol preparation procedures.
●
Minor clerical updates/typographical correction made throughout the protocol.
Rationale:  Revised text to correct typographical errors, improve consistency 
and readability throughout the protocol.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix E.


ABT-493/ABT-530
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EudraCT 2016-002491-26
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-942
Name of Study Drug:  ABT-493/ABT-530, 
sofosbuvir (SOF), ribavirin (RBV)
Phase of Development:  3b
Name of Active Ingredient:  ABT-493/ABT-530, 
SOF, RBV
Date of Protocol Synopsis:  06 November 2017
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of 
ABT-493/ABT-530 in Combination with Sofosbuvir and Ribavirin in Chronic Hepatitis C (HCV) 
Infected Subjects Who Have Experienced Virologic Failure in AbbVie HCV Clinical Studies 
(MAGELLAN-3)
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving a 12-week post-treatment sustained virologic failure response (SVR12) in 
each treatment arm and safety of ABT-493/ABT-530 plus SOF and RBV in adults or 
adolescents with chronic HCV GT1-6 infection who previously failed HCV treatment in an 
AbbVie HCV clinical study, designated as an AbbVie HCV parent study.  
!
Secondary objectives are to assess the percentage of subjects with HCV on-treatment virologic 
failure, and the percentage of subjects with HCV virologic relapse. 
Investigators:  Multicenter; investigator information on file at AbbVie
Study Sites:  Approximately 40 sites who participated in an AbbVie HCV parent study.  
Study Population:  Subjects who have experienced virologic failure after receiving regimens containing 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have experienced virologic failure 
during or after receiving ombitasvir/paritaprevir/r + dasabuvir (3D), ombitasvir/paritaprevir/r (2D) in an 
AbbVie HCV parent study may be enrolled at AbbVie's discretion.
Number of Subjects to be Enrolled:  Approximately 50 subjects.


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Methodology:
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy and safety of 
ABT-493/ABT-530 in combination with SOF and RBV in HCV GT1 – 6-infected subjects including 
subjects with compensated cirrhosis and/or HIV-1 coinfection who have experienced virologic failure 
while participating in an AbbVie HCV parent study.  Approximately 50 subjects will be enrolled.  
Treatment arm allocation will be based on HCV genotype, cirrhosis status, and treatment experience 
with protease inhibitor (PI) and/or NS5A inhibitor (NS5Ai)-containing regimens prior to enrolling in the 
AbbVie HCV parent study.
Treatment Arm Allocation in Study M15-942
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI- and/or NS5Ai-exp 
Prior to the AbbVie 
HCV Parent Study
1, 2, 4, 5 and/or 6
NC
No
A
3
Any
Any
B
Any 
C
Any
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic
**
If the subject's HCV GT at Screening is unknown, or if it is mixed and includes GT3, then the subject will be 
assigned to Arm B (16 weeks), regardless of the cirrhosis status or PI and/or NS5Ai use prior to the AbbVie 
HCV Parent Study.
!
Arm A:  Subjects will receive orally ABT-493/ABT-530 300/120 mg QD, SOF 400 mg QD, 
RBV 600 mg to 1200 mg daily in two divided doses (based on baseline age and weight) for 
12 weeks
!
Arm B:  Subjects will receive orally ABT-493/ABT-530 300/120 mg QD, SOF 400 mg QD, 
RBV 600 mg to 1200 mg daily in two divided doses (based on baseline age and weight) for 
16 weeks
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 45 subjects.  All 
subjects administered at least one dose of study drugs will be followed for 24 weeks in the Post-
Treatment Period to monitor HCV RNA and to evaluate efficacy and the emergence and/or persistence 
of resistance-associated viral variants.
Planned visits in the Treatment Period consist of Day 1, Weeks 2, 4, 8, and 12 for all subjects and an 
additional Week 16 visit for subjects in Arm B.  During the Post-Treatment Period, subjects will have 
visits at Post-Treatment Weeks 4, 12, and 24.  Efficacy and safety data will be monitored throughout the 
study.  As this is an open-label study, safety will be reviewed by AbbVie.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female subjects must be adults (18 years of age or older) or adolescents (12 to less than 
18 years of age weighing at least 35 kg).  
2.
Subject must have experienced virologic failure during or after treatment with ABT-493/ABT-530 
in an AbbVie HCV parent study.  Subjects who have experienced virologic failure during or after 
receiving ombitasvir/paritaprevir/r + dasabuvir (3D), or ombitasvir/paritaprevir/r (2D) in an AbbVie 
HCV parent study may be enrolled at AbbVie's discretion.  Treatment in the parent study must have 
been completed or discontinued at least 1 month prior to the Screening Visit.
3.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements.
4.
Cirrhotic Subjects must have compensated cirrhosis, (Child-Pugh score of ≤ 6) at Screening and no 
current or past evidence of Child-Pugh B or C Classification or no clinical history of liver 
decompensation, including ascites noted on physical exam, hepatic encephalopathy or esophageal 
variceal bleeding.
5.
Cirrhotic Subjects must have absence of hepatocellular carcinoma (HCC) as indicated by a negative 
ultrasound (US), computed tomography (CT) scan or magnetic resonance imaging (MRI) within 
3 months prior to Screening or a negative US at Screening.
Main Exclusion:
1.
History of severe, life-threatening or other clinically significant sensitivity to any study drug or 
drug component.
2.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study or for 4 months after the last dose of study drug, or as directed per the local RBV label, 
whichever is more restrictive.
3.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol in the opinion of the investigator, and failure in an AbbVie 
HCV parent study due to non-virologic reasons.
4.
Positive test result at Screening for hepatitis B surface antigen (HBsAg).
5.
Screening laboratory analyses showing calculated creatinine clearance < 30 mL/min.
6.
Discontinuation from the AbbVie HCV parent study for reasons other than virologic failure 
(e.g., non-adherence, lost to follow-up, and/or the occurrence of an adverse event).
7.
Receipt of any HCV treatment after failing the treatment regimen in the AbbVie HCV parent study.


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Investigational Products:
ABT-493/ABT-530 mg 100 mg/40 mg Film-coated Tablet 
Sofosbuvir 400 mg Film-coated Tablet
Ribavirin 200 mg Film-coated Tablet
Doses:
ABT-493/ABT-530:  300 mg/120 mg QD (3 tablets)
Sofosbuvir:  400 mg QD (1 tablet)
Ribavirin:  
!
For subjects aged 18 or more:  1000 mg or 1200 mg daily in 
two divided doses
!
For subjects 12 less than 18 years old:  600 mg to 1200 mg 
daily in two divided doses
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Dose:
N/A
Mode of Administration:
N/A
Duration of Treatment:  12 or 16 weeks.
Criteria for Evaluation:
Efficacy:
Efficacy will be assessed utilizing plasma HCV RNA levels throughout the study.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects receiving study drug 
with available samples, the variants at baseline at signature resistance-associated amino acid positions 
relative to the appropriate prototypic reference sequence; and 2) for subjects who do not achieve SVR12
and who have a post-baseline sample, all treatment-emergent variants relative to baseline.
Pharmacokinetic:
Individual plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF 
(GS-331007), and RBV will be tabulated and summarized.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.


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Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug) in each treatment arm and overall.  The primary 
endpoint will be analyzed based on intention to treat (ITT) population.  The number and percentage of 
subjects achieving SVR12 will be summarized along with a two-sided 95% confidence interval using the 
normal approximation to the binomial distribution, unless the number of virologic failures is less than 5, 
then the Wilson's score method will be used for the confidence interval instead.
The secondary efficacy variables are:
!
The percentage of subjects with on-treatment HCV virologic failure in each treatment arm and 
overall;
!
The percentage of subjects with post-treatment HCV virologic relapse in each treatment arm 
and overall.
The number and percentage of subjects meeting each secondary efficacy endpoint will be summarized 
along with a two-sided 95% confidence interval using the Wilson score method.  Analyses of additional 
efficacy endpoints and efficacy subgroup analyses will be performed.
Resistance:
For all subjects receiving study drugs and with available samples, the variants at signature resistance-
associated amino acid positions at baseline identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drugs who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
variants in available post-baseline samples identified by NGS and comparison to the baseline sequence, 
2) the amino acid variants in available post-baseline samples at signature resistance-associated positions 
identified by NGS and comparison to the appropriate prototypic reference sequence, and 3) the 
persistence of viral variants by NGS.
Pharmacokinetic:
Plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF (GS-331007), and RBV 
will be tabulated for each subject and treatment arm.  Summary statistics will be computed for each 
treatment arm.
Safety:
All subjects who receive at least one dose of study drugs will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Safety summaries will be provided by treatment arm and overall.  The number and percentage of 
subjects with treatment-emergent adverse events (i.e., any event that begins or worsens in severity after 
initiation of study drug) will be tabulated by MedDRA System Organ Class (SOC) and preferred term 
(PT).  The tabulation of the number of subjects with treatment-emergent adverse events also will be 
provided by grade and relationship to study drug.  Change from baseline in laboratory tests and vital 
signs measurements to each time point of collection will be summarized, and values that are potentially 
clinically significant, according to predefined criteria, will be summarized by treatment arm and overall.


ABT-493/ABT-530
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
2D
Paritaprevir/ritonavir/ombitasvir
3D
Paritaprevir/ritonavir/ombitasvir + dasabuvir
3TC
Lamivudine
Ab
Antibody
ABC
Abacavir
ABT-450
Paritaprevir
ADC
AIDS-Defining Conditions
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APRI
Aminotransferase/platelet ratio index
aPTT
Activated partial thromboplastin time 
ART
Antiretroviral Treatment
AST
Aspartate aminotransferase
BID
Twice Daily
BMI
Body Mass Index
BOC
Boceprevir
BUN
Blood urea nitrogen
CBP
Childbearing potential
COBI
Cobicistat
CrCl
Creatinine clearance
CRF
Case report form
CT
Computed Tomography
DAA
Direct-acting antiviral agent
D/C
Discontinuation
DCV
Daclatasvir
DNA
Deoxyribonucleic acid
DRV
Darunavir
DSV
Dasabuvir
DTG
Dolutegravir
EC
Ethics Committee


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ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EU
European Union
EVG
Elvitegravir
FDV
Faldaprevir
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GAM
Generalized additive method
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
Hemoglobin A1c
Glycated hemoglobin
HIV
Human immunodeficiency virus
HIV-1
Human immunodeficiency virus type 1
HIV-2
Human immunodeficiency virus type 2
HIV Ab
Human immunodeficiency virus antibody
HCC
Hepatocellular carcinoma
ICH
International Council on Harmonisation
IEC
Independent ethics committee
IFN
Interferon
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International units
IUD
Intrauterine device
LDV
Ledipasvir
LLOD
Lower limit of detection


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LLOQ
Lower limit of quantification
LPV
Lopinavir
LPV/r
Lopinavir and ritonavir
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NGS
Next generation sequencing
NS3A
Nonstructural viral protein 3A
NS4A
Nonstructural viral protein 4A
NS5A(i)
Nonstructural viral protein 5A (inhibitor)
NS5B(i)
Nonstructural viral protein 5B (inhibitor)
OTVF
On-treatment Virologic Failure 
PegIFN
Pegylated-interferon alfa-2a or alfa-2b
PegIFN/RBV
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin
PI
Protease Inhibitor
POR
Proof of Receipt
PR
pegInterferon and ribavirin
PT
Post-Treatment/preferred term
QD
Once daily
RAL
Raltegravir
RBC
Red blood cells
RBV
Ribavirin
RDV
Ravidasvir
RNA
Ribonucleic acid
RPV
Rilpivirine
RTV or r
Ritonavir
SAE
Serious adverse event
SAM
S-adenosyl-L-methionine
SD
Standard Deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMV
Simeprevir
SOF
Sofosbuvir
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response


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SVR4
Sustained virologic response 4 weeks post dosing
SVR12
Sustained virologic response 12 weeks post dosing
SVR24
Sustained virologic response 24 weeks post dosing
TAF
Tenofovir alafenamide
TA MD
Therapeutic Area Medical Director
TA SD
Therapeutic Area Scientific Director
TDF
Tenofovir disoproxil fumarate
TVR
Telaprevir
ULN
Upper limit of normal
US
Ultrasound
WBC
White blood cells
Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
AUC0-24
AUC for the 24-hour dosing interval
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
NONMEM
Non-linear mixed-effect modeling
PK
Pharmacokinetic
Tmax
Time to maximum observed plasma concentration (Cmax)
V/F
Apparent Volume of distribution
Definition of Terms
Study Drug
ABT-493, ABT-530, Sofosbuvir and Ribavirin
Study Day 1
First day of study drug dosing 
AbbVie HCV Parent Study
The most recent AbbVie study in which a subject experienced virologic 
failure prior to entering Study M15-942
Treatment Period
Day 1 through last dose of study drug
Post-Treatment Period
Day after the last dose of study drug through Post-Treatment Week 24 or 
Post-Treatment Discontinuation


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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................................................................................................. 7
1.3
List of Abbreviations and Definition of Terms...................................... 12
2.0
Table of Contents ................................................................ 16
3.0
Introduction......................................................................... 21
3.1
Differences Statement .......................................................................... 32
3.2
Benefits and Risks................................................................................ 32
4.0
Study Objective ................................................................... 34
5.0
Investigational Plan.............................................................34
5.1
Overall Study Design and Plan:  Description ........................................ 34
5.1.1
Screening ............................................................................................. 37
5.1.1.1
Rescreening.......................................................................................... 37
5.1.2
Treatment Period.................................................................................. 38
5.1.3
Post-Treatment Period.......................................................................... 39
5.2
Selection of Study Population............................................................... 40
5.2.1
Inclusion Criteria.................................................................................. 40
5.2.2
Exclusion Criteria................................................................................. 43
5.2.3
Prior and Concomitant Therapy............................................................ 46
5.2.3.1
Prior HCV Therapy .............................................................................. 47
5.2.3.2
Prior and Concomitant HIV-1 Therapy................................................. 47
5.2.3.3
Other Concomitant Therapy ................................................................. 47
5.2.3.4
Prohibited Therapy............................................................................... 48
5.2.4
Contraception Recommendations ......................................................... 50
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 52
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 52
5.3.1.1
Study Procedures.................................................................................. 52
5.3.1.2
Meals and Dietary Requirements.......................................................... 64
5.3.1.3
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples................................................................................. 64


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5.3.2
Drug Concentration Measurements....................................................... 65
5.3.2.1
Collection of Samples for Analysis....................................................... 65
5.3.2.2
Handling/Processing of Samples........................................................... 65
5.3.2.3
Disposition of Samples......................................................................... 65
5.3.2.4
Measurement Methods ......................................................................... 66
5.3.3
Efficacy Variables................................................................................ 66
5.3.3.1
Primary Variable .................................................................................. 66
5.3.3.2
Secondary Variables............................................................................. 66
5.3.4
Resistance Variables............................................................................. 66
5.3.5
Safety Variables ................................................................................... 67
5.3.6
Pharmacokinetic Variable..................................................................... 67
5.3.7
Pharmacogenetic Exploratory Research Variables ................................ 67
5.4
Removal of Subjects from Therapy or Assessment ............................... 68
5.4.1
Discontinuation of Individual Subjects ................................................. 68
5.4.1.1
HCV Virologic Failure Criteria ............................................................ 69
5.4.1.2
Failure to Maintain HIV Virologic Suppression.................................... 70
5.4.2
Discontinuation of Entire Study............................................................ 71
5.5
Treatments ........................................................................................... 71
5.5.1
Treatments Administered...................................................................... 71
5.5.2
Identity of Investigational Products ...................................................... 72
5.5.2.1
Packaging and Labeling........................................................................ 72
5.5.2.2
Storage and Disposition of Study Drug................................................. 73
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 73
5.5.4
Selection and Timing of Dose for Each Subject .................................... 74
5.5.5
Blinding ............................................................................................... 74
5.5.6
Treatment Compliance ......................................................................... 74
5.5.7
Drug Accountability ............................................................................. 75
5.6
Discussion and Justification of Study Design........................................ 76
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 76
5.6.2
Appropriateness of Measurements........................................................ 76
5.6.3
Suitability of Subject Population .......................................................... 77
5.6.4
Selection of Doses in the Study ............................................................ 77
5.6.4.1
Rationale for Dose Selections............................................................... 77


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5.6.4.2
Rationale for Duration Selections ......................................................... 78
6.0
Complaints........................................................................... 80
6.1
Medical Complaints ............................................................................. 81
6.1.1
Definitions ........................................................................................... 81
6.1.1.1
Adverse Event...................................................................................... 81
6.1.1.2
Serious Adverse Events........................................................................ 82
6.1.2
Adverse Event Severity ........................................................................ 83
6.1.3
Relationship to Study Drug................................................................... 84
6.1.4
Adverse Event Collection Period.......................................................... 85
6.1.5
Adverse Event Reporting...................................................................... 86
6.1.6
Pregnancy............................................................................................. 87
6.1.7
Toxicity Management........................................................................... 88
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities and/or Adverse Events ............ 89
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities ................................................ 89
6.1.7.3
Grade 3 or 4 Adverse Events or Serious Adverse Events ...................... 90
6.1.7.4
Management of Decreases in Hemoglobin for Subjects Receiving 
RBV..................................................................................................... 90
6.1.7.5
Management of Increases in ALT......................................................... 93
6.1.7.6
Management of Reductions in Creatinine Clearance for Subjects 
Receiving RBV .................................................................................... 93
6.1.8
Collection of Data Regarding Known AIDS-Defining Conditions ........ 95
6.2
Product Complaint................................................................................ 95
6.2.1
Definition............................................................................................. 95
6.2.2
Reporting ............................................................................................. 96
7.0
Protocol Deviations ............................................................. 96
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 97
8.1
Statistical and Analytical Plans............................................................. 97
8.1.1
Demographics ...................................................................................... 98
8.1.2
Efficacy................................................................................................ 99
8.1.2.1
Primary Efficacy Endpoints.................................................................. 99
8.1.2.2
Secondary Efficacy Endpoints.............................................................100
8.1.2.3
Sensitivity Analysis.............................................................................100


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8.1.2.4
Subgroup Analysis ..............................................................................100
8.1.2.5
Additional Efficacy Endpoints.............................................................102
8.1.3
HCV Resistance Analyses ...................................................................102
8.1.4
HIV Resistance Analyses ....................................................................105
8.1.5
Safety..................................................................................................105
8.1.5.1
Adverse Events....................................................................................105
8.1.5.2
Clinical Laboratory Data .....................................................................106
8.1.5.3
Vital Signs Data ..................................................................................106
8.1.5.4
HCV/HIV-1 Co-Infection....................................................................107
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................107
8.2
Determination of Sample Size .............................................................109
8.3
Randomization Methods......................................................................109
9.0
Ethics.................................................................................. 110
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................110
9.2
Ethical Conduct of the Study...............................................................110
9.3
Subject Information and Consent.........................................................111
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 112
10.1
Source Documents...............................................................................112
10.2
Case Report Forms..............................................................................112
11.0
Data Quality Assurance .................................................... 113
12.0
Use of Information ............................................................ 113
13.0
Completion of the Study ................................................... 114
14.0
Investigator's Agreement.................................................. 115
15.0
Reference List.................................................................... 116
List of Tables
Table 1.
In Vitro Antiviral Activity of ABT-493 and Other Protease 
Inhibitors Against HCV Genotypes 1, 2, 3, 4, and 6.............................. 22
Table 2.
Anti-Viral Activity of ABT-493 and Other PIs Against Common 
HCV GT1 NS3 Single-Position Variants .............................................. 23


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Table 3.
In vitro Antiviral Activity of ABT-530 and Other NS5A Inhibitors 
Against HCV Genotypes 1 through 6.................................................... 24
Table 4.
Anti-Viral Activity of ABT-530 and Other NS5A Inhibitors 
Against Common HCV GT1 NS5A Single-Position Variants ............... 24
Table 5.
SVR Rates Observed in HCV-Mono-Infected and HCV/HIV-1 
Co-Infected Patients Treated with All-Oral HCV DAA Regimens ........ 27
Table 6.
SVR12 Rates of ABT-493/ABT-530 300 mg/120 mg in the 
Phase 2 Studies M14-867, M14-868 and M15-410 ............................... 30
Table 7.
Treatment Arm Allocation in Study M15-942....................................... 35
Table 8.
Ribavirin Dosing Recommendations..................................................... 36
Table 9.
Medications and Supplements Prohibited with 
ABT-493/ABT-530 Administration...................................................... 49
Table 10.
Clinical Laboratory Tests ..................................................................... 56
Table 11.
Child-Pugh (Child-Turcotte-Pugh) Classification of Severity of 
Cirrhosis............................................................................................... 60
Table 12.
Identity of Investigational Products ...................................................... 72
Table 13.
Management of Hemoglobin Decreases................................................ 92
List of Figures
Figure 1.
Study Schematic (Treatment Period) .................................................... 35
Figure 2.
Adverse Event Collection..................................................................... 86
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................122
Appendix B.
List of Protocol Signatories .................................................................124
Appendix C.
Study Activities...................................................................................125
Appendix D.
List of AIDS-Defining Conditions.......................................................130
Appendix E.
Protocol Amendment:  List of Changes ...............................................132


ABT-493/ABT-530
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3.0
Introduction
Hepatitis C virus (HCV) infection is a global health problem, with over 
170 million individuals infected worldwide.1  There are six major HCV genotypes (GT), 
GT1 to GT6, and each genotype expresses a distinct epidemiological pattern across the 
world.  Patients with chronic HCV infection are at high risk of developing cirrhosis, death 
related to the complications of cirrhosis, and developing hepatocellular carcinoma.2  
Successful treatment of HCV was shown to significantly reduce the risk of disease 
progression and related mortality as well as the development of hepatocellular 
carcinoma.3,4
Currently approved IFN-free and, in some cases, RBV-free DAA combination regimens, 
such as sofosbuvir (SOF)/ledipasvir (LDV), ombitasvir/paritaprevir/ritonavir with (3D) or 
without (2D) dasabuvir, SOF and daclatasvir (DCV), and elbasvir/grazoprevir represent 
substantial progress in the treatment of HCV infection.  These regimens are associated 
with significant improvement of the sustained virologic response (SVR) rate and safety 
profile in the approved patient populations.  However, these IFN-free regimens are not 
equally potent across all HCV genotypes and subtypes, and across all subpopulations.  
They may require co-administration with RBV in some sub-populations.
The next generation DAA regimens have high potencies across all HCV genotypes and 
across patient subpopulations, including Abbvie's ABT-493/ABT-530 or 
glecaprevir/pibrentasvir (GLE/PIB).  GLE/PIB is approved in some parts of the world, 
including Europe and the United States, under the brand name MAVIRET® or 
MAVYRET™, respectively.
ABT-493 (NS3/4A protease inhibitor [PI]) and ABT-530 (NS5A inhibitor [NS5Ai]) are 
denoted as next generation compounds because they each demonstrated potent pan-
genotypic antiviral activity against all major HCV genotypes, i.e., GT1 through GT6 and 
they are potent against known common single resistance-associated amino acid variants 
with no or little loss of potency.


ABT-493/ABT-530
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EudraCT 2016-002491-26
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ABT-493
ABT-493 is an NS3/4A protease inhibitor (PI) with potent, pangenotypic activity and a 
high barrier to resistance with activity against common variants that emerge following 
exposure to first generation PIs.  AbbVie is developing ABT-493 to be used in 
combination with the NS5A inhibitor ABT-530 for the treatment of chronic HCV 
infection.  ABT-493 is highly active against replicons containing wild-type HCV NS3 
from GT1, 2, 3, 4, and 6.  ABT-493 activity against GT5 NS3 is unknown because a 
replicon with GT5 NS3 is not currently available (Table 1).  Based on findings that each 
of 5 well characterized HCV PIs, including 2 linear and 3 macrocyclic PIs, demonstrated 
similar activity against GT2a, 5a, and 6a NS3 protease,5 it is predicted ABT-493 would 
inhibit NS3 protease of GT5a with activity similar to that of GT2a and 6a.
Table 1.
In Vitro Antiviral Activity of ABT-493 and Other Protease 
Inhibitors Against HCV Genotypes 1, 2, 3, 4, and 6
Stable HCV Replicon EC50 (nM)
Protease Inhibitor
GT1a
GT1b
GT2a
GT3a
GT4a
GT6a
ABT-493
0.85
0.94
2.2a
1.9
2.8
0.86
Paritaprevir1
1.0
0.21
5.3a
19
0.09
0.68
Simeprevir2,3
13
9.4
15
472
NA
NA
Asunaprevir4
4.0
1.2
230
1162
NA
NA
Grazoprevir
0.38
0.87
1.3
36
1.2
0.89
GS-94515
13
5.4
316
NA
NA
NA
GS-98576
3.9
3.3
3.7
6.1
2.9
1.5
NA = not available
a.
Study conducted at Southern Research Institute.
1.
AbbVie.  Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir Investigator's Brochure Edition 1.  2016.6
2.
Simeprevir prescribing information.7
3.
Chase R, et al.  IAPAC, 2013.8
4.
McPhee F, et al.  AAC, 2012.9
5.
Yang H, et al.  AAC, 2014.10
6.
Taylor J, et al.  EASL, 2015.11


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ABT-493 retains activity against common GT1 NS3 single-position resistance-associated 
variants in comparison with other PIs as described in Table 2.
Table 2.
Anti-Viral Activity of ABT-493 and Other PIs Against Common 
HCV GT1 NS3 Single-Position Variants
HCV Transient Replicon EC50 (nM)
GT1a
GT1b
Inhibitor
Wild Type
R155K
D168A
D168V
Wild Type
R155K
D168V
ABT-493
0.28
0.16
0.84
0.93
0.54
0.32
1.3
Paritaprevir
1.4
51
70
135
0.11
4.4
17
Grazoprevir
0.3
0.9
29
11
0.4
0.5
5.9
Simeprevir
4.0
172
100
3120
11
260
17,920
Asunaprevir
0.76
16
17
283
0.86
23
241
References:  Chase R et al,8 Lenz O et al,12 McPhee F et al9
The pharmacokinetics of ABT-493 has been evaluated at doses up to 1200 mg QD.  
ABT-493 reached Tmax around 3 to 4 hours with an elimination half-life of 6 to 9 hours.  
ABT-493 exposures increased in a greater than dose proportional manner across the 
25 mg to 1200 mg dose range.  Orally administered ABT-493 was predominantly cleared 
through the biliary-fecal route.  The percentages of the ABT-493 dose recovered in urine 
were less than 4%.  No metabolite was identified in systemic circulation.
In summary, ABT-493 is a potent, pangenotypic PI with high potential for treatment of 
chronic HCV infection.  A detailed discussion of the preclinical toxicology, metabolism, 
and pharmacology and Phase I data can be found in the Investigator's Brochure.13
ABT-530
ABT-530 is an NS5A inhibitor (NS5Ai) with potent, pangenotypic activity and a high 
barrier to resistance with activity against common variants that emerge following 
exposure to first generation NS5Ai.  ABT-530 is highly active against HCV replicons 
containing wild-type HCV NS5A from GT1, 2, 3, 4, 5, and 6 (Table 3).


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Table 3.
In vitro Antiviral Activity of ABT-530 and Other NS5A Inhibitors 
Against HCV Genotypes 1 through 6.
Stable HCV Replicon EC50 (pM)
NS5A Inhibitor
GT1a
GT1b
GT2a
GT2b
GT3a
GT4a
GT5a
GT6a
ABT-530
2
4
2a
2
2
2
1
3
Ombitasvir
14
5
12
4
19
2
3
366
Daclatasvir
22
3
13,000
NA
530
13
5
74
Ledipasvir
31
4
21,000
16,000
168,000
390
150
1100
Velpatasvir
12
15
9
8
12
9
75
6
Elbasvir
4
3
3
3000
20
3
1
3
MK-8408
1
2
1
4
2
2
1
4
NA =  not available
a.
Study conducted at Southern Research Institute. 
References:
Wang C, et al. AAC, 2014;14 Cheng G, et al. EASL, 2012;15 Harvoni prescribing information;16
Cheng G, et al. EASL, 2013;17 Liu R, et al. EASL, 2012;18 Asante-Appiah E, AASLD, 201419
ABT-530 retains activity against common single resistance-associated amino acid variants 
in NS5A (Table 4).  ABT-530 is > 100-fold more active than the first generation NS5Ai 
(ombitasvir, daclatasvir, and ledipasvir) against key resistance-associated variants selected 
by these inhibitors in the clinic at GT1 NS5A amino acid positions 28, 30, 31, and 93.  Its 
genetic barrier to resistance is higher than that of ombitasvir across all GTs.
Table 4.
Anti-Viral Activity of ABT-530 and Other NS5A Inhibitors Against 
Common HCV GT1 NS5A Single-Position Variants
HCV Replicon EC50 (pM)
GT1a
GT1b
Inhibitor
Wild Type
M28T
Q30R
L31M
Y93H
Wild Type
Y93H
Y93N
ABT-530
0.72
1.5
1.2
0.76
4.8
2.2
1.4
1.0
Ombitasvir
2.7
24,500
2180
4.8
> 100,000
0.79
60
167
Daclatasvir
6.0
4050
7300
2020
32,200
2.5
62
74
Ledipasvir
51
1801
12,420
14,610
86,430
4.0
5200
NA
References:  Fridell RA et al,20 Wong KA et al21


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The pharmacokinetics of ABT-530 has been evaluated at doses up to 600 mg QD.  
ABT-530 reached a Tmax around 3 to 5 hours, with an elimination half-life of 12 to 
17 hours.  ABT-530 exposures increased in a greater than dose-proportional manner 
across the 1.5 mg to 120 mg dose range and approximately dose proportionally from the 
120 mg to 600 mg single doses.  ABT-530 undergoes minimum renal elimination.  Orally 
administered ABT-530 was predominantly cleared through the biliary-fecal route as 
unchanged parent drug.
In summary, ABT-530 is a potent, pangenotypic NS5Ai with high potential for treatment 
of chronic HCV infection.  A detailed discussion of the preclinical toxicology, 
metabolism, and pharmacology and Phase 1 data can be found in the Investigator's
Brochure.13
ABT-493 and ABT-530
When ABT-493 was given in combination with ABT-530 in healthy volunteers, 
preliminary results showed ABT-493 exposures were not significantly changed when co-
administered with ABT-530 (≤ 31% difference); however, the exposure of ABT-530 
increased in an ABT-493-dose-dependent manner (from 1.5-fold at 100 mg ABT-493 up 
to 3- to 4-fold at 400 mg ABT-493).
Results of clinical DDI studies conducted to date have shown that as perpetrators of DDIs, 
ABT-493/ABT-530 combination had no clinically meaningful impact on drugs that are 
substrates of CYP or UGT enzymes.  The ABT-493/ABT-530 combination increased 
exposure of substrates for P-gp, BCRP, OATP1B1, and OATP1B3 transporters.  
Except for some OATP inhibitors (e.g., high dose cyclosporine), ritonavir-boosted 
protease inhibitors and P-gp inducers, ABT-493 and ABT-530 exposures were minimally 
affected by co-administrations of other drugs.  ABT-493 is a substrate of OATP and 
inhibition of OATP increases ABT-493 exposure.  When ABT-493 + ABT-530 was 
administered with cyclosporine (400 mg), an OATP inhibitor, ABT-493 exposure was up 
to 5.1-fold of DAAs alone.  The increased exposures observed were not associated with 


ABT-493/ABT-530
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clinically significant safety findings.  Protease inhibitors, as a class, have potential to 
inhibit OATP, thus larger exposure increases in ABT-493 with ritonavir boosted protease
inhibitors than with ritonavir alone may result from interaction of ABT-493 with both the 
protease inhibitor and ritonavir components.
ABT-493/ABT-530 possesses greater antiviral activity as compared to the 
ombitasvir/paritaprevir/ritonavir + dasabuvir regimen, while also maintaining adequate 
activity against variants that confer resistance to ombitasvir and paritaprevir.22-24
For a more detailed discussion of drug-drug interaction studies please refer to the 
Investigator's Brochure.13
HCV/HIV-1 Co-Infection
HCV and HIV-1 co-infection is associated with accelerated hepatic fibrosis progression 
and higher rates of liver decompensation and death compared to HCV monoinfection, and 
liver disease is a leading cause of non-AIDS-related mortality among HIV-1-infected 
patients.25-27  Treatment of HIV-1 with antiretroviral therapy and treatment of HCV have 
independently been shown to delay the progression of fibrosis and reduce complications 
from end-stage liver disease among co-infected patients.28,29
According to data from different trials, the effectiveness of DAA-based therapy appears to 
be similar between HCV mono-infected individuals and HCV/HIV-1 co-infected 
individuals, as shown in Table 5.30  Per the most recent AASLD treatment guidelines, it is 
recommended that HCV/HIV-1 co-infected patients be treated and re-treated the same as 
HCV mono-infected patients, albeit with attention paid to potential drug-drug interactions 
with anti-retroviral medications.31


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Table 5.
SVR Rates Observed in HCV-Mono-Infected and HCV/HIV-1 Co-
Infected Patients Treated with All-Oral HCV DAA Regimens
Study
Regimen, Duration, 
Population Studied
ITT SVR12 Rate in 
HCV/HIV-1 
Co-Infected 
Population
ITT SVR12 Rate in 
Similar HCV 
Mono-Infected 
Population (Study or 
Studies)
TURQUOISE-I32
Ombitasvir/Paritaprevir/ritonavir 
+ Dasabuvir + RBV, 12 weeks, 
GT1 HCV/HIV-1 Co-infection
94%
92% – 96% 
(SAPPHIRE-I and –II, 
TURQUOISE-II)33-35
ION-436
Sofosbuvir/Ledipasvir, 
12 weeks, GT1, 4 HCV/HIV-1 
Coinfection
96%
93% – 99% (ION-1, -2 
and -3)37-39
ALLY-240
Sofosbuvir + Daclatasvir, 
12 weeks, GT1 – 4 HCV/HIV-1 
Coinfection
97%
95% (A1444040)41
C-EDGE 
CO-INFECTION42
Grazoprevir/Elbasvir, 12 weeks, 
GT1, 4, 6 HCV/HIV-1 
Coinfection
96%
91% – 97% (C-EDGE 
TN, C-EDGE TE, 
C-WORTHY)43,44
ARV Drug-Drug Interaction Studies with ABT-493 and ABT-530
Phase 1 DDI studies of the ABT-493 + ABT-530 combination with HIV antiretroviral 
(ARV) drugs have been conducted in healthy volunteers and/or HIV-1 infected subjects.
The ABT-493 + ABT-530 combination had no clinically meaningful impact on the 
exposures (≤80%) of evaluated ARV regimens: ritonavir-boosted protease inhibitors 
(darunavir, lopinavir), rilpivirine, raltegravir, emtricitabine and tenofovir disoproxil 
fumarate (TDF).  ABT-493 and ABT-530 exposures were not affected by rilpivirine and 
raltegravir.  
Dolutegravir, lamivudine and abacavir (Triumeq®) coadministered with ABT-493 + 
ABT-530 has recently been evaluated in a DDI Study M15-584.  Coadministration was 
safe and well tolerated with mild side effects reported.  ABT-493 and ABT-530 had no 
impact on dolutegravir, lamivudine and abacavir exposures.  There was a mild decrease in 
ABT-493 and ABT-530 exposures of no clinical significance.


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Efavirenz induces P-gp and exposures of ABT-493 and ABT-530 in the presence of 
efavirenz were approximately 3- and 2-fold lower, respectively, and thus will not be 
allowed in this study.
When ABT-493 was administered with ritonavir, exposure of ABT-493 was 2-fold of 
ABT-493 exposure alone.  Coadministration of ABT-493 + ABT-530 with ritonavir 
boosted protease inhibitors, darunavir QD or lopinavir BID resulted in further increases in 
ABT-493 exposure of 3- to < 5-fold and < 2 fold exposure to ABT-530 without change in 
the LPV or DRV exposures.  In spite of the increase in ABT-493 exposures while 
coadministered with DRV/r or LPV/r, it was well tolerated, with mild side effects.  
Coadministration of ABT-493 + ABT-530 with ritonavir boosted atazanavir was studied 
in a DDI study that was terminated early due to an increase in ABT-493 exposure up to 
16-fold and ABT-530 exposure up to 3-fold with Grade 1 and 2 increases in alanine 
aminotransferase (ALT) and Grade 2 to 3 increase in total bilirubin (predominately 
indirect).  
Study M15-584 evaluated the drug interaction profile when ABT-493/ABT-530 
300 mg/120 mg is co-administered with Genvoya® (elvitegravir 150 mg, cobicistat 
150 mg, emtricitabine 200 mg, tenofovir alafenamide10 mg QD).  Co-administration was 
safe and well tolerated, with mild side effects reported and one grade 3 neutropenia 
deemed related to the combination of Genvoya, ABT-493 and ABT-530 in a black male 
subject with baseline low absolute neutrophil count (ANC), leading to premature study 
drug discontinuation.  The ABT-493 exposure increased 3-fold and the ABT-530 
exposure increased 57%, with non-clinically significant increase in elvitegravir and 
cobicistat exposures.  Thus, cobicistat boosted elvitegravir will be allowed in this study.  
In addition, ritonavir and cobicistat-boosted HIV-1 protease inhibitors (darunavir and 
lopinavir) will be allowed in the non-cirrhotic arm only.  These HIV-1 protease inhibitors 
will not be allowed in cirrhotic subjects, as the ABT-493 predicted exposures in this 
population approach the ALT 5% Grade 2 threshold.


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For a more detailed discussion of drug-drug interaction studies please refer to the 
Investigator's Brochure.13
Clinical Study Results
Studies M14-867 and M14-868 (data on file)13 are Phase 2 studies designed to assess the 
efficacy and safety of the combination of ABT-493 and ABT-530 in cirrhotic and non-
cirrhotic subjects with HCV GT1 – 6 infection following 8 or 12 weeks of administration.  
In these two studies, high SVR rates have been achieved for the combination of ABT-493 
and ABT-530 at the dose strength consistent with the Phase 3 doses, i.e., ABT-493 
300 mg and ABT-530 120 mg (Table 6).  In Studies M14-867 and M14-868, all subjects 
(N = 147) with HCV GT1, GT2, GT4, GT5 and GT6 infection have achieved SVR12, 
following 8 or 12 weeks of treatment and a high SVR12 rate of 96% has been achieved for 
GT3 infected subjects (107/111).
Study M15-410 is a Phase 2 study designed to assess the efficacy and safety of the 
combination of ABT-493 and ABT-530 in subjects who failed a prior DAA-containing 
therapy.  Prior DAA treatment regimens among enrolled include SOF/LDV (n = 8), SMV 
+ SOF ± RBV (n = 8), 3D ± RBV (n = 4), DSV + FDV + RDV ± RBV (n = 4), SAM + 
SMV (n = 2), TVR + PR (n = 8), BOC + PR (n = 10), DCV ± PR (n = 2).  The most 
common NS3 RAVs at baseline include Q80 (n = 22), R155 (n = 4), and D168 (n = 4), 
and the most common NS5A RAVs at baseline include Q30 (n = 14) and Y93 (n = 10).  
Six out of 6 subjects on ABT-493 200 mg and ABT-530 120 mg, and 20 out of 
22 subjects on ABT-493 300 mg and ABT-530 120 mg plus RBV 800 mg have achieved 
SVR12.  Twenty one out of 22 subjects (95%) who were treated with the ABT-493 300 mg 
and ABT-530 120 mg combination therapy have achieved SVR12.  A summary of the 
SVR rates of ABT-493/ABT-530 300 mg/120 mg in the Phase 2 Studies M14-867, 
M14-868 and M15-410 is presented in Table 6.


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Table 6.
SVR12 Rates of ABT-493/ABT-530 300 mg/120 mg in the Phase 2 
Studies M14-867, M14-868 and M15-410
Treatment 
Arms
M14-867 
Arm K
M14-868 
Arm A
M14-868 
Arm J
M14-868 
Arm D
M14-868 
Arm L
M14-868 
Arm O
M14-867 
Arm I
M15-410 
Arm C
Genotype
GT1
GT2
GT2
GT3
GT3
GT3
GT4, 
GT5, 
GT6
GT1
Cirrhotic
Yes
No
No
No
No
Yes
No
No
Total N
34
25
54
30
53
28
34
22
PR-Exp
5
3
7
3
24
4
5
-
DAA-Exp
0
0
0
0
0
0
0
22
Duration 
(Weeks)
8
12
8
12
8 (TN)/ 
12 (PR-
Exp)
12 (TN)/ 
16 (PR-
Exp)
12
12
SVR12
(Overall)
100%
100%
100%
97%
96%
96%
100%
95%
SVR12
(TN)
100%
100%
100%
100%
100%
100%
100%
-
SVR12
(TE^)
100%
100%
100%
67%
92%
75%
100%
95%
DAA-EXP = direct acting antiviral-experienced; PR-Exp = pegIFN/RBV experienced; SVR12 = sustained virologic 
response 12 weeks post-treatment; TN = Treatment Naïve; TE = Treatment-experienced
^
TE include pegIFN experienced (PR-Exp) or DAA-experienced.
The combination therapy of ABT-493 and ABT-530 is well tolerated and the most 
frequently reported adverse events were fatigue, nausea, and headache (occurring in > 5% 
of subjects) with the majority being Grade 1 or 2 in severity.  Among the 274 subjects
who received at least one dose of study drug in the Phase 2 studies, Studies M14-867 and 
M14-868, there were 4 (1.5%) treatment-emergent SAEs reported:  pneumonia, atrial 
fibrillation, B-cell lymphoma, and metastatic prostate cancer, and all assessed as having 
no reasonable possibility of being related to ABT-493 or ABT-530.  Two subjects (0.7%; 
2/274) discontinued due to treatment-emergent adverse events.  One subject with history 
of irritable bowel disease discontinued due to Grade 2 AE of abdominal pain assessed as 
having a reasonable possibility of being related to both the DAAs and RBV.  In all 
subjects with baseline ALT elevations in Studies M14-867 and M14-868, the ALT levels 


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were normalized or trended toward normal with DAA treatment, and there have been no 
on-treatment ALT elevations above baseline.
A total of 2,376 subjects were randomized or enrolled in the registrational studies or 
supportive Phase 2 studies to receive GLE 300 mg QD and PIB 120 mg QD.  Of these, 
2,369 subjects received at least 1 dose of study drug.
Sofosbuvir (SOF)
SOF is a nucleotide analog NS5B polymerase inhibitor active against all major genotypes.  
SOF is indicated for the treatment of chronic hepatitis C infection as a component of a 
combination antiviral treatment regimen.  The approved dose is 400 mg orally once daily, 
without regard to food.45  
A study to assess the PK and safety of co-administration of 400 mg QD SOF in 
combination with ABT-493 400 mg QD and ABT-530 120 mg QD in healthy subjects 
(Study M14-532) showed minimal effect (≤ 16% change in central values) on the steady-
state exposures of ABT-493 and ABT-530 compared to the administration of 
ABT-493/ABT-530 combination alone.  SOF Cmax and AUC0-24 central values were 
increased by 66% and 125%, respectively, compared to SOF alone, however, GS-331007 
Cmax and AUC0-24 were minimally affected (≤ 21% change in central values).
Comprehensive safety, efficacy and PK information is contained within the SOF 
USPI/SmPC/local label.
Ribavirin (RBV)
RBV is a guanosine analogue that has little or no effect on HCV RNA as monotherapy, 
but when combined with interferon-based therapies, RBV improves SVR rate over 
conventional or pegIFN monotherapy.46,47
RBV is a known teratogen (FDA category X).  Pregnancy should be avoided following 
RBV therapy (Refer to Section 6.1.6).  Comprehensive safety, efficacy and PK 
information is contained within the RBV USPI/SmPC/local label.


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3.1
Differences Statement
Study M15-942 is the first study to investigate ABT-493/ABT-530 in combination with 
SOF and RBV as a retreatment option for subjects infected with HCV GT1 – 6, with or 
without HIV-1 co-infection, who experienced virologic failure following treatment with 
ABT-493/ABT-530 in a previous AbbVie HCV clinical trial, designated as the AbbVie 
HCV parent study.  Subjects who have experienced virologic failure following treatment 
with 3D or 2D in an AbbVie HCV parent study may be enrolled at AbbVie's discretion.
3.2
Benefits and Risks
Benefits
Subjects who have experienced virologic failure following treatment with 
ABT-493/ABT-530, as well as treatment with 3D or 2D, are difficult patient populations 
to cure and need effective and safe options for retreatment.  Study M15-942 is designed to 
retreat these subjects with an intensified regimen that contains ABT-493, an NS3/4A 
inhibitor; ABT-530, an NS5A inhibitor; SOF, an NS5B inhibitor and RBV, for either 
12 weeks or 16 weeks.  
One of the potential benefits of retreatment with ABT-493/ABT-530 plus SOF and RBV 
is that the co-administration of drugs of distinct mechanisms of action can potently inhibit 
the viral replication of HCV variants present in DAA treatment-experienced subjects 
effectively, thus leading to a higher cure rate.
ABT-493/ABT-530 demonstrates excellent antiviral activity with high genetic barrier to 
development of drug resistance which has been translated into high SVR12 rates in clinical 
studies.  
The addition of SOF and RBV to ABT-493/ABT-530 provides additional mechanism(s) 
of action that may overcome resistant variants selected in subjects exposed to 
ABT-493/ABT-530 alone.  The longer treatment duration of 16 weeks for cirrhotic 
subjects, subjects with GT3 infection, and subjects who have previously failed a PI-


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and/or NS5Ai-containing regimen before experiencing virologic failure in an AbbVie 
HCV parent study is expected to improve the chances of achieving SVR12.
SVR rates among HCV/HIV-1 co-infected patients treated with new, all-oral HCV DAA 
regimens are comparable to those observed in HCV-monoinfected patients, and this 
similar efficacy finding is anticipated following treatment with ABT-493/ABT-530.  In 
addition, successfully treating these patients is expected to address the risk of increased 
disease progression in untreated HCV/HIV-1 co-infected patients (accelerated hepatic 
fibrosis progression and higher rates of liver decompensation and death compared to HCV 
monoinfection).  Also, liver disease is a leading cause of non-AIDS-related mortality 
among HIV-1-infected patients.25-27
Risks
The likelihood of successfully retreating HCV infection with ABT-493/ABT-530 plus 
SOF and RBV is not known.  
The safety profile of SOF and RBV are well established.  Adverse events that are known 
as well as those not previously described may occur with the combination of 
ABT-493/ABT-530 plus SOF and RBV, as detailed in the informed consent for this study.  
In addition, subjects may experience inconvenience or discomfort related to the study 
visits or study procedures.  Additional safety data for each drug alone and the combination 
of ABT-493/ABT-530 plus SOF and RBV are detailed in Section 3.0 and in the 
Investigator's Brochure or product package inserts.
Additional risks associated with ABT-493/ABT-530 plus SOF and RBV, including the 
risks of toxicity, virologic failure, and development of resistance-associated variants 
(Section 5.6.4), appear to be limited and manageable based upon the available data. 
Virologic failure criteria have been incorporated into the study to ensure subjects are 
exposed to appropriate durations of the regimen.  


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Given the potential benefits of expected high SVR12 rates in a population of subjects who 
failed multiple classes of DAAs, as well as the limited risks associated with the planned 
therapy, the risk-benefit assessment is favorable.
4.0
Study Objective
●
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving a 12-week post-treatment sustained virologic 
response (SVR12) in each treatment arm and safety of ABT-493/ABT-530 plus 
SOF and RBV in adults or adolescents with chronic HCV GT1 - 6 infection 
who previously failed HCV treatment in an AbbVie HCV clinical study, 
designated as an AbbVie HCV parent study.
●
Secondary objectives are to assess the percentage of subjects with HCV 
on-treatment virologic failure, and the percentage of subjects with HCV 
virologic relapse.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy 
and safety of ABT-493/ABT-530 in combination with SOF and RBV in HCV GT1 –
6-infected subjects, including subjects with compensated cirrhosis and/or HIV-1 
coinfection, who have experienced virologic failure while participating in an AbbVie 
HCV parent study.  
It is anticipated that approximately 50 HCV infected subjects who have experienced 
virologic failure following treatment with ABT-493/ABT-530 or 3D or 2D regimens in 
one of the AbbVie HCV parent studies will be enrolled. Besides meeting the eligibility 
criteria (Section 5.2), additional subject eligibility to enroll in Study M15-942 will be 
evaluated at the discretion of AbbVie based upon the characteristics of subject's HCV 
infection, prior treatment history, and the evolving data from on-going clinical studies.
A study schematic (Treatment Period) is shown below in Figure 1.


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Figure 1.
Study Schematic (Treatment Period)
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 
45 subjects.  Subjects will be allocated to one of two treatment arms based on HCV 
genotype, cirrhosis status, and treatment experience with PI and/or NS5Ai-containing 
regimens prior to enrolling in the AbbVie HCV parent study, as defined in Table 7 below.
Table 7.
Treatment Arm Allocation in Study M15-942
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI and/or NS5Ai-exp Prior to 
the AbbVie HCV Parent Study
1, 2, 4, 5 and/or 6
NC
No
A
3
Any
Any
B
Any 
C
Any
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic.
**
If the subject's HCV GT at Screening is unknown, or if it is mixed and includes GT3, then the subject will be 
assigned to Arm B (16 weeks), regardless of the cirrhosis status or PI and/or NS5Ai use prior to the AbbVie HCV 
Parent Study.


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●
Arm A:  Subjects will receive orally ABT-493/ABT-530 300 mg/120 mg QD, 
SOF 400 mg QD, and RBV 600 mg to 1200 mg daily in two divided doses 
(based on baseline age and weight)* for 12 weeks.
●
Arm B:  Subjects will receive orally ABT-493/ABT-530 300 mg/120 mg QD, 
SOF 400 mg QD, and RBV 600 mg to 1200 mg daily in two divided doses 
(based on baseline age and weight)* for 16 weeks.
*
As defined on Table 8.
Table 8.
Ribavirin Dosing Recommendations
Age at 
Baseline 
(Years)
Body 
Weight at 
Baseline 
(kg)
Daily Dose 
(mg)
Number of 200 mg Tablets Per Period of the Day
≥ 18
< 75
1000
2 tablets A.M. + 3 tablets P.M.*
≥ 75
1200
3 tablets A.M. + 3 tablets P.M.
≥ 12 and < 18
35 – 46
600
1 tablet A.M. + 2 tablets P.M.*
47 – 59
800
2 tablets A.M. + 2 tablets P.M.
60 – 74
1000
2 tablets A.M. + 3 tablets P.M.*
≥75
1200
3 tablets A.M. + 3 tablets P.M.
*
The A.M and P.M. pills can be taken in reverse order.
Alternative RBV dosing can be used if agreed upon by AbbVie TA MD prior to 
implementation.
All subjects administered at least one dose of study drugs will be followed for 24 weeks in 
the Post-Treatment Period to monitor for safety, HCV RNA, and the emergence and/or 
persistence of resistance-associated viral variants.
The planned duration of the study (excluding Screening) will be up to 40 weeks.
As this is an open-label study, safety will be reviewed by AbbVie.  Virologic failure 
criteria for subject management, as detailed in Section 5.4.1.1, will be evaluated and 
applied by the investigator.


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5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures will receive a unique subject number via the 
Interactive Response Technology (IRT) system.
The investigator will evaluate whether the subject meets all of the eligibility criteria 
specified in Section 5.2.1 and Section 5.2.2 during the period from the Screening Visit 
through Study Day 1 prior to dosing and record the results of this assessment and the 
details of the informed consent process in the subject's medical records.  Eligible subjects 
have up to 42 days following the Screening Visit to enroll into the study.
5.1.1.1
Rescreening
Subjects who test positive at Screening for any of the following parameters are not 
eligible to rescreen:
●
Positive Hepatitis B surface antigen (HBsAg);
●
A positive HIV-2 test;
●
A positive serum pregnancy test (if female).
In addition, subjects who develop decompensated liver disease, including ascites noted on 
physical exam, hepatic encephalopathy or esophageal variceal bleeding during the 
screening period will not be eligible for rescreening.
Otherwise, subjects may be retested/rescreened only once without approval of the AbbVie 
Therapeutic Area Scientific Director (TA SD)/TA MD, as follows:
●
Subjects who have exclusionary laboratory parameter(s) are allowed to retest 
within the screening period on the related panel(s) (e.g., exclusionary ALT 
requires a repeat chemistry panel) within the same screening period and must 
meet all eligibility laboratory criteria on any panel that is repeated.  If the retest 
result(s) are also exclusionary, the subject may not be rescreened or retested 
again.


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●
Subjects who fail to enroll within 42 days of Screening, regardless of the 
reason for falling outside the 42-day screening window, may rescreen only 
once and must be rescreened for all eligibility criteria (except those noted 
below), not just those that were exclusionary.
Subjects may rescreen once for any other reason, with approval of the AbbVie TA SD/TA 
MD.
Subjects being rescreened do not need to be retested for HBsAg, HIV-2 Ab, HCV 
genotype and subtype, and FibroScan/liver biopsy.
5.1.2
Treatment Period
Prior to the Study Day 1 visit, after all eligibility criteria have been confirmed, subjects 
will be allocated via IRT into one of two treatment arms based on their HCV genotype, 
cirrhotic status, and prior treatment experience with PI- and/or NS5Ai-containing 
regimens before experiencing virologic failure in an AbbVie HCV parent study.  Subjects 
will be administered study drugs at the site on Study Day 1, and provided with dosing 
instructions.
Study visits during the Treatment Period are detailed in Appendix C.  Safety and 
tolerability will be assessed throughout the study.  Laboratory testing will include 
chemistry, hematology, and urinalysis as specified in Table 10.  Plasma samples for 
pharmacokinetic analysis and HCV RNA analysis will be collected as detailed in 
Section 5.3.1.1 and Section 5.3.3.1, respectively.  Blood samples for optional 
pharmacogenetic analysis will be collected as detailed in Appendix C.
All subjects will continue to return to the site on an outpatient basis as outlined in 
Appendix C.  Sites should ensure that subjects adhere to all the study visits.  Subjects who 
cannot complete their study visit per the visit schedule should ensure that they do not run 
out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.


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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.
Virologic failure criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.1.1.  Subjects meeting on-treatment virologic failure (OTVF) criteria will be 
discontinued from study drugs.
Subjects who discontinue from the study drugs during the Treatment Period regardless of 
the reason for discontinuation should return for a Treatment Discontinuation Visit and
undergo the study procedures as outlined in Appendix C and as described in Section 5.4.1.
Subjects who take at least one dose of study drug and complete or discontinue treatment 
will enter the Post-Treatment Period as detailed in Section 5.1.3.
5.1.3
Post-Treatment Period
All subjects who received at least one dose of study drug and either complete or 
discontinue treatment will be monitored for an additional 24 weeks following the last dose 
of study drug for safety, HCV RNA and the emergence, persistence of resistance-
associated viral variants, and – for HCV/HIV-1 coinfected subjects – plasma HIV-1 RNA 
and HIV drug resistance.
The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.  Study visits during the Post-Treatment Period are detailed in Appendix C and 
Section 5.3.1.1.
Some of the Post-Treatment Period study visits and visit activities (including but not 
limited to vital signs, clinical laboratory tests, 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.


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Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a Post-Treatment discontinuation visit as outlined in Appendix C.
5.2
Selection of Study Population
The study population consists of chronic HCV GT1 – 6-infected adult or adolescent 
subjects who experienced virologic failure while participating in an AbbVie HCV parent 
study.  Subjects must meet all the inclusion criteria and none of the exclusion criteria.  In 
addition, the eligibility of a subject to enroll in Study M15-942 will be evaluated at the 
discretion of AbbVie based upon the characteristics of the subject's HCV infection, prior 
treatment history, and the evolving data from on-going clinical studies.
5.2.1
Inclusion Criteria
1.
Male or female subjects must be adults (18 years or more) or adolescents (12 to 
less than 18 years).  Adolescent subjects must weigh at least 35 kg.  
2.
Subject must have experienced virologic failure during or after treatment with 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have 
experienced virologic failure during or after receiving ombitasvir/paritaprevir/r + 
dasabuvir (3D), or ombitasvir/paritaprevir/r (2D) in an AbbVie HCV parent study 
may be enrolled at AbbVie's discretion.  Treatment in the parent study must have 
been completed or discontinued at least 1 month prior to the Screening Visit.
3.
If female, subject must be either
●
Postmenopausal, OR 
●
Permanently surgically sterile, OR 
●
Women of Childbearing Potential (CBP), practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at Study Day 1 
through at least 4 months after the last dose of study drug or as directed by the 
local RBV label, whichever is more restrictive.
4.
If a male subject is sexually active with female partner(s) of CBP, he must agree to 
practice the protocol specified contraception (Section 5.2.4), from Study Day 1 


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through 7 months after the last dose of study drug, or as directed by the local RBV 
label, whichever is more restrictive. 
5.
Female subjects of CBP must have a negative serum pregnancy test result at 
Screening, and a negative urine pregnancy test at Study Day 1.
Females not of CBP at Screening do not require pregnancy testing.
6.
Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements.
7.
Must voluntarily sign and date an informed consent form, approved by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the 
initiation of any screening or study specific procedures.
8.
Cirrhotic subjects must have compensated cirrhosis, defined as a Child-Pugh score 
of ≤ 6 at Screening and:
●
No current or past evidence of Child-Pugh B or C Classification
●
No clinical history of liver decompensation, including ascites noted on 
physical exam, hepatic encephalopathy or esophageal variceal bleeding.
9.
Cirrhotic subjects must demonstrate absence of hepatocellular carcinoma (HCC) as 
indicated by a negative ultrasound (US), computed tomography (CT) scan or 
magnetic resonance imaging (MRI) within 3 months prior to Screening or a 
negative US at Screening.  Subjects who have an ultrasound with results suspicious 
of HCC followed by a subsequent negative CT or MRI of the liver will be eligible 
for the study,
In additional to Inclusion Criteria 1 to 9, subjects with HCV/HIV-1 co-infection must also 
meet the following criteria:
10.
Subject must be:
●
Naïve to HIV treatment with any antiretroviral therapy (ART) and have no 
plans to initiate ART treatment while participating in this study, or 


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●
On a stable, qualifying HIV-1 ART regimen for at least 8 weeks prior to 
Screening.  
●
The HIV-1 ART regimen must include at least one of the following ARV 
agents:
○
For cirrhotic and non-cirrhotic subjects:
●
Raltegravir (RAL) PO BID
●
Dolutegravir (DTG) PO QD or PO BID
●
Rilpivirine (RPV) PO QD 
●
Elvitegravir/cobicistat (EVG/COBI) PO QD
○
For non-cirrhotic subjects:
●
Darunavir (DRV) co-administered with ritonavir (RTV) PO QD
●
Darunavir/cobicistat (DRV/COBI) PO QD
●
Lopinavir/ritonavir (LPV/r) PO BID
In addition to the above medications, subjects may take a nucleoside/nucleotide 
reverse transcriptase inhibitor (N(t)RTI) backbone containing any of the following:
●
Tenofovir disoproxil fumarate (TDF) PO QD 
●
Tenofovir alafenamide (TAF) PO QD
●
Abacavir (ABC) PO QD or BID
●
Emtricitabine (FTC) PO QD 
●
Lamivudine (3TC) PO QD or BID
Subjects receiving any other HIV-1 ART in addition to those noted above would 
not be eligible for enrollment in the study.
11.
Subjects naïve to ART must have a CD4+ count ≥ 500 cells/mm3 (or CD4+ % 
≥29%) at Screening.
Subjects on a stable ART regimen must have the following:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening; 
●
and Plasma HIV-1 RNA < 50 copies/mL at Screening (by the COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once (HIV-1 
< 50 copies/mL) during the 12 months prior to Screening (by an approved 


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plasma HIV-1 RNA quantitative assay including but not limited to:  COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 
assay).
Rationale for Inclusion Criteria
1, 2, 8 – 11
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation
3 – 5
RBV has known teratogenic effects.  The impact of ABT-493 and 
ABT-530 on human pregnancies has not been established.  However, 
assessment of the completed nonclinical reproductive toxicology studies 
indicates that there is no drug-related effect on 
teratogenicity/fetotoxicity.  In addition, the compounds are non-
genotoxic.  No adequate human data are available to establish whether 
or not sofosbuvir poses a risk to pregnancy outcomes.  In animal 
reproduction studies, no evidence of adverse developmental outcomes 
was observed with the components of sofosbuvir at exposures greater 
than those in humans at the recommended human dose16
6, 7
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
History of severe, life-threatening or other clinically significant sensitivity to or 
inability to take any study drug or drug component.
2.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for 4 months after the last dose of study drug, or as directed per 
the local RBV label, whichever is more restrictive.  
3.
Male subject who is considering fathering a child or whose partner is pregnant 
during the study or for 7 months after the last dose of the study drug, or as directed 
per the local RBV label, whichever is more restrictive.
4.
Positive test result at Screening for hepatitis B surface antigen (HBsAg).
5.
Positive Human Immunodeficiency virus, type 2 (HIV-2) Ab at Screening. 


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6.
Requirement for and inability or unwillingness to safely discontinue the 
medications or supplements listed in Table 9 at least 2 weeks prior to the first dose 
of any study drug.
7.
Requirement for chronic use of systemic immunosuppressants during the study, 
including but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day 
for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
8.
Use of any of the following:
●
Any prohibited therapy including potent P-gp inducers (including, St. John's 
Wort, carbamazepine, phenytoin, and rifampin) within 2 weeks or 10 half-lives 
(whichever is longer) prior to study drug administration (Section 5.2.3.4).
●
Any medications that are contraindicated to be used in combination with SOF 
or RBV, as per local label.
9.
Clinically significant abnormalities, other than HCV monoinfection or HCV/HIV-1 
co-infection, based upon the results of a medical history, physical examination, 
vital signs, laboratory profile, and a 12-lead electrocardiogram (ECG) that make 
the subject an unsuitable candidate for this study in the opinion of the investigator, 
including, but not limited to:
●
Uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) 
level > 8% during Screening.
●
Active or suspected malignancy or history of malignancy (other than basal cell 
skin cancer or cervical carcinoma in situ) in the past 5 years.
●
Uncontrolled cardiac, respiratory, gastrointestinal, hematologic, neurologic, 
psychiatric, or other medical disease or disorder, which is unrelated to the 
existing HCV infection.
10.
Treatment for an AIDS-Defining Condition (ADC) (Appendix D) within 6 months 
of Screening.
11.
Any cause of liver disease other than chronic HCV-infection, including but not 
limited to the following:
●
Hemochromatosis


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●
Alpha-1 antitrypsin deficiency
●
Wilson's disease
●
Autoimmune hepatitis
●
Alcoholic liver disease
●
Steatosis or steatohepatitis on liver biopsy considered to be the primary cause 
of the liver disease rather than concomitant/incidental with HCV infection
12.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
ALT > 10 × ULN 
●
AST > 10 × ULN 
●
Albumin < 2.8 g/dL 
●
International normalized ratio (INR) > 1.5, unless subject has known 
hemophilia or is on a stable anticoagulant regimen affecting INR
●
Hemoglobin < 10 g/dL, or as per local RBV label, if more restrictive.
●
Platelets < 50,000 cells per mm3 for subjects aged ≥ 18 years, or < 40,000 cells 
per mm3 for subjects aged < 18 years.
●
Calculated creatinine clearance < 30 mL/min
13.
History of solid organ transplantation.
14.
Receipt of any HCV treatment after failing the treatment regimen in the AbbVie 
HCV parent study.
15.
Discontinuation of the prior HCV treatment in the AbbVie HCV parent study for 
reasons other than virologic failure (e.g., non-adherence, lost to follow-up, and/or 
the occurrence of an adverse event).
16.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
17.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-493, ABT-530, SOF, or RBV.


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18.
Subject who cannot participate in the study per local law. 
19.
Current enrollment in another interventional clinical study or previous enrollment 
in this study (except the AbbVie HCV parent study).  Concurrent participation in a 
non-interventional, epidemiologic or registry trials may be permitted with approval 
by the AbbVie TA SD/TA MD.
20.
Subject has confirmation of HCV reinfection at screening visit (as defined in 
Section 5.4.1.1).
Rationale for Exclusion Criteria
1, 2, 3, 8, 10 – 12, 17 –
19
In order to ensure safety of the subjects throughout the study
6, 7, 13 – 19, 20
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
4, 9, 11
To exclude subjects with liver diseases other than HCV
5
To exclude subjects with HIV-2 co-infection
5.2.3
Prior and Concomitant Therapy
Use of medications/supplements (including prescription or over-the-counter, vitamins 
and/or herbal supplements) or vaccines from the time of signing the informed consent 
through the Treatment Period and 30 days after study drugs are stopped, must be recorded 
in the electronic case report form (eCRF) at each study visit indicated in the Treatment 
Period (Appendix C) along with the reason for use, date(s) of administration including 
start and end dates, and dosage information including dose, route and frequency.  The 
investigator should review all concomitant medications for any potential interactions.
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and/or 


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HIV and medications prescribed in association with a serious adverse event (SAE) will be 
recorded in EDC.
The AbbVie TA SD/TA MD should be contacted if there are any questions regarding 
concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
The HCV drug treatment regimen and its duration given as a part of the subject's 
participation in an AbbVie HCV parent study, as well as all other past HCV treatment 
regimens and their durations received by the subject, will be recorded in the eCRF.
5.2.3.2
Prior and Concomitant HIV-1 Therapy
If a subject is on an HIV-1 ART regimen, it must include at least one of the ARV agents 
defined on Inclusion Criterion 10 (Section 5.2.1).
Subjects will maintain the same dose and dosing interval of their HIV-1 ART regimen 
upon initiating the study drugs regimen.
Subjects must remain on the same HIV-1 ART regimen for the entire Treatment Period.  
Any change to an allowed HIV-1 ART regimen during the Treatment Period must be 
discussed with the AbbVie TA SD/TA MD prior to the change, unless the change is being 
made to address an immediate safety concern.
Subjects receiving any other HIV-1 ART in addition to those listed in Inclusion 
Criterion 10 (Section 5.2.1) would not be eligible for enrollment in the study.
5.2.3.3
Other Concomitant Therapy
Subjects should be on a stable dose of concomitant medications for at least 14 days prior 
to initiation of study drugs.  The investigator should confirm that a concomitant 
medication/supplement can be safely administered with study drugs.  Some medications 
may require dose adjustments due to the potential for drug-drug interactions.


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During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, up to 14 days following 
discontinuation of study drugs, if applicable.
Flu shots and all essential vaccinations are allowed during Screening through the Post-
Treatment Period for all subjects.  Flu shots and vaccinations may affect plasma HIV-1 
RNA levels.
5.2.3.4
Prohibited Therapy
Medications or supplements prohibited to be administered with ABT-493/ABT-530 are 
listed in Table 9.  For subjects in the study in countries where ABT-493/ABT-530 
(glecapravir/pibrentasvir) has received marketing authorization, any medications in the 
local label that are contraindicated to be administered with ABT-493/ABT-530 
(glecapravir/pibrentasvir) are also considered to be prohibited medications.  Subjects must 
be able to safely discontinue any prohibited medications or supplements at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of any study drug and not use 
these during the entire Treatment Period and for 14 days following discontinuation of 
study drugs.  The Informed Consent Form must be signed and dated prior to discontinuing 
any prohibited medications or supplements for the purpose of meeting study inclusion 
criteria.


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Table 9.
Medications and Supplements Prohibited with ABT-493/ABT-530 
Administration
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Tipranavir/r, atazanavir, efavirenz, etravirine, nevirapine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drug.  After signing the informed consent form, subjects receiving these statins should either (a) switch to 
pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug 
or (b) interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives (whichever 
is longer) prior to the first dose of study drug and until 14 days after the last dose of study drug, based on 
investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to either 
1) reduce or limit the pravastatin or rosuvastatin dose in accordance with the ABT-493/ABT-530 
(glecapravir/pibrentasvir) product label (if approved in the country) when taking with the study drug; or 2) reduce 
the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug, if 
ABT-493/ABT-530 (glecapravir/pibrentasvir) is not yet approved in the country.
In addition, refer to the current package insert or product label for SOF and RBV for a 
complete list of medications prohibited to be used with those drugs, which should not be 
used at least 14 days prior to the first dose of any study drug, throughout the entire 
Treatment Period and for 14 days following discontinuation of study drugs.
Contraceptives and/or hormonal replacement therapies containing only 
progestins/progestogens (such as those containing norethindrone, desogestrel, or 
levonorgestrel) or those containing progestins/progestogens with non-ethinyl estradiol 
estrogens (e.g., esterified or conjugated) may be used with ABT-493/ABT-530 at the 
discretion of the Investigator.
Anti-HCV medications other than those specified in the protocol will not be allowed 
during the Treatment Period of the study.


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For HCV/HIV-1 coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 14 days prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 14 days following discontinuation of study drugs.  
Use of hematopoietic growth factors is permitted during this study only with the approval 
of the TA SD/TA MD.  Management of hematologic growth factor therapy is the 
responsibility of the investigator; growth factors will not be provided by AbbVie, and 
AbbVie will not reimburse for the expense of growth factors or their use.
Investigators should refer to the package inserts for erythropoiesis stimulating agents for 
additional information regarding their use.
5.2.4
Contraception Recommendations 
Female Subjects
If female, subject must be either postmenopausal defined as:
●
Age ≥55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).


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OR 
Females subjects of CBP must be:
●
Practicing at least one of the following methods of birth control, on Study 
Day 1 (or earlier) through at least 4 months after the last dose of study drug, or 
as directed by the local RBV label, whichever is more restrictive.
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation or bilateral tubal occlusion via 
hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms 
success of the procedure.
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the CBP trial participant.
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
True abstinence:  Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject (periodic 
abstinence] e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
Male Subjects
Male subjects who are sexually active with a female partner of CBP, even if the male 
subject has undergone a successful vasectomy, must agree to use condoms from Study 
Day 1 through at least 7 months after the last dose of study drug and his female partner(s) 
must use at least one of the contraceptive measures (as defined in the protocol for female 


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study subjects of childbearing potential).  If the local RBV label for the subject has more 
restrictive recommendations, they must be followed instead.
Male subject must agree not to donate sperm from Study Day 1 through at least 7 months 
after the last dose of study drug (or as directed by the local RBV label, whichever is more 
restrictive).
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
Informed Consent and RBV Information
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed.  All subjects will be given the RBV Medication Guide (where 
applicable/locally available).  Male subjects will be given an additional copy of the RBV 
Medication Guide (where applicable/locally available) to share with their female 
partner(s) (where applicable/locally available).  Details about how informed consent will 
be obtained and documented are provided in Section 9.3.
Medical History
The subject's medical history including history of tobacco, alcohol use and drug use, 
recorded in the AbbVie HCV parent study, will be updated at the Screening Visit with any 
relevant information that was not collected in the previous AbbVie study and any new 
medical history that occurred between the end of the previous AbbVie study and this 
study.  In some cases, the medical history recorded in the previous AbbVie study will be 
electronically transferred into the eCRFs in this study and in other cases it will need to be 


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manually entered into the eCRFs by the site due to differences between the medical 
history eCRFs for the previous AbbVie study and the current study.  The subject's medical 
history will also be updated, as needed, at the Study Day 1 Visit.  This updated medical 
history will serve as the baseline for clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C, or 
upon subject discontinuation.  A symptom-directed physical examination may be 
performed at any other visit, when necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Height will be measured only at Screening.
Vital Signs and Weight
Body temperature, blood pressure, waist circumference, pulse and body weight will be 
measured at each study visit as specified in Appendix C or upon subject discontinuation.  
Blood pressure and pulse rate should be measured after the subject has been sitting for at 
least 3 minutes and prior to blood collection.  The subject will wear lightweight clothing 
and no shoes during weighing.
Pregnancy Testing
A serum and urine pregnancy test will be performed for all female subjects of 
childbearing potential at Screening and Day 1.  Additional urine pregnancy tests will be 
performed every 4 weeks, starting at Day 1 (prior to enrollment) during the treatment 
period, including at the last treatment period visit and until 4 months after the last study 
drug dose (or as directed by local RBV label, whichever is more restrictive), as indicated 
in Appendix C.  Determination of postmenopausal status will be made during the 
Screening period, based on the subject's history.


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Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined above) at Screening do not require pregnancy testing.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained at Screening.  The ECG should be performed 
prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign and date all ECG tracings and will 
provide his/her global interpretation as a written comment on the tracing using the 
following categories:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in 
Table 10 at the visits indicated in Appendix C.
Blood samples for serum chemistry tests 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.  At the Study Day 1 
visit, a fasting blood sample should be collected prior to the first dose of study drug.  
Blood samples should still be drawn if the subject did not fast for at least 8 hours.  Fasting 


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or non-fasting status will be recorded in the source documents and on the laboratory 
requisition.  The baseline laboratory test results for clinical assessment for a particular test 
will be defined as the last measurement prior to the initial dose of study drug.
A central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.  The certified laboratory chosen 
for this study is Covance.  Samples will be sent to the following addresses:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
(For sites in North America)
Covance
7 rue Moise-Marcinhes
1217 Meyrin
Geneva Switzerland
(For sites in Europe)
Covance (Asia) Pte Ltd
1 International Business Park
#01-01 The Synergy
Singapore 609917
(For sites in Asia, Australia and New Zealand)


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Table 10.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Reticulocyte count
Prothrombin Time/INRa
Activated partial thromboplastin 
time (aPTT)
Blood Urea Nitrogen (BUN)
Uric Acid 
Creatinine
Creatinine clearance (Cockcroft-
Gault calculation)
eGFR (MDRD method)
Total bilirubina
Direct and indirect bilirubin
Serum Alanine Aminotransferase 
(ALT)
Serum Aspartate 
Aminotransferase (AST)
Alkaline phosphatase
Gamma-glutamyl transferase 
(GGT)
Total protein 
Albumina
Glucose
Total insulin
Sodium
Potassium
Calcium
Inorganic phosphorus
Chloride
Bicarbonate
Magnesium
Cholesterol
Triglycerides
Low Density Lipoproteins 
(LDL)b,c,d
High Density Lipoprotein 
(HDL)b,d
Anti-HIV Abe
FSH (all females)e
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG) for 
femalesf
HCV RNA
HIV-1 RNAb
Hemoglobin A1Ce
HCV genotype and subtypee
Pharmacogenetic sample 
(optional)
Alpha2-macroglobuling
Haptoglobing
Apolipoprotein A1g
CD4, CD4%b
CD8, CD8%b
CD4:CD8b
Anti-Hepatitis A Virus IgMh
Anti-Hepatitis A Virus Totalh
Anti-Hepatitis E Virus IgGh
Anti-Hepatitis E Virus IgMh
HEV RNAh
HBsAge,h
Anti-HBc IgMh
Anti-HBc Totalh
Anti-HBsh
HBV DNAh
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
Albumini
a.
Also a component of the Child-Pugh Assessment (along with ascites and encephalopathy).
b.
Only for known HCV/HIV-1 co-infected subjects.
c.
Directly measured.
d.
Performed only at Day 1.
e.
Performed only at Screening.
f.
Females not of CBP at Screening do not require pregnancy testing as defined in Section 5.2.1 Criterion 5.


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Table 10.
Clinical Laboratory Tests (Continued)
g.
Component of FibroTest and collected only if needed during the Screening Period.
h.
Performed for management of transaminase elevation (Section 6.1.7.5).  
i.
Collected for confirmed Creatinine Clearance < 50 mL/min, if clinically indicated as defined in Section 6.1.7.6.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or requires a subject to receive treatment will be recorded as an adverse 
event.
The management of laboratory abnormalities that may occur during the study is described 
in Section 6.1.7.
Hepatitis B and HIV Screen
HBsAg (hepatitis B surface antigen) and anti-HIV Ab will be performed at Screening.  
The investigator must discuss any local reporting requirements to local health agencies 
with the subject.  The site will report these results per local regulations, if necessary.  The 
HBsAg results will be reported by the central laboratory to the clinical database.
Liver Diagnostic Testing
Subjects categorized as cirrhotic in the AbbVie HCV parent studies will be categorized 
as being cirrhotic in this study.
Subjects categorized as non-cirrhotic in the AbbVie HCV parent studies, who do not 
have a qualifying liver biopsy showing absence of cirrhosis within the previous 12 months 
from Screening or qualifying FibroScan showing absence of cirrhosis with the previous 
6 months from Screening, but who otherwise meet all of the inclusion criteria and none of 


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the exclusion criteria will undergo liver biopsy or non-invasive testing (FibroTest/APRI 
or FibroScan) prior to enrollment.  Selection of liver biopsy or non-invasive testing 
performed should be based on local standard practice.
Subjects must be documented as non-cirrhotic or cirrhotic defined as meeting one of the 
following criteria: 
Non-Cirrhotic
A liver biopsy within 12 months prior to or during Screening demonstrating the 
absence of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, Scheuer, or 
Laennec fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; or
A FibroScan® score of < 12.5 kPa within ≤ 6 months of Screening or during Screening 
period (FibroScan® must be approved by the local regulatory agency to qualify for 
entrance criteria); or
A Screening FibroTest score of ≤ 0.48 and Aspartate Aminotransferase to Platelet 
Ratio Index (APRI) < 1.
Cirrhotic
Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., METAVIR, Batts-
Ludwig, Knodell, IASL, Scheuer, or Laennec fibrosis score of > 3, Ishak score of > 4 
or on a liver biopsy conducted during Screening; or
A FibroScan® score of ≥ 12.5 kPa at any time prior to Screening or during Screening 
period (FibroScan® must be approved by the local regulatory agency); or
A Screening FibroTest result that is ≥ 0.75 and an APRI > 2.
In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
FibroTest/APRI using the above criteria (indeterminate FibroTest [0.48 < result 
< 0.75], or conflicting FibroTest and APRI results [e.g., FibroTest ≤ 0.48, but APRI 


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≥1]), a liver biopsy or FibroScan® is required.  Liver biopsy results will supersede 
Fibrotest/APRI or FibroScan® results and be considered definitive.
Subjects who are categorized as cirrhotic in this study according to the criteria above 
must also meet Inclusion Criteria 8 and 9.
When performed within the specified timeframes, the result of the liver biopsy 
supersedes the results of FibroScan and FibroTest/APRI and result of FibroScan 
supersedes the results of FibroTest/APRI.
Child-Pugh (Child-Turcotte-Pugh) Score and Category
The Child-Pugh (Child-Turcotte-Pugh) score uses five clinical measures of liver disease 
(3 laboratory parameters and 2 clinical assessments) as shown in Table 11.  Child-Pugh 
score will be determined only for subjects with compensated cirrhosis at the visits 
indicated in Appendix C.


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Table 11.
Child-Pugh (Child-Turcotte-Pugh) Classification of Severity of 
Cirrhosis
Points Assigned for Observed Findings
Parameter
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2
(or suppressed with medication)
Grade 3 or 4
(or refractory)
*
None; Slight ascites = Ascites detectable only by ultrasound examination; Moderate ascites = Ascites manifested 
by moderate symmetrical distension of the abdomen; Severe ascites = Large or gross ascites with marked 
abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram; Grade 1:  restless, 
sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves; Grade 2:  lethargic, time-disoriented, 
inappropriate behavior, asterixis, ataxia, slow triphasic waves; Grade 3:  somnolent, stuporous, place-disoriented, 
hyperactive reflexes, rigidity, slower waves; Grade 4:  unarousable coma, no personality/behavior, decerebrate, 
slow 2 to 3 cps delta activity.
Clinical Assessment of Hepatic Decompensation
A clinical assessment of hepatic encephalopathy and ascites will be performed only for 
subjects with compensated cirrhosis at Study Day 1 prior to dosing to confirm the subject 
has not progressed to hepatic decompensation since screening.
Hepatocellular Carcinoma Screening:  Liver Ultrasound
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Study Visit and at the last Post-treatment Study Visit, as indicated in 
Appendix C, for subjects with compensated cirrhosis only.  Between those visits, HCC 
screening should be performed according to standard of care.
At the Screening Study Visit and at the last Post-treatment Study Visit, subjects with 
compensated cirrhosis will be required to perform a liver ultrasound to screen for HCC, 


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unless the subject has a historical liver ultrasound, CT or MRI performed for HCC 
screening within 3 months prior to those visits, in which case the result of the historical 
US, CT or MRI will be used as the result for that Study Visit assessment.  A positive 
ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  Alternate 
methods of screening for HCC (i.e., MRI or CT) at a study visit should be discussed with 
the TA MD.
Enrollment and Assignment of Subject Numbers
All screening activities must be completed and reviewed prior to enrollment.  Subjects 
who meet the eligibility criteria will proceed to enrollment via the IRT system on Day 1 
(Treatment Period).  Subject numbers will be unique 5-digit numbers starting with 10001.  
The first 3 digits will represent the investigative site and the last 2 digits will represent the 
subjects screened at that site.  Enrolled subjects will keep their subject number throughout 
the study.
Study Drug Compliance for Kits
Bottles of ABT-493/ABT-530, SOF and RBV will be provided for subject dosing to the 
site.  Each subject will have compliance documented by the site in the subject's source 
notes for ABT-493/ABT-530, SOF and RBV.  At each drug accountability visit in 
Appendix C, the overall number of tablets of ABT-493/ABT-530, SOF and RBV 
remaining in each bottle will be recorded in the source and transferred to the IRT system 
along with the date of reconciliation.
HCV Genotype and Subtype
Plasma samples for HCV genotype and subtype will be collected at Screening.  Genotype 
and subtype will be assessed using the Versant® HCV Genotype Inno LiPA Assay, 
Version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY).  If the 
LiPA assay is unable to genotype/subtype a sample, its genotype/subtype will be 
determined by a Sanger sequencing assay of a region of the NS5B gene (Covance).


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HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C.  
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the COBAS® AmpliPrep/COBAS® TaqMan HCV Quantitative Test, 
v2.0.  For this assay, the lower limit of detection (LLOD) and the lower limit of 
quantification (LLOQ) are both 15 IU/mL.
HCV Resistance Testing Sample
A plasma sample for HCV resistance testing will be collected prior to dosing on Day 1 
and at the study visits indicated in Appendix C.  Specific instructions for preparation and 
storage of HCV RNA and HCV resistance samples will be provided by the central 
laboratory, AbbVie, or its designee.
Archive Serum and Plasma Sample
Archive serum and plasma samples will be collected at the study visits, indicated in 
Appendix C.  Archive serum and plasma samples are being collected for possible 
additional analyses, including but not limited to, study drug or metabolite measurements, 
HCV RNA levels, safety/efficacy assessments, HCV gene sequencing, HCV resistance 
testing, biomarkers of inflammation or fibrosis, and other possible predictors of response 
including biomarker for other causes of liver diseases, as determined by AbbVie.
Specific instructions for preparation and storage of archive samples will be provided by 
the central laboratory, AbbVie, or its designee.
Study Drug Dosing Card
Subjects will be provided with self-administration instructions and study drug dosing 
cards to record the exact date, time (record to the nearest minute) and number of tablets of 
study drug administration (ABT-493/ABT-530, SOF, and RBV) for the last 2 doses of 
each study drug taken prior to the scheduled pharmacokinetic sample collection during the 
Treatment Period.


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The site staff will record the information about the last 2 doses taken prior to the 
scheduled pharmacokinetic sample collection from the study drug dosing card into the 
eCRF.  In the event that the dosing card is not available, the site may obtain dosing 
information via patient interview and record this information in the source notes.
To facilitate proper dosing of study drug before pharmacokinetic evaluation blood 
samples are taken, the following procedures should be performed:
●
The study coordinator should make sure the subject is given the dosing card at 
the visits listed in Appendix C.
●
The Investigator or designee will contact the subject approximately 2 days 
before the scheduled visit date to review the importance of proper study drug
administration relative to the pharmacokinetic blood collection and 
documentation of dosing times on the dosing card.  The date and time of the 
contact will be entered into the subject's source documents.
●
The completed dosing card will be collected by the Investigator or designee on 
the day of the visit and be kept as a source record of dosage administration 
times documented in the eCRF.
Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
For subjects with HCV/HIV-1 coinfection, samples for plasma HIV-1 RNA levels and 
flow cytometry (including but not limited to CD4+ T-cell and CD8+ T-cell counts 
[absolute and percent]) will be obtained at the times specified in Appendix C.  Plasma 
HIV-1 RNA will be measured by the central laboratory using the Roche COBAS 
AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 HIV-1 Assay.  Results below the 
LLOD are reported as:  "Not Detected."  Subjects will also have blood samples drawn and 
archived at the study visits indicated in Appendix C.  These samples may be used for 
other analyses including drug resistance testing.  These samples may be tested at the 
discretion of AbbVie.
If a HIV-1 RNA level result of a subject on stable HIV-1 ART is ≥ 200 copies/mL, the 
subject's HIV-1 RNA is to be repeated as noted in Section 5.4.1.2.  At the time the repeat 


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plasma HIV-1 RNA is drawn, a sample should be obtained for HIV-1 genotypic resistance 
testing.  If the subject's repeat HIV-1 RNA is ≥ 500 copies/mL, the sample obtained for 
HIV-1 genotypic resistance testing will be analyzed.
HIV-1 protease (PR), reverse transcriptase (RT) and integrase (IN) sequences, as 
applicable, will be analyzed by Monogram Biosciences using the GenoSure® Prime drug 
resistance assay.
If the subject's repeat HIV-1 RNA is < 200 copies/mL, then the subject will resume 
routine plasma HIV-1 RNA assessments as shown in Appendix C, and described in 
Section 5.4.1.1.
Specific instructions for preparation and storage of flow cytometry, plasma HIV-1 RNA, 
archive and HIV resistance samples will be provided by the central laboratory, AbbVie, or 
its designee.
5.3.1.2
Meals and Dietary Requirements
All study drugs should be dosed together and each dose should be taken with food.
5.3.1.3
Collection and Handling of Pharmacogenetic Exploratory 
Research Samples
Subjects will have the option to provide samples for optional pharmacogenetic 
exploratory research.  Subjects may still participate in the main study even if they decide 
not to participate in this optional exploratory research.
Optional whole blood samples for DNA and RNA isolation will be collected on Day 1 
and Post-Treatment Week 12 from each subject who consents to provide samples for 
exploratory research.  The procedure for obtaining and documenting informed consent for 
exploratory research samples is discussed in Section 9.0.
Specific instructions for collection, storage and shipment of pharmacogenetic samples will 
be provided by the central laboratory, AbbVie, or its designee.  AbbVie (or people or 


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companies working with AbbVie) will store the optional pharmacogenetic exploratory 
research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on ABT-493/ABT-530 (or 
drugs of this class) or this disease and related conditions continues, but for no longer than 
20 years after study completion.  The procedure for obtaining and documenting informed 
consent for exploratory research samples is discussed in Section 9.3.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of ABT-493, ABT-530, SOF, primary 
metabolite of SOF (GS-331007), and RBV will be collected by venipuncture at each study 
visit indicated below and in Appendix C.  
●
All Treatment Period visits except for Study Day 1:  two samples (4 mL each) 
will be collected without regard to the time.  The date and time of blood 
sample collection and the two previous doses of the study drug will be 
recorded to the nearest minute in the source documents.  
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, 
SOF, primary metabolite of SOF (GS-331007) and RBV will be provided by the central 
laboratory, the Sponsor, or its designee.
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, SOF, 
primary metabolite of SOF (GS-331007), RBV, and archive serum and plasma samples 
will be packed in dry ice sufficient to last during transport, and transferred from the study 
site to the central laboratory.


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The central laboratory will then ship the ABT-493, ABT-530, SOF, primary metabolite of 
SOF (GS-331007), and RBV samples to the reference laboratories following separately 
provided instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of ABT-493 and ABT-530, SOF, GS-331007 and RBV will be 
determined using validated assay methods under the supervision of the Drug Analysis 
Department at AbbVie.  Plasma concentrations of possible metabolites of any analytes 
listed above may also be determined using either validated or non-validated methods.
5.3.3
Efficacy Variables
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 1 through 24 weeks after completion of treatment.
5.3.3.1
Primary Variable
The primary efficacy variable is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug) in each treatment arm, and overall.
5.3.3.2
Secondary Variables
The secondary efficacy variables are:
●
The percentage of subjects with HCV on-treatment virologic failure in each 
treatment arm and overall.
●
The percentage of subjects with HCV virologic relapse in each treatment arm 
and overall.
5.3.4
Resistance Variables
For all subjects receiving study drug, the variants at signature resistance-associated amino 
acid positions at baseline identified by next generation sequencing (NGS) will be 
compared to the appropriate prototypic reference sequence.


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The following resistance information will be analyzed for subjects receiving study drugs 
who do not achieve SVR12 and who have a post-baseline sample with HCV RNA 
≥1000 IU/mL:  1) the amino acid variants in available post-baseline samples identified by 
NGS and comparison to the baseline sequence, 2) the amino acid variants in available 
post-baseline samples at signature resistance associated positions identified by NGS and 
comparison to the appropriate prototypic reference sequence, and 3) the persistence of 
viral resistance by NGS.
5.3.5
Safety Variables
The following safety evaluations will be performed during the study:  adverse events, vital 
signs, physical examination, and laboratory tests assessments.
5.3.6
Pharmacokinetic Variable
Individual plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of 
SOF (GS-331007), and RBV will be tabulated and summarized.  Additional parameters 
may be calculated if useful in the interpretation of the data.
5.3.7
Pharmacogenetic Exploratory Research Variables
Optional pharmacogenetic samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be 
analyzed as part of a multi-study assessment of factors influencing the subjects' response 
to the study drug (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods or technologies.  The results 
from these analyses are exploratory in nature and may not be included with the study 
report.


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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 
(D/C), the procedures outlined for the applicable Premature D/C Visit should be 
completed as defined in Appendix C.  Ideally this should occur on the day of study drug 
discontinuation, but no later than 2 days after their final dose of study drug and prior to 
the initiation of any other anti-HCV therapy.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  The last dose of any study drug and reason for discontinuation will be recorded 
in the EDC (electronic data capture) system.  The subject should then begin the Post-
Treatment Period where the subject will be monitored for 24 weeks for HCV RNA, the 
emergence and persistence of resistant viral variants.
If a subject is discontinued from study drugs or during the Post-Treatment Period with an 
ongoing adverse event or an unresolved laboratory result that is significantly outside of 
the reference range, the investigator will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of RBV (if 
applicable) to that subject must be discontinued immediately.  DAAs may be continued at 
the Principal Investigator's discretion after discussion with the subject, if the benefit of 
continuing DAAs is considered to outweigh the risk.  Specific instructions regarding 
subject pregnancy can be found in Section 6.1.6.  Subjects will be monitored for SVR in 


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the Post-Treatment Period as described in Section 5.1.3.  The investigator is also 
encouraged to report the pregnancy information to the voluntary RBV Pregnancy 
Registry.
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of OTVF, for the purposes of subject 
management, leading to discontinuation of study drug: 
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment; or
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
Confirmatory testing should be completed as soon as possible and the subject should 
remain on study drug treatment until the OTVF criterion has been confirmed.  Subjects 
with confirmed OTVF will be discontinued from study drug and will continue to be 
followed in the Post-Treatment Period for the emergence and persistence of resistant viral 
substitutions until 24 weeks post-treatment (Appendix C).
Post-treatment relapse is defined as confirmed HCV RNA ≥ LLOQ (defined as 
2 consecutive HCV RNA measurements ≥ LLOQ) at any post-treatment visit, for subjects 
who completed treatment (defined as study drug duration ≥ 77 days for subjects who 
received 12 weeks or ≥ 103 days for subjects who received 16 weeks) and had HCV RNA 
< LLOQ at the final treatment visit, excluding cases of reinfection, as defined below.  
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the post-
treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis performed by the sponsor of the HCV 
NS3, NS5A, and/or NS5B gene sequences.  Reinfection in the case of the same HCV 
subtype is defined as a clade switch, as indicated by the lack of clustering between the 


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baseline and post-treatment sequences by phylogenetic analysis.  If phylogenetic analysis 
is not possible due to technical difficulties, HCV reinfection may be determined with a 
confirmed HCV genotype or subtype switch by the Versant HCV Genotype Inno-LiPA 
Assay v2.0 or Sanger assay.
5.4.1.2
Failure to Maintain HIV Virologic Suppression
HIV-1 RNA will be assessed at each scheduled study visit during the Treatment and 
Post-Treatment Period, as detailed in Appendix C.
The criteria for failure to maintain HIV virologic suppression among subjects on stable 
ARTs is as follows:
●
HIV-1 RNA ≥ 200 copies/mL confirmed on 2 consecutive tests at least 
2 weeks apart, in a subject compliant with their HIV ARV therapy
At the time a confirmatory HIV-1 RNA is drawn, a sample for HIV-1 genotypic resistance 
testing should also be obtained; this sample will be analyzed if the subject's repeat plasma 
HIV-1 RNA is ≥ 500 copies/mL.  Subjects should remain on HCV study drug treatment 
and his/her current ART regimen while the failure to maintain HIV virologic suppression 
is being confirmed.  A confirmatory HIV-1 RNA and HIV-1 genotypic resistance blood 
draw can be done as an unscheduled visit.  However, if this blood draw falls on the date of 
a scheduled study visit (Appendix C), only a single HIV-1 RNA and HIV-1 genotypic 
resistance blood draw needs to be performed at this visit.
During the Treatment Period, subjects with confirmed failure to maintain HIV-1 RNA 
suppression should continue HCV study drug treatment unless there is a requirement for 
prohibited concomitant medications (Section 5.2.3.2) to construct a new HIV ART 
regimen.
Clinical management of failure to maintain HIV virologic suppression during the study 
(Treatment and Post-Treatment Period) will be handled by the Investigator according to 
current HIV treatment guidelines and local standard of care.


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If the investigator wishes to change the HIV-1 ART regimen for a subject, it must be 
discussed with the AbbVie TA MD prior to the change being made, unless the change is 
being made to address an immediate safety concern.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of study drug (ABT-493/ABT-530, SOF, and RBV) will be dispensed in the 
form of tablets at the visits listed in Appendix C.  The date and time of dosing will be 
recorded to the nearest minute in the source documents (or study drug dosing card) and 
the eCRF for the 2 days immediately prior to each study visit starting prior to the Week 2 
visit.
AbbVie will provide ABT-493/ABT-530 as 100 mg/40 mg film-coated tablets.  
ABT-493/ABT-530 will be taken orally as three tablets QD (total daily dose of 
300 mg/120 mg) and with food.
AbbVie will provide SOF as 400 mg tablets.  SOF will be taken orally as 1 tablet QD, 
with food.
AbbVie will provide RBV as 200 mg tablets.  RBV dosing is determined based on the age 
and weight of the subject at the Day 1 visit, as described in Table 8.  RBV should be taken 


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with food.  The RBV dose established at Day 1 should be maintained throughout the 
entire treatment, regardless of ulterior changes in age or weight, unless a dose 
modification is needed due to toxicity (see Section 6.1.7).
Study drug must not be dispensed without contacting the IRT system.  Study drug may 
only be dispensed to subjects enrolled in the study through the IRT system.  At the end of 
the Treatment Period or at the Premature D/C Visit from the Treatment Period, the site 
will contact the IRT system to provide visit date information and study drug return 
information for each kit (Section 5.5.7).
In the event that there is an issue with the study drug supply during the Treatment Period, 
commercial drug may be provided only with prior AbbVie approval, so that the subject 
does not experience treatment interruptions.  If commercial drug is provided, AbbVie will 
provide instructions for documentation.
5.5.2
Identity of Investigational Products
Information about the study drugs to be used in this study is presented in Table 12.
Table 12.
Identity of Investigational Products
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
ABT-493/ABT-530
AbbVie
Oral
Film-coated Tablet
100 mg/40 mg
Sofosbuvir
Gilead
Oral
Film-coated Tablet
400 mg
Ribavirin
Roche or Generic 
Manufacturer
Oral
Film-coated Tablet
200 mg
5.5.2.1
Packaging and Labeling
All study drugs will be supplied in bottles.
Each bottle will be labeled as required per country requirements.


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The labels must remain affixed to the bottles.  All blank spaces should be completed by 
site staff prior to dispensing to subject.
5.5.2.2
Storage and Disposition of Study Drug
Study Drug
Storage Conditions*
ABT-493/ABT-530 bottles
15° to 25°C (59° to 77°F)
Sofosbuvir bottles
15° to 25°C (59° to 77°F)
Ribavirin bottles
15° to 25°C (59° to 77°F)
*
Please refer to clinical label for detailed storage conditions.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie.
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria, the site personnel 
must contact the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study.  Subjects will be allocated to one of two arms based on their HCV 
genotype (1 to 6), cirrhosis status (presence/absence), and prior treatment experience with 
PI- and/or NS5Ai-containing regimens before experiencing virologic failure in an AbbVie 
HCV parent study.  For enrollment of eligible subjects into the study, the site will utilize 
the IRT system in order to receive a unique study drug kit numbers.  The study drug kit 
numbers will be assigned according to schedules computer-generated before the start of 
the study by the AbbVie Statistics Department.  Upon receipt of study drug, the site will 
acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.


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Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Study drug dosing will 
be initiated at the Study Day 1 Visit.
ABT-493/ABT-530 (3 tablets) will be dosed QD with food.
SOF (1 tablet) will be dosed QD, at the same time as ABT-493/ABT-530.
RBV (3 to 6 tablets based on age and weight of the subject at Day 1) will be dosed twice 
daily with food.  For example, if a subject takes 5 tablets of RBV per day, 2 tablets should 
be taken in the morning, and 3 tablets should be taken in the evening.  One of the two 
daily RBV doses will be taken at the same time as ABT-493/ABT-530 and SOF.  The 
other RBV dose should be taken approximately 12 hours apart.
The timing of study drugs administration should be kept consistent during the treatment 
period.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
At the start of the study, each subject should receive counseling regarding the importance 
of dosing adherence with the treatment regimen with regard to virologic response and 
potential development of resistance.


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At each study visit after Day 1 during the Treatment Period, subjects will be instructed to 
bring all bottles of study drug (full, partial or empty) for assessment of treatment 
compliance.  At post-baseline dispensing visits denoted in Appendix C, study site 
personnel will assess subject compliance by inspecting the contents of the bottles and 
record the status of each one, as well as the exact number of remaining tablets of 
ABT-493/ABT-530, SOF and RBV in IRT.  Treatment compliance will be based on the 
number of tablets dispensed, as recorded in IRT, and the number of remaining tablets.  If 
poor compliance is noted, the subject should be counseled and this should be documented 
in the subject's source.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  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 dispensed, subject number, 
initials of person who dispensed study drug and date dispensed for each subject.  An 
overall accountability of the study drug will be performed and verified by the AbbVie 
monitor throughout the Treatment Period.  The monitor will review study drug 
accountability on an ongoing basis.  Final accountability will be verified by the monitor at 
the end of study drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug bottle of 
ABT-493/ABT-530, SOF, or RBV, the IRT system must be contacted and informed of the 
misplaced or damaged study drug.  If the bottle is damaged, the subject will be requested 
to return the remaining study drug to the site.  Replacement study drug may only be 
dispensed to the subject by contacting the IRT system.  Study drug replacement(s) and an 
explanation of the reason for the misplaced or damaged study drug(s) will be documented 
within the IRT system.  Study drug start dates for each drug and the last dose of the 
regimen will be documented in the subject's source documents and recorded on the 
appropriate eCRF.  The status of each bottle, number of tablets remaining in each bottle 


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returned, and the date of reconciliation will be documented in the IRT system.  The 
monitor will review study drug accountability on an ongoing basis.
Upon completion of or discontinuation from the Treatment Period, all original study drug 
bottles (containing unused study drugs) will be returned to AbbVie (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  The number of tablets of each type of study drug returned in each bottle will 
be noted in the IRT system or on a drug accountability log (if appropriate).  Labels must 
remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is an open-label, non-randomized, multicenter study exploring the efficacy and safety 
of the combination regimen of ABT-493/ABT-530 plus SOF and RBV in subjects with 
chronic HCV GT1 – 6 infection who experienced virologic failure in HCV treatment in an 
AbbVie HCV parent study.
The primary efficacy is measured by the percentage of patients achieving SVR12 in each 
treatment arm.  The study design will provide additional data on ABT-493/ABT-530 in 
combination with SOF and RBV, such as response rates in subjects infected with different 
HCV genotypes, with or without cirrhosis, the PI and/or NS5Ai treatment experience 
prior to the AbbVie HCV parent study pharmacokinetics, resistance, and the nature of 
virologic failure (e.g., OTVF or post-treatment relapse).
No control group is included in this study.  This study does not aim to establish non-
inferiority or superiority to the standards of care, thus a comparator arm is not needed.  
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.


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5.6.3
Suitability of Subject Population
This study will enroll subjects infected with chronic HCV GT1 – 6 who experienced 
virologic failure following treatment with ABT-493/ABT-530, 3D or 2D regimens in an 
AbbVie HCV parent study, in order to assess the efficacy, safety of ABT-493/ABT-530 
plus SOF and RBV as a retreatment regimen.
5.6.4
Selection of Doses in the Study
5.6.4.1
Rationale for Dose Selections
HCV infected patients who were treated and experienced virologic failure in an AbbVie 
HCV parent study, will be treated with ABT-493/ABT-530 300 mg/120 mg in 
combination with SOF 400 mg and weight-based RBV for 12 or 16 weeks in the current 
protocol.  The dose of 300 mg/120 mg of ABT-493/ABT-530 was selected based on 
multiple HCV clinical trials including Studies M14-867, M14-868 and M15-410 in order 
to optimize efficacy of the combination while maintaining an acceptable safety profile, is 
consistent with the dose used in AbbVie HCV Phase 3 studies and is the approved dose 
for commercial use.
In Studies M14-867 and M14-868, high SVR rates have been achieved for the 
combination of ABT-493 300 mg and ABT-530 120 mg (Table 6).  All subjects (N = 147) 
with HCV GT1, GT2, GT4, GT5 and GT6 infection have achieved SVR12, following 8 or 
12 weeks of treatment and a high SVR12 rate of 96% has been achieved for GT3 infected 
subjects (107/111).  In Study M15-410 Part 1, 21 out of 22 subjects (95%) who were 
previous DAA-experienced and treated with the ABT-493 300 mg and ABT-530 120 mg 
combination therapy in the study have achieved SVR12.  
ABT-493 and ABT-530 regimens including the ABT-493/ABT-530 300 mg/120 mg QD 
regimen used in the current study have been well-tolerated and safe across all Phase 2b 
study arms including cirrhotic subjects.  All ABT-493 and ABT-530 doses studied had a 
similar safety profile.  The most frequently reported adverse events were fatigue, nausea 
and headache and were mostly Grade 1 or 2 in severity.  In all subjects with baseline ALT 


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elevations, ALT levels normalized or trended toward normal with DAA treatment, and 
there have been no on-treatment ALT elevations above baseline grade.
SOF, an HCV nucleotide analog NS5B polymerase inhibitor, is approved for use at a dose 
of 400 mg per day.  At this dose, SOF has been investigated in various studies in 
combination with RBV, pegIFN/RBV, and with the protease inhibitor simeprevir and the 
NS5A inhibitors DCV and LDV with or without RBV in cirrhotic and non-cirrhotic 
subjects, including those with prior failure of pegIFN and a protease inhibitor.48,49  This 
dose has been shown to demonstrate significant antiviral activity with only modest 
treatment limiting toxicities and a safety profile that is similar to that of the AbbVie 
DAA's regimen.  Therefore this dose will used in this study.
Weight based RBV, 600 mg to 1200 mg, will be dose-divided to twice daily.  This dose is 
approved for treatment of adult and adolescent patients with chronic HCV infection in 
combination with pegIFN.  The same dose is selected for this study because its safety 
profile has been well characterized when administered with pegIFN, including incidence 
of hemolytic anemia, and there are well-defined dose reduction criteria in the event of 
RBV-induced anemia as noted in Section 6.1.7.4.  In addition, the RBV dose was studied 
in the absence of pegIFN in adults in Studies M12-267, M12-746, M12-998, M11-652, 
M11-646, M13-098, M13-389, M13-961, M14-002, and M14-004, and in adolescents in 
Study M14-748, and the RBV dose was found to be generally safe and well tolerated and 
resulted in high SVR rates.  It has been demonstrated that for previous virologic failures, 
the inclusion of additional drugs that have different mechanisms of action in the 
combination retreatment regimen will increase the probability to achieve SVR.50  
5.6.4.2
Rationale for Duration Selections
HCV infected patients who were treated and experienced a virologic failure in an AbbVie 
HCV parent study, will receive a regimen of ABT-493/ABT-530 in combination with 
SOF 400 mg and weight based RBV for 12 or 16 weeks in the current protocol.  
Treatment duration for the study was selected based on available data from 
Study M15-410 and it is dependent upon the subject's HCV genotype, cirrhotic status and 


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prior treatment experience with PI- and/or NS5Ai-containing regimens before 
experiencing HCV virologic failure in an AbbVie HCV parent study.  In Part 1 of 
Study M15-410, the efficacy and safety of ABT-493 and ABT-530 with or without RBV 
in adults with chronic HCV GT1 infection without cirrhosis who previously failed 
treatment with a DAA-containing regimen were assessed.  The interim results from this 
study, as summarized in Section 3.0, demonstrate high SVR12 rates (mITT rates of 95 –
100%) following a 12-week treatment regimen of ABT-493 and ABT-530 with or without 
RBV.  In the current study, the addition of SOF and RBV to ABT-493/ABT-530 offers 
multiple mechanisms of action in the retreatment regimen and will increase the 
probability to achieve SVR following similar treatment duration.  
In order to increase the probability to achieve SVR for subjects who are more difficult to 
treat, such as subjects with HCV GT3 infection, subjects with compensated cirrhosis and 
subjects who previously failed PI and/or NS5Ai-containing regimens prior to 
experiencing a virologic failure in an AbbVie HCV parent study, the treatment duration 
will be extended to 16 weeks.  Since ABT-493/ABT-530 has pangenotypic activity, 
subjects with mixed infections and undetermined genotypes will be allowed to be treated 
in this study.  The extended treatment duration of 16 weeks for subjects with GT3 
infection was based on the study design of Part 3 of Study M14-868.  In Part 3 of 
Study M14-868, GT3-infected subjects who were treatment-naïve are allocated to the 
12 week arm, GT3-infected subjects who were IFN-experienced with compensated 
cirrhosis are allocated to the 16 week arm, GT3-infected subjects who were IFN-
experienced subjects without compensated cirrhosis are allocated at a 1:1 ratio to the 
12 week and 16 week treatment arms.  To be consistent with the rationale of duration 
selection in Study M14-868, a longer treatment duration of 16 weeks with an intensified 
regimen of ABT-493/ABT-530 in combination with SOF and RBV is selected in 
Study M15-942 for subjects with GT3 infection, in order to increase the probability to 
achieve SVR in HCV GT3 infected subjects who have already failed a DAA-containing 
regimen.


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Subjects with compensated cirrhosis have historically required longer treatment durations 
versus patients without cirrhosis.  The ABT-493/ABT-530 regimen was evaluated for 
12 week treatment duration in Study M14-172 for subjects with HCV GT1, 2, 4, 5, and 
6 infection with compensated cirrhosis, who are either treatment-naïve, or PI- and NS5Ai-
naïve.  In Study M14-867, subjects infected with HCV GT1 with cirrhosis were evaluated 
following an 8 week treatment duration with ABT-493/ABT-530.  All subjects who have 
completed the treatment (33 of 34) have achieved SVR.  One subject prematurely 
discontinued at treatment Week 4 due to an AE, and at the time of discontinuation, the 
subject had no detectable virus.
Subjects who failed multiple DAA regimens are considered to be a difficult to treat 
patient population.  The ABT-493/ABT-530 regimen was evaluated for a 12 week and 
16 week treatment duration in Study M15-410, Part 2 for DAA treatment-experienced 
subjects with HCV GT1, 4, 5, and 6 infection with or without compensated cirrhosis.  It is 
anticipated that a treatment duration of 16 weeks with ABT-493/ABT-530 in combination 
with SOF and RBV for subjects who have failed multiple DAA treatment regimens will 
maximize the probability of achieving SVR, and reduce the chance of HCV virologic 
failures across genotypes.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.6.  For product complaints, please refer to Section 6.2.


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


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interruption, necessitate therapeutic medical intervention, meets protocol specific criteria 
(see Section 6.1.7 regarding toxicity management) and/or are deemed clinically 
significant by the investigator should be recorded as AEs or SAEs as defined in 
Section 6.1.1.1 and Section 6.1.1.2.
An elective surgery/procedure scheduled to occur during the 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 due to worsening of the pre-existing condition), then the deterioration 
of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a SAE 
within 24 hours of the site being made aware of the serious adverse event:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.


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


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CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity.
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
6.1.3
Relationship to Study Drug
Assessment of relatedness will be made separately with respect to ABT-493/ABT-530, 
SOF, and RBV.  The investigator will use the following definitions to assess the 
relationship of the adverse event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.


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For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it as not 
assessable, AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, "Other" cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related non-serious adverse events 
(e.g., infection at liver biopsy site) will be collected from the time the subject signed the 
study-specific informed consent until the administration of the first dose of study drug.  
From the time of the administration of the first dose of study drug until 30 days following 
discontinuation of study treatment, all adverse events and serious adverse events will be
collected, whether solicited or spontaneously reported by the subject.
After 30 days following completion of study treatment and throughout the Post-Treatment 
Period, all spontaneously reported SAEs will be collected (nonserious AEs will not be 
collected).
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system or if RAVE is not operable should be documented on 
the SAE Non-CRF forms and emailed (preferred route) or should be faxed to Clinical 
Pharmacovigilance within 24 hours of the site becoming aware of the serious adverse 
event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Team
Dept. R48S, Bldg. AP30-3
1 North Waukegan Road
North Chicago, IL 60064
Office:
(847) 938-1870
Email:
SafetyManagement_Virology@abbvie.com


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For any subject safety concerns, please contact the physician listed below:
Therapeutic Area Medical Director:
1 North Waukegan Road
North Chicago, IL 60064
Contact Information:
Office:
Mobile:
eFAX:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  +1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Global and Local Regulations.  The reference document used for SUSAR reporting will 
be the most current version of the Investigator's Brochure.  The reference document used 
for SUSAR reporting in the EU countries will be the most current version of the Summary 
of Product Characteristics (SmPC).
6.1.6
Pregnancy
Subjects and their partners should avoid pregnancy, and males should avoid sperm 
donation, starting with Study Day 1 until 4 months for females subjects and 7 months for 
male subjects and their female partners after stopping RBV, or as directed by local RBV 
label, whichever is more restrictive.


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Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Follow Section 5.4.1 if a female subject has a positive 
pregnancy test during the Treatment Period.  Subjects will be monitored for SVR in the 
Post-Treatment Period as described in Section 5.1.3.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies through the duration of the study (or per local 
RBV label).  The investigator is encouraged to report the 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.
6.1.7
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.  All adverse events and 
laboratory abnormalities will be managed and followed to a satisfactory clinical 
resolution.  A toxicity is deemed "clinically significant" based on the medical judgment of 
the investigator.  Please refer to Section 6.1.7.1, Section 6.1.7.2, Section 6.1.7.3, 
Section 6.1.7.4, Section 6.1.7.5, and Section 6.1.7.6 for details on Toxicity Grades.
Interruption of DAA therapy is not recommended, and if interruption occurs under 
extenuating circumstances (e.g., due to hospitalization of the subject), it should be less 
than 7 consecutive days.  If study drug interruption lasts for longer than 7 days, the 
investigator should contact the AbbVie Study TA MD.  The Investigator should ensure 
that any study drug interruptions or RBV dose modifications and associated adverse 
events are promptly entered into the appropriate eCRFs.
The toxicity management guidelines below should be followed throughout the Treatment 
Period of the study.  Specific toxicity management guidelines apply to the instances of:  


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decreases in hemoglobin for subjects receiving RBV (Section 6.1.7.4), increases in ALT 
(Section 6.1.7.5), and reductions in Creatinine Clearance (Section 6.1.7.6).
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities and/or Adverse 
Events
Subjects who develop Grade 1 or 2 laboratory abnormalities or adverse events may 
continue study drugs with appropriate medical management and follow-up per study 
protocol.
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities
With the exception of Grade 3 or higher abnormalities of uric acid, phosphorus, total 
cholesterol, triglycerides, or glucose (in subjects with a history of diabetes), if a subject 
experiences a Grade 3 or greater laboratory abnormality during the treatment period, the 
abnormal laboratory test should be repeated (repeat testing should be done on a re-drawn 
sample).  If the Grade 3 or greater abnormality is confirmed, the investigator should 
assess whether the abnormality can be managed medically as per local practice without 
interruption of study drug or whether study drugs should be interrupted and the laboratory 
parameter followed until it improves.
If study drugs are interrupted and restarted and the abnormality recurs, then study drugs 
should be permanently discontinued.
Decreases in hemoglobin level should be managed according to the guidance in 
Section 6.1.7.4, elevations of serum ALT should be managed according to the guidance in 
Section 6.1.7.5 and reductions in creatinine clearance for subjects receiving RBV should 
be managed according to the guidance in Section 6.1.7.6.  Grade 3 or greater 
abnormalities of uric acid, phosphorus, total cholesterol, triglycerides or glucose (in 
subjects with a history of diabetes) should be managed medically as appropriate and do 
not require confirmation or study drug interruption, unless deemed necessary by the 
investigator.


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6.1.7.3
Grade 3 or 4 Adverse Events or Serious Adverse Events
If a subject experiences a Grade 3 or 4 adverse event or a serious adverse event that the 
investigator considers to have a reasonable possibility of relationship to study drug, the 
investigator should assess whether the adverse event can be managed medically without 
interruption of study drug, or whether study drugs should be interrupted until it improves.  
If study drugs are interrupted and restarted and the adverse event recurs, then study drugs 
should be permanently discontinued.
If a subject experiences a Grade 3 or 4 adverse event or serious adverse event that is 
considered unrelated (no reasonable possibility) to the study drugs, it is not necessary to 
interrupt study drugs unless an interruption is required because of the nature of the event 
(e.g., unable to take oral medications).
The investigator should ensure that all serious adverse events are reported to AbbVie 
within 24 hours of awareness.  Serious adverse event follow-up information, including 
associated dose interruptions (or discontinuations), must be reported to AbbVie within 
24 hours of awareness by entering updated SAE information into the appropriate eCRFs.
Grade 3 or 4 adverse events and any associated dose interruptions (or discontinuations) 
should be entered into the appropriate eCRFs.
6.1.7.4
Management of Decreases in Hemoglobin for Subjects 
Receiving RBV
Reductions in hemoglobin are a well characterized side effect of RBV exposure.  If a 
subject experiences a hemoglobin decrease that meets the criteria outlined in Table 13, a 
confirmatory test should be performed.  If the hemoglobin decrease is confirmed to meet 
the criteria, the management guidelines in Table 13 should be followed, unless local RBV 
label requires a more stringent management.  Management will be different for subjects 
without a history of known cardiac disease and subjects with known cardiac disease.


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Use of hematologic growth factors (such as erythropoietin, filgrastim), or blood 
transfusions is not recommended and is permitted only with approval of the AbbVie 
Study TA MD.  Management of hematologic growth factor therapy is the responsibility of 
the investigator, and growth factors will not be provided by AbbVie.
Alternate management of hemoglobin decreases outside of these criteria requires approval 
of the AbbVie Study TA MD, except for more stringent management requirement from a 
local RBV label.


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Table 13.
Management of Hemoglobin Decreases
Hemoglobin Reduction in Patients Without Cardiac Disease or 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 QD* and continue to monitor hemoglobin levels 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
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Hemoglobin 
< 8.5 g/dL
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Reduction in Patients with Stable Cardiac Disease or History of Stable Cardiac Disease
Hemoglobin decrease 
of ≥ 2 g/dL during a 
4-week treatment 
period (Hemoglobin 
≥10 g/dL)
Study drugs may be continued
Reduce RBV dose to 600 mg QD* and continue to monitor hemoglobin levels per protocol
If a subsequent hemoglobin result is greater than the level that triggered the dose 
reduction, the investigator may elect to increase RBV, with gradual, 200 mg dose 
increases towards the original dose
If the subject has symptoms consistent with their cardiac disease, manage subject as 
medically appropriate and AbbVie Study TA MD may be contacted
If hemoglobin does not increase, investigator may manage the subject as medically 
appropriate.  If hemoglobin decreases to < 10 g/dL see appropriate row below
Hemoglobin 
< 10.0 g/dL, but 
≥8.5 g/dL
Study drugs may be continued
Continue at reduced RBV dose as above (or reduce RBV dose to 600 mg QD* if this is the 
initial reduction) 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 hemoglobin < 10 g/dL despite being for 4 weeks on the reduced RBV dose, permanently 
discontinue RBV and manage the subject as medically appropriate
Hemoglobin 
< 8.5 g/dL or 
< 12 g/dL after 
4 weeks of dose 
reduction
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
*
For subjects aged 12 to less than 18, RBV dose reduction should be per local RBV label.
Management of other hematologic parameters besides hemoglobin (like WBC, platelets, 
neutrophils, etc.) should be performed according to the local RBV label.  Alternative RBV 
dosing can be used if agreed upon by AbbVie TA MD.


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6.1.7.5
Management of Increases in ALT
If a subject experiences a post-baseline ALT value ≥ 5 × ULN that is also ≥ 2 × Baseline 
value, the subject should have a confirmatory test should be performed.  If, the ALT is 
value confirmed ≥ 5 × ULN, and ≥ 2 × Baseline value, the recommendations below 
should be followed:
●
Complete hepatic questionnaire
●
Evaluate for alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable),
and obtain Anti-HAV IgM, Anti-HAV Total, Anti-HBc IgM, Anti-HBc Total, 
Anti-HBs, HBV DNA, HBsAg, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, 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 in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis.
○
At the discretion of the investigator.
Alternate management of confirmed ALT increases requires approval of the AbbVie 
Study TA MD.
6.1.7.6
Management of Reductions in Creatinine Clearance for 
Subjects Receiving RBV
Estimated glomerular filtration rate (eGFR, calculated using the MDRD equation) and 
Creatinine clearance (CrCl, estimated using the Cockcroft-Gault equation) will be 
calculated throughout the study.  Both results will be provided to the investigators, but 
toxicity management and RBV dose adjustment will be performed based on CrCl values 
only.  


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If a subject experiences an CrCl value below 50 mL/min, a confirmatory test should be 
performed as soon as possible.  If CrCl is confirmed to be below 50 mL/min, medical 
evaluation should include a full review of concurrent medications, including those taken 
on an as needed basis, those which are sold over the counter, and any dietary and herbal 
supplements.  
In addition, the following should occur:
●
Concomitant medication dose reduction based on CrCl or eGFR should be 
done as per local prescribing information of the concomitant medication (if 
applicable).  
●
The AbbVie Study TA MD should be contacted to discuss whether dose 
modification or drug substitution may be required for concomitant medications 
given the reduced kidney function as well as potential drug interactions with 
the DAAs.  Drug interactions between concomitant medications and the 
DAAs, for example, could potentially increase antihypertensive medications' 
exposures, especially in the setting of reduced kidney function and may result 
in further deterioration of renal function.  Also, if anti-hypertensive 
medications are adjusted, vital signs must be closely monitored to ensure 
appropriate blood pressure control.
●
The dose of RBV should be adjusted as follows:  
○
for CrCl between 30 and 50 mL/min:  alternating doses of 200 and 400 mg 
every other day; 
○
for CrCl less than 30 mL/min – 200 mg daily.  
●
A urine specimen should be obtained for urinalysis (including urine for 
albumin), and a separate urine specimen for archive should be obtained.
●
Creatinine clearance and any other necessary analytes should be repeated 
within 7 days and as clinically indicated until resolution.
○
If CrCl improves to > 50 mL/min within 14 days after RBV dose 
modification, consideration should be given to increase RBV dose towards 
the original value.  If CrCl decreases below 50 mL/min again, RBV should 
be permanently discontinued.


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The investigator should ensure that any concomitant medication changes, RBV dose 
modifications, study drug interruption and study drug discontinuations, as well as related 
adverse events are entered into the appropriate eCRFs.
Alternative management of RBV dose in the setting of reduced renal function will require 
approval of the AbbVie Study TA MD, unless it is a more stringent management required 
by local RBV label.
6.1.8
Collection of Data Regarding Known AIDS-Defining 
Conditions
HIV-1 infected subjects participating in clinical trials may develop conditions typically 
associated with AIDS.  A list of these known AIDS-Defining Conditions (ADCs) is 
presented in Appendix D.  The events listed in Appendix D will be summarized as HIV-
related events, not as adverse events.  These ADCs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.


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6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.  
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitors:




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Safety, and demographic analyses will be performed on all subjects who receive at least 
one dose of study drug.  Analyses, as specified in the statistical analysis plan, will be 
presented by treatment arm and overall.  Efficacy analyses will be performed on the 
intent-to-treat (ITT) population defined as all enrolled subjects who receive at least 
one dose of study drug, unless otherwise specified.  Sensitivity analyses of the primary 
efficacy endpoint, when applicable, will be performed on the intention-to-treat population 
modified to exclude subjects who did not achieve SVR12 for reasons other than virologic 
failure (mITT-VF).
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data).  HCV RNA values will be selected for the analyses of all 
SVR endpoints (e.g., SVR4, SVR12, and SVR24) based on defined visit windows.  A 
backward imputation method will be used to impute missing responses for SVR analyses.
8.1.1
Demographics 
Demographics and baseline characteristics will be summarized for all treated subjects by 
treatment arm and overall.  Demographics include age, weight, height, waist 
circumference, BMI, gender, race and ethnicity.  Baseline characteristics will be 
summarized as continuous variables (where appropriate) and as categorical variables, 
including all subgroup variables defined in Section 8.1.2.4, and include HCV genotype, 
DAA regimen received in prior AbbVie HCV study, treatment experience prior to 
enrolling in the AbbVie HCV parent study, baseline RAVs prior to entering the current re-
treatment study, other previous HCV regimens, HCV genotype, baseline HCV RNA 
levels, baseline fibrosis stage (F0 – F1, F2, F3, F4), baseline homeostasis model of 
assessment – insulin resistance (HOMA-IR), tobacco (user, ex-user, or non-user) and 
alcohol use (drinker, ex-drinker, or non-drinker) status, former injection drug user (yes, 
within last 12 months; yes, more than 12 months ago; or no), use of stable opiate 
substitution, history of diabetes, history of bleeding disorders, history of depression or 
bipolar disorder, history of cardiovascular disease, and geographic region.


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Summary statistics (N, mean, median, SD, and range) will be presented 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).
Study drug exposure and compliance will be summarized.  Treatment compliance to study 
drug will be calculated based on the percentage of tablets taken relative to the total tablets 
expected to be taken.  A subject is considered to be compliant if the percentage is between 
80% and 120%.  Compliance will be calculated for each subject and summarized with the 
mean, median, standard deviation, minimum, and maximum.  The percentage of 
compliant subjects will be summarized for each treatment arm.
8.1.2
Efficacy
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL that are HCV RNA detected or HCV RNA not detected.  HCV RNA ≥ LLOQ 
are all quantifiable values.
8.1.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint is the percentage of subjects in the ITT population who 
achieve SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drug), by 
treatment arm and overall.  The number and percentage of subjects achieving SVR12 will 
be summarized along with a two-sided 95% confidence interval using the normal 
approximation to the binomial distribution, unless the number of virologic failures is less 
than 5, then the Wilson's score method will be used for the confidence interval instead.
A summary of reason for SVR12 non-response (e.g., OTVF, relapse, other) will be 
provided.


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8.1.2.2
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are:
●
The percentage of subjects with HCV on treatment virologic failure by 
treatment arm and overall;
●
The percentage of subjects with post-treatment HCV virologic relapse by 
treatment arm and overall.  Subjects with reinfection will be summarized 
separately.
For the analysis of HCV virologic relapse, completion of treatment is defined as any 
subject with study drug duration of 77 days and 103 days or greater for subjects allocated 
to treatment durations of 12 weeks and 16 weeks, respectively.  
For each treatment arm and overall, as applicable, the number and percentage of subjects 
meeting each secondary efficacy endpoint will be summarized along with a two-sided 
95% confidence interval using Wilson's score method.
8.1.2.3
Sensitivity Analysis 
The two-sided 95% confidence interval using Wilson's score method will also be 
calculated as a sensitivity analysis for the primary endpoint of SVR12 based on ITT 
population.
As sensitivity analyses, the number and percentage of subjects in the mITT-VF 
populations achieving SVR12, as applicable, will be summarized along with a two-sided 
95% confidence interval using Wilson's score interval and the Normal approximation to 
the binomial distribution by treatment arm and overall.
8.1.2.4
Subgroup Analysis
The summary statistics of subjects with SVR12 will be provided for the following 
subgroups:
●
HCV genotype (1, 2, 3 4, 5, or 6);


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●
DAA-containing regimen received in the AbbVie HCV parent study: 
○
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○
3D or 2D
●
Previous treatment experience prior to enrolling in the AbbVie HCV parent 
study:
○
Treatment naive
○
Treatment experienced, DAA-naïve
○
Treatment experienced, PI-experienced only
○
Treatment experienced, NS5Ai-experienced only
○
Treatment experienced, PI- and NS5Ai-experienced 
○
Treatment experienced, NS5Bi-experienced only
○
Treatment experienced, NS5Bi- and PI-experienced 
○
Treatment experienced, NS5Bi- and NS5Ai-experienced
○
Treatment experienced, NS5Bi-, PI- and NS5Ai-experienced
●
Baseline RAVs prior to entering the current re-treatment study: NS3A alone, 
NS5A alone, NS5B alone, NS3A and NS5A, NS3A and NS5B, NS5A and 
NS5B, NS3A and NS5A and NS5B;
●
Baseline fibrosis stage (F0 – F1, F2, F3, or F4);
●
Baseline HCV RNA level (< 6,000,000 or ≥ 6,000,000 IU/mL) and 
(< 2,000,000, ≥ 2,000,000 to < 6,000,000, ≥ 6,000,000 to < 10,000,000, or 
≥10,000,000 IU/mL);
For subjects with cirrhosis only:
●
Baseline Child-Pugh Score (5, 6, or > 6);
●
Baseline APRI (≤ 2 or > 2);
●
Baseline platelets (< 90 or ≥ 90 × 109/L; < 50 or ≥ 50 × 109/L; < 100 or 
≥100 × 109/L; < 150 or ≥ 150 × 109/L);
●
Baseline albumin (< 35 or ≥ 35 g/L);
●
Any of baseline platelets < 90 × 109/L and baseline albumin < 35 g/L;


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Further details about subgroup analysis will be described in the statistical analysis plan.
8.1.2.5
Additional Efficacy Endpoints
The following additional efficacy endpoints will be summarized by treatment arm and 
overall:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects who achieve SVR 4 weeks after the last actual dose 
of study drug (SVR4);
●
The percentage of subjects who achieve SVR 24 weeks after the last actual 
dose of study drug (SVR24);
●
The percentage of subjects who relapse after achieving SVR12.
The number and percentage of subjects meeting each additional efficacy endpoint will be 
summarized along with a two-sided 95% confidence interval using the Wilson's score 
interval.
8.1.3
HCV Resistance Analyses
The genes of interest for NGS in this study are those encoding full length NS3/4A, NS5A 
and NS5B.  For each DAA target, signature resistance-associated amino acid positions 
will be identified by AbbVie Clinical Virology.  An appropriate prototypic reference 
sequence will be used for comparison with sequences from samples.
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore, if the HCV 
RNA level at the time of HCV virologic failure or treatment discontinuation is 
< 1000 IU/mL, the sample closest in time after HCV virologic failure/treatment 
discontinuation with an HCV RNA level ≥1000 IU/mL will be used.  Included time 
points for analyses on samples from subjects who do not achieve SVR12 are 1) the sample 
closest in time after failure/discontinuation with an HCV RNA level of ≥ 1000 IU/mL,


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and 2) 24 weeks post-DAA treatment, provided that resistance-associated variants were 
detected by NGS at the time of HCV virologic failure/treatment discontinuation.
The following definitions will be used in the HCV resistance analyses:
●
Baseline variant: a variant (by NGS) in a baseline sample (≥ 2% or ≥ 15% 
prevalence within a subject's viral population depending on variant frequency 
threshold utilized) that was not present in appropriate prototypic reference 
amino acid sequence for a given DAA target.
●
Post-baseline variant:  an amino acid variant in a post-baseline time point 
sample that was not detected at baseline (< 2%) in the subject and is detectable 
in ≥ 2% of the sequences from the post-baseline sample in a given DAA target.
●
Enriched variant:  variant present in both the baseline and a post-baseline 
sample whose prevalence in the post-baseline sample is at least 20 percentage 
points greater than the prevalence in the baseline sample [(post-baseline % –
baseline %) ≥ 20]
●
Treatment-emergent variant: A post-baseline variant or an enriched variant.
●
Variant at signature amino acid position:  variant (relative to reference) present 
in a baseline or a post-baseline sample at a signature amino acid position.
The following analyses will be performed for all subjects:
To characterize prior HCV DAA resistance patterns in the study population, available 
resistance analysis data obtained at the time of the subject's virologic failure of the 
previous DAA treatment will be collected and reported.
For all subjects, the following will be provided:
●
The number and percentage of subjects with baseline variants at detection-
thresholds of ≥ 2% and ≥ 15% for variants at signature amino acid positions, 
and ≥ 15% for variants at non-signature positions.
●
A listing of all baseline variants (≥ 2% detection threshold) at signature 
resistance-associated amino acid positions for each DAA target.


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●
A listing of all baseline variants (≥ 15% detection threshold) at non-signature 
resistance-associated amino acid positions for each DAA target.
●
A listing of subjects with multiple baseline variants at signature amino acid 
positions (each at ≥ 15% prevalence within a subject's viral population), either 
within a DAA target or across any 3 DAA targets.
●
The impact of baseline variants on treatment outcome will be assessed as 
follows:  for each variant, the SVR12 rate will be calculated for subjects with 
and without the variant and the 2 rates will be compared.  Analyses will be 
grouped by subject's HCV subtype and DAA target.  Subjects not achieving 
SVR12 due to non-virologic reasons will be excluded from this analysis.  These 
analyses will be performed based on the following criteria:
○
An analysis will be performed based on amino acid position, using 
detection thresholds of ≥ 2% and ≥ 15% for all variants at each signature 
amino acid position and a detection threshold of ≥ 15% for all variants at 
each non-signature amino acid position.
○
An additional analysis will be performed using detection thresholds of 
≥2% and ≥ 15% for the impact of each specific variant as specified by 
clinical virology.
The following will be provided for subjects who do not achieve SVR12 and have post-
baseline resistance data available:
●
A listing by subject of all treatment-emergent variants relative to the baseline 
sequence will be provided for each DAA target
●
A listing by subject of all variants at signature amino acid positions
●
The number and percentage of subjects (with subject listing) with variants 
emerging at an amino acid position relative to baseline
●
The number and percentage of subjects (with subject listing) with certain 
specific emerged variants
The persistence of post-baseline variants at signature resistance-associated amino acid 
positions for each target will be assessed by NGS at Post-Treatment Week 24.  A listing 


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by subject and time point of all post-baseline variants relative to the baseline amino acid 
sequence will be provided for each DAA target.
If resistance-associated variants are not detected in a given target for a subject at the time 
of failure/discontinuation, then that target may not be sequenced in subsequent samples 
from that subject.
Phylogenetic analysis will be conducted on HCV sequences from available baseline 
samples from all subjects in the study in order to accurately determine their subtypes.  The 
resulting subtype information will be presented in summaries of baseline characteristics 
and efficacy subgroup analyses.
8.1.4
HIV Resistance Analyses
If a subject develops a confirmed, plasma HIV-1 RNA level ≥ 500 copies/mL after 
starting the study, the subject's HIV-1 PR, RT, and/or IN sequences, as applicable, will be 
analyzed by Monogram Biosciences using the GenoSure® Prime drug resistance assays.  
The number of subjects who demonstrate HIV genotypic resistance and the genotypic 
resistant mutations detected in the samples obtained from these subjects will be tabulated 
and summarized.  Resistance will be defined as described by the IAS-USA Panel.48
8.1.5
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.  All safety analysis will be done by treatment arm and overall.
8.1.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT).  The tabulation of the number of subjects 
with treatment-emergent adverse events by severity grade (Grades 1 – 5) and relationship 


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to each study drug also will be provided.  Subjects reporting more than one adverse event 
for a given MedDRA preferred term will be counted only once for that term using the 
most severe grade for the severity grade table and the most related for the relationship to 
study drug tables.  Subjects reporting more than one type of event within a SOC will be 
counted only once for that SOC.
Additional analyses will be described in the statistical analysis plan.
8.1.5.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last non-missing measurement prior to the initial dose of study drug.  Mean changes from 
baseline to each post-baseline visit, including Final Treatment Visit, will be summarized 
descriptively.
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 percentage of subjects who 
experience post-baseline shifts during treatment in clinical laboratory values from 
low/normal to high and high/normal to low based on the normal range will be 
summarized.
In addition, the number and percentage of subjects with post-baseline values meeting pre-
specified criteria for Potentially Clinically Significant laboratory values or toxicity grades 
during treatment will be summarized.
8.1.5.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight 
from baseline to each post-baseline visit, including Final Treatment Visit, will be 
summarized.  The number and percentage of subjects with post-baseline values meeting 
pre-defined criteria for Potentially Clinically Significant vital signs values during 
treatment will be summarized.


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8.1.5.4
HCV/HIV-1 Co-Infection
The following additional safety data will be summarized and analyzed for subjects with 
HCV/HIV-1 co-infection overall and in each treatment arm:
●
The percentage of subjects with plasma HIV-1 RNA suppression at the end of 
treatment and at Post-Treatment Week 12 using the FDA Snapshot Algorithm;
●
The number and percentage of subjects with plasma HIV-1 RNA 
< 20 copies/mL at each applicable time point;
●
Change from baseline in CD4+ T-cell count (absolute and percent) to each 
applicable post-baseline time point;
●
Change from baseline in lymphocytes (count and percentage) and CD8+ T-cell 
counts (absolute and percent) to each applicable post-baseline time point;
●
The listing of subjects with a plasma HIV-1 RNA value ≥ 200 copies/mL at 
any baseline or post-baseline visit during the study.
The analysis of change from baseline in CD4+ T-cell count (absolute and percent), 
lymphocytes (count and percentage) and CD8+ T-cell counts (absolute and percent) will 
report the mean and median values at baseline and at each applicable post-baseline visit, 
as well as N, mean, median, standard deviation (SD), minimum and maximum values for 
the change from baseline overall and within each treatment arm.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of ABT-530, ABT-493, RBV, SOF and GS-331007 and 
pharmacokinetic parameter values for ABT-493 and ABT-530 will be tabulated for each 
subject and group.  Summary statistics will be computed for each time and visit.
Plasma concentration data from this study may be combined with data from other studies 
and analyzed using the following general methodology:
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 


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structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of 
major interest in the NONMEM analyses.  If necessary, other parameters, including the 
parameters describing absorption characteristics, may be fixed if useful in the analysis.  
The evaluation criteria described below will be used to examine the performance of 
different models.
●
The objective function of the best model is significantly smaller than the 
alternative model(s).
●
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept 
and a slope of one) than the alternative model(s).
●
Visual inspection of model fits, standard errors of model parameters and 
change in inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates CL/F and V/F values with only 
potentially physiologically relevant or clinically meaningful covariates (such as subject 
age, sex, body weight, concomitant medications, laboratory markers of hepatic or renal 
function, etc.) will be explored using stepwise forward selection method, or a generalized 
additive method (GAM), or another suitable regression/smoothing method at a 
significance level of 0.05.  After identification of all relevant covariates, a stepwise 
backward elimination of covariates from the full model will be employed to evaluate the 
significance (at P < 0.005, corresponding to an increase in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
In general, all continuous covariates will be entered in the model, initially in a linear 
fashion, with continuous covariates centered around the median value.  Linear or non-


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linear relationships of primary pharmacokinetic parameters with various covariates may 
also be explored.  For example:
TVCLi = Theta(1) + Theta(2) (Comedication [1,2,…] + Theta(3) (WTi-median value) + 
Theta(4) (AGEi – median value).
Where TVCLi = Typical value of clearance for an individual i1, Theta(1) is the intercept 
and Theta(2) – (4) are regression parameters relating the fixed effects (weight and age 
centered on the median value) to clearance.
Relationship between exposure (e.g., population pharmacokinetic model predicted 
concentrations over time or average concentrations or AUC or trough concentrations of 
the individual model-predicted pharmacokinetic profiles, or some other appropriate 
measure of exposure) and clinical observations (antiviral activity) will be explored.  
Exposure-response relationships for primary and secondary efficacy variables and/or 
some safety measures of interest may also be explored.
Additionally, relationship between exposure and safety endpoints of interest may also be 
explored.  Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
It is anticipated that approximately 50 HCV infected, DAA treatment-experienced 
subjects who have experienced virologic failure in an AbbVie HCV parent study will be 
enrolled.  
8.3
Randomization Methods
This study is not randomized.  Eligible subjects will be allocated to a treatment arm 
according to their HCV genotype, cirrhosis status (presence/absence), and prior treatment 
experience with PI- and/or NS5Ai-containing regimens before experiencing virologic 
failure in the AbbVie HCV parent study.


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


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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.
The optional pharmacogenetic testing and analyses will only be performed if the subject 
has voluntarily signed and dated the IRB/IEC approved pharmacogenetic informed 
consent, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  The pharmacogenetic informed consent must be signed 
before the pharmacogenetic testing is performed.  If the subject does not consent to the 
additional pharmacogenetic testing, it will not impact the subject's participation in the 
study.
In the event a subject withdraws from the main study, optional pharmacogenetic 
exploratory research samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for the optional samples.  If consent is withdrawn for the 
optional sampling, the subject must inform their study doctor, and once AbbVie is 
informed, the optional samples will be destroyed.  However, if the subject withdraws 
his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.


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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
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 will be 
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.


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The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will continuously, throughout 
the study, verify that all subjects sign the informed consent prior to any study specific 
procedures being conducted, that the protocol procedures are being followed 
appropriately, and that the information provided in the eCRF is complete, accurate, and 
supported by information in source documents.  Computer logic and manual checks will 
be created to identify items such as inconsistent study dates.  Any necessary corrections 
will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional pharmacogenetic exploratory research 
samples from this study will be experimental in nature and the results will not be suitable 
for clinical decision making or patient management.  Hence, the subject will not be 


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informed of individual results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, researchers will have no access to subject 
identifiers.  Individual results will not be reported to anyone not directly involved in this 
research other than for regulatory purposes.  Aggregate data from optional 
pharmacogenetic exploratory research may be provided to investigators and used in 
scientific publications or presented at medical conventions.  Optional pharmacogenetic 
exploratory research information will be published or presented only in a way that does 
not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and other applicable regulatory requirements.  If the investigator is 
not able to retain the records, he/she must notify AbbVie to arrange alternative archiving 
options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for 
Glecaprevir/Pibrentasvir, and the product labeling for SOF and RBV.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-Label, Multicenter Study to Evaluate the Efficacy and 
Safety of ABT-493/ABT-530 in Combination with Sofosbuvir and 
Ribavirin in Chronic Hepatitis C (HCV) Infected Subjects Who 
Have Experienced Virologic Failure in AbbVie HCV Clinical 
Studies (MAGELLAN-3)
Protocol Date:
06 November 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
World Health Organization.  Worldwide Statistics for HCV.  Weekly 
Epidemiological Record No. 49.  10 December 1999.
2.
Kershenobich D, Razavi HA, Sánchez-Avila JF, et al.  Trends and projections of 
hepatitis C virus epidemiology in Latin America.  Liver Int.  
2011;31 (Suppl 2):18-29.
3.
Sievert W, Altraif I, Razavi HA, et al.  A systematic review of hepatitis C virus 
epidemiology in Asia, Australia and Egypt.  Liver Int.  2011;31 (Suppl 2):61-80.
4.
Manos MM, Shvachko VA, Murphy RC, et al.  Distribution of hepatitis C virus 
genotypes in a diverse US integrated health care population.  J Med Virol.  
2012;84(11):1744-50.
5.
Gottwein JM, Scheel TK, Jensen TB, et al.  Differential efficacy of protease 
inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant 
viruses.  Gastroenterology.  2011;141(3):1067-79.
6.
AbbVie.  Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir Investiagtor's Brochure 
Edition 1.  09 June 2016.
7.
OLYSIO® (Simeprevir) [US prescribing information].  Titusville, NJ; Janssen 
Products, LP, 2013.
8.
Chase R, Black S, McMonagle P, et al.  Characterization of resistance associated 
variants selected in GT1, GT2 and GT3 replicons by the HCV NS3A/4A protease 
inhibitor MK-5172.  Presented at the International Conference on Viral Hepatitis, 
New York City, United States, March 2013.
9.
McPhee F, Friborg J, Levine S, et al.  Resistance analysis of hepatitis C virus NS3 
protease inhibitor asunaprevir.  Antimicrob Agents Chemother.  
2012;56(7):3670-81.
10.
Yang H, Robinson M, Corsa AC, et al.  Preclinical characterization of the novel 
hepatitis C virus NS3 protease inhibitor GS-9451.  Antimicrob Agents Chemother.  
2014;58(2):647-53.


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11.
Taylor J, Appleby T, Barauskas O, et al.  Preclinical profile of the pangenotypic 
HCV NS3/4A protease inhibitor GS-9857.  EASL – The International Liver 
Congress 2015.  50th annual Meeting of the European association for the Study of 
the Liver Vienna, Austria.  April 22-26, 2015.
12.
Lenz O, Verbinnen T, Lin TI, et al.  In vitro resistance profile of the hepatitis C 
virus NS3/4A protease inhibitor TMC435.  Antimicrob Agents Chemother.  
2010;54(5):1878-87.
13.
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's 
Brochure Edition 3.  29 August 2017.
14.
Wang C, Jia L, O'Boyle DR 2nd, et al.  Comparison of daclatasvir resistance 
barriers on NS5A from hepatitis C virus genotypes 1 to 6:  implications for cross-
genotype activity.  Antimicrob Agents Chemother.  2014;58(9):5155-63.
15.
Cheng G, Peng B, Corsa A, et al.  Antiviral activity and resistance profile of the 
novel HCV NS5A inhibitor GS-5885.  EASL.  47th Annual Meeting 
April 18th – 22nd 2012.
16.
HARVONI® (ledipasvir and sofosbuvir) [US prescribing information].  Foster City, 
CA; Gilead Sciences, Inc., 2014.
17.
Cheng G, Tian Y, Yu M, et al.  GS-5816, a second-generation HCV NS5A 
inhibitor with potent antiviral activity, broad genotypic coverage, and a high 
resistance barrier.  EASL.  48th Annual Meeting April 24th – 28th 2013.
18.
Liu R, Kong R, Mann P, et al.  In vitro resistance analysis of Merck's HCV NS5a 
inhibitor MK-8742 demonstrates increased potency against clinical resistance 
variants and improved resistance profile.  EASL.  47th Annual Meeting
April 18th – 22nd 2012.
19.
Asante-Appiah E, Liu R, Curry S, et al.  MK-8408, a potent and selective NS5A 
inhibitor with a high genetic barrier to resistance and activity against HCV 
genotypes 1-6.  65th Annual Meeting of the American Association for the Study of 
Liver Diseases.  Boston, MA Nov 7-11 2014.


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20.
Fridell RA, Qiu D, Wang C, et al.  Resistance analysis of the hepatitis C virus 
NS5A inhibitor BMS-790052 in an in vitro replicon system.  Antimicrob Agents 
Chemother. 2010;54(9):3641-50.
21.
Wong KA, Worth A, Martin R, et al.  Characterization of hepatitis C virus 
resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885.  
Antimicrob Agents Chemother.  2013;57(12):6333-40.
22.
Ng T, Krishnan P, Kati W, et al.  ABT-530, an HCV NS5A inhibitor with potent 
pangenotypic activity and high genetic barrier to resistance.  Poster 639, CROI, 
2014.
23.
Ng T, Reisch T, Middleton T, et al.  ABT-493, a potent HCV NS3/4A protease 
inhibitor with broad genotype coverage.  Poster 639, CROI, 2014.
24.
Ng T, Pilot-Matias T, Lu L et al.  A Next Generation HCV DAA Combination:  
Potent, Pangenotypic Inhibitors ABT-493 and ABT-530 with High Barriers to 
Resistance.  Poster 1946, AASLD, 2014.
25.
Konerman MA, Mehta SH, Sutcliffe CG, et al.  Fibrosis progression in human 
immunodeficiency virus/hepatitis C virus coinfected adults:  prospective analysis 
of 435 liver biopsy pairs.  Hepatology.  2014;59(3):767-75.
26.
Lo Re V III, Kallan MJ, Tate JP, et al.  Hepatic decompensation in antiretroviral 
treated patients co-infected with HIV and hepatitis C virus compared with 
hepatitis C virus-monoinfected patients:  a cohort study.  Ann Intern Med.  
2014;160(6):369-79.
27.
Monga HK, Rodriguez-Barradas MC, Breaux K, et al.  Hepatitis C virus infection 
related morbidity and mortality among patients with human immunodeficiency 
virus infection.  Clin Infect Dis.  2001;33(2):240-47.
28.
Sulkowski MS.  HCV therapy in HIV-infected patients.  Liver Int.  
2013;33 (Suppl 1):63-7.
29.
Kitahata MM, Gange SJ, Abraham AG, et al.  Effect of early versus deferred 
antiretroviral therapy for HIV on survival.  N Engl J Med.  2009;360(18):1815-26.


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30.
Karageorgopoulos DE, Allen J, Bhagani S.  Hepatitis C in human 
immunodeficiency virus co-infected individuals:  is this still a "special 
population"?  World J Hepatol.  2015;7(15):1936-52.
31.
AASLD and IDSA.  Patients with HIV/HCV coinfection.  Available from:  
www.HCVGuidance.org.  Available on:  October 02, 2017.
32.
Sulkowski MS, Eron JJ, Wyles D, et al.  Ombitasvir, paritaprevir co-dosed with 
ritonavir, dasabuvir and ribavirin for hepatitis C in patients co-infected with HIV-1:  
a randomized trial.  JAMA.  2015;313(12):1223-31.
33.
Feld JJ, Kowdley KV, Coakley E, et al.  Treatment of HCV with ABT-450/r 
ombitasvir and dasabuvir with ribavirin.  N Engl J Med.  2014;370(17):1594-603.
34.
Zeuzem S, Jacobson IM, Baykal T, et al.  Retreatment of HCV with ABT-450/r 
ombitasvir and dasabuvir with ribavirin.  N Engl J Med.  2014;370(17):1604-14.
35.
Poordad F, Hezode C, Trinh R, et al.  ABT-450/r-ombitasvir and dasabuvir with 
ribavirin for hepatitis C with cirrhosis.  N Engl J Med.  2014;370(21):1973-82.
36.
Naggie S, Cooper C, Saag M, et al.  Ledipasvir and sofosbuvir for HCV in patients 
coinfected with HIV-1.  N Engl J Med.  2015;373(8):705-13.
37.
Afdhal N, Zeuzem S, Kwo P, et al.  Ledipasvir and sofosbuvir for untreated HCV 
genotype 1 infection.  N Engl J Med.  2014;370(20):1889-98.
38.
Afdhal N, Reddy KR, Nelson DR, et al.  Ledipasvir and sofosbuvir for previously 
treated HCV genotype 1 infection.  N Engl J Med.  2014;370(16):1483-93.
39.
Kowdley KV, Gordon SC, Reddy KR, et al.  Ledipasvir and sofosbuvir for 8 or 
12 weeks for chronic HCV without cirrhosis.  N Engl J Med.  
2014;370(20):1879-88.
40.
Wyles DL, Ruane PJ, Sulkowski MS, et al.  Daclatasvir plus sofosbuvir for HCV in 
patients coinfected with HIV-1.  N Engl J Med.  2015;373(8):714-25.
41.
Sulkowski MS, Gardiner DF, Rodrigues-Torres M, et al.  Daclatasvir plus 
sofosbuvir for previously treated or untreated chronic HCV infection.  N Engl J 
Med.  2014;370(3):211-21.


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42.
Rockstroh JK, Nelson M, Katlama C, et al.  Efficacy and safety of grazoprevir 
(MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co 
infection (C-EDGE CO-INFECTION):  a non-randomised, open-label trial.  Lancet 
HIV.  2015;2(8):e319-27.
43.
Zeuzem S, Ghalib R, Reddy KR, et al.  Grazoprevir-elbasvir combination therapy 
for treatment-naïve cirrhotic and noncirrhotic patients with chronic hepatitis C 
virus genotype 1, 4, or 6 infection:  a randomized trial.  Ann Intern Med.  
2015;163(1):1-13.
44.
Kwo P, Gane E, Peng CY, et al.  Efficacy and safety of grazoprevir/elbasvir +/–
RBV for 12 or 16 weeks in patients with HCV G1, G4, or G6 infection who 
previously failed peginterferon/RBV:  C-EDGE treatment-experienced.  Presented 
at:  the 50th Annual Meeting of the European Association for the Study of the 
Liver; April 22-26, 2015; Vienna, Italy.  Abstract P0886.  Available from:  
http://www.natap.org/2015/EASL/EASL_04.htm.
45.
Gilead Sciences.  Solvadi US Package Insert.  November 2014.
46.
Poynard T, Marcellin P, Lee SS, et al.  Randomised trial of interferon alpha2b plus 
ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 
48 weeks for treatment of chronic infection with hepatitis C virus.  International 
Hepatitis Interventional Therapy Group (IHIT).  Lancet.  1998;352(9138):1426-32.
47.
McHutchinson JG, Gordon SC, Schiff EF, et al.  Interferon alfa-2b alone or in 
combination with ribavirin as initial treatment for chronic hepatitis C.  Hepatitis 
Interventional Therapy Group.  N Engl J Med.  1998;339(21):1485-92.
48.
DAKLINZA™ (daclatasvir) [package insert].  Princeton, NJ; Bristol-Myers Squibb 
Company, 2016.
49.
Lawitz E, Sulkowski MS, Ghalib R, et al.  Simeprevir plus sofosbuvir, with or 
without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in 
non-responders to pegylated interferon and ribavirin and treatment-naive patients:  
the COSMOS randomised study.  Lancet.  2014;384(9956):1756-65.


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50.
Ahmed A, Felmlee DJ.  Mechanisms of hepatitis C viral resistance to direct acting 
antivirals.  Viruses.  2015;7(12):6716-29.


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


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not making 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
Statistics
Clinical
Bioanalysis


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Appendix C.
Study Activities
Study Activities – Treatment Period
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
(Arm B Only)
EOT/Premature D/C 
from Treatmentb
Informed Consentc
X
Medical History
X
X
Physical Exam
X
X
X
Vital Signs, Weight, Waist Circumference, 
Heightd
X
X
X
X
X
X
X
ECG
X
Hematology/Chemistry/ Urinalysis/Coagulation 
Panel
X
X
X
X
X
X
X
Pregnancy Test (serum [s] urine [u])e
X (s, u)
X (s, u)
X (u)
X (u)
X (u)
X (u)
FSH (all females)
X
HBsAg, Anti-HIV Ab
X
Hemoglobin A1c
X
HCV Genotype and Subgenotype 
X
FibroTest/APRI or FibroScan® or Liver Biopsyf
X
Total Insulin
X
X
Concomitant Medication Assessment
X
X
X
X
X
X
X
Adverse Event Assessmentg
X
X
X
X
X
X
X
Study Drugs Dispensed
X
X
X
X


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Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
(Arm B Only)
EOT/Premature D/C 
from Treatmentb
Study Drug Accountability and for Compliance 
X
X
X
X
X
Dispense/Review Study Drug Dosing Card
X 
(Dispense 
only)
X
X
X
X
X (Review only)
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sample
X
X
X
X
X
X
Archive Serum and Plasma Sample
X
X
X
X
X
X
X
Pharmacokinetic Samplesh
X
X
X
X
X
Optional Pharmacogenetic Samples
X
Child-Pugh Scorei
X
X
Clinical Assessment of Hepatic 
Decompensationi
X
HCC Screening:  Liver Ultrasoundi
X
HIV-1 RNAj
X
X
X
X
X
X
X
Flow cytometry samplej
X
X
X
X
Wk = Week; EOT = End of treatment; D/C = Discontinuation
a.
All procedures to be performed prior to first dose.
b.
Subjects who prematurely discontinue the Treatment Period should return to the site to complete the Premature D/C Visit Procedures (preferably prior to the initiation of any 
other anti-HCV therapy).
c.
Subjects need to sign an IRB/IEC approved informed consent for the study (prior to performing any screening or study-specific procedures) and the optional pharmacogenetic 
sample(s), if applicable.
d.
Height will be measured at the Screening Visit only.  Waist circumference will be measured at the Screening Visit, but if it is not measured at Screening, it may be measured 
on Day 1.


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e.
Females not of CBP at Screening do not require pregnancy testing (Section 5.2.4).
f.
For subjects who were categorized as non-cirrhotic in the AbbVie parent study and have not had a qualifying liver biopsy within the previous 12 months or a qualifying
FibroScan within the previous 6 months.
g.
See specific information regarding adverse event collection in Section 6.1.4.
h.
PK samples will be collected at each scheduled study visit except Day 1.  Detail regarding timing of samples is provided in Section 5.3.2.1.
i.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation and Liver Ultrasound are only performed for subjects with compensated cirrhosis as described in 
Section 5.3.1.1.
j.
For HCV/HIV-1 co-infected subjects.


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Study Activities – Post-Treatment (PT) Period
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Vital Signs and Weight
X
Hematology/Chemistry/Urinalysis/Coagulation Panel
X
Xb
Xb,c
Monthly Pregnancy Test (females)d
X (u)
X (u) (PT Weeks 8, 12, 16)
X (u)c
Concomitant Medication Assessmente
X
X
X
Adverse Event Assessmentf
X
X
X
HCV RNA Samples
X
X
X
HCV Resistance Sample
X
X
X
Archive Serum and Plasma Sample
X
X
X
Optional Pharmacogenetic samples
X
Child-Pugh Scoreg
X
X
HCC Screening:  Liver Ultrasoundg
X
HIV-1 RNAh
X
X
Flow cytometry sampleh
X
X
Wk = Week; PT = Post-Treatment; D/C = Discontinuation
a.
Subjects who prematurely discontinue from the Post-Treatment Period should return to the site to complete the PT D/C Visit procedures.
b.
For the subjects enrolled with cirrhosis at Day 1.  Chemistry and Coagulation Panel are required to calculate the Child Pugh Score.
c.
Hematology/Chemistry/Urinalysis/Coagulation Panel and Pregnancy Test are not required at PT Wk 24, but only at PT D/C if subject discontinued prior to PT Wk 4.
d.
Females not of CBP at Screening do not require pregnancy testing.  Pregnancy testing should be completed every 4 weeks for 4 months after the last dose of RBV (or as 
directed per the local RBV label, whichever is more restrictive).  At PT Weeks 8 and 16 subjects may have an unscheduled office visit for pregnancy testing or elect to 
perform the tests at home with test kits provided by the site.  Additional testing may be required per local RBV label.
e.
Only medications taken for SAEs and for the treatment of HCV and HIV will be collected after 30 days post-dosing.


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f.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  Only SAEs will be collected thereafter, see Section 6.1.4.
g.
Required only for subjects with compensated cirrhosis as described in Section 5.3.1.1.
h.
For subjects with HCV/HIV-1 co-infected subjects.
Note:
Day 1 of the Post-Treatment Period is defined as the day after the last day of study drug.


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Appendix D.
List of AIDS-Defining Conditions
Collection of data regarding known AIDS-Defining Conditions (ADCs) is covered in 
Section 6.1.8.
AIDS-Defining Conditions:
●
Bacterial infections, multiple or recurrent*
●
Candidiasis of bronchi, trachea, or lungs
●
Candidiasis of esophagus†
●
Cervical cancer, invasive§
●
Coccidioidomycosis, disseminated or extrapulmonary
●
Cryptococcosis, extrapulmonary
●
Cryptosporidiosis, chronic intestinal (> 1 month's duration)
●
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 
> 1 month
●
Cytomegalovirus retinitis (with loss of vision)†
●
Encephalopathy, HIV related
●
Herpes simplex:  chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, 
or esophagitis (onset at age > 1 month)
●
Histoplasmosis, disseminated or extrapulmonary
●
Isosporiasis, chronic intestinal (> 1 month's duration)
●
Kaposi sarcoma†
●
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*†
●
Lymphoma, Burkitt (or equivalent term)
●
Lymphoma, immunoblastic (or equivalent term)
●
Lymphoma, primary, of brain
●
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary†
●
Mycobacterium tuberculosis of any site, pulmonary,†§ disseminated,† or 
extrapulmonary†


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●
Mycobacterium, other species or unidentified species, disseminated† or 
extrapulmonary†
●
Pneumocystis jirovecii pneumonia†
●
Pneumonia, recurrent†§
●
Progressive multifocal leukoencephalopathy
●
Salmonella septicemia, recurrent
●
Toxoplasmosis of brain, onset at age > 1 month†
●
Wasting syndrome attributed to HIV
*
Only among children aged < 13 years. 
†
Condition that might be diagnosed presumptively.
§
Only among adults and adolescents aged > 13 years.
Cross reference:  Morbidity and Mortality Weekly Report (MMWR).  AIDS Defining Conditions.  2008.  Available 
from:  https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2 htm.




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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M15-942
Name of Study Drug:  ABT-493/ABT-530, 
sofosbuvir (SOF), ribavirin (RBV)
Phase of Development:  3b
Name of Active Ingredient:  ABT-493/ABT-530, 
SOF, RBV
Date of Protocol Synopsis:  19 October 2017
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of 
ABT-493/ABT-530 in Combination with Sofosbuvir and Ribavirin in Chronic Hepatitis C (HCV) 
Infected Subjects Who Have Experienced Virologic Failure in AbbVie HCV Clinical Studies 
(MAGELLAN-3)
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving a 12-week post-treatment sustained virologic failure response (SVR12) in 
each treatment arm and safety of ABT-493/ABT-530 plus SOF and RBV in adults with chronic 
HCV GT1-6 infection who previously failed HCV treatment in an AbbVie HCV clinical study, 
designated as an AbbVie HCV parent study.  
!
Secondary objectives are to assess the percentage of subjects with HCV on-treatment virologic 
failure, and the percentage of subjects with HCV virologic relapse. 
Investigators:  Multicenter; investigator information on file at AbbVie
Study Sites:  Approximately 40 sites who participated in an AbbVie HCV parent study.  
Study Population:  Subjects who have experienced virologic failure after receiving regimens containing 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have experienced virologic failure 
during or after receiving ombitasvir/paritaprevir/r + dasabuvir (3D), ombitasvir/paritaprevir/r (2D) in 
AbbVie HCV parent study may be enrolled at AbbVie's discretion.
Number of Subjects to be Enrolled:  Approximately 50 subjects.


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Methodology:
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy and safety of 
ABT-493/ABT-530 in combination with SOF and RBV in HCV GT1 – 6-infected subjects who have 
experienced virologic failure while participating in an AbbVie HCV parent study. Approximately 
50 subjects will be enrolled.  Treatment arm allocation will be based on HCV genotype, cirrhosis status, 
and treatment experience with protease inhibitor (PI) and/or NS5A inhibitor (NS5Ai)-containing 
regimens prior to enrolling in the AbbVie HCV parent study.
Treatment Arm Allocation in Study M15-942
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI- and/or NS5Ai-exp 
Prior to the AbbVie 
HCV Parent Study
1, 2, 4, 5, 6
NC
No
A
3
NC
No
B
Any 
C
No
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic
**
Subjects with mixed HCV genotype will be allocated to the longer treatment duration based on genotypes.
!
Arm A:  ABT-493/ABT-530 300/120 mg QD + SOF 400 mg QD + RBV 1000 – 1200 mg 
(weight-based) BID for 12 weeks
!
Arm B:  ABT-493/ABT-530 300/120 mg QD + SOF 400 mg QD + RBV 1000 – 1200 mg 
(weight-based) BID for 16 weeks
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 45 subjects.  All 
subjects administered at least one dose of study drugs will be followed for 24 weeks in the Post-
Treatment Period to monitor HCV RNA and to evaluate efficacy and the emergence and/or persistence 
of resistance-associated viral variants.
Planned visits in the Treatment Period consist of Day 1, Weeks 2, 4, 8, and 12 for all subjects and an 
additional Week 16 visit for subjects in Arm B.  During the Post-Treatment Period, subjects will have 
visits at Post-Treatment Weeks 4, 12, and 24.  Efficacy and safety data will be monitored throughout the 
study.  As this is an open-label study, safety will be reviewed by AbbVie.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female subjects (12 years of age and older, and weighing at least 45 kg), who experienced 
virologic failure during or after treatment with ABT-493/ABT-530 in an AbbVie HCV parent 
study.  Subjects who have experienced virologic failure during or after receiving 
ombitasvir/paritaprevir/r + dasabuvir (3D), ombitasvir/paritaprevir/r (2D) in AbbVie HCV parent 
study may be enrolled at AbbVie's discretion.
2.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements.
3.
Cirrhotic Subjects must have compensated cirrhosis, (Child-Pugh score of ≤ 6) at Screening and no 
current or past evidence of Child-Pugh B or C Classification or no clinical history of liver 
decompensation, including ascites noted on physical exam, hepatic encephalopathy or esophageal 
variceal bleeding.
4.
Cirrhotic Subjects must have absence of hepatocellular carcinoma (HCC) as indicated by a negative 
ultrasound (US), computed tomography (CT) scan or magnetic resonance imaging (MRI) within 
3 months prior to Screening or a negative US at Screening.
Main Exclusion:
1.
History of severe, life-threatening or other clinically significant sensitivity to any study drug or 
drug component.
2.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study or for 4 months after the last dose of study drug, or as directed per the local RBV label.
3.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol in the opinion of the investigator, and failure in an AbbVie 
HCV parent study due to non-virologic reasons.
4.
Positive test result at Screening for hepatitis B surface antigen (HBsAg).
5.
Screening laboratory analyses showing creatinine clearance < 30 mL/min.
6.
Discontinuation from the AbbVie HCV parent study for reasons other than virologic failure 
(e.g., non-adherence, lost to follow-up, and/or the occurrence of an adverse event).
7.
Receipt of any HCV treatment after failing the treatment regimen in the AbbVie HCV parent study.
Investigational Products:
ABT-493/ABT-530 mg 100 mg/40 mg Film-coated Tablet 
Sofosbuvir 400 mg Film-coated Tablet
Ribavirin 200 mg Film-coated Tablet
Doses:
ABT-493/ABT-530:  300 mg/120 mg QD (3 tablets)
Sofosbuvir:  400 mg QD (1 tablet)
Ribavirin:  weight-based 1000 mg or 1200 mg per day in two divided 
doses (5 or 6 tablets)
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Dose:
N/A
Mode of Administration:
N/A


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Duration of Treatment:  12 or 16 weeks.
Criteria for Evaluation:
Efficacy:
Efficacy will be assessed utilizing plasma HCV RNA levels throughout the study.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects receiving study drug 
with available samples, the variants at baseline at signature resistance-associated amino acid positions 
relative to the appropriate prototypic reference sequence; and 2) for subjects who do not achieve SVR12
and who have a post-baseline sample, all treatment-emergent variants relative to baseline.
Pharmacokinetic:
Individual plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF 
(GS-331007), and RBV will be tabulated and summarized.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.
Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug) in each treatment arm and overall.  The primary 
endpoint will be analyzed based on intention to treat (ITT) population.  The number and percentage of 
subjects achieving SVR12 will be summarized along with a two-sided 95% confidence interval using the 
normal approximation to the binomial distribution, unless number of virologic failures is less than 5, 
then the Wilson's score method will be used for the confidence interval instead.
The secondary efficacy variables are:
!
The percentage of subjects with on-treatment HCV virologic failure in each treatment arm and 
overall;
!
The percentage of subjects with post-treatment HCV virologic relapse in each treatment arm 
and overall.
The number and percentage of subjects meeting each secondary efficacy endpoint will be summarized 
along with a two-sided 95% confidence interval using the Wilson score method.  Analyses of additional 
efficacy endpoints and efficacy subgroup analyses will be performed.
Resistance:
For all subjects receiving study drugs and with available samples, the variants at signature resistance-
associated amino acid positions at baseline identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drugs who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
variants in available post-baseline samples identified by NGS and comparison to the baseline sequence, 
2) the amino acid variants in available post-baseline samples at signature resistance-associated positions 
identified by NGS and comparison to the appropriate prototypic reference sequence, and 3) the 
persistence of viral variants by NGS.


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF (GS-331007), and RBV 
will be tabulated for each subject and treatment arm.  Summary statistics will be computed for each 
treatment arm.
Safety:
All subjects who receive at least one dose of study drugs will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Safety summaries will be provided by treatment arm and overall.  The number and percentage of 
subjects with treatment-emergent adverse events (i.e., any event that begins or worsens in severity after 
initiation of study drug) will be tabulated by MedDRA System Organ Class (SOC) and preferred term 
(PT).  The tabulation of the number of subjects with treatment-emergent adverse events also will be 
provided by grade and relationship to study drug.  Change from baseline in laboratory tests and vital 
signs measurements to each time point of collection will be summarized, and values that are potentially 
clinically significant, according to predefined criteria, will be summarized by treatment arm and overall.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M15-942
Name of Study Drug:  ABT-493/ABT-530, 
sofosbuvir (SOF), ribavirin (RBV)
Phase of Development:  3b
Name of Active Ingredient:  ABT-493/ABT-530, 
SOF, RBV
Date of Protocol Synopsis:  06 November 2017
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of 
ABT-493/ABT-530 in Combination with Sofosbuvir and Ribavirin in Chronic Hepatitis C (HCV) 
Infected Subjects Who Have Experienced Virologic Failure in AbbVie HCV Clinical Studies 
(MAGELLAN-3)
Objectives:
!
The primary objectives of this study are to assess the efficacy by evaluating the percentage of 
subjects achieving a 12-week post-treatment sustained virologic failure response (SVR12) in 
each treatment arm and safety of ABT-493/ABT-530 plus SOF and RBV in adults or 
adolescents with chronic HCV GT1-6 infection who previously failed HCV treatment in an 
AbbVie HCV clinical study, designated as an AbbVie HCV parent study.  
!
Secondary objectives are to assess the percentage of subjects with HCV on-treatment virologic 
failure, and the percentage of subjects with HCV virologic relapse. 
Investigators:  Multicenter; investigator information on file at AbbVie
Study Sites:  Approximately 40 sites who participated in an AbbVie HCV parent study.  
Study Population:  Subjects who have experienced virologic failure after receiving regimens containing 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have experienced virologic failure 
during or after receiving ombitasvir/paritaprevir/r + dasabuvir (3D), ombitasvir/paritaprevir/r (2D) in an 
AbbVie HCV parent study may be enrolled at AbbVie's discretion.
Number of Subjects to be Enrolled:  Approximately 50 subjects.


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Methodology:
This is a Phase 3b, open-label, non-randomized, multicenter study to evaluate the efficacy and safety of 
ABT-493/ABT-530 in combination with SOF and RBV in HCV GT1 – 6-infected subjects including 
subjects with compensated cirrhosis and/or HIV-1 coinfection who have experienced virologic failure 
while participating in an AbbVie HCV parent study.  Approximately 50 subjects will be enrolled.  
Treatment arm allocation will be based on HCV genotype, cirrhosis status, and treatment experience 
with protease inhibitor (PI) and/or NS5A inhibitor (NS5Ai)-containing regimens prior to enrolling in the 
AbbVie HCV parent study.
Treatment Arm Allocation in Study M15-942
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI- and/or NS5Ai-exp 
Prior to the AbbVie 
HCV Parent Study
1, 2, 4, 5 and/or 6
NC
No
A
3
Any
Any
B
Any 
C
Any
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic
**
If the subject's HCV GT at Screening is unknown, or if it is mixed and includes GT3, then the subject will be 
assigned to Arm B (16 weeks), regardless of the cirrhosis status or PI and/or NS5Ai use prior to the AbbVie 
HCV Parent Study.
!
Arm A:  Subjects will receive orally ABT-493/ABT-530 300/120 mg QD, SOF 400 mg QD, 
RBV 600 mg to 1200 mg daily in two divided doses (based on baseline age and weight) for 
12 weeks
!
Arm B:  Subjects will receive orally ABT-493/ABT-530 300/120 mg QD, SOF 400 mg QD, 
RBV 600 mg to 1200 mg daily in two divided doses (based on baseline age and weight) for 
16 weeks
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 45 subjects.  All 
subjects administered at least one dose of study drugs will be followed for 24 weeks in the Post-
Treatment Period to monitor HCV RNA and to evaluate efficacy and the emergence and/or persistence 
of resistance-associated viral variants.
Planned visits in the Treatment Period consist of Day 1, Weeks 2, 4, 8, and 12 for all subjects and an 
additional Week 16 visit for subjects in Arm B.  During the Post-Treatment Period, subjects will have 
visits at Post-Treatment Weeks 4, 12, and 24.  Efficacy and safety data will be monitored throughout the 
study.  As this is an open-label study, safety will be reviewed by AbbVie.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female subjects must be adults (18 years of age or older) or adolescents (12 to less than 
18 years of age weighing at least 35 kg).  
2.
Subject must have experienced virologic failure during or after treatment with ABT-493/ABT-530 
in an AbbVie HCV parent study.  Subjects who have experienced virologic failure during or after 
receiving ombitasvir/paritaprevir/r + dasabuvir (3D), or ombitasvir/paritaprevir/r (2D) in an AbbVie 
HCV parent study may be enrolled at AbbVie's discretion.  Treatment in the parent study must have 
been completed or discontinued at least 1 month prior to the Screening Visit.
3.
Subjects must be able to understand and adhere to the study visit schedule and all other protocol 
requirements.
4.
Cirrhotic Subjects must have compensated cirrhosis, (Child-Pugh score of ≤ 6) at Screening and no 
current or past evidence of Child-Pugh B or C Classification or no clinical history of liver 
decompensation, including ascites noted on physical exam, hepatic encephalopathy or esophageal 
variceal bleeding.
5.
Cirrhotic Subjects must have absence of hepatocellular carcinoma (HCC) as indicated by a negative 
ultrasound (US), computed tomography (CT) scan or magnetic resonance imaging (MRI) within 
3 months prior to Screening or a negative US at Screening.
Main Exclusion:
1.
History of severe, life-threatening or other clinically significant sensitivity to any study drug or 
drug component.
2.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study or for 4 months after the last dose of study drug, or as directed per the local RBV label, 
whichever is more restrictive.
3.
Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that 
could preclude adherence to the protocol in the opinion of the investigator, and failure in an AbbVie 
HCV parent study due to non-virologic reasons.
4.
Positive test result at Screening for hepatitis B surface antigen (HBsAg).
5.
Screening laboratory analyses showing calculated creatinine clearance < 30 mL/min.
6.
Discontinuation from the AbbVie HCV parent study for reasons other than virologic failure 
(e.g., non-adherence, lost to follow-up, and/or the occurrence of an adverse event).
7.
Receipt of any HCV treatment after failing the treatment regimen in the AbbVie HCV parent study.


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Investigational Products:
ABT-493/ABT-530 mg 100 mg/40 mg Film-coated Tablet 
Sofosbuvir 400 mg Film-coated Tablet
Ribavirin 200 mg Film-coated Tablet
Doses:
ABT-493/ABT-530:  300 mg/120 mg QD (3 tablets)
Sofosbuvir:  400 mg QD (1 tablet)
Ribavirin:  
!
For subjects aged 18 or more:  1000 mg or 1200 mg daily in 
two divided doses
!
For subjects 12 less than 18 years old:  600 mg to 1200 mg 
daily in two divided doses
Mode of Administration:
Oral with food
Reference Therapy:
N/A
Dose:
N/A
Mode of Administration:
N/A
Duration of Treatment:  12 or 16 weeks.
Criteria for Evaluation:
Efficacy:
Efficacy will be assessed utilizing plasma HCV RNA levels throughout the study.
Resistance:
The following information will be tabulated and summarized:  1) for all subjects receiving study drug 
with available samples, the variants at baseline at signature resistance-associated amino acid positions 
relative to the appropriate prototypic reference sequence; and 2) for subjects who do not achieve SVR12
and who have a post-baseline sample, all treatment-emergent variants relative to baseline.
Pharmacokinetic:
Individual plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF 
(GS-331007), and RBV will be tabulated and summarized.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests, and vital signs.


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Statistical Methods:
Efficacy:
The primary efficacy endpoint is the percentage of subjects who achieve SVR12 (HCV RNA < LLOQ 
12 weeks after the last actual dose of study drug) in each treatment arm and overall.  The primary 
endpoint will be analyzed based on intention to treat (ITT) population.  The number and percentage of 
subjects achieving SVR12 will be summarized along with a two-sided 95% confidence interval using the 
normal approximation to the binomial distribution, unless the number of virologic failures is less than 5, 
then the Wilson's score method will be used for the confidence interval instead.
The secondary efficacy variables are:
!
The percentage of subjects with on-treatment HCV virologic failure in each treatment arm and 
overall;
!
The percentage of subjects with post-treatment HCV virologic relapse in each treatment arm 
and overall.
The number and percentage of subjects meeting each secondary efficacy endpoint will be summarized 
along with a two-sided 95% confidence interval using the Wilson score method.  Analyses of additional 
efficacy endpoints and efficacy subgroup analyses will be performed.
Resistance:
For all subjects receiving study drugs and with available samples, the variants at signature resistance-
associated amino acid positions at baseline identified by next generation sequencing (NGS) and 
comparison to the appropriate prototypic reference sequence will be analyzed.
The following resistance information will be analyzed for subjects receiving study drugs who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL:  1) the amino acid 
variants in available post-baseline samples identified by NGS and comparison to the baseline sequence, 
2) the amino acid variants in available post-baseline samples at signature resistance-associated positions 
identified by NGS and comparison to the appropriate prototypic reference sequence, and 3) the 
persistence of viral variants by NGS.
Pharmacokinetic:
Plasma concentrations of ABT-493, ABT-530, SOF, primary metabolite of SOF (GS-331007), and RBV 
will be tabulated for each subject and treatment arm.  Summary statistics will be computed for each 
treatment arm.
Safety:
All subjects who receive at least one dose of study drugs will be included in the safety analyses.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Safety summaries will be provided by treatment arm and overall.  The number and percentage of 
subjects with treatment-emergent adverse events (i.e., any event that begins or worsens in severity after 
initiation of study drug) will be tabulated by MedDRA System Organ Class (SOC) and preferred term 
(PT).  The tabulation of the number of subjects with treatment-emergent adverse events also will be 
provided by grade and relationship to study drug.  Change from baseline in laboratory tests and vital 
signs measurements to each time point of collection will be summarized, and values that are potentially 
clinically significant, according to predefined criteria, will be summarized by treatment arm and overall.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
"HIV-1," "CPB" and "PT" previously read:
HIV-1
Human immunodeficiency virus
CPB
Childbearing potential
PT
Post-Treatment
Has been changed to read:
HIV-1
Human immunodeficiency virus type 1
CBP
Childbearing potential
PT
Post-Treatment/preferred term
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
ADC 
AIDS-Defining Conditions 
HCC 
Hepatocellular carcinoma 
OTVF
On-treatment Virologic Failure
US
Ultrasound
CrCl
Creatinine clearance


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
sAFP
Serum Alpha-Fetoprotein
ASV
Asunaprevir
CPK
Creatine phosphokinase
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
GCSF
Granulocyte colony stimulating factor
HCV Ab
Hepatitis C virus antibody
LLN
Lower limit of normal
PCR
Polymerase Chain Reaction
QTc
QT interval corrected for heart rate
QTcF
QTc using Fridericia's correction formula
RT-PCR
Reverse transcriptase PCR
SOC
System Organ Class/Standard of Care
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Pharmacokinetic and Statistical Abbreviations
Previously read:
AUC
Area under the plasma concentration-time curve
AUC24
AUC for the 24-hour dosing interval
β
Apparent terminal phase elimination rate constant
CL/F
Apparent oral plasma clearance
CR/CL
Creatinine clearance
Cmax
Maximum observed plasma concentration
Ctrough
Pre-dose trough plasma concentration
MAD
Multiple Ascending Dose
NONMEM
Non-linear mixed-effect modeling
PK
Pharmacokinetic
SAD
Single Ascending Dose
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration (Cmax)
V/F
Apparent Volume of distribution


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Has been changed to read:
AUC
Area under the plasma concentration-time curve
AUC0-24
AUC for the 24-hour dosing interval
CL/F
Apparent oral plasma clearance
Cmax
Maximum observed plasma concentration
NONMEM
Non-linear mixed-effect modeling
PK
Pharmacokinetic
Tmax
Time to maximum observed plasma concentration (Cmax)
V/F
Apparent Volume of distribution
Section 3.0  Introduction
Third paragraph previously read:
The next generation DAA regimens with high potencies across all HCV genotypes and 
across patient subpopulations are under investigation, including AbbVie's next generation 
DAAs combination therapy, ABT-493/ABT-530, currently in Phase 3 clinical 
development.
Has been changed to read:
The next generation DAA regimens have high potencies across all HCV genotypes and 
across patient subpopulations, including Abbvie's ABT-493/ABT-530 or 
glecaprevir/pibrentasvir (GLE/PIB).  GLE/PIB is approved in some parts of the world, 
including Europe and the United States, under the brand name MAVIRET® or 
MAVYRET™, respectively.
Table 1.  In Vitro Antiviral Activity of ABT-493 and Other Protease Inhibitors 
Against HCV Genotypes 1, 2, 3, 4, and 6
Row "ABT-493" previously read:
Stable HCV Replicon EC50 (nM)
Protease Inhibitor
GT1a
GT1b
GT2a
GT3a
GT4a
GT6a
ABT-493
0.85
0.94
2.7a
1.6
2.8
0.86


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Has been changed to read:
Stable HCV Replicon EC50 (nM)
Protease Inhibitor
GT1a
GT1b
GT2a
GT3a
GT4a
GT6a
ABT-493
0.85
0.94
2.2a
1.9
2.8
0.86
Section 3.0  Introduction
Subsection ABT-493
Last paragraph, last sentence previously read:
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology and 
Phase I data can be found in the Investigator's Brochure.13
Has been changed to read:
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology and 
Phase I data can be found in the Investigator's Brochure.13
Section 3.0  Introduction
Subsection ABT-530
Last paragraph, last sentence previously read:
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology and 
Phase 1 data can be found in the Investigator's Brochure.22
Has been changed to read:
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology and 
Phase 1 data can be found in the Investigator's Brochure.13
Section 3.0  Introduction
Subsection HCV/HIV-1 Co-Infection
Last paragraph, last sentence previously read:
Per the most recent AASLD treatment guidelines, it is recommended that HCV/HIV-1 co-
infected patients be treated and re-treated the same as HCV mono-infected patients, albeit 
with attention paid to potential drug-drug interactions with anti-retroviral medications.


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Has been changed to read:
Per the most recent AASLD treatment guidelines, it is recommended that HCV/HIV-1 co-
infected patients be treated and re-treated the same as HCV mono-infected patients, albeit 
with attention paid to potential drug-drug interactions with anti-retroviral medications.31
Section 3.0  Introduction
Subsection ARV Drug-Drug Interaction Studies with ABT-493 and ABT-530
Fifth paragraph, last sentence previously read:
Coadministration of ABT-493 + ABT-530 with ritonavir boosted atazanavir was studied 
in a DDI study that was terminated early due to an increase in ABT-493 exposure up to 
16-fold and ABT-530 exposure up to 3-fold with Grade 1 and 2 increases in ALT and 
Grade 2 to 3 increase in total bilirubin (predominately indirect).  
Has been changed to read:
Coadministration of ABT-493 + ABT-530 with ritonavir boosted atazanavir was studied 
in a DDI study that was terminated early due to an increase in ABT-493 exposure up to 
16-fold and ABT-530 exposure up to 3-fold with Grade 1 and 2 increases in alanine 
aminotransferase (ALT) and Grade 2 to 3 increase in total bilirubin (predominately 
indirect).  
Section 3.0  Introduction
Subsection ARV Drug-Drug Interaction Studies with ABT-493 and ABT-530
Sixth paragraph, first and second sentence previously read:
A recently completed study (Study M15-584) evaluating the drug interaction profile when 
ABT-493/ABT-530 300 mg/120 mg is co administered with Genvoya® (elvitegravir 
150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide10 mg QD), 
Study M15-584 has recently been completed.  Coadministration was safe and well 
tolerated, with mild side effects reported and one grade 3 neutropenia deemed related to 
the combination of Genvoya, ABT-493 and ABT-530 in a black male subject with 
baseline low ANC, leading to premature study drug discontinuation.


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Has been changed to read:
Study M15-584 evaluated the drug interaction profile when ABT-493/ABT-530 
300 mg/120 mg is co-administered with Genvoya® (elvitegravir 150 mg, cobicistat 
150 mg, emtricitabine 200 mg, tenofovir alafenamide10 mg QD).  Co-administration was 
safe and well tolerated, with mild side effects reported and one grade 3 neutropenia 
deemed related to the combination of Genvoya, ABT-493 and ABT-530 in a black male 
subject with baseline low absolute neutrophil count (ANC), leading to premature study 
drug discontinuation.  
Section 3.0  Introduction
Subsection ARV Drug-Drug Interaction Studies with ABT-493 and ABT-530
Last paragraph previously read:
For a more detailed discussion of drug-drug interaction studies please refer to the 
ABT-493 and ABT-530 Fixed-Dose Combination Investigator's Brochure.26
Has been changed to read:
For a more detailed discussion of drug-drug interaction studies please refer to the 
Investigator's Brochure.13
Section 3.0  Introduction
Subsection Clinical Study Results
Last paragraph previously read:
In addition to these studies, 6 Phase 3 studies evaluating approximately 1,940 subjects are 
currently ongoing.  Data from these studies is not yet available.
Has been changed to read:
A total of 2,376 subjects were randomized or enrolled in the registrational studies or 
supportive Phase 2 studies to receive GLE 300 mg QD and PIB 120 mg QD.  Of these, 
2,369 subjects received at least 1 dose of study drug.


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Section 3.0  Introduction
Subsection Ribavirin (RBV)
Last paragraph, second sentence previously read:
Pregnancy should be avoided (or as directed per the local label) following RBV therapy 
(Refer to Section 6.1.6).  
Has been changed to read:
Pregnancy should be avoided following RBV therapy (Refer to Section 6.1.6).  
Section 3.2  Benefits and Risks
Subsection Risks
Fourth paragraph previously read:
Virologic stopping criteria have been incorporated into the study to ensure subjects are 
exposed to appropriate durations of the regimen.  
Has been changed to read:
Virologic failure criteria have been incorporated into the study to ensure subjects are 
exposed to appropriate durations of the regimen.  
Section 4.0  Study Objectives
First bullet previously read:
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving a 12-week post-treatment sustained virologic response 
(SVR12) in each treatment arm and safety of ABT-493/ABT-530 plus SOF and RBV in 
adults with chronic HCV GT1 - 6 infection who previously failed HCV treatment in an 
AbbVie HCV parent study.
Has been changed to read:
The primary objectives of this study are to assess the efficacy by evaluating the 
percentage of subjects achieving a 12-week post-treatment sustained virologic response 
(SVR12) in each treatment arm and safety of ABT-493/ABT-530 plus SOF and RBV in 


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adults or adolescents with chronic HCV GT1 - 6 infection who previously failed HCV 
treatment in an AbbVie HCV clinical study, designated as an AbbVie HCV parent study.
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, first sentence previously read:
It is anticipated that approximately 40 HCV infected subjects who have experienced 
virologic failure following treatment with ABT-493/ABT-530 or 3D or 2D regimens in 
one of the AbbVie HCV parent studies will be enrolled.
Has been changed to read:
It is anticipated that approximately 50 HCV infected subjects who have experienced 
virologic failure following treatment with ABT-493/ABT-530 or 3D or 2D regimens in 
one of the AbbVie HCV parent studies will be enrolled.
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph, first sentence previously read:
Arm A will enroll approximately 15 subjects, and Arm B will enroll approximately 
25 subjects.
Has been changed to read:
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 
45 subjects.


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Figure 1.  Study Schematic (Treatment Period)
Previously read:
Has been changed to read:


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Table 7.  Treatment Arm Allocation in Study M15-942
Previously read:
Patient Population
Study M15-942 
Treatment Arm
Genotype
Cirrhotic Status*
PI and/or NS5Ai-exp Prior to 
the AbbVie HCV Parent Study
1, 2, 4, 5, 6
NC
No
A
3
NC
No
B
Any 
C
No
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic.
Has been changed to read:
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI and/or NS5Ai-exp Prior to 
the AbbVie HCV Parent Study
1, 2, 4, 5 and/or 6
NC
No
A
3
Any
Any
B
Any 
C
Any
B
Any 
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic.
**
If the subject's HCV GT at Screening is unknown, or if it is mixed and includes GT3, then the subject will be 
assigned to Arm B (16 weeks), regardless of the cirrhosis status or PI and/or NS5Ai use prior to the AbbVie HCV 
Parent Study.
Section 5.1  Overall Study Design and Plan:  Description
First and second bullet previously read:
●
Arm A:  ABT-493/ABT-530 300 mg/120 mg QD, SOF 400 mg QD and 
weight-based RBV* BID for 12 weeks.
●
Arm B:  ABT-493/ABT-530 300 mg/120 mg QD, SOF 400 mg QD and 
weight-based RBV* BID for 16 weeks.


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Has been changed to read:
●
Arm A:  Subjects will receive orally ABT-493/ABT-530 300 mg/120 mg QD, 
SOF 400 mg QD, and RBV 600 mg to 1200 mg daily in two divided doses 
(based on baseline age and weight)* for 12 weeks.
●
Arm B:  Subjects will receive orally ABT-493/ABT-530 300 mg/120 mg QD, 
SOF 400 mg QD, and RBV 600 mg to 1200 mg daily in two divided doses 
(based on baseline age and weight)* for 16 weeks.
Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph previously read:
*
RBV will be administered as a weight-based dose (subjects weighing < 75 kg may 
take RBV orally as 2 tablets in the morning and 3 tablets in the evening which 
corresponds to a 1000 mg total daily dose; subjects weighing ≥ 75 kg may take RBV 
orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 1200 
mg total daily dose), unless required otherwise per local RBV label.  Alternative RBV 
dosing can be used if agreed upon by AbbVie TA MD.
Has been changed to read:
*
As defined on Table 8.


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Table 8.  Ribavirin Dosing Recommendations
Add:  new table title and text
Table 8.
Ribavirin Dosing Recommendations
Age at 
Baseline 
(Years)
Body 
Weight at 
Baseline 
(kg)
Daily Dose 
(mg)
Number of 200 mg Tablets Per Period of the Day
≥ 18
< 75
1000
2 tablets A.M. + 3 tablets P.M.*
≥ 75
1200
3 tablets A.M. + 3 tablets P.M.
≥ 12 and < 18
35 – 46
600
1 tablet A.M. + 2 tablets P.M.*
47 – 59
800
2 tablets A.M. + 2 tablets P.M.
60 – 74
1000
2 tablets A.M. + 3 tablets P.M.*
≥75
1200
3 tablets A.M. + 3 tablets P.M.
*
The A.M and P.M. pills can be taken in reverse order.
Section 5.1  Overall Study Design and Plan:  Description
Last paragraph previously read:
As this is an open-label study, safety will be reviewed by AbbVie.  Virologic stopping 
criteria for subject management, as detailed in Section 5.4.1.1, will be evaluated and 
applied by the investigator.
Has been changed to read:
As this is an open-label study, safety will be reviewed by AbbVie.  Virologic failure 
criteria for subject management, as detailed in Section 5.4.1.1, will be evaluated and 
applied by the investigator.
Section 5.1.1  Screening
Last paragraph
Delete:  second sentence
In addition, subjects with HCV/HIV-1 co-infection will be provided with an HIV-1 ARV 
dosing card as described in Section 5.3.1.1.


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Section 5.1.1.1  Rescreening
Third paragraph previously read:
Otherwise, subjects may be retested/rescreened only once without approval of the AbbVie 
TA SD/TA MD, as follows:
Has been changed to read:
Otherwise, subjects may be retested/rescreened only once without approval of the AbbVie 
Therapeutic Area Scientific Director (TA SD)/TA MD, as follows:
Section 5.1.1.1  Rescreening
First paragraph
Delete:  third bullet
HCV genotype indicating co-infection with more than one genotype;
Section 5.1.1.1  Rescreening
Last paragraph previously read:
Subjects being rescreened do not need to be retested for HBV, HIV, HCV genotype and 
subtype, and FibroScan/liver biopsy.
Has been changed to read:
Subjects being rescreened do not need to be retested for HBsAg, HIV-2 Ab, HCV 
genotype and subtype, and FibroScan/liver biopsy.
Section 5.1.2  Treatment Period
First paragraph, first sentence previously read:
At the Study Day 1 visit, after all eligibility criteria have been confirmed, subjects will be 
allocated via IRT into one of two treatment arms based on their HCV genotype, cirrhotic 
status, and prior treatment experience with PI- and/or NS5Ai-containing regimens before 
experiencing virologic failure in an AbbVie HCV parent study.


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Has been changed to read:
Prior to the Study Day 1 visit, after all eligibility criteria have been confirmed, subjects 
will be allocated via IRT into one of two treatment arms based on their HCV genotype, 
cirrhotic status, and prior treatment experience with PI- and/or NS5Ai-containing 
regimens before experiencing virologic failure in an AbbVie HCV parent study.
Section 5.1.2  Treatment Period
Fifth paragraph previously read:
Virologic stopping criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.1.1.  Subjects meeting virologic stopping criteria will be discontinued from 
study drugs.
Has been changed to read:
Virologic failure criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.1.1.  Subjects meeting on-treatment virologic failure (OTVF) criteria will be 
discontinued from study drugs.
Section 5.2  Selection of Study Population
Previously read:
The study population consists of chronic HCV GT1 – 6-infected adult subjects who 
experienced virologic failure while participating in an AbbVie HCV parent study.  
Subjects must meet all the inclusion criteria and none of the exclusion criteria.  In 
addition, the eligibility of subject to enroll in Study M15-942 will be evaluated at the 
discretion of AbbVie based upon the characteristics of subject's HCV infection, prior 
treatment history, and the evolving data from on-going clinical studies.
Has been changed to read:
The study population consists of chronic HCV GT1 – 6-infected adult or adolescent 
subjects who experienced virologic failure while participating in an AbbVie HCV parent 
study.  Subjects must meet all the inclusion criteria and none of the exclusion criteria.  In 


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addition, the eligibility of a subject to enroll in Study M15-942 will be evaluated at the 
discretion of AbbVie based upon the characteristics of the subject's HCV infection, prior 
treatment history, and the evolving data from on-going clinical studies.
Section 5.2.1  Inclusion Criteria
Criterion 1 previously read:
1.
Male or female subjects (12 years of age and older, and weighing at least 45 kg), 
who experienced virologic failure during or after treatment with 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have 
experienced virologic failure during or after receiving ombitasvir/paritaprevir/r + 
dasabuvir (3D), ombitasvir/paritaprevir/r (2D) in AbbVie HCV parent study may 
be enrolled at AbbVie's discretion.  Treatment in the parent study must have been 
completed or discontinued at least 1 month prior to the Screening Visit.
Has been changed to read:
1.
Male or female subjects must be adults (18 years or more) or adolescents (12 to 
less than 18 years).  Adolescent subjects must weigh at least 35 kg.
2.
Subject must have experienced virologic failure during or after treatment with 
ABT-493/ABT-530 in an AbbVie HCV parent study.  Subjects who have 
experienced virologic failure during or after receiving ombitasvir/paritaprevir/r + 
dasabuvir (3D), or ombitasvir/paritaprevir/r (2D) in an AbbVie HCV parent study 
may be enrolled at AbbVie's discretion.  Treatment in the parent study must have 
been completed or discontinued at least 1 month prior to the Screening Visit.
Section 5.2.1  Inclusion Criteria
Criterion 3
Last bullet previously read:
For Women of Childbearing Potential (CBP, as defined in Section ), practicing at least 
one protocol specified method of birth control (Section 5.2.4), starting at Study Day 1 


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through at least 4 months after the last dose of study drug or as directed by the local RBV 
label.
Has been changed to read:
Women of Childbearing Potential (CBP), practicing at least one protocol specified 
method of birth control (Section 5.2.4), starting at Study Day 1 through at least 4 months 
after the last dose of study drug or as directed by the local RBV label, whichever is more 
restrictive.
Section 5.2.1  Inclusion Criteria
Criterion 4 previously read:
If a male subject is sexually active with female partner(s) of CBP, he must agree to 
practice the protocol specified contraception (Section 5.2.4), from Study Day 1 through 
7 months after the last dose of study drug, or as directed by the local RBV label.
Has been changed to read:
If a male subject is sexually active with female partner(s) of CBP, he must agree to 
practice the protocol specified contraception (Section 5.2.4), from Study Day 1 through 
7 months after the last dose of study drug, or as directed by the local RBV label, 
whichever is more restrictive.
Section 5.2.1  Inclusion Criteria
First paragraph previously read:
In additional to Inclusion Criteria 1 to 8, subjects with HCV/HIV-1 co-infection must also 
meet the following criteria:
Has been changed to read:
In additional to Inclusion Criteria 1 to 9, subjects with HCV/HIV-1 co-infection must also 
meet the following criteria:


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Section 5.2.1  Inclusion Criteria
Delete:  Criterion 9
Subjects who are on stable opioid replacement must be on a therapy with methadone or 
buprenorphine with or without naloxone for at least 6 months prior to screening.
Section 5.2.1  Inclusion Criteria
Criterion 10, bullet list previously read:
Subjects on a stable ART regimen must have the following:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening; and plasma 
HIV-1 RNA below < 50 copies/mL at Screening (by the COBAS® 
Ampliprep/COBAS® Taqman HIV 1 Test, v 2.0) and at least once (HIV-1 < 
50 copies/mL) during the 12 months prior to Screening (by an approved 
plasma HIV-1 RNA quantitative assay including but not limited to:  COBAS® 
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 
assay).
Has been changed to read:
●
CD4+ count ≥ 200 cells/mm3 (or CD4+ % ≥ 14%) at Screening; 
●
and Plasma HIV-1 RNA < 50 copies/mL at Screening (by the COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0) and at least once (HIV-1 
< 50 copies/mL) during the 12 months prior to Screening (by an approved 
plasma HIV-1 RNA quantitative assay including but not limited to:  COBAS®
Ampliprep/COBAS® Taqman HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 
assay).
Section 5.2.1  Inclusion Criteria
Subsection Rationale for Inclusion Criteria
Previously read:
1, 7 – 10
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation


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2 – 4
RBV has known teratogenic effects.  The impact of ABT-493 and 
ABT-530 on human pregnancies has not been established.  However, 
assessment of the completed nonclinical reproductive toxicology studies 
indicates that there is no drug-related effect on 
teratogenicity/fetotoxicity.  In addition, the compounds are non-
genotoxic. No adequate human data are available to establish whether 
or not sofosbuvir poses a risk to pregnancy outcomes.  In animal 
reproduction studies, no evidence of adverse developmental outcomes 
was observed with the components of sofosbuvir at exposures greater 
than those in humans at the recommended human dose16
5, 6
In accordance with harmonized Good Clinical Practice (GCP)
Has been changed to read:
1, 2, 8 – 11
In order to select the appropriate subject population with appropriate 
disease characteristics for evaluation
3 – 5
RBV has known teratogenic effects.  The impact of ABT-493 and 
ABT-530 on human pregnancies has not been established.  However, 
assessment of the completed nonclinical reproductive toxicology studies 
indicates that there is no drug-related effect on 
teratogenicity/fetotoxicity.  In addition, the compounds are non-
genotoxic.  No adequate human data are available to establish whether 
or not sofosbuvir poses a risk to pregnancy outcomes.  In animal 
reproduction studies, no evidence of adverse developmental outcomes 
was observed with the components of sofosbuvir at exposures greater 
than those in humans at the recommended human dose16
6, 7
In accordance with harmonized Good Clinical Practice (GCP)
Section 5.2.2  Exclusion Criteria
Criterion 1 and 2 previously read:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for 4 months after the last dose of study drug, or as directed per 
the local RBV label.  


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2.
Male subject who is considering fathering a child or whose partner is pregnant 
during the study or for 7 months after the last dose of the study drug, or as directed 
per the local RBV label.
Has been changed to read:
1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for 4 months after the last dose of study drug, or as directed per 
the local RBV label, whichever is more restrictive.  
2.
Male subject who is considering fathering a child or whose partner is pregnant 
during the study or for 7 months after the last dose of the study drug, or as directed 
per the local RBV label, whichever is more restrictive.
Section 5.2.2  Exclusion Criteria
Criterion 8
Delete:  first bullet
Any herbal supplements (including milk thistle) within 2 weeks prior to study drug 
administration.
Section 5.2.2  Exclusion Criteria
Criterion 10 previously read:
Treatment for an AIDS-associated opportunistic infection (OI) (Appendix D) within 
6 months of Screening.
Has been changed to read:
Treatment for an AIDS-Defining Condition (ADC) (Appendix D) within 6 months of 
Screening.
Section 5.2.2  Exclusion Criteria
Criterion 12, sixth and seventh bullet previously read:
●
Platelets < 60,000 cells per mm3


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●
Creatinine clearance < 30 mg/dL
Has been changed to read:
●
Platelets < 50,000 cells per mm3 for subjects aged ≥ 18 years, or 40,000 cells 
per mm3 for subjects aged < 18 years.
●
Calculated creatinine clearance < 30 mL/min
Section 5.2.2  Exclusion Criteria
Criterion 13 and 16 previously read:
13.
History of solid organ transplantation, other than liver or kidney transplantation.
16.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator (see Section 5.6.3 for information about subjects using opioid 
replacement therapy).
Has been changed to read:
13.
History of solid organ transplantation.
16.
Recent (within 6 months prior to study drug administration) history of drug or 
alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
Section 5.2.2  Exclusion Criteria
Criterion 19, first sentence previously read:
Current enrollment in another interventional clinical study or previous enrollment in this 
study.  
Has been changed to read:
Current enrollment in another interventional clinical study (except the AbbVie HCV 
parent study) or previous enrollment in this study.


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Section 5.2.2  Exclusion Criteria
Add:  new Criterion 20
Subjects who have been confirmed to have documented re-infection.  (Refer to 
Section 5.1). 
Section 5.2.2  Exclusion Criteria
Criterion 20 previously read:
Subject has confirmation of HCV reinfection at screening visit (as defined in 
Section 5.4.1.11).
Has been changed to read:
Subject has confirmation of HCV reinfection at screening visit (as defined in 
Section 5.4.1.1).
Section 5.2.2  Exclusion Criteria
Subsection Rationale for Exclusion Criteria
Previously read:
1, 2, 8, 10 – 12, 17 – 19
In order to ensure safety of the subjects throughout the study
3, 6, 7, 13 – 19
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
4, 5, 9
To exclude subjects with liver diseases other than HCV
Has been changed to read:
1, 2, 3, 8, 10 – 12, 17 –
19
In order to ensure safety of the subjects throughout the study
6, 7, 13 – 19, 20
In order to avoid bias for the evaluation of efficacy and 
safety, including concomitant use of other medications
4, 9, 11
To exclude subjects with liver diseases other than HCV
5
To exclude subjects with HIV-2 co-infection


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Section 5.2.3  Prior and Concomitant Therapy
First paragraph, first and second sentence previously read:
Use of medications (prescription or over-the-counter, including vitamins, herbal 
supplements, and vaccines) from the time of signing the informed consent through the 
Treatment Period and 30 days after study drugs are stopped, must be recorded in the 
electronic case report form (eCRF) at each study visit indicated in the Treatment Period 
(Appendix C) along with the reason for use, date(s) of administration including start and 
end dates, and dosage information including dose, route and frequency.  Thereafter, only 
medications taken for SAEs and treatment of HCV will be recorded in the eCRF at each 
study visit in the Post-Treatment Period (Appendix C).
Has been changed to read:
Use of medications/supplements (including prescription or over-the-counter, vitamins
and/or herbal supplements) or vaccines from the time of signing the informed consent 
through the Treatment Period and 30 days after study drugs are stopped, must be recorded 
in the electronic case report form (eCRF) at each study visit indicated in the Treatment 
Period (Appendix C) along with the reason for use, date(s) of administration including 
start and end dates, and dosage information including dose, route and frequency.  
Section 5.2.3  Prior and Concomitant Therapy
Add:  new second paragraph
During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  After 30 days post-treatment, during the 
Post-Treatment Period, only antiviral therapies related to the treatment of HCV and/or 
HIV and medications prescribed in association with a serious adverse event (SAE) will be 
recorded in EDC.
Section 5.2.3.2  Prior Prior and Concomitant HIV-1 Therapy
First paragraph previously read:
If a subject is on an HIV-1 ART regimen, it must include at least one of the ARV agents 
defined on Inclusion Criterion 9 (Section 5.2.1).


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Has been changed to read:
If a subject is on an HIV-1 ART regimen, it must include at least one of the ARV agents 
defined on Inclusion Criterion 10 (Section 5.2.1).
Section 5.2.3.2  Prior Prior and Concomitant HIV-1 Therapy
Last paragraph previously read:
Subjects receiving any other HIV-1 ART in addition to those listed in Inclusion 
Criterion 9 (Section 5.2.1) would not be eligible for enrollment in the study.
Has been changed to read:
Subjects receiving any other HIV-1 ART in addition to those listed in Inclusion 
Criterion 10 (Section 5.2.1) would not be eligible for enrollment in the study.
Section 5.2.3.3  Other Concomitant Therapy
First paragraph, first sentence previously read:
Subjects should be on a stable dose of concomitant medications for at least 2 weeks prior 
to initiation of study drugs.
Has been changed to read:
Subjects should be on a stable dose of concomitant medications for at least 14 days prior 
to initiation of study drugs.
Section 5.2.3.3  Other Concomitant Therapy
Second paragraph previously read:
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, up to 30 days following 
discontinuation of study drugs, if applicable.


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Has been changed to read:
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements and subjects may resume previously prohibited 
medications/supplements or revert to pre-study doses, up to 14 days following 
discontinuation of study drugs, if applicable.
Section 5.2.3.4  Prohibited Therapy
First paragraph previously read:
Subjects must be able to safely discontinue any medications or supplements prohibited to 
be administered with ABT-493/ABT-530 (listed in Table 9) at least 2 weeks prior to the 
first dose of any study drug and not use these during the entire Treatment Period and for 
30 days following discontinuation of study drugs.  Informed Consent Form must be 
signed and dated prior to discontinuing any prohibited medications or herbal supplements 
for the purpose of meeting study inclusion criteria.
Has been changed to read:
Medications or supplements prohibited to be administered with ABT-493/ABT-530 are 
listed in Table 9.  For subjects in the study in countries where ABT-493/ABT-530 
(glecapravir/pibrentasvir) has received marketing authorization, any medications in the 
local label that are contraindicated to be administered with ABT-493/ABT-530 
(glecapravir/pibrentasvir) are also considered to be prohibited medications.  Subjects must 
be able to safely discontinue any prohibited medications or supplements at least 14 days 
or 10 half-lives (whichever is longer) prior to the first dose of any study drug and not use 
these during the entire Treatment Period and for 14 days following discontinuation of 
study drugs.  The Informed Consent Form must be signed and dated prior to discontinuing 
any prohibited medications or supplements for the purpose of meeting study inclusion 
criteria.


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Table 8.  Medications and Supplements Prohibited with ABT-493/ABT-530 
Administration
Previously read:
Medication or Supplement Name
Any herbal supplements (including milk thistle), red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Tipranavir/r, Atazanavir, Efavirenz, Etravirine, Nevirapine
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drugs.  Subjects receiving these statins should either switch to pravastatin or rosuvastatin prior to the 
first dose of study drugs or may interrupt statin therapy throughout the treatment period and until 30 days after the 
last dose of study drug based on the investigator's judgment.  If switching to or continuing pravastatin or 
rosuvastin, it is recommended to reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD 
when taking with the study drugs.
Has been changed to read:
Medication or Supplement Name
Red yeast rice (monacolin K), St. John's Wort
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, rifampin
Atorvastatin, lovastatin, simvastatin*
Astemizole, cisapride, terfenadine
Tipranavir/r, atazanavir, efavirenz, etravirine, nevirapine
Ethinyl estradiol
*
Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
the study drug.  After signing the informed consent form, subjects receiving these statins should either (a) switch to 
pravastatin or rosuvastatin at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug 
or (b) interrupt statin therapy throughout the treatment period beginning at least 14 days or 10 half-lives (whichever 
is longer) prior to the first dose of study drug and until 14 days after the last dose of study drug, based on 
investigator's judgment.  If switching to or continuing pravastatin or rosuvastatin, it is recommended to either 
1) reduce or limit the pravastatin or rosuvastatin dose in accordance with the ABT-493/ABT-530 
(glecapravir/pibrentasvir) product label (if approved in the country) when taking with the study drug; or 2) reduce 
the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study drug, if 
ABT-493/ABT-530 (glecapravir/pibrentasvir) is not yet approved in the country.


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Section 5.2.3.4  Prohibited Therapy
Second and third paragraph previously read:
In addition, refer to the current package insert or product label for SOF and RBV for a 
complete list of medications prohibited to be used with those drugs, which should not be 
used at least 2 weeks prior to the first dose of any study drug, throughout the entire 
Treatment Period and for 30 days following discontinuation of study drugs.
The use of ethinyl estradiol containing oral contraceptives with ABT-493 and ABT-530 
combination was associated with ALT increases in some healthy female subjects.  
Hormonal contraceptives (including oral, topical [including vaginal rings], injectable, or 
implantable varieties) containing ethinyl estradiol may not be used from 2 weeks prior to 
the first dose of ABT-493/ABT-530 until 30 days after the end of ABT-493/ABT-530 
dosing.  Progestin-only contraceptives, such as those containing norethindrone, 
desogestrel, or levonorgestrel, without ethinyl estradiol, may be used with 
ABT-493/ABT-530.  Post-menopausal hormone replacement therapy, such as with 
esterified or conjugated estrogens, i.e., not containing ethinyl estradiol, may be used with 
ABT-493/ABT-530 at the discretion of the Investigator.
Has been changed to read:
In addition, refer to the current package insert or product label for SOF and RBV for a 
complete list of medications prohibited to be used with those drugs, which should not be 
used at least 14 days prior to the first dose of any study drug, throughout the entire 
Treatment Period and for 14 days following discontinuation of study drugs.
Contraceptives and/or hormonal replacement therapies containing only 
progestins/progestogens (such as those containing norethindrone, desogestrel, or 
levonorgestrel) or those containing progestins/progestogens with non-ethinyl estradiol 
estrogens (e.g., esterified or conjugated) may be used with ABT-493/ABT-530 at the 
discretion of the Investigator.


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Section 5.2.3.4  Prohibited Therapy
Fifth paragraph previously read:
For HCV/HIV-1 coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 2 weeks prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 30 days following discontinuation of study drugs.  
Has been changed to read:
For HCV/HIV-1 coinfected subjects, the investigator must refer to the current package 
insert(s) or product label(s) of a subject's ART regimen for a complete list of medications 
prohibited to be used with those drugs, which should not be used at least 14 days prior to 
the first dose of any study drug and not use these during the entire Treatment Period and 
for 14 days following discontinuation of study drugs.  
Section 5.2.4  Contraception Recommendations
Subsection Female Subjects
Heading "Females Subjects of CBP must be:"
First bullet previously read:
Practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 4 months after the last dose of study drug, or as directed by the 
local RBV label.
Has been changed to read:
Practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 4 months after the last dose of study drug, or as directed by the 
local RBV label, whichever is more restrictive.


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Section 5.2.4  Contraception Recommendations
Subsection Female Subjects
Heading "Females Subjects of CBP must be:"
Second and third sub bullet previously read:
○
Bilateral tubal occlusion/ligation
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the CBP trial participant.
Has been changed to read:
○
Bilateral tubal occlusion/ligation or bilateral tubal occlusion via 
hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms 
success of the procedure.
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the CBP trial participant.
Section 5.2.4  Contraception Recommendations
Susection Male Subjects
Previously read:
Subject must be surgically sterile (having performed vasectomy with medical assessment 
confirming surgical success) or have a female partner who is postmenopausal or 
permanently sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy), or, 
if sexually active with female partner(s) of CBP must agree from Study Day 1 through 7 
months (or as directed by the local RBV label), after the last dose of study drug to practice 
contraception with:
●
Condom use.
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence e.g., calendar, ovulation, symptothermal, post-ovulation methods 
and withdrawal are not acceptable).


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Additionally, male subject must agree not to donate sperm from Study Day 1 through 
7 months after the last dose of study drug, (or as directed by the local RBV label).
Has been changed to read:
Male subjects who are sexually active with a female partner of CBP, even if the male 
subject has undergone a successful vasectomy, must agree to use condoms from Study 
Day 1 through at least 7 months after the last dose of study drug and his female partner(s) 
must use at least one of the contraceptive measures (as defined in the protocol for female 
study subjects of childbearing potential).  If the local RBV label for the subject has more 
restrictive recommendations, they must be followed instead.
Male subject must agree not to donate sperm from Study Day 1 through at least 7 months 
after the last dose of study drug (or as directed by the local RBV label, whichever is more 
restrictive).
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Testing
First paragraph, first and second sentence previously read:
A serum pregnancy test will be performed for all female subjects of childbearing potential 
at Screening and Day 1.  Additional urine pregnancy tests will be performed every 
4 weeks, starting at Day 1 (prior to enrollment) during the treatment period, including at 
the last Treatment Period visit and until 30 days of last study drug dose, as indicated in 
Appendix C.
Has been changed to read:
A serum and urine pregnancy test will be performed for all female subjects of 
childbearing potential at Screening and Day 1.  Additional urine pregnancy tests will be 
performed every 4 weeks, starting at Day 1 (prior to enrollment) during the treatment 
period, including at the last treatment period visit and until 4 months after the last study 
drug dose (or as directed by local RBV label, whichever is more restrictive), as indicated 
in Appendix C.  


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Table 9.  Clinical Laboratory Tests
Column "Other Tests"
Test "Hepatitis A Virus IgMh," "Hepatitis A Virus Totalh," "Hepatitis E Virus 
IgGh" and "Hepatitis E Virus IgMh" previously read:
Hepatitis A Virus IgMh
Hepatitis A Virus Totalh
Hepatitis E Virus IgGh
Hepatitis E Virus IgMh
Has been changed to read:
Anti-Hepatitis A Virus IgMh
Anti-Hepatitis A Virus Totalh
Anti-Hepatitis E Virus IgGh
Anti-Hepatitis E Virus IgMh
Table 9.  Clinical Laboratory Tests
Column "Other Tests"
Add:  
HEV RNAh
HBV DNAh
Table 9.  Clinical Laboratory Tests
Column "Other Tests"
Add:  
Females not of CBP at Screening do not require pregnancy testing as defined in 
Section 5.2.1 Criterion 4.
Has been changed to read:
Females not of CBP at Screening do not require pregnancy testing as defined in 
Section 5.2.1 Criterion 5.


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Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
Heading "Non-Cirrhotic"
First paragraph previously read:
A liver biopsy within 24 months prior to or during Screening demonstrating the absence 
of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec 
fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; or
Has been changed to read:
A liver biopsy within 12 months prior to or during Screening demonstrating the absence 
of cirrhosis, e.g., a METAVIR, Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec 
fibrosis score of ≤ 3, Ishak fibrosis score of ≤ 4; or
Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
Heading "Cirrhotic"
Second paragraph previously read:
A FibroScan® score of ≥ 12.5 kPa at any time prior to Screening or during Screening 
period (FibroScan® must be approved by the local regulatory agency); or
Has been changed to read:
A FibroScan® score of ≥ 12.5 kPa at any time prior to Screening or during Screening 
period (FibroScan® must be approved by the local regulatory agency); or
Section 5.3.1.1  Study Procedures
Subsection Liver Diagnostic Testing
Heading "Cirrhotic"
Fourth and fifth paragraph previously read:
In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
Fibrotest/APRI using the above criteria (indeterminate FibroTest [0.48 < result < 0.75], or 
conflicting FibroTest and APRI results [e.g., FibroTest ≤ 0.48, but APRI ≥1]), a liver 
biopsy or FibroScan® is required.


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Subjects who are categorized as cirrhotic in this study according to the criteria above must 
also meet Inclusion Criteria 7 and 8.
Has been changed to read:
In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
FibroTest/APRI using the above criteria (indeterminate FibroTest [0.48 < result < 0.75], 
or conflicting FibroTest and APRI results [e.g., FibroTest ≤ 0.48, but APRI ≥1]), a liver 
biopsy or FibroScan® is required.
Subjects who are categorized as cirrhotic in this study according to the criteria above must 
also meet Inclusion Criteria 8 and 9.
Section 5.3.1.1  Study Procedures
Subsection Child-Pugh (Child-Turcotte-Pugh) Score and Category
First sentence previously read:
The Child-Pugh (Child-Turcotte-Pugh) score uses five clinical measures of liver disease 
(3 laboratory parameters and 2 clinical assessments).
Has been changed to read:
The Child-Pugh (Child-Turcotte-Pugh) score uses five clinical measures of liver disease 
(3 laboratory parameters and 2 clinical assessments) as shown in Table 11.
Section 5.3.1.1  Study Procedures
Subsection Hepatocellular Carcinoma Screening:  Liver Ultrasound
Previously read:
Subjects with compensated cirrhosis who do not have a historical qualifying liver 
ultrasound, CT, or MRI will have an ultrasound performed during Screening.  A positive 
ultrasound result suspicious for HCC at screening will be confirmed with CT scan or MRI
during the screening period.  Suspicious ultrasound lesions confirmed by CT or MRI at 
Screening are exclusionary.


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Has been changed to read:
HCC screening will be required as a protocol-specified study procedure only at the 
Screening Study Visit and at the last Post-treatment Study Visit, as indicated in 
Appendix C, for subjects with compensated cirrhosis only.  Between those visits, HCC 
screening should be performed according to standard of care.
At the Screening Study Visit and at the last Post-treatment Study Visit, subjects with 
compensated cirrhosis will be required to perform a liver ultrasound to screen for HCC, 
unless the subject has a historical liver ultrasound, CT or MRI performed for HCC 
screening within 3 months prior to those visits, in which case the result of the historical 
US, CT or MRI will be used as the result for that Study Visit assessment.  A positive 
ultrasound result suspicious of HCC will be confirmed with CT scan or MRI.  Alternate 
methods of screening for HCC (i.e., MRI or CT) at a study visit should be discussed with 
the TA MD.
Section 5.3.1.1  Study Procedures
Subsection HIV-1 ARV Regimen Dosing Card
Delete:  subsection title and text
HIV-1 ARV Regimen Dosing Card
For subjects with HCV/HIV-1 coinfection, a dosing card will be provided to subjects on 
stable ART treatment at each study visit in order to collect information for the last 
two doses of their HIV-1 ARV medications taken prior to each scheduled 
pharmacokinetic sample collection as specified in Appendix C.
The information recorded on the dosing cards may be used to guide HIV-1 ARV 
treatment compliance discussion and to assess pharmacokinetic (PK) collection time 
relative to HIV-1 ARV dose.  If poor adherence is noted, the subject should be counseled 
and this should be documented in the subject's source.
Site personnel will provide training on its proper use and subjects will be instructed to 
complete the required information and ensure that entries are up-to-date prior to arrival at 


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the study site on study visit days.  In addition, the investigator or designee will contact the 
subject approximately 2 days prior to the scheduled pharmacokinetic sample collection 
date to review the importance of proper HIV-1 ARV administration and documentation of 
dosing times on the dosing card.  The date and time of the phone contact will be entered 
into source documentation.
Subjects will be required to enter the exact date, time, and number of pills taken for each 
medication of the ART regimen separately.  The information recorded will be reviewed 
by the site staff; then site staff will enter the information for the last 2 doses taken prior to 
the scheduled pharmacokinetic sampling into the eCRF.  The completed dosing card will 
be collected by the site personnel on the day of the pharmacokinetic sampling and will be 
kept as a source record of dosage administration.
In the event that the dosing card is not available at the time of pharmacokinetic sample 
collection, the site may obtain dosing information via patient interview and record the 
information for the last 2 doses taken prior to the scheduled pharmacokinetic sampling in 
the source notes and the eCRF.
Section 5.3.1.1  Study Procedures
Subsection Flow Cytometry, HIV RNA and HIV Resistance Testing Samples
Second paragraph, first sentence previously read:
If a HIV-1 RNA level result of subject on stable HIV-1 ART is ≥ 200 copies/mL, the 
subject's HIV-1 RNA is to be repeated as noted in Section 5.4.1.2.
Has been changed to read:
If a HIV-1 RNA level result of a subject on stable HIV-1 ART is ≥ 200 copies/mL, the 
subject's HIV-1 RNA is to be repeated as noted in Section 5.4.1.2.


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Section 5.3.2.1  Collection of Samples for Analysis
Previously read:
Blood samples for pharmacokinetic assay of ABT-493, ABT-530, SOF, primary 
metabolite of SOF (GS-331007), RBV, and for the assay of HIV-1 ARVs (if applicable)
will be collected by venipuncture at each study visit indicated below and in Appendix C.  
All Treatment Period visits except for Study Day 1:  two samples (4 mL each) will be 
collected without regard to the time.  The date and time of blood sample collection and the 
two previous doses of the study drug will be recorded to the nearest minute in the source 
documents.  The two previous doses of HIV-1 ARVs, if applicable, will be recorded to the 
nearest minute in the dosing card or the source documents and on the eCRF.
Has been changed to read:
Blood samples for pharmacokinetic assay of ABT-493, ABT-530, SOF, primary 
metabolite of SOF (GS-331007), and RBV will be collected by venipuncture at each study 
visit indicated below and in Appendix C.  
●
All Treatment Period visits except for Study Day 1:  two samples (4 mL each) 
will be collected without regard to the time.  The date and time of blood 
sample collection and the two previous doses of the study drug will be 
recorded to the nearest minute in the source documents.
Section 5.3.2.2  Handling/Processing of Samples
Previously read:
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, 
SOF, primary metabolite of SOF (GS-331007) RBV and HIV ARVs (if applicable) will 
be provided by the central laboratory, the Sponsor, or its designee.


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Has been changed to read:
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, 
SOF, primary metabolite of SOF (GS-331007) and RBV will be provided by the central 
laboratory, the Sponsor, or its designee.
Section 5.3.2.3  Disposition of Samples
Previously read:
The frozen plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, SOF, 
primary metabolite of SOF (GS-331007), RBV, HIV ARVs, and archive serum and 
plasma samples will be packed in dry ice sufficient to last during transport, and 
transferred from the study site to the central laboratory.
The central laboratory will then ship the ABT-493, ABT-530, SOF, primary metabolite of 
SOF (GS-331007), RBV and HIV ARV samples to the reference laboratories following 
separately provided instructions
Has been changed to read:
The frozen plasma samples for the pharmacokinetic assays of ABT-493, ABT-530, SOF, 
primary metabolite of SOF (GS-331007), RBV, and archive serum and plasma samples 
will be packed in dry ice sufficient to last during transport, and transferred from the study 
site to the central laboratory.
The central laboratory will then ship the ABT-493, ABT-530, SOF, primary metabolite of 
SOF (GS-331007), and RBV samples to the reference laboratories following separately 
provided instructions.
Section 5.3.2.4  Measurement Methods
Delete:  last paragraph
The samples for HIV ARVs for individual subjects, a group of subjects or for the whole 
study may be analyzed based on safety, HCV RNA and plasma HIV-1 RNA results.  If 


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requested, the plasma concentrations of HIV ARVs will be determined at PPD using 
validated assay methods under the supervision of the Drug Analysis Department at 
AbbVie.
Section 5.3.6  Pharmacokinetic Variable
Delete:  second sentence
Values for the pharmacokinetic parameters of ABT-493, ABT-530, SOF, primary 
metabolite of SOF (GS-331007), and RBV, including apparent clearance (CL/F) and 
apparent volume of distribution (V/F) will be estimated using population pharmacokinetic 
modeling procedures.  
Section 5.4.1.1  HCV Virologic Criteria
Section title and text previously read:
5.4.1.1
HCV Virologic Stopping Criteria
Virologic stopping criteria are defined as the following:
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
treatment; or
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during treatment
When confirmatory testing is required it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic stopping criteria has been 
confirmed.  Subjects meeting the virologic stopping criteria will be discontinued from 
study drug and will continue to be followed in the Post-Treatment Period, as per 
Appendix C.


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Has been changed to read:
5.4.1.1
HCV Virologic Failure Criteria
The following criteria will be considered evidence of OTVF, for the purposes of subject 
management, leading to discontinuation of study drug: 
●
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV
RNA measurement of > 1 log10 IU/mL above nadir) at any time point during 
study drug treatment; or
●
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during study drug 
treatment.
Confirmatory testing should be completed as soon as possible and the subject should 
remain on study drug treatment until the OTVF criterion has been confirmed.  Subjects 
with confirmed OTVF will be discontinued from study drug and will continue to be 
followed in the Post-Treatment Period for the emergence and persistence of resistant viral 
substitutions until 24 weeks post-treatment (Appendix C).
Post-treatment relapse is defined as confirmed HCV RNA ≥ LLOQ (defined as 
2 consecutive HCV RNA measurements ≥ LLOQ) at any post-treatment visit, for subjects 
who completed treatment (defined as study drug duration ≥ 77 days for subjects who 
received 12 weeks or ≥ 103 days for subjects who received 16 weeks) and had HCV RNA 
< LLOQ at the final treatment visit, excluding cases of reinfection, as defined below.  
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the post-
treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis performed by the sponsor of the HCV 
NS3, NS5A, and/or NS5B gene sequences.  Reinfection in the case of the same HCV 
subtype is defined as a clade switch, as indicated by the lack of clustering between the 
baseline and post-treatment sequences by phylogenetic analysis.  If phylogenetic analysis 
is not possible due to technical difficulties, HCV reinfection may be determined with a 


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confirmed HCV genotype or subtype switch by the Versant HCV Genotype Inno-LiPA 
Assay v2.0 or Sanger assay.
Section 5.5.1  Treatments Administered
Previously read:
Each dose of study drug (ABT-493/ABT-530, SOF, and RBV) will be dispensed in the 
form of tablets at the visits listed in Appendix C.  The date and time of dosing will be 
recorded to the nearest minute in the source documents and the eCRF for the 2 days 
immediately prior to each study visit starting prior to the Week 2 visit.  On Study Day 1, 
subjects will have their dose administered by study site personnel and blood samples 
collected for assay of study drugs.  The date and time of dosing and blood sample 
collection will be recorded to the nearest minute in the source document.
ABT-493/ABT-530 will be taken orally as ABT-493/ABT-530 300 mg/120 mg 
(three × ABT-493 100 mg/ABT-530 40 mg film-coated tablets) QD and with food.
RBV will be provided by AbbVie to the investigator for use in this study.  RBV will be 
provided as 200 mg tablets.  RBV has weight-based dosing 1000 to 1200 mg divided 
twice daily per prescribing information.  (For example, subjects weighing < 75 kg may 
take RBV orally as 2 tablets in the morning and 3 tablets in the evening which 
corresponds to a 1000 mg total daily dose.  Subjects weighing ≥ 75 kg may take RBV 
orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 
1200 mg total daily dose.)  RBV should be taken with food.
SOF will be provided by AbbVie as 400 mg tablets.  SOF will be taken orally as 1 tablet 
QD, with food.
Study drug must not be dispensed without contacting the IRT system.  Study drug may 
only be dispensed to subjects enrolled in the study through the IRT system.  At the end of 
the Treatment Period or at the Premature D/C Visit from the Treatment Period, the site 
will contact the IRT system to provide visit date information and study drug return 
information for each kit (Section 5.5.7).


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Has been changed to read:
Each dose of study drug (ABT-493/ABT-530, SOF, and RBV) will be dispensed in the 
form of tablets at the visits listed in Appendix C.  The date and time of dosing will be 
recorded to the nearest minute in the source documents (or study drug dosing card) and 
the eCRF for the 2 days immediately prior to each study visit starting prior to the Week 2 
visit.
AbbVie will provide ABT-493/ABT-530 as 100 mg/40 mg film-coated tablets.  
ABT-493/ABT-530 will be taken orally as three tablets QD (total daily dose of 
300 mg/120 mg) and with food.
AbbVie will provide SOF as 400 mg tablets.  SOF will be taken orally as 1 tablet QD, 
with food.
AbbVie will provide RBV as 200 mg tablets.  RBV dosing is determined based on the age 
and weight of the subject at the Day 1 visit, as described in Table 8.  RBV should be taken 
with food.  The RBV dose established at Day 1 should be maintained throughout the 
entire treatment, regardless of ulterior changes in age or weight, unless a dose 
modification is needed due to toxicity (see Section 6.1.7).
Study drug must not be dispensed without contacting the IRT system.  Study drug may 
only be dispensed to subjects enrolled in the study through the IRT system.  At the end of 
the Treatment Period or at the Premature D/C Visit from the Treatment Period, the site 
will contact the IRT system to provide visit date information and study drug return 
information for each kit (Section 5.5.7).
In the event that there is an issue with the study drug supply during the Treatment Period, 
commercial drug may be provided only with prior AbbVie approval, so that the subject 
does not experience treatment interruptions.  If commercial drug is provided, AbbVie will 
provide instructions for documentation.


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Section 5.5.2.2  Storage and Disposition of Study Drug
Table header row previously read:
Study Drug
Storage Conditions
Has been changed to read:
Study Drug
Storage Conditions*
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Last paragraph previously read:
Subjects meeting the eligibility criteria will be enrolled as described in Section 9.3.
Has been changed to read:
Subjects meeting the eligibility criteria will be enrolled as described in Section 8.3.
Section 5.5.4  Selection and Timing of Dose for Each Subject
Second paragraph previously read:
ABT-493/ABT-530 (three tablets) will be dosed QD with food.
Has been changed to read:
ABT-493/ABT-530 (3 tablets) will be dosed QD with food.
Section 5.5.4  Selection and Timing of Dose for Each Subject
Fourth paragraph previously read:
RBV (5 or 6 tablets based on weight) will be dosed BID with food e.g., 2 to 3 tablets 
taken in the morning, and 3 RBV tablets should be taken in the evening.  One of the 
two daily RBV doses will be taken at the same time as ABT-493/ABT-530 and SOF.
Has been changed to read:
RBV (3 to 6 tablets based on age and weight of the subject at Day 1) will be dosed twice 
daily with food.  For example, if a subject takes 5 tablets of RBV per day, 2 tablets should 


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be taken in the morning, and 3 tablets should be taken in the evening.  One of the 
two daily RBV doses will be taken at the same time as ABT-493/ABT-530 and SOF.  The 
other RBV dose should be taken approximately 12 hours apart.
Section 5.6.1  Discussion of Study Design and Choice of Control Groups
Second paragraph, last sentence previously read:
The study design will provide additional data on ABT-493/ABT-530 in combination with 
SOF and RBV, such as response rates in subjects infected with different HCV genotypes, 
with or without cirrhosis, the PI and/or NS5Ai treatment experience prior to the AbbVie 
HCV parent study pharmacokinetics, resistance, and the nature of virologic failure 
(e.g., on-treatment or post-treatment relapse).
Has been changed to read:
The study design will provide additional data on ABT-493/ABT-530 in combination with 
SOF and RBV, such as response rates in subjects infected with different HCV genotypes, 
with or without cirrhosis, the PI and/or NS5Ai treatment experience prior to the AbbVie 
HCV parent study pharmacokinetics, resistance, and the nature of virologic failure 
(e.g., OTVF or post-treatment relapse).
Section 5.6.3  Suitability of Subject Population
Delete:  last paragraph
In order to be enrolled in the study, subjects who are on stable opiate replacement must be 
on a therapy with methadone or buprenorphine with or without naloxone for at least 
6 months prior to screening.  This is based on the results from Study M13-602 that 
evaluated the pharmacokinetic, pharmacodynamic, safety, and tolerability effects of the 
co-administration of methadone or buprenorphine/naloxone and GLE/PIB in adult 
subjects on stable opioid therapy, which showed acceptable safety and no relevant 
pharmacokinetic or pharmacodynamic interactions.


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Section 5.6.4.1  Rationale for Dose Selections
First paragraph previously read:
HCV infected patients who were treated and experience virologic failure an AbbVie HCV 
parent study, will be treated with ABT-493/ABT-530 300 mg/120 mg in combination 
with SOF 400 mg and weight based RBV for 12 or 16 weeks in the current protocol.  The 
doses of 300 mg ABT-493 and 120 mg ABT-530 were selected based on multiple HCV 
clinical trials including Studies M14-867, M14-868 and M15-410 in order to optimize 
efficacy of the combination while maintaining an acceptable safety profile, and to be 
consistent with the dose selection for ABT-493 and ABT-530 in the currently on-going 
AbbVie HCV Phase 3 studies.
Has been changed to read:
HCV infected patients who were treated and experienced virologic failure in an AbbVie 
HCV parent study, will be treated with ABT-493/ABT-530 300 mg/120 mg in 
combination with SOF 400 mg and weight-based RBV for 12 or 16 weeks in the current 
protocol.  The dose of 300 mg/120 mg of ABT-493/ABT-530 was selected based on 
multiple HCV clinical trials including Studies M14-867, M14-868 and M15-410 in order 
to optimize efficacy of the combination while maintaining an acceptable safety profile, is 
consistent with the dose used in AbbVie HCV Phase 3 studies and is the approved dose 
for commercial use.
Section 5.6.4.1  Rationale for Dose Selections
Second paragraph, first sentence previously read:
In Studies M14-867, M14-868, high SVR rates have been achieved for the combination of 
ABT-493 300 mg and ABT-530 120 mg (Table 6).
Has been changed to read:
In Studies M14-867 and M14-868, high SVR rates have been achieved for the 
combination of ABT-493 300 mg and ABT-530 120 mg (Table 6).


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Section 5.6.4.1  Rationale for Dose Selections
Delete:  fourth paragraph
The maximum dose of ABT-493/ABT-530 will not exceed 300 mg/120 mg per day for up 
to 16 weeks.
Section 5.6.4.1  Rationale for Dose Selections
Last paragraph, first and second sentence previously read:
Weight based RBV, 1000 mg to 1200 mg, will be dose-divided to twice daily.  This dose 
is approved for treatment of adult patients with chronic HCV infection in combination 
with pegIFN.  
Has been changed to read:
Weight based RBV, 600 mg to 1200 mg, will be dose-divided to twice daily.  This dose is 
approved for treatment of adult and adolescent patients with chronic HCV infection in 
combination with pegIFN.  
Section 5.6.4.1  Rationale for Dose Selections
Last paragraph, fourth sentence previously read:
In addition, this dose was studied in the absence of pegIFN in Studies M12-267, 
M12-746, M12-998, M11-652, M11-646, M13-098, M13-389, M13-961, M14-002, and 
M14-004 and was found to be generally safe and well tolerated and resulted in high SVR 
rates.  
Has been changed to read:
In addition, the RBV dose was studied in the absence of pegIFN in adults in 
Studies M12-267, M12-746, M12-998, M11-652, M11-646, M13-098, M13-389, 
M13-961, M14-002, and M14-004, and in adolescents in Study M14-748, and the RBV 
dose was found to be generally safe and well tolerated and resulted in high SVR rates.


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Section 5.6.4.2  Rationale for Duration Selections
First paragraph, fourth sentence previously read:
The interim results from this ongoing study, as summarized in Section 3.0, demonstrate 
high SVR12 rates (mITT rates of 95 – 100%) following a 12-week treatment regimen of 
ABT-493 and ABT-530 with or without RBV
Has been changed to read:
The interim results from this study, as summarized in Section 3.0, demonstrate high 
SVR12 rates (mITT rates of 95 – 100%) following a 12-week treatment regimen of 
ABT-493 and ABT-530 with or without RBV
Seciton 5.6.4.2  Rationale for Duration Selections
Second paragraph
Add:  new second sentence
Since ABT-493/ABT-530 has pangenotypic activity, subjects with mixed infections and 
undetermined genotypes will be allowed to be treated in this study.
Seciton 5.6.4.2  Rationale for Duration Selections
Second paragraph, second and third sentence previously read:
The extended treatment duration of 16 weeks for subjects with GT3 infection was based 
on the study design of the on-going Part 3 of Study M14 868.  In Part 3 of 
Study M14-868, GT3-infected subjects who are treatment-naïve are allocated to the 
12 week arm, GT3-infected subjects who are IFN-experienced with compensated cirrhosis 
are allocated to the 16 week arm, GT3-infected subjects who are IFN-experienced 
subjects without compensated cirrhosis are allocated at a 1:1 ratio to the 12 week and 
16 week treatment arms.
Has been changed to read:
The extended treatment duration of 16 weeks for subjects with GT3 infection was based 
on the study design of Part 3 of Study M14-868.  In Part 3 of Study M14-868, GT3-
infected subjects who were treatment-naïve are allocated to the 12 week arm, GT3-


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infected subjects who were IFN-experienced with compensated cirrhosis are allocated to 
the 16 week arm, GT3-infected subjects who were IFN-experienced subjects without 
compensated cirrhosis are allocated at a 1:1 ratio to the 12 week and 16 week treatment 
arms.
Seciton 5.6.4.2  Rationale for Duration Selections
Third paragraph, second sentence previously read:
The ABT-493/ABT-530 regimen is being evaluated for 12 week treatment duration in 
Study M14-172 for subjects with HCV GT1, 2, 4, 5, and 6 infection with compensated 
cirrhosis, who are either treatment-naïve, or PI- and NS5Ai-naïve.
Has been changed to read:
The ABT-493/ABT-530 regimen was evaluated for 12 week treatment duration in 
Study M14-172 for subjects with HCV GT1, 2, 4, 5, and 6 infection with compensated 
cirrhosis, who are either treatment-naïve, or PI- and NS5Ai-naïve.
Seciton 5.6.4.2  Rationale for Duration Selections
Last paragraph, second sentence previously read:
Currently, theThe ABT-493/ABT-530 regimen is beingwas evaluated for a 12 week and 
16 week treatment duration in Study M15-410, Part 2 for DAA treatment-experienced 
subjects with HCV GT1, 4, 5, and 6 infection with or without compensated cirrhosis.
Has been changed to read:
The ABT-493/ABT-530 regimen was evaluated for a 12 week and 16 week treatment 
duration in Study M15-410, Part 2 for DAA treatment-experienced subjects with HCV 
GT1, 4, 5, and 6 infection with or without compensated cirrhosis.
Section 6.0  Complaints
Previously read:
For adverse events, please refer to Sections 6.1 through 6.1.7.6.


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Has been changed to read:
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.6.  For product complaints, please refer to Section 6.2.
Section 6.1.3  Relationship to Study Drug
In-text table previously read:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
Has been changed to read:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
Section 6.1.5  Adverse Event Reporting
First paragraph, last sentence previously read:
Serious adverse events that occur prior to the site having access to the RAVE® system or 
if RAVE is not operable should be faxed to Clinical Pharmacovigilance within 24 hours 
of the site becoming aware of the serious adverse event.


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Has been changed to read:
Serious adverse events that occur prior to the site having access to the RAVE® system or 
if RAVE is not operable should be documented on the SAE Non-CRF forms and emailed 
(preferred route) or should be faxed to Clinical Pharmacovigilance within 24 hours of the 
site becoming aware of the serious adverse event.
Section 6.1.5  Adverse Event Reporting
Fifth paragraph previously read:
In case of subject safety concerns or medical emergencies, where the Study TA MD be 
unavailable, please call the following central back-up number:
Has been changed to read:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Section 6.1.5  Adverse Event Reporting
Last paragraph previously read:
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.
Has been changed to read:
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Global and Local Regulations.  The reference document used for SUSAR reporting will 
be the most current version of the Investigator's Brochure.  The reference document used 


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for SUSAR reporting in the EU countries will be the most current version of the Summary 
of Product Characteristics (SmPC).
Section 6.1.6  Pregnancy
First paragraph previously read:
Subjects and their partners should avoid pregnancy, and males should avoid sperm 
donation, starting with Study Day 1 until 4 months for females subjects and 7 months for 
male subjects and their female partners after stopping RBV, or as directed by local RBV 
label.
Has been changed to read:
Subjects and their partners should avoid pregnancy, and males should avoid sperm 
donation, starting with Study Day 1 until 4 months for females subjects and 7 months for 
male subjects and their female partners after stopping RBV, or as directed by local RBV 
label, whichever is more restrictive.


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Table 13.  Management of Hemoglobin Decreases
Previously read:
Hemoglobin Reduction in Patients Without Cardiac Disease or 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 QD and continue to monitor hemoglobin levels 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
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Hemoglobin 
< 8.5 g/dL
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Reduction in Patients with Stable Cardiac Disease or History of Stable Cardiac Disease
Hemoglobin decrease 
of ≥ 2 g/dL during a 
4-week treatment 
period (Hemoglobin 
≥10 g/dL)
Study drugs may be continued
Reduce RBV dose to 600 mg QD and continue to monitor hemoglobin levels per protocol
If a subsequent hemoglobin result is greater than the level that triggered the dose 
reduction, the investigator may elect to increase RBV, with gradual, 200 mg dose 
increases towards the original dose
If the subject has symptoms consistent with their cardiac disease, manage subject as 
medically appropriate and AbbVie Study TA MD may be contacted
If hemoglobin does not increase, investigator may manage the subject as medically 
appropriate.  If hemoglobin decreases to < 10 g/dL see appropriate row below
Hemoglobin 
< 10.0 g/dL, but 
≥8.5 g/dL
Study drugs may be continued
Continue at reduced RBV dose as above (or reduce RBV dose to 600 mg QD if this is the 
initial reduction) 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 hemoglobin < 10 g/dL despite being for 4 weeks on the reduced RBV dose, permanently 
discontinue RBV and manage the subject as medically appropriate
Hemoglobin 
< 8.5 g/dL or 
< 12 g/dL after 
4 weeks of dose 
reduction
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event


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Has been changed to read:
Hemoglobin Reduction in Patients Without Cardiac Disease or 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 QD* and continue to monitor hemoglobin levels 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
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Hemoglobin 
< 8.5 g/dL
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
Reduction in Patients with Stable Cardiac Disease or History of Stable Cardiac Disease
Hemoglobin decrease 
of ≥ 2 g/dL during a 
4-week treatment 
period (Hemoglobin 
≥10 g/dL)
Study drugs may be continued
Reduce RBV dose to 600 mg QD* and continue to monitor hemoglobin levels per protocol
If a subsequent hemoglobin result is greater than the level that triggered the dose 
reduction, the investigator may elect to increase RBV, with gradual, 200 mg dose 
increases towards the original dose
If the subject has symptoms consistent with their cardiac disease, manage subject as 
medically appropriate and AbbVie Study TA MD may be contacted
If hemoglobin does not increase, investigator may manage the subject as medically 
appropriate.  If hemoglobin decreases to < 10 g/dL see appropriate row below
Hemoglobin 
< 10.0 g/dL, but 
≥8.5 g/dL
Study drugs may be continued
Continue at reduced RBV dose as above (or reduce RBV dose to 600 mg QD* if this is the 
initial reduction) 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 hemoglobin < 10 g/dL despite being for 4 weeks on the reduced RBV dose, permanently 
discontinue RBV and manage the subject as medically appropriate
Hemoglobin 
< 8.5 g/dL or 
< 12 g/dL after 
4 weeks of dose 
reduction
Permanently discontinue RBV and manage the subject as medically appropriate
Enter discontinuation into appropriate eCRFs and create corresponding adverse event
*
For subjects aged 12 to less than 18, RBV dose reduction should be per local RBV label.


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Section 6.1.7.5  Management of Increases in ALT
Previously read:
If a subject experiences a post-baseline ALT value ≥ 5 × ULN that is also ≥ 2 × Baseline a 
confirmatory test should be performed.  If, the ALT is value confirmed ≥ 5 × ULN and 
≥2 × Baseline the recommendations below should be followed:
●
Complete hepatic questionnaire, evaluate for alternate etiology of ALT 
elevation; document in the source, update the medical history and concomitant 
medications eCRF (if applicable), and obtain additional testing as appropriate 
(e.g., hepatitis A, B and E panel).
●
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.
●
Interrupt study drugs if any of the following is observed at any time:
○
ALT level is ≥ 20 × ULN in the absence of an alternate etiology.
○
Concurrent increases in direct bilirubin or INR or presence/onset of 
symptoms/signs of hepatitis.
○
At the discretion of the investigator.
Alternate management of confirmed ALT increases requires approval of the AbbVie 
Study TA MD.
Has been changed to read:
If a subject experiences a post-baseline ALT value ≥ 5 × ULN that is also ≥ 2 × Baseline 
value, the subject should have a confirmatory test should be performed.  If, the ALT is 
value confirmed ≥ 5 × ULN, and ≥ 2 × Baseline value, the recommendations below 
should be followed:
●
Complete hepatic questionnaire
●
Evaluate for alternate etiology of ALT elevation; document in the source, 
update the medical history and concomitant medications eCRF (if applicable), 
and obtain Anti-HAV IgM, Anti-HAV Total, Anti-HBc IgM, Anti-HBc Total, 


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Anti-HBs, HBV DNA, HBsAg, Anti-HEV IgM, Anti-HEV IgG and HEV 
RNA, and other additional tests, 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 in the absence of an alternate etiology.
○
Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis.
○
At the discretion of the investigator.
Alternate management of confirmed ALT increases requires approval of the AbbVie 
Study TA MD.
Section 6.1.8 Collection of Data Regarding Known AIDS-Associated Opportunistic 
Infections
Previously read:
6.1.8
Collection of Data Regarding Known AIDS-Associated 
Opportunistic Infections
HIV-1 infected subjects participating in clinical trials may develop infections typically 
associated with AIDS.  A list of these known AIDS-associated opportunistic infections 
(OI) is presented in Appendix D.  The events listed in Appendix D will be summarized as 
HIV-related events, not as adverse events.  These OIs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
Has been changed to read:
6.1.8
Collection of Data Regarding Known AIDS-Defining 
Conditions
HIV-1 infected subjects participating in clinical trials may develop conditions typically 
associated with AIDS.  A list of these known AIDS-Defining Conditions (ADCs) is 
presented in Appendix D.  The events listed in Appendix D will be summarized as HIV-


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related events, not as adverse events.  These ADCs will be collected from the time of 
study drug administration until 30 days following discontinuation of study drug.
Section 6.2.2  Reporting
First paragraph, first sentence previously read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.
Has been changed to read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.
Section 7.0  Protocol Deviations
First paragraph previously read:
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 personnel:
Has been changed to read:
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitors:


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Section 7.0  Protocol Deviations
"Alternate Contact:" previously read:
Hub South West Europe & Africa
41-45 Marinou Antypa
Athens, Greece
Office:
Cell:
Fax:
Email:
Has been changed to read:
1 North Waukegan Road
North Chicago, IL 60064
Office:
Cell:
Fax:
Email:
Section 8.1  Statistical and Analytical Plans
First paragraph
Add:  new last sentence 
An interim analysis may be conducted for the purpose of regulatory interaction.


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Section 8.1  Statistical and Analytical Plans
Third paragraph, last sentence previously read:
Sensitivity analyses of the primary efficacy endpoint, when applicable, will be performed 
on the intention-to-treat population modified to exclude subjects not of an eligible 
genotype according to phylogenetic analyses (mITT-GT), and on the mITT-GT 
population modified to exclude subjects who did not achieve SVR12 for reasons other than 
virologic failure (mITT-GT-VF).
Has been changed to read:
Sensitivity analyses of the primary efficacy endpoint, when applicable, will be performed 
on the intention-to-treat population modified to exclude subjects who did not achieve 
SVR12 for reasons other than virologic failure (mITT-VF).
Section 8.1.2.1  Primary Efficacy Endpoints
First paragraph, last sentence previously read:
The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the rate for SVR12 is 100%, then the Wilson's score method will be 
used for the confidence interval instead.
Has been changed to read:
The number and percentage of subjects achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval using the normal approximation to the binomial 
distribution, unless the number of virologic failure is less than 5, then the Wilson's score 
method will be used for the confidence interval instead.
Section 8.1.2.1  Primary Efficacy Endpoints
Last paragraph previously read:
A summary of reason for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.


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Has been changed to read:
A summary of reason for SVR12 non-response (e.g., OTVF, relapse, other) will be 
provided.
Section 8.1.2.2  Secondary Efficacy Endpoints
Second paragraph previously read:
For the analysis of HCV virologic relapse, completion of treatment is defined as any 
subject with study drug duration of 77 days and 105 days or greater for subjects allocated 
to treatment durations of 12 weeks and 16 weeks, respectively.  
Has been changed to read:
For the analysis of HCV virologic relapse, completion of treatment is defined as any 
subject with study drug duration of 77 days and 103 days or greater for subjects allocated 
to treatment durations of 12 weeks and 16 weeks, respectively.
Section 8.1.2.3  Sensitivity Analysis
Last paragraph previously read:
As sensitivity analyses, the number and percentage of subjects in the mITT-GT and 
mITT-GT-VF populations achieving SVR12, as applicable, will be summarized along with 
a two-sided 95% confidence interval using Wilson's score interval and the Normal 
approximation to the binomial distribution by treatment arm and overall.
Has been changed to read:
As sensitivity analyses, the number and percentage of subjects in the mITT-VF 
populations achieving SVR12, as applicable, will be summarized along with a two-sided 
95% confidence interval using Wilson's score interval and the Normal approximation to 
the binomial distribution by treatment arm and overall.


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Section 8.2  Determination of Sample Size
Previously read:
It is anticipated that approximately 40 HCV infected, DAA treatment-experienced 
subjects who have experienced virologic failure in a AbbVie HCV parent study will be 
enrolled.  
Has been changed to read:
It is anticipated that approximately 50 HCV infected, DAA treatment-experienced 
subjects who have experienced virologic failure in an AbbVie HCV parent study will be 
enrolled.  
Section 9.1  Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB)
Second paragraph, last sentence previously read:
The investigator will be required to submit, maintain and archive study essential 
documents according to ICH GCP.
Has been changed to read:
The investigator will be required to submit, maintain and archive study essential 
documents according to ICH GCP and all other applicable regulatory authorities.
Section 9.3  Subject Information and Consent
Second paragraph
Add:  new second sentence
The pharmacogenetic informed consent must be signed before the pharmacogenetic 
testing is performed.


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Section 10.1  Source Documents
First paragraph
Add:  new fourth and fifth sentence
The Investigator Awareness Date (SAE CRF) may serve as the source for this data point.  
This adverse event data point required for eCRF completion can be entered directly in the 
eCRF.
Section 13.0  Completion of Study
Second paragraph, first sentence previously read:
The investigator must retain any records related to the study according to local 
requirements.
Has been changed to read:
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and other applicable regulatory requirements.  
Section 14.0  Investigator's Agreement
Item 1 previously read:
I have received and reviewed the Investigator's Brochure for ABT-493/ABT-530, and the 
product labeling for SOF and RBV.
Has been changed to read:
I have received and reviewed the Investigator's Brochure for Glecaprevir/Pibrentasvir, and 
the product labeling for SOF and RBV.
Section 15.0  Reference List
Reference 13 previously read:
AbbVie.  ABT-493 Investigator's Brochure Edition 3.  12 September 2014.


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Has been changed to read:
AbbVie.  Glecaprevir/Pibrentasvir Fixed-Dose Combination Investigator's Brochure 
Edition 3.  29 August 2017.
Section 15.0  Reference List
Delete:  Reference 22, 24, 46 – 50, and 56 
22.
AbbVie.  ABT-530 Investigator's Brochure Edition 3.  12 September 2014.
24.
AbbVie.  ABT-493/ABT-530 Fixed-Dose Combination Investigator's Brochure 
Edition 1.  23 September 2015.
46.
Lam AM, Espiritu C, Bansal S, et al.  Genotype and subtype profiling of PSI-7977 
as a nucleotide inhibitor of hepatitis C virus.  Antimicrob Agents Chemother.  
2012;56(6):3359-68.
47.
Zeuzem S, Dusheiko GM, Salupere R, et al.  Sofosbuvir and ribavirin in HCV 
genotypes 2 and 3.  N Engl J Med.  2014;370(21):1993-2001.
48.
Lawitz E, Mangia A, Wyles D, et al.  Sofosbuvir for previously untreated chronic 
hepatitis C infection.  N Engl J Med.  2013;368(20):1878-87.
49.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.  Daclatasvir plus 
sofosbuvir for previously treated or untreated chronic HCV infection.  N Engl J 
Med.  2014;370(3):211-21.
50.
German P, Mathias A, Pang PS, et al.  Lack of a clinically significant 
pharmacokinetic drug-drug interaction between sofosbuvir (GS-7977) and GS 5885 
or GS-9669 in healthy volunteers.  63rd Annual Meeting of the American 
Association for the Study of Liver Diseases (AASLD).  09-13 November 2012; 
Boston, MA.  Abstract 1888.
56.
Johnson VA, Calvez V, Gunthard HF, et al.  Update of the drug resistance mutations 
in HIV-1:  March 2013.  Top Antivir Med.  2013;21(1):6-14.


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Section 15.0  Reference List
Reference 31 previously read:
AASLD/IDSA HCV Guidance Panel.  Hepatitis C guidance:  AASLD-IDSA 
recommendations for testing, managing, and treating adults infected with hepatitis C 
virus.  Hepatology.  2015;62(3):932-54.
Has been changed to read:
AASLD and IDSA.  Patients with HIV/HCV coinfection.  Available from:  
www.HCVGuidance.org.  Available on:  October 02, 2017.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Pharmacokinetics
Clinical
Statistics
Clinical
Global Drug Supply Management
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Clinical
Pharmacokinetics
Clinical
Statistics
Clinical
Bioanalysis


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period
Activity "FibroTest or FibroScan® or Liver Biopsyf" previously read:
FibroTest or FibroScan® or Liver Biopsyf
Has been changed to read:
FibroTest/APRI or FibroScan® or Liver Biopsyf
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period
Activity "HgbA1c" previously read:
HgbA1c
Has been changed to read:
Hemoglobin A1c


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period
Delete:  activity "Dispense/Review HIV-1 ART Dosing Card, if applicablej" previously read:
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
(Arm B Only)
EOT/Premature D/C 
from Treatmentb
Dispense/Review HIV-1 ART Dosing Card, if 
applicablej
X
(Dispense 
only)
X
X
X
X
X
X (Review only)
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period
Activity "Pharmacokinetic Samplesh" previously read:
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
(Arm B Only)
EOT/Premature D/C 
from Treatmentb
Pharmacokinetic Samplesh
X
X
X
X
X
X
Has been changed to read:
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
(Arm B Only)
EOT/Premature D/C 
from Treatmentb
Pharmacokinetic Samplesh
X
X
X
X
X


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period
Table note "a.," "h.," "i.," and "j." previously read:
a.
All procedures to be performed prior to first dose, with the exception of the additional post-dose pharmacokinetic 
samples.
h.
PK samples will be collected at each scheduled study visit.  Detail regarding timing of samples is provided in 
Section 5.3.2.1.
i.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation and Liver Ultrasound are only performed for 
subjects in Arm B (compensated cirrhotic) as described in Section 5.3.1.1.
j.
For subjects with HCV/HIV-1 co-infected subjects.
Has been changed to read:
a.
All procedures to be performed prior to first dose.
h.
PK samples will be collected at each scheduled study visit except Day 1.  Detail regarding timing of samples is 
provided in Section 5.3.2.1.
i.
Child-Pugh Score, Clinical Assessment of Hepatic Decompensation and Liver Ultrasound are only performed for 
subjects with compensated cirrhosis as described in Section 5.3.1.1.
j.
For HCV/HIV-1 co-infected subjects.


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Appendix C.  Study Activities
Subsection Study Activities – Post-Treatment (PT) Period
Activity "Monthly Pregnancy Test (females)d" previously read:
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Monthly Pregnancy Test (females)d
X (u)
(PT Weeks 12, 16, 20)
Xc
Has been changed to read:
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
Monthly Pregnancy Test (females)d
X (u)
(PT Weeks 8, 12, 16)
Xc
Appendix C.  Study Activities
Subsection Study Activities – Post-Treatment (PT) Period
Add:  new activity "HCC Screening:  Liver Ultrasoundh" 
Activity
PT Wk 4
PT Wk 12
PT Wk 24 or PT D/Ca
HCC Screening:  Liver Ultrasoundh
X


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Appendix C.  Study Activities
Subsection Study Activities – Post-Treatment (PT) Period
Table note "d." and "e." previously read:
d.
Females not of CPB at Screening do not require pregnancy testing.  Pregnancy testing should be completed every 
4 weeks for 4 months after the last dose of RBV label.  At PT Weeks 16 and 20, subjects may have an unscheduled 
office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site.  Additional 
testing may be required per local RBV label.
e.
Only medications taken for SAEs and for the treatment of HCV will be collected after 30 days post-dosing.
Has been changed to read:
d.
Females not of CBP at Screening do not require pregnancy testing.  Pregnancy testing should be completed every 4 
weeks for 4 months after the last dose of RBV (or as directed per the local RBV label, whichever is more 
restrictive).  At PT Weeks 8 and 16 subjects may have an unscheduled office visit for pregnancy testing or elect to 
perform the tests at home with test kits provided by the site.  Additional testing may be required per local RBV 
label.
e.
Only medications taken for SAEs and for the treatment of HCV and HIV will be collected after 30 days post-
dosing.
Appendix C.  Study Activities
Subsection Study Activities – Post-Treatment (PT) Period
Table note "g." previously read:
Procedure applicable only to subjects enrolled with cirrhosis.
Has been changed to read:
Required only for subjects with compensated cirrhosis as described in Section 5.3.1.1.
Appendix D.  List of AIDS-Associated Opportunistic Infections
Previously read:
Appendix D.
List of AIDS-Associated Opportunistic Infections
Collection of data regarding known AIDS-associated opportunistic infections is covered 
in Section 6.1.8.
●
Aspergillosis
●
Bartonellosis


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●
Candidiasis (*Bronchi; *Esophagus; *Lungs; Oropharyngeal [Thrush]; 
*Trachea; Vulvovaginal [Persistent, Frequent, or Poorly Responsive to 
Therapy])
●
*Coccidioidomycosis
●
*Cryptococcosis
●
*Cryptosporidiosis
●
Cytomegalovirus (*Retinitis; *Cytomegalovirus Disease [other than liver, 
spleen or nodes])
●
Enteric infections, Recurrent (Bacterial)
●
Herpes Simplex Virus (*Bronchitis; *Esophagitis; *Pneumonitis; *Chronic 
Ulcer(s) [> 1 month in duration])
●
*Histoplasmosis
●
Human Herpesvirus-8 Disease (Kaposi Sarcoma, Primary Effusion 
Lymphoma, Multicentric Castleman's Disease)
●
Human Papilloma Virus Infections
●
*Isosporiasis (Cystoisosporiasis)
●
Microsporidiosis
●
*Mycobacterium avium – Complex Disease (Disseminated)
●
*Mycobacterium tuberculosis – Infection and Disease
●
*Pneumonia
●
*Pneumonia, recurrent bacterial (and/or other respiratory infections including 
sinusitis, bronchitis, otitis)
●
*Progressive multifocal leukoencephalopathy (JC Virus Infection)
●
Syphilis
●
*Toxoplasma Gondii Encephalitis
●
Varicella Zoster Virus Diseases
*
AIDS-defining event as described by CDC Surveillance Case Definition of 1993.
Cross reference:  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV Infected Adults and 
Adolescents.  Available from:  http://aidsinfo nih.gov/guidelines.


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Has been changed to read:
Appendix D.
List of AIDS-Defining Conditions
Collection of data regarding known AIDS-Defining Conditions (ADCs) is covered in 
Section 6.1.8.
AIDS-Defining Conditions:
●
Bacterial infections, multiple or recurrent*
●
Candidiasis of bronchi, trachea, or lungs
●
Candidiasis of esophagus†
●
Cervical cancer, invasive§
●
Coccidioidomycosis, disseminated or extrapulmonary
●
Cryptococcosis, extrapulmonary
●
Cryptosporidiosis, chronic intestinal (> 1 month's duration)
●
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age 
> 1 month
●
Cytomegalovirus retinitis (with loss of vision)†
●
Encephalopathy, HIV related
●
Herpes simplex:  chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, 
or esophagitis (onset at age > 1 month)
●
Histoplasmosis, disseminated or extrapulmonary
●
Isosporiasis, chronic intestinal (> 1 month's duration)
●
Kaposi sarcoma†
●
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*†
●
Lymphoma, Burkitt (or equivalent term)
●
Lymphoma, immunoblastic (or equivalent term)
●
Lymphoma, primary, of brain
●
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary†


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●
Mycobacterium tuberculosis of any site, pulmonary,†§ disseminated,† or 
extrapulmonary†
●
Mycobacterium, other species or unidentified species, disseminated† or 
extrapulmonary†
●
Pneumocystis jirovecii pneumonia†
●
Pneumonia, recurrent†§
●
Progressive multifocal leukoencephalopathy
●
Salmonella septicemia, recurrent
●
Toxoplasmosis of brain, onset at age > 1 month†
●
Wasting syndrome attributed to HIV
*
Only among children aged < 13 years. 
†
Condition that might be diagnosed presumptively.
§
Only among adults and adolescents aged > 13 years.
Cross reference:  Morbidity and Mortality Weekly Report (MMWR).  AIDS Defining Conditions.  2008.  Available 
from:  https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2 htm.


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Appendix E.  Clinical Toxicity Grades
Delete:  appendix title and text
Appendix E.
Clinical Toxicity Grades


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SAP_001.pdf: 
ABT-493/ABT-530
M15-942 – Statistical Analysis Plan
Version 1.0 – 28 July 2020
1
1.0
Title Page
Statistical Analysis Plan
Study M15-942
An Open-Label, Multicenter Study to Evaluate the 
Efficacy and Safety of ABT-493/ABT-530 in 
Combination with Sofosbuvir and Ribavirin in 
Chronic Hepatitis C (HCV) Infected Subjects Who 
Have Experienced Virologic Failure in AbbVie HCV 
Clinical Studies
(MAGELLAN-3)
Date:  28 July 2020
Version 1.0
NCT02939989


ABT-493/ABT-530
M15-942 – Statistical Analysis Plan
Version 1.0 – 28 July 2020
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................6
4.1
Objectives ..................................................................................................6
4.2
Design Diagram .........................................................................................6
4.3
Sample Size................................................................................................8
4.4
Planned Analyses .......................................................................................9
5.0
Analysis Populations .............................................................10
5.1
Definition for Analysis Populations.........................................................10
5.1.1
Intention-to-Treat (ITT) Population.........................................................10
5.1.2
Modified Intention-to-Treat (mITT) Populations ....................................10
5.1.3
Safety Population.....................................................................................10
6.0
Analysis Conventions ............................................................10
6.1
Definition of Baseline, Final Treatment, and Final Post-Treatment 
Assessments .............................................................................................10
6.1.1
Baseline....................................................................................................10
6.1.2
Study Days...............................................................................................11
6.2
Definition of Analysis Windows .............................................................12
6.3
Missing Data Imputation..........................................................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications...........................................15
7.1
Demographic and Baseline Characteristics .............................................16
7.2
Medical History .......................................................................................22
7.3
Prior, Concomitant, and Post-Treatment Medications.............................23
8.0
Subject Disposition................................................................24
8.1
Disposition of Safety Population .............................................................24
9.0
Study Drug Duration and Compliance................................25
9.1
Study Drug Duration................................................................................25
9.2
Compliance ..............................................................................................25
10.0
Efficacy Analysis....................................................................26


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10.1
General Considerations............................................................................26
10.2
Handling of Multiplicity ..........................................................................31
10.3
Primary Efficacy Analysis .......................................................................31
10.4
Secondary Efficacy Analyses...................................................................31
10.5
Sensitivity Analyses for SVR ..................................................................32
10.6
Efficacy Subgroup Analysis ....................................................................32
10.7
Additional Efficacy Analyses ..................................................................33
10.8
Resistance Analyses.................................................................................34
10.8.1
HCV Drug-Resistance Analyses..............................................................34
10.8.2
HIV Drug-Resistance Analysis................................................................38
11.0
Safety Analysis.......................................................................39
11.1
General Considerations............................................................................39
11.2
Analysis of Adverse Events.....................................................................39
11.2.1
Treatment-Emergent Adverse Events ......................................................39
11.2.2
Tabulations of Treatment-Emergent Adverse Events..............................39
11.2.3
Adverse Events of Special Interest ..........................................................43
11.2.4
Listing of Adverse Events........................................................................44
11.3
AIDS Defining Conditions ......................................................................44
11.4
Analysis of Laboratory Data....................................................................44
11.4.1
Variables and Criteria Defining Abnormality..........................................44
11.4.2
Statistical Methods...................................................................................46
11.5
Analysis of Vital Signs Data....................................................................49
11.5.1
Variables and Criteria Defining Abnormality..........................................49
11.5.2
Statistical Methods...................................................................................49
11.6
Analysis of HIV-1 RNA and Flow Cytometry ........................................50
12.0
Summary of Changes ............................................................50
12.1
Summary of Changes Between the Latest Version of the Protocol 
and SAP ...................................................................................................50
13.0
References...............................................................................51
List of Tables
Table 1.
Treatment Arm Allocation in Study M15-942...........................................7


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Table 2.
Ribavirin Dosing Recommendations .........................................................8
Table 3.
The 95% CIs Using the Wilson's Score Method for a Given 
Number of Failures ....................................................................................9
Table 4.
Analysis Time Windows for HCV RNA and Resistance 
Endpoints, Safety Laboratory and Vital Sign Measurements, and 
Child-Pugh Scores (Treatment Period)....................................................13
Table 5.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)...........................................................................14
Table 6.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements and Child-Pugh Score (Post-Treatment Period) ..............14
Table 7.
Baseline Fibrosis Stage............................................................................19
Table 8.
Child-Pugh Classification of Severity of Cirrhosis .................................20
Table 9.
Medical History eCRF .............................................................................22
Table 10.
Signature Amino Acid Positions and the Key Subsets of Amino 
Acid Positions ..........................................................................................35
Table 11.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................45
Table 12.
Criteria for Potentially Clinically Significant Vital Sign Values.............49
List of Figures
Figure 1.
Study Schematic.........................................................................................8


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
AbbVie Statistics and Statistical Programming for Study M15-942.
Study M15-942 evaluates the efficacy and safety of ABT-493/ABT-530, also known as 
glecaprevir (GLE)/pibrentasvir (PIB), in combination with sofosbuvir (SOF) and ribavirin 
(RBV) in chronic hepatitis C virus (HCV) genotype (GT) 1 – 6-infected subjects who 
previously experienced virologic failure in AbbVie HCV clinical studies (designated as 
AbbVie HCV parent studies), including subjects with compensated cirrhosis and/or 
human immunodeficiency virus-1 (HIV-1) co-infection and/or post-liver or post-renal 
transplant.  Subjects will receive 12 or 16 weeks of ABT-493/ABT-530 + SOF + RBV, 
depending on HCV GT, cirrhosis status, and treatment experience with protease inhibitor 
(PI) and/or NS5A inhibitor (NS5Ai)-containing regimens prior to enrolling in the AbbVie 
HCV parent studies.  Enrollment in Study M15-942 can include subjects who have 
experienced virologic failure following treatment with AbbVie's ABT-493/ABT-530, or 
ombitasvir/paritaprevir/ritonavir ± dasabuvir (3D or 2D) in an AbbVie HCV parent study.
This SAP (Version 1.0) provides details to further elaborate the statistical methods 
outlined in Clinical Study Protocol M15-942 incorporating Amendment 1 dated 
31 August 2016, Administrative Change 1 dated 09 February 2017, Amendment 2 dated 
06 November 2017, Amendment 2.01 (New Zealand only) dated 20 December 2017 (with 
an approval date of 12 January 2018), Amendment 2.02 (China only) dated 20 May 2019, 
Administrative Change 3 (China only) dated 05 June 2020.  It describes analysis 
conventions to guide the statistical programming.  Unless noted otherwise, all analyses 
will be performed using SAS® Version 9.4 (SAS Institute Inc., Carry, NC 27513) or later 
under the Unix operating system.
The SAP will not be updated in the case of future administrative or minor amendments to 
the protocol unless the changes have any impact on the analysis of study data.


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4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the efficacy (by evaluating the 
percentage of subjects achieving a 12-week post-treatment sustained virologic response,
SVR12) and safety of ABT-493/ABT-530 plus SOF and RBV in adults or adolescents with 
chronic HCV GT1 – 6 infection who previously failed HCV treatment in an AbbVie HCV 
clinical study, designated as an AbbVie HCV parent study.
The secondary objectives are to assess the rates of HCV on-treatment virologic failure and 
HCV virologic relapse.
4.2
Design Diagram
Study M15-942 is a Phase 3b, open-label, non-randomized, multicenter study to evaluate 
the efficacy and safety of ABT-493/ABT-530 in combination with SOF and RBV in HCV 
GT1 – 6 infected subjects, including subjects with compensated cirrhosis and/or HIV-1 
co-infection and/or post-liver or post-renal transplant, who have experienced virologic 
failure while participating in an AbbVie HCV parent study.
It is anticipated that approximately 50 HCV-infected subjects who have experienced 
virologic failure following treatment with regimens containing ABT-493/ABT-530, 3D or 
2D in one of the AbbVie HCV parent studies will be enrolled.  Subjects will be allocated 
to the 12-week treatment duration (Arm A) or the 16-week treatment duration (Arm B) 
based on HCV GT, cirrhosis status, and treatment experience with PI and/or NS5Ai-
containing regimens prior to enrolling in the AbbVie HCV parent studies, as defined in 
Table 1.


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Table 1.
Treatment Arm Allocation in Study M15-942
Patient Population
Study M15-942 
Treatment Arm
Genotype**
Cirrhotic Status*
PI and/or NS5Ai-Experienced 
Prior to the AbbVie HCV 
Parent Study
1, 2, 4, 5 and/or 6
NC
No
A
3
Any
Any
B
Any
C
Any
B
Any
Any
Yes
B
*
NC = non-cirrhotic; C = cirrhotic
**
If the subject's HCV GT at Screening is unknown, or if it is mixed and includes GT3, then the subject will be 
assigned to Arm B (16 weeks), regardless of the cirrhosis status or PI and/or NS5Ai use prior to the AbbVie HCV 
Parent Study.
Arm A will enroll approximately 5 subjects, and Arm B will enroll approximately 
45 subjects.  Subjects will receive ABT-493/ABT-530 300 mg/120 mg QD, SOF 400 mg 
QD, and RBV 600 to 1200 mg daily in two divided doses, orally, for 12 (Arm A) or 
16 (Arm B) weeks (Figure 1).  Dosing of RBV will be based on baseline age and weight 
as defined in Table 2.
Scheduled visits for subjects in the Treatment Period consist of Day 1 and Weeks 2, 4, 8, 
and 12 for all subjects and an additional Week 16 visit for subjects in Arm B.  Subjects 
who complete or prematurely discontinue study drug will be followed for 24 weeks.  
During the Post-Treatment Period, all subjects will have visits at Post-Treatment Weeks 4, 
12, and 24.


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Figure 1.
Study Schematic
Table 2.
Ribavirin Dosing Recommendations
Age at 
Baseline 
(Years)
Body 
Weight at 
Baseline 
(kg)
Daily Dose 
(mg)
Number of 200 mg Tablets Per Period of the Day
≥ 18
< 75
1000
5 tablets
≥ 75
1200
6 tablets
≥ 12 and < 18
35 – 46
600
3 tablets
47 – 59
800
4 tablets
60 – 74
1000
5 tablets
≥ 75
1200
6 tablets
4.3
Sample Size
This study serves to provide data on using ABT-493/ABT-530 in combination with SOF 
and RBV as a retreatment option for subjects infected with HCV GT1 – 6 who 
experienced virologic failure following treatment with regimens containing 
ABT-493/ABT-530 or 3D or 2D.  No formal hypothesis will be tested in this study.  The 
sample size of this study is determined based on the projected number of virologic failures 
in AbbVie HCV parent studies.


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The two-sided 95% confidence intervals (CIs) based on Wilson's score method1 for a 
given number of failures are shown in Table 3 for Arm A, B, and overall.  The Wilson's 
score method is expected to be used instead of the normal approximation method because 
the number of SVR12 non-responders is expected to be less than 5 (see Section 10.3).
Table 3.
The 95% CIs Using the Wilson's Score Method for a Given Number 
of Failures
Number of failures for 
Arm A, B, or overall
Arm A (N = 5)
Arm B (N = 45)
Overall (N = 50)
0
(56.6%, 100.0%)
(92.1%, 100.0%)
(92.9%, 100.0%)
1
(37.6%, 96.4%)
(88.4%, 99.6%)
(89.5%, 99.6%)
2
(23.1%, 88.2%)
(85.2%, 98.8%)
(86.5%, 98.9%)
3
(11.8%, 76.9%)
(82.1%, 97.7%)
(83.8%, 97.9%)
4
(3.6%, 62.4%)
(79.3%, 96.5%)
(81.2%, 96.8%)
4.4
Planned Analyses
All analyses will be conducted by statisticians and programmers at AbbVie or designees 
according to the methodologies specified in this SAP.
The primary analysis will occur after all subjects have completed the Post-Treatment 
Week 12 Visit or prematurely discontinued the study.  For the primary analysis, data will 
be locked after performing appropriate data cleaning.  An interim analysis may be 
conducted for the purpose of regulatory interaction.  If there is no interim analysis, the 
primary analysis and the database lock will occur after all subjects have completed the 
Post-Treatment Week 24 Visit or prematurely discontinued the study and data cleaning 
has been performed.
There is no intention of stopping the study early based on efficacy findings from an 
interim analysis.  The intention is to follow all subjects who receive study drug for 
24 weeks following treatment.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
All enrolled subjects who receive at least one dose of study drug will be included in the 
ITT population.  Efficacy, demographic, baseline characteristics, study drug duration, 
compliance, concomitant medication and medical history analyses will be performed on 
the ITT population overall and according to the treatment arm assignment, i.e., subject 
grouping will be based on the arm to which the subject was assigned.
5.1.2
Modified Intention-to-Treat (mITT) Populations
Sensitivity analyses of SVR12 as described in Section 10.5, when applicable, will be 
performed on the ITT population modified to exclude subjects who do not achieve SVR12
for reasons other than virologic failure (mITT-VF).
5.1.3
Safety Population
All subjects who receive at least one dose of study drug will be included in the safety 
population.  Safety analyses will be performed for the overall safety population.
6.0
Analysis Conventions
6.1
Definition of Baseline, Final Treatment, and Final Post-
Treatment Assessments
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug is received.
The protocol specifies that all Day 1 assessments are to be performed prior to 
administering the first dose of study drug. Therefore, all Day 1 assessments for which 
time is not collected will be assumed to be pre-dose and the baseline value will be the last 


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non-missing measurement collected on or before the first day of study drug 
administration.  All Day 1 assessments with time collected must be before the time of
first dose to be considered baseline and the last non-missing measurement collected 
before the date and time of the first dose of study drug will be considered the baseline 
value. If multiple measurements that are prior to dosing are recorded on the same date 
and with the same time or if time is not available, then the average of these measurements 
will be considered the baseline value.
The same baseline value will be used for analyses of the Treatment and Post-Treatment 
Periods.
Safety assessments that are related to a serious adverse event that occurred on the
first dose day are excluded when applying this algorithm.
6.1.2
Study Days
Study Days (Days Relative to the First Dose of Study Drug)
Study days are calculated for each time point relative to the first dose of study drug.  
Study days are negative values when the time point of interest is prior to the first study 
drug dose day.  Study days are positive values when the time point of interest is after the 
first study drug dose day.  There is no Study Day 0.  Study Day 1 is the day of the 
first dose of study drug.
Study Drug End Days (Days Relative to the Last Dose of Study Drug)
Study drug end days are calculated for each time point relative to the last dose of study 
drug.  The last day of study drug dosing is defined as Study Drug End Day 0.  Days 
before it have negative study drug end days and days after it have positive study drug end 
days.


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Final Treatment Value
The final treatment value is defined as the last non-missing measurement collected after 
Study Day 1 and on or before Study Drug End Day 2.
Final Post-Treatment Value
The final post-treatment value for each subject is the last non-missing measurement 
collected after Study Drug End Day 2 and on or before Study Drug End Day 999.
6.2
Definition of Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 4
and Table 5 describe how these data are assigned to protocol-specified time points during 
the Treatment and Post-Treatment Periods, respectively.  All time points and 
corresponding time windows are defined based on the date/time of blood sample 
collection.
For samples of plasma HIV-1 RNA levels and flow cytometry (including but not limited 
to CD4+ T-cell and CD8+ T-cell counts [absolute and percent]), the time windows 
specified in Table 4 describe how data are assigned to protocol-specified time points.
For safety laboratory data, Child-Pugh Score, and vital signs, the time windows specified 
in Table 4 and Table 6 describe how data are assigned to protocol-specified time points.
If more than one assessment is included in a time window, the assessment closest (except 
for when used in analyses of SVR) to the nominal time will be used.  If there are 
two observations equally distant to the nominal time, the later one will be used in 
analyses.  For analyses of SVR (e.g., SVR12), the last value in the window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used to calculate descriptive 
statistics and in analyses of the mean change from baseline.  For summaries of shifts from 
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multiple values on the same day will not be averaged; all values will be considered for 
these analyses.
Table 4.
Analysis Time Windows for HCV RNA and Resistance Endpoints, 
Safety Laboratory and Vital Sign Measurements, and Child-Pugh 
Scores (Treatment Period)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Day 1/Baselinea
1
≤ 1a
Week 2
14
2 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Week 16b
112
99 to 126
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
For Arm B only.
c.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the last dose of study drug.
Note:
For all windows, data must be on or before Study Drug End Day 2.  The result closest to the scheduled time 
point will be used.  Child-Pugh scores are only collected for subjects with compensated cirrhosis at the 
Screening Visit and End of Treatment Visit (Week 12 Visit for Arm A and Week 16 Visit for Arm B, or 
Premature Discontinuation Visit).


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Table 5.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 999
SVR4b
28
3 to 56
SVR12b
84
57 to 126
SVR24b
168
127 to 210
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  For all 
windows, data must occur after Study Drug End Day 2.  Study Drug End Day 0 is defined as the day of the 
last dose of study drug.
Table 6.
Analysis Time Windows for Safety Laboratory and Vital Sign 
Measurements and Child-Pugh Score (Post-Treatment Period)
Scheduled Timea
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 999
Final Post-Treatment Visita
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable to subjects who received at least one dose of study drug.
b.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment value.  
The lower bound of this Final window is Study Drug End Day 3.  Study Drug End Day 0 is defined as the day of 
the last dose of study drug.
Note:
The result closest to the scheduled time point will be used.  For all windows, data must occur after Study Drug 
End Day 2.  Vital signs are collected at Post-Treatment Week 4 only; hematology, chemistry, urinalysis, and 
coagulation panels are collected at Post-Treatment Week 4 Visit or at Post-Treatment Discontinuation Visit if 
subject discontinues during the Post-Treatment Week 4 window.  Child-Pugh scores are only collected for 
subjects with compensated cirrhosis at Post-Treatment Weeks 12, 24, and the Premature Discontinuation 
Visit.


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6.3
Missing Data Imputation
Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.2.
For analyses of SVR, subjects' missing visit values will have backward imputation 
applied, if possible.  For backward imputation, if the nearest HCV RNA value after the 
SVR window is unquantifiable or undetectable, then it will be used to impute the HCV 
RNA value in the SVR window.  If a subject is missing an HCV RNA value within the 
appropriate SVR window after performing backward imputation, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value will be missing.  Subjects with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 
failure for summaries of viral response at all time points after the start of the new HCV 
treatment.
Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Other Medications
The ITT population will be used to summarize demographics, baseline characteristics, 
medical history and previous, concomitant, and post-treatment medications; data will be 
summarized across all subjects and by assigned treatment arm.


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7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects in each category.  Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean, 
standard deviation, median, minimum and maximum).  For categorical variables, the 
number of missing observations will be displayed, if applicable, on the summary tables.  
Percentages will be calculated based on the number of non-missing observations.
Continuous demographic variables include age, weight, height, waist circumference, and 
body mass index (BMI).  Categorical demographic variables include sex, race, Black race 
(Black or non-Black), ethnicity, age category (< 65 or ≥ 65 years; < 75 or ≥ 75 years), 
BMI category (< 30, or ≥ 30 kg/m2), country, and geographic region (North America, 
Europe, Asia, or rest of world [ROW]).
When defining geographic region, sites in the United States and Canada will be grouped 
under North America; sites in Switzerland, Germany, Sweden, Spain, Russia and the 
United Kingdom will be grouped under Europe; sites in China and South Korea will be 
grouped under Asia; sites in Brazil, Australia and New Zealand will be grouped together 
as ROW.
Continuous baseline characteristics include baseline log10 HCV RNA level, creatinine 
clearance (Cockcroft-Gault calculation), eGFR (using the modification of diet in renal 
disease [MDRD] formula), platelet count, albumin, GGT, APRI, FIB-4, AST, ALT, total, 
direct, and indirect bilirubin, and homeostasis model of assessment – insulin resistance 
(HOMA-IR) for all subjects.
Categorical baseline characteristics include:
●
HCV GT (1, 2, 3, 4, 5, 6, mixed, or unknown) and available subtype (as 
determined by the central laboratory);


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●
HCV GT (1, 2, 3, 4, 5, 6, mixed, or unknown) and available subtype (as 
determined by phylogenetic analysis, if available, or by the central laboratory 
if phylogenetic analysis is not available)
●
DAA-containing regimen received in the AbbVie HCV parent study
(ABT-493/ABT-530, 3D or 2D); 
●
Type of treatment response for AbbVie HCV parent study (on-treatment non-
responder, breakthrough, post-treatment relapse, or unknown/other);
●
Prior AbbVie HCV parent study number;
●
Previous treatment experience prior to enrolling in the AbbVie HCV parent 
study:
○
Treatment naïve/DAA-naïve
○
Treatment experienced, PI-experienced only
○
Treatment experienced, NS5Ai-experienced only
○
Treatment experienced, PI- and NS5Ai-experienced 
○
Treatment experienced, NS5Bi-experienced only
○
Treatment experienced, NS5Bi- and PI-experienced
○
Treatment experienced, NS5Bi- and NS5Ai-experienced
○
Treatment experienced, NS5Bi-, PI- and NS5Ai-experienced
●
HCV mono-infected vs. HCV/HIV-1 co-infected;
●
Cirrhotic vs. non-cirrhotic;
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
●
Baseline HCV RNA level (< 1,000,000, ≥ 1,000,000 to 
< 2,000,000, ≥2,000,000 IU/mL);
●
History of diabetes (yes/no);
●
History of bleeding disorders (yes/no);
●
History of depression or bipolar disorder (yes/no);
●
History of cardiovascular disease (yes/no);
●
Injection drug user (yes, within last 12 months; yes, more than 12 months ago; 
or no);
●
Use of stable opiate substitution (yes/no);


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●
Tobacco use (current, former, never, or unknown);
●
Alcohol use (current, former, never, or unknown);
●
Concomitant use of proton pump inhibitors (PPIs) [yes/no];
For subjects with cirrhosis, the following will be summarized:
●
Baseline Child-Pugh Score (5, 6, or > 6).
Any concomitant medication coded to the WHO Drug Dictionary ATC code of A02BC 
will be counted as a PPI.
HOMA-IR is defined as fasting glucose (mmol/L) × fasting insulin (μIU/mL) ÷ 22.5.  
Subjects who do not have concurrent fasting glucose and fasting insulin values at baseline 
will be excluded from the summary of baseline HOMA-IR.
Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores, 
FibroScan scores, or FibroTest scores.  Only one score will be used to categorize each 
subject even if a subject has more than one score recorded.  If a biopsy score is present, 
then it will be used to categorize the subject, regardless of the FibroScan/FibroTest score.  
Similarly, if a FibroScan score is present along with a FibroTest score but biopsy score is 
absent, then the FibroScan score will be used to categorize the subject.  If biopsy and 
FibroScan scores are not present and more than one FibroTest result is available, then the 
baseline FibroTest result (i.e., last non-missing FibroTest result on or before Day 1) will 
be used to categorize the subject.  Subjects will be categorized as F0 – F1, F2, F3, or F4 
according to Table 7.


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Table 7.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, 
Batts Ludwig, Knodell, 
IASL, Scheuer, or 
Laennec Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest*
F0 – F1
0 or 1
0, 1, or 2
< 8.8
≤ 0.48
F2
2
3
≥ 8.8 to < 9.6
0.49 to < 0.59
F3
3
4
≥ 9.6 to < 12.5
0.59 to < 0.75
F4
4
≥ 5
≥ 12.5
≥ 0.75
*
APRI will not be used to derive Baseline Fibrosis Stage.  However, per inclusion/exclusion criteria, subjects need 
to have concordant FibroTest and APRI scores in order to determine fibrosis stage.  Discordance between 
FibroTest and APRI will require FibroScan or liver biopsy to determine subject fibrosis stage.
Presence or absence of cirrhosis will be determined as collected in EDC ("What is the 
subject's cirrhosis status?" – "cirrhotic" or "non-cirrhotic").
Baseline Child-Pugh score will be calculated for subjects with cirrhosis according to 
Table 8.


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Table 8.
Child-Pugh Classification of Severity of Cirrhosis
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to 
severe
Hepatic encephalopathy**
None
Grade 1 or 2
(or suppressed with medication)
Grade 3 or 4
(or refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
None:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Baseline APRI and FIB-4 are defined as the equations below.  Subjects who do not have 
concurrent AST and platelet values at baseline will be excluded from the summary of 
baseline APRI.  Age is defined in years at baseline.  Subjects who do not have concurrent 
values of AST, ALT, and platelet count at baseline, or subjects who are missing age will 
be excluded from the summary of FIB-4.
APRI =
AST Level (U/L)
AST (Upper Limit of Normal)(U/L)
Platelet Count (10!/L)
× 100
FIB-4 =
Age (years) × AST Level (U/L)
(Platelet Count (109/L)×√ALT (U/L)


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The central laboratory calculates the estimated creatinine clearance (CrCl) based on the 
following Cockcroft-Gault formula:
CrCl (mL/min) = [(140 – age) × (weight in kg) × (0.85 if female)]/[serum creatinine 
(mg/dL) × 72].
The central laboratory calculates the eGFR by MDRD based on the following formula 
except for data collected from the sites in China:
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine in mg/dL)–1.154 × (Age)–0.203 × (0.742 
if female) × (1.212 if Black or African American).
The central laboratory calculates the eGFR by the MDRD formula modified for the 
Chinese population (C-MDRD) for data collected from the sites in China using the 
following formula:
eGFR (mL/min/1.73 m2) = 175 × (Serum Creatinine in mg/dL)–1.234 × (Age)–0.179 × (0.79 
if female).
Histories of diabetes, bleeding disorders, depression or bipolar disorder, and 
cardiovascular disease will be based on the Medical History (MH) eCRF, as defined in 
Table 9.


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Table 9.
Medical History eCRF
Medical History eCRF
Subgroup
Body System
Condition/Diagnosis
Diabetes
Metabolic
Diabetes mellitus
Bleeding disorders
Blood
Clotting/bleeding problems
Factor deficiency
Hemophilia
Von Willebrand disease
Depression or bipolar disorder
Neurologic and Psychiatric
System
Bipolar disorder
Depression
Cardiovascular disease
Cardiovascular
Angina
Cardiac arrhythmia
Cardiovascular disease
Congenital heart disease
Congestive heart failure
Coronary artery disease
Hypertension
Myocardial infarction
Myocarditis
Peripheral vascular disease-arterial
Peripheral vascular disease-venous
Valvular heart disease
Vasculitis
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.


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7.3
Prior, Concomitant, and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug.  A concomitant medication is defined as any medication that started prior to 
the date of the first dose of study drug and continued to be taken on or after the first dose 
of study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug.  A post-treatment medication for 
the treatment of HCV is defined as any medication taken on or after the last dose of study 
drug and entered as "Post treatment HCV medications" on the "Concomitant Medications 
and Supplements" eCRF.
Prior medications will be divided into the following categories:
●
Prior HCV medications taken by subjects who were treatment-experienced 
prior to entering the AbbVie HCV parent study (collected on the "Previous 
HCV Therapy (Prior to the AbbVie HCV Parent Study)" eCRF); 
●
Prior HCV medications taken during the AbbVie HCV Parent Study (collected 
on the "Screening Failure" eCRF as "Treatment Regimen for AbbVie HCV 
Parent Study");
●
All other non-HCV and non-HIV prior medications for all treated subjects.
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment HCV medications will be summarized by generic drug 
name based on the WHO Drug Dictionary.
If this study enrolls HCV/HIV co-infected subjects, prior HIV medications (collected on 
the "Prior and Concomitant HIV Therapy" eCRF) and concomitant HIV medications 
(entered as "Other HIV medications" on the "Concomitant Medications and Supplements"
eCRF) will not be included in the summaries mentioned above but will be presented as 
data listings for HCV/HIV co-infected subjects.


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8.0
Subject Disposition
The number and percentage of subjects who screen failed for any reason, and for each 
screen fail reason, will be summarized for all subjects who screen failed.
8.1
Disposition of Safety Population
The number of subjects in each of the following categories will be summarized by 
investigator for each treatment arm and overall.
●
Subjects enrolled in this study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed all study drugs;
●
Subjects who completed all DAAs (including those who discontinued RBV)
●
Subjects who prematurely discontinued all study drugs;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study;
The number and percentage of subjects who discontinued all study drugs will be 
summarized by reason (all reasons) and by primary reason (per eCRF) for each treatment 
arm and overall.  Similar summaries will be provided for discontinuations from the study.
The number and percentage of subjects will be calculated for:
●
Subjects with interruption of all DAAs;
●
Subjects with interruption of any DAA;
●
Subjects with interruption of ABT-493/ABT-530;
●
Subjects with interruption of SOF;
●
Subjects with RBV dose modification.
DAA interruptions and RBV dose modifications will be summarized by treatment arm 
and overall.  Reasons for study drug interruptions and RBV dose modifications will be 
presented in the CSR listings.


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9.0
Study Drug Duration and Compliance
Study drug duration and compliance will be summarized on the ITT population by 
treatment arm and overall.
9.1
Study Drug Duration
Study drug duration is defined for each subject as the last study drug dose date minus the 
first study drug dose date plus 1 day.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will 
be presented for study drug duration.
Study drug duration will be summarized with frequencies and percentages using the 
following categories:
●
1 to 15 days
●
16 to 30 days
●
31 to 45 days
●
46 to 60 days
●
61 to 75 days
●
76 to 90 days
●
91 to 105 days
●
> 105 days
In addition, the number and percentage of subjects with study drug duration of ≥ 77 days 
for the 12-week arm or study drug duration ≥ 103 days for the 16-week arm will be 
summarized.
9.2
Compliance
For each kit (ABT-493/ABT-530, SOF, and RBV), the total number of tablets dispensed 
and returned is recorded for each of the three components of the study drug 
(ABT-493/ABT-530, SOF, and RBV).  The compliance of a subject for each component 


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of the study drug during the Treatment Period will be calculated as the percentage of 
tablets taken relative to the total expected to be taken, which will be derived according to 
the duration of that subject's Treatment Period (date of last dose of study drug – date of 
first dose of study drug + 1).  For ABT-493/ABT-530 and SOF, study drug interruptions 
recorded on the eCRF will not be subtracted from the treatment duration of that study 
drug.  For RBV compliance, RBV dose modifications and interruptions (modification to 
0 mg) as recorded on the RBV Dose Modifications eCRF will be used to modify the total 
number of RBV tablets expected to be taken.  If a subject is not able to return any of the 
dispensed kit, that subject's compliance will be regarded as missing.
A subject is considered to be compliant for a component of the study drug 
(ABT-493/ABT-530, SOF, or RBV) if the percentage is between 80% and 120%.  
Compliance will be calculated for each subject and each component and will be 
summarized with the mean, median, standard deviation, minimum, and maximum by 
treatment arm and overall.  A listing of compliance for each subject on each component 
will also be provided.  The percentage of compliant subjects for each component will be 
summarized by treatment arm and overall, based on data as observed.  Subjects with 
missing values for compliance will not be included in the denominator.
10.0
Efficacy Analysis
10.1
General Considerations
General Considerations
All efficacy analyses will be performed on the ITT population by treatment arm and 
overall, unless otherwise specified.  To support the primary analysis, sensitivity analyses 
will also be conducted using the mITT-VF population.
Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR and virologic failure.


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Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
Definitions for Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 
HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.


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


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Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as any 
subject with study drug duration of 77 days or greater for Arm A and 103 days or greater 
for Arm B.  If the last available post-treatment value is ≥ LLOQ, then the subject will be 
considered a relapse (i.e., will not require confirmation).
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the post-
treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis of the NS3/4A, and/or NS5A, and/or 
NS5B gene sequences.  Reinfection in the case of the same HCV subtype is defined as a 
clade switch, as indicated by the lack of clustering between the baseline and post-
treatment sequences by phylogenetic analysis.  If phylogenetic analysis is not possible due 
to technical difficulties, HCV reinfection may be determined with a confirmed HCV 
genotype or subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and no genotype, subtype, or clade switch compared with baseline as 
determined by phylogenetic analysis of the NS3/4A, and/or NS5A, and/or NS5B gene 
sequences.  If phylogenetic analysis is not possible due to technical difficulties, the 
subject will be defined as having a post-treatment relapse unless an HCV genotype or 
subgenotype switch is confirmed by the Versant HCV Genotype Inno-LiPA Assay v2.0 or 
Sanger assay.
Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure;
2.
HCV reinfection;


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3.
Relapse12;
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 77 days for Arm A, or < 103 days for Arm B] and did not 
meet the On-treatment virologic failure or HCV reinfection definitions);
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as any SVR12 non-responder not meeting the definitions of 
[1] – [5]).
Reasons for SVR24 Non-Response
Subjects who do not achieve SVR24 (SVR24 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure;
2.
HCV reinfection;
3.
Relapse12;
4.
Relapse24;
5.
Prematurely discontinued study drug with no on-treatment virologic failure (defined 
as any SVR24 non-responder who prematurely discontinued study drug [study drug 
duration < 77 days for Arm A, or < 103 days for Arm B] and did not meet the On-
treatment virologic failure, HCV reinfection, Relapse12, or Relapse24
definitions);
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
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7.
Other (defined as any SVR24 non-responder not meeting the definitions of 
[1] – [6]).
For the reasons for SVR12 and SVR24 nonresponse defined above, subjects are only to be 
counted in one category in the order shown above.
10.2
Handling of Multiplicity
No multiplicity adjustment is needed for this study because there is no hypothesis testing.
10.3
Primary Efficacy Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after the last 
actual dose of study drug).  The number and percentage of subjects in the ITT population 
achieving SVR12 will be calculated along with a two-sided 95% CI using the normal 
approximation to the binomial distribution, unless the number of SVR12 non-responders is 
less than 5, where the Wilson's score method1 will be used to calculate the CI instead.
A summary of reasons for SVR12 non-response (e.g., on-treatment virologic failure, 
relapse, other) will be provided.  A listing of subjects who do not achieve SVR12 by 
reason for non-response will also be provided.
10.4
Secondary Efficacy Analyses
The secondary efficacy endpoints are:
●
The percentage of subjects with on-treatment virologic failure;
●
The percentage of subjects with Relapse12.
The number and percentage of subjects with on-treatment virologic failure and Relapse12
in the ITT population will be summarized along with two-sided 95% Wilson score CIs.


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10.5
Sensitivity Analyses for SVR
As sensitivity analyses, the number and percentage of subjects in the mITT-VF population 
achieving SVR12 will be summarized along with two-sided 95% CIs using the normal 
approximation to the binomial distribution and the Wilson's score method.
A different CI from that used for the primary analysis will be calculated for the primary 
endpoint of SVR12 based on the ITT population as a sensitivity analysis.  If the number of 
SVR12 non-responders is ≥ 5, then the two-sided 95% CI using Wilson's score method 
will be calculated.  If the number of SVR12 non-responders is < 5, the two-sided 95% CI 
using the normal approximation to the binomial distribution will be calculated.
Listings of subjects excluded from the mITT-VF population will be provided, as 
applicable.
10.6
Efficacy Subgroup Analysis
The percentage of subjects with SVR12 in the ITT population will be presented.  
Two-sided 95% Wilson score CIs will also be presented for the following subgroups if 
there are at least 10 subjects in the subgroup:
●
HCV genotype (1, 2, 3 4, 5, 6, mixed, or unknown) (based on final HCV 
genotype and subtype determination specified in Section 10.8);
●
DAA-containing regimen received in the AbbVie HCV parent study 
(ABT-493/ABT-530, 3D or 2D);
●
Previous treatment experience prior to enrolling in the AbbVie HCV parent 
study:
○
Treatment naïve/DAA-naïve
○
Treatment experienced, PI-experienced only
○
Treatment experienced, NS5Ai-experienced only
○
Treatment experienced, PI- and NS5Ai-experienced
○
Treatment experienced, NS5Bi-experienced only
○
Treatment experienced, NS5Bi- and PI-experienced


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○
Treatment experienced, NS5Bi- and NS5Ai-experienced
○
Treatment experienced, NS5Bi-, PI- and NS5Ai-experienced
●
Baseline fibrosis stage (equivalent to Metavir F0 – F1, F2, F3, or F4);
●
Baseline HCV RNA level (< 1,000,000, ≥ 1,000,000 to 
< 2,000,000, or ≥2,000,000 IU/mL).
10.7
Additional Efficacy Analyses
The following additional efficacy endpoints will be summarized for the ITT population:
●
The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit 
in the Treatment Period (using data as observed);
●
The percentage of subjects with SVR4;
●
The percentage of subjects with SVR24;
●
The percentage of subjects who relapse after achieving SVR12 (Relapse24).
●
The percentage of subjects with virologic failure through Post-Treatment 
Week 24 (i.e., the SVR24 non-responders due to on-treatment virologic 
failure or Relapseoverall).
For each of the above endpoints, a two-sided 95% CI using Wilson's score method will be 
calculated along with the number and percentage of subjects.  Imputations for missing 
data will be performed as described in Section 6.3 for all the additional endpoints listed 
above except the first one.
For the ITT population, a summary of the subjects who completed treatment and relapsed 
(defined as Relapseoverall) will be prepared displaying the number of subjects relapsing at 
any timepoint and by the SVR visit window where the first relapse occurred (within the 
SVR4, SVR12, or SVR24 window or after the SVR24 window); subject numbers will be 
listed.  A similar summary will be prepared for subjects who prematurely discontinued 
treatment and relapsed after having HCV RNA < LLOQ at their Final Treatment Visit.


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The number and percentage of subjects who do not achieve SVR24 will be summarized by 
reason for non-response (as defined in Section 10.1) for the ITT population.  A listing of 
subject numbers and reason for non-response will be prepared.
The concordance between SVR12 and SVR24 will be assessed for the overall population 
(across genotype and treatment arm) by the agreement between SVR12 and SVR24 and the 
positive predictive value (PPV) and negative predictive value (NPV) of SVR12 on SVR24.  
The agreement between SVR12 and SVR24 is a percentage defined as the number of 
subjects achieving both SVR12 and SVR24 and the number of subjects where both SVR12
and SVR24 are not achieved.  The PPV of SVR12 on SVR24 is the proportion of subjects 
who achieve SVR24 out of all subjects who achieved SVR12.  The NPV of SVR12 on 
SVR24 is the proportion of subjects who do not achieve SVR24 out of all subjects who did
not achieve SVR12.  Similarly, the concordance between SVR4 and SVR12 will be 
summarized for the overall population.
10.8
Resistance Analyses
10.8.1
HCV Drug-Resistance Analyses
For all subjects, full length NS3/4A and NS5A will be sequenced from baseline samples 
by next generation sequencing (NGS).  For all subjects who experience virologic failure 
(on-treatment virologic failure or Relapseoverall as defined in Section 10.1), full length 
NS3/4A, NS5A and NS5B genes from the first sample after virologic failure with HCV 
RNA ≥1000 IU/mL will be sequenced by NGS.  For all other subjects who do not 
achieve SVR12 or SVR24 (for non-virologic failure reasons as defined in Section 10.1) but 
have a post-treatment time point with HCV RNA ≥1000 IU/mL, full length NS3/4A, 
NS5A and NS5B genes from the first post-treatment sample with HCV 
RNA ≥1000 IU/mL will also be sequenced by NGS.
For all subjects who do not achieve SVR12 or SVR24, a listing by subject that includes 
HCV genotype/subtype, reason for SVR12 or SVR24 non-response, baseline resistance data 
availability, and key baseline characteristics will be produced by treatment arm.


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For each DAA target, signature amino acid positions and the key subset of amino acid 
positions for the respective inhibitor class are shown in Table 10.  Appropriate subtype-
specific prototypic reference sequences will be used for comparison with sequences from 
samples.
Table 10.
Signature Amino Acid Positions and the Key Subsets of Amino Acid 
Positions
Target
Signature Amino Acid Positions
Key Subset of Amino Acid 
Positions
GT1 NS3
36, 43 (GT1a only), 54, 55, 56, 80, 107, 122, 
132 (GT1a only), 155, 156, 158, 168, 170, 175 
(GT1b only)
155, 156, 168 (all GTs)
GT2, 3, 4, 5, 6 NS3
36, 43, 54, 55, 56, 80, 155, 156, 166 (GT3 
only), 168
GT1 NS5A
24, 28, 29, 30, 31, 32, 54 (GT1b only), 58, 62, 
92, 93
24, 28, 30, 31, 58, 92, 93 
(all GTs)
GT2, 3, 4, 5, 6 NS5A
24, 28, 29, 30, 31, 32, 58, 92, 93
GT1, 2, 3, 4, 5, 6 NS5B
96, 142, 159, 237, 282, 289, 320, 321
282
Included time points for analyses of samples from subjects who do not achieve SVR12 are 
1) the sample closest in time after failure/discontinuation with an HCV RNA level of 
≥1000 IU/mL, and 2) 24 weeks post-DAA treatment, provided that resistance-associated 
substitutions were detected at the time of failure/discontinuation.
The following definitions will be used in the resistance analyses:
●
Baseline polymorphism:  a polymorphism by NGS in a baseline sample (≥ 2% 
or ≥ 15% prevalence within a subject's viral population depending on 
polymorphism frequency threshold utilized) that was not present in the 
appropriate prototypic reference amino acid sequence for a given DAA target 
(NS3, NS5A, or NS5B).
●
Post-baseline substitution:  an amino acid substitution in a post-baseline time 
point sample that was not detected at baseline (< 2%) in the subject and is 
detectable in ≥ 2% of the sequences from the post-baseline sample.


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●
Enriched variant:  a variant present in both the baseline and a post-baseline 
sample whose prevalence in the post-baseline sample is at least 20 percentage 
points greater than the prevalence in the baseline sample [(post-baseline % –
baseline %) ≥ 20]
●
Treatment-emergent substitution:  A post-baseline substitution or an enriched 
variant.
●
Substitution at signature amino acid position: a substitution in a post-baseline 
sample observed at ≥ 2% prevalence within a subject's viral population that 
was not present in the appropriate prototypic reference amino acid sequence 
for a given DAA target (NS3/4A, NS5A, or NS5B).
Analysis 1
The following analyses will be performed for all subjects, separated by arm, HCV 
genotype/subtype, and previous treatment experience prior to enrolling in the AbbVie 
HCV parent study (including total):
●
A listing of baseline polymorphisms (2% detection threshold) at signature 
amino acid positions for each DAA target (NS3, NS5A, and NS5B) in the ITT 
population.  HCV genotype/subtype and treatment outcome (SVR12 or reason 
for SVR12 non-response) will also be displayed for each subject.
●
The number and percentage of subjects with baseline polymorphisms at 
signature amino acid positions at detection thresholds of 2% and 15% for 
subjects in the ITT population.  This analysis includes prevalence of each 
baseline polymorphism, and a summary of the number of subjects with 
polymorphisms in NS3 only, NS5A only, NS5B only, any in NS3, any in 
NS5A, any in NS5B, any in NS3 or NS5A or NS5B, any in NS3 + NS5A, any 
in NS3 + NS5B, any in NS5A + NS5B, and any in NS3 + NS5A + NS5B.
●
Total number and percentage of subjects in the ITT population with baseline 
polymorphisms in the key subset of amino acid positions at detection 
thresholds of 15% for subjects in the ITT population.  This analysis 
summarizes the number of subjects with polymorphisms in NS3 only, NS5A 
only, NS5B only, any in NS3, any in NS5A, any in NS5B, any in NS3 or 


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NS5A or NS5B, any in NS3 + NS5A, any in NS3 + NS5B, any in NS5A + 
NS5B, and any in NS3 + NS5A + NS5B.
Analysis 2
The impact of baseline polymorphisms at the key subset of amino acid positions on 
treatment outcome (the SVR12 rate) will be assessed for the mITT-VF population by 
presenting the SVR12 rates for the following groups, using detection thresholds of 2% and 
15%, separated by arm, HCV genotype/subtype (including total), and previous treatment 
experience prior to enrolling in the AbbVie HCV parent study:
●
in NS3 only versus none in NS3, NS5A, or NS5B
●
in NS5A only versus none in NS3, NS5A, or NS5B
●
in NS5B only compared to none in NS3, NS5A, or NS5B
●
any in both NS3 and NS5A versus none in NS3 or NS5A
●
any in both NS3 and NS5B versus none in NS3 or NS5B
●
any in both NS5A and NS5B versus none in NS5A or NS5B
●
any in each of NS3, NS5A and NS5B versus none in NS3, NS5A, or NS5B
●
any in NS3 versus none in NS3
●
any in NS5A versus none in NS5A
●
any in NS5B versus none in NS5B
●
any in NS3 or NS5A or NS5B versus none in NS3, NS5A, or NS5B
Analysis 3
The following listings will be produced for subjects who do not achieve SVR12 or SVR24
and have post-baseline resistance data available.  HCV genotype/subtype and reason for 
SVR12 or SVR24 non-response will be displayed for each subject by treatment, and 
previous treatment experience prior to enrolling in the AbbVie HCV parent study.


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●
Listing by subject and time point of all treatment-emergent substitutions
relative to the baseline amino acid sequence will be provided for each DAA 
target (NS3, NS5A, and NS5B).
●
Listing by subject and time point of all substitutions at signature amino acid 
positions in a post-baseline time point relative to the appropriate prototypic 
reference amino acid sequence will be provided for each DAA target (NS3,
NS5A, and NS5B).
HCV Genotype/Subtype
Phylogenetic analysis will be conducted on HCV sequences from baseline samples for all 
subjects in order to accurately determine subtype.
Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A NS5A, and/or NS5B sequences performed by AbbVie.  
If the phylogenetic analysis is available, then it will be used to determine the subject's 
HCV genotype and subtype.  If it is not available, then the Sanger sequencing assay result 
will be used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis result nor the Sanger sequencing assay results is 
available, then the Inno-LIPA assay results will be used to categorize the subject.
This subtype information will be presented in summaries of efficacy subgroup analyses.
A summary of HCV subtype as provided by the central laboratory (Sanger sequencing or 
Inno-LiPA 2.0 Assay [if Sanger sequencing not available]) versus phylogenetic analysis 
also will be provided if any differ.
10.8.2
HIV Drug-Resistance Analysis
If an HCV/HIV-1 co-infected subject develops a confirmed, plasma HIV-1 RNA level 
≥500 copies/mL after starting the study, the subject's HIV-1 PR, RT, and/or IN 


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sequences, as applicable, will be analyzed by Monogram Biosciences using the 
GenoSure® Prime drug resistance assays.  If available and incorporated in the SAS 
datasets, these results will be presented as data listings.
11.0
Safety Analysis
11.1
General Considerations
Safety data will be summarized using the safety population.  Data will be summarized for 
the overall population.
11.2
Analysis of Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The actual version of the MedDRA coding dictionary will be 
noted in the clinical study report.
AIDS-Defining Conditions (ADC) will be presented separately (Section 11.3) and will be 
excluded from all analyses of AEs described below in the rest of Section 11.2.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with an onset date that is after the 
first dose of study drug and no more than 30 days after the last dose of study drug.  Events 
where the onset date is the same as the study drug start date are assumed to be treatment-
emergent.  If an incomplete onset date was collected for an AE, the event will be assumed 
to be treatment-emergent, unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).
11.2.2
Tabulations of Treatment-Emergent Adverse Events
Adverse Event Overview
An overview of AEs will be presented that consists of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:


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●
Any treatment-emergent AE;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
ABT-493/ABT-530;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
SOF;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
RBV;
●
Treatment-emergent AEs of Grade 3 or higher;
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to ABT-493/ABT-530;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to SOF;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to RBV;
●
Treatment-emergent AEs leading to discontinuation of all study drugs;
●
ABT-493/ABT-530-related treatment-emergent AEs leading to discontinuation 
of all study drugs;
●
SOF-related treatment-emergent AEs leading to discontinuation of all study 
drugs;
●
RBV-related treatment-emergent AEs leading to discontinuation of all study 
drugs;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to ABT-493/ABT-530;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to SOF;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to RBV;
●
Serious treatment-emergent AEs leading to discontinuation of all study drugs;
●
Treatment-emergent AEs leading to interruption of study drug;


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●
Treatment-emergent AEs leading to RBV dose modifications (RBV dose 
increased or reduced);
●
Treatment-emergent AEs leading to death;
●
Deaths.
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects with treatment-emergent AEs will be tabulated by 
primary MedDRA System Organ Class (SOC) and preferred term (PT) for the summaries 
listed below.  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.
●
Treatment-emergent AEs;
●
Treatment-emergent serious AEs;
●
Treatment-emergent serious AEs with a "reasonable possibility" of being 
related to ABT-493/ABT-530;
●
Treatment-emergent serious AEs with a "reasonable possibility" of being 
related to SOF;
●
Treatment-emergent serious AEs with a "reasonable possibility" of being 
related to RBV;
●
Treatment-emergent AEs leading to discontinuation of all study drugs;
●
ABT-493/ABT-530-related treatment-emergent AEs leading to discontinuation 
of all study drugs;
●
SOF-related treatment-emergent AEs leading to discontinuation of all study 
drugs;
●
RBV-related treatment-emergent AEs leading to discontinuation of all study 
drugs;
●
Treatment-emergent AEs leading to death.
Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most related incident for the relationship tables).  Subjects reporting more than 


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one AE within an SOC will be counted only once for that SOC.  Subjects reporting more 
than one AE will be counted only once in the overall total.
If a subject has an AE with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same AE with a relationship assessment of "reasonable possibility."  In 
this case, the subject will be counted under the "reasonable possibility" category.
A listing of treatment-emergent AEs grouped by SOC and PT with subject numbers will 
be created for the overall safety population.
Adverse Events by PT
The following summaries of treatment-emergent AEs tabulated according to PT and 
sorted by the overall frequency across the two treatment arms will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
ABT-493/ABT-530;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
SOF;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
RBV;
●
Treatment-emergent AEs of Grade 3 or higher;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to ABT-493/ABT-530;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to SOF;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to RBV.


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Subjects reporting more than one AE for a given PT will be counted only once for that 
term (most severe/highest grade incident for the severity tables and most related incident 
for the relationship tables).  Subjects reporting more than one AE will be counted only 
once in the overall total.
Adverse Events by Maximum Severity Grade Level
Treatment-emergent AEs will be summarized by maximum severity grade level of each 
PT tabulated by SOC.  Each AE will be assigned a grade level (Grade 1, 2, 3, 4, or 5) by 
the investigator.  If a subject has an AE with unknown severity, then the subject will be 
counted in the severity grade level category of "unknown," even if the subject has another 
occurrence of the same event with a severity present.  The only exception is if the subject 
has another occurrence of the same AE with the highest grade level (Grade 5).  In this 
case, the subject will be counted under the "Grade 5" category.  The same analyses will be 
performed for treatment-emergent AEs with a "reasonable possibility" of being related to 
the study drug, separated by ABT-493/ABT-530, SOF, and RBV.
11.2.3
Adverse Events of Special Interest
Adverse events of special interest include the following:
●
Hepatic decompensation/hepatic failure events, identified using the AbbVie 
Product MedDRA Query (PMQ) of "Hepatic Decompensation and Hepatic 
Failure."
●
Hepatocellular carcinoma (HCC) events, identified using the MedDRA PTs of 
hepatocellular carcinoma, hepatic neoplasm, hepatic cancer, hepatic cancer 
metastatic, and hepatic cancer recurrent.
For the hepatic decompensation/ hepatic failure AE of special interest, the number and 
percentage of subjects experiencing at least one treatment-emergent AE in the search will 
be presented by SOC and PT and across all SOCs/PTs. In addition, a by-subject listing of 
treatment-emergent AEs meeting the search criterion will be provided.


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For the hepatocellular carcinoma AE of special interest, a by-subject listing of all post-
baseline (i.e., including both treatment-emergent and non-treatment emergent) AEs 
meeting the search criterion will be provided.
11.2.4
Listing of Adverse Events
The following listings of AEs will be prepared:
●
All serious AEs (from the time the subject signed the study-specific informed 
consent through the end of the study),
●
Treatment-emergent serious AEs,
●
Treatment-emergent AEs leading to discontinuation of all study drugs,
●
Treatment-emergent AEs leading to interruption of study drug,
●
Treatment-emergent AEs leading to RBV dose modification,
●
Treatment-emergent AEs leading to death.
11.3
AIDS Defining Conditions
A by-subject listing of reported AIDS-Defining Conditions (ADCs), as specified in the 
protocol, will be provided.
11.4
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to a serious AE, will be used in all analyses.
11.4.1
Variables and Criteria Defining Abnormality
Hematology variables to be summarized include:  hematocrit, hemoglobin, red blood cell 
(RBC) count, white blood cell (WBC) count, neutrophils, bands, lymphocytes, 
monocytes, basophils, eosinophils, platelet count, reticulocyte count, prothrombin time 
(PT), international normalized ratio (INR), and activated partial thromboplastin time 
(aPTT).


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Chemistry variables to be summarized include:  blood urea nitrogen (BUN), creatinine, 
total bilirubin, direct and indirect bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, sodium, potassium, calcium, inorganic 
phosphorus, cholesterol, total protein, glucose, triglycerides, albumin, chloride, 
bicarbonate, magnesium, total insulin, gamma-glutamyl transferase (GGT), creatinine 
clearance (calculated using Cockcroft-Gault formula), and eGFR (calculated using 
MDRD equation).
Urinalysis variables to be summarized include:  specific gravity and pH.
The definitions of toxicity grades for laboratory parameters are presented in Table 11.
Table 11.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase 
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
GGT
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin 
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
White blood cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Absolute 
Neutrophil Count
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 109/L
< 25.0 × 109/L
INR
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
Glucose 
(increased)
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 – 27.8 mmol/L
> 27.8 mmol/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Creatinine 
clearance
< LLN – 60 mL/min
< 60 – 30 mL/min
< 30 – 15 mL/min
< 15 mL/min
Cholesterol
> ULN – 7.75 mmol/L
> 7.75 –
10.34 mmol/L
> 10.34 –
12.92 mmol/L
> 12.92 mmol/L
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--


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11.4.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 
the time of first dose if time is available.  The same baseline value will be used for 
changes to Treatment Period visits and changes to Post-Treatment Period visits.
Visit Values
For each protocol-specified laboratory parameter, values at each visit (baseline and post-
baseline, including applicable post-treatment visits) will be summarized with the sample 
size, mean, standard deviation, minimum, median, and maximum.
Change from Baseline
For each laboratory parameter listed in Section 11.4.1, changes from baseline to each 
post-baseline visit, including applicable post-treatment visits, will be summarized with the 
sample size, baseline mean; visit mean; and change from baseline mean, standard 
deviation, minimum, median, and maximum.
Shift Tables
Individual changes in the laboratory parameters listed in Section 11.4.1 will be tabulated 
using shift tables.  Laboratory data values will be categorized as low, normal, or high 
based on normal ranges of the laboratory used for each sample.  Shift tables from baseline 
to minimum value and maximum value during the Treatment Period will be created. For 
each parameter, the shift tables will cross tabulate the frequency of subjects with baseline 
values below/within the normal range to maximum above the normal range and with 
baseline values within/above the normal range to minimum below the normal range.
Maximum Toxicity Grade
The laboratory parameters listed in Table 11 will be assigned a toxicity grade of 1, 2, 3, 
or 4.  The number and percentage of subjects with a maximum toxicity grade of 1, 2, 3 


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or 4 during the Treatment Period will be tabulated.  To be counted, the post-baseline value 
must have a toxicity grade that is more extreme than the toxicity grade corresponding to 
the baseline value.  For each laboratory parameter in Table 11, the summary will also 
include the number and percentage of subjects with a post-baseline maximum of at least 
Grade 3.  A listing of all relevant laboratory parameters will be provided for each subject 
who had an increase to Grade 2 or higher for any laboratory variable in Table 11.
Assessment of Hepatic Laboratory Values
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized:
●
Post-nadir (preceding value is lower than the subsequent value) 
ALT > 5 × ULN (regardless of grade change);
●
Total bilirubin ≥ 2 × ULN and > baseline (i.e., a post-baseline value must be 
more extreme than the baseline value to be considered);
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin ≤ 2 × ULN.
Four listings (one for each bullet above) of all hepatic laboratory values including ALT, 
AST, total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.
Hepatic Laboratory Abnormalities of Interest 
Among the events assessed under "Assessment of Hepatic Laboratory Values," the 
following criteria are of interest:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and a concurrent total bilirubin > 2 × ULN with a 
direct/total bilirubin ratio > 0.4.


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To support the assessment of hepatic laboratory abnormalities of interest, the following 
potential events will be summarized:
●
Confirmed post-nadir ALT > 5 × ULN;
●
Post-nadir ALT > 3 × ULN and total bilirubin > 2 × ULN and direct/total 
bilirubin ratio > 0.4.
Two listings (one for each bullet) of all hepatic laboratory values including ALT, AST, 
total, indirect and direct bilirubin, ratio of direct to total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met the criterion defined above.
For the assessments of hepatic laboratory values and hepatic laboratory 
abnormalities of potential interest, the maximum ratio relative to the ULN will be used 
to determine if subjects meet any of the criteria listed above.  The ALT and total bilirubin 
values do not need to be concurrent in order to meet the defined criteria in statistical 
summaries.  For ALT, the post-baseline value must represent an increase from the 
first nadir (including baseline) to be counted.  First nadir is defined as the last value prior 
to the first increase.  For total bilirubin, a subject will be counted if the post-baseline 
laboratory value meets the above criteria regardless of the baseline laboratory value 
(i.e., the post-baseline laboratory value does not need to be worse than the baseline 
laboratory value), except where noted above. A confirmed post-nadir increase in ALT is 
defined as two consecutive values of ALT > 5 × ULN after nadir, either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement. A single post-nadir ALT value of greater than 5 × ULN followed by lost to 
follow-up (no additional ALT values) also will be considered (i.e., will not require 
confirmation). The ratio of direct to total bilirubin will be calculated using the same 
date/time sample corresponding to the total bilirubin elevation.


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11.5
Analysis of Vital Signs Data
11.5.1
Variables and Criteria Defining Abnormality
Vital sign variables are body temperature, sitting systolic blood pressure, sitting diastolic 
blood pressure, sitting pulse rate, and body weight.
The criteria for Potentially Clinically Significant (PCS) vital sign findings are presented in 
Table 12.
Table 12.
Criteria for Potentially Clinically Significant Vital Sign Values
Test/Measurement
Very Low (VL)
Very High (VH)
Systolic Blood Pressure
≤ 90 mmHg AND A decrease of 
≥20 mmHg from baseline
≥ 180 mmHg AND An increase of 
≥20 mmHg from baseline
Diastolic Blood Pressure
≤ 50 mmHg AND A decrease of 
≥15 mmHg from baseline
≥ 105 mmHg AND An increase of 
≥15 mmHg from baseline
Pulse Rate
≤ 50 bpm AND A decrease of 
≥15 bpm from baseline
≥ 120 bpm AND An increase of 
≥15 bpm from baseline
Weight
A decrease of ≥ 15% from baseline
An increase of ≥ 15% from baseline
Body Temperature
> 38.3°C AND An increase of
≥1.1°C from baseline
11.5.2
Statistical Methods
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study drug.  The same baseline value will be used for change to Treatment 
Period visits and change to Post-Treatment Period visits.
For each vital sign parameter listed in Section 11.5.1, values at each visit (baseline and 
post-baseline, including applicable post-treatment visits) will be summarized with the 
sample size, mean, standard deviation, minimum, median, and maximum.
The number and percentage of subjects with on-treatment values meeting the specified 
criteria for PCS vital sign values (Table 12) will be summarized.  A post-baseline value 
must be more extreme than the baseline value to be considered a PCS finding.  A separate 


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listing will be provided that presents all vital sign values for the subjects meeting PCS 
criteria during treatment.
11.6
Analysis of HIV-1 RNA and Flow Cytometry
If this study enrolls HCV/HIV co-infected subjects, plasma HIV-1 RNA and flow 
cytometry data will be presented in subject data listings.
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of the 
Protocol and SAP
1.
The planned analyses (Section 4.4) have been updated for better clarity.
2.
The category cutoffs of baseline HCV RNA level have been changed (Section 7.1
and Section 10.6) to reflect current HCV project standards.
3.
Certain efficacy subgroup variables have been changed (Section 10.6) because of 
the small sample size of the study and the current HCV project standards.
4.
The resistance analyses (Section 10.8) have been updated to reflect current HCV 
project standards.
5.
Analyses for HCV/HIV co-infected subjects (Section 7.3, Section 10.8.2, 
Section 11.3) have been deleted because of the anticipated small sample size of the 
HIV-1 co-infected subjects; subject-level data will be presented in listings.
6.
For subgroups of treatment experience prior to enrolling in the AbbVie HCV 
parent study, "treatment-naïve" and "treatment-experience, DAA-naïve" are 
combined as "treatment-naïve/DAA-naïve" (Section 7.1 and Section 10.6) because 
of the small sample size of the study and because the recommended regimens of 
ABT-493/ABT-530 are the same for treatment-naïve and DAA-naïve GT1, 2, 4, 5, 
6 subjects.


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7.
The percentage of subjects with virologic failure through Post-Treatment Week 24
has been added to additional efficacy analyses (Section 10.7) to reflect current 
HCV project standards.
8.
Safety analyses will only be performed for the overall population (Section 11.1) 
because of the small sample size of the study and the current HCV project 
standards.
9.
Analyses for vital signs have been updated (Section 11.5.2) according to the 
current HCV project standards.
13.0
References
1.
Newcombe RG.  Two-sided confidence intervals for the single proportion:  
comparison of seven methods.  Stat Med.  1998;17(8):857-72.