ING200336: A Prospective, Interventional Pharmacokinetic and Safety Study of DTG/ABC/3TC in Pregnant Women
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections, Arthralgia
Sponsor: ViiV Healthcare

2013N166290_03
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The ViiV Healthcare and the GlaxoSmithKline group of companies
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
ING200336: A Prospective, Interventional Pharmacokinetic and 
Safety Study of DTG/ABC/3TC in Pregnant Women
Compound Number:
GSK1349572+GR109714+GI265235
Development Phase:
III B
Effective Date:
19-JUN-2018
Protocol Amendment Number:  03
Author (s):
 
Copyright 2018 the ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N166290_00
2013-DEC-18
Original
2013N166290_01
2014-APR-15
Amendment No.: 01 
Editorial changes, including corrections of minor typographical errors and/or 
inconsistencies in the Time and Events Table 6 and the protocol, inclusion of infant HIV 
status if available, and edits to Appendix 3 wording
2013N166290_02
2014-APR-23
Amendment No. 02
Correction of typographical errors in Amendment 1: Specifically, in the Summary of 
Revisions, page 1, the reader is referred to Time and Events Table 6; it should be Table 4.  
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events was 
added as a new appendix, changing numbers of other appendices. It’s inclusion also 
needed to be added to Appendix 6.  Lastly, where the Summary of Revisions says 
Appendix 3, it should be Appendix 4.
2013N166290_03
2018-JUN-19
Amendment No. 03
Changes were made to the protocol to manage and mitigate risks following identification 
of a potential safety issue related to neural tube defect in infants born to women with 
exposure to dolutegravir at the time of conception.

The Rationale and Risk Assessment sections (Section 1.2. and Section 1.3.1.) were
updated to include language regarding risk and mitigation of neural tube defects.

The Withdrawal Criteria (Section 4.5.) were updated to include a reminder that post-
delivery, subjects who desire to be pregnant, or who state they are not willing/no 
longer willing to comply with the approved pregnancy avoidance methods, should be 
withdrawn from the study.

The Time and Events table (Section 6.) was updated to include a footnote to clarify 
the requirement for pregnancy tests post-delivery, and a reminder for investigators to 
check at every post-delivery visit that subjects are avoiding pregnancy.

Contraception Requirements for the Post-Partum and Continuation Phases (Section 
6.5.4.8.) were updated with the most recent list of ‘highly effective methods for 
avoiding pregnancy in females of reproductive potential’, which excludes the double 
barrier method of contraception.
Administrative updates were made.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
200336
This study is sponsored by ViiV Healthcare LLC. GlaxoSmithKline is responsible for 
implementing and managing all aspects of this study.  The study is performed in 
compliance with Standard Operating Procedures for all processes involved, including the 
archiving of essential documents.
Sponsor Legal Registered Address:
ViiV Healthcare UK Limited
908 Great West Road
Brentford, Middlesex, TW8 9GS, United Kingdom
Telephone: 
Sponsor Contact Address
ViiV Healthcare Company
Five Moore Drive
Research Triangle Park
North Carolina, United States of America
Telephone: 
In some countries, the clinical trial sponsor may be the local ViiV affiliate company (or 
designee). Where applicable, the details of the Sponsor and contact person will be 
provided to the relevant regulatory authority as part of the clinical trial submission.
Medical Monitor Contact Information and Serious Adverse Events (SAE) Contact 
Information:
 MD
ViiV Healthcare,
5 Moore Drive, 
Research Triangle Park, NC 27709, USA
Mobile:
Facsimile: 
e-mail:
Regulatory Agency Identifying Number(s): US IND 75,382; EudraCT 2013-003527-11
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200336
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................17
1.1.
Background ................................................................................................17
1.2.
Rationale ....................................................................................................21
1.2.1.
Drug Interactions .........................................................................23
1.2.1.1.
Use of Calcium and Iron Supplements with 
DTG: Study ING116898 .............................................23
1.3.
Benefit:Risk Assessment ............................................................................24
1.3.1.
Risk Assessment .........................................................................24
1.3.2.
Benefit Assessment.....................................................................31
1.3.3.
Overall Benefit:Risk Conclusion...................................................32
2.
OBJECTIVE(S) ......................................................................................................33
3.
INVESTIGATIONAL PLAN.....................................................................................33
3.1.
Study Design ..............................................................................................33
3.2.
Discussion of Design ..................................................................................38
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................38
4.1.
Number of Subjects ....................................................................................38
4.2.
Inclusion Criteria.........................................................................................39
4.3.
Exclusion Criteria........................................................................................40
4.4.
Other Eligibility Criteria Considerations.......................................................41
4.5.
Withdrawal Criteria .....................................................................................41
4.5.1.
Virologic Criteria for Subject Management and Viral 
Resistance...................................................................................43
4.6.
Screening Failures......................................................................................44
5.
STUDY TREATMENTS..........................................................................................44
5.1.
Investigational Product and Other Study Treatment....................................44
5.1.1.
Tablet Formulation of DTG/ABC/3TC...........................................45
5.2.
Treatment Assignment................................................................................45
5.2.1.
Dosage and Administration..........................................................45
5.3.
Blinding.......................................................................................................45
5.4.
Product Accountability ................................................................................45
5.5.
Treatment Compliance................................................................................45
5.6.
Concomitant Medications and Non-Drug Therapies....................................46
5.6.1.
Permitted Medications and Non-Drug Therapies..........................46
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................46
5.6.2.1.
Prohibited medications for subjects taking 
DTG/ABC/3TC FDC ...................................................47
5.7.
Treatment after the End of the Study ..........................................................47
5.8.
Treatment of Study Treatment Overdose....................................................48
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
 
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6.1.
Critical Baseline Assessments....................................................................52
6.1.1.
Screening Assessments ..............................................................52
6.2.
Pharmacokinetics .......................................................................................53
6.2.1.
Pharmacokinetic Endpoints .........................................................53
6.2.2.
PK Sample Collection ..................................................................54
6.3.
Efficacy.......................................................................................................55
6.4.
Endpoints....................................................................................................56
6.4.1.
Maternal and Infant......................................................................56
6.4.2.
Efficacy........................................................................................56
6.5.
Safety .........................................................................................................56
6.5.1.
Safety Endpoints..........................................................................58
6.5.2.
Toxicity Management...................................................................59
6.5.3.
Specific Toxicities/Adverse Event Management...........................60
6.5.4.
Liver chemistry stopping and follow up criteria.............................60
6.5.4.1.
Restarting Investigational Product ..............................63
6.5.4.2.
CPK Elevation ............................................................64
6.5.4.3.
Decline in Renal Function...........................................64
6.5.4.4.
Proteinuria..................................................................64
6.5.4.5.
Allergic Reaction ........................................................65
6.5.4.6.
Abacavir Hypersensitivity Reaction (ABC HSR)..........65
6.5.4.7.
Skin reactions without other symptoms that are 
typical of ABC HSR ....................................................66
6.5.4.8.
Contraception Requirements for the Post-
Partum and Continuation Phase Only.........................68
6.5.5.
Adverse Events............................................................................69
6.5.5.1.
Definition of an AE......................................................69
6.5.5.2.
Definition of an SAE ...................................................70
6.5.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................71
6.5.7.
Cardiovascular Events.................................................................71
6.5.8.
Death Events...............................................................................72
6.5.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................72
6.5.10.
Suicidality Monitoring...................................................................72
6.5.11.
Pregnancy ...................................................................................73
6.5.11.1.
Pregnancy Testing during the Post-partum and 
Continuation Phases ..................................................73
6.5.11.2.
Action to be taken if Pregnancy occurs.......................73
6.5.11.2.1.
Time Period for Collecting 
Pregnancy Information............................74
6.5.12.
Time Period and Frequency of Detecting AEs and SAEs.............74
6.5.13.
Method of Detecting AEs and SAEs.............................................74
6.5.14.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................75
6.5.14.1.
Regulatory Reporting Requirements for SAEs............76
6.5.15.
Other Safety Outcomes ...............................................................77
6.6.
Viral Genotyping and Phenotyping..............................................................77
6.6.1.
Virology Endpoints.......................................................................77
6.6.2.
HIV-1 pol Viral Genotyping and Phenotyping ...............................78
6.6.3.
HIV-1 Exploratory Analysis ..........................................................78
6.7.
Pharmacogenetic Research........................................................................78
 
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7.
DATA MANAGEMENT ...........................................................................................78
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................79
8.1.
Hypotheses.................................................................................................79
8.2.
Study Design Considerations......................................................................79
8.2.1.
Sample Size Assumptions ...........................................................79
8.2.2.
Analysis Populations....................................................................79
8.2.3.
Treatment Comparisons ..............................................................79
8.2.4.
Interim Analysis ...........................................................................79
8.2.5.
Key Elements of Analysis Plan ....................................................79
8.2.5.1.
Pharmacokinetic Analyses..........................................80
8.2.5.2.
Safety Analyses..........................................................80
8.2.5.3.
Efficacy Analyses .......................................................81
8.2.5.4.
Viral Genotyping/Phenotyping Analyses.....................81
8.2.5.5.
Pharmacogenetic Analyses ........................................81
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................81
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............81
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................81
9.3.
Quality Control (Study Monitoring) ..............................................................82
9.4.
Quality Assurance.......................................................................................83
9.5.
Study and Site Closure ...............................................................................83
9.6.
Records Retention......................................................................................83
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................84
10. REFERENCES.......................................................................................................85
11. APPENDICES........................................................................................................88
11.1.
Appendix 1: CDC Classification System for HIV-1 Infections (1993) ...........88
11.2.
Appendix 2:  Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events............................................................91
11.3.
Appendix 3 Pharmacogenetic Research ...................................................110
11.4.
Appendix 4: Country Specific Requirements.............................................116
11.5.
Appendix 5: Liver Safety Drug Restart or Rechallenge Guidelines............117
11.6.
Appendix 6: Protocol Amendment Changes..............................................124
 
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LIST OF ABBREVIATIONS
g
Microgram
3TC
Lamivudine, EPIVIR™
AAG
Alpha-1 acid glycoprotein
ABC
Abacavir, ZIAGEN™
AE
Adverse Event
AGA
Adequate gestational age
ALT
Alanine Aminotransferase
APR
Antiviral Pregnancy Registry
ART
Antiretroviral Therapy
ARV
Antiretroviral
AST
Aspartate Aminotransferase
AUC(0-24)
Area under the concentration-time curve during a 24-hour 
interval at steady state
BID
Twice Daily
BUN
Blood urea nitrogen
C
Drug concentration at the end of dosing interval
c/mL
Copies/milliliter
C0
Drug concentration immediately prior to dosing at steady 
state
Caverage
Average Concentration
CC
Calcium carbonate
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 
(cluster of differentiation 4)
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance
Cmax
Maximal drug concentration
Cmin
Minimal drug concentration 
CPK
Creatine Phosphokinase
CrCl
Creatinine Clearance
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug Induced Liver Injury
dL
Decilitre
DTG
Dolutegravir
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFD
Embryo Fetal Development
EFV
Efavirenz
ELV
Elvitegravir
FDA
Food and Drug Administration
FDC
Fixed dose combination
FF
Ferrous Fumarate
FRP
Females of Reproductive Potential
FTC
Emtricitabine
FU
Follow-up
 
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g
Gram
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
HELLP
Hemolysis, elevated liver enzymes and low platelet count
HIV-1
Human Immunodeficiency Virus type 1
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
Ig
Immunoglobulin
INI
Integrase Inhibitor
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IRIS
Immune reconstitution inflammatory syndrome
LBW
Low Birth Weight
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LGA
Large gestational age
LLOD
Lower Limit of Detection
mg
Milligrams
mL
Millilitre
MSDS
Material Safety Data Sheet
MTCT
Mother-to-Child Transmission
NOAEL
No adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
NVP
Nevirapine
PGx
Pharmacogenetics
PI
Protease Inhibitor
PK
Pharmacokinetic
PMTCT
Prevention of Mother-to-Child Transmission
QWBA
Quantitative Whole Body Autoradiography
RAL
Raltegravir
RAP
Reporting Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic Acid
RTV
Ritonavir
SAE
Serious Adverse Event
SGA
Small gestational age
SJS
Stevens Johnson Syndrome
SoC
Standard of Care
 
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SPM
Study Procedures Manual
SRT
Safety Review Team
t1/2
Half-life
TDF
Tenofovir disoproxil fumarate, Viread
TEN
Toxic Epidermal Necrolysis
tmax
Time to observed maximal drug concentration
ULN
Upper Limit of Normal
US
United States
Vss/F
Steady state volume of distribution
WBC
White Blood Cell
WD
Withdrawal
ZDV
Zidovudine, Retrovir
Trademark Information
Trademarks of  ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
COMBIVIR
GenoSure
EPIVIR
Phenosense
EPZICOM
Quest Diagnostics
KIVEXA
SAS
RETROVIR
TRIZIVIR
ZIAGEN
 
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PROTOCOL SUMMARY
Rationale
In this protocol, the dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) fixed dose 
combination (FDC) tablet is being made available to women who become pregnant while 
participating in study ING117172.  Continuation of antiretroviral therapy (ART) is key to 
both mother and the unborn fetus in order to maintain virologic suppression in the mother 
(thereby decreasing the risk for maternal disease progression), but also to reduce the risk 
of maternal-fetal transmission of human immunodeficiency virus type 1 (HIV-1) to her 
unborn child.
This study also offers the first opportunity to investigate the impact of pregnancy on DTG 
pharmacokinetics (PK).
Objective(s)
Primary
Mother:

To describe the total plasma DTG PK parameters with the DTG/ABC/3TC FDC 
during Weeks 18-26 and Weeks 30 to 36 of the pregnancy and 8-12 weeks 
postpartum;

To characterize the safety and tolerability of DTG/ABC/3TC FDC when used 
during pregnancy.
Secondary
Mother:

To assess the antiviral activity of the DTG/ABC/3TC FDC when administered 
during pregnancy;

To assess the immunologic activity of DTG/ABC/3TC FDC;

To assess the incidence of treatment-emergent genotypic and phenotypic 
resistance in subjects who meet virologic withdrawal criteria;

To evaluate the unbound DTG concentrations in plasma during Weeks 18-26 and 
Weeks 30-36 of the pregnancy and 8-12 weeks postpartum;

To compare the DTG concentrations from cord blood with those in maternal 
plasma at the time of delivery;

To characterize birth outcomes;
 
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
To characterize pregnancy outcomes.
Infant:

To characterize infant outcomes at birth. 
Study Design
ING200336 is an open-label Phase IIIb, prospective, interventional, study to evaluate PK 
and safety, as well as birth outcomes in pregnant women while receiving treatment with 
the fixed dose combination tablet of DTG/ABC/3TC once daily. The study will be 
conducted by the HIV provider, therefore, it will be necessary for the HIV provider to 
communicate with, and coordinate collection of, obstetric data with the subject’s 
pregnancy provider (ie., obstetrician or mid-wife). Eligible subjects are HIV-1 infected 
women participating in study ING117172 who become pregnant and are required to be 
withdrawn from that study.  The number of women that will be enrolled into this protocol 
cannot be established a priori, as unintended pregnancies cannot be determined in 
advance. The maximum number of women would include women randomized to 
DTG/ABC/3TC FDC in ING117172 (n 237), though unintended pregnancies in all of 
those women would not be anticipated.  Based on pregnancy rates from two recent DTG 
studies in ART-naive women, the anticipated rate of unintended pregnancy over 48 
weeks would be approximately 5% (n 12)  [GlaxoSmithKline Document Number
RM2011N118494_00, GlaxoSmithKline Document Number RM2011N117164_01].  If 
12 subjects were to enroll in ING200336, at least 8 subjects providing evaluable DTG PK 
parameters during Weeks 18-26, Weeks 30-36 and Weeks 8-12 postpartum would be 
needed to estimate PK parameters with adequate accuracy.
Key objectives of the study are to characterize DTG PK parameters following treatment 
with the DTG/ABC/3TC FDC based on intensive sampling during pregnancy (Weeks 18-
26 and Weeks 30-36) and postpartum (8-12 weeks post delivery), to characterize 
pregnancy outcomes, birth and infant outcomes, and to further characterize the safety, 
tolerability and antiviral activity of DTG/ABC/3TC FDC when used during pregnancy.  
All study subjects will continue to receive DTG/ABC/3TC FDC through the 8-12 weeks 
post partum visit.  Subjects are considered to have completed the study after completing 
the postpartum evaluation. Women may continue to receive DTG/ABC/3TC FDC after 
study completion (in which case they will be followed q12weeks) until study medications 
are locally approved and commercially available, the subject meets a protocol-defined 
reason for discontinuation or until they no longer receive clinical benefit.
The primary outcome analyses will take place after the last subject enrolled gives birth 
and completes their last visit.  As this study will remain open until ING117172 is closed, 
additional analyses of data may be conducted in this open label study prior to this 
timepoint as required by the Sponsor (e.g., when an adequate number of subjects with PK 
data are available, or for regulatory filings).
Subjects will participate in a short screening period which includes an assessment for 
potential pregnancy complications (e.g., hypertension, diabetes, and underlying 
infections.) and a thorough obstetric history (including gravidity, previous complications 
 
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and/or risks, etc.).  Any subject who became pregnant and who meets the virologic 
withdrawal criteria in ING117172 will not be eligible to participate in this study.  
Because obstetric care will not be specifically provided via this study the subject must 
also establish appropriate obstetric care per local standard of care (SoC).  It will be 
necessary for the subject to be willing to share medical information, as necessary, to the 
HIV investigator for both herself and her infant to facilitate collection of delivery, birth 
and infant outcomes by the investigator.
Once the subject learns she is pregnant, there are two scenarios for enrollment:
1. If the subject wants to enter the pregnancy study, and has been seen within 28 
days for a regularly scheduled ING117172 visit, the site would schedule a 
Withdrawal visit, which still must remain within the 28 day window of the 
visit when pregnancy was documented. The previous visit results will be 
used as the “screening visit” to qualify the subject for enrollment and the 
Withdrawal visit is used for the Baseline (Day 1) visit (with verification that 
the subject still meets all entry criteria) for ING200336. A urine pregnancy 
test, as well as a urine dipstick to check for protein, must be performed on 
Day 1.
2. If the subject is determined to be pregnant outside of a study visit and wants 
to enter ING200336 but has not been seen within the 28 day window, the site 
is to perform an unscheduled ING117172 visit to collect adverse 
events/serious adverse events (AEs/SAEs), plasma HIV-1 RNA and 
laboratory results, including a serum pregnancy test, as well as a urine 
dipstick to check for protein, in order to document the subject’s current 
medical status. If the pregnancy is confirmed, the site would then schedule 
the Withdrawal visit within 28 days of the unscheduled visit. The 
unscheduled visit results will be used to qualify the subject for enrollment 
(i.e., is the screening visit) and the Withdrawal visit is used for the Baseline 
(Day 1) visit (with verification that the subject still meets all entry criteria) 
for ING200336.
3. In both scenarios the Withdrawal visit for ING117172 will also be Day 1 for 
ING200336 to ensure no disruption in provision of study treatment.   In the 
event the subject miscarries or electively terminates the pregnancy prior to 
Day 1 (Baseline) of ING200336, she must still be discontinued from 
ING117172 and followed per the requirements of ING117172 and may not 
continue enrollment into study ING200336.
In both of these scenarios new demographic, Baseline characteristics, concomitant 
medications, medical history and HIV associated conditions will be collected on Day 1, 
as well as an obstetric history.  
If there is an ongoing, unresolved AE and/or SAE at the time of the Withdrawal visit in 
ING117172 the AE/SAE will be followed for event outcome, which will be recorded in 
the eCRF, as part of ING117172 (i.e., followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up).
The AE/SAE will be transcribed as medical history in ING200336.  Any exacerbation or 
worsening of the AEs and/or SAEs from ING117172 during subject participation in 
 
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ING200336, will be recorded as a new entry in the AE or SAE eCRF pages for 
ING200336 with a start date reflecting the clinical worsening, and will not be recorded 
for ING117172.  All SAEs (including those assessed as related to study participation 
[e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy] or related to a GSK or ViiV concomitant medication) and any non serious AEs 
of special interest (defined in the study procedure manual) occurring from the withdrawal 
visit in ING117172 through to administration of IP at Day 1 of ING200336, will be 
recorded in the eCRF for ING117172.
All AEs and SAEs occurring from Day 1 in ING200336 through to the follow up contact 
will be collected and recorded in the eCRF for ING200336, regardless of relationship to 
study participation or any other causality. 
After all ING117172 Withdrawal procedures have been completed subjects who fulfil 
eligibility requirements may be enrolled.  Subjects will begin Day 1 and will continue to 
receive DTG/ABC/3TC FDC treatment in an open-label fashion in ING200336.  During 
the second trimester (Weeks 18-26) of pregnancy, the third trimester (Weeks 30-36) of 
pregnancy, as well as postpartum (8 -12 weeks post delivery), subjects will undergo 
intensive PK visits.  Serial plasma samples will be collected during each PK visit for the 
determination of DTG (total and unbound) concentrations.  All subjects will participate in 
a postpartum evaluation, including the PK assessment, 8-12 weeks post delivery.  
Subjects will continue to have access to DTG/ABC/3TC FDC postpartum until it is either 
locally approved and commercially available, the patient no longer derives clinical 
benefit, the patient meets a protocol-defined reason for discontinuation, or development 
of DTG/ABC/3TC FDC is terminated. 
Given the requirement that subjects who become pregnant on ING117172 be withdrawn 
from the study, sites that are interested in enrolling pregnant women from ING117172 
onto ING200336 should seek IRB/EC approval for ING200336 in advance of identifying 
such subjects, in order that DTG/ABC/3TC FDC treatment may be continued without 
interruption.
Study Endpoints/Assessments
No formal hypothesis testing will be performed.  Summarized data will provide only 
descriptive information regarding outcomes.
The primary outcome measure for this study will be to evaluate the PK (area under the 
concentration-time curve during a 24-hour interval at steady state [AUC24], maximal drug 
concentration [Cmax], drug concentration at the end of dosing interval [C], apparent 
clearance [CL/F[, steady state volume of distribution [Vss/F] and the half life [t½]) of 
DTG during Weeks 18-26, Weeks 30-36 of the third trimester of pregnancy and at 8-12
weeks postpartum.  The study will also evaluate maternal and pregnancy outcomes and 
characterize the tolerability of DTG/ABC/3TC FDC when administered during 
pregnancy.  Secondary outcomes include PK (Tmax, C0), unbound concentrations at 3 and 
24 hours post dose in the third trimester and postpartum, plasma DTG concentration in 
cord blood and maternal plasma at the time of delivery, efficacy measures (including 
proportion with HIV-1 RNA < 400 c/mL and HIV-1 RNA < 50 c/mL over time, and 
absolute values and change from Baseline in CD4+ cell counts over time).  Infant 
 
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outcomes, pregnancy outcomes, and maternal AEs and laboratory parameters will be 
assessed to to characterize the safety and tolerability of DTG/ABC/3TC FDC
administered during pregnancy.  Virology endpoints will include an assessment of the 
development of viral resistance in subjects meeting confirmed virologic withdrawal 
criteria.
 
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1.
INTRODUCTION
Pregnancy increases the risk of HIV progression, while HIV increases the risk for 
maternal complications from pregnancy and poses the risk of perinatal HIV transmission
to the unborn fetus.  Mother to child transmission (MTCT) of HIV can occur during 
pregnancy, labor, delivery or postpartum through breastfeeding.  In the absence of any 
interventions, vertical HIV transmission rates approximate 35%, but fall below 5% with 
effective interventions [WHO, 2010].  In the United States and other developed countries, 
the risk of perinatal infection has decreased from 25% without intervention to less than 
2% with intervention [WHO, 2012].  The HIV-infected mother who breastfeeds her 
infant while taking ARVs herself or giving ARVs to her infant reduces the risk of 
transmission to about 2% after 6 months of breastfeeding, or 4% over 12 months 
(UNAIDS, 2011).
The 2013 WHO Guidelines thus recommend (strong recommendation, moderate-quality 
evidence) all pregnant and breastfeeding women with HIV should initiate triple ARVs 
(ART), which should be maintained at least for the duration of mother-to-child 
transmission risk. Women meeting treatment eligibility criteria should continue lifelong 
ART (WHO, 2013). 
The ART recommendation for pregnant women prioritizes the health of women over 
potential risks and increased cost.  For women who are on ARV therapy at the time that 
they become pregnant, the World Health Organization (WHO) recommends that women 
continue such therapy if they are responding to the ARV.
In line with this recommendation, this study will allow those women participating in 
ING117172 who are virologically responding to dolutegravir/abacavir/3TC fixed dose 
combination tablet (DTG/ABC/3TC FDC) but become pregnant on study, to continue 
DTG/ABC/3TC FDC in order to maintain their effective regimen with minimal 
disruption.  The objective of ING200336 is to describe the pharmacokinetics (PK) of 
DTG, characterize the safety of DTG/ABC/3TC FDC administered during pregnancy, 
and to characterize maternal, birth and infant outcomes following treatment with 
DTG/ABC/3TC FDC.
1.1.
Background
The global benefits anticipated from ART in pregnant women who are eligible for 
treatment include treatment of the mother’s underlying HIV disease, eliminating pediatric 
transmission/infection and reducing sexual transmission of HIV.  However, pregnancy 
impacts all components of drug disposition – absorption, distribution, metabolism, and 
excretion.  These physiological changes in pregnancy can result in measurable changes in 
drug disposition, and in some cases necessitate dose administration adjustments.  
ABC and 3TC
Both ABC and 3TC have been studied during pregnancy.  3TC, used frequently during 
pregnancy as a component of lamivudine/zidovudine [3TC/ZDV]; COMBIVIR™), 
 
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[PETRA, SAINT studies] crosses the placenta by simple diffusion, and the median ratio 
of 3TC concentration in maternal plasma at the time of delivery and cord blood is around 
1 [Bloom, 1997; Mandelbrot, 2001].  3TC accumulates in amniotic fluid where the 
concentration at the time of delivery is 5-fold more than maternal plasma concentration 
without an impact on pregnancy outcomes [Bloom, 1997].  Pregnant women can receive 
the once daily adult dose of 3TC (300 mg once daily).
A Phase I study of abacavir (ABC) in pregnant women indicated that the area under the 
time concentration curve (AUC) drug concentration during the third trimester of 
pregnancy is similar to the drug concentration observed at 6 and 12 weeks postpartum, 
and to concentrations observed in non-pregnant females [Best, 2006].  Cord blood ABC 
concentrations averaged 110% of maternal plasma concentration at the time of delivery.  
Pregnant women can receive the adult dose of ABC (600 mg once daily).
Data are available on association between ABC and 3TC exposure in women during 
pregnancy and birth outcomes. The Antiretroviral Pregnancy Registry (APR), an 
international, voluntary, prospective cohort study, provides an early signal of 
teratogenicity associated with prenatal ARV use.  Using APR data on 13,537 
prospectively reported singleton pregnancies from HIV-infected women, frequency 
estimates of adverse birth outcomes in women a) exposed to ABC containing regimens 
compared to those exposed to non-ABC ARV regimens and b) exposed to 3TC 
containing regimens compared to those exposed to non-3TC ARV regimens were 
undertaken.
Of 1864 outcomes with ABC exposure, 1782 (95.6%) were live births and 82 (4.4%) 
resulted in spontaneous/induced abortions or still births. Among live births 16.2% had 
low birth weight (LBW), 11.7% were preterm, and 3% had birth defects. Of 11,673 
outcomes with non-ABC exposure, 11,049 (94.7%) were live births and 624 (5.3%) 
resulted in spontaneous/induced abortions or still births. Among live births, 16% had 
LBW, 12.5% were preterm, and 2.9% had birth defects. The odds ratios comparing 
exposure to ABC-containing to non-ABC ARV regimen were, for spontaneous abortion 
0.96 (95% confidence interval [CI] 0.67-1.36); induced abortion 0.82 (95%CI: 0.56-
1.21); still birth 0.60 (95%CI: 0.35-1.03); preterm birth 0.93 (95%CI: 0.79-1.09), and 
LBW 1.02 (95%CI: 0.88-1.17).Of 10,531 outcomes with 3TC exposure, 10,032 (95.3%) 
were live births and 499 (4.7%) resulted in spontaneous/induced abortions or still births. 
Among live births 16% had LBW, 11.8% were preterm, and 3% had birth defects. Of 
3006 outcomes with non-3TC exposure, 2799 (93.1%) were live births and 207 (6.9%) 
resulted in spontaneous/induced abortions or still births. Among live births 16% had 
LBW, 14.5% were preterm, and 2.8% had birth defects. The odds ratios comparing 
exposure to 3TC-containing to non-3TC ARV regimen were, for spontaneous abortion 
0.63 (95%CI: 0.49-0.82); induced abortion 0.54 (95%CI: 0.42-0.70); still birth 1.19 
(95%CI: 0.81-1.74); preterm birth 0.79 (95%CI: 0.70-0.89), and LBW 1.00 (95%CI: 
0.88-1.12). There was also no difference in the incidence of LBW, prematurity, or birth 
defects, and no specific pattern of birth defects has been discerned for either ABC or 3TC 
containing regimen [Vannappagari, 2013].
In a randomized controlled clinical study data of ABC exposure during pregnancy and 
breast-feeding [Powis, 2011], 560 HIV-1 infected pregnant women with CD4+ ≥200
 
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cells/mm3 were randomly assigned to receive co-formulated ABC, zidovudine (ZDV), 
and 3TC (TRIZIVIR™, the nucleoside reverse transcriptase inhibitor [NRTI] group,
n=285) or lopinavir−ritonavir plus zidovudine−lamivudine (lopinavir−ritonavir + 
COMBIVIR: the protease inhibitor [PI] group n=275) from 26 to 34 weeks’ gestation 
through planned weaning by 6 months post partum.  A further 170 women with CD4+ < 
200 cells per cubic millimeter (mm3) received nevirapine plus Combivir (the 
observational group). Infants received single-dose nevirapine at birth and ZDV from birth 
through 4 weeks.
There were 709 live-born infants (283 nucleoside reverse transcriptase inhibitor (NRTI) 
group, 270 protease inhibitor (PI) group, and 156 observational group) and 24 stillbirths
[8 in the nucleoside reverse transcriptase inhibitor (NRTI) group (3%), 5 in the PI group 
(2%), and 11 in the observational group (7%)].  Although not powered to detect MTCT
differences between the treatment groups, the overall rates of MTCT were low: by 6 
months of age, 8 of 709 live-born infants (1.1%) were infected [6 in utero (4 NRTI group, 
1 PI group and1 observational group)], and 2 were infected during the breast-feeding 
period (both in NRTI group). Treatment-limiting AEs occurred in 2% of women in the 
NRTI group, 2% in the PI group, and 11% in the observational group.
Congenital abnormalities were reported in 5 infants in each group and included 
polydactyly (6), undescended testis (7), dextrocardia (1), and hydrocephalus (1); all were 
determined to be “not related” or “probably not related” to study drugs [Shapiro, 2010].  
Prematurity was more common in the PI group than the NRTI group (23% vs. 15%). The 
proportion of infants with low birth weight did not differ significantly (13% NRTI, 17% 
PI and 15% in the observational group [Powis, 2011].
Thus, the risks of ABC and 3TC during pregnancy appear no greater than that associated 
with alternative regimens.
Dolutegravir (DTG)
No studies have been conducted with DTG in pregnant women as pregnant women were 
excluded from the Phase IIb/III DTG clinical studies and subjects who became pregnant 
were required to discontinue from the studies.  Forty one pregnancies were reported 
across the DTG clinical studies and compassionate use program through 26Oct2013; 25 
for DTG- containing ART and 16 for comparator. Thirty-two of the pregnancies were 
reported in the ART-naïve population (17 were exposed to DTG [16 in female subjects 
directly receiving DTG and one in a partner potentially exposed to DTG via the semen of 
a male subject], 7 on efavirenz/tenofovir/emtricitabine [EFV/TDF/FTC], 6 on raltegravir 
[RAL], and 2 on darunavir+ritonavir [DRV+RTV]).  Five were reported in the ART-
experienced (integrase inhibitor [INI]-naïve) population (4 on DTG- and 1 on RAL-
containing ART). Three were reported in the ART experienced (INI- resistant) population 
(DTG) and one was reported in a completed Phase I, healthy volunteer study (DTG).
Of the 41 pregnancies, 15 resulted in delivery of a normal healthy baby (including the 
partner pregnancy), 12 in elective termination, one was ectopic (EFV/TDF/FTC) and 6
resulted in spontaneous abortions (2 each for DTG and EFV/TDF/FTC and 1 each for
RAL and DRV+RTV; all between 2 and 10 weeks gestation).  In seven cases, the 
 
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pregnancy was either ongoing or unknown (5 on DTG and one each on EFV/TDF/FTC or 
DRV+RTV).  For one of the ongoing pregnancies, involving an ART-experienced (INI-
naïve) subject exposed to DTG plus abacavir, atazanavir and RTV, a routine ultra sound 
at 31 weeks gestation indicated a congenital anomaly of double outlet right ventricle with 
ventricular septal defect in the foetus, which was considered reasonably attributable to IP 
by the reporting investigator.  However, this finding has not yet been confirmed post-
partum.  The subject was exposed to IP for approximately 75 weeks before conception 
and approximately 6 weeks post her date of last menstrual period, before being 
permanently discontinued from IP and withdrawn from the study due to the pregnancy. 
Thus the foetus was exposed to DTG for approximately the first month of the first 
trimester.  With the exception of this case, no other congenital anomalies have been
reported.
To date there has been no preclinical findings or evidence for an increased risk for 
teratogenic effects for DTG. The overall nonclinical reproductive and developmental 
toxicity profile for DTG in rats and rabbits suggests that DTG is not teratogenic and has a 
low potential for fetal risk.
There were no effects on fertility or early embryonic development in rats orally 
administered DTG at 1000 mg/kg/day in males or females. The no adverse effect level
(NOAEL) was 1000 mg/kg/day, which corresponds to 33X the expected human 
exposure for a 50 mg once daily, based on gender averaged mean exposures achieved in 
the 4 week rat toxicity study.
No adverse effects on fetal development were observed in pregnant rats orally 
administered DTG at 1000 mg/kg/day. The NOAEL for maternal and fetal toxicity 
was1000 mg/kg/day, which corresponds to 38X the expected human exposure for a 
50  mg once daily dose.
In an embryofetal development (EFD) study in rabbits, DTG was orally administered at 
40, 200, or 1000 mg/kg/day to pregnant rabbits. Suppressed body weight gain (13.6% on 
gestation Day 19), decreased food consumption (up to 53%) and scant or no feces/urine 
associated with the decreased food consumption were noted in the 1000 mg/kg/day dams.  
Maternal toxicity at this dose precluded dosing DTG at higher doses in rabbits because 
maternal toxicity can confound teratogenicity assessment.  Therefore, the dose of 1000 
mg/kg/day was the maximal dose that could be administered in this embryo fetal 
development EFD study.
The NOAEL was 200 mg/kg/day for maternal general toxicity (0.27X the expected 
human exposure for a 50 mg once daily dose) and 1000 mg/kg/day for maternal 
reproductive function and embryofetal development (0.56X the expected human exposure 
for a 50 mg once daily dose,).  Of note, there were no teratogenic effects at 
1000 mg/kg/day, a dose that exceeded the NOAEL for maternal toxicity.
In a pre-and postnatal development study, DTG was administered to female rats at doses 
of 5, 50 or 1000 mg/kg/day from Day 6 of gestation to Day 20 of lactation. Suppressed 
body weight gain and decreased food consumption were noted in dams (F0) in the 
1000 mg/kg/day group during the lactation period, which were associated with mild 
 
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decreases in body weights in the offspring in the 1000 mg/kg/day group from pre-
weaning until adolescence. There were no adverse effects on maternal pregnancy, 
parturition, lactation or offspring (F1) survival, behavioral or reproductive function. The 
NOAEL for maternal reproductive function was 1000 mg/kg/day (32X above the 
expected human exposure for a 50 mg once daily dose, based on exposures achieved in 
female rats in the 4 week toxicity study). Due to the decreased body weights of the 
offspring observed at higher doses, the NOAEL for pre- and postnatal development of the 
offspring (F1) was 50 mg/kg/day. This is 25X above the expected human exposure for a 
50 mg once daily dose (extrapolated from gender mean exposures achieved in the rat 14 
day toxicity study). Based on the fact that effects on offspring body weights were noted at 
doses where maternal toxicity was observed, and the presence of considerable safety 
margins expected at the proposed clinical doses, there is minimal risk for adverse effects 
on postnatal development in offspring of mothers receiving DTG.
DTG is excreted in the milk of lactating rats. Following oral administration (50 mg/kg) to 
lactating rats on Day 10 post partum, total radiocarbon concentrations in milk were up to 
2-fold greater than those in maternal blood. The metabolite profile of milk indicated that 
parent DTG represented more than 95% of the total radiocarbon, consistent with the 
findings in plasma from female rats in an earlier study. These data suggest that F1 
offspring in the pre- and postnatal toxicity study were exposed to the drug via the milk. 
Following oral administration of DTG (50 mg/kg) to pregnant rats on Day 18 post 
conception, DTG-related material was found, by quantitative whole body 
autoradiography (QWBA) analysis, to be widely distributed to the fetuses over the 24-
hour sampling period. These data indicate that DTG is able to cross the placental barrier.
1.2.
Rationale
Few studies have been conducted with DTG in pregnant women. DTG was not 
anticipated to increase the risk of adverse development or reproductive outcomes in 
humans. Recently, early results from an unplanned interim analysis of an ongoing birth 
outcome surveillance study in Botswana showed that 4/426 (0.9%) of women who were 
taking DTG when they became pregnant had babies with neural tube defects compared to 
a background rate of 0.1%.  Extensive clinical data is available on ABC and 3TC, and 
this data suggests that the use of ABC and 3TC do not lead to adverse outcomes for the 
mother or baby when used in pregnancy.  Additionally, for women who are already 
receiving, tolerating and responding virologically to DTG/ABC/3TC, there may be 
benefit in continuing the regimen after pregnancy is confirmed (if after the first 
trimester), as the mother may be more likely to continue a familiar and effective regimen.  
Additional PK, safety and efficacy data is required to further inform the use of DTG and 
DTG/ABC/3TC in pregnancy. 
To date, the efficacy, PK, safety and drug interaction potential of DTG have been 
evaluated in an extensive program of Phase I to III clinical trials. Data are summarized in 
the current Investigator Brochure.  In both ART-naïve and ART-experienced (INI- naïve) 
patients, the safety profile for DTG 50 mg once daily was comparable to raltegravir 
(RAL) and generally favorable to EFV/TDF/FTC and EFV (studies ING113086 
[SPRING-2] and ING114467 [SINGLE], respectively). The most frequently observed 
adverse events (AEs) across patient populations were diarrhea, nausea, and headache, 
 
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which were generally Grade 1 or 2 in severity, and typically did not lead to 
discontinuation from studies.  In treatment-naïve HIV-infected adult subjects, DTG 50 
mg once daily was shown to be efficacious, and non-inferior to RAL in combination with
a background regimen with dual NRTI [SPRING-2]. When used in combination with 
ABC/3TC (EPZICOM/KIVEXA™), DTG was shown to be superior to EFV/TDF/FTC, a 
result driven by better tolerability of the DTG based regimen [SINGLE].  Furthermore, 
DTG 50 mg once daily may have a higher barrier to resistance in INI-naive patients, as 
suggested in the treatment-experienced (INI-naive) SAILING study where significantly 
fewer virologic failures and significantly fewer subjects with INI resistance were 
observed when compared with RAL. 
DTG is primarily metabolized through UGT1A1 with minimal renal excretion (<1% of 
total dose given orally). DTG is a drug with low clearance (~1 L/hr for CL/F after oral 
dosing), low volume of distribution (~12.5 L for Vd/F after oral dosing), and high plasma 
protein binding (>99%). The following physiologic changes during pregnancy may have 
impact on DTG PK (Table 1):
Table 1
Physiological Change During Pregnancy and Potential Impact on 
DTG Pharmacokinetics
Possible Physiological Changes During 
Pregnancy*
Potential Impact on DTG PK
Changes in total body weight and body fat 
composition.
Increase clearance (CL) as well as the volume 
of distribution (Vd)
Delayed gastric emptying and prolonged 
gastrointestinal transit time.
Increase oral bioavailability, delayed time to 
observed maximal drug concentration (tmax) 
Increase in extra cellular fluid and total body 
water.
Increase Vd
Increased cardiac output, increased stroke 
volume, and elevated maternal heart rate.
Unlikely to have effect
Decreased albumin concentration with reduced 
protein binding.
Increase unbound fraction, CL, and Vd
Increased blood flow to the various organs (e.g., 
kidneys, uterus).
Unlikely to have effect
Increased glomerular filtration rate.
Unlikely to have effect
Changed hepatic enzyme activity, including 
phase I CYP450 metabolic pathways (e.g., 
increased CYP2D6 activity), xanthine oxidase, 
and phase II metabolic pathways (e.g., N-
acetyltransferase).
May affect CL
*FDA Guidance for Industry (2004): Pharmacokinetics in Pregnancy — Study Design, Data Analysis, and Impact 
on Dosing and Labeling.
In previous studies DTG has not been  prone to changes by demographic factors (age, 
gender, weight, etc) based on population PK analyses. Accumulated safety data showed 
that DTG is in general well tolerated and no PK/Pharmacodynamic (PD) relationship for 
safety measures has been identified. Therefore, despite the potential impacts of 
physiological changes on DTG PK, it is expected that DTG PK should not change 
 
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significantly during pregnancy. The clinical dose of 50mg once daily will be used in this 
study and no therapeutic drug monitoring is needed.
1.2.1.
Drug Interactions
1.2.1.1.
Use of Calcium and Iron Supplements with DTG: Study ING116898
Drug interactions relevant to the use of ABC and 3TC are described in approved product 
labels.  A description of the drug interaction profile for DTG is included in the current 
IB; the recently completed interaction study for calcium and iron supplements is 
described below.
The PK effect of DTG 50 mg co-administered with a single dose of calcium carbonate 
(CC) 1200mg or ferrous Fumarate (FF) was evaluated in a Phase I, randomized, four-
period crossover study (ING116898) in healthy adult subjects.
Twelve subjects were enrolled into one of the two cohorts and received each of four 
treatments in a randomized fashion: 1) A single dose of DTG 50 mg administered under 
fasted conditions; 2) A single dose of DTG 50 mg co-administered with a single dose of 
CC 1200 mg or FF 324 mg under fasted conditions; 3) A single dose of DTG 50 mg co-
administered with a single dose of CC or FF with a moderate-fat meal; 4) A single dose 
of DTG 50 mg administered under fasted conditions 2 hours prior to administration of a 
single dose of CC or FF. There was a washout period of at least 7 days between 
treatments. Serial PK samples were collected during each treatment period for the 
measurement of plasma DTG concentrations.
Under fasted conditions, co-administration of CC reduced DTG exposure by 37-39% and 
FF reduced DTG exposure by 54-57%; food (a moderate fat meal) and 2hr separation 
completely eliminated the negative effect of calcium carbonate on DTG exposure (See 
Table 2 and Table 3). 
Table 2
Statistical Comparison of Plasma DTG Pharmacokinetic Parameters 
(Calcium Carbonate Cohort)
Comparison
Ratio of GLS Means (90% CI)
DTG + CC vs DTG 
Alone (fasted)
DTG + CC (fed) vs 
DTG Alone (fasted)
DTG 2hr prior to 
CC vs DTG Alone 
(fasted)
DTG + CC (fed) vs 
DTG+ CC (fasted)
AUC(0-t)
0.61 (0.48, 0.79)
1.10 (0.84, 1.43)
0.95 (0.73, 1.24)
1.79 (1.37, 2.33)
AUC(0-)
0.61 (0.47, 0.79)
1.09 (0.84, 1.43)
0.94 (0.72, 1.23)
1.78 (1.36, 2.33)
Cmax
0.63 (0.50, 0.81)
1.07 (0.83, 1.38)
1.00 (0.78, 1.29)
1.70 (1.32, 2.18)
C24
0.61 (0.47, 0.80)
1.08 (0.81, 1.42)
0.90 (0.68, 1.19)
1.76 (1.33, 2.33)
CI=confidence interval
 
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Table 3
Statistical Comparison of Plasma DTG Pharmacokinetic Parameters 
(Ferrous Fumarate Cohort)
Comparison
Ratio of GLS Means (90% CI)
DTG + FF  vs DTG 
Alone (fasted)
DTG + FF (fed) vs 
DTG Alone (fasted)
DTG 2hr prior to FF 
vs DTG Alone 
(fasted)
DTG + FF (fed) vs 
DTG+ FF (fasted)
AUC(0-t)
0.45 (0.37, 0.54)
0.98 (0.81, 1.19)
0.94 (0.78, 1.14)
2.18 (1.80, 2.64)
AUC(0-)
0.46 (0.38, 0.56)
0.97 (0.80, 1.19)
0.95 (0.78, 1.15)
2.12 (1.75, 2.58)
Cmax
0.43 (0.35, 0.52)
1.03 (0.85, 1.26)
0.99 (0.81, 1.21)
2.40 (1.97, 2.94)
C24
0.44 (0.36, 0.54)
0.99 (0.80, 1.22)
0.92 (0.74, 1.13)
2.25 (1.83, 2.77)
In summary, DTG can be given concurrently with calcium or iron supplements with food; 
without food, DTG should be given 2 hours prior to or 6 hours after calcium or iron 
supplements.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DTG, 
ABC, 3TC and/or ABC/3TC FDC can be found in the most current version of the DTG 
Investigator’s Brochure (IB) and the approved labels for ABC and 3TC. The following 
section outlines the risk assessment and mitigation strategy of the DTG/ABC/3TC FDC 
in this protocol.
1.3.1.
Risk Assessment
There are no shared metabolism pathways between the components of DTG/ABC/3TC, 
and no common target organs were identified in respective pre-clinical studies.  As such, 
there is no pharmacologic data that would predict increased safety risk for the 
DTG/ABC/3TC FDC formulation beyond that identified for the individual active 
moieties DTG, ABC and 3TC.  Early in clinical development, no drug-drug interaction 
between DTG and ABC/3TC was apparent given the safety and efficacy profile observed 
in the Phase IIb study ING112276 [SPRING-1] in which 67 subjects received DTG in 
combination with ABC/3TC for up to 96 weeks.  Clinical safety data from the subjects 
treated with DTG + ABC/3TC in the Phase IIIa studies ING114467 [SINGLE] and study 
ING113086 [SPRING-2] were consistent with the safety profile of the individual active 
moieties.
Risks in ING200336 are primarily related to those that accrue to the fetus with regards to 
the DTG/ABC/3TC FDC regimen, and the risks associated with unknown effects of 
pregnancy on DTG exposure.  ABC and 3TC do not pose additional safety risks to 
women beyond those recognized for all patients in the approved country product label for 
the ABC/3TC FDC [Vannappagari, 2013], and as noted above, ABC and 3TC have been 
given to pregnant women without increased adverse outcomes for the mother or baby.  
For DTG, risks to the mother are outlined in the most current DTG IB [GSK Document 
Number RM2007/00683/11, GSK Document Number 2017N352880_00, GSK Document 
Number 2017N352880_01]; no effect of gender on safety profile of DTG has been 
 
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observed (beyond what might be expected; e.g., more anaemia in women).  It is unknown 
at this time if the physiologic differences experienced in pregnancy would amplify 
particular risks identified with DTG, but based on the recognized risks and 
absorption/distribution/metabolism/excretion of DTG, no additional risk would be 
anticipated.
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment.  Considerations when using DTG/ABC/3TC FDC are 
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Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
Potential teratogenic effects of DTG/ABC/3TC; 

DTG: Neural Tube Defects
The safe use of DTG/ABC/3TC in human pregnancy has 
not been established.  DTG, ABC and 3TC have been 
shown to cross the placenta in reproductive toxicity studies 
in animals.  3TC and ABC, but not DTG, have been 
associated with findings in animal reproductive studies but 
have been used in human pregnancy without evidence for 
increased risk of teratogenicity. See the most current DTG 
IB for additional information [Antiretroviral Pregnancy 
Registry Steering Committee, 2013; Vannappagari, 
2013;[GSK Document Number RM2007/00683/11, GSK 
Document Number 2017N352880_00, GSK Document 
Number 2017N352880_01]
There has been no association between ABC or 3TC and 
overall birth defects observed in the Antiretroviral 
Pregnancy Registry (APR), although there are some 
limitations to these data (http://apregistry.com/index.htm).
In one ongoing birth outcome surveillance study in 
Botswana, early results from an unplanned interim analysis 
show that 4/426 (0.9%) of women who were taking DTG 
when they became pregnant had babies with neural tube 
defects compared to a background rate of 0.1%.
1. A subject is eligible to continue in the study post-
delivery if she is not pregnant, and agrees to follow
one of the options listed in the Modified List of Highly 
Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (see Section 6.5.4.8.)
until at least 2 weeks after discontinuation of IP.
2. Subjects who are post-delivery and desire to be 
pregnant, or who state they are not willing/no longer 
willing to comply with the approved pregnancy 
avoidance methods, will have study treatment 
discontinued and be withdrawn from the study.
3. Subjects who are post-delivery are reminded re: 
pregnancy avoidance and adherence to contraception 
requirements at every study visit.
4. Pregnancy status is monitored at every study visit
post-delivery.
Pregnancies must be followed up to determine outcome 
(including premature termination) and status of mother and 
child.  GSK’s central safety department will also forward 
this information to the APR (Section 6.5.11).
Pregnancy can increase risks of HIV progression, 
complications and perinatal transmission
The safe use of DTG/ABC/3TC in human pregnancy has 
not been established.  DTG, ABC and 3TC have been 
shown to cross the placenta in reproductive toxicity studies 
in animals.  3TC and ABC, but not DTG, have been 
associated with findings in animal reproductive studies. 
Treatment of the underlying HIV disease.  Additionally 
women taking ART during pregnancy can reduce risk of 
transmission to infant (i.e., early control of viral replication 
important in prevention)
 
 
 
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Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
See the most current DTG IB and approved ABC/3TC 
product label for additional information [GSK Document 
Number RM2007/00683/11, GSK Document Number
2017N352880_00, GSK Document Number
2017N352880_01].
There has been no association between ABC or 3TC 
overall birth defects observed in the Antiretroviral 
Pregnancy Registry (APR), although there are some 
limitations to these data (http://apregistry.com/index.htm).
Rationale described in Section 1.1 and reference is made 
to the HIV WHO treatment guidelines: Antiretroviral drugs 
are used to treat pregnant women and prevent HIV 
infection in infants (See Section 10 References)
It is highly recommended that the subject also establish 
appropriate Obstetric care or nurse/mid-wife care per local 
standard of care (SoC) routine management.
Mitochondrial toxicity in children with in utero/post-natal 
exposure to nucleoside analogues
There have been reports of mitochondrial dysfunction in 
HIV-negative infants exposed in utero and/or post-natally 
to nucleoside analogues; however, these have generally 
involved thymidine analogues.
In vitro studies assessing mtDNA depletion provided the 
following rank order for NRTI effects: ddC >ddI >d4T >ZDV 
>3TC =ABC =TDF [BIRKUS, 2002].  In addition, there is a 
large body of historic evidence from switch for toxicity 
populations, which demonstrates the advantages of 
switching patients on certain NRTIs, PIs or NNRTIs to ABC 
-3TC.
Any child exposed in utero to nucleoside and nucleotide 
analogues, even HIV-negative children, should have 
clinical and laboratory follow-up and should be fully 
investigated for possible mitochondrial dysfunction in case 
of relevant signs or symptoms. 
The benefits from preventing vertical transmission of HIV 
infection from mother to child are considered to outweigh 
the risks of infants developing mitochondrial dysfunction.
Hypersensitivity (including abacavir hypersensitivity 
reaction [ABC HSR]) and rash
A well characterised, idiosyncratic, drug-related HSR is the 
most important risk associated with ABC (See Section 
6.5.4.6).  Exclusion of individuals found to carry the Human 
Subjects positive for HLA-B*5701 were excluded from 
participating.in the ING117172 study  Additionally, subjects 
with history of allergy/sensitivity to any of the study drugs 
 
 
 
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Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
Leukocyte Antigen (HLA)-B*5701 allele from ABC therapy 
reduces the risk of HSR.  Rash, icluding Stevens-Johnson 
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and 
Erythema Multiforme have been reported in patients taking 
ABC (See Section 6.5.4.6 and Section 6.5.4.7).
HSR has been observed uncommonly with DTG.  Rash 
was commonly reported in DTG Phase IIb/III clinical trials; 
episodes were generally mild to moderate in intensity; no 
episodes of severe rash, such as SJS, TEN and Erythema 
Multiforme were reported.  Data on HSR for DTG and 
DTG+ABC/3TC FDC suggest that there will not be 
additional risk from HSR in HLA-B*5701 negative subjects 
receiving the DTG/ABC/3TC FDC.
are excluded (Section 4.3).
Specific/detailed toxicity management guidance is 
provided for suspected HSR with DTG (Section 6.5.4.6) or 
ABC (Section 6.5.4.6), and skin reactions without systemic 
involvement (Section 6.5.4.7).
The subject informed consent form includes information on 
this risk and the actions subjects should take in the event 
of a HSR or associated signs and symptoms.  Subjects are 
be reminded to read the ABC HSR Warning Card 
accompanying their study medication and of the 
importance of keeping this card with them at all times.
Drug induced liver injury (DILI) and other clinically 
significant liver chemistry elevations
Non-clinical data suggested a possible, albeit low, risk for 
hepatobiliary toxicity with DTG.    Drug-related hepatitis is 
considered an uncommon risk for ART containing DTG 
regardless of dose or treatment population.  For subjects 
with hepatitis B (HBV) virus and/or hepatitis C (HCV) virus 
co-infection, improvements in immunosuppression as a 
result of HIV virologic and immunologic responses to DTG-
containing ART, along with inadequate therapy for HBV co-
infected subjects, likely contributed to significant elevations 
in liver chemistries. 
Current treatment guidelines [DHHS, 2013; EACS, 2012] 
do not recommend monotheraphy with 3TC for patients 
Subjects meeting the following criteria during the screening 
period are excluded from participating (Section 4.3).
Alanine aminotransferase (ALT) 5 times the upper limit of 
normal (ULN) or ALT 3xULN and bilirubin 1.5xULN (with 
>35% direct bilirubin).
Subjects positive for HBV at screening (hepatitis B virus 
surface antigen positive [+HBsAg]), or with an anticipated 
need for HCV therapy during the study.
Specific/detailed liver stopping criteria and toxicity 
management guidance is provided for suspected DILI or 
other clinically significant liver chemistry elevations 
 
 
 
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Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
with HBV infection, which is what subjects randomised to 
DTG/ABC/3TC would effectively be receiving.  Additionally, 
discontinuation of 3TC in HBV coinfected subjects can 
result in severe exacerbations of HBV. 
(Section 6.5.4).
Theoretical serious drug interaction with dofetilide or 
pilsicainide
Co-administration of DTG may increase dofetilide or 
pilsicainide plasma concentration via inhibition of OCT2 
transporter, resulting in potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide
is prohibited in the study (Section 5.6.2).
Gastrointestinal (GI) intolerance
Non- clinical studies showed upper and lower GI toxicity, 
including vomiting, diarrhea and gastric erosions observed 
in monkey toxicology studies (thought to be related to local 
and not systemic toxicity).
Mild to moderate GI intolerance (mainly diarrhoea and 
nausea) is associated with DTG treatment in a small 
proportion of subjects; however there were no indications 
of an increased risk for peptic ulcers or serious erosions.
Routine monitoring of GI symptoms will be performed.
Renal function
Mild elevations of creatinine have been observed with DTG 
which are related to a likely benign effect on creatinine 
secretion with blockade of OCT-2 receptor.  DTG has been 
shown to have no significant effect on glomerular filtration 
rate (GFR) or effective renal plasma flow. Measurement of 
albumin/creatinine ratio confirmed there was no difference 
in the effect of DTG on albumin excretion compared with 
EFV or RAL. 3TC is eliminated by renal excretion and 
exposure increases in patients with renal dysfunction.
Due to requirements for dose reduction of 3TC in patients 
with renal dysfunction, subjects with a creatinine clearance 
(CrCL) <50 mL/min are excluded from participating 
(Section 4.3).
Specific/detailed toxicity management guidance is 
provided for subjects who develop a decline in renal 
function (Section 6.5.4.3) and/or proteinuria (Section 
6.5.4.4). 
Psychiatric disorders
Psychiatric disorders including suicide ideation and 
behaviours are common in HIV infected patients. The 
psychiatric profile for DTG (incl. suicidality, depression, 
Subjects who in the investigator’s judgment, poses a 
significant suicidality risk, will be excluded from 
participating in the study (Section 4.3).
 
 
 
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Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
bipolar and hypomania, anxiety and abnormal dreams) 
was similar or favourable compared with other ART. 
The reporting rate for insomnia was statistically higher for 
blinded DTG+ABC/3TC compared to EFV/TDF/FTC in 
ING114467;however, this was not duplicated in any other 
Phase IIb/III study conducted with DTG.  See the IB for 
additional information.
Because of the elevated risk in the HIV- infected 
population, treatment emergent assessment of suicidality 
will be monitored during this study. Investigators are 
advised to consider mental health consultation or referral 
for subjects who experience signs of suicidal ideation or 
behaviour.  Detailed information on subjects developing 
these events will be collected on designated CRF pages 
(Section 6.5.10).
Creatine phosphokinase (CPK) elevations
Asymptomatic CPK elevations mainly in association with 
exercise have been reported with DTG therapy.
Specific detailed toxicity management guidance is 
provided for subjects who develop Grade 3 to 4 CPK 
elevations (Section 6.5.4.2).
Increased occurrence of Immune reconstitution 
inflammatory syndrome (IRIS)
With rapid HIV-1 RNA decline and early recovery of CD4+ 
cell counts there could ,theoretically, be an increase in
cases of IRIS.
The increased risk for HBV and HCV IRIS with DTG-
containing ART is addressed above; there was a low rate 
of other medical conditions frequently implicated in IRIS 
cases.  See the IB for additional information.
Subjects positive for HBsAb at screening or with active 
HCV  illness (anticipated to require therapy)  are excluded 
from participating. Subects will have routine laboratory 
monitoring.
1.
Careful monitoring of events will be conducted using SAE reports and alerts for Grade 3/4 laboratory toxicities (per Division of Aquired Immunodeficiency Syndrome (DAIDS)
toxicity gratings for HIV infected patients). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of investigational product (IP), and will be 
followed to resolution as per Sponsor’s standard Medical Monitoring practices 
2.
Clinical Safety Data will be routinely reviewed in GlaxoSmithKline (GSK) Safety Review Team (SRT) meetings. This will include in-stream review of data from this clinical trial 
on a regular basis; review of aggregate data on a protocol and program basis when available; and review of competitor data from the literature
 
 
 
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1.3.2.
Benefit Assessment
Pregnancy increases the risk of HIV progression whilst HIV increases the risk for 
maternal complications from pregnancy and poses the risk of perinatal HIV transmission
to the unborn fetus. While antiretroviral treatments have significantly improved survival 
rates and decreased maternal-fetal transmission, earlier HIV diagnosis still remains 
problematic, especially in limited resource settings.  Recent recommendation updates to 
treatment guidelines have included objectives to increase HIV screening of patients, 
including pregnant women (noting the importance of adopting HIV screening to be a part 
of prenatal care).
The 2012 WHO guidelines recommend starting all HIV-infected pregnant women on 
ART therapy based on CD4+ cell counts and/or WHO Stage 3 or 4 disease for life.  The 
reduction of maternal-fetal transmission is currently being shown with the 2010 UNAIDS
vision ‘zero new HIV infections’, and the UN General Assembly of the United Nations 
adoption of the 2011 Political Declaration on HIV and AIDS target to reduce the number 
of children infected with HIV by 2015, progress is being made toward reaching its goal 
of eliminating vertical transmission by 90% [United Nations General Assembly, 65th
Session, Agenda Item 10, 28 March 2011]. The percentage of children newly infected 
today is 24% lower than in 2009 [UNAIDS, 2012] and it is expected with accelerated 
efforts the 90% reduction in the number of children acquiring HIV infection can be met 
by 2015.  Global progress in HIV treatment and prevention continues to see dramatic 
declines in new infections among children as more pregnant women receive effective 
antiretroviral treatment to prevent transmission (57% today, up from 48% in 2010).
Additionally, in an examination of data from 2543 HIV-infected pregnant women 
participating in the Women and Infants Transmission Study (WITS), review of maternal 
and adverse pregnancy outcomes found that ART use according to regimen potency or 
class of agent was independently associated with few adverse outcomes and with a 
decreased odds ratio for some obstetric outcomes.  Recognizing that new ART therapies 
must be continually reassessed, the study provides strong evidence that ART regimens 
used during pregnancy are not associated with major adverse maternal outcomes 
[Tuomala, 2005].
In conclusion, ART prevents HIV disease progression and mother-to-child transmission 
(MTCT) in pregnant women.
Novel effective and well tolerated drugs are needed for all sectors of the HIV population. 
DTG/ABC/3TC FDC is being developed as a treatment for ART- naive adult patients, 
and has distinct advantages over the most widely used therapies for treatment-naive 
patients in the following manner:
For treatment-naïve patients who initiate a regimen of 2 NRTIs plus a third antiretroviral 
drug, DTG/ABC/3TC offers high potency, favourable tolerability, high barrier to drug 
resistance, and once daily dosing.  DTG/ABC/3TC is the first drug to combine all these 
characteristics, with demonstrated statistical superiority over Atripla 
(efavirenz/emtricitabine/tenofovir disoproxil fumarate), which is the preferred fixed-dose 
 
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combination regimen for treatment-naïve patients, including continuation in pregnant 
women (DHHS guidelines, 2013; WHO, 2013).
A regimen comprised of DTG administered with ABC/3TC has been shown to be highly 
efficacious and well tolerated in treatment-naive subjects.  In the Phase III double-blind 
SINGLE study (ING114467), 833 therapy-naive adults were randomized to DTG 50 mg 
plus ABC/3TC once daily once daily or a guidelines-preferred single tablet regimen of 
EFV/TDF/FTC once daily.  At Week 48, the proportion with HIV-1 RNA <50 copies/mL 
in the DTG+ABC/3TC arm (88%) was superior to the EFV/TDF/FTC arm (81%), 
P=0.003.  Time to viral suppression (median 28 vs. 84 days; P<0.001) and increases in 
CD4 cell counts (+267.1 vs. +208.2 cells/mm3; P<0.001) also favored DTG+ABC/3TC. 
No subjects on DTG+ABC/3TC had detectable antiviral resistance; 1 TDF-associated and 
4 EFV-associated mutations were detected in EFV/TDF/FTC subjects with viral failure.  
In a by gender analysis, Week 48 responses in women (85%) were higher in recipients of 
DTG + ABC/3TC when compared to EFV/TDF/FTC (75%).
The proportion of subjects discontinuing for AEs was lower with DTG+ABC/3TC (2%) 
than EFV/TDF/FTC (10%); rash and neuropsychiatric events (including abnormal 
dreams, anxiety, dizziness, and somnolence) were significantly more common on 
EFV/TDF/FTC, whereas insomnia was reported more frequently on DTG+ABC/3TC.
The DTG/ABC/3TC FDC thus have the potential to provide a convenient, once daily 
single tablet regimen, without need for a PK booster or food/fluid restrictions, and with
limited safety implications resulting from theoretical or actual drug: drug interactions 
compared to other antiretroviral agents (including EFV and those requiring a PK
booster).
1.3.3.
Overall Benefit:Risk Conclusion
Based on animal data, DTG is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans.  Both ABC and 3TC have been 
studied during pregnancy (See Section 1.1), pregnancy outcomes from these studies are 
monitored through the ARV Pregnancy Registry (APR).  In summary, taking into account 
the measures taken to minimize risk to subjects participating in this study, the potential 
risks identified in association with DTG/ABC/3TC FDC are justified by the anticipated 
benefits that may be afforded to pregnant women with HIV infection (decreased disease 
progression due to maintenance of suppression) and their unborn children (reduction in 
HIV transmission).
 
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2.
OBJECTIVE(S)
Objective(s)
Primary
Mother:

To describe the total plasma DTG PK parameters with the DTG/ABC/3TC FDC 
during Weeks 18-26, Weeks 30 – 36 of the third trimester of the pregnancy and 
8-12 weeks postpartum;

To further characterize the safety and tolerability of DTG/ABC/3TC FDC when 
used during pregnancy.
Secondary
Mother:

To assess the antiviral activity of the DTG/ABC/3TC FDC when administered 
during pregnancy;

To assess the immunologic activity of DTG/ABC/3TC FDC;

To assess the incidence of treatment-emergent genotypic and phenotypic 
resistance in subjects who meet confirmed virologic withdrawal criteria;

To evaluate the unbound DTG concentrations in plasma during Weeks 18-26 
and Weeks 30-36 of the pregnancy and 8-12 weeks postpartum;

To compare the DTG concentrations in plasma from cord blood with those in 
maternal plasma at the time of delivery;

To characterize birth outcomes;

To characterize pregnancy outcomes.
Infant:

To characterize infant outcomes at birth;
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
ING200336 is a single arm open-label interventional study for women who become 
pregnant while participating in ING117172.  It is interventional in design with the goal to 
evaluate DTG PK and safety in pregnancy during treatment with 
DTG 50 mg/ABC 600 mg/3TC 300 mg FDC once daily.  Eligible subjects are HIV-1 
infected women participating in study ING117172 who become pregnant and are
required to be withdrawn.  The ING200336 study is being offered only to those women 
 
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who were on the DTG/ABC/3TC FDC treatment arm. Note: While the WHO’s treatment 
guidance recommends that women who are on ART at the time they become pregnant 
continue such therapy if they are responding to that ARV treatment, it’s important that 
the investigator refer to local country guidelines with regards to recommendations on 
selection (or switching) of ARVs when the pregnancy is identified; treatment should 
minimally reflect that of local standard of care. The number of women that will be 
enrolled into this protocol cannot be established a priori, as unintended pregnancies 
cannot be determined in advance (See Section 4.1 for further details).
Subjects will continue to receive DTG/ABC/3TC FDC once daily after completion of the 
primary and secondary assessments.  The primary outcome analyses will take place after 
the last subject enrolled gives birth.  As this study will remain open until ING117172 is 
closed, analyses of data may be conducted in this open label study prior to this timepoint 
as required by the Sponsor (e.g., when an adequate number of subjects with PK data are 
available, for regulatory filings).
Given the requirement that subjects who become pregnant on ING117172 be withdrawn, 
sites who are interested in enrolling pregnant women from ING117172 onto ING200336 
should seek IRB/EC approval for ING200336 in advance of identifying such subjects, in 
order that DTG/ABC/3TC FDC treatment may be continued without interruption.  
Screening Period
Subjects will participate in a short screening period which includes an assessment for 
potential pregnancy complications (e.g., hypertension, diabetes, and underlying 
infections) and a thorough obstetric history (including gravidity, previous complications 
and/or risks, etc.) at Screening or up through Day 1.  Any subject who became pregnant 
but meets virologic withdrawal criteria on ING117172 will not be eligible to participate 
in this study.  The subject must also establish appropriate obstetric care per local SoC.  It 
will be necessary for the subject to be willing to share medical information, as necessary, 
to the HIV investigator for both herself and her infant to facilitate collection of delivery,
birth and infant outcomes by the investigator.  Once the subject learns she is pregnant, 
there are two scenarios for enrollment:
1.If the subject wants to enter the pregnancy study, and has been seen within 28 days 
for a regularly scheduled ING117172 visit, the site would schedule a Withdrawal 
visit, which still must remain within the 28 day window of the visit when pregnancy 
was documented. The previous visit results will be used as the “screening visit” to 
qualify the subject for enrollment and the Withdrawal visit is used for the Baseline 
(Day 1) visit (with verification that the subject still meets all entry criteria) for 
ING200336. A urine pregnancy test, as well as a urine dipstick to monitor protein, 
must be performed on Day 1.
2.If the subject is determined to be pregnant outside of a study visit and wants to enter 
ING200336 but has not been seen within the 28 day window, the site is to perform an 
unscheduled ING117172 visit to collect adverse events/serious adverse events 
(AEs/SAEs), plasma HIV-1 RNA and laboratory results, including a serum pregnancy 
test, as well as a urine dipstick to monitor protein, in order to document the subject’s 
current medical status. If the pregnancy is confirmed, the site would then schedule 
 
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the Withdrawal visit within 28 days of the unscheduled visit. The unscheduled visit 
results will be used to qualify the subject for enrollment (i.e., is the screening visit) 
and the Withdrawal visit is used for the Baseline (Day 1) visit (with verification that 
the subject still meets all entry criteria) for ING200336.
3.In both scenarios the Withdrawal visit for ING117172 will also be Day 1 for 
ING200336 to ensure no disruption in provision of study treatment.   In the event the 
subject miscarries or electively terminates the pregnancy prior to Day 1 (Baseline) of 
ING200336, she must still be discontinued from ING117172 and followed per the 
requirements of ING117172, and may not continue enrollment into study 
ING200336.
In both of these scenarios new demographic, Baseline characteristics, concomitant 
medications, medical history and HIV associated conditions will be collected on Day 1, 
as well as a thorough maternal history which includes an assessment for pregnancy risks 
(e.g., live births, still births, elective terminations, previous miscarriage, pre-term labor 
(before Week 37) preterm birth, preeclampsia, low amniotic fluid (oligohydramnios), 
gestational diabetes, ectopic pregnancy, placenta previa or abruption, drug induced 
hepatitis, poor weight gain, anemia, poor nutrition, and an incompetent cervix.) and any
previous pregnancy history (including gravidity).  If the subject provided consent and a 
PGx sample was collected in study ING117172, there will be no requirement to take 
another PGx sample (the original sample will linked to the ING117172 subject treatment 
numbers in both studies. If the subject consented, but no PGx sample was drawn while 
participating in ING117172, a new consent will be provided for ING200336 and a PGx 
sample will be drawn in this study (if the subject consents to participate).  
If there is an ongoing, unresolved AE and/or SAE at the time of the Withdrawal visit in 
ING117172 the AE/SAE will be followed for event outcome, which will be recorded in 
the eCRF, as part of ING117172 (i.e., followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up).
The AE/SAE will be transcribed as medical history in ING200336.  Any exacerbation or 
worsening of the AEs and/or SAEs from ING117172 during subject participation in 
ING200336, will be recorded as a new entry in the AE or SAE eCRF pages for 
ING200336 with a start date reflecting the clinical worsening, and will not be recorded 
for ING117172.  All SAEs (including those assessed as related to study participation 
[e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy] or related to a GSK or ViiV concomitant medication) and any non serious AEs 
of special interest (defined in the study procedure manual) occurring from the withdrawal 
visit in ING117172 through to administration of IP at Day 1 of ING200336, will be 
recorded in the eCRF for ING117172.
All AEs and SAEs occurring from Day 1 in ING200336 through to the follow up contact 
will be collected and recorded in the eCRF for ING200336, regardless of relationship to 
study participation or any other causality. 
Pregnancy Period and Delivery
Please note: The HIV provider is responsible for HIV care and will collaborate and share 
information with the subject’s obstetric care provider, discuss the subject’s participation 
 
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in this study, the necessary procedures at delivery, to share HIV information, and to 
collect birth and infant outcomes from the subject’s obstetric care provider and/or the 
pediatric health provider for the infant.
Mothers:
After all Withdrawal procedures for ING117172 have been completed and results are 
available and documented, subjects who sign informed consent and fulfil eligibility 
requirements may be enrolled in ING200336.  Subjects will begin Day 1 and continue to 
receive DTG/ABC/3TC FDC treatment in an open-label fashion of ING200336.
All subjects will have serial PK sampling while on study, one during Weeks 18 - 26, one 
during Wks 30-36 and one at 8-12 weeks postpartum. Serial plasma samples will be 
collected during each PK visit for the determination of DTG (total and unbound) 
concentrations. Samples will be collected prior to dosing and at 1, 2, 3, 4, 6, 8, 12, and 24 
hours post dosing.  Subjects should be reminded prior to their PK visit that they will need 
to come to the site two days in a row in order to complete the 24 hour PK sampling and 
that no doses can be missed during the 3 days prior to the scheduled PK visit.  
Instructions regarding the PK visit can be found in the Study Procedures Manual (SPM).  
A plasma HIV-1 RNA and CD4+ cell count sample will be drawn within 24 hours of 
delivery and on the day of the post-partum PK evaluation.  At delivery, if feasible, a cord 
blood and a time-match maternal blood sample will be collected to evaluate 
DTG/ABC/3TC FDC concentrations in plasma.
HIV-1 RNA, CD4+ cell counts, and laboratory testing will be conducted at each visit (see 
Time and Events Table in Section 6.1).
Pregnancy related complications and diagnoses will be captured as AEs and SAEs as 
outlined in Section 6.5.5.
Following Day 1, no changes or intensification of the ART regimen will be permitted, 
except the additional use of ZDV as required at delivery (e.g., per local guidelines).  
Note: Nevirapine (NVP) may not be used in lieu of ZDV for peripartum prophylaxis.  
Nevirapine could significantly decrease the levels of DTG due to enzyme induction and 
result in PK variability (See Section 5.6.2).
Medications other than DTG/ABC/3TC FDC will not be provided by the study.  It is 
recommended the subject begin prenatal multivitamins and folate supplementation early 
in the pregnancy as per local guidelines (See Section 5.6.1 and Section 5.6.2, Permitted 
and Prohibited Concomitant Meds); appropriate prophylaxis for opportunistic infections, 
as well as vaccinations, should be coordinated and/or administered as guided by local 
SoC.  It will be necessary for the subject to be willing to share medical information for 
both herself and her infant from her obstetric care provider to facilitate collection of 
delivery, birth and infant outcomes by the investigator.
Please note: In the event of a spontaneous loss of pregnancy during the study, pregnancy 
outcomes are collected in the eCRF “Delivery Visit”.  After the loss is confirmed the 
subject may continue to receive DTG/ABC/3TC FDC unless they meet the criteria for
confirmed virologic withdrawal.  They may continue to receive DTG/ABC/3TC FDC 
 
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after completion of the primary and secondary assessments (in which case they will be 
followed q12 weeks) until study medications are locally approved and commercially 
available or until they no longer receive benefit.  In this case the subject must agree to use 
contraception to avoid a ‘new’ pregnancy (See Section 6.5.4.8).
Infants: At delivery, it will be necessary for the HIV investigator to contact the subject’s 
obstetric care and pediatric health provider for the infant to obtain information about the 
newborn examination.  Data collection of infant outcomes includes gestational age, birth 
weight, length and head circumference at the 8-12 week post-partum visit measurements, 
Apgar scores (at 1 and 5 minutes), whether the infant is small, appropriate or large for 
gestational age [SGA, AGA, or LGA], intrauterine growth restriction [IUGR], birth 
defects and the presence or absence of major congenital abnormalities to be recorded in 
the CRF.  Details of the CBC with differential assessment on or after the first day of life 
and any chemistry assessment on or after 1 day of life, if standard of care, should also be 
collected and recorded in the CRF by the HIV provider (see Section 6.5).  HIV status of 
the infant, if known, should also be recorded in the CRF.
Newborn ARV prophylaxis treatment as per local country guidelines should still be 
followed by the pediatric health provider.  An international APR has been established to 
track pregnancy-related AEs and fetal outcomes.  Pregnancy outcomes and status of the 
mother and fetus/child will be reported by the ING200336 investigator to GSK who will 
report information collected to the APR.
Study Completion
Subjects are considered to have completed the study after completing the postpartum 
evaluation approximately 8-12 weeks post delivery.
Continuation Phase
Women may continue to receive DTG/ABC/3TC FDC after completion of the primary 
and secondary assessments until study medications are locally approved and 
commercially available or until they no longer receive benefit, the subject meets a 
protocol-defined reason for discontinuation or development of DTG/ABC/3TC is 
terminated.  During this time, subjects will be monitored every 12 weeks to ensure they 
continue to derive clinical benefit from DTG/ABC/3TC FDC. Note: the duration of the 
study completion will vary from country to country and is dependent on the recruitment 
time for the study and the time taken to achieve local approval and availability for 
marketing.
Should the subject become pregnant during the Continuation phase, she must be 
withdrawn from the study and transitioned to the commercial supply of components DTG 
and ABC/3TC or DTG/ABC/3TC FDC if available.
Follow-up
Subjects with ongoing AEs or laboratory abnormalities considered to be AEs will attend 
a follow-up (FU) visit approximately four weeks after their last visit. Assessments at the 
 
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FU visit should reflect any ongoing complaints (e.g., blood draws to follow any clinically 
significant laboratory abnormality). The FU visit is not required for successful 
completion of the study.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 6.1), are essential and required for study 
conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
One of the primary study objectives is to characterize the PK of DTG (total and unbound) 
in pregnant HIV-infected women using DTG/ABC/3TC FDC.  A longitudinal design is 
used in this study with PK evaluations based on intensive PK sampling to be performed 
serially during pregnancy as well as postpartum in each of subjects to be enrolled. As the 
changes in PK during pregnancy are most prominent in the third trimester, the study will 
evaluate the steady-state PK of DTG during the 2nd and 3rd trimester compared to that 
observed at 8-12 weeks postpartum. The design allows each woman to serve as her own 
control to evaluate the significance of change in DTG PK during pregnancy comparison 
versus the non-pregnant state (postpartum).
As DTG is a drug with low apparent clearance (CL/F) and high protein binding; its PK, 
especially unbound concentration in plasma is sensitive to plasma protein level. As a 
reduction in plasma protein is often observed during pregnancy, the impact of pregnancy 
on unbound DTG concentration is also evaluated in this study.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
This is an open-label study.  The number of women that will be enrolled into this 
protocol cannot be established a priori, as unintended pregnancies cannot be determined 
in advance. The maximum number of women would include all of those women 
randomized to DTG/ABC/3TC FDC (n~237), though unintended pregnancies in all of 
these women would not be anticipated.  Based on pregnancy rates from 2 recent DTG 
studies, the anticipated rate of unintended pregnancy over 48 weeks would be 
approximately ~5% (n~12).  Should 12 subjects enroll, this would likely be sufficient to 
obtain at least 8 subjects providing evaluable DTG PK parameters in the third trimester 
and postpartum.
 
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4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the IP or other study treatment that may impact subject 
eligibility is provided in the most current version of the DTG IB, IB supplements, product 
labels, and/or local prescribing information.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in the study must meet all of the following criteria unless 
stated otherwise.  In addition to these criteria, Investigators must exercise clinical 
discretion regarding selection of appropriate study subjects, taking into 
consideration any local treatment practices or guidelines and good clinical practice 
(GCP).
Eligible subjects must 

be able to understand and comply with protocol requirements, instructions, and 
restrictions;

be likely to complete the study as planned;

be considered an appropriate candidate for participation in an investigative 
clinical trial with oral medication (e.g. no active substance abuse, acute major 
organ, disease, or planned long term work assignments out of the country, etc.).
Subjects eligible for enrolment in the study must meet all of the following criteria unless 
stated otherwise: 
1. HIV infected females participating in ING117172 on the DTG/ABC/3TC 
treatment arm who became pregnant with a singleton and have not met any safety 
or confirmed virologic withdrawal criteria;
2. Signed and dated written informed consent is obtained from the subject or the 
subject’s legal representative prior to screening;
3. Willingness and intent to continue pregnancy;
4. Willingness to continue to receive DTG/ABC/3TC FDC;
5. Willingness to enter the Antiretroviral Pregnancy Registry;
6. Willingness to share medical information about herself and her infant for 
collection of delivery and infant outcomes as it relates to this study;
7. Subjects enrolled in France: a subject will be eligible for inclusion in this study 
only if either affiliated to or a beneficiary of a social security category.
 
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4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary medical conditions
1. History of allergy/sensitivity to DTG, ABC and/or 3TC;
2. History of severe preeclampsia, eclampsia, or HELLP;
3. Any evidence of an active Center for Disease Control and Prevention (CDC) 
Category C disease [CDC, 1993], except cutaneous Kaposi’s sarcoma not requiring 
systemic therapy or historic or current CD4+ cell levels <200cells/mm3;
4. Subjects with any degree of hepatic impairment;
5. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, 
or resected, non-invasive cutaneous squamous cell carcinoma, or cervical 
intraepithelial neoplasia; other localized malignancies require agreement between 
the investigator and the Study medical monitor for inclusion of the subject;
6. Subjects who in the investigator’s judgment, poses a significant suicidality risk. 
Recent history of suicidal behavior and/or suicidal ideation may be considered as 
evidence of serious suicide risk;
7. Subjects with evidence of ongoing hepatitis B infection at screening, or anticipated 
need for HCV therapy during the study.
Exclusionary Treatments prior to Screening or Day 1
8. Treatment with any of the following agents within 28 days of Baseline: radiation 
therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter 
immune responses.
9. Subjects enrolled in France: the subject has participated in any study, other than 
ING117172, using an investigational drug during the previous 60 days or 5 half-
lives, or twice the duration of the biological effect of the experimental drug or 
vaccine, whichever is longer, prior to screening for the study or the subject will 
participate simultaneously in another clinical study.
Exclusionary Laboratory Values or Clinical Assessments at Screening
10. Any verified Grade 4 laboratory abnormality with the exception of Grade 4 lipid 
abnormalities (total cholesterol, triglycerides, high density lipoprotein [HDL]
cholesterol, low density lipoprotein [LDL] cholesterol). A single repeat test is 
allowed during the Screening period to verify a result.
 
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11. Any acute laboratory abnormality observed in ING117172 or in any Screening 
laboratory assessments for ING200336, which, in the opinion of the Investigator, 
would preclude the subject’s participation in the study;
12. Hyperbilirubinemia of unknown etiology;
13. Confirmed (with no more than 1 repeat evaluation) Grade 2 urine  protein
(dipstick), serum creatinine, total bilirubin, ALT or AST at the time of the screening 
lab; 
14. Subject has CrCL of <50 mL/min via Cockroft-Gault method at the time of the 
screening visit.
Notwithstanding these minimum inclusion and exclusion criteria, Investigators must 
also follow country specific guidelines where they exist when making decisions about
subjects who are eligible for study participation.
4.4.
Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the Investigator 
must refer to the DTG IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions,
contraindications, AEs, drug interactions, and other significant data pertaining to the IPs.
4.5.
Withdrawal Criteria
Subjects permanently discontinuing study treatments prior to the 8-12 week post-partum 
visit are considered to be withdrawn from the study treatment and also from the study.  
Similarly, subjects who enter the Continuation Phase but permanently discontinue 
participation in the Continuation Phase prior to local commercially available 
DTG/ABC/3TC FDC, are considered to be withdrawn from the study treatments and also 
from the study.
A subject may voluntarily discontinue participation in this study at any time. The 
Investigator may also, at their discretion, discontinue the subject from participating in this 
study at any time.
Subjects may be prematurely discontinued from the study for any of the following 
reasons: 

Subject or Investigator noncompliance;

At the request of the subject, Investigator, or Sponsor;

The subject requires concurrent prohibited medications during the course of the 
study.  The subject may remain in the study if in the opinion of the Investigator 
and the medical monitor, such medication will not interfere with the conduct or 
interpretation of the study or compromise the safety of the subject.
 
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Subjects must be prematurely discontinued from the study for any of the following 
reasons:

The subject refuses further treatment and/or follow-up evaluations and decides 
to discontinue participation or is lost to follow-up;

It is determined at any time during the study that the subject is pregnant with 
more than one baby; 

Continued participation in the study would be detrimental to the subject’s or 
baby’s health or well-being;

Subject requires substitution or dose adjustment of DTG, ABC or 3TC;

Liver toxicity where stopping criteria specified in Section 6.5.4 are met and no 
compelling alternate cause is identified;

Virologic withdrawal criterion as specified in Section 4.5.1 are met;

Grade 4 clinical AE considered causally related to IP;

Renal toxicity where specified in Section 6.5.4.3 are met and no compelling 
alternate cause is identified;

Clinically suspected ABC HSR as described in the Section 6.5.4.6.

Rash toxicity as specified in Section 6.5.4.7 is met and no compelling alternate 
cause is identified;

A new pregnancy during the Continuation Phase as described in Section 3.1. As 
a reminder, subjects who are post-delivery and desire to be pregnant, or who 
state they are not willing/no longer willing to comply with the approved 
pregnancy avoidance methods, should also be withdrawn from the study.
If a subject is prematurely or permanently withdrawn from the study, perform the 
procedures described in the Time and Events Table (Section 6.1) for the Withdrawal and 
Follow Up visits. All data from the Withdrawal visit will be recorded, as they comprise 
an essential evaluation that should be done prior to discharging any subject from the 
study.  Subjects with on-going clinical or clinically significant laboratory AEs at the time 
of Withdrawal should return for the Follow-up visit.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible.  The site 
should also counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study based on previous non-compliance.  In cases where the subject does not return for 
the rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (e.g., via telephone calls and/or  
sending a certified letter to the subject’s last known mailing address) so that they can 
appropriately be withdrawn from the study.  These contact attempts should be 
documented in the subject’s medical record.  Should the subject continue to be 
unreachable, then he/she will be considered to have withdrawn from the study with a 
 
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primary reason of “Lost to Follow-up”.  For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the electronic case 
report form (eCRF).
Subjects are not obligated to state the reason for withdrawal. However, the reasons for 
withdrawal, or failure to provide a reason, must be documented by the Investigator on the 
Completion/Withdrawal section of the eCRF. Every effort should be made by the 
Investigator to follow up subjects who withdraw from the study. In the event that a 
subject is prematurely discontinued from the study at any time due to an AE (see Section 
6.5.5), the procedures stated must be followed. Subjects who are withdrawn from the 
study will not be replaced.
Subjects may have a temporary interruption to their study treatment for management of 
toxicities (Section 6.5.2).
4.5.1.
Virologic Criteria for Subject Management and Viral Resistance
For the purpose of clinical management in this study, subjects with plasma HIV-1 RNA 
levels >400 c/mL at any time point must have HIV-1 levels reassessed using the 
algorithms below (Figure 1) which details protocol defined clinical management for 
subjects who have met a “suspected or confirmed virologic withdrawal criterion”. 
Investigators should not schedule reassessment blood draws in the presence of factors 
that could be associated with virologic blips, such as intercurrent infection, treatment 
interruption due to toxicity management or non-compliance, or vaccination. Subjects 
should have received full doses of DTG/ABC/3TC FDC for at least 2 weeks at the time 
of HIV-1 RNA reassessment for any HIV-1 RNA level >400 c/mL.
Virologic Criteria for Subject Management
Figure 1
Virologic Criteria for Subject Management
Any Visit
Current HIV-1 RNA 400 c/mL
During Study 
Participation
During the 
Continuation 
Phase
If previous HIV-1 RNA was < 400c/mL, 
reassess plasma HIV-1 RNA at the next 
scheduled visit
Subject has met “Suspected Virologic 
Withdrawal Criterion”
If previous HIV-1 RNA was 400c/mL, 
perform an unscheduled visit in approximately 
4-6 weeks to reassess plasma HIV-1 RNA 
Subject has met “Confirmed Virologic 
Withdrawal Criterion”
If HIV-1 RNA level remains ≥400 c/mL, a plasma for storage sample from the 
“suspected virologic withdrawal criterion” visit will be used for HIV-1 
 
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genotype/phenotype testing.  Subjects may continue to receive IP at the discretion of the 
Investigator until results of resistance testing are available at which time the subject must 
be discontinued from the study.  If a subject is prematurely discontinued from the study, 
the Investigator must make every effort to perform the evaluations outlined in the Time 
and Events Table.  These data will be recorded as they comprise essential evaluations 
needed to be done before discharging any subject from the study.
Note: Plasma samples with <400 c/mL of HIV-1 RNA will not be analyzed, as the 
protease/reverse transcriptase/integrase assays used in this study are not validated for 
plasma HIV-1 RNA levels <400 c/mL
4.6.
Screening Failures
A subject is considered a screen failure if after providing informed consent, the subject’s 
circumstances or conditions change or the outcome of a test or assessment becomes 
available which results in the subject’s failure to meet one or more of the entry criteria, or 
results in the investigator deciding that the subject is no longer an appropriate study 
candidate.
A single repeat test (re-test) per analyte or assessment is allowed during the screening 
period to determine eligibility.
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
This study has an open-label design.  The dolutegravir 50 mg /abacavir 600 mg 
/lamivudine 300 mg FDC tablet is defined as the IP throughout this study and will be 
provided by GSK.   All other ART (i.e., ARVs given to the subject during delivery as per 
SOC) is not considered to be IP and is not provided by GSK.  Note: Nevirapine (NVP) 
may not be used in lieu of ZDV during delivery.  NVP could significantly decrease the 
levels of DTG due to enzyme induction and result in PK variability (See Section 
5.6.2).The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the IP will be limited to the 
 
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investigator and authorised site staff.  Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Note:  Newborn ARV prophylaxis treatment as per SoC should be recommended to the 
obstetric and/or pediatric care provider, however, is not considered to be IP and is not 
provided by GSK.
5.1.1.
Tablet Formulation of DTG/ABC/3TC
The dolutegravir 50 mg /abacavir 600 mg /lamivudine 300 mg FDC tablet is a purple, 
oval, biconvex tablets debossed with ‘572 Trı’ on one side and plain on the other side. 
The tablet contains 52.6 mg DTG sodium which is equivalent to 50 mg DTG free acid, 
702 mg ABC sulphate which is equivalent to 600 mg ABC and 300 mg 3TC. The tablets 
are packaged into high density polyethylene (HDPE) bottles with child-resistant closures 
that include induction seals. The bottles contain a desiccant.  Tablets must be stored in 
the original package with the bottle tightly closed. Desiccants must be kept in the bottle 
to protect from moisture.
5.2.
Treatment Assignment
Subjects will initiate therapy with DTG/ABC/3TC FDC following confirmation of 
fulfilment of study entry criteria.  A unique treatment number will be assigned for each 
subject participating in the study. Subjects who are enrolled into the trial and 
subsequently withdrawn may not be re-screened.
5.2.1.
Dosage and Administration
This is an open-label study.  All subjects will be administered DTG 50 mg/ABC 
600 mg/3TC 300 mg FDC tablet administered once daily, with or without food.
5.3.
Blinding
NA, this is an open-label study.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of IP
dispensed and/or administered to study subjects, the amount returned by study subjects, 
and the amount received from and returned to GSK, when applicable.  Product 
accountability records must be maintained throughout the course of the study.
5.5.
Treatment Compliance
Treatment compliance will be evaluated using pill counts of unused IP. This assessment 
will be conducted each time the subject receives a new (refill) supply of study medication
 
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through the Withdrawal visit or study completion.  These data will be recorded in the 
subject’s CRF, but will not be summarized for analysis purposes.
5.6.
Concomitant Medications and Non-Drug Therapies
Subjects should be advised to notify their Investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
for interactions between such treatments and the study medications. All concomitant 
medications taken during the study will be recorded in the CRF. The minimum 
requirement is that the drug name and the dates of administration are to be recorded.
5.6.1.
Permitted Medications and Non-Drug Therapies
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 5.6.2) or those routinely used as local standard of care (e.g., IV Zidovudine 
during delivery). Chemoprophylaxis for HIV-associated conditions is encouraged, if 
appropriate, at the discretion of the subject and their physician. All concomitant 
medications, blood products, and vaccines taken during the study will be recorded in the 
CRF with dates of administration.
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn. This approach will 
minimize the risk of non-specific increases in the level of HIV-1 plasma RNA at the next 
scheduled assessment.
DTG/ABC/3TC FDC should be administered 2 hours before or 6 hours after taking 
antacid products or sucralfate containing divalent cations (e.g. aluminium and 
magnesium). Proton pump inhibitors and H2-antagonists may be used in place of antacids 
with no scheduling restrictions. Concurrent administration with multivitamins is 
acceptable.
DTG/ABC/3TC FDC can be co-administered with calcium or iron supplements if taken 
with a meal. Under fasted conditions, DTG/ABC/3TC FDC should be given 2hr prior to 
OR 6 hr after calcium or iron supplements 
Metformin concentrations may be increased by DTG. Subjects should be monitored 
during therapy and a metformin dose adjustment may be required.
5.6.2.
Prohibited Medications and Non-Drug Therapies
HIV immunotherapeutic vaccines are not permitted at any time during the study (see 
Section 5.6.1 for guidance regarding non-HIV vaccines). Other experimental agents, 
antiretroviral drugs, cytotoxic chemotherapy, or radiation therapy may not be 
administered (see Exclusion Criteria, Section 4.3).  Systemically administered 
immunomodulators that directly affect immune responses are prohibited.  HCV therapy 
during study will not be permitted as approved HCV therapies at present include 
interferon.
 
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For a detailed list of prohibited medications, please consult the SPM.
5.6.2.1.
Prohibited medications for subjects taking DTG/ABC/3TC FDC
The following medications or their equivalents must not be administered concurrently 
with DTG/ABC/3TC FDC due to induction of UGT1A1 and/or CYP3A4 leading to the 
potential for reduction in dolutegravir levels.

barbiturates

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

rifampin/rifapentine

St. John’s wort

dofetilide 
Dofetilide is prohibited, as the DTG component of DTG/ABC/3TC FDC may inhibit 
their renal tubular secretion, resulting in increased dofetilide concentrations and potential 
for toxicity.
Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided; however, 
short treatment courses (for example, 30 days or less), replacement therapy (e.g., for 
Addison’s Disease) and topical, inhaled, or intranasal use of glucocorticosteroids will be 
allowed.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.
Acetaminophen is not to be used in patients with acute viral hepatitis.
5.7.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
Continuation Phase
Women will be given the opportunity to continue to receive DTG/ABC/3TC FDC after 
study completion (in which case they will be followed every 12 weeks) until one of the 
following occurs:

DTG/ABC/3TC FDC is locally approved and commercially available,
 
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
The subject no longer derives clinical benefit from DTG/ABC/3TC FDC,

The subject meets a protocol-defined reason for discontinuation or

The development of DTG/ABC/3TC FDC is discontinued.
See Section 3.1, Study Completion, for complete details.
Note:  Should the subject become pregnant during the Continuation phase, she must be 
withdrawn from the study and transitioned to the commercial supply of components DTG 
and ABC/3TC or DTG/ABC/3TC FDC if available.
5.8.
Treatment of Study Treatment Overdose
For this study any tablet intake exceeding the randomized daily number of tablets for IP 
will be considered an overdose.
For the purposes of this study, an overdose is not an AE (Refer to Section 6.5.5.1) unless 
it is accompanied by a clinical manifestation associated with the overdose. If the clinical 
manifestation presents with serious criteria, the event is a SAE, see Section 6.5.5.2.
If an overdose occurs and is associated with an AE requiring action, all study medications 
should be temporarily discontinued until the AE resolves.
The Investigator should use clinical judgment and also refer to the prescribing 
information for approved ARTs, as appropriate in treating overdose, as GSK is unable to 
recommend specific treatment.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
Table 4
Time and Events Table
Procedures
Screen*, **
Day 1
Ante partum
Delivery
Post-Partum
Continuation 
Phase
Withdrawal
Follow-up14
Monthly – every 4 
weeks
8-12 weeks 
post delivery
Every 12 weeks 
after Post 
Partum Visit
Written Informed Consent
X
Inclusion/Exclusion 
Criteria
X
X
Subject Demography
X
Medical History1
X
X
X
Concurrent medical 
conditions 
X
CDC HIV-1 classification
X
HIV-associated conditions 
X
X
X
X
X
X
Cardiovascular risk 
assessment2
*
Prior Art history
*
Gravidity Maternal history
X
Pregnancy risk 
assessment
X
X
X
Uteroplacental Outcomes 
at Delivery3
X
Infant Outcomes4
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
Limited Physical 
Examination5
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
 
 
 
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Procedures
Screen*, **
Day 1
Ante partum
Delivery
Post-Partum
Continuation 
Phase
Withdrawal
Follow-up14
Monthly – every 4 
weeks
8-12 weeks 
post delivery
Every 12 weeks 
after Post 
Partum Visit
Serious Adverse Events6
X
X
X
X5
X
X
X
X
Pharmacokinetic 
Sampling7
X6
X
X
Cord & maternal blood
sample8
X
Columbia Suicidality 
Severity Rating Scale9
X
X
X
X
X
Laboratory Assessments
Pregnancy Assessment15
X
X
X
Hematology


X
X
X
X
X
Clinical Chemistry


X
X
X
X
X
Urinalysis. 
Including 
dipstick 
for 
protein 
analysis

X
X
X
X
Quantitative plasma HIV-1 
RNA10


X
X
X
X
X
Lymphocyte subsets


X
X5
X
X
X
PGx Sampling11
X
Plasma for storage12
X
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X13
*Baseline information, including cardiovascular risk and prior ART therapy will be transferred from ING117172 to serve as baseline/screening data in this study.
**HIV-1 RNA, lymphocyte subset, and laboratory assessment (hematology, chemistry, and urinalysis including a dipstick) data collected at the ING117172 unscheduled or last 
visit within 28 days of learning of the pregnancy will be transferred to serve as screening data in this study.  The ING117172 Withdrawal visit will serve as the ING200336 Day 1.  
Gravidity:  Maternal history and pregnancy risk assessment may occur at either Screening or Day 1 visit.
 
 
 
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1.
Medical History includes any changes in smoking status
2.
Assessment for cardiovascular risk will include height, weight, blood pressure, smoking history, medical conditions and will have previously been collected in ING117172
3.
Assessment of pregnancy outcomes (e.g., spontaneous losses, induced abortions, still births, pre-term births, preeclampsia)
4.
Assessment of maternal and infant outcomes, including live births, gestational age, presence or absence of major congenital abnormalities, and infant height, weight, [including 
percentiles, SGA, AGA, LGA, IUGR], head circumference, and presence or absence of major congenital abnormalities) at birth (See Section 6.4.1). If known, HIV status of the 
infant will be collected at the 8-12 week post-partum visit.
5.
Limited physical examination to include blood pressure at Baseline (recorded in eCRF), heart rate and weight at each visit (recorded in eCRF at Baseline and on lab requisition at 
all visits) for determination of CrCL. Blood pressure to be measured after resting in a semi-supine position for at least 5 minutes.
6.
From the time a subject consents to participate in ING200336 and administration of IP at Day 1, only SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded in the eCRF for ING200336. Only SAEs 
related to study participation or to a concomitantly administered GSK or ViiV product will be collected between obtaining informed consent and administration of IP at Day 1.  
Note: At the time of the Withdrawal visit in ING117172 if there is an ongoing, unresolved adverse event (AE) and/or serious adverse event (SAE) it will be left in ING117172 as 
unresolved and transcribed as medical history in ING200336.  If the AE and/or SAE worsen after enrollment into ING200336 it will be recorded on the AE/SAE forms in 
ING200336.
7.
Intensive PK visit: The PK evaluations should be scheduled for study visits at Weeks 18-26, Weeks 30-36 and 8-12 weeks postpartum. The DTG dose on serial PK sampling days 
is to be given with a light meal/snack PK should be scheduled so that witnessed dosing of DTG/ABC/3TC FDC is as close as possible to 24 hours (generally 22-26 hours) after 
the previous dosing.The PK visit should be re-scheduled  if the subject took their morning dose prior to coming into the clinic on the PK sampling day.  See SPM for additional 
details.
8.
If feasible, a cord and maternal blood sample will also be collected at delivery and if possible within 30 minutes of each other.  
9.
Suicidality Questionnaire will  be conducted q 12 weeks during the Continuation Phase.
10. HIV-1 RNA and lymphocyte to be drawn within 24 hours of delivery and on the day of the post-partum PK evaluation.
11. The PGx sample should be collected at Day 1 if not collected during participation in ING117172, however this sample may be collected at any time during the study.
12. Plasma samples for storage will be collected at each visit for possible future analyses (including but not limited to HIV-1 RNA genotypic and phenotypic analyses in confirmed
cases of subject withdrawal, HIV-1 RNA levels, when samples are lost or arrive at the laboratory unevaluable, and immunological parameters; see Section 6.5.3)
13. Only for subjects who continue DTG/ABC/3TC and are seen in the clinic every 12 weeks until DTG/ABC/3TC is commercially available locally.  Note: after delivery, subjects must 
use one of the contraception methods to avoid a ‘new’ pregnancy
14. A Follow up visit may be conducted approximately 4 weeks after the last dose of study provided IP, and is required only if the subject has ongoing SAEs or non-serious AEs (as 
outlined in the SPM) at the last on study visit. The assessments performed should reflect what is considered medically necessary to assess the event(s).
15. Serum pregnancy tests will be performed at the Post-Partum and Continuation Phase visits.  Remind subjects who are post-delivery of the need to avoid pregnancy while in the 
study and adherence to the study’s contraception requirements.
 
 
 
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6.1.
Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject (or her 
legal representative) by study site personnel prior to the initiation of any Screening 
procedures as outlined in this protocol. The consent form must have been approved by 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC). After signing 
an informed consent, subjects will complete Screening assessments to determine subject 
eligibility. Each subject being screened for study enrollment evaluation will be assigned a 
subject number. This number will be given sequentially in chronological order of subject 
presentation according to a numeric roster provided by GSK.
Eligibility criteria must be carefully assessed at the Screening and Day 1 visits. Physical 
exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the CRF.
6.1.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events Table 
(Section 6.1).  Subjects will participate in a minimal screening period which includes an 
assessment for potential pregnancy complications (e.g., hypertension, diabetes, etc.) and a 
thorough obstetric history (including gravidity, previous complications and/or risks, etc.).  
Any subject meeting safety, virologic withdrawal and/or withdrawal criteria on 
ING117172 will not be eligible to participate in this study.  
Once the subject learns she is pregnant, there are two scenarios for enrollment:
1. If the subject is determined to be pregnant, wants to enter ING200336, and has 
been seen within 28 days for a regularly scheduled ING117172 visit, the site
would perform an ING117172 Withdrawal visit, which still must remain within 
the 28 day window of the visit when pregnancy was documented. The previous 
visit results will be used as the “screening visit” to qualify the subject for 
enrollment and the Withdrawal visit is used for the Baseline (Day 1) visit (with 
verification that the subject still meets all entry criteria) for ING200336. A urine 
pregnancy test and a urine dipstick to evaluate protein must be performed on Day 
1.
2. If the subject is determined to be pregnant and wants to enter ING200336 but has 
not been seen within 28 days for a regularly scheduled ING11712 visit, the site is 
to perform an unscheduled ING117172 visit to collect adverse events/serious 
adverse events (AEs/SAEs), plasma HIV-1 RNA and laboratory results, including 
a serum pregnancy test and a urine dipstick to evaluate protein, in order to 
document the subject’s current medical status. If the pregnancy is confirmed, the 
site must perform an ING117172 Withdrawal visit within 28 days of the 
unscheduled visit. The unscheduled visit results will be used to qualify the subject 
for enrollment (i.e., is the screening visit) and the Withdrawal visit is used for the 
Baseline (Day 1) visit (with verification that the subject still meets all entry 
criteria) for ING200336. 
 
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In both scenarios the Withdrawal visit for ING117172 will also be Day 1 for ING200336 
to assure no disruption in provision of study treatment.   In the event the subject 
miscarries or electively terminates the pregnancy prior to Day 1 (Baseline) of 
ING200336, she must still be discontinued from ING117172 and followed per the 
requirements of ING117172 and may not continue enrollment into study ING200336.
In both of these scenarios, new demographic, Baseline characteristics, concomintant 
medications (other than previous ARVs), medical history and HIV associated conditions 
will be collected on Day 1, as well as an obstetric history.  If the subject provided consent 
and a PGx sample was collected in study ING117172, there will be no requirement to 
take another PGx sample (the original sample will be linked to the ING117172 subject 
ID’s in both studies.). If the subject consented, but no PGx sample was drawn while 
participating in ING117172 a new consent will be provided for ING200336 and a PGx 
sample will be drawn in this study.
At the time of the Withdrawal visit in ING117172 if there is an ongoing, unresolved 
adverse event (AE) and/or serious adverse event (SAE) it will be left in ING117172 as 
unresolved and transcribed as medical history in ING200336.  If the AE and/or SAE 
worsen after enrollment into ING200336 it will be recorded on the AE/SAE forms in 
ING200336. 
6.2.
Pharmacokinetics
Samples for determination of DTG concentrations in plasma (total and unbound) and 
cord plasma (total) will be collected in the study. 
6.2.1.
Pharmacokinetic Endpoints
Primary PK endpoints
DTG AUC (0-) , Cmax, C, CL/F, Vss/F, and t½ based on intensive PK sampling during 
the second and third trimesters of pregnancy (Weeks 18-26 and 30-36) and at 8-12 weeks 
postpartum.
Secondary PK endpoints

Tmax and C0 based on intensive PK sampling during the third trimester of 
pregnancy and at 8-12 weeks postpartum

C0 and Tmax based on intensive PK sampling during the second and third trimesters
of pregnancy (Weeks 18-26 and 30-36) and at 8-12 weeks postpartum

Unbound DTG concentrations in plasma at 3 and 24 hours post dose at the PK visits 
during the second and third trimesters and at 8-12 weeks postpartum

Total DTG concentrations in plasma from cord blood compared to those in maternal 
plasma at the time of delivery.
 
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6.2.2.
PK Sample Collection
Blood samples (2 mL each except for the 3-hour and 24-hour post dose samples which 
require 6 mL samples) for evaluation of total DTG plasma concentrations will be 
collected during study visits within Wks 18-26 and Wks 30-36 of pregnancy, and at 8-12 
weeks post partum.  At each PK visit, samples will be collected prior to dosing and at 1, 
2, 3, 4, 6, 8, 12 and 24 hours post dosing. The pre-dose sample should be collected within 
15 minutes prior to the dose on the day of PK visit. Subjects should be reminded prior to 
their PK visit that:
1. she will need to come to the site two days in a row in order to complete the 24 
hour PK sampling;
2. no doses can be missed during the 3 days prior to the scheduled PK visit;
3. she should not take the dose at home on the PK day as the dose will be taken at 
the site under supervision after the pre-dose sample is collected;
4. she should switch to morning dosing at least 3 days prior to the PK visit if she 
usually takes the dose at night.
Instructions regarding the PK visit can be found in the SPM.
At delivery: If feasible, a cord and maternal blood sample will also be collected at 
delivery and if possible within 30 minutes of each other.  Note: at time of delivery, 
witnessed dosing of DTG/ABC/3TC FDC prior to delivery must occur and the time of 
previous dose taken must be collected. .
Plasma will be extracted from the blood samples collected and shipped to GSK or its 
designee for determination of DTG plasma concentrations (total and unbound) by a 
validated LC/MS/MS assay.
Important Information on collection of PK samples
Please refer to the SPM for PK sample collection, processing, and shipping instructions.
The actual date and time of each PK sample collection will be recorded in the eCRF. In 
addition, to enhance the quality of PK data collection, subjects will be asked to complete 
a dosing card for the three doses prior to each PK visit (with the exception of PK 
sampling at delivery), with the following information which will be recorded in the 
eCRF.

Actual date and time of dosing.

Whether or not the subject vomited within 4 hours of dosing (this applies only to 
the dose taken immediately prior to the PK visit).

The dosing information recorded in the eCRF will be derived from dosing cards 
that are provided to the subjects. If the dosing card is missing, blank, or 
incomplete, obtain the missing information by oral interview by site personnel 
and retain in source documents.
Site personnel will contact each subject prior to the PK visit to remind and inform 
subjects of the following:
 
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
When their next visit is scheduled, time to arrive at the site and any other 
practical information and instructions with regard to the PK sampling;

To complete all sections of the dosing card before the visit;

Study drug will be administered at the study site at the PK visits; subjects should 
NOT take their DTG/ABC/3TC FDC dose prior to coming to the site.
On the days of the PK sampling visits (other than at Delivery):

Review dosing cards and obtain missing information by oral interview and 
retain in source documents, as appropriate. If a subject presents at the clinic for 
PK sample collection having already taken the morning dose the PK sample 
should not be collected as planned and the study visit should be rescheduled.  If 
the subject has not taken the morning dose but has missed one of the previous 
three doses, collect as much information as possible and continue with PK 
sample collection.

Administer study drug and record date and time of dosing and if subject vomits 
within 4 hours of dosing.
6.3.
Efficacy
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
schedule (Section 6.1).  Methods to be used may include but are not limited to the Abbott 
RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL.  In some cases (e.g., 
where the HIV-1 RNA is below the LLOD for a given assay) additional exploratory 
methods may be used to further characterize HIV-1 RNA levels.  
Lymphocyte Subsets
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ lymphocyte counts according to Time 
and Events schedule (Section 6.1).
HIV Associated Conditions
HIV-associated conditions will be recorded as per Time and Events schedule. HIV-
associated conditions will be assessed according to the 1993 CDC Revised Classification 
System for HIV Infection in Adults (Appendix 1). Indicators of clinical disease 
progression are defined as:
CDC Category A at enrollment → Category C event;
CDC Category B at enrollment → Category C event;
CDC Category C at enrollment → New Category C Event;
CDC Category A, B or C at enrollment → Death
 
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6.4.
Endpoints
6.4.1.
Maternal and Infant
Maternal/Uteroplacental outcomes: To characterize pregnancy outcomes (including but 
not limited to Caesarean section, premature rupture of membranes, pre-term labor [prior 
to Week 37 of pregnancy], pre-term delivery, preeclampsia, eclampsia, hemolysis-
elevated-liver enzymes-low platelet count [HELLP], pre-gestational diabetes, gestational 
diabetes, hypertension, multiple gestation, chromosomal abnormalities, intrauterine
infection, and drug-induced hepatitis).
Infant: To characterize infant outcomes (i.e., infant gestational age, length, weight
[including percentiles, SGA, AGA, LGA, IUGR], and head circumference, and presence 
or absence of major congenital abnormalities) at birth.
Infant
6.4.2.
Efficacy

Proportion of subjects with plasma HIV-1 RNA < 50 c/mL over time ;

Proportion of subjects with plasma HIV-1 RNA < 400 c/mL over time 

Absolute values and changes from Baseline in CD4+ T cell counts over time;

Incidence of disease progression (HIV-associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
6.5.
Safety
Safety assessments will be conducted to characterize the safety and tolerability of 
DTG/ABC/3TC FDC administered during pregnancy according to the Time and Events 
schedule (Section 6.1) and includes:

Monitoring and recording all AEs and SAEs. Additional information on the 
Time Period and Frequency of Detecting AEs and SAEs is provided in Section 
6.5.12.

Regular monitoring of hematology and blood chemistry (parameters to be tested 
listed below).

Physical exams should be conducted as part of normal routine clinical care but 
will not be collected systematically in the CRF. Abnormalities noted during any 
exam must be recorded in the CRF (e.g., in the current medical conditions or AE 
logs).

Monitoring and recording birth and maternal outcomes (see Section 6.4.1)
Note:  Because obstetric and/or pediatric care will not be specifically provided via this 
study, the subject must also establish appropriate obstetric and pediatric care (including 
prenatal care) per local standard of care (SoC) in parallel.  It will be necessary for the 
subject to provide a release of medical information for both herself and her infant to her 
 
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obstetric and pediatric care providers to facilitate collection of delivery, birth and infant 
outcomes by the investigator.

Periodic assessment of urinalysis parameters as described below;

Evaluation and documentation of all concomitant medications and blood
products;

Suicidality monitoring using the Columbia Suicide-Severity Rating Scale 
(Section 6.5.10).
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments. A central laboratory chosen by GSK will 
undertake all routine scheduled laboratory evaluations within the study. Refer to the 
central laboratory manual for specific instructions on sample collection, processing, 
storage, and shipping for each laboratory test.
Table 5
Maternal Laboratory Assessments
Hematology
Platelet Count
Automated WBC Differential:
Red Blood Count
Neutrophils
White Blood Count (WBC) absolute
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
Mean Corpuscular Volume
Basophils
Clinical Chemistry
alpha1-acid glycoprotein 
(AAG)
Sodium
Lipase
Phosphate
Blood Urea Nitrogen
Potassium
AST
Total bilirubin*
Creatinine
Chloride
ALT
Albumin
Glucose
Total CO2
Alkaline phosphatase
CPK
*Direct bilirubin will be reflexively performed for all total bilirubin values > 1.5X ULN
Glomerular Filtration Rate (GFR) will be estimated by the central laboratory using the 
Cockcroft-Gault method [Cockroft, 1976] according to the Time and Events schedule 
(Section 6.1).
Other Tests
Plasma HIV-1 RNA
CD4+ cell counts
Urinalysis and urine microalbumin/creatinine ratio and urine protein/creatinine ratio 
Infant Laboratory Assessment
Laboratory assessment(s) of the newborn is not mandated by this protocol, however, if a 
laboratory assessment on or after the first day of life is performed per local SoC please 
collect the following assessment information if available:
 
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Hematology
Platelet Count
Automated WBC Differential:
Red Blood Count
Neutrophils
White Blood Count (WBC) absolute
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
Mean Corpuscular Volume
Basophils
If available within 36 hours of delivery please collect the following assessment 
information if available: 
Clinical Chemistry
Sodium
Alkaline phosphatase
Phosphate
Blood Urea Nitrogen
Potassium
AST
Total bilirubin*
Creatinine
Chloride
ALT
Albumin
Glucose
Total CO2
In addition, the infant outcomes will also be captured and the following parameters will 
be captured on the neonate at the time of delivery:

Gestational age

Neonatal length and weight

Neonatal head circumference

Absence or presence of congenital malformations, with description of 
malformations where present

APGAR scores

SGA, AGA, LGA

IUGR
HIV status of the infant, if known, should be collected and recorded in the CRF.
6.5.1.
Safety Endpoints

To characterize the safety and tolerability of DTG/ABC/3TC FDC administered 
during pregnancy, the study will capture the following endpoints for the pregnant 
women:

Incidence and severity of AEs and laboratory abnormalities; 

Absolute values and changes over time in laboratory parameters;

Proportion of subjects who discontinue treatment due to AEs.
 
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
To characterize the safety of DTG/ABC/3TC FDC to the developing fetus, the study 
will capture the following endpoints:

Proportion of pregnancies with and without demonstrated congenital 
malformations
6.5.2.
Toxicity Management
Adverse events that occur during the trial should be evaluated by the Investigator and
graded according to the DAIDS toxicity scales (see Section 11.2). Additional information 
regarding detecting, documenting and reporting AEs and SAEs are available in Section 
6.5.5.
IP may be interrupted at the discretion of the Investigator and according to the severity of 
the AE. 
No toxicity-related dose reductions of IP will be allowed. Decisions regarding temporary 
interruption should be made with the understanding that these changes may result in 
incomplete viral suppression and selection of resistant virus. Guidance is provided below 
on general subject management and IP interruptions based on the severity of the AE; for 
specific toxicities, please refer to Section 6.5.3 “Specific Toxicities/Adverse Event 
Management.
NOTE: In the event of the discontinuation of DTG/ABC/3TC FDC for any reason, 
reinitiation of this drug should be undertaken with caution. The investigator must obtain a
complete history of the events surrounding the discontinuation of DTG/ABC/3TC FDC,
evaluate for the possibility of a clinically suspected HSR, and initiate subject 
management as outlined in the DTG IB, regardless of a subject’s HLA-B*5701 status.
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the
discretion of the Investigator. (NOTE: see Section 6.5.3 “Specific Toxicities/Adverse
Event Management” for exceptions to this guideline). Subjects who choose to withdraw
from study due to a Grade 1 or 2 AE should have study withdrawal and follow-up
evaluations completed.
Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or toxicity should be managed as follows:
If the Investigator has compelling evidence that the Grade 3 AE or toxicity has not been
caused by IP, dosing may continue after discussion with the medical monitor.
Subjects who develop a Grade 3 AE or toxicity, which the Investigator considers related
or possibly related to the IP, should have the IP withheld and be rechecked each week
until the AE returns to Grade 2. Once the AE is Grade ≤2, IP may be re-started.
 
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Should the same Grade 3 AE recur within 28 days in the same subject, the IP should be
permanently discontinued and the subject withdrawn from study. Subjects experiencing
Grade 3 AEs requiring permanent discontinuation of IP should be followed weekly until
resolution of the AE and encouraged to have withdrawal study evaluations completed. A
Follow-Up visit should be performed 4 weeks after the last dose of IP.
Subjects with Grade 3 asymptomatic laboratory abnormalities should be investigated for
all potential non-drug related causes, and, following discussion with the medical monitor, 
may continue IP if the Investigator has compelling evidence that the toxicity is not related 
to IP.
Exceptions are noted below for lipid abnormalities.
Grade 4 Toxicity/Adverse Event
Subjects who develop a Grade 4 AE or toxicity should have IP permanently discontinued.
However, if the Investigator has compelling evidence that the AE is not causally related
to the IP, dosing may continue after discussion with and assent from the medical monitor. 
Subjects should be rechecked each week until the AE returns to Grade 2.
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of IP should be
followed weekly until resolution of the AE and encouraged to complete the withdrawal
and follow-up study evaluations as noted above.
Subjects with Grade 4 asymptomatic laboratory abnormalities should be investigated for
all potential non-drug related causes, and, following discussion with the medical monitor, 
may continue therapy if the Investigator has compelling evidence that the toxicity is not 
related to IP. Exceptions are noted below for lipid abnormalities. A FU visit should be
performed 4 weeks after the last dose of study medication if AEs or laboratory
abnormalities are ongoing.
6.5.3.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be
related or possibly related to IP are provided below.
Subjects who permanently discontinue IP for reasons of toxicity should be followed
weekly until resolution of the AE and encouraged to complete the withdrawal and FU 
study evaluations as noted above.
6.5.4.
Liver chemistry stopping and follow up criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety
and to evaluate liver event etiology during administration of IP and the follow-up period. 
IP will be stopped if any of the following liver chemistry criteria are met:

ALT ≥ 3xULN and bilirubin ≥2xULN (>35% direct bilirubin; bilirubin 
fractionation required)
 
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NOTE: serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable 
and a subject meets the criterion of total bilirubin ≥2xULN, then the event meets liver 
stopping criteria;

ALT ≥8xULN;

ALT ≥3xULN (if baseline ALT is < ULN) with symptoms or worsening of acute
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia, OR;

ALT ≥3x baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT ≥5xULN and <8xULN that persists 2 weeks (with bilirubin <2xULN and 
no signs or symptoms of acute hepatitis or hypersensitivity);

ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks;
Subjects who develop ALT ≥5xULN should be followed weekly until resolution or
stabilization (ALT <5xULN on 2 consecutive evaluations).
When any of the liver chemistry stopping criteria is met, do the following:

Immediately hold IP.

Report the event to the medical monitor within 24 hours of learning its occurrence 
(see Table 5 and Table 6, Section 6.5.12);

Complete the liver event eCRF and SAE eCRF, where applicable, (see Section
6.5.14.1);

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed;

Perform liver event follow up assessments (described below), and monitor the 
subject until liver chemistries resolve, stabilize, or return to baseline values as
described below;

Make every reasonable attempt to have subjects return to clinic within 24 hours for
repeat liver chemistries, liver event follow up assessments (see below), and close
monitoring;

A specialist or hepatology consultation is strongly recommended;

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline
phosphatase, bilirubin) resolve, stabilize or return to within baseline values;
Make every attempt to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

HBsAg and Hepatitis B Core Antibody (IgM);
 
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
Hepatitis C RNA;

Hepatitis E IgM antibody;

Cytomegalovirus IgM antibody, Toxoplasma IgM or PCR;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile
antibody or monospot testing);

Syphilis screening;

Drugs of abuse screen including alcohol;

Complete blood count (to assess platelets);

Serum acetaminophen test (APAP adduct test). The site must contact GSK when this 
test is required. Please refer to the SPM.

Blood sample for PK analysis, obtained within 60 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM.

Serum CPK and lactate dehydrogenase (LDH);

Fractionate bilirubin, if total bilirubin is greater than 1.5xULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney
microsomal antibodies;

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to
evaluate liver disease;

Record the appearance or worsening of clinical symptoms of hepatitis, or
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain,
jaundice, fever, or rash as relevant on the AE report form;

Record use of concomitant medications, acetaminophen, herbal remedies, other over
the counter medications, or putative hepatotoxins, on the concomitant medications
report form. Record alcohol use on the liver event alcohol intake case report form.
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.
Note: Also evaluate for HELLP (Hypertension Elevated Liver enzymes Low Platelets) 
Syndrome and pregnancy-related steatosis in subjects with ongoing pregnancy.
 
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6.5.4.1.
Restarting Investigational Product
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by ViiV Safety and Labelling Committee (VSLC) for drug restart can be 
considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and 
no effective alternative therapy is available.  Ethics Committee or Institutional 
Review Board approval of drug restart/rechallenge must be obtained, as required.

If the restart/rechallenge is approved by VSLC in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.  

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge.  Documentation of informed consent must be recorded in the 
study chart.  

Study drug must be administered at the dose specified by VSLC.

Subjects approved by VSLC for restart/rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
Refer to Appendix 5, Section 11.5 for further details. 
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by VSLC for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN).  Ethics Committee or IRB approval of drug 
restart/rechallenge must be obtained, as required.

If restart of drug is approved by VSLC in writing, the subject must be provided with 
a clear description of the possible benefits and risks of drug administration, including 
the possibility of recurrent, more severe liver injury or death.  

The subject must also provide signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study chart.  

Study drug must be administered at the dose specified by VSLC.
Subjects approved by the VSLC for restarting IP must return to the clinic once a week for 
liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol. If protocol defined stopping criteria 
for liver chemistry elevations are met, study drug must be stopped.
Refer to Appendix 5, Section 11.5 for further details.
 
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6.5.4.2.
CPK Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4
weeks to ensure the result is transient or due to exercise and will not require a change in
study treatment. A history regarding use of drugs known to cause increase of CPK (such
as statins) or physical activity or exercise preceding the CPK evaluation should be 
obtained. Grade 4 elevations in CPK should have a repeat assessment after the subject 
has abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations that are
considered possibly or probably related to the IP, IP should be discontinued and the
subject withdrawn from the study.
6.5.4.3.
Decline in Renal Function
Subjects who experience an increase in creatinine from Baseline of 45 Mol/L (or 
0.5 mg/dL) without associated evidence for proteinuria should return for a confirmatory 
assessment within 2 to 4 weeks.  A urinalysis and urine microalbumin/creatinine ratio 
should be done at this confirmatory visit.  If the creatinine increase is confirmed, the 
investigator should contact the study Medical Monitor to discuss additional follow-up 
and medical management.
The following criteria are defined based on Cockcroft-Gault estimates of GFR. The
criteria are based on recommendations for changes in dosing administration for 
DTG/ABC/3TC FDC. The DTG/ABC/3TC IB and the current local prescribing 
information for ABC/3TC FDC should be consulted for additional details on dosing in 
renally impaired subjects.
Subjects who have a decline in CrCL of >50% must return for a confirmatory assessment 
as soon as possible. A urinalysis and urine total protein/creatinine and 
microalbumin/creatinine ratios should be done at this confirmatory visit. If the estimated 
CrCL has declined by >50% (confirmed), then IP should be withheld and the investigator 
should contact the Study Medical Monitor to discuss the rationale for restarting study 
drugs (if appropriate).  Consideration for confounding factors (e.g. other medications, 
dehydration, concurrent conditions) should be taken into account, and a nephrology 
consult may be obtained.  If IP is reinitiated, it should have been withheld for no more 
than 4 weeks.  If IP is not reinitiated the subject must be withdrawn.
6.5.4.4.
Proteinuria
Subjects with an abnormal urine microalbumin/creatinine ratio (>0.3mg/mg, >300mg/g 
or >34mg/mmol) that represents a change from Baseline and no associated increase in 
creatinine, should have a repeat spot urine microalbumin/creatinine ratio and blood 
pressure performed, as well as notify the subject’s obstetric care provider immediately. If
confirmed, then consideration should be made for additional evaluation after consultation
with the Study medical monitor and the subject’s obstetric care provider for further 
evaluation. Additional evaluation may include a 24 hr urine protein and creatinine 
measurement and nephrology referral.
 
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Subjects with an abnormal urine albumin/creatinine ratio (>0.3mg/mg, 300 mg/g or
>34mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 Mol/L (or 0.5 mg/dL) should have confirmation of both results, a repeat blood 
pressure assessment, and notify the subject’s obstetric care provider immediately.  If 
confirmed, with or without evidence of hypertension, the subject’s obstetric provider 
should be immediately contacted.  Agreement on further management should be 
discussed amongst the obstetric care provider, the investigator and Medical Monitor
where possible.
6.5.4.5.
Allergic Reaction
Subjects may continue IP for Grade 1 or 2 allergic reactions at the discretion of the
Investigator. The subject should be advised to contact the Investigator immediately if
there is any worsening of symptoms or if further systemic signs or symptoms develop.
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed.
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or probably
related to the IP should permanently discontinue the IP regimen and the subject should be
withdrawn from the study. Subjects should be treated as clinically appropriate and
followed until resolution of the AE.
Subjects should be managed in terms of a clinically suspected ABC hypersensitivity, as 
described below.
Note:  If allergic reaction is solely pruritus, with no rash, and the subject is in her 
third trimester of pregnancy the investigator should contact the subject’s obstetric 
care practioner for further evaluation.
6.5.4.6.
Abacavir Hypersensitivity Reaction (ABC HSR)
The most significant toxicity associated with ABC is the well-characterized drug-related
HSR. A detailed clinical description of this reaction (including the type and severity of 
events that can occur on re-challenge or reintroduction following ABC interruption for 
non-HSR reasons) and guidance regarding its management are included in the IB.  
Investigators must familiarize themselves with this information on ABC HSR in the IB 
for each of these products prior to initiating subjects on ABC therapy.
Studies have shown that carriage of the HLA-B*5701 allele is associated with a
significantly increased risk of a HSR to ABC. In the prospective study CNA106030
(PREDICT-1), the use of pre-therapy screening for the presence of HLA-B*5701 and
subsequently avoiding ABC in HLA-B*5701 positive patients, significantly reduced the
incidence of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803)
(p<0.0001). In clinical studies EPZ108859 (ARIES) and CNA109586 (ASSERT), 0.8%
(4/515) and 3.1% (6/192) of subjects who were HLA-B*5701 negative and who received
ABC developed a clinically suspected ABC HSR, respectively.
In any subject treated with ABC, the clinical diagnosis of suspected HSR (as
detailed in the IB) must remain the basis of clinical decision making. Regardless of 
 
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HLA-B*5701 status, it is important to permanently discontinue ABC and not re-
challenge with DTG/ABC/3TC (i.e., ZIAGEN™, EPZICOM, KIVEXA or 
TRIZIVIR) if a HSR cannot be ruled out on clinical grounds, due to the potential 
for a severe or even fatal reaction.
Essential Patient Information
With reference to the IB and the ‘Subject Information and Consent Form’, Investigators 
must ensure that subjects are fully informed regarding the following information on the 
hypersensitivity reaction prior to commencing ABC therapy:

Subjects must be made aware of the possibility of a hypersensitivity reaction to ABC
that may result in a life-threatening reaction or death and that the risk of a HSR is 
increased in individuals who are HLA-B*5701 positive.

Subjects must also be informed that HLA-B*5701 negative individuals can also
experience ABC HSR. Therefore, ANY subject who develops signs or symptoms 
consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT 
their doctor IMMEDIATELY.

Subjects who are hypersensitive to ABC should be reminded that they must never
take any abacavir containing medicinal products (e.g. DTG/ABC/3TC, ZIAGEN, 
EPZICOM, KIVEXA or TRIZIVIR) again, regardless of their HLA-B*5701 status.

In order to avoid restarting abacavir, subjects who have experienced a HSR should 
be asked to return any remaining DTG/ABC/3TC tablets to the Investigator or site 
staff.

Subjects who have stopped ABC for any reason, and particularly due to possible
adverse reactions or illness, must be advised to contact their doctor before restarting
DTG/ABC/3TC.

Each subject should be reminded to read the Package Leaflet included in the
ABC/3TC pack. They should be reminded of the importance of removing the Alert 
Card included in the pack, and keeping it with them at all times.
Reporting of Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC meets one of the International Conference 
on Harmonization (ICH)-E2A definitions of seriousness listed in Section 6.5.5.2, then, in 
addition to reporting the case as an SAE, the ABC HSR CRF should also be completed 
within one week of the onset of the hypersensitivity reaction.
6.5.4.7.
Skin reactions without other symptoms that are typical of ABC HSR
Including serious skin reactions such as Stevens Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN), Erythema Multiforme or rash with significant liver 
dysfunction 
Subjects should be instructed to contact the Investigator as soon as possible if they 
develop a rash while on study.
 
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Subjects who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as SJS, TEN or Erythema Multiforme. SJS, 
TEN and Erythema Multiforme have been reported very rarely in patients taking ABC-
containing products.  These patients generally do not have the cluster of additional 
symptoms (e.g., gastrointestinal and respiratory) that characterize the ABC HSR, but they 
do have features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s) 
suspected in the Investigators causality assessment) should be discontinued, and the 
subject should not be re-challenged with any ABC-containing medicinal product (i.e., 
DTG/ABC/3TC, ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the subject is receiving should also be reviewed and 
discontinued as appropriate.
Severe, potentially life-threatening, and fatal skin reactions, including cases of SJS and 
TEN are listed events in the Local Country Prescribing Information for the first marketed 
integrase inhibitor, RAL [Isentress US Package Insert, revised April 2013; Isentress EU 
Summary of Product Characteristics, revised Mar 2013], and hypersensitivity reactions 
have been reported with integrase inhibitors, including dolutegravir, and were 
characterized by rash, constitutional findings, and sometimes, organ dysfunction, 
including liver injury. For additional information on rash associated with dolutegravir, 
please see the current version of the DTG IB [GSK Document Number
RM2007/00683/11, GSK Document Number 2017N352880_00, GSK Document Number
2017N352880_01]
The following guidance is provided for clinical management of subjects who experience 
rash alone in the absence of accompanying diagnosis of ABC HSR, systemic or allergic 
symptoms or signs of mucosal or target lesions.
Subjects with an isolated Grade 1 rash may continue IP at the Investigator’s discretion. 
The subject should be advised to contact the Investigator immediately if there is any 
worsening of the rash, if any systemic signs or symptoms worsen, or if mucosal 
involvement develops.
Subjects may continue IP for an isolated Grade 2 rash. However, IP (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) should be 
permanently discontinued for any Grade ≥2 rash that is associated with an increase in 
ALT (see Section 6.5.4.). The subject should be advised to contact the physician 
immediately if rash fails to resolve (after more than two weeks), if there is any worsening 
of the rash, if any systemic signs or allergic symptoms develop, or if mucosal 
involvement develops.
Subjects should permanently discontinue IP (and all other concurrent medication(s) 
suspected in the Investigators causality assessment) for an isolated Grade 3 or 4 rash, and 
the subject should be withdrawn from the study. Subjects should be treated as clinically 
appropriate and followed until resolution of the AE.
 
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The rash and any associated symptoms should be reported as AEs (see Section 6.5.5) and 
appropriate toxicity ratings should be used to grade the events (see Appendix 2, Section
11.2).
If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to 
a specific medical event or a concomitant non-study medication, routine management 
should be performed and documentation of the diagnosis provided.
6.5.4.8.
Contraception Requirements for the Post-Partum and Continuation 
Phase Only
A subject will be eligible to enter and participate in the Continuation Phase if she agrees 
to use one of the following approved methods to avoid a ‘new’ pregnancy:
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.  Contraceptive subdermal implant
2.  Intrauterine device or intrauterine system
3.  Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.  Injectable progestogen [Hatcher, 2011]
5.  Contraceptive vaginal ring [Hatcher, 2011]
6.  Percutaneous contraceptive patches [Hatcher, 2011]
7.  Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject [Hatcher, 
2011]. The documentation on male sterility can come from the site personnel’s review 
of subject’s medical records, medical examination, and/or semen analysis, or medical 
history interview provided by her or her partner.
Any contraception method must be used consistently, in accordance with the approved 
product label and for at least 2 weeks after discontinuation of IP.  The investigator is 
responsible for ensuring that subjects understand how to properly use these methods of 
contraception.
All subjects participating in the study should be counselled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/spermicide).
 
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6.5.5.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
6.5.5.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
 
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6.5.5.2.
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.

Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
For this study, hospitalization for a term pregnancy (37 weeks gestation) or 
planned Caesarean section will not be recorded as a SAE.  Pre-term delivery or 
emergency Caesarean section will be recorded as a SAE.

Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.

Is a congenital anomaly/birth defect

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
 
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required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record the presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then the 
event is still reported as an SAE. If INR is obtained, include values on the SAE 
form. INR elevations >1.5 suggest severe liver injury.
6.5.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., electrocardiographs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator are to be recorded 
as AEs or SAEs. It is important to note that grading for laboratory abnormalities (See 
Section 11.2) is an objective assessment conducted at the central laboratory and does not 
translate directly into similarly graded AEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.5.7.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
 
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6.5.8.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.5.9.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(see Appendix 1) will be recorded on the HIV Associated Conditions CRF page if they 
occur.  However, these individual events or outcomes, as well as any sign, symptom, 
diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these 
events or outcomes are not reported to GSK as AEs and SAEs even though such event or 
outcome may meet the definition of an AE or SAE, unless the following conditions 
apply:

the Investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (see Section 6.5.5.2), or

the event or outcome is in the Investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, or

death occurring for any reason during a study, including death due to a disease-
related event, will always be reported promptly.
Lymphomas and invasive cervical carcinomas are excluded from this exemption; they 
must be reported as SAEs even if they are considered to be HIV related.
6.5.10.
Suicidality Monitoring
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior). Therefore, it is appropriate to monitor 
subjects for suicidality before and during treatment. It is recommended that the 
Investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behavior.
Treatment emergent assessment of suicidality will be monitored during this study using 
the Columbia Suicide-Severity Rating Scale. The definition of behavioral suicidal events 
used in this scale are based on those used in the Columbia Suicide History Form 
[Oquendo, 2003]. Questions are asked on suicidal behavior, suicidal ideation and 
intensity of ideation. The C-SSRS is to be administered using an interactive voice 
response system at the time-points specified in Section 6.1.
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the AE (Non-serious or SAEs) eCRF 
form on any subject that experiences a possible suicidality-related adverse event while 
 
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participating in this study. This may include, but is not limited to, an event that involves 
suicidal ideation, a preparatory act toward imminent suicidal behavior, a suicide attempt, 
or a completed suicide.  The investigator will exercise his or her medical and scientific 
judgment in deciding whether an event is possibly suicide-related.  PSRAE forms should 
be completed and reported to GSK within one week of the investigator diagnosing a 
possible suicidality-related adverse event.
6.5.11.
Pregnancy
Pregnancy complications (e.g., preeclampsia or eclampsia, prolonged hospitalization after 
delivery, for wound infections etc, seizures) and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with the pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
6.5.11.1.
Pregnancy Testing during the Post-partum and Continuation Phases
Pregnancy testing will also be conducted during the Post-partum and Continuation Phases 
as per the Time and Events Table (See Section 6.1) and at anytime during the trial when 
pregnancy is suspected.
Additionally, a pregnancy test should also be performed prior to IP re-administration, 
when administration is disrupted for more than 7 days (e.g. temporary interruption of IP) 
during the Continuation Phase.
6.5.11.2.
Action to be taken if Pregnancy occurs
Any female who becomes pregnant (intrauterine) while participating in the Post-partum 
or Continuation Phase must be withdrawn from the study and discontinue IP.
Any pregnancy that occurs during  the Post-partum or Continuation Phase must be 
reported using a clinical trial pregnancy form, and, to ensure subject safety, must be 
reported to GSK within 2 weeks of learning of its occurrence.  The pregnancy must be 
followed up to determine outcome (including pre-term termination) and status of mother 
and child.  Pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy occurring during the Post-partum or 
Continuation Phase, brought to the investigator’s attention after the subject has completed 
the study and considered by the investigator as possibly related to the study treatment, 
must be promptly reported to GSK.
GSK’s central safety department will also forward this information to the Antiretroviral 
Pregnancy Registry. The international registry is jointly sponsored by manufacturers or 
licensees of antiretroviral products. Additional information and a list of participating 
manufacturers/licensees are available from http://apregistry.com/index.htm.
 
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6.5.11.2.1. Time Period for Collecting Pregnancy Information
Information on the occurrence of ‘new’ pregnancies in female subjects during the Post-
partum or Continuation Phase will be collected following delivery of the original 
pregnancy that qualified subjects for participation in ING200336 and ending at the final 
on-study or Follow-up visit.  Follow-up information will only be collected for 
pregnancies occurring to the final on-study or Follow-up visit.
6.5.12.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
If there is an ongoing, unresolved AE and/or SAE at the time of the Withdrawal visit in 
ING117172, it will be:

followed for event outcome, which will be recorded in the eCRF, as part of 
ING117172. (i.e., followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up).

recorded in the medical history eCRF page as part of ING200336

any exacerbation or worsening of AEs and/or SAEs from ING117172 during subject 
participation in ING200336, will be recorded as a new entry in the AE or SAE eCRF 
pages for ING200336 with a start date reflecting the clinical worsening, and will not 
be recorded for ING117172.
All SAEs (including those assessed as related to study participation [e.g., study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy] or related to 
a GSK or ViiV concomitant medication) and any non serious AEs of special interest 
(defined in the study procedure manual) occurring from the withdrawal visit in 
ING117172 through to administration of IP at Day 1 of ING200336, will be recorded in 
the eCRF for ING117172.
All AEs and SAEs occurring from Day 1 in ING200336 through to the follow up contact 
will be collected and recored in the eCRF for ING200336, regardless of relationship to 
study participation or any other causality.
All SAEs will be reported to GSK within 24 hours, as indicated in Section 6.5.14. 
6.5.13.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
 
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“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?”
6.5.14.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs and liver function abnormalities meeting pre-defined criteria will be reported 
promptly by the investigator to GSK as described in the Table 6 and Table 7 once the 
investigator determines that the event meets the protocol definition for that event.
Table 6
Events and Reporting Time Periods for SAEs
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” data 
collection tool
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) 
24 hours1
“SAE” data 
collection tool.  
“Liver Event 
CRF” and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” Documents2
1.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
2.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
 
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Table 7
Other Events Requiring Prompt Reporting
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Suspected ABC HSR 
1 Week
ABC HSR CRF
1 Week
Updated ABC HSR 
CRF3
ALT≥5xULN that 
persists ≥2 weeks 
24 hours1
Liver Event CRF2
24 hours 
Updated Liver Event 
CRF2
ALT ≥8xULN 
24 hours1
Liver Event CRF2
24 hours 
Updated Liver Event 
CRF2
ALT ≥3xULN or ALT ≥3 
fold increase from 
baseline value with 
24 hours1
Liver Event CRF2
24 hours 
Updated Liver Event 
CRF2
appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
1.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
2.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
3.
ABC HSR CRF required only event meets one of the ICH-E2A definitions of seriousness’.
Table 8
Other Events Requiring Prompt Reporting during the Continuation 
Phase Only
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow 
up Form 
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM.  Procedures 
for post-study AEs/SAEs are provided in the SPM.
6.5.14.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.5.15.
Other Safety Outcomes
Laboratory Assessments
All protocol required maternal laboratory assessments, as defined in Table 4, must be 
performed by the central laboratory, Quest Diagnostics. Laboratory assessments must be 
conducted in accordance with the Central Laboratory Manual and Protocol Time and 
Events Schedule. Laboratory requisition forms must be completed and samples must be 
clearly labelled with the subject number, protocol number, site/centre number, and visit 
date. Details for the preparation and shipment of samples will be provided by Quest 
Diagnostics. Reference ranges for all safety parameters will be provided to the site by 
Quest Diagnostics.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.
6.6.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
storage samples according to the Time and Events Schedule (Section 6.1) for potential 
viral genotypic and phenotypic analyses (“Plasma for Storage Samples”).
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately. Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard Phenosense and GenoSure testing 
methods for protease (PRO) and reverse transcriptase (RT), or with their GeneSeq 
Integrase and PhenoSense Integrase assays.
6.6.1.
Virology Endpoints
Incidence of treatment-emergent genotypic and/or phenotypic resistance in subjects who 
meet confirmed virologic withdrawal criteria.
 
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6.6.2.
HIV-1 pol Viral Genotyping and Phenotyping
Subjects meeting ‘confirmed virologic withdrawal criterion’ will have plasma samples 
tested for HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype 
and phenotype from both Baseline samples of ING117172 (pre IP) and from samples 
collected at the time of meeting ‘suspected virologic withdrawal criterion’ (additional 
subsequent samples may be analyzed); these results will be reported to the Investigator as 
soon as available to provide guidance for election of an alternative regimen.
6.6.3.
HIV-1 Exploratory Analysis
Additional exploratory analyses for HIV-1 polymerase (pol) resistance may include viral 
genotyping and/or phenotyping on a representative subset of Baseline samples or 
virologic analysis on stored plasma samples from other time points. These analyses may 
also include but are not limited to additional viral genotyping and/or phenotyping, as well 
as other virologic evaluations such as linkage and minority species analyses, super low 
HIV-1 RNA quantitation and measurement of viral replicative capacity. HIV-1 PRO and 
RT genotype and phenotype and HIV-1 integrase genotype and phenotype will also be 
determined on the last on-treatment isolates from all subjects who have HIV-1 RNA 
>400 c/mL regardless of confirmatory HIV-1 RNA.
6.7.
Pharmacogenetic Research
Information regarding PGx research is included in Appendix 3 (Section 11.3).  
The IEC/IRB and, where required, the applicable regulatory agency must approve the 
PGx assessments before these can be conducted at the site. The approval(s) must be in 
writing and will clearly specify approval of the PGx assessments (i.e., approval of 
Appendix 3). In some cases, approval of the PGx assessments can occur after approval is 
obtained for the rest of the study. If so, then the written approval will clearly indicate 
approval of the PGx assessments is being deferred and the study, except for PGx 
assessments, can be initiated. When PGx assessments will not be approved, then the 
approval for the rest of the study will clearly indicate this and therefore, PGx assessments 
will not be conducted.
7.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy.
 
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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This is an open-label, PK and intervention study.  No formal hypotheses testing will be 
performed.  An estimation approach will be used to evaluate PK parameters difference 
between third trimester during pregnancy and at 8-12 weeks postpartum. Point estimates 
and corresponding 90% confidence intervals will be constructed for the comparisons of 
interest.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The number of women that will be enrolled into this protocol cannot be established a 
priori, as unintended pregnancies cannot be determined in advance therefore, there is no 
pre-determined limit on enrollment.  Based on the number of pregnancies in the Phase III 
programs it is estimated there could potentially be approximately 12 subjects in 
ING117172 who would enroll in this study.  The goal is to obtain at 8 subjects providing 
evaluable DTG PK parameters in the third trimester and postpartum.
8.2.2.
Analysis Populations
The Safety and Intent-to-Treat, exposed (ITTE) populations will both be comprised of all 
patients who have received at least one dose of study treatment medication within this 
protocol.  The Safety population will be used for analyses of safety data and the ITTE 
population will be used for the analysis of study population and antiviral response data. 
Further populations may be detailed in the RAP. Analysis Data Sets
8.2.3.
Treatment Comparisons
This is a single arm, open-label study therefore there is no treatment comparison.
8.2.4.
Interim Analysis
No interim analyses are planned, however further data cuts and analyses may be 
conducted as necessary to support regulatory requests, submissions and/or publications.
8.2.5.
Key Elements of Analysis Plan
For safety and efficacy analyses data gathered after subjects withdraw from IP will be 
listed but will not be included in summary tables.  Data collected from extra visits within 
a window will be listed but summary tables using OC datasets will only use the data 
captured closest to the target visit date. Detailed explanations of the derivation of visit 
windows will be included in the RAP. Any deviations from planned analyses will be 
detailed in the clinical study report (CSR).
 
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8.2.5.1.
Pharmacokinetic Analyses
PK analysis will be the responsibility of the Clinical PKs Modeling & Simulation 
department within GlaxoSmithKline.  Plasma DTG concentration-time data will be 
analyzed by non-compartmental methods with WinNonlin 5.2 or higher.  Calculations 
will be based on the actual sampling times recorded during the study.  From the plasma 
concentration-time data, the following PK parameters will be determined, as data permit: 
area under the plasma concentration time curve at steady state during a dosing interval 
AUC(0-), maximum observed plasma concentration (Cmax), time to Cmax (tmax), pre-
dose concentration (C0), concentration at 24h post-dose (C), apparent oral clearance 
(CL/F), apparent volume of distribution after extravascular (e.g., oral) administration
(Vss/F), half-life (t½), unbound DTG concentration in plasma at 3 hours post dose 
(C3h,u), 24 hours post dose (C24h, u). Weight-normalized CL/F and Vss/F will be 
calculated as well. CL/F values will be presented in both L/hr and L/hr/kg). Vss/F values 
will be presented in both L and L/kg. 
Unbound fraction (fu) will be calculated using the total and unbound plasma 
concentration of DTG data generated at 3 and 24 hours post dose for both normal and 
hepatic impairment subjects using the following formula:
fu = Cunbound/Ctotal
where Cunbound and Ctotal are the unbound and total concentration of DTG in 
plasma, respectively.
PK data will be presented in graphical and/or tabular form and will be summarized by 
cohort descriptively. All PK data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GSK.
Log-transformed PK parameters except tmax will be analyzed by analysis of variance 
(ANOVA). This analysis will consider period (during pregnancy or postpartum) as fixed 
effect, subject as random effect. The analysis will be performed using the mixed linear 
models procedure within the SAS/STAT module of the SAS system (Version 9.1 or 
higher). For each log-transformed PK parameter, point estimate and its associated 90% 
CI will be constructed for the treatment difference and this difference and its 90%CI will 
be exponentiated to obtain the ratio of geometric least-squares (GLS) means and its 90% 
CI. For tmax, Hodeges-Lehmann estimate of difference and 90% CI will be provided.
8.2.5.2.
Safety Analyses
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarized.  The proportion of subjects reporting AEs will be tabulated.  The following 
summaries of AEs will be provided:

Incidence and severity of all AEs
 
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
Incidence and severity of treatment related AEs

Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
Laboratory data will be summarized by visit.  In addition, the number and percentage of 
subjects with graded laboratory toxicities (based on DAIDS categories) will be 
summarized.
SAEs will be summarized and categorized by the DAIDS toxicity scale.  The SAE
analyses will take place upon closure of the protocol; however, data cuts and analyses 
may be conducted as necessary in order to support regulatory submissions and/or 
publications.
Descriptive listings will be provided.
8.2.5.3.
Efficacy Analyses
The proportion of subjects with HIV-1 RNA below 400 c/ml at time of delivery observed 
analysis) and the absolute values and change from baseline in HIV-RNA over time over 
time will be presented using the OC analysis datasets. Further details of secondary 
efficacy analyses will be included in the RAP.
8.2.5.4.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment emergent genotypic and phenotypic resistance will be 
summarized. Details of the analyses to be performed will be specified in the RAP.
8.2.5.5.
Pharmacogenetic Analyses
See Appendix 3 for details about the Pharmacogenetics Analysis Plan.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH GCP and 
applicable country-specific regulatory requirements.
 
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The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/ IEC review and favourable opinion/approval of study protocol and any 
subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol, the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 3, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
 
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9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
Unless terminated early, this study will be considered completed after the last subject 
completes the last study-related clinic visit or assessment.
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
 
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including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
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10.
REFERENCES
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry 
International Interim Report for 1 January 1989 through 31 January 2013. Wilmington, 
NC: Re gistry Coordinating Center; 2013. Available from URL: www.APRegistry.com.
Best BM,Mirochnck M, Capparelli E, et al.  Impact of pregnancy on abacavir 
pharmacokinetics.  AIDS.  Feb 28, 2006: 20 (4):553-560.
Birkus G, Hitchcock MJM, and Cihlar T. Assessment of Mitochondrial Toxicity in 
Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse 
Transcriptase Inhibitors.  Antimicrob Agents Chemother. 2002 March; 46(3): 716–723. 
Bloom SL, Dias KM, Bawdon RE, et al. The maternal-fetal transfer of lamivudine in the 
ex vivo human placenta. Am J Obstet Gynecol 1997; 176: 291-3.
Centers for Disease Control and Prevention (CDC) 1993 revised classification system for 
HIV infection and expanded surveillance case definition for AIDS among adolescents 
and adults.  MMWR 1992;41(No. RR-17):1-19.
Cockroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  
Nephron 1976;16:31-41.
Department of Health and Human Services (US DHHS). Panel on Antiretroviral 
Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in 
HIV-1-infected adults and adolescents. Updated February 12, 2013. Available at 
http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. 
European AIDS Clinical Society (EACS) Guidelines for the clinical management and 
treatment of HIV Infected Adults in Europe, 2012. Available at 
http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-
v6.1-2edition.pdf.
FDA Guidance for Industry (2004):  US Department of Health and Human Services, 
FDA, Center for Drug Evaluation and Research.  Guidance for Industry: 
Pharmacokinetics in Pregnancy – Study Design, Analysis and Impact on Dosing and 
Labeling.  October, 2004.  Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/ucm072133.pdf
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01, December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02, June 2018.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure., Version 11, October 2017.
 
2020N453116_00

2013N166290_03
CONFIDENTIAL
200336
86
GlaxoSmithKline Document Number RM2011N117164_01: GSK1349572 Compared to 
Raltegravir Clinical Study Report.  November 2012.
GlaxoSmithKline Document Number RM2011N118494_00: GSK1349572 plus 
Abacavir-Lamivudine Fixed Dose Combination Clinical Study Report.  September 2012.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50.
Table 3-2.
Isentress EU Summary of Product Characteristics, March 2013.
Isentress US Product Information, April 2013. 
Mandelbrot L, Peytavin G, Firtion G, et al. Maternal-fetal transfer and amniotic fluid 
accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. 
Am J Obstet Gynecol 2001; 184 (2): 153-8.
Oquendo MA, Mann J. Risk Factors for suicidal behaviour: utility and limitations of 
research instruments (2003). In M.B. First [Ed] Standardized Evaluation in Clinical 
Practice, pp 103- 130.
Powis KM, Kitch D, Ogwu A, Hughes MD, et al. Increased Risk of Preterm Delivery 
Among HIV Infected Women Randomized to Protease Versus Nucleoside Reverse 
Transcriptase Inhibitor-Based HAART During Pregnancy. J Infect Dis 2011 Aug 15;
204(4):506-14.
Shapiro RL, Hughes MD, Ogwu A, etal.  Antiretrovirals in Pregnancy and Breastfeeding 
in Botswana.  N Engl J Med. 2010 June 17; 362(24): 2282–2294.
Tuomala RE, Watts DH, Li D, Vajaranant M, etal. Improved Obstetric Outcomes and 
Few Maternal Toxicities Are Associated With Antiretroviral Therapy, Including Highly 
Active Antiretroviral Therapy During Pregnancy.  JAIDS 2005, 38 (4): 449-473
UNAIDS (2009). Children and AIDS: Fourth Stocktaking Report, 2009. Available online 
at:http://www.unicef.org/publications/files/Children_and_AIDS_Fourth_Stocktaking_Re
port_EN_120209.pdf,  accessed 5 Feb 2013.
UNAIDS (2010). AIDS at 30: Nations at the Crossroads.  Available on online at:  
http://unaidspcbngo.org/wp-
content/uploads/2011/06/letter_AIDS30_EXTERNAL_KEY_FINDINGS.pdf
UNAIDS Reference Group on Estimates, Modelling and Projections. Working Paper on 
Mother-to-Child HIV Transmission Rates for use in Spectrum, 6 June 2011. Available 
online at http://www.epidem.org/Publications/MTCTratesworkingpaper.pdf.
UNAIDS World AIDS Day Report. 2012.  Available online at 
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2
012/jc2434_worldaidsday_results_en.pdf
 
2020N453116_00

2013N166290_03
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200336
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United Nations General Assembly, 65th Session, Agenda Item 10, 28 March 2011
Vannappagari V, Albano J, Tilson H, Gee C, et al.  Abacavir and Lamivudine Exposure 
during Pregnancy and Birth Outcomes: Data from The Antiretroviral Pregnancy Registry. 
Presented at 20th Conference on Retroviruses and Opportunistic Infections, 3-
6March2013, Atlanta, GA, Poster 923.  
Whitmore SK, Taylor AW, Espinoza L, Shouse RL, Lampe MA, Nesheim S. Correlates 
of mother-to-child transmission of HIV in the United States and Puerto Rico. Pediatrics. 
Jan 2012;129(1):e74-81. Available at http://www.ncbi.nlm.nih.gov/pubmed/22144694.
World Health Organization (WHO) (2010). Antiretroviral drugs for treating pregnant 
women and preventing HIV infection in infants: Recommendations for a public health 
approach.  Available online at: 
http://whqlibdoc.who.int/publications/2010/9789241599818_eng.pdf, accessed 6 Feb 
2013.
World Health Organization (WHO) (2012). Antiretroviral Treatment as Prevention 
(TasP) of HIV and TB:  2012 Update.  June 2012, Available online at: 
http://www.who.int/hiv/pub/mtct/programmatic_update_tasp/en/index.html
World Health Organization (WHO) (2013). Consolidated Guidelines on the Use of 
Antiretroviral Drugs for Treating and Preventing HIV Infection. 30 June 2013.  Available 
online at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html
 
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11.
APPENDICES
11.1.
Appendix 1: CDC Classification System for HIV-1 Infections 
(1993)
Reference - 1993 revised classification system for HIV infection and expanded 
surveillance case definition for AIDS among adolescents and adults. MMWR, 1992;41 
(No. RR-17):1-19.
Clinical Categories
The clinical categories of HIV infection are defined as follows:
Category A
Category A consists of one or more of the conditions listed below in an adolescent or 
adult (>13 years) with documented HIV infection.  Conditions listed in Categories B and 
C must not have occurred.

Asymptomatic HIV infection

Persistent generalized lymphadenopathy

Acute (primary) HIV infection with accompanying illness or history of acute HIV 
infection
Category B (Symptomatic non-AIDS conditions)
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult 
that are not included among conditions listed in clinical Category C and that meet at least 
one of the following criteria:  a) the conditions are attributed to HIV infection or are 
indicative of a defect in cell-mediated immunity; or b) the conditions are considered by 
physicians to have a clinical course or to require management that is complicated by HIV 
infection.  Examples of conditions in clinical Category B include, but are not limited 
to:

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least two distinct episodes or more than one 
dermatome

Idiopathic thrombocytopenic purpura
 
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
Listeriosis

Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in
Category A.  For example, someone previously treated for oral or persistent vaginal 
candidiasis (and who has not developed a Category C disease) but who is now 
asymptomatic should be classified in clinical Category B.
Category C (AIDS indicator conditions as defined by diagnostic or presumptive 
measures).
Category C includes the clinical conditions listed in the AIDS surveillance case 
definition.  For classification purposes, once a Category C condition has occurred, the 
person will remain in Category C.
Conditions in Category C include:

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

Herpes simplex:  chronic ulcer(s) (>1 month’s duration);or bronchitis, pneumonitis, 
or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month’s duration)

Kaposi’s sarcoma

Lymphoma, Burkitt’s (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary
 
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
Pneumocystis carinii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome due to HIV
Non-CDC, HIV-associated conditions
 
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11.2.
Appendix 2:  Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events
VERSION 1.0, DECEMBER 2004; CLARIFICATION AUGUST 2009
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized 
for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE 
term.
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE1
Clinical adverse event NOT 
identified elsewhere in this DAIDS 
AE grading table
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions OR Medical or 
operative intervention indicated to 
prevent permanent impairment, 
persistent disability, or death
SYSTEMIC
Acute systemic allergic reaction
Localized urticaria (wheals) with 
no medical intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild bronchospasm
Acute anaphylaxis OR Life-threatening 
bronchospasm OR laryngeal edema
Chills
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
NA
Fatigue
Malaise
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Incapacitating fatigue/malaise 
symptoms
causing inability to perform basic self-
care functions
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C
Pain (indicate body site)
DO NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain)
See also Headache, Arthralgia, 
and Myalgia
Pain causing no or minimal 
interference with usual social & 
functional activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to perform 
usual social & functional activities
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization (other than emergency 
room visit) indicated
Unintentional weight loss
NA
5 – 9% loss in body weight from 
baseline
10 – 19% loss in body weight from 
baseline
20% loss in body weight from 
baseline OR Aggressive intervention 
indicated [e.g., tube feeding or total 
parenteral nutrition (TPN)]
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
INFECTION
Infection (any other than HIV 
infection)
Localized, no systemic 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial treatment
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual social & 
functional activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening consequences (e.g., 
septic shock)
INJECTION SITE REACTIONS
Injection site pain (pain without 
touching)
Or
Tenderness (pain when area is 
touched)
Pain/tenderness causing no or 
minimal limitation of use of limb
Pain/tenderness limiting use of limb 
OR Pain/tenderness causing 
greater than minimal interference 
with usual social & functional 
activities
Pain/tenderness causing inability to 
perform usual social & functional 
activities
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than emergency 
room visit) indicated for management 
of pain/tenderness
Injection site reaction (localized)
Adult > 15 years
Erythema OR Induration of 5x5 
cm – 9x9 cm (or 25 cm2 – 81cm2)
Erythema OR Induration OR Edema 
> 9 cm any diameter (or > 81 cm2)
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess OR 
Drainage
Necrosis (involving dermis and deeper
tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR Edema 
> 2.5 cm diameter but < 50% 
surface area of the extremity 
segment (e.g., upper arm/thigh)
Erythema OR Induration OR Edema 
involving 50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and deeper 
tissue)
Pruritis associated with injection
See also Skin: Pruritis (itching - no 
skin lesions)
Itching localized to injection site 
AND Relieved spontaneously or 
with < 48 hours treatment
Itching beyond the injection site but 
not generalized OR Itching localized 
to injection site requiring 48 hours 
treatment
Generalized itching causing inability 
to perform usual social & functional 
activities
NA
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
SKIN – DERMATOLOGICAL
Alopecia
Thinning detectable by study 
participant (or by caregiver for 
young children and disabled 
adults)
Thinning or patchy hair loss 
detectable by health care provider
Complete hair loss
NA
Cutaneous reaction – rash
Localized macular rash
Diffuse macular, maculopapular, or 
morbilliform rash OR Target lesions
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site
Extensive or generalized bullous 
lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous 
membrane involving two or more 
distinct mucosal sites OR Toxic 
epidermal necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis (itching – no skin lesions)
(See also Injection Site Reactions: 
Pruritis associated with injection)
Itching causing no or minimal 
interference with usual social & 
functional activities
Itching causing greater than 
minimal interference with usual 
social & functional activities
Itching causing inability to perform 
usual social & functional activities
NA
CARDIOVASCULAR
Cardiac arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-urgent 
medical intervention indicated
Symptomatic, non-life-threatening 
AND Non-urgent medical intervention 
indicated
Life-threatening arrhythmia OR Urgent 
intervention indicated
Cardiac-ischemia/infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia
Unstable angina OR Acute myocardial 
infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No transfusion 
indicated
Symptomatic AND Transfusion of 2 
units packed RBCs (for children 10 
cc/kg) indicated
Life-threatening hypotension OR 
Transfusion of > 2 units packed RBCs 
(for children >10 cc/kg) indicated
Hypertension
Adult > 17 years
(with repeat testing at same 
visit)
140 – 159 mmHg systolic
OR
90 – 99 mmHg diastolic
160 – 179 mmHg systolic
OR
100 – 109 mmHg diastolic
180 mmHg systolic
OR
110 mmHg diastolic
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Pediatric 17 Years
(with repeat testing at same 
visit)
NA
91st – 94th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic)
95th percentile adjusted for age, 
height, and gender (systolic and/or 
diastolic)
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
Hypotension
NA
Symptomatic, corrected with oral 
fluid replacement
Symptomatic, IV fluids indicated
Shock requiring use of vasopressors or 
mechanical assistance to maintain 
blood pressure
Pericardial effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or larger 
effusion requiring no intervention
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent intervention 
indicated
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval
0.21 – 0.25 sec
PR interval
> 0.25 sec
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec
Complete AV block
Pediatric 16 Years
1st degree AV block (PR > normal 
for age and rate)
Type I 2nd degree AV block
Type II 2nd degree AV block
Complete AV block
Prolonged QTc
Adult > 16 years
Asymptomatic, QTc interval 
0.45-0.47 sec OR Increase 
interval <0.03 sec above baseline
Asymptomatic, QTc interval 
0.48-0.49 sec OR Increase in 
interval 0.03 – 0.05 sec above 
baseline
Asymptomatic, QTc interval 0.50 
sec OR Increase in interval 0.06 
sec above baseline
Life-threatening consequences, e.g., 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Pediatric 16 years
Asymptomatic, QTc interval 
0.450–0.464 sec
Asymptomatic, QTc interval 
0.465-0.479 sec
Asymptomatic, QTc
interval 0.480 sec
Life-threatening consequences, e.g., 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Thrombosis/embolism
NA
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus)
Vasovagal episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular dysfunction 
(congestive heart failure)
NA
Asymptomatic diagnostic finding 
AND intervention indicated
New onset with symptoms OR 
Worsening symptomatic congestive 
heart failure
Life-threatening congestive heart 
failure
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
GASTROINTESTINAL
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss
Loss of appetite associated with 
significant weight loss
Life-threatening consequences OR 
Aggressive intervention indicated [e.g., 
tube feeding or   total parenteral 
nutrition (TPN)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading anorexia, this is not a requirement and should 
not be used as a substitute for clinical judgment.
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences (e.g., 
sepsis or perforation)
Constipation
NA
Persistent constipation requiring 
regular use of dietary modifications, 
laxatives, or enemas
Obstipation with manual evacuation 
indicated
Life-threatening consequences (e.g., 
obstruction)
Diarrhea
Adult and
Pediatric 1 year
Transient or intermittent episodes 
of unformed stools OR Increase 
of 3 stools over baseline per 24-
hour period
Persistent episodes of unformed to 
watery stools OR Increase of 4 – 6 
stools over baseline per 24-hour 
period
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV fluid 
replacement indicated
Life-threatening consequences (e.g., 
hypotensive shock)
Pediatric < 1 year
Liquid stools (more unformed 
than usual) but usual number of 
stools
Liquid stools with increased number 
of stools OR Mild dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in severe 
dehydration with aggressive 
rehydration indicated OR Hypotensive 
shock
Dysphagia-
Odynophagia
Symptomatic but able to eat usual 
diet
Symptoms causing altered dietary 
intake without medical intervention 
indicated
Symptoms causing severely altered 
dietary intake with medical 
intervention indicated
Life-threatening reduction in oral intake
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Mucositis/stomatitis (clinical 
exam)
Indicate site (e.g., larynx, oral)
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-Odynophagia 
and Proctitis
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations
Confluent pseudomembranes or 
ulcerations OR Mucosal bleeding with 
minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking)
Nausea
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake
Persistent nausea resulting in 
decreased oral intake for 24 – 48 
hours
Persistent nausea resulting in 
minimal oral intake for > 48 hours OR 
Aggressive rehydration indicated 
(e.g., IV fluids)
Life-threatening consequences (e.g., 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND Hospitalization 
not indicated (other than emergency 
room visit)
Symptomatic AND Hospitalization 
indicated (other than emergency 
room visit)
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, sepsis)
Proctitis (functional-symptomatic)
Also see Mucositis/stomatitis for 
clinical exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Operative intervention 
indicated
Life-threatening consequences (e.g., 
perforation)
Vomiting
Transient or intermittent vomiting 
with no or minimal interference 
with oral intake
Frequent episodes of vomiting with 
no or mild dehydration
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(e.g., IV fluids)
Life-threatening consequences (e.g., 
hypotensive shock)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
NEUROLOGIC
Alteration in personality-behavior 
or in mood (e.g., agitation, 
anxiety, depression, mania, 
psychosis)
Alteration causing no or minimal 
interference with usual social & 
functional activities
Alteration causing greater than 
minimal interference with usual 
social & functional activities
Alteration causing inability to perform 
usual social & functional activities
Behavior potentially harmful to self or 
others (e.g., suicidal and homicidal 
ideation or attempt, acute psychosis) 
OR Causing inability to perform basic 
self-care functions
Altered Mental Status
For Dementia, see Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
Changes causing no or minimal 
interference with usual social & 
functional activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social & 
functional activities
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social & 
functional activities
Delirium OR obtundation, OR coma
Ataxia
Asymptomatic ataxia detectable 
on exam OR Minimal ataxia 
causing no or minimal interference 
with usual  social & functional 
activities
Symptomatic ataxia causing greater 
than minimal interference with usual 
social & functional activities
Symptomatic ataxia causing inability 
to perform usual social & functional 
activities
Disabling ataxia causing inability to 
perform basic self-care functions
Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
Disability causing no or minimal 
interference with usual social & 
functional activities OR 
Specialized resources not 
indicated
Disability causing greater than 
minimal interference with usual 
social & functional activities OR 
Specialized resources on part-time 
basis indicated
Disability causing inability to perform 
usual social & functional activities OR 
Specialized resources on a full-time 
basis indicated
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated
CNS ischemia (acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident (CVA, 
stroke) with neurological deficit
Developmental delay
– Pediatric 16 Years
Mild developmental delay, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting
Moderate developmental delay, 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, either 
motor or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting
Developmental regression, either motor 
or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Headache
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions OR 
Hospitalization indicated (other than 
emergency room visit) OR Headache 
with significant impairment of alertness 
or other neurologic function
Insomnia
NA
Difficulty sleeping causing greater 
than minimal interference with usual 
social & functional activities
Difficulty sleeping causing inability to 
perform usual social & functional 
activities
Disabling insomnia causing inability to 
perform basic self-care functions
Neuromuscular weakness 
(including myopathy & 
neuropathy)
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no or 
minimal interference with usual 
social & functional activities
Muscle weakness causing greater 
than minimal interference with usual 
social & functional activities
Muscle weakness causing inability to 
perform usual social & functional 
activities
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation
Neurosensory Alteration (including 
paresthesia and painful 
neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or minimal 
interference with usual social & 
functional activities
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social & 
functional activities
Sensory alteration or paresthesia 
causing inability to perform usual 
social & functional activities
Disabling sensory alteration or 
paresthesia causing inability to perform 
basic self-care functions
Seizure: (new onset)
– Adult 18 years
See also Seizure: (known pre-
existing seizure disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
Seizure: (known pre-existing 
seizure disorder)
– Adult 18 years
For worsening of existing epilepsy 
the grades should be based on an 
increase from previous level of 
control to any of these levels.
NA
Increased frequency of pre-existing 
seizures (non-repetitive) without 
change in seizure character OR 
Infrequent break-through seizures 
while on stable medication in a 
previously controlled seizure 
disorder
Change in seizure character from 
baseline either in duration or quality
(e.g., severity or focality)
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Seizure
– Pediatric < 18 years
Seizure, generalized onset with or 
without secondary generalization, 
lasting < 5 minutes with < 24 
hours post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting 5 – 20 minutes with <24 
hours post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting >20 minutes
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation
Syncope (not associated with a 
procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or minimal 
interference with usual social & 
functional activities
Vertigo causing greater than 
minimal interference with usual 
social & functional activities
Vertigo causing inability to perform 
usual social & functional activities
Disabling vertigo causing inability to 
perform basic self-care Functions
RESPIRATORY
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70-80%
FEV1 or peak flow 50–69%
FEV1 or peak flow 25–49%
Cyanosis OR FEV1 or peak flow < 25% 
OR Intubation
Dyspnea or respiratory distress
Adult 14 years
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities
Dyspnea at rest causing inability to 
perform usual social & functional 
activities
Respiratory failure with ventilatory 
support Indicated
Pediatric < 14 years
Wheezing OR minimal increase in 
respiratory rate for age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 –
95%
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 90%
Respiratory failure with ventilatory 
support indicated
MUSCULOSKELETAL
Arthralgia
See also Arthritis
Joint pain causing no or minimal 
interference with usual social & 
functional activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability to perform 
usual social & functional activities
Disabling joint pain causing inability to 
perform basic self-care Functions
Arthritis
See also Arthralgia
Stiffness or joint swelling causing 
no or minimal interference with 
usual social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling causing 
inability to perform usual social & 
functional activities
Disabling joint stiffness or swelling 
causing inability to perform basic self-
care functions
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Bone Mineral Loss
Adult 21 years
BMD t-score -2.5 to -1.0
BMD t-score < -2.5
Pathological fracture (including loss 
of vertebral height)
Pathologic fracture causing life-
threatening Consequences
Pediatric < 21 years
BMD z-score -2.5 to -1.0
BMD z-score < -2.5
Pathological fracture (including loss 
of vertebral height)
Pathologic fracture causing life-
threatening Consequences
Myalgia (non-injection site)
Muscle pain causing no or 
minimal interference with usual 
social & functional activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing inability to 
perform usual social & functional 
activities
Disabling muscle pain causing inability 
to perform basic self-care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR Operative 
intervention indicated
Disabling bone pain with radiographic 
findings causing inability to perform 
basic self-care functions
GENITOURINARY
Cervicitis (symptoms)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions
Cervicitis (clinical exam)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
Minimal cervical abnormalities on 
examination (erythema,
Mucopurulent discharge, or 
friability) OR Epithelial disruption < 
25% of total surface
Moderate cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption of 
25 – 49% total surface
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or friability) 
OR Epithelial disruption 50 – 75% 
total surface
Epithelial disruption > 75% total 
surface
Inter-menstrual bleeding (IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
examination
Inter-menstrual bleeding not greater 
in duration or amount than usual 
menstrual cycle
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle
Hemorrhage with life-threatening 
hypotension OR Operative intervention 
indicated
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Urinary tract obstruction (e.g., 
stone)
NA
Signs or symptoms of urinary tract 
obstruction without hydronephrosis 
or renal dysfunction
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction
Obstruction causing life-threatening 
consequences
Vulvovaginitis (symptoms)
(Use in studies evaluating topical 
study agents) 
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions
Vulvovaginitis (clinical exam)
(Use in studies evaluating topical 
study agents)
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
Minimal vaginal abnormalities on 
examination OR Epithelial 
disruption <25% of total surface
Moderate vaginal abnormalities on 
examination OR Epithelial 
disruption of 25 - 49% total surface
Severe vaginal abnormalities on 
examination OR Epithelial disruption 
50 - 75% total surface
Vaginal perforation OR Epithelial 
disruption > 75% total surface
OCULAR/VISUAL
Uveitis
Asymptomatic but detectable on 
exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR Operative 
intervention indicated
Disabling visual loss in affected eye(s)
Visual changes (from baseline)
Visual changes causing no or 
minimal interference with usual 
social & functional activities
Visual changes causing greater 
than minimal interference with usual 
social & functional activities
Visual changes causing inability to 
perform usual social & functional 
activities
Disabling visual loss in affected eye(s)
ENDOCRINE/METABOLIC
Abnormal fat accumulation (e.g., 
back of neck, breasts, abdomen)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious changes on 
casual visual inspection
NA
Diabetes mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current medications to regain 
glucose control
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-ketotic 
coma)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Gynecomastia
Detectable by study participant or 
caregiver (for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
Hyperthyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification
Life-threatening consequences (e.g., 
thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification
Life-threatening consequences (e.g., 
myxedema coma)
Lipoatrophy (e.g., fat loss from the 
face, extremities, buttocks)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
1.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Standard International Units are listed in italics
Absolute CD4+ count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
300 – 400/mm3
300 – 400/µL
200 – 299/mm3
200 – 299/µL
100 – 199/mm3
100 – 199/µL
< 100/mm3
< 100/µL
Absolute lymphocyte
count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
600 – 650/mm3
0.600 x 109 –
0.650 x 109/L
500 – 599/mm3
0.500 x 109 –
0.599 x 109/L
350 – 499/mm3
0.350 x 109 –
0.499 x 109/L
< 350/mm3
< 0.350 x 109/L
Comment:  Values in children 13 years are not given for the two parameters above because the absolute counts are variable.
Absolute neutrophil count (ANC)
Adult and Pediatric,
> 7 days
1,000 – 1,300/mm3
1.000 x 109 –
1.300 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
500 – 749/mm3
0.500 x 109 –
0.749 x 109/L
< 500/mm3
< 0.500 x 109/L
Infant*†, 2 – 7 days
1,250 – 1,500/mm3
1.250 x 109 –
1.500 x 109/L
1,000 – 1,249/mm3
1.000 x 109 –
1.249 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
< 750/mm3
< 0.750 x 109/L
Infant*†, 1 day
4,000 – 5,000/mm3
4.000 x 109 –
5.000 x 109/L
3,000 – 3,999/mm3
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm3
1.500 x 109 –
2.999 x 109/L
< 1,500/mm3
< 1.500 x 109/L
Fibrinogen, decreased
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
0.75 – 0.99 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
0.50 – 0.74 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
0.25 – 0.49 x LLN
< 50 mg/dL
< 0.50 g/L
OR
< 0.25 x LLN
OR
Associated with gross bleeding
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hemoglobin (Hgb)
Adult and Pediatric
57 days
(HIV POSITIVE ONLY)
8.5 – 10.0 g/dL
5.24 – 6.23 mmol/L
7.5 – 8.4 g/dL
4.62 – 5.23 mmol/L
6.50 – 7.4 g/dL
4.03 – 4.61 mmol/L
< 6.5 g/dL
< 4.03 mmol/L
Adult and Pediatric
57 days
(HIV NEGATIVE ONLY)
10.0 – 10.9 g/dL
6.18 – 6.79 mmol/L
OR
Any decrease
2.5 – 3.4 g/dL
1.58 – 2.13 mmol/L
9.0 – 9.9 g/dL
5.55 – 6.17 mmol/L
OR
Any decrease
3.5 – 4.4 g/dL
2.14 – 2.78 mmol/L
7.0 – 8.9 g/dL
4.34 – 5.54 mmol/L
OR
Any decrease
4.5 g/dL
2.79 mmol/L
< 7.0 g/dL
< 4.34 mmol/L
Infant*†, 36 – 56 days
(HIV POSITIVE OR NEGATIVE)
8.5 – 9.4 g/dL
5.24 – 5.86 mmol/L
7.0 – 8.4 g/dL
4.31 – 5.23 mmol/L
6.0 – 6.9 g/dL
3.72 – 4.30 mmol/L
< 6.00 g/dL
< 3.72 mmol/L
Infant*†, 22 – 35 days
(HIV POSITIVE OR NEGATIVE)
9.5 – 10.5 g/dL
5.87 – 6.54 mmol/L
8.0 – 9.4 g/dL
4.93 – 5.86 mmol/L
7.0 – 7.9 g/dL
4.34 – 4.92 mmol/L
< 7.00 g/dL
< 4.34 mmol/L
Infant*†, 21 days
(HIV POSITIVE OR NEGATIVE)
12.0 – 13.0 g/dL
7.42 – 8.09 mmol/L
10.0 – 11.9 g/dL
6.18 – 7.41 mmol/L
9.0 – 9.9 g/dL
5.59 – 6.17 mmol/L
< 9.0 g/dL
< 5.59 mmol/L
International Normalized
Ratio of prothrombin time
(INR)
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0 – 10.0%
10.1 – 15.0%
15.1 – 20.0%
> 20.0%
Prothrombin Time (PT)
1.1 – 1.25 x ULN
1.26 – 1.50 x ULN
1.51 – 3.00 x ULN
> 3.00 x ULN
Partial Thromboplastin
Time (PTT)
1.1 – 1.66 x ULN
1.67 – 2.33 x ULN
2.34 – 3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm3
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm3
50.000 x 109 –
99.999 x 109/L
25,000 –
49,999/mm3
25.000 x 109 –
49.999 x 109/L
< 25,000/mm3
< 25.000 x 109/L
WBC, decreased
2,000 – 2,500/mm3
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm3
1.500 x 109 –
1.999 x 109/L
1,000 – 1,499/mm3
1.000 x 109 –
1.499 x 109/L
< 1,000/mm3
< 1.000 x 109/L
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
CHEMISTRIES
Standard International Units are listed in italics
Acidosis
NA
pH < normal, but 7.3
pH < 7.3 without life-threatening 
consequences
pH < 7.3 with life-threatening 
consequences
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/dL
< 20 g/L
NA
Alkaline Phosphatase
1.25 – 2.5 x ULN†
2.6 – 5.0 x ULN†
5.1 – 10.0 x ULN†
> 10.0 x ULN†
Alkalosis
NA
pH > normal, but 7.5
pH > 7.5 without life-threatening 
consequences
pH > 7.5 with life-threatening 
consequences
ALT (SGPT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
AST (SGOT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
Bilirubin (Total)
Adult and Pediatric >14 days
1.1 – 1.5 x ULN
1.6 – 2.5 x ULN
2.6 – 5.0 x ULN
> 5.0 x ULN
Infant*†, 14 days (non-
hemolytic)
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
25.1 – 30.0 mg/dL
429 – 513 µmol/L
> 30.0 mg/dL
> 513.0 µmol/L
Infant*†, 14 days (hemolytic)
NA
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
> 25.0 mg/dL
> 428 µmol/L
Calcium, serum, high (corrected for albumin)
Adult and Pediatric 7 days
10.6 – 11.5 mg/dL
2.65 – 2.88 mmol/L
11.6 – 12.5 mg/dL
2.89 – 3.13 mmol/L
12.6 – 13.5 mg/dL
3.14 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Infant*†, < 7 days
11.5 – 12.4 mg/dL
2.88 – 3.10 mmol/L
12.5 – 12.9 mg/dL
3.11 – 3.23 mmol/L
13.0 – 13.5 mg/dL
3.245 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Calcium, serum, low 
Adult and Pediatric 7 days
7.8 – 8.4 mg/dL
1.95 – 2.10 mmol/L
7.0 – 7.7 mg/dL
1.75 – 1.94 mmol/L
6.1 – 6.9 mg/dL
1.53 – 1.74 mmol/L
< 6.1 mg/dL
< 1.53 mmol/L
Infant*†, < 7 days
6.5 – 7.5 mg/dL
1.63 – 1.88 mmol/L
6.0 – 6.4 mg/dL
1.50 – 1.62 mmol/L
5.50 – 5.90 mg/dL
1.38 – 1.51 mmol/L
< 5.50 mg/dL
< 1.38 mmol/L
Cardiac troponin I (cTnI)
NA
NA
NA
Levels consistent with myocardial 
infarction or unstable angina as defined 
by the manufacturer
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cardiac troponin T (cTnT)
NA
NA
NA
0.20 ng/mL
OR
Levels consistent with myocardial 
infarction or unstable angina as defined 
by the manufacturer
Cholesterol (fasting)
Adult 18 years
200 – 239 mg/dL
5.18 – 6.19 mmol/L
240 – 300 mg/dL
6.20 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Pediatric < 18 years
170 – 199 mg/dL
4.40 – 5.15 mmol/L
200 – 300 mg/dL
5.16 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Creatine Kinase
3.0 – 5.9 x ULN†
6.0 – 9.9 x ULN†
10.0 – 19.9 x ULN†
20.0 x ULN†
Creatinine
1.1 – 1.3 x ULN†
1.4 – 1.8 x ULN†
1.9 – 3.4 x ULN†
3.5 x ULN†
Glucose, serum, high
Nonfasting
116 – 160 mg/dL
6.44 – 8.88 mmol/L
161 – 250 mg/dL
8.89 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Fasting
110 – 125 mg/dL
6.11 – 6.94 mmol/L
126 – 250 mg/dL
6.95 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Glucose, serum, low
Adult and Pediatric 1 month
55 – 64 mg/dL
3.05 – 3.55 mmol/L
40 – 54 mg/dL
2.22 – 3.06 mmol/L
30 – 39 mg/dL
1.67 – 2.23 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Infant*†, < 1 month
50 – 54 mg/dL
2.78 – 3.00 mmol/L
40 – 49 mg/dL
2.22 – 2.77 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Lactate
ULN - < 2.0 x ULN without 
acidosis
2.0 x ULN without
acidosis
Increased lactate with pH < 7.3 without life-
threatening consequences
Increased lactate with pH <7.3 with life-
threatening consequences
LDL cholesterol (fasting)
Adult 18 years
130 – 159 mg/dL
3.37 – 4.12 mmol/L
160 – 190 mg/dL
4.13 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Pediatric > 2 - < 18 years
110 – 129 mg/dL
2.85 – 3.34 mmol/L
130 – 189 mg/dL
3.35 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Lipase
1.1 – 1.5 x ULN
1.6 – 3.0 x ULN
3.1 – 5.0 x ULN
> 5.0 x ULN
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Magnesium, serum, low
1.2 – 1.4 mEq/L
0.60 – 0.70 mmol/L
0.9 – 1.1 mEq/L
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L
0.30 – 0.44 mmol/L
< 0.60 mEq/L
< 0.30 mmol/L
Pancreatic amylase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Phosphate, serum, low
Adult and Pediatric > 14 years
2.5 mg/dL – < LLN
0.81 mmol/L – < LLN
2.0 – 2.4 mg/dL
0.65 – 0.80 mmol/L
1.0 – 1.9 mg/dL
0.32 – 0.64 mmol/L
< 1.00 mg/dL
< 0.32 mmol/L
Pediatric 1 year – 14 years
3.0 – 3.5 mg/dL
0.97 – 1.13 mmol/L
2.5 – 2.9 mg/dL
0.81 – 0.96 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Pediatric < 1 year
3.5 – 4.5 mg/dL
1.13 – 1.45 mmol/L
2.5 – 3.4 mg/dL
0.81 – 1.12 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Potassium, serum, high
5.6 – 6.0 mEq/L
5.6 – 6.0 mmol/L
6.1 – 6.5 mEq/L
6.1 – 6.5 mmol/L
6.6 – 7.0 mEq/L
6.6 – 7.0 mmol/L
> 7.0 mEq/L
> 7.0 mmol/L
Potassium, serum, low
3.0 – 3.4 mEq/L
3.0 – 3.4 mmol/L
2.5 – 2.9 mEq/L
2.5 – 2.9 mmol/L
2.0 – 2.4 mEq/L
2.0 – 2.4 mmol/L
< 2.0 mEq/L
< 2.0 mmol/L
Sodium, serum, high
146 – 150 mEq/L
146 – 150 mmol/L
151 – 154 mEq/L
151 – 154 mmol/L
155 – 159 mEq/L
155 – 159 mmol/L
160 mEq/L
160 mmol/L
Sodium, serum, low
130 – 135 mEq/L
130 – 135 mmol/L
125 – 129 mEq/L
125 – 129 mmol/L
121 – 124 mEq/L
121 – 124 mmol/L
120 mEq/L
120 mmol/L
Triglycerides (fasting)
NA
500 – 750 mg/dL
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL
8.49 – 13.56 mmol/L
> 1,200 mg/dL
> 13.56 mmol/L
Uric acid
7.5 – 10.0 mg/dL
0.45 – 0.59 mmol/L
10.1 – 12.0 mg/dL
0.60 – 0.71 mmol/L
12.1 – 15.0 mg/dL
0.72 – 0.89 mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
URINALYSIS
Standard International Units are listed in italics
Hematuria (microscopic)
6 – 10 RBC/HPF
> 10 RBC/HPF
Gross, with or without clots OR with RBC 
casts
Transfusion indicated
Proteinuria, random
Collection
1 +
2 – 3 +
4 +
NA
 
 
 
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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Proteinuria, 24 hour collection
Adult and Pediatric  10 years
200 – 999 mg/24 h
0.200 – 0.999 g/d
1,000 – 1,999 mg/24 h
1.000 – 1.999 g/d
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d
> 3,500 mg/24 h
> 3.500 g/d
Pediatric > 3 mo -< 10 years
201 – 499 mg/m2/24 h
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 g/d
Values are for term infants.  Preterm infants should be assessed using local normal ranges.
† Use age and sex appropriate values (e.g., bilirubin).
 
 
 
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11.3.
Appendix 3 Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
Chung, 2010; 
Ferrell, 2008
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
 
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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to dolutegravir 50mg/abacavir 
600mg/lamivudine 300mg.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
dolutegravir 50mg/abacavir 600mg/lamivudine 300mg.  If at any time it appears there is 
potential variability in response in this clinical study or in a series of clinical studies with 
dolutegravir 50mg/abacavir 600mg/lamivudine 300mg, the following objectives may be 
investigated – the relationship between genetic variants and study treatment with respect 
to:

Relationship between genetic variants and the pharmacokinetics and/or 
pharmacodynamics of DTG/ABC/3TC or other medicines used in this study

Relationship between genetic variants and safety and/or tolerability of 
DTG/ABC/3TC or other medicines used in this study

Relationship between genetic variants and efficacy of DTG/ABC/3TC or other 
medicines used in this study
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
 
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Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
In addition to any blood samples taken for the clinical study, a whole blood sample (~6 
ml) will be collected for the PGx research using a tube containing EDTA.  It is 
recommended that the blood sample be taken at the first opportunity after a subject has 
been randomised and provided informed consent for PGx research, but may be taken at 
any time while the subject is participating in the clinical study.

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
dolutegravir 50mg/abacavir 600mg/lamivudine 300mg has been completed and the 
clinical study data reviewed.  In some cases, the samples may not be studied. e.g., no 
questions are raised about how people respond to dolutegravir 50mg/abacavir 
600mg/lamivudine 300mg.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
 
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If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to dolutegravir 50mg/abacavir 
600mg/lamivudine 300mg.  The genes that may code for these proteins may also be 
studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarised as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
 
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Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood being taken for 
PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarise the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
 
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References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.
 
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11.4.
Appendix 4: Country Specific Requirements
United Kingdom
This requirement has been included based on requests from the Medicines and Healthcare 
products Regulatory Agency (MHRA) to include information on the specific duration of 
the Open-Label/Continuation Phase for similar Phase III trials being conducted with 
dolutegravir.
Study Duration
The Continuation Phase is intended to provide subjects on DTG/ABC/3TC FDC with 
post study access to DTG/ABC/3TC FDC until the time to achieve local approval.
Therefore, the duration of the Continuation Phase will vary from country to country and 
is dependent on the recruitment time for the ING117172 (ARIA) study and the time taken 
to achieve local approval for marketing. However, in the UK, the Continuation Phase will 
not determine the date of last study treatment administration to subjects. The last date of 
treatment administration for ING117172 (ARIA) in the randomized study phase is 
predicted to be February 2016. Because it is a possibility that the last subject on ARIA 
could present for her final visit pregnant, we have taken into account an additional 9 
months for the duration of pregnancy and the 8-12 week post-partum final study visit; 
therefore the last subject/last visit for ING200336 would be conducted by 28 February 
2017. 
 
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11.5.
Appendix 5: Liver Safety Drug Restart or Rechallenge 
Guidelines
VSLC Guidelines for Drug Restart or Rechallenge after stop for Liver 
criteria
1. Drug rechallenge may be considered for a subject exhibiting compelling benefit 
for a critical medicine following drug-induced liver injury, if favorable benefit: 
risk and no alternative medicine available (Table 9, Figure 1)
2. In Phase III, drug restart may be considered for liver events with a clear 
underlying cause (e.g. biliary, pancreatic events, hypotension, acute viral 
hepatitis), if not associated with drug-induced liver injury, alcoholic hepatitis or 
hypersensitivity, and drug not associated with HLA marker of liver injury, when 
liver chemistries improve to within 1.5xbaseline and ALT<3xULN) (Table 10, 
Figure 2).
Background: Following drug-induced liver injury, drug rechallenge is associated with 
a 13% mortality across all drugs in prospective studies.  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane re-administered in one month of initial 
injury [Andrade, 2009].  However, some drugs seldom result in recurrent liver injury or 
fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) [Andrade,
2009]

jaundice or bilirubin2xULN with initial liver injury 

prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment) [Hunt, 2010] 
VSLC Decision Process for Drug Rechallenge Approval or Disapproval 
(Figure 2): 

Principal Investigator (PI) requests consideration of drug rechallenge for a 
subject receiving compelling benefit from a critical or life-saving drug, who 
exhibits liver chemistry elevation meeting subject stopping criteria, with no 
alternative treatment

By definition treatment naïve subjects will only be considered for rechallenge if 
they were infected with a multi-resistant virus.

Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP)
Physician to review the subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 9).
 
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
The Medical Monitor and GCSP Physician are accountable to review and agree
on:
–
compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history 
–
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:
Initial liver injury event included: fever, rash, eosinophilia, or 
bilirubin2xULN (or direct bilirubin >35% of total, if available)
subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total, if available), or INR1.5
SAE or fatality has earlier been observed with IP rechallenge
IP associated with known preclinical hepatic liability/ injury

Relevant physicians must review and agree on request for drug rechallenge:  
Safety Team Leader, VP, or Senior Safety Physician (GSK)
Medicines Development Leader and Project Physician Leader 
(GSK)Request is taken to full VSLC for final decision 
 
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Figure 2
VSLC process for drug rechallenge approval or disapproval
The local operating company (LOC) ViiV medical director (and GSK where applicable) 
should be informed that study drug rechallenge is under consideration and of the final 
decision, whether or not to proceed.
 
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Table 9
Checklist for drug rechallenge for critical medicine  (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin2xULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
o
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
o
IP associated with known preclinical hepatic liability/ injury
o
Source data defining the patients current resistance profile
o
Previous drug history
Drug Restart
Phase III “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:

immunoallergic injury /HLA association with injury

DILI

alcoholic hepatitis
Study is drug held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval (Figure 
3): 

PI requests consideration of drug re-initiation for a subject stable or improving 
on IP, who exhibits liver chemistry elevation meeting subject stopping criteria, 
which is transient, non-drug-related, and liver chemistries improve to within 
1.5x baseline and ALT< 3xULN. 

GSK Medical Monitor and Clinical Safety Physician to review the subject’s 
diagnosis, restart risk factors and complete checklist (Table 10).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The LOC ViiV medical director (and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.
 
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Table 10
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chemistry 1.5x 
baseline & ALT<3xULN
Yes
No
Is subject stable or improving on the investigational product (IP)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

IP has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate)
Source data defining the patients current resistance profile
Previous drug history

Relevant physicians must review and agree on request for drug restart:  

Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader (GSK).

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this subject must 
be recorded by GCSP Physician and sent to the VSLC Secretary.

VSLC must approve drug re-initiation and dosing regimen
 
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Figure 3
VSLC process for drug restart approval or disapproval
1. Andrade, 2009; 2. Papay, 2009; 3. Hunt, 2010
Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and Medical Monitor must record note 
in study files.

The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC

All severe reactions (rechallenge associated with bilirubin>2xULN or jaundice, 
or INR1.5), SAEs or fatalities with drug rechallenge (or restart) must be 
immediately reported to Line Management, VSLC Chair, VP Global Medical 
Strategy (ViiV) and EU Qualified Person for Pharmacovigilance. 
 
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Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of 
drug rechallenge or restart, as required. 

If drug re-initiation VSLC-approved, the patient must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.
–
Targeted drug rechallenge or drug restart consent form must be used.

The patient’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for one month or for as long as clinically 
indicated following drug re-initiation.  If subject exhibits protocol-defined liver 
chemistry elevations, IP should be discontinued as protocol specified.
VSLC and the Ethics Comm. or Institutional Review Board must be informed of the 
patient’s outcome following drug rechallenge or restart.
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject stopping criteria

3 = serious adverse event

4 = fatality
REFERENCES:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 
 
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11.6.
Appendix 6: Protocol Amendment Changes
Amendment 01
Removal of Reference in Table of Content
Correction of misspellings in the abbreviation list (LLDO to LLOD, Fumerate to 
Fumarate, VSS/F [volme to volume)
Section 1: Introduction revised based on newest WHO guidelines
Section 3.1:

Mothers: addition of “if feasible” to “At delivery, if feasible, a cord blood and 
time-match maternal blood sample will be collected…”

Addition of “pregnancy outcomes are collected in the eCRF “Delivery Visit’”: 
Please note: In the event of a spontaneous loss of pregnancy during the study, 
pregnancy outcomes are collected in the eCRF “Delivery Visit”.  
Section 4.1: removal of “we”: Should 12 subjects enroll, this would likely be sufficient
to obtain at least 8 subjects providing evaluable DTG PK parameters in the third trimester 
and postpartum.
Section 5.6.2.1: barbiturates added to prohibited medication list
Section 6: Study Assessments and Procedures Table

Added footnote to Medical History and “tick marks” at post-partum and 
continuation visits.  
Note this additional footnote changed the numbering order of the footnotes.

* footnote, typo correction (“and data” removed)

5Limited PE: heart rate was added

7Intensive PK: note regarding Cord and Maternal blood removed and sentence 
revised for clarity

8Cord and Maternal Blood footnote added as stand alone footnote

13 “methods” added:  Note: after delivery, subjects must use one of the 
contraception methods to avoid a ‘new’ pregnancy 
Section 6.2.2.: Important Information on collection of PK samples

Sentence changed for clarity: If the dosing card is missing, blank, or incomplete, 
obtain the missing information by oral interview by site personnel and retain 
in source documents

Final paragraph revised: On the days of the PK sampling visits (other than 
Delivery)
 
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Table 5: Chlorine corrected to chloride
Section 6.5.12: Section reference corrected (Section 6.4.1 to Section 6.5.14) 
References: Cockroft – Typo correction (Pediction to Prediction)
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events was 
added as a new appendix, changing Appendix numbers for all other appendices.  It’s now 
Appendix 2
Appendix 3 changed to Appendix 4; this UK specific amendment was revised to provide 
clarity regarding the LSLV
 
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Amendment 02
Amendment 02 corrected typographical errors in Amendment 1: 

Specifically, in the Summary of Revisions, page 1, the reader is referred to Time 
and Events Table 6; it should be Table 4.  

The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events was added as a new appendix, changing numbers of other appendices. It’s 
inclusion also needed to be added to Appendix 6.  

Lastly, where the Summary of Revisions says Appendix 3, it should be 
Appendix 4.
 
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Protocol Amendment 03
This protocol amendment applies to all participating sites.
Rationale for Protocol Amendment 03:
Changes were made to the protocol to manage and mitigate risks following identification 
of a potential safety issue related to neural tube defect in infants born to women with 
exposure to dolutegravir at the time of conception.

The Rationale and Risk Assessment sections (Section 1.2. and Section 1.3.1.) were
updated to include language regarding risk and mitigation of neural tube defects.

The Withdrawal Criteria (Section 4.5.) were updated to include a reminder that post-
delivery, subjects who desire to be pregnant, or who state they are not willing/no 
longer willing to comply with the approved pregnancy avoidance methods, should be 
withdrawn from the study.

The Time and Events table (Section 6.) was updated to include a footnote to clarify 
the requirement for pregnancy tests post-delivery, and a reminder for investigators to 
check at every post-delivery visit that subjects are avoiding pregnancy.

Contraception Requirements for the Post-Partum and Continuation Phases (Section 
6.5.4.8.) were updated with the most recent list of ‘highly effective methods for 
avoiding pregnancy in females of reproductive potential’, which excludes the double 
barrier method of contraception.
Administrative changes were made.
LIST OF SPECIFIC CHANGES
Unless stated otherwise, new text is represented in bold font, and deleted text in 
strikethrough font.

Authors
 

Title Page
Copyright 2018 the ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited

Sponsor Information Page; Medical Monitor Contact Information and Serious 
Adverse Events (SAE) Contact Information: 
, MD
GlaxoSmithKline
 
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Research Triangle Park
Five Moore Drive, Research Triangle Park, NC (USA)
Telephone:
Mobile:
e-mail:
 MD
ViiV Healthcare,
5 Moore Drive, 
Research Triangle Park, NC 27709, USA
Mobile:
Facsimile:
e-mail:

Section 1.2. Rationale
While noFew studies have been conducted with DTG in pregnant women, DTG iswas
not anticipated to increase the risk of adverse development or reproductive outcomes in 
humans. Recently, early results from an unplanned interim analysis of an ongoing 
birth outcome surveillance study in Botswana showed that 4/426 (0.9%) of women 
who were taking DTG when they became pregnant had babies with neural tube 
defects compared to a background rate of 0.1%.  Extensive clinical data is available 
on ABC and 3TC, and this data suggests that the use of ABC and 3TC do not lead to 
adverse outcomes for the mother or baby when used in pregnancy.  Additionally, for 
women who are already receiving, tolerating and responding virologically to 
DTG/ABC/3TC, there may be benefit in continuing the regimen after pregnancy is 
confirmed (if after the first trimester), as the mother may be more likely to continue a 
familiar and effective regimen.  Additional PK, safety and efficacy data is required to 
further inform the use of DTG and DTG/ABC/3TC in pregnancy.
 
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Section 1.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy1,2
Investigational Product (IP) [DTG/ABC/3TC FDC]
Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on ABC/3TC
Fetuses are most susceptible 
to potential teratogenic 
effects of drugs during 1st
trimester
With other ART agents, there are 
concerns with regard to teratogenicity 
(e.g., EFV) and maternal hepatic/rash 
toxicity (i.e., nevirapine).
ABC and 3TC have high level of 
transplacental transfer.
Data available for teratogenic risk 
described in Section 1.2.  See the IB 
and product labels for additional 
information.
There is no specific mitigation of risk to the 
fetus however, the risk is felt to be low 
based on all available data for DTG, ABC 
and 3TC.  Frequent visits to monitor 
clinical and laboratory parameters and 
routine care by the HIV care provider (via 
this protocol), and routine care by 
appropriate provider of healthcare to 
pregnant women
Potential teratogenic effects 
of DTG/ABC/3TC: DTG: 
Neural Tube Defects
The safe use of DTG/ABC/3TC in 
human pregnancy has not been 
established.  DTG, ABC and 3TC have 
been shown to cross the placenta in 
reproductive toxicity studies in animals.  
3TC and ABC, but not DTG, have been 
associated with findings in animal 
reproductive studies but have been 
used in human pregnancy without 
evidence for increased risk of 
teratogenicity. See the most current IB 
for additional information [Antiretroviral 
Pregnancy Registry Steering 
Committee, 2013; Vannappagari, 2013; 
GlaxoSmithKline Document Number 
RM2007/00683/] [GSK Document 
Number RM2007/00683/11, GSK 
Document Number 2017N352880_00, 
GSK Document Number
2017N352880_01]
.
There has been no association between 
ABC or 3TC and overall birth defects 
observed in the Antiretroviral Pregnancy 
Registry (APR), although there are 
some limitations to these data 
(http://apregistry.com/index.htm).
In one ongoing birth outcome 
surveillance study in Botswana, early 
results from an unplanned interim 
analysis show that 4/426 (0.9%) of 
women who were taking DTG when 
they became pregnant had babies 
with neural tube defects compared to 
a background rate of 0.1%.
There is no specific mitigation of risk to the 
fetus however, the risk is felt to be low 
based on all available data for DTG, ABC 
and 3TC.  
1.
A subject is eligible to continue in 
the study post-delivery if she is 
not pregnant, and agrees to follow 
one of the options listed in the 
Modified List of Highly Effective 
Methods for Avoiding Pregnancy 
in Females of Reproductive 
Potential (FRP) (see Section 
6.5.4.8.) until at least 2 weeks after 
discontinuation of IP.
2. Subjects who are post-delivery and 
desire to be pregnant, or who state 
they are not willing/no longer 
willing to comply with the 
approved pregnancy avoidance 
methods, will have study treatment 
discontinued and be withdrawn 
from the study. 
3. Subjects who are post-delivery are 
reminded re: pregnancy avoidance 
and adherence to contraception 
requirements at every study visit.
4. Pregnancy status is monitored at 
every study visit post-delivery.
Pregnancies must be followed up to 
determine outcome (including premature 
termination) and status of mother and 
child.  GSK’s central safety department will 
also forward this information to the APR 
(Section 6.5.11).
 
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
Section 4.5. Withdrawal Criteria
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

A new pregnancy during the Continuation Phase as described in Section 3.1.  As a 
reminder, subjects who are post-delivery and desire to be pregnant, or who state 
they are not willing/no longer willing to comply with the approved pregnancy 
avoidance methods, should also be withdrawn from the study.

Section 6. Table 4. Time and Events Table
Footnote number ‘15’ has been added:
15. Serum pregnancy tests will be performed at the Post-Partum and Continuation 
Phase visits.  Remind subjects who are post-delivery of the need to avoid pregnancy 
while in the study and adherence to the study’s contraception requirements.
Corrections to the footnote referencing have also been made for footnotes 11 and 12.

Section 6.5.4.8. Contraception Requirements for the Post-Partum and 
Continuation Phase Only
A subject will be eligible to enter and participate in the Continuation Phase if she agrees 
to use one of the following approved methods of contraception to avoid a ‘new’ 
pregnancy:

Complete abstinence from intercourse from delivery, throughout the study, 
and for at least 2 weeks after discontinuation of all study medications;

Double barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide);

Any intrauterine device (IUD) with published data showing that the expected 
failure rate is <1% per year (not all IUDs meet this criterion, see the SPM for 
an example listing of approved IUDs);

Any other method with published data showing that the expected failure rate 
is <1% per year.
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and 
will continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
1.  Contraceptive subdermal implant
2.  Intrauterine device or intrauterine system
 
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3.  Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.  Injectable progestogen [Hatcher, 2011]
5.  Contraceptive vaginal ring [Hatcher, 2011]
6.  Percutaneous contraceptive patches [Hatcher, 2011]
7.  Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination, and/or 
semen analysis, or medical history interview provided by her or her partner. 
Any contraception method must be used consistently, in accordance with the approved 
product label and for at least 2 weeks after discontinuation of IP.  The investigator is 
responsible for ensuring that subjects understand how to properly use these 
methods of contraception.
All subjects participating in the study should be counselled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/spermicide).

Section 10. References
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01, December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02, June 2018.
GlaxoSmithKline Document Number RM2007/00683/0611: GSK1349572 Clinical 
Investigator's Brochure. February 2013. Version 11, October 2017.
References to the DTG IB were also updated throughout the protocol to reference the 
current DTG IB.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, 
Inc., 2011: 50. Table 3-2.
 
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