Clinical trial NCT02227238
Conditions: HIV Infections
Keywords: integrase inhibitor non-inferiority dolutegravir lopinavir/ritonavir second-line treatment HIV-1 antiretroviral therapy-experienced
Sponsor: ViiV Healthcare
Start date: 2014-12-11; Completion date: 2022-02-14
Enrollment: 627 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment and subjects originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.

Detailed description:

Arms: arm 1: Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator arm 2: Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator
Interventions: intervention 1: DTG intervention 2: LPV/RTV intervention 3: Two NRTIs
Intervention descriptions: intervention 1: DTG is supplied as 50 mg tablets intervention 2: LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV intervention 3: Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC

Protocol documents:
Prot_002.pdf: 
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ViiV Healthcare and the GlaxoSmithKline group of companies
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N172672_00
2014-APR-01
Original
2013N172672_01
2014-APR-30
Amendment No. 1
This amendment includes the removal of exclusion criterion 18 (subject has creatinine 
clearance of <50 mL/min via the CKD-EPI method).  Allergic reaction criteria are 
referred to in Section 4.5 “Withdrawal criteria”.  Furthermore, the sequence of 
administration of the HIVTSQ status and change versions has been amended.  Other 
minor clarifications and corrections have been incorporated.
2013N172672_02
2017-APR-19
Amendment No. 2
This amendment includes a change in the study design giving subjects originally 
randomised to the LPV/RTV arm the option to switch to the DTG arm prior to study 
completion.  This change is being implemented following an IDMC recommendation to 
discontinue the LPV/RTV arm.  Revisions to the Suicidality Monitoring and data analysis 
sections and edits to the Time and Events Table are also included.  Other minor 
clarifications and corrections have been incorporated.
2013N172672_03
2018-JUN-19
Amendment No. 3
This amendment includes changes to manage and mitigate risks following identification 
of a potential safety issue related to neural tube defects in infants born to women with 
exposure to dolutegravir at the time of conception. The changes include updates to the 
Risk Assessment and acceptable methods of contraception, and a reminder that females 
of childbearing potential who change their minds and desire to be pregnant or who do not 
wish to comply with the approved pregnancy avoidance methods, should be withdrawn 
from the study.  Investigators are also reminded to check at every visit that females of 
childbearing potential are avoiding pregnancy. Other minor clarifications and corrections 
have been incorporated.


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Cli nic al St u d y I de ntifier: 2 0 0 3 0 4
T his st u d y  is s p o ns ore d b y Vii V Healt hcare.  Gla x o S mit h Kli ne is s u p p orti n g Vii V 
Healt hcare i n t he c o n d uct of t h is st u d y.
S p o ns or N a me a n d Le g al Re gistere d A d dress (e xcl u di n g U S) :
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le gal e ntit y. I n t hese i nsta nces, t he a p pr o priate c o m pa n y t o be i de ntifie d as s p o ns or m ust 
be a gree d wit h t he gl o bal Vii V Healt hcare cli nical tea m a n d si g ne d off b y t he V P a n d 
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Me dic al M o nit or C o nt act I nf or m ati o n a n d Seri o us A d verse E ve nts ( S A E) C o nt act 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200304
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...........................................................................................10
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................18
1.1.
Background ................................................................................................18
1.2.
Rationale ....................................................................................................20
1.3.
Benefit:Risk Assessment ............................................................................20
1.3.1.
Risk Assessment .........................................................................20
1.3.2.
Benefit Assessment.....................................................................25
1.3.2.1.
Analysis of subjects receiving DTG + 1-2 
NRTIs in SAILING ......................................................25
1.3.3.
Overall Benefit:Risk Conclusion...................................................26
2.
OBJECTIVES.........................................................................................................26
3.
INVESTIGATIONAL PLAN.....................................................................................27
3.1.
Study Design ..............................................................................................27
3.2.
Discussion of Design ..................................................................................31
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................32
4.1.
Number of Subjects ....................................................................................32
4.2.
Inclusion Criteria.........................................................................................32
4.3.
Exclusion Criteria........................................................................................35
4.4.
Other Eligibility Criteria Considerations.......................................................36
4.5.
Withdrawal Criteria .....................................................................................37
4.6.
Virologic Criteria for Subject Management and Viral Resistance 
Testing........................................................................................................38
4.6.1.
Virologic Withdrawal Criteria........................................................39
4.6.2.
Managing Subjects Meeting Suspected Virologic 
Withdrawal Criteria ......................................................................39
4.6.3.
Managing Subjects Meeting Confirmed Virologic 
Withdrawal Criteria ......................................................................40
4.7.
Retest Criteria for Subjects with Plasma HIV-1 RNA Levels between 
50 c/mL and <400 c/mL at Week 48..........................................................41
4.8.
Screening Failures......................................................................................41
5.
STUDY TREATMENTS..........................................................................................41
5.1.
Investigational Product and Other Study Treatment....................................41
5.1.1.
Tablet Formulation of DTG ..........................................................42
5.1.2.
Tablet Formulation of LPV/RTV ...................................................42
5.1.3.
Background NRTIs ......................................................................42
5.1.4.
Dosage and Administration..........................................................43
5.1.5.
Protocol-Permitted Substitutions..................................................43
5.2.
Treatment Assignment................................................................................44
5.3.
Blinding.......................................................................................................44
5.4.
Product Accountability ................................................................................44
5.5.
Treatment Compliance................................................................................45


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5.6.
Concomitant Medications and Non-Drug Therapies....................................45
5.6.1.
Permitted Medications and Non-Drug Therapies..........................45
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................46
5.6.3.
Prohibited medications for subjects randomised to DTG..............46
5.6.4.
Prohibited medications for subjects randomised to 
LPV/RTV......................................................................................47
5.7.
Treatment of Tuberculosis ..........................................................................48
5.8.
Treatment after the End of the Study ..........................................................48
5.9.
Treatment of Study Treatment Overdose....................................................49
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
6.1.
Time and Events Schedule .........................................................................50
6.2.
Critical Screening and Baseline Assessments ............................................54
6.2.1.
Screening Assessments ..............................................................54
6.2.2.
Baseline (Day 1) Assessments ....................................................55
6.2.3.
Subjects Co-infected with Hepatitis B Virus (HBV).......................55
6.2.4.
Subjects Co-infected with Hepatitis C Virus (HCV) ......................56
6.3.
Efficacy.......................................................................................................56
6.3.1.
Efficacy Evaluations.....................................................................56
6.3.2.
Primary Endpoint .........................................................................57
6.3.3.
Secondary Efficacy Endpoints .....................................................57
6.4.
Safety .........................................................................................................57
6.4.1.
Safety Evaluations.......................................................................57
6.4.2.
Safety Endpoints..........................................................................58
6.4.3.
Toxicity Management...................................................................59
6.4.4.
Specific Toxicities/Adverse Event Management...........................60
6.4.4.1.
Liver chemistry stopping and follow up criteria............61
6.4.4.2.
Restarting investigational product...............................63
6.4.4.3.
Hypertriglyceridemia/hypercholesterolemia ................64
6.4.4.4.
CPK elevation.............................................................64
6.4.4.5.
Decline in renal function .............................................64
6.4.4.6.
Allergic reaction..........................................................65
6.4.4.7.
Rash...........................................................................65
6.4.5.
Adverse Events............................................................................66
6.4.5.1.
Definition of an AE......................................................66
6.4.5.2.
Definition of an SAE ...................................................67
6.4.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................68
6.4.7.
Cardiovascular Events.................................................................69
6.4.8.
Death Events...............................................................................69
6.4.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................69
6.4.10.
Suicidality Monitoring...................................................................70
6.4.11.
Pregnancy ...................................................................................70
6.4.11.1.
Pregnancy testing.......................................................70
6.4.11.2.
Action to be taken if pregnancy occurs .......................71
6.4.11.3.
Time period for collecting pregnancy
information .................................................................71
6.4.12.
Time Period and Frequency of Detecting AEs and SAEs.............71
6.4.13.
Method of Detecting AEs and SAEs.............................................72
6.4.14.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................72


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6.4.14.1.
Regulatory reporting requirements for SAEs ..............73
6.4.15.
Other Safety Outcomes ...............................................................74
6.5.
Health Outcomes........................................................................................74
6.5.1.
Health Outcome Endpoints ..........................................................75
6.6.
Viral Genotyping and Phenotyping..............................................................75
6.6.1.
Virology Endpoint.........................................................................75
6.6.2.
HIV-1 Pol Viral Genotyping and Phenotyping...............................75
6.6.3.
HIV-1 Exploratory Analysis ..........................................................76
6.7.
Pharmacogenetic Research........................................................................76
7.
DATA MANAGEMENT ...........................................................................................76
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................77
8.1.
Hypotheses.................................................................................................77
8.2.
Study Design Considerations......................................................................77
8.2.1.
Sample Size Assumptions ...........................................................77
8.2.2.
Sample Size Sensitivity................................................................79
8.2.3.
Sample Size Re-estimation..........................................................79
8.3.
Data Analysis Considerations .....................................................................79
8.3.1.
Analysis Populations....................................................................79
8.3.2.
Analysis Data Sets.......................................................................80
8.3.3.
Treatment Comparisons ..............................................................81
8.3.3.1.
Primary comparisons of interest .................................81
8.3.3.2.
Other comparisons of interest.....................................81
8.3.3.3.
Secondary comparisons .............................................81
8.3.4.
Interim Analysis ...........................................................................82
8.3.4.1.
Week 24 data cut .......................................................82
8.3.4.2.
IDMC interim analyses ...............................................82
8.3.5.
Key Elements of Analysis Plan ....................................................84
8.3.5.1.
Efficacy analyses........................................................84
8.3.5.2.
Safety analyses..........................................................86
8.3.5.3.
Health outcomes analyses..........................................86
8.3.5.4.
Viral genotyping/phenotyping analyses.......................87
8.3.5.5.
Pharmacogenetic analyses.........................................87
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................88
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............88
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................88
9.3.
Quality Control (Study Monitoring) ..............................................................88
9.4.
Quality Assurance.......................................................................................89
9.5.
Study and Site Closure ...............................................................................89
9.6.
Records Retention......................................................................................90
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................90
9.8.
Independent Data Monitoring Committee (IDMC) .......................................91
10. REFERENCES.......................................................................................................92
11. APPENDICES........................................................................................................96
11.1.
Appendix 1: Child-Pugh Classification ........................................................96
11.2.
Appendix 2: CDC Classification System for HIV-1 Infections (1993) ...........97


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11.3.
Appendix 3: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events...................................................................100
11.4.
Appendix 4: Liver Safety Drug Restart or Rechallenge Guidelines............118
11.5.
Appendix 5: Pharmacogenetic Research ..................................................124
11.6.
Appendix 6: Country Specific Requirements.............................................130
11.7.
Appendix 7: Protocol Changes..................................................................131
11.7.1.
Protocol Amendment 01 ............................................................131
11.7.2.
Protocol Amendment 02 ............................................................134
11.7.3.
Protocol Amendment 03 ............................................................142


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LIST OF ABBREVIATIONS
3TC
Lamivudine, EPIVIR
AE
Adverse event
ABC
Abacavir, ZIAGEN
ABC/3TC 
Abacavir/Lamivudine, EPZICOM, KIVEXA
ACTG
AIDS Clinical Trials Group
AIDS
Acquired immune deficiency syndrome
ALT
Alanine aminotransferase
anti-HBc
Antibody to hepatitis B core antigen
anti-HCV
Antibody to hepatitis C virus
APAP
Acetaminophen
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
ATV
Atazanavir, Reyataz
BUN
Blood urea nitrogen
c/mL
Copies/millilitre
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 
(cluster of differentiation 4)
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
COBI
Cobicistat, Tybost
CPK
Creatine phosphokinase
CRF/eCRF
Case report form/electronic case report form
CSR
Clinical study report
C-SSRS
Columbia Suicidality Severity Rating Scale
d4T
Stavudine
DAIDS
Division of Acquired Immune Deficiency Syndrome
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DTG
Dolutegravir
ECG
Electrocardiograph
EFV
Efavirenz
ELV
Elvitegravir
EMA
European Medicines Agency
FDA
Food and Drug Administration
FTC
Emtricitabine
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance  
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
GSRS
Gastrointestinal Symptom Rating Scale
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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HDL
High density lipoprotein
HDPE
High density polyethylene
HIV-1
Human immunodeficiency virus type 1
HIVTSQ
HIV Treatment Satisfaction Questionnaire
HIVTSQs
HIVTSQ status version
HIVTSQc
HIVTSQ change version
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
Investigator’s brochure
ICH
International Conference on Harmonization 
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IgM
Immunoglobulin M
INI
Integrase inhibitor
IP
Investigational product
IRB
Institutional review board
IRIS
Immune reconstitution inflammatory syndrome
ITT
Intent to Treat
IUD
Intrauterine device
IVRS
Interactive voice recognition system
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LLOD
Lower limit of detection
LPV/RTV
Lopinavir/ritonavir, Kaletra
LSLV
Last subject’s last visit
MCV
Mean corpuscular volume
MMAS-8
Morisky 8-Item Medication Adherence Scale
MSDF
Missing, switch or discontinuation = failure
MSDS
Material safety data sheet 
mg
Milligram
mL
Millilitre
NCEP
National Cholesterol Education Program
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
OCT2
Organic cation transporter 2
PBMC
Peripheral blood mononuclear cell
PDVF
Protocol defined virologic failure
PGx
Pharmacogenetic
PI
Protease inhibitor
PK
Pharmacokinetic
Pol
Polymerase
PP
Per protocol
PRO
Protease
PSRAE
Possible suicidality related adverse event
QTC
Corrected QT interval
RAL
Raltegravir, Isentress
RAP
Reporting and analysis plan


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RBC
Red blood cells
RNA
Ribonucleic acid
RT
Reverse transcriptase
RTV
Ritonavir, Norvir
SAE
Serious adverse event
SDAC
Statistics Data Analysis Centre
SJS
Stevens Johnson Syndrome
SPM
Study procedure manual
STR
Single tablet regimen
TAM
Thymidine analogue mutation
TC
Total cholesterol
TEN
Toxic epidermal necrolysis
TDF
Tenofovir disoproxil fumarate, Viread
ULN
Upper limit of normal
US
United States
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Atripla 
(efavirenz/tenofovir/emtricitabine)
EPZICOM
GenoSure
KIVEXA
Isentress (raltegravir)
TIVICAY
Kaletra (lopinavir/ritonavir)
TRIZIVIR
Monogram Biosciences
ZIAGEN
Norvir (ritonavir)
Phenosense
Quest Diagnostics
Reyataz (atazanavir)
Stribild (elvitegravir/cobicistat/ 
tenofovir/emtricitabine)
Tybost (cobicistat)
Vitekta (elvitegravir)


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PROTOCOL SUMMARY
Rationale
Access to antiretroviral therapy (ART) in low-income and middle-income countries has 
been scaled-up effectively over recent years. Despite these advances, the number of 
patients failing on their first-line regimen is increasing thereby requiring a switch to 
second-line treatment to reduce accumulation of drug-resistance mutations, disease 
progression, human immunodeficiency virus (HIV) transmission, and death.  Publicly 
funded programmes tend to follow World Health Organization (WHO) guidelines to use 
a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside 
reverse transcriptase inhibitors (NRTIs) for first-line ART; however, there is a need for 
further data on the best treatment options for people with HIV-1 who have virological 
failure with this first-line regimen.  WHO guidelines recommend second-line 
antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease 
inhibitor (PI); atazanavir plus ritonavir (ATV+RTV) or lopinavir (LPV)/RTV are the 
preferred boosted PI options.
Several studies have been conducted or are currently underway to investigate novel 
treatment strategies (i.e. NRTI-sparing regimens) in patients requiring second-line ART.  
There are currently no studies ongoing to explore the potential option of PI-sparing 
second-line ART.  This strategy, especially with the availability of agents from non-PI 
classes with a high barrier to resistance, may have some advantages over PI-based 
regimens, particularly from a safety and tolerability perspective.  This study compares a 
second-line regimen of dolutegravir (DTG) plus two NRTIs with a WHO-recommended 
regimen of LPV/RTV plus two NRTIs.
Objectives
Primary Objective

To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-recommended 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy.
Secondary Objectives

To demonstrate non-inferior antiviral activity at 24 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a recommended WHO 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy;

To evaluate the antiviral and immunological activity and incidence of disease 
progression (HIV-associated conditions, AIDS and death) of DTG compared to 
LPV/RTV over time;


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
To assess the development of viral resistance in subjects meeting confirmed 
virologic withdrawal criteria;

To evaluate the safety, tolerability, and laboratory parameters of DTG compared to 
LPV/RTV over time; 

To compare the effects of DTG and LPV/RTV on fasting lipids over time;

To compare the effects of DTG and LPV/RTV on the occurrence of gastrointestinal 
adverse events over time;

To compare the change in gastrointestinal symptom rating score for subjects treated 
with DTG and LPV/RTV over time;

To compare the satisfaction with treatment of patients with DTG compared to the 
LPV/RTV over time;

To compare patients’ adherence with DTG compared to the LPV/RTV over time;

To evaluate the effect of patient demographics and baseline characteristics (e.g. 
demographic factors, HIV-1 subtype, baseline CD4+ cell count) on response to DTG 
compared to LPV/RTV over time.
Study Design
This study is a Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel 
group, non-inferiority study.  Approximately 612 adult patients with confirmed virologic 
failure (HIV-1 RNA 400 copies/mL [c/mL] on two occasions) on their first 
antiretroviral regimen consisting of one NNRTI + two NRTIs will be recruited.  Subjects 
will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV (800/200 mg once 
daily or 400/100 mg twice daily, in accordance with investigator decision and local 
label), each added to an investigator selected background regimen consisting of two 
NRTIs.  The background regimen shall be constructed by the investigator based on viral 
resistance testing at Screening and be composed of at least one fully active NRTI plus 
one more NRTI which may or may not be active.  In consultation with the medical 
monitor, lamivudine (3TC) may be added as a third NRTI to a dual-NRTI background 
regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC 
(e.g. M184V).  3TC cannot be added to regimens that include FTC. 
Randomisation will be stratified by Screening plasma HIV-1 RNA (100,000 c/mL or 
>100,000 c/mL) and number of fully active NRTIs in the investigator selected study 
background regimen (2 versus <2).
The study will comprise a Screening Phase (approximately 28 to 42 days), a Randomised 
Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase.
The 4-week treatment extension up to Week 52 within the Randomised Phase is to allow 
for the collection of a confirmatory viral load measurement in subjects presenting with 
HIV-1 RNA 50 c/mL at the Week 48 visit.  The primary efficacy endpoint corresponds 


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to viral load measurements collected within a 6 week window around the Week 48 visit 
(including data from the Week 52 visit), as per the FDA’s Snapshot algorithm, and for 
this reason, the primary analysis is denoted as occurring at Week 48 with the 
understanding that data from the Week 52 visit may be included.
The primary analysis at Week 48 will take place after the last subject completes 52 weeks 
on therapy (Day 1 to Week 48 plus a 4-week treatment extension). An interim analysis 
and data cut will be conducted after the last subject completes 24 weeks on therapy, with 
the intent to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  A switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily 
and the opposite switch and a single change of one of the background NRTIs for toxicity 
or tolerability management is allowed.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing. A switch from 3TC to 
emtricitabine (FTC) (or vice versa) will not be considered a background NRTI change 
and is permitted.  No other dose reductions, modifications in dosage, or changes in the 
frequency of dosing will be allowed in this study.
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
will continue to have access to DTG (Continuation Phase) until it is either locally 
approved and commercial supplies are available to patients (e.g. through public health 
services), the patient no longer derives clinical benefit, or the patient meets a protocol-
defined reason for discontinuation.  Subjects randomised to the LPV/RTV arm will 
receive LPV/RTV through their Week 48 visit and during the 4-week treatment extension
only, after which they will complete the study and will need to have alternate 
arrangements in place to access antiretroviral medication.
An IDMC has been instituted to perform periodic reviews of the accumulating data to 
ensure that subjects are not being sub-optimally treated.  The IDMC completed two of 
the three pre-planned analyses.  Prior to interim analysis #3, the IDMC conducted 
an ad-hoc review of trial data and observed significant, clinically relevant 
differences between treatment arms in favour of DTG.  The IDMC recommended to 
the sponsor that the LPV/RTV treatment arm be discontinued and subjects
currently receiving LPV/RTV in the study be switched to a regimen with DTG as 
the third drug, if considered appropriate by the Investigator.  As per Protocol 
Amendment No. 2, subjects randomised to the LPV/RTV arm will either (i) continue 
receiving LPV/RTV and complete the study after the 4-week treatment extension 
(see above), or (ii) switch to the DTG arm prior to study completion at Week 52 and
continue to have access to DTG in the Continuation Phase until DTG is either 
locally approved and commercial supplies are available to patients (e.g. through 
public health services), the patient no longer derives clinical benefit, or the patient 
meets a protocol-defined reason for discontinuation.  Subjects originally randomised 
to DTG and receiving DTG in the Randomised Phase or in the Continuation Phase 
are not affected by this IDMC recommendation and Protocol Amendment No. 2.


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Study Endpoints/Assessments
The primary endpoint for this study will be the proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot algorithm (Missing, Switch or 
Discontinuation = Failure) for the intent-to-treat exposed (ITT-E) population.
Secondary efficacy endpoints will include: 

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm; 

Proportion of subjects with plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48 
using the Snapshot algorithm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack 
of efficacy);

Time to viral suppression (HIV-1 RNA <50 c/mL);

Absolute values and changes from Baseline in CD4+ cell counts at Weeks 24 and 48;

Incidence of disease progression (HIV-associated conditions, AIDS and death).
Safety endpoints will include: 

Incidence and severity of AEs and laboratory abnormalities; 

Absolute values and changes over time in laboratory parameters; 

Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48; 

Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48;

Incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 24 and 48; 

Incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Weeks 24 and 48;

Proportion of subjects who discontinue treatment due to AEs. 
Health outcome endpoints will include: 

Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS), at 
Week 4, Week 24, and Week 48; 

Change from Baseline in treatment satisfaction, using the HIV-Treatment 
Satisfaction Questionnaire (HIVTSQ), at Weeks 4, 24, and 48;

Change from Baseline in adherence with treatment, using the Morisky Medication 
Adherence eight item scale (MMAS-8), at Weeks 4, 24 and 48.
Virology endpoints will include:


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
Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, 
LPV/RTV and other on-study ART in subjects meeting confirmed virologic 
withdrawal criteria.


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1.
INTRODUCTION
1.1.
Background
Integrase inhibitors (INIs) are a relatively new class of antiretroviral drugs designed to 
block the action of the integrase viral enzyme, which catalyzes several key steps in the 
human immunodeficiency virus type 1 (HIV-1) life cycle and is responsible for insertion 
of the viral genome into the deoxyribonucleic acid (DNA) of the host cell. Since 
integration is an essential step in retroviral replication, it is an attractive target for HIV 
therapy.  The first HIV INI, raltegravir (RAL) [Isentress Package Insert, 2013; Isentress, 
Summary of Product Characteristics, 2013], was approved by the United States (US) 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2007.  
Elvitegravir (ELV), another HIV INI, was approved by the US FDA in 2012 and by the 
EMA in 2013 as part of a single tablet regimen (STR) with cobicistat (COBI), tenofovir 
(TDF), and emtricitabine (FTC) [Stribild Package Insert, 2013; Stribild Summary of 
Product Characteristics, 2013] as well as for use as an individual drug by the EMA in 
November 2013 [Vitekta Summary of Product Characteristics, 2013].  
Dolutegravir (DTG) is a next-generation INI with low-moderate inter-subject 
pharmacokinetic variability, a predictable exposure-response relationship and a 14-hour 
plasma half-life that supports once daily dosing without the need for the PK boosters that 
are required with ELV.  DTG was approved by the US FDA in August 2013 and by the 
EMA in January 2014 [TIVICAY Package Insert, 2017; TIVICAY Summary of Product 
Characteristics, 2017].
To date, the efficacy, pharmacokinetics, safety and drug interaction potential of DTG 
have been evaluated in an extensive program of Phase I to III clinical trials.  Data are 
summarised in the Investigator’s Brochure (IB [GlaxoSmithKline Document Number 
.RM2007/00683/11]; IB Supplement 01 [GlaxoSmithKline Document Number
[2017N352880_00]; IB Supplement 02 [GlaxoSmithKline Document Number
2017N352880_01]).  In both antiretroviral therapy (ART)-naïve and ART-experienced 
(INI- naïve) patients, the safety profile for DTG 50 mg once daily was comparable to 
RAL and darunavir plus ritonavir (DRV+RTV) and generally favourable to the STR of 
efavirenz (EFV)/TDF/FTC (Atripla) (studies ING113086 [SPRING-2], ING111762 
[SAILING], ING114915 [FLAMINGO] and ING114467 [SINGLE]).  The most 
frequently observed AEs across patient populations were diarrhoea, nausea, and 
headache, which were generally Grade 1 or 2 in severity, and typically did not lead to 
discontinuation from studies.  With regards to antiviral efficacy, 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 dual nucleoside reverse transcriptase inhibitor 
(NRTI) background regimen [SPRING-2].  In study ING114915 [FLAMINGO], 
virologic suppression (HIV-1 RNA <50 copies/mL [c/mL]) in the DTG arm was 
statistically superior to the DRV+RTV arm at Week 48.  DTG used in combination with 
abacavir/lamivudine (ABC/3TC, EPZICOM/KIVEXA™) was also shown to be superior 
to EFV/TDF/FTC at Week 48, a result driven by better tolerability of the DTG-based 
regimen [SINGLE].  DTG also demonstrated superior virologic suppression (HIV-1 RNA 
<50 c/mL) compared with RAL in combination with investigator selected two drug 
background regimen for INI-naïve treatment experienced patients in the Phase III study 


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ING111762 [SAILING].  Finally, DTG also showed good efficacy in ART-experienced 
patients with INI resistance in ING112574 [VIKING-3].  
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 with INI resistance were observed when compared 
with RAL. Data from Phase III studies [SPRING-2, SINGLE and FLAMINGO] in 
treatment-naive subjects are also supportive of a high barrier to resistance.
Access to ART in low-income and middle-income countries has been scaled-up 
effectively over recent years reaching 8 million people by the end of 2011 [UNAIDS, 
2012]. Despite these advances, the number of patients failing on their first-line regimen is 
increasing thereby requiring a switch to second-line treatment to reduce accumulation of 
drug-resistance mutations, disease progression, HIV transmission, and death [WHO, 
2011].  Publicly funded programmes tend to follow WHO guidelines to use a non-
nucleoside reverse transcriptase inhibitor (NNRTI) combined with two NRTIs for first-
line ART [WHO, 2013; WHO, 2016]; however, there is a need for further data on the 
best treatment options for people with HIV-1 who have virological failure with this first-
line regimen. WHO guidelines recommend second-line ART for adults consisting of two 
NRTIs + a ritonavir-boosted protease inhibitor (PI) with atazanavir (ATV)+RTV or 
LPV/RTV as the preferred boosted PI options [WHO, 2013; WHO, 2016].
In many low to middle income countries, LPV/RTV is the most widely used PI for 
second-line ART although the use of ATV+RTV is increasing. LPV/RTV is associated 
with lipid and gastrointestinal side effects [Molina, 2008; Ortiz, 2008; Mills, 2009].  PIs 
have also been associated with increased risk of decreased bone mineral density, renal 
impairment and cardiovascular disease, although the pathogenesis of complications in 
each organ is multi-factorial and complex [Brown, 2006; Ryom, 2013; Currier, 2008].  
A sequence of second-line NRTI options are recommended based on the likely activity of 
each NRTI against predicted resistance to ZDV/stavudine (d4T), 3TC/FTC and/or TDF 
when used in first line treatment [WHO, 2013; WHO, 2016]. This strategy is particularly 
useful in settings where resistance testing is not available. Depending on the development 
of resistance and taking into account local standard of care as well as drug availability, 
other NRTIs such as abacavir (ABC) may be considered in other settings.
Several studies have been conducted or are currently underway to investigate novel 
treatment strategies (i.e. NRTI-sparing regimens) in patients requiring second-line ART.  
The SECOND-LINE Study is a randomised clinical trial, which has demonstrated that the 
efficacy of a novel dual-treatment approach combining LPV/RTV with the integrase 
inhibitor (INI) raltegravir (RAL) was non-inferior to a WHO-recommended second-line 
treatment regimen of LPV/RTV plus two or three NRTIs over 96 weeks [SECOND-LINE 
Study Group, 2013]. Findings from this study show that the WHO-recommended second-
line treatment is an efficacious rescue regimen and also provide evidence for an 
alternative NRTI-sparing approach. In the Europe-Africa Research Network for 
Evaluation of Second-line Therapy (EARNEST) Trial, a second-line regimen consisting 
of LPV/RTV (400 mg/100 mg twice daily) plus two NRTIs has also led to good 


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outcomes; the NRTI-sparing regimen with LPV/RTV plus RAL evaluated in the study 
was not superior, and LPV/RTV monotherapy was inferior [Paton, 2013].
The HIV STAR study showed that in patients failing initial therapy on an NNRTI + two 
NRTI regimen, treatment with LPV/RTV monotherapy led to a significantly lower 
proportion of patients achieving HIV RNA <50 c/mL at Week 48 compared to LPV/RTV 
+ TDF/FTC treatment [Bunupuradah, 2012].
The 2LADY study (ANRS 12169) is a clinical trial evaluating three different second-line 
combinations (LPV/RTV + TDF/FTC, LPV/RTV + ABC + ddI, and DRV + RTV + 
TDF/FTC) in Sub-Saharan Africa enrolling patients on ART who meet the WHO 
immunologic or clinical failure criteria.  After undergoing a month of adherence support, 
patients are randomised to one of the three arms of the study unless they show a 
significant decrease of viral load and are kept on first-line therapy [Mazoyer, 2010]. The 
96-week SELECT Study (A5273) compares, like the SECOND-LINE Study, two second-
line regimens, LPV/RTV with RAL versus LPV/RTV plus two or three NRTIs [ACTG, 
2014].
1.2.
Rationale
There are currently no studies ongoing to explore the potential option of PI-sparing 
second-line ART.  This strategy, especially with the availability of agents from non-PI 
classes with a high barrier to resistance, may have some advantages over PI-based 
regimens, particularly from a safety and tolerability perspective.  This study compares a 
second-line regimen of DTG plus two NRTIs with a WHO-recommended regimen of 
LPV/RTV with two NRTIs.
1.3.
Benefit:Risk Assessment
Summaries of DTG can be found in the IB [GlaxoSmithKline Document Number
RM2007/00683/11, GlaxoSmithKline Document Number 2017N352880_00, and 
GlaxoSmithKline Document Number 2017N352880_01].  The following section outlines 
the risk assessment and mitigation strategy for DTG in this protocol.  Where available, 
the approved country product label should be referenced.
For LPV/RTV and background NRTIs, the approved country product labels should be 
referenced.  The comparator regimen, LPV/RTV plus two NRTIs, is a preferred treatment 
regimen for HIV-infected patients requiring second-line ART according to current WHO 
guidelines [WHO, 2013; WHO, 2016].
1.3.1.
Risk Assessment
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment.  Considerations when using DTG are as follows:


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Hypersensitivity and rash
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 Stevens-Johnson 
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and erythema multiforme 
were reported. 
Subjects with history of allergy/sensitivity to any of the study drugs 
are excluded (Section 4.3).
Specific/detailed toxicity management guidance is provided for HSR 
(Section 6.4.4.6) and rash (Section 6.4.4.7).
The subject informed consent form includes information on this risk 
and the actions subjects should take in the event of an HSR or 
associated signs and symptoms.
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 virus (HBV) and/or hepatitis C virus (HCV) 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.  
Subjects meeting either of 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 with an anticipated need for hepatitis C virus (HCV) 
therapy during the Randomised Phase (Day 1 to Week 48 plus 
a 4-week treatment extension)
Investigators should consult current treatment guidelines when 
considering choice of NRTIs for subjects with chronic HBV infection.  
Additional treatment considerations should be guided by local 
treatment guidelines.  Adequate HBV therapy must be administered 
to subjects with chronic HBV infection (see Section 6.2.3).
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 6.4.4.1).  


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Theoretical serious drug 
interaction with dofetilide and
pilsicainide
Co-administration of DTG may increase dofetilide/pilsicainide plasma 
concentration via inhibition of organic cation transporter (OCT2) transporter, 
resulting in potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 5.6.3).
Gastrointestinal (GI) 
intolerance
Non-clinical studies showed upper and lower GI toxicity, including vomiting, 
diarrhoea 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 OCT2 
receptor.  DTG has been shown to have no significant effect on glomerular 
filtration rate (GFR) or effective renal plasma flow.
Specific/detailed toxicity management guidance is provided for 
subjects who develop a decline in renal function (Section 6.4.4.5). 
Psychiatric disorders
Psychiatric disorders including suicide ideation and behaviours are common in 
HIV-infected patients. The psychiatric profile for DTG (including suicidality, 
depression, bipolar and hypomania, anxiety and abnormal dreams) was 
similar to RAL- or favourable compared with EFV-based regimens. 
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.  
Subjects who in the investigator’s judgment, poses a significant 
suicidality risk, are excluded from participating (Section 4.3).
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 (Section 6.4.10).
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 
6.4.4.4).


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
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. 
Based on medical adjudication of IRIS-like events in ING111762, ART-
experienced (INI-naïve) subjects with hepatitis B or C virus co-infection 
receiving DTG may be at greater risk for IRIS than those receiving RAL, due to 
improved HIV virologic and immunologic responses with DTG compared to 
RAL, and withdrawal (or lack) of HBV active therapy in HIV/HBV co-infected 
subjects.  
Subjects will have frequent liver chemistry monitoring.  Robust liver 
chemistry stopping criteria and liver event follow up assessments 
are included.  Investigators are expected to follow local HBV and 
HCV treatment guidelines (see Section 6.2.3. and Section 6.2.4).
Functional monotherapy with 
DTG or LPV/RTV
Subjects are at risk of receiving functional monotherapy with their second-line 
regimen due to recycling of NRTIs to which their virus has already developed 
partial or full resistance.
The study requires that eligible subjects receive at least one fully 
active NRTI within the background regimen based on Screening 
genotypic resistance testing results as well as prior treatment history 
and, if available, any previous genotypic (and phenotypic) results 
showing resistance to an agent; a lack of resistance in previous 
results does not confirm susceptibility.  
Neural tube defects
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 female subject is eligible to participate if she is not pregnant, 
and, if she is a female of childbearing potential, agrees to follow 
one of the options for prevention of pregnancy listed in the
Inclusion Criterion 2 (see Section 4.2) during treatment with 
study drug and until at least 2 weeks after the last dose of 
study medication.
2. Women who become pregnant, or who desire to be pregnant 
while in the study will have study treatment discontinued and 
be withdrawn from the study.
3. Females of childbearing potential are reminded re: pregnancy 
avoidance and adherence to contraception requirements at 
every study visit.
4. Pregnancy status is monitored at every study visit.


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1. Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired Immune Deficiency 
Syndrome [DAIDS] toxicity gradings 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.  
Clinical Safety Data will be routinely reviewed in GlaxoSmithKline (GSK) Safety Review Team meetings. This will include in-stream review of data from this clinical trial on a routine 
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
DTG is conveniently dosed once daily, 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).
The safety profile for DTG 50 mg once daily was comparable to RAL and DRV+RTV 
and generally favourable to the EFV/TDF/FTC STR (Atripla) in both ART-naïve and 
ART-experienced (INI-naïve) patients (studies ING113086 [SPRING-2], ING111762 
[SAILING], ING114915 [FLAMINGO] and ING114467 [SINGLE]).  The most 
frequently observed AEs across patient populations were diarrhoea, nausea, and 
headache, which were generally Grade 1 or 2 in severity, and typically did not lead to 
discontinuation from studies.  With regards to antiviral efficacy, in treatment-naïve HIV-
infected adult subjects, DTG 50 mg once daily was shown to be non-inferior to RAL in 
combination with a dual NRTI background regimen [SPRING-2].  In study ING114915 
[FLAMINGO], virologic suppression (HIV-1 RNA <50 c/mL) in the DTG arm (90%) 
was statistically superior to the DRV+RTV arm (83%) at Week 48.  When used in 
combination with ABC/3TC, DTG was shown to be superior to EFV/TDF/FTC, a result 
driven by better tolerability of the DTG based regimen [SINGLE].  In study ING111762 
[SAILING], 71% of in INI-naïve ART-experienced patients receiving DTG achieved 
undetectable viral load (<50 c/mL) compared with 64% of those taking RAL at Week 48, 
reaching the threshold for statistical superiority [Cahn, 2013]. Excellent antiviral activity 
of DTG in patients with INI resistance was demonstrated in study ING112574 [VIKING-
3].  
Furthermore, DTG 50 mg once daily may have a higher barrier to resistance than RAL in 
INI-naïve patients. 
Uncertainty remains about the best treatment for HIV-1 infected patients who have 
virological failure with first-line ART of an NNRTI + two NRTIs. This study compares a 
new PI-sparing second-line regimen with a WHO-recommended regimen. This strategy, 
especially with the availability of agents from non-PI classes with a high barrier to 
resistance, may have some advantages over PI-based regimens, particularly from a safety 
and tolerability perspective.
The study requires that eligible subjects receive at least one fully active NRTI within the 
background regimen based on Screening genotypic resistance testing results. Previous 
genotypic (and phenotypic) results can provide evidence of resistance but cannot provide 
proof of a lack of resistance.  
Study participants may also benefit from the medical tests and screening procedures 
performed as part of the study.
1.3.2.1.
Analysis of subjects receiving DTG + 1-2 NRTIs in SAILING
In order to inform the study design, an exploratory analysis of subjects receiving DTG + 
1-2 NRTIs in ING111762 (SAILING) was conducted.  SAILING compared DTG and 


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raltegravir (RAL) in combination with up to two investigator selected background 
antiretroviral drugs (at least 1 being fully active) in antiretroviral therapy-experienced, 
integrase inhibitor-naïve adults with ongoing virologic failure and at least two-class drug 
resistance [Cahn, 2013].  Of the 715 subjects randomised, 32 subjects in each arm 
received an NRTI-based background regimen; all subjects received two NRTIs except for 
one subject in the DTG arm receiving only one NRTI. 
None of the 32 subjects in the DTG arm experienced protocol defined virologic failure 
(PDVF) by Week 48, including no cases of virologic failure in 13 subjects receiving less 
than 2 fully active NRTIs by phenotype (12 received one fully active NRTI and 1 
received two inactive NRTIs).  In the RAL arm, 7/32 (22%) of subjects experienced 
PDVF by Week 48, of which 4/13 (31%) experienced failure with 1 fully active NRTI 
and 3/19 (16%) failed with 2 fully active NRTIs.  Of the 13 subjects who had the M184V 
mutation detected at baseline and received DTG + 3TC/FTC + a second NRTI, none met 
PDVF criteria, including 10 subjects for whom the second NRTI was active (by 
phenotype) and 3 subjects with 2 or more thymidine analogue mutations (TAMs). Four of 
12 subjects (33%) who received RAL + 3TC/FTC + a second NRTI in the setting of 
baseline M184V experienced PDVF, despite the fact that the second NRTI was active by 
phenotype in all these cases.   
Based on this exploratory analysis, DTG + two NRTIs appears to have good activity 
through 48 weeks in treatment-experienced patients who are experiencing virologic 
failure when at least one of NRTIs was fully active by phenotype.  However, the sample 
size is small, and an increased risk of virologic failure in subjects receiving DTG with 
less than two fully active NRTIs cannot be ruled out based on these data alone.
1.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential risks identified in association with DTG are justified by the 
anticipated benefits that may be afforded to HIV-1 infected adults with treatment failure 
on first line therapy.
2.
OBJECTIVES
Primary Objective

To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-recommended 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy.
Secondary Objectives

To demonstrate non-inferior antiviral activity at 24 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a recommended WHO 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy;


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
To evaluate the antiviral and immunological activity and incidence of disease 
progression (HIV-associated conditions, AIDS and death) of DTG compared to 
LPV/RTV over time;

To assess the development of viral resistance in subjects meeting confirmed 
virologic withdrawal criteria;

To evaluate the safety, tolerability, and laboratory parameters of DTG compared to 
LPV/RTV over time; 

To compare the effects of DTG and LPV/RTV on fasting lipids over time;

To compare the effects of DTG and LPV/RTV on the occurrence of gastrointestinal 
adverse events over time;

To compare the change in gastrointestinal symptom rating score for subjects treated 
with DTG and LPV/RTV over time;

To compare the satisfaction with treatment of patients with DTG compared to the 
LPV/RTV over time;

To compare patients’ adherence with DTG compared to the LPV/RTV over time;

To evaluate the effect of patient demographics and baseline characteristics (e.g. 
demographic factors, HIV-1 subtype, baseline CD4+ cell count) on response to DTG 
compared to LPV/RTV over time.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This study is a Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel 
group, non-inferiority study.  
Approximately 612 adult patients with confirmed virologic failure (HIV-1 RNA 400 
c/mL on two occasions) on their first antiretroviral regimen consisting of one NNRTI + 
two NRTIs will be recruited.
Subjects will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV (800/200 
mg once daily or 400/100 mg twice daily, in accordance with investigator decision and 
local label), each added to an investigator selected background regimen consisting of two 
NRTIs with at least one fully active NRTI (see Section 5.1.3).  In consultation with the 
medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background 
regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC 
(e.g. M184V) (see Section 6.2.3).
The primary analysis at Week 48 will take place after the last subject completes 52 weeks 
on therapy (Day 1 to Week 48 plus a 4-week treatment extension). An interim analysis 
and data cut will be conducted after the last subject completes 24 weeks on therapy, with 


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the intent to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  A switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily 
and the opposite switch and a single change of one of the background NRTIs for toxicity 
or tolerability management is allowed.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing.  A switch from 3TC to FTC 
(or vice versa) will not be considered a background NRTI change and is permitted.  No 
other dose reductions, modifications in dosage, or changes in the frequency of dosing will 
be allowed in this study.
An IDMC has been instituted to perform periodic reviews of the accumulating data to 
ensure that subjects are not being sub-optimally treated.  The IDMC completed the first 
two of the three pre-planned analyses (see Section 8.3.4.2).  Prior to the third 
interim analysis, the IDMC conducted an ad hoc review of trial data and the IDMC 
observed significant, clinically relevant differences between treatment arms in 
favour of DTG.  The IDMC recommended to the sponsor that the LPV/RTV 
treatment arm be discontinued and subjects currently receiving LPV/RTV in the 
study be switched to a regimen with DTG as the third drug, if considered 
appropriate by the Investigator.
Assuming a true response rate of 70% for both DTG and LPV/r arms, the study requires 
306 subjects per arm to have 90% power with a 12% non-inferiority margin and a one-
sided 2.5% significance level (see Section 8.2.1).
The study design is summarised in Figure 1 and comprises the following Phases:
Screening Period
Randomisation may occur as soon as all Screening procedures have been completed and 
results are available and on file.  Subjects will participate in a Screening period of up to 
28 days, which may be extended to 42 days to ensure eligibility (e.g. receipt of final 
Screening laboratory results) and scheduling.  Eligibility criteria must be fulfilled by 
current resistance testing, i.e. Screening results.
Subjects are allowed to re-screen for this study one time; this will require a new subject 
number. A single repeat test (re-test) per analyte or assessment is allowed during the 
screening period to determine eligibility (with the exception of a disqualifying Screening 
genotype which may not be retested; however, a single repeat test for a failed genotype 
[no result] is permitted during the Screening period).
Randomised Phase: Day 1 to Week 48 + 4-week treatment extension
Subjects who fulfil eligibility requirements will be randomised 1:1 to receive DTG once 
daily + two NRTIs or LPV/RTV once or twice daily + two NRTIs.  The investigator 
selected background regimen must be determined and documented prior to randomisation 
and should take into account Screening genotypic resistance testing results as well as 
prior treatment history and, if available, any previous genotypic (and phenotypic) results.  
The background regimen shall be composed of at least one fully active NRTI based on 
Screening resistance testing plus one more NRTI which may or may not be active (as 


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defined in Section 5.1.3).  For further detail on the definition of full or partial activity, see
Section 5.1.3.
When constructing a subject’s background NRTI regimen, certain combinations of 
NRTIs are prohibited (see Section 5.1.3).  Following Day 1, no changes or intensification 
of background regimen will be permitted prior to meeting confirmed virologic 
withdrawal criteria or Week 52, with the exception of one allowed background NRTI 
change for management of drug toxicity as described in Section 6.4.4, “Specific 
Toxicities/Adverse Event Management”.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing.  A switch from 3TC to FTC 
(or vice versa) will not be considered a background NRTI change and will not incur a 
penalty as per the FDA’s Snapshot algorithm (Missing, Switch or Discontinuation = 
Failure) (see Section 6.3.2 and Section 8.3.2). 
In order to achieve balance across the two treatment groups of the study, randomisation 
will be stratified by:

Screening plasma HIV-1 RNA (100,000 c/mL or >100,000 c/mL);

Number of fully active NRTIs in the investigator selected background regimen 
based on Screening genotype (as defined in Section 5.1.3): 2 versus <2.
During the Randomised Phase, subjects will attend the clinic at Baseline/Day 1 and at 
Weeks 4, 8, 16, 24, 36, 48 and 52 of treatment. 
Subjects are considered to have completed the Randomised Phase of the study if they 
remain on therapy (i.e. have not permanently discontinued IP) through completion of the 
Week 52 visit.
Following the Week 48 visit, subjects will stay on their DTG or LPV/RTV-based 
regimen for another 4 weeks (i.e. the 4-week treatment extension).  Any subject with a 
viral load of 50 c/mL at Week 48 will have their viral load confirmed by a second 
measurement performed at the Week 52 visit.  As per the primary endpoint, if the retest 
viral load is <50 c/mL then the subject will be considered to have met the primary 
endpoint of virologic responder by FDA’s Snapshot algorithm at Week 48 (see Section 
6.3.2). If the retest viral load is 50 c/mL then the subject will be considered to be a 
virologic non-responder at Week 48 by Snapshot analysis.  Thus, the treatment extension 
up to Week 52 will allow for a robust assessment of treatment response in the primary 
endpoint analysis at Week 48 (windowed) as transient blips in HIV RNA 50 c/mL are 
censored.
All subjects will attend the clinic at Week 52.
Following the IDMC’s recommendation and as per Protocol Amendment No. 2, 
subjects randomised to the LPV/RTV arm will either (i) continue receiving 
LPV/RTV and complete the study after the 4-week treatment extension at Week 52, 
or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to 
have access to DTG in the Continuation Phase.


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The primary efficacy endpoint corresponds to viral load measurements collected within a 
6 week window around the Week 48 visit (including data from the Week 52 visit), as 
per the FDA’s Snapshot algorithm, and for this reason, the primary analysis is denoted as 
occurring at Week 48 with the understanding that data from the Week 52 visit may be 
included.
DTG Continuation Phase
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
and subjects originally randomised to receive LPV/RTV but switched to DTG prior to 
Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 
available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
Subjects randomised to the LPV/RTV arm will receive LPV/RTV + two NRTIs through 
their Week 52 visit only, after which subjects will complete the study and will need to 
have alternate arrangements in place to access antiretroviral medication (unless mandated 
by local regulation).  Subjects randomised to the LPV/RTV arm, who switch to the DTG 
arm prior to study completion at Week 52, will continue to have access to DTG 
(Continuation Phase) as mentioned above.
Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomised to LPV/RTV + two NRTIs and completed the Randomised Phase 
including the Week 52 study visit;

Randomised to LPV/RTV + two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase including the Week 52 study visit, and did not enter 
the Continuation Phase;

Randomised to LPV/RTV+ two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase, including the Week 52 study visit, entered and 
completed the Continuation Phase (defined as remaining on study until commercial 
supplies of DTG become locally available to patients [e.g. through public health 
services]).

Randomised to DTG + two NRTIs, completed the Randomised Phase including the 
Week 52 study visit, and did not enter the Continuation Phase;

Randomised to DTG + two NRTIs, completed the Randomised Phase, including the 
Week 52 study visit, entered and completed the Continuation Phase (defined as 
remaining on study until commercial supplies of DTG become locally available to 
patients [e.g. through public health services]).


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Follow Up
Subjects with ongoing AEs or laboratory abnormalities considered to be AEs will attend 
a Follow-up visit approximately four weeks after their last dose of IP (DTG or 
LPV/RTV).  Assessments at the Follow-up visit should reflect any ongoing complaints 
(e.g. blood draws to follow a laboratory abnormality).  The Follow-Up visit is not 
required for successful completion of the study.
Figure 1
Study Schematic
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
The design of this study (1:1 randomised, open-label, active-controlled, multicentre, 
parallel group) is well established for confirming the non-inferiority of an investigational 
agent compared to an active comparator and is generally accepted by regulatory 
authorities as rigorous proof of antiviral activity.
The primary endpoint, proportion of subjects at Week 48 with plasma HIV-1 RNA below 
the assay lower limit of detection (LLOD, e.g. <50 c/mL), is a reasonable well-
established surrogate endpoint for prognosis of HIV-1 infection and disease progression.
LPV/RTV is one of two PIs currently recommended by WHO for treatment of patients 
experiencing virologic failure on a first line regimen [WHO, 2013; WHO, 2016] and is 
widely used (in combination with NRTIs) for second line treatment in low to middle 


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income countries. Several ongoing studies exploring the role of alternative treatment 
strategies in this patient group have similarly included LPV/RTV as the comparator 
[SECOND-LINE Study Group, 2013; Paton, 2013].
Consistent with other Phase IIIb and IV studies for other antiretrovirals, the potential for 
once or twice daily dosing of LPV/RTV and because of the concerns about pill burden, 
this study will be open-label.  However, no summaries of the study data according to 
actual randomised treatment groups will be available to sponsor staff prior to the planned 
Week 24 interim analysis.
An IDMC will be used to provide independent review of the accumulating data to ensure 
subjects are not being sub-optimally treated in either arm (see Section 8.3.4.2 and Section 
9.8). 
This study is designed to show the potency and safety of DTG compared to LPV/RTV in 
patients failing first-line ART and to explore the potential of DTG to be used as an 
alternative option to boosted PIs in second-line treatment regimens.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Sufficient subjects will be screened in order to ensure a total of approximately 612 
subjects will be randomised, approximately 306 to each study arm. Subjects will be 
enrolled from multiple geographic regions.
Subjects
Screened
~815
Randomised
~612
Evaluable
~612
All randomised and treated subjects (per the ITT-E definition, see Section 8.3.1) are 
considered evaluable for the primary efficacy analysis, with subjects who discontinue 
from the study prior to Week 48 being imputed as non-responders.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the 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 are allowed to re-screen for this study one time; this will require a new subject 
number. A single repeat test (re-test) per analyte or assessment is allowed during the 


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Screening period to determine eligibility (with the exception of a disqualifying Screening 
genotype which may not be retested; however, a single repeat test for a failed genotype 
[no result] is permitted during the Screening period).  A subject that does not have a fully 
active NRTI based on a resistance test which is successful during Screening should not 
re-screen.
The following are study specific eligibility 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 appropriate candidates for participation in an investigative clinical trial 
with oral medication (e.g. no active substance abuse, acute major organ disease).
Laboratory results from central laboratory services provided by this trial will be used to 
assess eligibility.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
HIV-1 infected subjects 18 years of age.
2.
A female subject may be eligible to enter and participate in the study if she:
a.
is of non-childbearing potential defined as either post-menopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of 
becoming pregnant with documented tubal ligation, hysterectomy, or bilateral 
oophorectomy or,
b.
is of child-bearing potential, with a negative pregnancy test at both Screening 
and Day 1 and agrees to use one of the following methods of contraception to 
avoid pregnancy throughout the study and for at least 2 weeks after 
discontinuation of all study medication:

Complete abstinence from intercourse from 2 weeks prior to administration 
of IP.

Approved hormonal contraception for subjects randomised to the DTG arm 
including:
o
Combined oestrogen and progestogen oral contraceptive [Hatcher, 
2011])
o
Contraceptive subdermal implant
o
Injectable progestogen [Hatcher, 2011]
o
Contraceptive vaginal ring [Hatcher, 2011]


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o
Percutaneous contraceptive patches [Hatcher, 2011]

Approved hormonal contraception (as for subjects randomised to the DTG 
arm; see above) and a barrier method for subjects randomised to the 
LPV/RTV arm.

Intrauterine device or intrauterine system.

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 other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently and in accordance with the 
approved product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. Note: these contraceptive requirements do not 
apply to females of childbearing potential with same sex partners only, when this is their 
preferred and usual lifestyle.
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).
3.
HIV-1 infection as documented by HIV-1 RNA 400 c/mL at Screening. 
4.
Subject has been on a first-line treatment regimen consisting of an NNRTI plus two 
NRTIs for at least 6 months and is currently experiencing virologic failure to this 
first-line regimen defined as two consecutive (7 days apart) HIV-1 RNA results of 
400 c/mL (which can include Screening HIV-1 RNA results).
In addition to HIV-1 RNA 400 c/mL at Screening, at least one previous HIV-1 
RNA result of 400 c/mL within the 3 months prior to Screening must be 
documented.  If an additional HIV-1 RNA within 3 months prior to Screening is not 
available, a second HIV-1 RNA must be performed and have results 400 c/mL 
during the Screening period [after the first result is available and 7 days apart] to 
serve as a confirmatory sample.
5.
Subjects must receive at least one fully active agent within the dual-NRTI 
background regimen for second line treatment. Fully active is defined by the 
Screening genotypic resistance report of the central laboratory (or a laboratory 
contracted by the central laboratory) showing no evidence of full or of partial 
resistance for a given NRTI which will be taken on study.


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6.
Subject is PI-naïve and INI-naïve, defined as no prior or current exposure to any PI 
or INI.
7.
Subject or the subject’s legal representative is willing and able to understand and 
provide signed and dated written informed consent prior to screening.
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. 
A single repeat test (re-test) per analyte is allowed during the Screening period (with the 
exception of a disqualifying Screening genotype which may not be retested; however, a 
single repeat test for a failed genotype [no result] is permitted during the Screening 
period).
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary medical conditions
1.
Women who are breastfeeding.
2.
Any evidence of an active Centers for Disease Control and Prevention (CDC) 
Category C disease (Section 11.2). Exceptions include cutaneous Kaposi’s sarcoma 
not requiring systemic therapy and historic or current CD4+ cell levels <200 
cells/mm3.
3.
Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh 
classification (see Appendix 1, Section 11.1).
4.
Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones).
5.
Anticipated need for hepatitis C virus (HCV) therapy during the Randomised Phase 
of the study.
6.
History or presence of allergy or intolerance to the study drugs or their components 
or drugs of their class.
7.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial 
neoplasia; other localised malignancies require agreement between the investigator 
and the Study medical monitor for inclusion of the subject.
8.
Subjects who in the investigator’s judgment, poses a significant suicidality risk. 
Recent history of suicidal behaviour and/or suicidal ideation may be considered as 
evidence of serious suicide risk.


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Exclusionary Treatments prior to Screening or Day 1
9. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
10. Treatment with any of the following agents within 28 days of Screening: 
radiation therapy,
cytotoxic chemotherapeutic agents,
systemically administered immunomodulators.
11. Treatment with any agent, other than licensed ART as allowed above (Section 4.2), 
with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of 
IP.  The exception is use of entecavir, in appropriate clinical situations, for treatment 
of hepatitis B (e.g. prior intolerance to TDF, viral resistance to 3TC /FTC) after 
discussion and agreement between the investigator and the medical monitor.
12. Exposure to an experimental drug or experimental vaccine within either 28 days, 
5 half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to the first dose of IP.
Exclusionary Laboratory Values or Clinical Assessments at Screening
13. Any evidence of primary viral resistance to PIs or INIs based on the presence of any 
major resistance-associated mutation [Johnson, 2013].
14. The subject’s virus does not yield results using genotype at Screening (assay data is 
essential for eligibility determination). 
15. Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 
triglycerides.  A single repeat test is allowed during the Screening period to verify a 
result. 
16. Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the subject’s participation in the study of an 
investigational compound.
17. Alanine aminotransferase (ALT) 5 times the upper limit of normal (ULN) or ALT 
3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).
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 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 IP.


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4.5.
Withdrawal Criteria
Subjects permanently discontinuing study treatments prior to Week 52 are considered to 
be withdrawn from the study treatments and also from the study. Similarly, subjects in 
the DTG arm who enter the Continuation Phase but permanently discontinue 
participation in the Continuation Phase prior to commercial supplies of DTG becoming 
available to patients (e.g. through public health services), are considered to be withdrawn 
from study treatment 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. Withdrawn subjects will not be replaced.
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

Subject or Investigator non-compliance;

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.
Subjects must be discontinued from the study for any of the following reasons:

Confirmed virologic withdrawal criteria as described in Section 4.6.1 are met;

Subject requires substitution or dose modification of DTG, or substitution of 
LPV/RTV (a switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice 
daily or the opposite switch is allowed; as per Protocol Amendment No. 2, a switch 
from LPV/RTV to DTG will also be allowed);

Subject requires a second switch of background therapy prior to Week 52 (one 
switch in NRTIs is allowed for toxicity management but any NRTI change must 
ensure a fully active NRTI is still present based on Screening resistance testing, see 
Section 6.4.4).  A switch from 3TC to FTC (or vice versa) will not be considered a 
background NRTI change and will not incur a penalty as per the Snapshot algorithm 
(see Section 6.3.2 and Section 8.3.2).

Liver toxicity where stopping criteria specified in Section 6.4.4.1 are met and no 
compelling alternate cause is identified;

Grade 4 clinical AE considered causally related to IP (see Section 6.4.3);

Renal toxicity criteria as specified in Section 6.4.4.5 are met and no compelling 
alternate cause is identified;


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
Allergic reaction or rash criteria as described in Section 6.4.4.6 and Section 6.4.4.7
respectively, are met and no compelling alternate cause is identified;

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
6.4.11).  As a reminder, females of childbearing potential who changed their minds 
and desire to become pregnant, or who state they are 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 visit 
and if necessary the Follow Up visit. 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.  A Follow-up visit may occur approximately 4 weeks after the last 
dose of study treatment and is only required in subjects with ongoing clinical or 
laboratory AEs at the time of Withdrawal.
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 
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 CRF. 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 
6.4.3) the procedures stated in the Time and Events Table (Section 6.1) 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 6.4.3).
4.6.
Virologic Criteria for Subject Management and Viral 
Resistance Testing
For the purposes of clinical management in this study, suspected or confirmed virologic 
withdrawal criteria are defined in Section 4.6.1 wherein the virologic withdrawal criteria 


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defined below revolve around the HIV-1 RNA cut-off of 400 c/mL. Notably, this allows 
for more reliable generation of data required for subject management as the primary 
genotypic and phenotypic resistance assays are not validated for RNA levels near the 
limits of detection (50 c/mL).
Following Day 1, no changes, or intensification of ART will be permitted prior to 
meeting confirmed virologic withdrawal criteria or Week 52, with the exception of a 
switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily or the opposite 
switch, a switch from LPV/RTV to DTG as per Protocol Amendment No. 2, and one 
allowed background NRTI change for management of drug toxicity as described in 
Section 6.4.4., “Specific Toxicities/Adverse Event Management”.  Any NRTI change 
must ensure a fully active NRTI is still present based on Screening resistance testing.  A 
switch from 3TC to FTC (or vice versa) will not be considered a background NRTI 
change and is permitted.  Subjects unable to manage drug toxicity or tolerate IP (DTG or 
LPV/RTV) must be discontinued from the study as described in Section 6.4.
4.6.1.
Virologic Withdrawal Criteria
Virologic withdrawal criteria must be confirmed for each criterion by a repeat and 
consecutive plasma HIV-1 RNA measurement between one and four weeks after the 
subject met a suspected virologic withdrawal criterion.  Subjects should receive full dose 
of IP across all plasma sampling times used for determining virologic non-response or 
rebound.  For these definitions, Baseline viral load is defined as the Day 1 HIV-1 RNA 
measurement.  For the purposes of clinical management in this study, virologic 
withdrawal criteria are defined as any of the following:
Virologic Non-response

A decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 16, with 
subsequent confirmation, unless plasma HIV-1 RNA is <400 c/mL.

Confirmed plasma HIV-1 RNA levels ≥400 c/mL on or after Week 24.
Virologic Rebound

Confirmed rebound in plasma HIV-1 RNA levels to ≥400 c/mL after prior confirmed 
suppression to <400 c/mL.
Subjects who meet any confirmed virologic withdrawal criterion must be discontinued 
from the study.
Cases of subjects meeting confirmed virologic withdrawal criteria will trigger virologic 
resistance testing.  Investigators should use their discretion as to the most appropriate 
clinical management of their subjects, if more stringent local guidelines apply.
4.6.2.
Managing Subjects Meeting Suspected Virologic Withdrawal 
Criteria
Only plasma HIV-1 RNA values determined by the central laboratory (or a laboratory 
contracted by the central laboratory) will be used to assess virologic withdrawal criteria.  


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Upon notification that a subject’s HIV-1 RNA plasma level qualifies him/her as meeting 
a suspected virologic withdrawal criterion, the Investigator should query the subject 
regarding intercurrent illness, recent immunisation, or interruption of therapy as 
inadequate adherence is a common cause of elevated HIV-1 RNA measurements.
All cases that meet a suspected virologic withdrawal criterion must be confirmed by 
a second measurement performed at least one week but not more than 4 weeks 
apart from the date of the original sample, unless one of the extenuating 
circumstances outlined below applies.
The following guidelines will be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the subject should receive full dose of all IP.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunisation, during which time the subject should receive full dose of IP.

If therapy is interrupted due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2 to 4 weeks following resumption 
of full dose of IP.

The subject should have received full doses of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA is done.
Sites should contact GSK to discuss individual subjects, whenever necessary.
At Week 48, repeat HIV-1 RNA testing is required for any HIV-1 RNA between 50 
c/mL and <400 c/mL and must be performed at the Week 52 study visit (see Section 4.7).
4.6.3.
Managing Subjects Meeting Confirmed Virologic Withdrawal 
Criteria
Once a subject has been confirmed as meeting a virologic withdrawal criterion, a ‘plasma 
for storage’ sample from the virologic failure visit and the Day 1 sample will be sent as 
soon as possible for genotypic and phenotypic resistance testing and the result made 
known to the Investigator when available.
A subject who meets a confirmed virologic withdrawal criterion must be 
discontinued from the study.
If a subject is prematurely discontinued from participation in the study, the Investigator 
must make every effort to perform the evaluations outlined in the Time and Events 
Schedule (Section 6.1).  These data will be recorded, as they comprise an essential 
evaluation that needs to be done before discharging any subject from the study.


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4.7.
Retest Criteria for Subjects with Plasma HIV-1 RNA Levels 
between 50 c/mL and <400 c/mL at Week 48
Subjects with plasma HIV-1 RNA levels between 50 c/mL and <400 c/mL at Week 48 
must have HIV-1 levels re-assessed by a second measurement performed at the Week 52 
visit.  Subjects should have received full doses of IP for at least 2 weeks at the time of 
HIV-1 RNA re-assessment for any HIV-1 RNA level 50 c/mL.
Subjects with plasma HIV-1 RNA levels ≥400 c/mL should have a second measurement 
performed as outlined in Section 4.6.2 “Managing Subjects Meeting Suspected Virologic 
Withdrawal Criteria”.
4.8.
Screening Failures
A subject is considered a screening 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.
Subjects are allowed to re-screen for this study one time (so long as the first screening 
does not exclude the subject based on lack of a fully active drug); re-screening will 
require a new subject number. There is no timeline restriction for re-screening.  
A single repeat test (re-test) per analyte or assessment is allowed during the screening 
period to determine eligibility (with the exception of a disqualifying Screening genotype 
which may not be retested; however, a single repeat test for a failed genotype [no result] 
is permitted during the Screening period to determine eligibility).
Laboratory results from central laboratory services provided by this trial will be used to 
assess eligibility.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Investigational product (IP) in this protocol refers to the investigational study drug DTG 
and the comparator drug LPV/RTV. These will be supplied by GlaxoSmithKline. For this 
protocol, other antiretrovirals administered in the study are not considered IP.
Investigators will choose a dual NRTI background regimen for each subject (see Section 
5.1.3).  Background antiretroviral therapy will be recorded on the Concomitant 
Antiretroviral Therapy (ConART) eCRF page.  For additional details, please consult the 
SPM.
Under normal conditions of handling and administration, IP 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.


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IP 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 investigator and 
authorised site staff.  IP must be dispensed or administered only to subjects enrolled in 
the study and in accordance with the protocol. 
The contents of the label will be in accordance with all applicable regulatory 
requirements.
5.1.1.
Tablet Formulation of DTG
DTG tablets are packaged into high density polyethylene (HDPE) bottles with child-
resistant closures that include induction seals.  The bottles may contain a desiccant. The 
recommended storage conditions and expiry date where required, are stated on the 
product label.
In general, subjects should keep IP in the original container.  However, subjects may use 
pill boxes for short term storage of 7 days.
5.1.2.
Tablet Formulation of LPV/RTV
LPV/RTV [Kaletra Package Insert, 2016; Kaletra EU Summary of Product 
Characteristics, 2017] is supplied as the LPV/RTV oral tablet, which contains 200 mg of 
LPV and 50 mg of RTV.  LPV/RTV tablets are manufactured by Abbvie.  Each HDPE 
bottle is closed with a propylene cap and contains 120 tablets.
5.1.3.
Background NRTIs
The investigator selected dual NRTI background regimen must be determined and 
documented prior to randomisation.  While Screening resistance test results must be used 
to determine one fully active agent, all available data (prior treatment history, Screening 
and historical resistance results) should be considered for selection of the background 
therapy.  The background regimen shall be composed of one of the following:

one fully active NRTI plus one inactive or partially active NRTI;

two fully active NRTIs;

one of the above plus, where required in subjects co-infected with HBV, 3TC. 
Note: In consultation with the medical monitor, 3TC may be added as a third NRTI to a 
dual-NRTI background regimen in subjects with chronic HBV infection and evidence of 
HIV resistance to 3TC (e.g. M184V) (see Section 6.2.3).  3TC cannot be added to 
regimens that include FTC.
Fully active is defined by the genotypic resistance report of the central laboratory (or a 
laboratory contracted by the central laboratory) showing no evidence of full or of partial 
resistance for a given NRTI. For additional details, please consult the SPM.
All triple NRTI (except for adding 3TC to a dual NRTI combination in subjects co-
infected with HBV; see Section 6.2.3) and the following dual NRTI combinations will be 


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prohibited in this protocol per current treatment guidelines and recommendations [HHS
2013; Gallant, 2005; Barnas, 2010]: 

ABC+TDF, 

3TC+FTC, 

AZT+d4T, 

ddI+ABC, 

ddI+TDF, 

ddI+d4T, 

ddI+3TC, 

ddI+FTC,

d4T+3TC,

d4T+FTC.
All background NRTIs are locally registered products.  GSK will not reimburse or supply 
the investigator selected background regimen unless requested by the local regulatory 
authority or IRB/IEC or unless previously agreed with study sites.
Those subjects for whom ABC is being considered as a component of the NRTI 
backbone should have been screened and be negative for the HLA-B*5701 allele before 
randomisation takes place (see Section 6.2.1).  This testing may be conducted as part of 
the study or may be performed by local laboratories.  Results must be available for source 
document verification.
5.1.4.
Dosage and Administration
Details of dosing for both randomised arms are outlined in the following table:
Treatment Arm
IP Dose and Dose Interval and background NRTI 
DTG
1 x 50 mg DTG tablet once daily plus 2 NRTIs selected by the investigator
LPV/RTV
4 x 200/50 mg LPV/RTV tablets once daily or 2 x 200/50 mg LPV/RTV 
tablets twice daily plus 2 NRTIs selected by the investigator 
IP may be administered with or without food.
5.1.5.
Protocol-Permitted Substitutions
A switch of DTG or LPV/RTV is not allowed except for a switch from LPV/RTV 
800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite switch.  As 
per Protocol Amendment No. 2, a switch from LPV/RTV to DTG will be allowed.
Switch of one background NRTI to an alternative approved NRTI for toxicity or 
tolerability management is allowed one time.  After the switch, based on Screening 
resistance testing results background ART must still consist of at least one fully active 


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NRTI and a second single NRTI  which may or may not be active (as defined in Section 
5.1.3).  A switch from 3TC to FTC (or vice versa) will not be considered a background 
NRTI change and is permitted.  The date of the decision to switch one background NRTI 
for toxicity or tolerability management must be documented in the eCRF.
Local prescribing information should be consulted for information regarding use of these 
medications. 
For more details on IP and protocol-permitted switch medications, refer to the SPM.
5.2.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule. Randomisation will occur at the Baseline (Day 1) visit and will be conducted 
via a central randomisation procedure following confirmation of fulfilment of study entry 
criteria. Subjects will be assigned (1:1) to study treatment in accordance with the 
computer generated randomisation schedule. The central randomisation schedule, 
including stratification, will be generated using the GSK validated randomisation 
software RandAll NG. Study site personnel will be required to contact the central 
randomisation service for assignment of a unique identifier (designating the subject’s 
randomisation code) for each subject participating in the study. A unique treatment 
number will be assigned for each subject participating in the study.  Subjects will 
maintain the assigned treatment group throughout the Randomised Phase (Day 1 to Week 
48 plus a 4-week treatment extension) and if applicable the Continuation Phase (after 
Week 52 for subjects randomised to the DTG arm).
Subjects who are randomised into the trial and subsequently withdrawn may not be re-
screened.
5.3.
Blinding
As this is an open-label study, blinding is not required.  No summaries of the study data 
according to actual randomised treatment groups will be available to sponsor staff prior 
to the planned Week 24 interim analysis.  According to the IDMC Charter, ViiV 
Healthcare/GSK personnel having direct responsibility for the conduct of the study and 
its analysis may however review summaries of data by treatment group if the IDMC 
recommends to the sponsor the termination of a treatment arm or the entire 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 
investigational product 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.


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5.5.
Treatment Compliance
Treatment compliance will be evaluated through the Morisky 8-Item Medication 
Adherence Scale (MMAS-8), a self-report measure of medication-taking behaviour (see 
Section 6.5).  Pill counts of unused IP will be assessed for monitoring purposes each time 
the subject receives a new (refill) supply of study medication through the Withdrawal 
visit or study completion. These data will be recorded in the subject’s CRF, but will not 
be summarised 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).  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 
minimise the risk of non-specific increases in the level of HIV-1 plasma RNA at the next 
scheduled assessment.
Entecavir and telbivudine are permitted, in appropriate clinical situations, for treatment of 
hepatitis B (e.g. prior intolerance or viral resistance to TDF, viral resistance to 3TC/FTC) 
after discussion and agreement between the investigator and the medical monitor (also 
see Section 6.2.3).
Approved hormonal contraception may be administered with DTG. However, the 
investigator should consult local prescribing information for guidance on the use of 
hormonal contraceptives with background ART as some antiretrovirals have clinically 
significant drug interactions with these products.
DTG should be administered 2 hours before or 6 hours after taking antacid products or 
sucralfate containing divalent cations (e.g. aluminum 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.


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DTG can be co-administered with calcium or iron supplements if taken with a meal.  
Under fasted conditions, DTG should be given 2 hours prior to OR 6 hours after calcium 
or iron supplements. 
Metformin concentrations may be increased by DTG. Subjects should be monitored 
during therapy and a dose adjustment of metformin may be considered.
Both LPV and RTV are inhibitors of the P450 isoform CYP3A. LPV/RTV is likely to 
increase plasma concentrations of medicinal products that are primarily metabolised by 
CYP3A. These increases of plasma concentrations of co-administered medicinal products 
could increase or prolong their therapeutic effect and adverse events. It is important to 
consult the current prescribing information for LPV/RTV prior to administering any 
concomitant medication together with LPV/RTV.
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 not otherwise specified in the protocol, cytotoxic chemotherapy, or 
radiation therapy may not be administered (see Exclusion Criteria, Section 4.3). 
Systemically administered immunomodulators are prohibited with the following 
exception.  HCV therapy will not be permitted during the Randomised Phase (Day 1 to 
Week 48 plus a 4-week treatment extension) of the study.  If HCV therapy is required 
during the Continuation Phase, subjects may be allowed to continue on study after 
discussion and agreement between the investigator and the medical monitor.
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.
Acetaminophen is not to be used in patients with acute viral hepatitis.
For a detailed list of prohibited medications, please consult the SPM.
5.6.3.
Prohibited medications for subjects randomised to DTG
The following medications or their equivalents may cause decreased concentrations of 
DTG. Therefore, the following medications must not be administered concurrently with 
DTG.

Carbamazepine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rifampicin or rifapentine (see Section 5.7 for substitutes for treatment of TB)


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
St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit their renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
For NRTIs used as background therapy, please refer to the local prescribing information 
for information on concurrent therapies.
5.6.4.
Prohibited medications for subjects randomised to LPV/RTV
Both LPV and RTV are inhibitors of the P450 isoform CYP3A. LPV/RTV should not be 
co-administered with medicinal products that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious 
and/or life threatening events.  For subjects randomised to LPV/RTV, the following 
medications or their equivalents must not be administered concurrently:

Alfuzosin

Amiodarone

Antihistamines (astemizole, terfenadine)

Cisapride

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Fusidic acid (in dermatological infections)

HMG Co-A reductase inhibitors (specifically lovastatin, simvastatin)

Pimozide

Rifampicin (see Section 5.7 for substitutes for treatment of TB)

Sildenafil (when used for the treatment of pulmonary arterial hypertension)

Vardenafil

Avanafil

Midazolam (oral)

Triazolam

St John’s wort (Hypericum perforatum)
Refer to the most up to date prescribing information for LPV/RTV for a listing of drugs 
with established or other potentially significant interactions with LPV/RTV.
For NRTIs used as background therapy, please refer to the local prescribing information 
for information on concurrent therapies.


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5.7.
Treatment of Tuberculosis
Patients who developed tuberculosis (TB) during the study may be managed according to 
local treatment guidelines with rifabutin substituted for rifampicin.  Rifabutin may be 
reimbursed by GSK.
Switching to DTG twice daily dosing in subjects who receive DTG in this study and 
require rifampicin treatment for tuberculosis, will not be allowed in this study. 
5.8.
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.
Subjects randomised to DTG
To provide continued access to unapproved investigational drug to subjects deriving 
therapeutic benefit, subjects randomised to receive DTG and who have successfully 
completed the Randomised Phase (Day 1 to Week 48 plus a 4-week treatment extension)
will be given the opportunity to continue to receive DTG until one of the following 
occurs:

DTG is locally approved and commercial supplies are available to patients (e.g. 
through public health services),

The subject no longer derives clinical benefit from treatment with DTG, or

The subject meets a protocol-defined reason for discontinuation.
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure access to these medications during and post study.
Subjects who complete the DTG Continuation Phase must return to clinic when 
transitioning to ART available, e.g. through public health services, to have the 
assessments performed as noted in the Continuation Phase schedule (see Section 6.1).
Subjects randomised to LPV/RTV
As subjects receiving LPV/RTV in the Randomised Phase (Day 1 to Week 48 plus a 4-
week treatment extension) complete the Week 52 visit, they will also complete the study.  
Investigative sites must make arrangements for provision of LPV/RTV early during the 
study to ensure continued access to medication post study.  Investigative sites must make 
arrangements for provision of background NRTIs to all subjects to ensure access to these 
medications during and post study. 
Subjects originally randomised to receive LPV/RTV but switched to the DTG arm prior 
to Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 


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available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
5.9.
Treatment of Study Treatment Overdose
Any tablet intake exceeding the randomised daily number of tablets for IP will be 
considered an overdose.
For the purposes of this study, an overdose is not an AE (see Section 6.4.5.1) 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 6.4.5.2).
If an overdose occurs and is associated with an adverse event requiring action, all study 
medications should be temporarily discontinued until the adverse event 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
6.1.
Time and Events Schedule
Table 1
Time and Events Table
Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
Clinical and Other Assessments
Written informed 
consent
X
Inclusion/Exclusion 
criteriad
X
Subject 
demography
X
Medical historye
X
Prior ART history
X
CDC HIV-1 
classification
X
X
Limited physical 
examinationf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and 
height
X
Current medical 
conditions
X
CV risk 
assessmentg
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
X
Columbia 
Suicidality Severity 
Rating Scale
Xh
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
SAEs
Xi
X
X
X
X
X
X
X
X
X
X
X
X
GSRS
X
X
X
X
Xj
HIVTSQs
X
X
X
X
Xj
HIVTSQc
X
Xj
MMAS-8
X
X
X
X
Xj
Laboratory Assessments
Quantitative 
plasma HIV-1 RNA 
PCR
X
X
X
X
X
X
X
X
Xk
X
X
X
Lymphocyte subset 
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for HIV 
genotyping
X
Plasma for storagel
X
X
X
X
X
X
X
X
X
X
X
X
HLA-B* 5701 
testingm
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucosen
X
X
X
X
Pregnancy testo
S
U
S
S
S
S
S
S
S
S
S
S
S
HBsAg, anti-HBc 
and anti-HCVp
X


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Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
HBV DNAq
X
Pharmacogenetic 
sampler
X
PBMCss
X
Investigational product
Interactive voice 
recognition 
system (IVRS)
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
X
X
Xt
X
X
IP accountability 
(pill counts)
X
X
X
X
X
X
X
X
X
X
a.
The 28-day Screening period may be extended to 42 days. Randomisation may occur as soon as all Screening results are available.
b.
For subjects who completed randomised DTG through Week 52 and entered into the DTG Continuation Phase: subjects completing the DTG Continuation Phase must return to 
the clinic when transitioning to commercial supplies. Conduct study assessments, with the exception of dispensing IP, as specified for all Continuation Phase visits at this end of 
Continuation Phase visit.
c.
A follow-up visit will be conducted 4 weeks after the last dose of study provided IP and is required only if a subject has ongoing AEs or laboratory abnormalities at the last on-study 
visit. The assessments performed should reflect what is considered medically necessary to assess the event(s).
d.
Inclusion/exclusion criteria will be fully assessed at the Screening visit. Changes between the screening visit and the Day 1 visit should be assessed to ensure eligibility, including 
additional assessments performed at Day 1.
e.
Full medical history will be collected. Targeted Medical History assessments will include cardiovascular, gastrointestinal (e.g. GI bleeding, PUD, etc), metabolic (e.g. Type I or II 
DM), psychiatric (e.g. depression), renal (e.g. nephrolithiasis, nephropathy, renal failure) and neurological disorders. 
f.
Limited physical examination to include blood pressure at Baseline (recorded in eCRF) for Framingham score assessment. Blood pressure to be measured after resting in a semi-
supine position for at least 5 minutes.
g.
Assessment for cardiovascular risk will include height, weight, blood pressure, smoking history, medical conditions, and family history of premature cardiovascular disease.
h.
On Day 1, the Columbia Suicidality Severity Rating Scale is to be administered prior to randomisation.
i.
Only SAEs related to study participation or to a concomitantly administered GSK/ViiV product will be collected between obtaining informed consent and administration of IP at Day 
1.
j.
Health outcomes assessments will only be conducted at Withdrawal if the Withdrawal visit occurs at or prior to Week 48.


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k.
At Week 52, repeat HIV-1 RNA testing will only be performed for subjects with HIV-1 RNA 50 c/mL at Week 48.
l.
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, HIV-1 RNA 
levels, and immunological parameters). These samples will be used when needed such as when samples are lost or arrive at the laboratory unevaluable. Additionally, for 
genotypic and phenotypic resistance analyses Baseline samples from all subjects will be used and later samples in cases of confirmed virologic withdrawal criteria met (for paired 
baseline and endpoint genotypes).
m.
Subjects starting ABC as one of the NRTIs should have been screened and be negative for the HLA-B*5701 allele.
n.
An overnight fast is preferred, however a minimum of a 6 hour fast is acceptable.
o.
Pregnancy testing will be conducted (women of child bearing potential only) on serum (S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of IP. Remind females of childbearing potential of the need to avoid pregnancy while on study and adherence to the study’s contraception requirements.
p.
Subjects who are hepatitis B surface antigen (HBsAg) positive require appropriate HBV therapy based on local guidelines (see Section 6.2.3 for details).
q.
HBV DNA testing will be performed on Day 1 for subjects with negative HBsAg and positive hepatitis B core antibody (anti-HBc) results at Screening.  Subjects with positive anti-
HBc and positive HBV DNA results require appropriate HBV therapy based on local guidelines (see Section 6.2.3 for details).
r.
Informed consent for optional pharmacogenetics (PGx) research must be obtained before collecting a sample. Collection of the PGx sample at Day 1 is preferred; however, this 
sample may be collected at any time during the study.
s.
Whole blood collection (please refer to the SPM).
t.
For subjects receiving DTG during the Continuation Phase only.


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6.2.
Critical Screening and Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject (or 
his/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 enrolment 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 visit.  Physical exams 
should be conducted as part of normal routine clinical care but will not be collected 
systematically in the CRF.
6.2.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events Table 
(Section 6.1).  
Eligible subjects may be randomised as soon as all Screening assessments are complete 
and the results are available and documented. All subjects will complete a Screening 
period of approximately 28 days prior to Baseline (Day 1) during which all clinical and 
laboratory assessments of eligibility must be performed and reviewed.  The Screening 
period may be extended to 42 days to accommodate availability of all Screening 
assessment results and scheduling.  All Screening results must be available prior to 
randomisation.
All subjects must provide a plasma sample for determination of viral genotypic resistance 
at the central laboratory (or a laboratory contracted by the central laboratory).  For 
eligibility the resistance report must show no evidence of either full or of partial 
resistance for at least one NRTI which will be taken by the subject during study.
Severe hepatic impairment is exclusionary and will be assessed by Child-Pugh grading at 
Screening (see Appendix 1, Section 11.1).  
Hepatitis B surface antigen (HBsAg) will be obtained at Screening to ensure that subjects 
with chronic active hepatitis B receive appropriate hepatitis B treatment in conjunction 
with appropriate HIV background regimens for the study.  For subjects with positive 
hepatitis B core antibody (anti-HBc) and negative HBsAg at Screening, HBV DNA 
testing will be performed on Day 1.
Subjects who meet all entry criteria are randomised and assigned a randomisation 
number. Subjects not meeting all inclusion and exclusion criteria at initial screen may be 
re-screened and receive a new subject number one time.  Subjects, who are randomised 
into the trial and subsequently withdrawn from the study for any reason, may not be re-
screened.


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Investigators must ensure subjects are prepared for randomisation on Day 1, including 
confirming arrangements for provision of the dual NRTI background regimen and 
ensuring that these medications will be available for use at the time of the Day 1 visit.  
Screening resistance test results must be used to determine one fully active agent, but all 
available data (prior treatment history, Screening and, if available, historical resistance 
results) should also be considered for selection of the background therapy.  Also see 
Section 5.1.3 for dual NRTI combinations prohibited in this trial.
Selection of the background regimen must be complete prior to randomisation; therefore, 
after successfully completing all screening procedures, the investigator will determine the 
most appropriate background regimen for use in the study.
Note: Where HLA-B*5701 screening is considered standard of care, it is recommended 
that Investigators screen for presence of the HLA-B*5701 allele in any subject for whom 
an abacavir (ABC)-containing product (e.g. ZIAGEN™, EPZICOM, KIVEXA) may be 
considered as part of background regimen and HLA-B*5701 status is unknown (even if 
the subject has previously tolerated ABC).   Use of ABC in subjects known to carry 
HLA-B*5701 is not recommended and should be considered only under exceptional 
circumstances where potential benefit outweighs the risk and only under close medical 
supervision.
6.2.2.
Baseline (Day 1) Assessments
Assessments to be conducted at Baseline (Day1) are provided in the Time and Events 
Table (Section 6.1). 
At Day 1 and prior to randomisation, any changes to the eligibility parameters must be 
assessed and any results required prior to randomisation (e.g. Day 1 urine pregnancy test 
for women of child bearing potential) must be available and reviewed.  
Cardiovascular medical history/risk factors will be assessed at Baseline, to include 
smoking status and history and family history of cardiac events. 
6.2.3.
Subjects Co-infected with Hepatitis B Virus (HBV)
Investigators should consult current treatment guidelines (e.g. [Thompson, 2012]) when 
considering choice of NRTIs for subjects with chronic HBV infection (HBsAg positive 
OR anti-HBc positive with HBV DNA present).  
In addition, clinical trial and marketed use of 3TC, FTC and TDF have shown that some 
subjects with chronic HBV disease may experience clinical or laboratory evidence of 
recurrent hepatitis upon discontinuation of 3TC, FTC or TDF, which may have more 
severe consequences in subjects with decompensated liver disease.  Subjects with HBV 
co-infection should be advised against self-discontinuation of any medications with anti-
HBV activity.  If 3TC, FTC or TDF is discontinued in subjects co-infected with HBV, 
periodic monitoring of both liver chemistry tests and markers of HBV replication should 
be performed.


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Entecavir and telbivudine are permitted, in appropriate clinical situations, for treatment of 
hepatitis B (e.g. prior intolerance or viral resistance to TDF, viral resistance to 3TC/FTC) 
after discussion and agreement between the investigator and the medical monitor.  
In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-
NRTI background regimen in subjects with chronic HBV infection and evidence of HIV 
resistance to 3TC (e.g. M184V).  3TC cannot be added to regimens that include FTC.
6.2.4.
Subjects Co-infected with Hepatitis C Virus (HCV)
Investigators should consult current treatment guidelines when considering choice of 
therapy for subjects with chronic HCV infection.  Subjects with an anticipated need for 
HCV therapy during the Randomised Phase (Day 1 to Week 48 plus a 4-week treatment 
extension) may not be enrolled into this study.
6.3.
Efficacy
6.3.1.
Efficacy Evaluations
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
Table (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 lower limit of detection for a given assay) additional 
exploratory methods may be used to further characterise 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 the 
Time and Events Table (Section 6.1).
HIV-associated Conditions
HIV-associated conditions will be recorded as per the Time and Events Table (Section 
6.1) and assessed according to the 1993 CDC Revised Classification System for HIV 
Infection in Adults (Appendix 2, Section 11.2).  Indicators of clinical disease progression 
are defined as:
CDC Category A at enrolment Category C event;
CDC Category B at enrolment Category C event;
CDC Category C at enrolment New Category C Event;
CDC Category A, B or C at enrolment Death.


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6.3.2.
Primary Endpoint
The primary endpoint for this study will be the proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot algorithm (Missing, Switch or 
Discontinuation = Failure) for the ITT-E population (see Section 8.3.3.1).
6.3.3.
Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48 
using the Snapshot algorithm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack 
of efficacy;

Time to viral suppression (HIV-1 RNA <50 c/mL);

Absolute values and changes from Baseline in CD4+ cell counts at Weeks 24 and 48;

Incidence of disease progression (HIV-associated conditions, AIDS and death).
6.4.
Safety
6.4.1.
Safety Evaluations
Safety assessments will include the following:

Monitoring and recording all AEs and SAEs.  Additional information on the Time 
Period and Frequency of Detecting AEs and SAEs is provided in Section 6.4.12;

Regular monitoring of haematology, blood chemistry and fasting lipids (parameters 
to be tested listed in Table 2 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);

Evaluation and documentation of all concomitant medications and blood products;

Suicidality monitoring using the Columbia Suicide-Severity Rating Scale (Section
6.4.10).
Any appropriately qualified site personnel (e.g. Investigator, sub-Investigator or study 
coordinator/nurse) can perform assessments.  A central laboratory chosen by GSK (or a 
laboratory contracted by this central laboratory) will undertake all routine scheduled 
laboratory evaluations within the study.  Refer to the Laboratory Manual for specific 
instructions on sample collection, processing, storage and shipping for each laboratory 
test.


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Table 2
Laboratory Assessments
Haematology
Platelet Count
Automated WBC Differential:
RBC Count
Neutrophils
WBC Count (absolute) 
Lymphocytes
Haemoglobin
Monocytes
Haematocrit
Eosinophils
MCV
Basophils
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells
Clinical Chemistry
BUN
Potassium
AST
Total bilirubina
Creatinineb
Chloride
ALT 
Albumin 
Glucose
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
BUN = blood urea nitrogen
a. Direct bilirubin will be reflexively performed for all total bilirubin values > 1.5X ULN.
b. Glomerular Filtration Rate (GFR) will be estimated by the central laboratory using the CKD-EPI method [Levey, 
2009].
Fasting Lipid Panela
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
a. For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6 hour fast is acceptable. 
Other tests
Plasma HIV-1 RNA
CD4+ cell counts
Hepatitis B (HBsAg, anti-HBc) and Hepatitis C (anti-HCV)a
Hepatitis B (HBV DNA)b
Pregnancy test for women of child bearing potentialc
HLA-B*5701 screeningd
a. Screening visit only.
b. Baseline visit only (subjects with negative HBsAg and positive anti-HBc results at Screening only).
c. Urine pregnancy test on Day 1; serum pregnancy test at Screening and Weeks 4, 8, 16, 24, 36, 48, and 52 (and at 
Week 60 and at 12 weeks intervals thereafter if applicable).
d. HLA-B*5701 screening will be only performed to examine candidates for ABC at discretion of the investigator.
6.4.2.
Safety Endpoints

Incidence and severity of AEs and laboratory abnormalities; 

Absolute values and changes over time in laboratory parameters;

Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48;

Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48;


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
The incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 24 and 48;

The incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Weeks 24 and 48;

The proportion of subjects who discontinue treatment due to AEs.
6.4.3.
Toxicity Management
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (Appendix 3, Section 
11.3). Additional information regarding detecting, documenting and reporting AEs and 
SAEs are available in Section 6.4.5.
IP may be interrupted at the discretion of the Investigator and according to the severity of 
the AE. If one or more antiretroviral medication is held due to toxicity or adverse events, 
all antiretroviral medications should be held to reduce the risk of development of 
resistance taking into account both the length of the planned interruptions and the 
pharmacokinetic half-life of each antiretroviral of the regimen, in a way to minimise the 
risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed (except for switch from 
LPV/RTV 800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite 
switch). IP should be restarted as soon as medically appropriate; in general, this should be 
no longer than 4 weeks after interruption (unless Grade 3 or 4 toxicities persist). 
Decisions regarding sequential reintroduction of IP or temporary interruption of one or 
more but not all drugs within the ART regimen 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 6.4.4
“Specific Toxicities/Adverse Event Management”. All changes in the IP must be 
accurately recorded in the subject’s eCRF.
Note: for subjects receiving an ABC-containing product as part of the background 
regimen, in the event of a discontinuation of ABC for any reason, reinitiation of this drug 
should be undertaken with caution. The investigator should obtain a complete history of 
the events surrounding the discontinuation of the ABC-containing product, evaluate for 
the possibility of a clinically suspected HSR, and initiate subject management as outlined 
in the Local Country Prescribing Information, regardless of a subject’s HLA-B*5701 
status. Screening for the presence of HLA-B*5701 is recommended prior to reinitiating 
treatment with ABC-containing products in subjects of unknown HLA-B*5701 status 
who have previously tolerated ABC.
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 6.4.4 “Specific Toxicities/Adverse 
Event Management” for exceptions to this guideline). Subjects who choose to withdraw 


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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.
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 (Section 6.4.4.3).
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 (Section 6.4.4.3).  A 
follow-up visit should be performed 4 weeks after the last dose of study medication if 
AEs or laboratory abnormalities are ongoing.
6.4.4.
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. 


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A switch from LPV/RTV 800/200 mg once daily to LPV/RTV 400/100 mg twice daily or 
the opposite switch is allowed.
Toxicities that the Investigator considers related or possibly related to one of the 
background NRTIs may be addressed by substitutions of the medication for another 
approved NRTI one time during the study, as indicated in Section 5.1.5 “Protocol-
Permitted Substitutions”.  Additional background substitutions for toxicity management 
are permitted after Week 52, but must be agreed first with the study medical monitor.
Toxicities that the Investigator considers related or possibly related to any background 
NRTI should be managed with reference to applicable product labelling.
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 
Follow-Up study evaluations as noted above.
6.4.4.1.
Liver chemistry stopping and follow up criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event aetiology 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);
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 (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;

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 
stabilisation (ALT <5xULN on 2 consecutive evaluations).


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When a liver chemistry stopping criterion is met, do the following:

Immediately hold IP;  

Report the event to the medical monitor within 24 hours of learning its occurrence 
(see Table 3 and Table 4, Section 6.4.14);

Complete the liver event eCRF and SAE eCRF, where applicable (see Section 
6.4.14);

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, stabilise, 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 recommended;

Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, bilirubin) resolve, stabilise or return 
to within baseline values;
Consider the following additional tests to further evaluate the liver event:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

HBsAg and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

Hepatitis E IgM antibody;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);

Syphilis screening;

Drugs of abuse screen including alcohol;

Serum acetaminophen test (APAP adduct test). The site must contact GSK when this 
test is required. Please refer to the SPM.

Blood sample for pharmacokinetic (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 IP prior to blood 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.


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
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 computerised 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.
6.4.4.2.
Restarting investigational product
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by the ViiV Safety and Labeling 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 the 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 the VSLC.

Subjects approved by the VSLC for rechallenge of IP must return to the clinic twice 
a week for liver chemistry tests for one month or for as long as clinically indicated 
and then laboratory monitoring may resume as per protocol.
Refer to Appendix 4, Section 11.4 for further details. 
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the 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 1.5x baseline and 


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ALT <3xULN). Ethics Committee or Institutional Review Board approval of drug 
restart/rechallenge must be obtained, as required.

If restart of drug is approved by the 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 the VSLC.

Subjects approved by the VSLC for restarting IP must return to the clinic once a 
week for liver chemistry tests for one month or for as long as clinically indicated 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 4, Section 11.4 for further details.
6.4.4.3.
Hypertriglyceridemia/hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events Table (Section 6.1). Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.
6.4.4.4.
CPK elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 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) 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.
6.4.4.5.
Decline in renal function
Subjects who experience an increase in creatinine from Baseline of 45 Mol/L (or 
0.5 mg/dL) should return for a confirmatory assessment within 2 to 4 weeks.  A 
urinalysis and urine albumin/creatinine and urine total protein/albumin ratios 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.
Subjects who have a decline in the estimated GFR (using the CKD-EPI method) of >50% 
must return for a confirmatory assessment as soon as possible. A urinalysis and urine 
albumin/creatinine and urine protein/creatinine ratios should be done at this confirmatory 
visit. If the estimated GFR 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 


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factors (e.g. background therapy, other medications, dehydration, concurrent conditions) 
should be taken into account, and a nephrology consult may be obtained.  If a subject is 
also receiving TDF, then a switch to an alternative nucleoside should be considered if 
restarting IP. One background NRTI change is allowed for management of drug toxicity 
as described in Section 6.4.4, “Specific Toxicities/Adverse Event Management”.   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.
6.4.4.6.
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 receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC hypersensitivity reaction (HSR) and 
managed appropriately as outlined in the local prescribing information.
6.4.4.7.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART.  
Episodes generally occur within the first ten weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within two to three weeks.  
No instances of serious skin reaction, including SJS, TEN and erythema multiforme, have 
been reported for DTG in clinical trials.  For further characterisation of HSR and rash 
observed with DTG-containing ART, please see the current version of the IB 
[GlaxoSmithKline Document Number RM2007/00683/11, GlaxoSmithKline Document 
Number 2017N352880_00, and GlaxoSmithKline Document Number 2017N352880_01].
TEN, SJS and erythema multiforme have been reported in patients receiving LPV/RTV 
[Kaletra US Package Insert, 2016; Kaletra EU Summary of Product Characteristics, 
2017].
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 6.4.4.1). 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 


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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.
The rash and any associated symptoms should be reported as adverse events (see 
Section 6.4.5) and appropriate toxicity ratings should be used to grade the events (see 
Appendix 3, Section 11.3).
If the aetiology 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.
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC HSR and managed appropriately as 
outlined in the local prescribing information.
6.4.5.
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.
6.4.5.1.
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 unfavourable 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.


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“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 fulfil 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
6.4.5.2.
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
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.
c.
Requires hospitalisation or prolongation of existing hospitalisation
Note:  In general, hospitalisation 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 hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
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.


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e.
Is a congenital anomaly/birth defect
f.
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 hospitalisation but may jeopardise 
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 hospitalisation, or development of 
drug dependency or drug abuse.
g.
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 
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 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.
Reporting of ABC Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC develops in subjects receiving ABC as part 
of their NRTI background regimen, and meets one of the International Conference on 
Harmonization (ICH)-E2A definitions of seriousness listed above, 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 (see Section 6.4.14).
6.4.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECGs, 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. 
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.
Additionally, diagnostic test results that represent a sign of a clinical condition that is 
already reported as an AE need not be reported as this would be redundant.
It is important to note that grading for laboratory abnormalities (see Section 11.3) is an 
objective assessment conducted at the central laboratory (or a laboratory contracted by 
the central laboratory) and does not translate directly into similarly graded AEs.


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6.4.7.
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.
6.4.8.
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 noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.4.9.
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 
(Appendix 2, Section 11.2 [CDC, 1992]) 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 6.4.5.2), 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.


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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.
6.4.10.
Suicidality Monitoring
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with a pre-
existing history of depression or psychiatric illness) in some patients being treated with 
INIs, including DTG.  Therefore, it is appropriate to monitor subjects for suicidality 
before and during treatment. 
Subjects should be monitored appropriately and observed closely for suicidal ideation 
and behaviour or any other unusual changes in behaviour.  It is recommended that the 
Investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behaviour.  Subjects presenting with new onset/treatment-
emergent depression should be advised to contact the investigator immediately if 
symptoms of severe acute depression (including suicidal ideation/attempts) develop, 
because medical intervention and discontinuation of the study medication may be 
required.
Assessment of treatment emergent suicidality will be monitored during this study using 
the Columbia Suicide Severity Rating Scale (C-SSRS). The definitions of behavioural 
suicidal events used in this scale are based on those used in the Columbia Suicide History 
Form [Oquendo, 2003]. Questions are asked on suicidal behaviour, suicidal ideation and 
intensity of ideation. Day 1 (Baseline) visit questions will be in relation to lifetime 
experiences and current experiences (within the past 2 months) and all subsequent 
questioning in relation to the last assessment. The C-SSRS is to be administered as a 
patient completed questionnaire 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 SAE) eCRF form 
on any subject that experiences a possible suicidality-related AE while participating in 
this study. This may include, but is not limited to, an event that involves suicidal ideation, 
a preparatory act toward imminent suicidal behaviour, 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 AE.
6.4.11.
Pregnancy
6.4.11.1.
Pregnancy testing
Women of childbearing potential must have a negative pregnancy test at Screening and 
Day 1 to be eligible for administration of IP.  Pregnancy testing will also be conducted as 
per the Time and Events Table (see Section 6.1) and at anytime during the trial when 
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Additionally, a pregnancy test should also be performed prior to study drug re-
administration, when administration is disrupted for more than 7 days (e.g. temporary 
interruption of study drug).
6.4.11.2.
Action to be taken if pregnancy occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study and discontinue IP.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature 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, 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.
6.4.11.3.
Time period for collecting pregnancy information
Information on the occurrence of pregnancies in female subjects will be collected over 
the period starting at Screening and ending at the final on-study or Follow-up visit. Only 
those pregnancies that occur following the first dose of IP will be reported to GSK. 
Follow-up information will only be collected for pregnancies occurring from Day 1 to the 
final on-study or Follow-up visit.
6.4.12.
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.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
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 from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.4.14. 


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6.4.13.
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?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?”
6.4.14.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in Table 3 and Table 4 once 
the investigator determines that the event meets the protocol definition for that event.
Table 3
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
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 
applicable2
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 4
Other Events Requiring Prompt Reporting
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Cardiovascular or death 
event
Initial and follow 
up reports to be 
completed within 
one week of 
when the 
cardiovascular 
event or death is 
reported 
“CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Suspected ABC HSR1
1 week
ABC HSR CRF
1 week
Updated ABC HSR 
CRF
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
ALT ≥5xULN and 
<8xULN that persists 
≥2 weeks 
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
ALT ≥8xULN 
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
ALT ≥3xULN (if 
baseline ALT ≤ULN) or 
ALT ≥3 fold increase 
from baseline value (if 
baseline ALT >ULN) 
with appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
1.
ABC HSR CRF required only if event meets one of the ICH-E2A definitions of ‘seriousness’.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
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.
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.
6.4.14.1.
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, Institutional Review Board (IRB)/Independent Ethics Committee 
(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.
6.4.15.
Other Safety Outcomes
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 2, must be performed 
by the central laboratory, Quest Diagnostics, or a laboratory contracted by the central 
laboratory. Laboratory assessments must be conducted in accordance with the 
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 required for cardiovascular events, additional specific local laboratory assessments will 
be recorded in the specific cardiovascular eCRF (see Section 6.4.7).   
6.5.
Health Outcomes
Health outcomes assessments will be conducted in all countries according the schedule in 
the Time and Events Table (Section 6.1).  Assessments are recommended to be 
administered at the beginning of the visit.
HIVTSQ: The HIV treatment satisfaction questionnaire status version (HIVTSQs) and 
HIVTSQ change version (HIVTSQc) are self-reported scales that measure overall 
satisfaction with treatment and by specific domains, e.g. convenience, flexibility 
[Woodcock, 2001; Woodcock, 2006]. The change version of the HIVTSQ was developed 
to overcome ceiling effects (i.e. where respondents score maximum or near-maximum 
satisfaction at Baseline and can show little or no improvement at follow-up.  The 
HIVTSQ will be administered as a paper questionnaire.
MMAS-8: The Morisky 8-Item Medication Adherence Scale (MMAS-8) is a self-report 
measure of medication-taking behaviour and addresses barriers to medication-taking 
[Morisky, 2008].  The MMAS-8 will be administered as a paper questionnaire. 
GSRS: The Gastrointestinal Symptom Rating Scale (GSRS) is a disease-specific 
instrument of 15 items combined into five symptom clusters depicting Reflux, 
Abdominal pain, Indigestion, Diarrhoea and Constipation [Svedlund, 1988].  The GSRS 
will be administered as a paper questionnaire. 


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6.5.1.
Health Outcome Endpoints

Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS), at 
Week 4, Week 24, and Week 48; 

Change from Baseline in treatment satisfaction, using the HIV-Treatment 
Satisfaction Questionnaire (HIVTSQ), at Week 4, Week 24, and Week 48;

Change from Baseline in adherence with treatment, using the Morisky 8-Item 
Medication Adherence Scale (MMAS-8), at Week 4, Week 24, and Week 48.
6.6.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject for Screening resistance 
testing at the central laboratory (or a laboratory contracted by the central laboratory) and 
on study ‘plasma for storage’ samples according to the Time and Events Schedule in 
Section 6.1 for viral genotypic and phenotypic analyses as required.
Details concerning the handling, labelling and shipping of these samples will be supplied 
separately.  Screening viral genotype will be performed through Quest Diagnostics as 
well as at location(s) to be described in the SPM.  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) and Integrase assays.  In addition, where Monogram Biosciences resistance testing 
is not possible, resistance testing may also be performed at location(s) to be described in 
the SPM.
Screening will include only viral genotype for eligibility determination and to guide the 
choice of NRTIs.
6.6.1.
Virology Endpoint

Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, 
LPV/RTV and other on-study ART in subjects meeting confirmed virologic 
withdrawal criteria.
6.6.2.
HIV-1 Pol Viral Genotyping and Phenotyping
Subjects meeting a ‘confirmed virologic withdrawal criterion’ (see Section 4.6.3) 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 and from samples 
collected at the time of meeting a ‘suspected virologic withdrawal criterion’; these results 
will be reported to the Investigator as soon as available to provide guidance for election 
of an alternative regimen.
HIV-1 PRO and RT genotype and phenotype will also be determined on the Baseline 
isolates from all subjects, if possible.  When samples cannot be analysed by Monogram 
Biosciences, Baseline isolate resistance testing may be performed at location(s) to be 
described in the SPM.  


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6.6.3.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried out on peripheral 
blood mononuclear cell (PBMC) samples collected at Baseline and/or on stored plasma 
samples from Baseline and other relevant time points.  These analyses may 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, low level 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 Baseline and the last on-treatment isolates from subjects who have 
HIV-1 RNA 400 c/mL regardless of confirmatory HIV-1 RNA.
6.7.
Pharmacogenetic Research
Information regarding pharmacogenetic (PGx) research is included in Appendix 5, 
Section 11.5.
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 5, Section 11.5).  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.  eCRFs (including queries and audit trails) will be retained by GSK, and 
copies will be sent to the investigator to maintain as the investigator copy.  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 study is designed to show that the antiviral effect of a regimen of DTG 
(administered once daily) + two NRTIs is non-inferior to LPV/RTV + two NRTIs. 
If rd is the response rate on DTG + two NRTIs and ra is the response rate on LPV/RTV + 
two NRTIs then the hypotheses can be written as follows:
H0: rd – ra ≤ -12% 
H1: rd – ra > -12%.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
Rationale for non-inferiority margin
The non-inferiority margin of 12% was chosen based on historical data from well-
controlled superiority trials in treatment naïve subjects which established a large 
quantitative contribution to viral suppression of a PI when added as a third drug to a dual 
NRTI background (approximately 45% using the lower confidence bounds) and the 
negligible viral load response (less than 5%) in regimens containing dual NRTIs alone 
[HHS, 2013].  In second-line therapy, the efficacy of optimised dual NRTI alone would 
be expected to be similar or worse than that seen in treatment naïve studies in light of 
possible emergence of resistance to NRTIs during virologic failure with first line therapy.   
Therefore, a non-inferiority margin of 12% is an acceptable margin since it is well below 
the expected treatment effect for LPV/RTV plus two NRTIs vs. two NRTIs alone. 
Response rate assumptions
There are limited randomised prospective study data to indicate response rates of patients 
receiving second line treatment.  Retrospective and cohort analyses of LPV/RTV 
containing regimens in treatment experienced patients have showed responses between 
56.4% and 85.7% at 48 weeks.  These studies mostly contained small numbers of patients 
and differed in their use of backbone agents and the degree of treatment experience of 
subjects.
The estimated treatment response rate chosen for the comparator (70%) is based on the 
results from comparable studies of second line ART and the most recent relevant studies 
of DTG and LPV/RTV in patient population with treatment experience greater than 
second-line ART. 
Studies evaluating second-line therapy

HIV STAR was a study conducted in Thailand (n=195, ITT) to compare LPV/RTV + 
TDF/FTC with LPV/RTV monotherapy in patients failing initial therapy on an 
NNRTI + two NRTI regimen [Bunupuradah, 2012].  In this trial, the primary 
endpoint of non-inferiority according to mean reduction in HIV RNA from Baseline 


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over 48 weeks was met with a 1.89 log decrease for the LPV/RTV +TDF/FTC arm 
compared with a decrease of 1.74 log in the monotherapy arm (difference: 0.15 log; 
95% CI: 0.04 to 0.33).  For the secondary outcome of proportion of subjects <50 
c/mL a lower response was seen for the monotherapy arm.  In this analysis, 83% of 
subjects achieved HIV-1 RNA <50 c/mL (ITT) at Week 48 in the triple therapy arm 
compared with 61% in the LPV/RTV monotherapy arm (difference: -22.2%, 95% CI 
-33.5 to -9.0, p <0.01) based on a missing equals failure imputation.  As noted in the 
above manuscript, the high virologic suppression rate in the LPV + TDF/FTC arm 
may not be applicable to those with a much more extensive duration of NNRTI-
based failure.  For the LPV + TDF/FTC, the median (IQR) duration of NNRTI-based 
HAART before enrolment was 2.3 years (1.2-4.0).

The SECOND LINE study compares the antiviral efficacy of second-line ART 
comprising LPV/RTV + 2-3 NRTIs with LPV/RTV + RAL, as measured by the 
proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 48 (n=541) 
[SECOND-LINE Study Group, 2013].  In this study, the LPV/RTV + RAL arm was 
found to be non-inferior to LPV/RTV + NRTIs at 48 weeks with 82.6% vs. 80.8% of 
patients respectively, achieving HIV-1 RNA  <200 c/mL (mITT, p=0.59).  Similarly, 
71.1% and 70.5% of participants achieved an HIV-1 RNA <50 c/mL (mITT, p=0.87) 
[Note: NC=F analysis or Snapshot equivalent showed 68.1% (184/270) vs 66.4% 
(180/271) of patients achieved HIV-1 RNA <50 c/mL at Week 48].  For the 
LPV/RTV + 2-3 NRTIs arm, the median (IQR) duration of NNRTI-based HAART 
before enrolment was 3.3 years (1.8-5.4) years.

The EARNEST study (ongoing, n=1270), conducted in sub-Saharan Africa was 
powered on 75% for the composite endpoint of ‘good HIV disease control’ at Week 
96.  At Week 96, 74% achieved HIV-1 RNA <50 c/mL with LPV/r + 2-3 NRTIs 
[Paton, 2013].
Studies in more treatment experienced populations

The TITAN study (LPV/RTV vs DRV+RTV):  the response rate for LPV/RTV arm 
was 68% (< 50 c/mL at 48 weeks, n=595) [Madruga, 2007]. This study population 
was more treatment experienced than the current study, with 47% of subjects having 
prior 3-class experience (NRTI + NNRTI + PI). 

The SAILING study (DTG vs RAL): in subjects receiving DTG in combination with 
1-2 investigator-selected background agents, the proportion of subjects with plasma 
HIV-1 RNA < 50 c/mL at Week 48 (Snapshot) was 71% (251/354) [Cahn, 2013].  
This study population had documented genotypic or phenotypic resistance to at least 
one member of each of at least two ART drug classes (NRTI, NNRTI, PI, fusion or 
entry inhibitor).
This study will randomise at least 306 subjects per arm.  Assuming a true response rate of 
70% in each arm, this sample size will provide 90% power to show non-inferiority for the 
proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 with a 12% non-
inferiority margin and a one-sided 2.5% significance level.  If we observe a 70% response 
rate in the LPV arm then non-inferiority would be declared if the observed treatment 
difference (DTG - LPV) was better than -4.6 percentage points.


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8.2.2.
Sample Size Sensitivity
Figure 2 shows the sensitivity of the required sample size to the true response rate for the 
control arm (assuming no true difference between arms).  Assuming identical response 
rates in each arm, if the true response rate is as low as 65%, the study will still have 88% 
power to meet its primary objective.  In this case, an extra 50 subjects (25 per arm) would 
be required to restore 90% power.
Figure 2
Sample Size Sensitivity
Power (%)
55
60
65
70
75
85
86
87
88
89
90
91
92
93
Control arm response rate (%)
a) How power changes with
control response (N=306/arm)
55
60
65
70
75
280
300
320
340
360
Subjects per arm
55
60
65
70
75
280
290
300
310
320
330
340
350
360
Control arm response rate (%)
b) Sample size needed
to guarantee 90% power
8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The following populations will be assessed.  The analysis population for genotypic and 
phenotypic analyses as well as for health outcomes assessments will be fully described in 
the reporting and analysis plan (RAP).
Intent-to-Treat Exposed (ITT-E) Population
This population will consist of all randomised subjects who receive at least one dose of 
study medication.  Subjects will be assessed according to their randomised treatment, 
regardless of the treatment they receive.  Unless stated otherwise, the ITT-E population 
will be used for summaries and analyses of efficacy.
Safety Population
The Safety Population is defined as all subjects who receive at least one dose of IP.  
Subjects will be analyzed according to the actual treatments received.


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Per-Protocol Population
This population will consist of subjects in the ITT-E population with the exception of 
major protocol violators, e.g. violations which could affect the assessment of antiviral 
activity.  The Per-Protocol (PP) population will be used for sensitivity analyses of the 
primary efficacy endpoint.
ITT Population (ITT)
This population will consist of all randomised subjects.  Subjects will be assessed 
according to their randomised treatment even if no study treatment was taken or the 
wrong treatment was received.  The ITT population will be used for sensitivity analyses 
of the primary efficacy endpoint.
8.3.2.
Analysis Data Sets
For the primary efficacy analysis, each subjects responses (e.g. <50 c/mL) will be 
calculated according to the FDA’s Snapshot algorithm.  This algorithm treats all subjects 
without HIV RNA data at the visit of interest (due to missing data or discontinuation of 
IP prior to visit window) as non-responders, as well as subjects who switch their 
concomitant ART prior to the visit of interest as follows:

Background ART substitutions not permitted per protocol;

Background ART substitutions permitted per protocol after Week 4 (or date of first 
on-treatment viral load collection, if earlier) where the last HIV-1 RNA result prior to 
the date of decision to switch is ≥50 c/mL.  
Note: if the last HIV-1 RNA result prior to the date of decision to switch is <50 c/mL 
then the permitted change in background ART will have no effect on the analysis.
Note: A switch from 3TC to FTC (or vice versa) will not be considered a background 
NRTI change and will not incur a penalty in the Snapshot algorithm, regardless of reason 
or date of switch, as these agents are assumed to be of equal efficacy.
Otherwise, virologic success or failure will be determined by the last available HIV-1 
RNA assessment while the subject is on-treatment within the visit of interest window (to 
be specified in the RAP).
Full details on this Snapshot algorithm will be contained in the RAP.
The observed case (OC) dataset, which uses only data that is available at a particular time 
point with no imputation for missing values, will be the primary dataset for assessing 
safety and will also be used for some analyses of efficacy and health outcomes.
Full details on methods to address missing data for secondary efficacy and health 
outcomes endpoints will be discussed in the RAP.


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8.3.3.
Treatment Comparisons
8.3.3.1.
Primary comparisons of interest
The primary analysis will be based on the ITT-E population using the Snapshot dataset.   
The primary comparison will be made at a one-sided 2.5% level of significance.  
Treatment with DTG + two NRTIs will be declared non-inferior to treatment with 
LPV/RTV + two NRTIs if the lower end of a two-sided 95% confidence interval for the 
difference between the two groups in response rates at Week 48 lies above -12%.
8.3.3.2.
Other comparisons of interest
The analysis described above in Section 8.3.3.1 will also be performed using the PP 
population and the results will be compared for consistency with the results from the ITT-
E population.  If both analyses show non-inferiority then the hypothesis that the antiviral 
effect of treatment with DTG + two NRTIs is superior to treatment with LPV/RTV + two 
NRTIs will be tested using the same level of significance as for the tests of non-
inferiority.  Superiority will be declared if the lower end of the confidence internal is 
above 0%.  The primary comparison will also be performed using the ITT population and 
will be compared for consistency with the results from the ITT-E and PP populations.
The supportive analysis using the ITT population will classify subjects randomised but 
not exposed to study treatment as non-responders and therefore conservatively addresses 
any selection bias that may occur given the open-label study design.
8.3.3.3.
Secondary comparisons
The following key secondary comparisons will be tested:

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to change from Baseline in fasting LDL cholesterol at Week 48 using the Safety 
population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to the incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Week 48 using the Safety population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to change from Baseline in fasting TC/HDL ratio at Week 48 using the Safety 
population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to the incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Week 48 using the Safety population;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack 
of efficacy);


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
Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to time to viral suppression (HIV-1 RNA <50 c/mL) using ITT-E population.
8.3.4.
Interim Analysis
The main analysis will be conducted to evaluate the primary objective of the protocol 
when all subjects have completed their Week 52 visit.  
8.3.4.1.
Week 24 data cut
An interim analysis will be conducted when all subjects have completed their Week 24 
visit in order to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  The analyses described in Section 8.3.3 and Section 8.3.5 will be performed 
with the sole difference being that the timepoint for these analyses will be Week 24 
instead of Week 48.  
No adjustment for multiplicity will be made for this analysis because the Week 24 
endpoints represent secondary objectives for the study which are subordinate to the 
primary analysis at Week 48.
8.3.4.2.
IDMC interim analyses
An IDMC has been instituted to provide independent review of the accumulating data, 
primarily to ensure subjects are not being sub-optimally treated in either arm. 
Three formal interim analyses were planned for review by the IDMC (Table 5).
Table 5
Timing of Planned IDMC Interim Analyses and Statistical Stopping 
Guidelines
Interim 
Analysis
Timing
Endpoint
Evaluation (guideline)
#1
Once 100 subjects (total) 
have completed their Week 
16 visit
Proportion of subjects with 
HIV-1 RNA <50 c/mL
at Week 16
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
#2
Once 300 subjects (total) 
have completed their Week 
24 visit
Proportion of subjects with
HIV-1 RNA <50 c/mL
at Week 24
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
#3
Once all subjects have 
completed their Week 24 
visit
Proportion of subjects with 
HIV-1 RNA <50 c/mL
at Week 48
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
Superiorityb (one-sided p<0.0001)
a.
Inferiority: significantly lower response rate with DTG than LPV/r.
b.
Superiority: significantly higher response rate with DTG than LPV/r.
It is intended that the second interim analysis will occur roughly halfway between the 
second and third interim analyses, although this will be affected by the actual rate of 
study recruitment.     


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The third interim analysis will occur after all subjects have completed Week 24, but the 
stopping guideline is provided for the proportion of subjects with suppression at Week 48 
(including all subjects randomised at least 48 weeks prior to the last subject completing 
Week 24). For this reason, the number of subjects with week 48 data at the third interim 
analysis cannot be specified in advance.
The IDMC completed interim analyses #1 and #2.  Prior to interim analysis #3, the 
IDMC conducted an ad hoc review of trial data and observed significant, clinically 
relevant differences between treatment arms in favour of DTG.  The IDMC 
recommended to the sponsor that the LPV/RTV treatment arm be discontinued and 
subjects currently receiving LPV/RTV in the study be switched to a regimen with 
DTG as the third drug, if considered appropriate by the Investigator. Interim
analysis #3 will no longer take place.
Stopping Guidelines
Proposed p-value boundaries that may lead to an IDMC recommendation to stop the 
study at each interim analysis are provided in Table 5.  These have been provided as a 
guide only, with the expectation that the IDMC will base its recommendation to stop or 
continue the study based on all available evidence and the IDMC’s collective judgment. 
This stopping guidance is not a substitute for the medical, scientific or statistical expertise 
of the IDMC.  Moreover, if a guideline boundary is crossed then the IDMC will be asked 
to undertake a thorough review of the data, including all available data on treatment- and 
efficacy-related discontinuations (discontinuations due to virologic failure, lack of 
efficacy, drug-related adverse events), viral load data at all timepoints, and response by 
number of fully active background NRTIs.
Formal assessments of inferiority will be conducted at each interim analysis.  Inferiority 
for this study is defined as evidence that DTG has a substantially lower response rate than 
LPV.  A statistical guideline of p<0.01 (one-sided) will be used for each inferiority 
evaluation.
A formal assessment for superiority will be conducted only at the third interim analysis.  
Superiority is defined as substantial evidence that DTG has a higher response rate than 
LPV.  A statistical guideline of p<0.0001 (one-sided) will be used for this evaluation of 
DTG superiority.
No adjustment for multiple comparisons will be made since the impact of these 
guidelines do not alter the Type I error rate in favour of DTG to any measurable degree 
(Table 6).
The analysis method for these comparisons will be the same as that used in the final 
primary analysis (i.e. adjusted difference in proportion based on stratified analysis). 
The statistical properties of the proposed stopping guidelines are explored below.  For 
illustrative purposes only, the p-value boundaries are assumed to be binding (i.e. if 
crossed the study must be stopped).  However, in practice, the p-value boundaries are not 
binding and are to be used as guides only: signaling that additional exploration of the data 
is warranted, as described previously.


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Table 6 presents simulated probabilities of crossing the p-value boundaries at each 
interim analysis, and for declaring non-inferiority/superiority at the final primary Week 
48 analysis.
Table 6
Probability of crossing boundary at each analysis time-point for the 
ITT-E population
Interim 
Analysis
Week 48 
True treatment effect= -12%
(null hypothesis)
Week 48
True treatment effect = 0% (alternative 
hypothesis)
Inferiority
Superiority
Non-
inferiority
Inferiority
Superiority
Non-
inferiority
1
2
3
Final
5.02%
13.3%
30.3%
-
-
-
0
0
-
-
-
2.35%
1.18%
0.97%
0.89%
-
-
-
0.01%
2.49%
-
-
-
88.2%
When the true treatment difference is -12% (i.e. under the null hypothesis that DTG is 
inferior to LPV), the probability of wrongfully claiming non-inferiority is estimated to be 
2.35%, which is conservatively below the desired false positive error of 2.5%.  The 
probability that the inferiority boundary will be crossed at any one of the three interim 
analyses is estimated to be 49%.
When the true treatment effect is 0% (i.e. under the alternative hypothesis that both arms 
have response rates of 70%), the probability to correctly claim non-inferiority (i.e. power) 
is estimated to be 88.2%, slightly below the planned 90% level.  The probability that an 
inferiority boundary will be wrongfully crossed at any one of the three interim analyses is 
estimated to be 3%.  The probability that the superiority boundary will be crossed at the 
third interim analysis is 0.01% and 2.49% at the final analysis, if the true population 
response rate is 70% in each arm.
The unblinded interim analysis will be performed and delivered to the IDMC by an 
independent Statistics Data Analysis Centre (SDAC) external to the sponsor, so that the 
IDMC is able to evaluate the questions described in the committee charter.  The IDMC 
will review the list of data to be assessed and potentially may decide to review other 
types of data. Further details regarding the operation of the IDMC, the use of a SDAC for 
generating unblinded data, and content of the reviews are described in the charter.
8.3.5.
Key Elements of Analysis Plan
The study design is open-label; however, the sponsor staff responsible for the conduct 
and analysis of the study will not review any summaries of data grouped by treatment 
prior to database freeze for the interim Week 24 analysis.
8.3.5.1.
Efficacy analyses
For the primary comparison, adjusted estimates of the difference in the rate of responders 
between the two arms will be presented along with CIs based on a stratified analysis 
using Cochran-Mantel-Haenszel (CMH) weights.  All CIs will be two-sided.  For the 


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statistical analysis, 4 strata (subgroups) will be formed according to the combinations of 
levels of the following categorical variables: 
Baseline plasma HIV-1 RNA (vs. >100,000 c/mL);
Number of fully active background NRTIs (<2 vs. 2) at Baseline.
For analysis purposes, fully active is defined at Baseline by the genotypic resistance 
reports of the central laboratory (or a laboratory contracted by the central laboratory) 
showing no evidence of full or of partial genotypic resistance for a given NRTI. If 
Baseline genotypic results are not available, then activity of the background regimen will 
be based on genotypic results at Screening. 
The CMH estimate of the common difference in rates across strata will be calculated as 
the weighted average of the strata-specific estimates of the difference in response rates 
between the two arms as follows:
If nk is the number of DTG treated subjects, mk is the number of LPV treated subjects, 
and Nk = nk + mk is the total number of subjects in the kth stratum, then the CMH 
estimate is given by



k
k
k
cmh
W
d
W
d
ˆ
ˆ
where
k
k
k
k
N
m
n
W 
are CMH weights and     are estimates of the differences in response rates between the 
two treatment arms, rd-ra, for the kth strata.
The corresponding two-sided 95% CI will be calculated as
)
ˆ
r(
aˆv
96
.1
ˆ
cmh
cmh
d
d


using the variance estimator           ,       given by [Sato, 1989], which is consistent in both 
sparse data and large strata.  The full equation for this variance estimate is provided in the 
RAP. 
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to test for one-
way homogeneity across the levels of each categorical variable, with each categorical 
variable considered separately. Following Lui and Kelly [Lui, 2000], ½ will be added to 
each cell in any strata for which the stratum-specific rate estimates of either rd or ra are 
zero or one, and tests will be one-sided. Full details will be contained in the RAP. Any 
heterogeneity found to be statistically significant will be explored and if necessary results 
will be reported for each level of the categorical variable. Investigation of heterogeneity 
k
dˆ
)
ˆ
r(
aˆ
v
cmh
d


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will be confined to the primary endpoint using the Week 48 Snapshot analysis. Tests of 
homogeneity will be assessed at the one-sided 10% level of significance.
Following the IDMC recommendation to switch LPV/RTV subjects to DTG, 
additional sensitivity analyses will be conducted for the primary endpoint.  Further 
details of these analyses and any other impacted analyses will be included in the 
RAP.
Details for secondary efficacy endpoints will be discussed in the RAP.
Data gathered after subjects withdraw from IP will be listed but will not be included in 
summary tables. Data will be allocated to visit windows using actual visit dates rather 
than nominal visit numbers. Data collected from extra visits within a window will be 
listed and will be included in the derivation of the Snapshot response at analysis visits of 
interest, 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).
8.3.5.2.
Safety analyses
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarised by treatment group. The proportion of subjects reporting AEs will be 
tabulated for each treatment group. The following summaries of AEs will be provided:

Incidence and severity of all AEs

Incidence and severity of treatment related AEs

Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
Laboratory and vital signs data will be summarised by visit and treatment group. In 
addition, the number and percentage of subjects with graded laboratory toxicities (based 
on DAIDS categories) will be summarised by treatment group. The proportion of subjects 
experiencing changes from Baseline in their National Cholesterol Education Program 
(NCEP) lipid categories will be summarised by treatment arm.
Further details of safety analyses will be included in the RAP.
8.3.5.3.
Health outcomes analyses
HIVTSQ
The HIVTSQ was developed to evaluate treatments for HIV and patient satisfaction 
[Woodcock, 2001; Woodcock, 2006].  The higher the score, the greater the improvement 
in treatment satisfaction as compared to the past few weeks.  A smaller score represents a 
decline in treatment satisfaction compared to the past few weeks.


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
8 7
T his st u d y  will use t he 1 4 -ite m HI V T S Qs (stat us versi o n) a n d t he 1 4- ite m HI V T S Qc 
(c ha n ge versi o n), b ot h i ncl u di n g t he 1 0 ite ms of t he sta n dar d HI V T S Q b ut ha vi n g f o ur 
a d diti o nal ite ms f or testi n g.  T hese meas ures will assess c ha n ge i n treat me nt satisfacti o n 
o ver ti me (i n t he sa me s u bjects) a n d c o m pare c urre nt satisfacti o n wit h pre vi o us treat me nt 
satisfacti o n, fr o m a n earlier ti me p oi nt.
M M A S- 8
T he ori gi nal M oris k y  Me dicati o n A d here nce Scale ( M M A S) was a f o ur ite m scale t hat 
was de vel o pe d t o assess me dicati o n a d here nce wit h c hr o nic c o n diti o ns, s uc h as 
a nti h yperte nsi ve a ge nts [ M oris k y , 1 9 8 6].  M ore rece ntl y, a n ei g ht-ite m self-re p orte d 
scale was de vel o pe d calle d t he M oris ky 8 -Ite m Me dicati o n A d here nce Scale ( M M A S-8) 
[M oris k y , 2 0 0 8].  Sc ores of 8 i n dicate 
, a n d sc ores of less 
t ha n 6 i n dicate 
 o n t he M M A S-8 scale.  
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
G S R S
T he Gastr oi ntesti nal S y m pt o m Rati n g Scale ( G S R S) has 1 5 ite ms a n d is di vi de d i nt o f o ur 
d o mai ns: a b d o mi nal pai n; d y s pe ptic sy n dr o me; i n di gesti o n s y n dr o me; a n d b o wel 
s yn dr o me.  T he scale ra n ges fr o m 
 (1 ) t o 
 ( 7). T he 
o verall sc ore is calc ulate d b y  a d di n g t he c o m plete d sc ores of i n di vi d ual ite ms i n eac h 
gr o u p, f or a p ossi ble t otal ra n gi n g fr o m 1 5 t o 1 0 5.  Hi g her sc ores s h o w greater se verit y of 
s ym pt o ms [ S ve dl u n d , 1 9 8 8].  T he G S R S has bee n use d a n d vali date d i n ot her 
a ntiretr o viral st u dies, w hic h e xa mi ne t he GI s y m pt o ms ass oc iate d wit h b o oste d PIs [Sáez 
de la F ue nte ; 2 0 0 9; Mta m b o , 2 0 1 3].
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
8. 3. 5. 4.
Vir al g e n ot y pi n g/ p h e n ot y pi n g a n al y s e s
T he i nci de nce of treat me nt e mer ge nt ge n ot y pic a n d p he n ot y pic resista nce t o N R TI s, PIs, 
a n d I NIs will be s u m marise d b y treat me nt ar m f or s u bjects meeti n g c o nfir me d vir ol o gic 
wit h dra wal criteria.  Details of t he a nalys es t o be perf or me d will be s pecifie d i n t he R A P.
8. 3. 5. 5.
P h ar m a c o g e n eti c a n al y s e s
See A p pe n di x 5 , Secti o n 1 1. 5 , f or details a b o ut t he P har mac o ge netics A nalysis Pla n.
C CI
C CI
C CI
C CI


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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 Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
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:

Institutional Review Board (IRB)/Independent Ethics Committee (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 5 (Section 11.5), 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 


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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.
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.


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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, 
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.


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9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  Planned stopping 
guidelines and schedule for interim analyses are provided in Section 8.3.4.2, with 
additional details described in the charter, which is available upon request.  
The IDMC completed pre-planned interim analyses #1 and #2 and following an ad hoc 
review of trial data prior to interim analysis #3, the IDMC observed significant, clinically 
relevant differences between treatment arms in favour of DTG.  The IDMC 
recommended that the LPV/RTV treatment arm be discontinued and subjects currently 
receiving LPV/RTV in the study be switched to a regimen with DTG as the third drug, if 
considered appropriate by the Investigator.  Interim analysis #3 will no longer take place.


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analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and 
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Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and 
osteoporosis: a meta-analytic review. AIDS 2006; 20:2165-74.
Bunupuradah T, Chetchotisakd P, Ananworanich J, et al. A randomized comparison of 
second-line lopinavir/ritonavir monotherapy versus 
tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV 
STAR study. Antivir Ther 2012; 17:1351-61.
Cahn P, Pozniak AL, Mingrone H, et al.  Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the 
randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700-8.
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.
Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardiovascular 
disease in HIV-infected patients and relationship to highly active antiretroviral therapy. 
Circulation 2008; 118:e29-e35.
Fleiss JL. Statistical Methods for Rates and Proportions. 2 ed. New York: John Wiley; 
1981.  
Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, 
abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005; 
192:1921-30.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, version 11. October 2017.
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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.
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th edition. 
Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.


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HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. Available at:
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 30 August 
2013)
Isentress EU Summary of Product Characteristics, August 2013.
Isentress US Product Information, October 2013.
Johnson VA, Calvez V, Günthard HF, et al. Update of the drug resistance mutations in 
HIV-1: March 2013. Top Antivir Med 2013; 21:6-14.
Kaletra EU Summary of Product Characteristics, February 2017.
Kaletra US Product Information, November 2016.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med 2009; 150:604-12.
Lui K-J, Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference. 
Biometrics. 2000; 56:309-15.
Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir 
compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-
infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370:49-
58.
Mazoyer E, Manirakiza G, Bikie A, et al. Never too late for adherence support: 
experience from the recruitment phase in ANRS 12169 - 2LADY trial. 18th International 
AIDS Conference (AIDS 2010). Vienna, 18-23 July 2010. TUPE0187.
Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. 
lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 
2009; 23:1679-88.
Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir 
versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and 
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week 
efficacy and safety results of the CASTLE study. Lancet 2008; 372:646-55.
Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication 
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Mtambo A, Harris M, Toy J, Guillemi S, et al. Evaluation of treatment tolerability, 
satisfaction and laboratory parameters in HIV+ patients switching from ritonavir capsule 
to tablet formulation. Curr HIV Res 2013; 11:231-7.
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TIVICAY US Product Information, March 2017.
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2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
9 6
1 1.
A P P E N DI C E S
1 1. 1.
A p p e n di x 1: C hil d -P u g h Cl a s sifi c ati o n
A s u bject is cla ssifie d wit h 
 ( Class A) if t heir o verall s u m of 
sc ores is 5- 6 p oi nts, 
 ( Class B) if t heir o verall s u m of sc ores 
is 7- 9 p oi nts, a n d 
 ( Class C) if t heir o verall s u m of sc ores is 1 0-
1 5 base d o n t he C hil d- P u g h s ys te m [P u g h , 1 9 7 3] sc ori n g descri be d i n t he f oll o wi n g ta ble 
(Ta ble 7 ).  F or s u bjects re q uiri n g a ntic oa g ulati o n t hera p y, disc ussi o n wit h t he st u d y 
me dic al m o nit or will be re q uire d.
T a bl e 7
C hil d -P u g h S y st e m
[P u g h , 1 9 7 3; L uc ey , 1 9 9 7]
R ef er e n c e s
L uce y  M R, Br o w n K A, E vers o n G T, et al. Mi ni mal criteria f or place me nt of a d ults o n 
t he li ver tra ns pla nt waiti n g list: a re p ort of a nati o nal c o nfere nce or ga nize d b y  t he 
A merica n S ociet y of Tra ns pla nt P h y sicia ns a n d t he A merica n Ass ociati o n f or t he St u d y 
of L i ver Diseases. Li ver Tra ns pl S ur g 1 9 9 7; 3: 6 2 8-3 7.
P u g h R N H, M urra y -L y o n I M, Da ws o n J L,  Pietr o ni M C, Willia ms R. Tra nsecti o n of t he 
oes o p ha g us f or blee di n g oes o p ha geal varices. Br J S ur g 1 9 7 3; 6 0: 6 4 6 - 9.
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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11.2.
Appendix 2: CDC Classification System for HIV-1 Infections 
(1993)
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 generalised 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

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 


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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

Pneumocystis carinii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicaemia, recurrent


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
Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
Reference
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. 


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11.3.
Appendix 3: 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 utilised for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.
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


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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)]
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


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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)
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


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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)


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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)


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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)
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.
2. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).
3. Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.
4. 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).
Reference
Division of AIDS, Regulatory Support Center. Manual for grading the severity of adult and pediatric adverse events. Version 1.0 -
December 2004 (Clarification dated August 2009) Bethesda, MD: DAIDS/RCC, 2009. Available at: http://rsc.tech-
res.com/safetyandpharmacovigilance/ (accessed 21 March, 2014)


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11.4.
Appendix 4: 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 favourable benefit: risk 
and no alternative medicine available (Table 8, Figure 3)
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 1.5x baseline and ALT<3xULN) (Table 9, Figure 4).
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 3):

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 8).


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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 INR1.5
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

Medicines Development Leader and Project Physician Leader.

Request is taken to full VSLC for final decision. 


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Figure 3
VSLC process for drug rechallenge approval or disapproval
The local operating company (LOC) medical director (ViiV and GSK where applicable) 
should be informed that study drug rechallenge is under consideration and of the final 
decision, whether or not to proceed.
Table 8
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


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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
•
drug-induced liver injury (DILI)
•
alcoholic hepatitis
Study drug is held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval 
(Figure 4):

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. 

Medical Monitor and Clinical Safety Physician to review the subject’s 
diagnosis, restart risk factors and complete checklist (Table 9).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The LOC medical director (ViiV and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.
Table 9
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 chem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:  


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
Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader.

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
Figure 4
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


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 2 3

All se vere reacti o ns (rec halle n ge ass ociate d wit h bilir u bi n > 2 x U L N or ja u n dice, 
or I N R 1. 5), S A Es or fatalities wit h dr u g rec halle n ge ( or restart) m ust be 
i m me diatel y re p orte d t o Li ne Ma na ge me nt, V S L C C hair, V P Gl o bal Me dical 
Strate g y  a n d E U Q ualifie d Pers o n f or P har mac o vi gila nce. 
Pri n ci p al I n v e sti g at or A cti o n s:

T he PI  m ust o btai n Et hics C o m mittee or Instit uti o nal Re vie w B oar d a p pr o val of 
dr u g rec halle n ge or restart, as re q uire d. 

If dr u g re-i nitiati o n V S L C-a p pr o ve d, t he patie nt m ust pr o vi de i nf or me d c o nse nt 
wit h a clear descri pti o n of p ossi ble be nefits a n d ris ks of dr u g a d mi nistrati o n 
i ncl u di n g rec urre nt, m ore se vere li ver i nj ur y or p ossi ble deat h.

T ar gete d dr u g rec h alle n ge or dr u g rest art c o nse nt f or m m ust be use d.

T he patie nt’s i nf or me d c o nse nt m ust be rec or de d i n t he st u d y  c hart, a n d t he dr u g 
a d mi nistere d at a gree d d ose, as c o m m u nicate d b y Me dical M o nit or.

Li ver c he mistries m ust be f oll o we d t wice wee kly f or ‘rec h alle n ge’ c ases a n d 
o nce wee kly f or ‘rest art’ c ases f or o ne m o nt h or f or as l o ng as cli nicall y 
i n dicate d f oll o wi n g dr u g re-i nitiati o n.  If s u bject e x hi bits pr ot oc ol-defi ne d li ver 
c he mistr y ele vati o ns, I P s h o ul d be disc o nti n ue d as pr ot oc ol s pecifie d.
V S L C a n d t he I R B/I E C m ust be i nf or me d of t he p atie nt’s o utc o me f oll o wi n g dr u g 
rec h all e n ge or rest art.
R e c h all e n g e/r e st art s af et y  o ut c o m e s:





R ef er e n c e s
A n dra de RJ, R o bles M, L uce na MI.  Rec halle n ge i n dr u g -i n d uce d li ver i nj ur y: t he 
attracti ve hazar d.  E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9- 7 1 4.
H u nt, C M.  Mit oc h o n drial a n d i m m u n oaller gic i nj ur y  i ncrease ris k of p ositi ve dr u g 
rec halle n ge after dr u g-i n d uce d li ver i nj ur y: A sys te matic re vie w.  He pat ol. 2 0 1 0; 
5 2: 2 2 1 6 - 2 2 2 2. 
Pa pa y  JI, Cli nes D, Rafi R, et al.  Dr u g-i n d uce d li ver i nj ur y f oll o wi n g p ositi ve dr u g 
rec halle n ge.  Re g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0. 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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11.5.
Appendix 5: 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:


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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.
Carbamazepine
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.
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 DTG or any of the HIV medicines 
included in this study. 


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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 DTG or 
any of the HIV medicines included in this study.  If at any time it appears there is 
potential variability in response in this clinical study or in a series of clinical studies with 
DTG, 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 or other HIV medicines used in this study;

Relationship between genetic variants and safety and/or tolerability of DTG or other 
HIV medicines used in this study;

Relationship between genetic variants and efficacy of DTG or other HIV 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.
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.


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The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
DTG (or any of the HIV medicines included in this study) 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 DTG (or any of the HIV medicines 
included in this study).
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 
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. 


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In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to DTG or any of the HIV medicines included 
in this study.  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.  
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. 
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.


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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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11.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 1
1 1. 7.
A p p e n di x 7: Pr ot o c ol C h a n g e s
1 1. 7. 1.
Pr ot o c ol A m e n d m e nt 0 1
T his pr ot oc ol a me n d me nt a p plies t o all p artici p ati n g sites.
R ati o n ale f or Pr ot oc ol A me n d me nt 0 1:
i. Me dical M o nit or C o ntact I nf or mati o n a n d Seri o us A d verse E ve nts ( S A E) C o ntact 
I nf or mati o n has bee n u p date d wit h a sec o n dar y c o ntact.
ii. Re m o val of e xcl u si o n criteri o n 1 8 w hic h pr o hi bits e nr ol me nt of s u bject wit h 
creati ni ne cleara nce of < 5 0 m L / mi n via t he C K D-E PI  met h o d.  T his e xcl usi o n 
criteri o n was i ncl u de d i n err or.  B ot h D T G a n d L P V/ R T V ca n be a d mi nistere d i n 
patie nts wit h re nal i m pair me nt, a n d n o d osa ge a dj ust me nts are re q uire d.
iii.Refere nce t o aller gic reacti o n criteria i n Secti o n 4. 5 “ Wit h dra wal Criteria” w hic h was 
o mitte d i n t he ori gi nal pr ot oc ol.  As per Secti o n 6. 4. 4. 6, s u bjects wit h Gra de ≥3 
aller gic reacti o ns t hat are c o nsi dere d t o be p ossi bl y  or pr o ba bly relate d t o t he I P 
s h o ul d per ma ne ntly disc o nti n ue t he I P re gi me n a n d t he s u bject s h o ul d be wit h dra w n 
fr o m t he st u d y. 
i v.T he HI V treat me nt satisfacti o n q uesti o n naire stat us versi o n ( HI V T S Qs) a n d HI V T S Q 
c ha n ge versi o n ( HI V T S Qc) will be a d mi nistere d at differe nt ti mes f oll o wi n g fee d bac k 
of t he de vel o per of t hese q uesti o n naires.  T he HI V T S Qs will be a d mi nistere d at 
Ba seli ne ( Da y 1), Wee k 4, Wee k 2 4, Wee k 4 8 a n d wit h dra wal w hile t he HI V T S Qc 
will be a d mi nistere d at Wee k 4 8 a n d at wit h dra wal (i n a d diti o n t o t he HI V T S Qs) 
rat her t ha n at Wee k 2 4.  T he HI V T S Qs-1 4 ite m meas ure, w hic h i ncl u des t he 1 0 ite ms 
i n t he sta n dar d HI V T S Qs b ut has f o ur a d diti o nal ite ms f or testi n g, will be use d i n t he 
st u d y.
v. I n Secti o n 6. 4. 4. 5 “ Decli ne i n re nal f u ncti o n”, esti mate d G F R ( by t h e C K D -E PI  
met h o d) is referre d t o i nstea d of Cr Cl i n or der t o clarif y w hat f or m ula s h o ul d be use d 
t o e val uate re nal f u ncti o n.
vi. U p dates t o refere nce [ Kaletra E U S u m mar y  of Pr o d uct C haracteristics; Kaletra U S 
Pr o d uct I nf or mati o n].
A list of s pecific c ha n ges is pr o vi de d bel o w.  U nless state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
S P O N S O R I N F O R M A TI O N P A G E
S p o ns or Me dical M o nit or C o ntact I nf or mati o n
a n d Seri o us A d verse E ve nts ( S A E) 
C o nt act I nf or m ati o n : 
 M D
Gl a x o S mit h Kli ne
Researc h Tria n gle Par k
P P D


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 2
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
Sec o n d ar y c o nt act:
 M D
Gl a x o S mit h Kli ne
C olle ge ville, P A ( U S A) 
Tele p h o ne: +
M o bile: +
S p o ns or Seri o us A d verse E ve nts ( S A E) C o nt act I nf or m ati o n:
Researc h Tria n gle Par k
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
4. 3. E x cl u si o n Crit eri a
T he f oll o wi n g te xt has bee n delete d:
1 8. S u bject has creati ni ne cleara nce of < 5 0 m L / mi n via t he C K D-E PI met h o d.
4. 5 Wit h dr a w al Crit eri a
S u bjects m ust be disc o nti n ue d fr o m t he st u d y  f or a n y of t he f oll o wi n g reas o ns:...

Aller gic re acti o n or ras h criteria as descri be d i n Secti o n 6. 4. 4. 6 a n d Secti o n 6. 4. 4. 7
res pecti vel y, are met a n d n o c o m pelli n g alter nate ca use is i de ntifie d;
6. 1. Ti m e a n d E v e nt s S c h e d ul e
Ta ble 1 Ti me a n d E ve nts Ta ble
I n a d diti o n t o Baseli ne ( Da y 1), Wee k 4, Wee k 4 8 a n d at wit h dra wal, t he HI V T S Qs will 
als o be a d mi nistere d at Wee k 2 4.  T he HI V T S Qc will be a d mi nistere d at Wee k 4 8 a n d 
als o at wit h dra wal rat her t ha n at Wee k 2 4.
Sa m ples f or q ua ntitati ve plas ma HI V -1 R N A P C R a n d l y m p h oc y te s u bset a n d plas ma f or 
st ora ge will n ot be c ollecte d at F oll o w- u p.
F o ot n ote b. has bee n a me n de d: F or s u bjects w h o c o m plete d ra n d o mise d D T G t hr o u g h 
Wee k 5 2 a n d e ntere d i nt o t he D T G C o nti n uati o n P hase: s u bjects c o m pleti n g t he D T G 
C o nti n uati o n P hase m ust ret ur n t o t he cl i nic w he n tra nsiti o ni n g t o c o m mercial s u p plies. 
C o n d uct st u d y  assess me nts, wit h t he e xce pti o n of dis pe nsi n g I P, as s pecifie d f or all 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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Continuation Phase visits per the follow-up visit schedule at this end of Continuation 
Phase visit.
6.4.4.5 Decline in renal function
Subjects who experience an increase in creatinine from Baseline of 45 Mol/L (or 
0.5 mg/dL) should return for a confirmatory assessment within 2 to 4 weeks.  A 
urinalysis and urine albumin/creatinine and urine total protein/albumin ratios 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.
Subjects who have a decline in CrCl the estimated GFR (using the CKD-EPI method) 
of >50% must return for a confirmatory assessment as soon as possible. A urinalysis and 
urine albumin/creatinine and urine protein/creatinine ratios should be done at this 
confirmatory visit.  If the estimated CrCl GFR 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. background therapy, other medications, dehydration, concurrent 
conditions) should be taken into account, and a nephrology consult may be obtained.  If a 
subject is also receiving TDF, then a switch to an alternative nucleoside should be 
considered if restarting IP.  One background NRTI change is allowed for management of 
drug toxicity as described in Section 6.4.4, “Specific Toxicities/Adverse Event 
Management”.   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.
8.3.5.3. Health outcomes analyses
HIVTSQ
The HIVTSQ was developed to evaluate treatments for HIV and patient satisfaction 
[Woodcock, 2001; Woodcock, 2006].  The higher the score, the greater the improvement 
in treatment satisfaction as compared to the past few weeks.  A smaller score represents a 
decline in treatment satisfaction compared to the past few weeks.
This study will use the 14-item HIVTSQ(s) (status version) and the revised14-item
HIVTSQ(c) (change version), both including the 10 items of the standard HIVTSQ 
but having four additional items for testing.  These measures will assess change in 
treatment satisfaction over time (in the same subjects) and compare current satisfaction 
with previous treatment satisfaction, from an earlier time point.
10. REFERENCES
The following references have been updated.
Kaletra EU Summary of Product Characteristics, February 2014May2013.
Kaletra US Product Information, NovemberJanuary 2013.


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 4
1 1. 7. 2.
Pr ot o c ol A m e n d m e nt 0 2
Pr ot oc ol c h a n ges f or A me n d me nt 0 2, fr o m pr ot oc ol c h a n ges t o A me n d me nt 0 1 ( 3 0 -
A pr - 2 0 1 4)
T his pr ot oc ol a me n d me nt a p plies t o all p artici p ati n g sites.
A m e n d me nt 0 2 S u m m ar y a n d R at i o n ale:
i. T he a ut h or list has bee n u p date d.
ii. S p o ns or, Me dical M o nit or a n d Seri o us A d verse E ve nts ( S A E) C o ntact I nf or mati o n 
has bee n u p dat e d.
iii.F oll o wi n g a n I D M C rec o m me n dati o n t o disc o nti n ue t he LP V/ R T V ar m a n d s witc h 
s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y t o a re gi me n wit h D T G, cha n ges t o 
t he st u d y desi g n ha ve bee n ma de acc or di n gly.   A d diti o nal se nsiti vit y  a nal yses are 
pla n ne d f or t he pri mar y e n d p oi nt as a c o nse q ue nce of t hese c ha n ges.
i v.T he secti o n o n S uici dalit y  m o nit ori n g has bee n u p date d wit h f urt her g ui da nce 
f oll o wi n g i ncl usi o n of a d diti o nal a d verse dr u g reacti o ns i n t he D T G i n vesti gat or’s 
br oc h ure : de pressi o n, s uici dal i deati o n or s uici de atte m pt ( partic ularl y i n patie nts wit h 
a pre-e xisti n g hist or y of de pressi o n or ps yc hi atric ill ness). 
v. U p dates t o t he Ti me & E ve nts Ta ble ( Secti o n 6. 1) a n d t he Healt h O utc o mes A nal yses 
secti o n t o pr o vi de clearer g ui da nce o n w he n healt h o utc o mes assess me nts will be 
c o n d ucte d i n t he case of earl y wit h dra wal fr o m t he st u d y a n d o n M M A S-8 a n d G S R S 
sc ores, res pecti vely.
vi. U p dates t o refere nce s: Kaletra E U S u m mar y  of Pr o d uct C haracteristics, Kaletra U S 
Pr o d uct I nf or mati o n , W H O treat me nt g ui deli nes, In vest i gat or’s Br oc h ure.
A list of s pecific c ha n ges is pr o vi de d bel o w.  U nless state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
List of S pecific C h a n ges
TI T L E P A G E
A ut h or(s):
S P O N S O R I N F O R M A TI O N P A G E
T his st u d y  is s p o ns ore d b y Vii V Healt hcare.  Gla x o S mit h Kli ne is i m ple me nti n g a n d 
ma na gi n g all as pects of t his st u d y .Gl a x o S mit h Kli ne is s u p p orti n g Vii V He alt hc are i n 
t he c o n d uct of t his st u dy.
P P D
P P D


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 5
S p o ns or N a me a n d Le g al Re gistere d A d dress (e xcl u di n g U S) S p o ns or Le gal 
Re gistere d A d dress :
Vii V Healt hcare U K Li mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
Tele p h o ne:  + 4 4 ( 0) 2 0 8 3 8 0 6 2 0 0
U S I N D S p o ns or N a me a n d Le g al Re gistere d A d dress S p o n s or C o ntact A d dress:
Vii V Healt hcare C o m p a n y
Fi ve M o ore Dri ve 
P. O. 1 3 3 9 8
Researc h Tria n gle Par k, N C 2 7 7 0 9 -3 3 9 8, U S A
Tele p h o ne: + 1 9 1 9 4 8 3 2 1 0 0
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y be t he l ocal Vii V Healt hcare affiliate 
c o m pa n y ( or desi g nee) . W here a p plica ble, t he details of t he S p o ns or a n d c o ntact pers o n 
will be pr o vi de d t o t he rele va nt re g ulat or y  a ut h orit y as part of t he cli nical trial 
s u b missi o n. I n s o me c o u ntries, l oc al l a w re q uires t h at t he Cli nic al Tri al s p o ns or is a 
l oc al c o m p a n y le g al e ntit y. I n t hese i nst a nces, t he a p pr o pri ate c o m p a n y t o be 
i de ntifie d as s p o ns or m ust be a gree d wit h t he gl o b al Vii V He alt hc are cli nic al te a m 
a n d si g ne d off b y t he V P a n d He a d, Gl o b al Rese arc h a n d Me dic al Str ate g y.
Me dical M o nit or C o ntact I nf or mati o n a n d Seri o us A d verse E ve nts ( S A E) C o ntact 
I nf or mati o n: 
 M D, P h D 
Vii V He alt hc are
9 8 0 Gre at West R o a d
Bre ntf or d , Mi d dlese x
T W 8 9 G S
U K
M o bile: +
Gla x o S mit h Kli ne
Researc h Tr ia n gle Par k
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
Sec o n dar y  c o ntact:
 M D
Vii V He alt hc are
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 6
5 M o ore Dri ve
Rese arc h Tri a n gle P ar k, N C  2 7 7 0 9
U S A
M o bile: +
, M D
Gla x o S mit h Kli ne
C olle ge ville, P A ( U S A) 
Tele p h o ne: +
M o bile: +
P R O T O C O L S U M M A R Y
St u d y Desi g n
T he f oll o wi n g te xt has bee n a d de d:
T he I D M C c o m plete d t w o of t he t hree pre- pl a n ne d a n al yses.  Pri or t o i nteri m 
a n al ysis # 3, t he I D M C c o n d ucte d a n a d -h oc re vie w of tri al d at a a n d o bser ve d 
si g nific a nt, cli nic all y rele v a nt differe nces bet wee n tre at me nt ar ms i n f a v o ur of D T G.  
T he I D M C rec o m me n de d t o t he s p o ns or t h at t he L P V/ R T V tre at me nt ar m be 
disc o nti n ue d a n d s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y be s witc he d t o 
a re gi me n wit h D T G as t he t hir d dr u g, if c o nsi dere d a p pr o pri ate b y t he 
I n vesti g at or.  As per P r ot oc ol A me n d me nt N o. 2 , s u bjects r an d o mise d t o t he 
L P V/ R T V ar m will eit her (i) c o nti n ue recei vi n g L P V/ R T V a n d c o m plete t he st u d y 
after t he 4- wee k tre at me nt e xte nsi o n (see a b o ve), or (ii) s witc h t o t he D T G ar m 
pri or t o st u d y c o m pleti o n at Wee k 5 2 a n d c o nti n ue t o h a ve access t o D T G i n t he 
C o n ti n u ati o n P h ase u ntil D T G is eit her l oc all y a p pr o ve d a n d c o m merci al s u p plies 
are a v ail a ble t o p atie nts (e. g. t hr o u g h p u blic he alt h ser vices), t he p atie nt n o l o n ger 
deri ves cli nic al be nefit, or t he p atie nt meets a pr ot oc ol -defi ne d re as o n f or 
disc o nti n u ati o n .  S u bjects ori gi n all y r a n d o mise d t o D T G a n d recei vi n g D T G i n t he 
R a n d o mise d P h ase or i n t he C o nti n u ati o n P h ase are n ot affecte d b y t his I D M C 
rec o m me n d ati o n a n d P r ot oc ol A me n d me nt N o. 2 .
1. 3. 1.
Ris k Assess me nt
Ris k Assess me nt Ta ble, Ps y c hiatric dis or ders
Ps y c hiatric dis or ders i ncl u di n g s uici de i deati o n a n d be ha vi o urs are c o m m o n i n HI V -
i nfecte d patie nts. T he ps yc hiatric pr ofile f or D T G (i ncl u di n g s uici dalit y, de pressi o n, 
bi p olar a n d h y p o ma nia, a n xiet y a n d a b n or mal drea ms) was si milar t o R A L- or 
fa v o ura ble co m pare d wit h E F V -b ase d re gi me ns ot her A R T .   
P P D
P P D
P P D
P P D
P P D
P P D


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3.1.
Study Design
An IDMC has been will be instituted to perform periodic reviews of the accumulating 
data to ensure that subjects are not being sub-optimally treated (see Section 8.3.4.2).  The 
IDMC completed the first two of the three pre-planned analyses (see Section 
8.3.4.2).  Prior to the third interim analysis, the IDMC conducted an ad hoc review 
of trial data and the IDMC observed significant, clinically relevant differences 
between treatment arms in favour of DTG.  The IDMC recommended to the 
sponsor that the LPV/RTV treatment arm be discontinued and subjects currently 
receiving LPV/RTV in the study be switched to a regimen with DTG as the third 
drug, if considered appropriate by the Investigator.
Randomised Phase: Day 1 to Week 48 + 4-week treatment extension
Following the IDMC’s recommendation and as per Protocol Amendment No. 2, 
subjects randomised to the LPV/RTV arm will either (i) continue receiving 
LPV/RTV and complete the study after the 4-week treatment extension at Week 52, 
or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to 
have access to DTG in the Continuation Phase.
The primary efficacy endpoint corresponds to viral load measurements collected within a 
6 week  window around the Week 48 visit (including data from the Week 52 visit), as 
per the FDA’s Snapshot algorithm, and for this reason, the primary analysis is denoted as 
occurring at Week 48 with the understanding that data from the Week 52 visit may be 
included.
DTG Continuation Phase
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
and subjects originally randomised to receive LPV/RTV but switched to DTG prior 
to Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 
available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
Subjects randomised to the LPV/RTV arm will receive LPV/RTV + two NRTIs through 
their Week 52 visit only, after which subjects will complete the study and will need to 
have alternate arrangements in place to access antiretroviral medication (unless mandated 
by local regulation).  Subjects randomised to the LPV/RTV arm, who switch to the 
DTG arm prior to study completion at Week 52, will continue to have access to DTG 
(Continuation Phase) as mentioned above.


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Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomised to LPV/RTV + two NRTIs and completed the Randomised Phase 
including the Week 52 study visit;

Randomised to LPV/RTV + two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase including the Week 52 study visit, and did not 
enter the Continuation Phase;

Randomised to LPV/RTV+ two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase, including the Week 52 study visit, entered 
and completed the Continuation Phase (defined as remaining on study until 
commercial supplies of DTG become locally available to patients [e.g. through 
public health services]).

Randomised to DTG + two NRTIs, completed the Randomised Phase including the 
Week 52 study visit, and did not enter the Continuation Phase;

Randomised to DTG + two NRTIs, completed the Randomised Phase, including the 
Week 52 study visit, entered and completed the Continuation Phase (defined as 
remaining on study until commercial supplies of DTG become locally available to 
patients [e.g. through public health services]).
Figure 1
Study Schematic
The figure was updated to indicate that a switch from LPV/RTV arm to DTG arm may 
occur prior to study completion at Week 52, based on Investigator judgement.
4.5.
Withdrawal Criteria
Subjects must be discontinued from the study for any of the following reasons:

Confirmed virologic withdrawal criteria as described in Section 4.6.1 are met;

Subject requires substitution or dose modification of DTG, or substitution of 
LPV/RTV (a switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice 
daily or the opposite switch is allowed; as per Protocol Amendment No. 2, a 
switch from LPV/RTV to DTG will also be allowed);
…
4.6.
Virologic Criteria for Subject Management and Viral Resistance Testing
Following Day 1, no changes, or intensification of ART will be permitted prior to 
meeting confirmed virologic withdrawal criteria or Week 52, with the exception of a 


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switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily or the opposite 
switch, a switch from LPV/RTV to DTG as per Protocol Amendment No. 2, and one 
allowed background NRTI change for management of drug toxicity as described in 
Section 6.4.4., “Specific Toxicities/Adverse Event Management”.  Any NRTI change 
must ensure a fully active NRTI is still present based on Screening resistance testing.  A 
switch from 3TC to FTC (or vice versa) will not be considered a background NRTI 
change and is permitted.  Subjects unable to manage drug toxicity or tolerate IP (DTG or 
LPV/RTV) must be discontinued from the study as described in Section 6.4.
5.1.5. Protocol-Permitted Substitutions
A switch of DTG or LPV/RTV is not allowed except for a switch from LPV/RTV 
800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite switch.  As 
per Protocol Amendment No. 2, a switch from LPV/RTV to DTG will be allowed.
5.3.
Blinding
As this is an open-label study, blinding is not required.  No summaries of the study data 
according to actual randomised treatment groups will be available to sponsor staff prior 
to the planned Week 24 interim analysis.  According to the IDMC Charter, ViiV 
Healthcare/GSK personnel having direct responsibility for the conduct of the study 
and its analysis may however review summaries of data by treatment group if the 
IDMC recommends to the sponsor the termination of a treatment arm or the entire 
study.
5.6.4. Prohibited medications for subjects randomised to LPV/RTV
Avanafil added to list of prohibited medications for subjects randomised to LPV/RTV.
5.8.
Treatment after the End of the Study
The following text has been added:
Subjects originally randomised to receive LPV/RTV but switched to the DTG arm 
prior to Week 52 (as per Protocol Amendment No. 2) will continue to have access to 
DTG (Continuation Phase) until it is either locally approved and commercial 
supplies are available to patients (e.g. through public health services), the patient no 
longer derives clinical benefit, or the patient meets a protocol-defined reason for 
discontinuation.  Investigative sites must make arrangements for provision of 
background NRTIs to all subjects to ensure continued access to these medications 


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during the DTG Continuation Phase (unless provision by the sponsor is mandated 
by local regulation).
6.1.
Time and Events Schedule
The following footnote has been added:
j. Health outcomes assessments will only be conducted at Withdrawal if the 
Withdrawal visit occurs at or prior to Week 48.
6.4.10.
Suicidality Monitoring
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with 
a pre-existing history of depression or psychiatric illness) in some patients being 
treated with INIs, including DTG.  Therefore, it is appropriate to monitor subjects for 
suicidality before and during treatment.
Subjects should be monitored appropriately and observed closely for suicidal 
ideation and behaviour or any other unusual changes in behaviour.  It is 
recommended that the Investigator consider mental health consultation or referral for 
subjects who experience signs of suicidal ideation or behaviour.  Subjects presenting 
with new onset/treatment-emergent depression should be advised to contact the 
investigator immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the 
study medication may be required.
6.6.2. HIV-1 Pol Viral Genotyping and Phenotyping
Subjects meeting a ‘confirmed virologic withdrawal criterion’ (see Section 4.6.3) 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 and from samples 
collected at the time of meeting a ‘suspected virologic withdrawal criterion’; these results 
will be reported to the Investigator as soon as available to provide guidance for election 
of an alternative regimen.
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype will also be determined on the Baseline isolates from all subjects, if possible.  
When samples cannot be analysed by Monogram Biosciences, Baseline isolate resistance 
testing may be performed at location(s) to be described in the SPM.  
8.3.4.2.
IDMC interim analyses


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 4 1
A n I D M C will be h as bee n i nstit ute d t o pr o vi de i n de pe n de nt re vie w of t he acc u m ulati n g 
data, pri maril y t o e ns ure s u bjects are n ot bei n g s u b -o pti mall y  treate d i n eit her ar m. 
T hree f or mal i nteri m a nal y ses are were pla n ne d f or re vie w b y t he I D M C ( Ta ble 5).
…
T he I D M C c o m plete d i nteri m a n al yses # 1 a n d # 2.  Pri or t o i nteri m a n al ysis # 3, t he 
I D M C c o n d ucte d a n a d h oc re vie w of tri al d at a a n d o bser ve d si g nific a nt, cli nic all y 
rele v a nt differe nces bet wee n tre at me nt ar ms i n f a v o ur of D T G.  T he I D M C 
rec o m me n de d t o t he s p o ns or t h at t he L P V/ R T V tre at me nt ar m be disc o nti n ue d a n d 
s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y be s witc he d t o a re gi me n wit h 
D T G as t he t hir d dr u g, if c o nsi dere d a p pr o pri ate b y t he I n vesti g at or.  I nteri m 
a n al ysis # 3 will n o l o n ger t a ke pl ace.
8. 3. 5. 1.
Effic ac y a n al yses
T he f oll o wi n g te xt has bee n a d de d:
F oll o wi n g t he I D M C rec o m me n d ati o n t o s witc h L P V/ R T V s u bjects t o D T G, 
a d diti o n al se nsiti vit y a n al yses will be c o n d ucte d f or t he pri m ar y e n d p oi nt.  F urt her 
det ails of t hese a n al yses a n d a n y ot her i m p acte d a n al yses will be i ncl u de d i n t he 
R A P.
8. 3. 5. 3. He alt h o utc o mes a n al yses
M M A S- 8
T he ori gi nal M oris k y Me dicati o n A d here nce Scale ( M M A S) was a f o ur ite m scale t hat 
was de vel o pe d t o assess me dicati o n a d here nce wit h c hr o nic c o n diti o ns, s uc h as 
a nti h yperte nsi ve a ge nts [ M oris k y , 1 9 8 6].  M ore rece ntl y, a n ei g ht-ite m self-re p orte d 
scale was de vel o pe d calle d t he M oris ky 8 -Ite m Me dicati o n A d here nce Scale ( M M A S-8) 
[M oris k y , 2 0 0 8].  Sc ores of 8 i n dicate 
, a n d sc ores of less 
t h a n 6 or less i n dicate 
 o n t he M M A S-8 scale.  
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
G S R S
T he Gastr oi ntesti nal S y m pt o m Rati n g Scale ( G S R S) has 1 5 ite ms a n d is di vi de d i nt o f o ur 
d o mai ns: a b d o mi nal pai n; d y s pe ptic sy n dr o me; i n di gesti o n s y n dr o me; a n d b o wel 
s yn dr o me.  T he scale ra n ges fr o m 
 (0 1 ) t o 
 ( 7). T he 
o verall sc ore is calc ulate d b y  a d di n g t he c o m plete d sc ores of i n di vi d ual ite ms i n eac h 
gr o u p, f or a p ossi ble t otal ra n gi n g fr o m 0 1 5 t o 1 0 5.  Hi g her sc ores s h o w greater se verity 
of s y m pt o ms [S ve dl u n d , 1 9 8 8].  T he G S R S has bee n use d a n d vali dated i n ot her 
C CI
C CI
C CI
C CI


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antiretroviral studies, which examine the GI symptoms associated with boosted PIs [Sáez 
de la Fuente; 2009; Mtambo, 2013].
9.8.
Independent Data Monitoring Committee (IDMC)
The following text has been added:
The IDMC completed pre-planned interim analyses #1 and #2 and following an ad 
hoc review of trial data prior to interim analysis #3, the IDMC observed significant, 
clinically relevant differences between treatment arms in favour of DTG.  The 
IDMC recommended that the LPV/RTV treatment arm be discontinued and 
subjects currently receiving LPV/RTV in the study be switched to a regimen with 
DTG as the third drug, if considered appropriate by the Investigator.  Interim 
analysis #3 will no longer take place.
10. REFERENCES
The following reference has been added:
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and 
preventing HIV infection: Recommendations for a public health approach. Second 
edition 2016. Available at: http://www.who.int/hiv/pub/arv/arv-2016/en/ (accessed 
29 March 2017).
The following references have been updated:
GlaxoSmithKline Document Number RM2007/00683/07RM2007/00683/10: 
GSK1349572 Clinical Investigator's Brochure. February 2014October 2016.
Kaletra EU Summary of Product Characteristics, February 20142017.
Kaletra US Product Information, November 20132016.
TIVICAY Summary of Product Characteristics, January 2014February 2017.
TIVICAY US Product Information, August 2013March 2017.
11.7.3.
Protocol Amendment 03
Protocol changes for Amendment 03, from protocol changes to Amendment 02 (19-
Apr-2017)
This protocol amendment applies to all participating sites.
Amendment 03 Summary and Rationale:


2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 4 3
C ha n ges were ma de t o t he pr ot oc ol t o ma na ge a n d miti gate ris ks f oll o wi n g i de ntificati o n 
of a p ote ntial safet y  iss ue related t o ne ural t u be defect i n i nfa nts b or n t o w o me n wit h 
e x p os ure t o d ol ute gra vir at t he ti me of c o nce pti o n.

Refere nces t o t he m ost rece nt versi o n of t he D T G i n vesti gat or’s br oc h ure a n d 
s u p ple me nts were i ncl u de d.

T he Ris k Assess me nt ta ble ( Secti o n 1. 3. 1) was u p date d t o i ncl u de la n g ua ge re gar di n g 
ris k a n d miti gati o n of ne ural t u be defects .

I ncl usi o n criteri o n 2 ( Secti o n 4. 2) was u p date d t o e xcl u de t he d o u ble barrier met h o d 
of c o ntrace pti o n, w hic h d oes n ot meet u p date d G S K/ Vii V Healt hcare criteria f or a 
hi g hl y e ffecti ve met h o d.  Acce pta ble met h o ds of c o ntrace pti o n were clarifie d a n d 
pr o vi de d wit hi n t he pr ot oc ol; details of t hese are n o l o n ger pr o vi de d i n t he S P M .

T he Wit h dra wal Criteria ( Secti o n 4. 5) were u p date d t o i ncl u de a re mi n der t hat 
fe males of c hil d beari n g p ote ntial w h o c ha n ge t heir mi n ds a n d desire t o be pre g na nt
s h o ul d als o be wit h dra w n fr o m t he st u d y.

T he Ti me a n d E ve nts Ta ble ( Secti o n 6. 1). was u p date d t o i ncl u de a re mi n der f or 
i n vesti gat ors t o c hec k at e ver y visit t hat fe males of c hil d beari n g p ote ntial are a v oi di n g 
pre g na nc y .

T he Refere nces ( Secti o n 1 0) was u p date d t o i ncl u de a refere nce citi n g met h o ds of 
hi g hl y effecti ve c o ntrace pti o n a n d u p date t he refere nce t o t he c urre nt D T G 
I n vesti gat or’s Br oc h ure.
A list of s pecific c ha n ges is pr o vi de d bel o w.  U n less state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
List of S pecific C h a n ges
A ut h ors
A ut h or(s):
Refere nces t o I n vesti g at or’s Br oc h ure a n d S u p ple me nts
T he D T G i n vesti gat or br oc h ure versi o n n u m ber was u p date d i n Secti o n 1. 1, Secti o n 1. 3, 
a n d 6. 4. 4. 7, a n d refere nces t o I B s u p ple me nts were a d de d.
Secti o n 1. 3. 1   Ris k Assess me nt
A n a d diti o nal ris k a n d miti gati o n strate g y  was a d de d t o t he ta ble i n t his secti o n as s h o w n 
bel o w.  
P P D
P P D
P P D
P P D


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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Neural tube defects
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 female subject is eligible to participate if 
she is not pregnant, and, if she is a female 
of childbearing potential, agrees to follow 
one of the options for prevention of 
pregnancy listed in the Inclusion Criterion 2 
(see Section 4.2) during treatment with 
study drug and until at least 2 weeks after 
the last dose of study medication.
2. Women who become pregnant, or who 
desire to be pregnant while in the study will 
have study treatment discontinued and be 
withdrawn from the study.
3. Females of childbearing potential are 
reminded re: pregnancy avoidance and 
adherence to contraception requirements at 
every study visit.
4. Pregnancy status is monitored at every 
study visit.
Section 4.2 Inclusion Criteria, inclusion criterion 2
2.     A female subject may be eligible to enter and participate in the study if she:
a.
is of non-childbearing potential defined as either post-menopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of 
becoming pregnant with documented tubal ligation, hysterectomy, or bilateral 
oophorectomy or,
b. is of child-bearing potential, with a negative pregnancy test at both Screening and 
Day 1 and agrees to use one of the following methods of contraception to avoid 
pregnancy throughout the study and for at least 2 weeks after discontinuation 
of all study medication:

Complete abstinence from intercourse from 2 weeks prior to administration 
of IP, 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).

Approved hormonal contraception for subjects randomised to the DTG arm
(see the SPM for a listing of examples of approved hormonal contraception),
including:
o
Combined oestrogen and progestogen oral contraceptive 
[Hatcher, 2011])
o
Contraceptive subdermal implant
o
Injectable progestogen [Hatcher, 2011]


2013N172672_03
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o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011]

Approved hormonal contraception (as for subjects randomised to the DTG 
arm; see above) and a barrier method for subjects randomised to the 
LPV/RTV arm (see the SPM for a listing of examples of approved hormonal 
contraception).

Intrauterine device or intrauterine system. 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 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).

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 other method with published data showing that the expected failure rate
is <1% per year.
Any contraception method must be used consistently and in accordance with the 
approved product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. Note: these contraceptive 
requirements do not apply to females of childbearing potential with same sex 
partners only, when this is their preferred and usual lifestyle.
Section 4.5 Withdrawal/Stopping Criteria, last bullet

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
6.4.11).  As a reminder, females of childbearing potential who changed their 
minds and desire to become pregnant, or who state they are no longer willing 
to comply with the approved pregnancy avoidance methods, should also be 
withdrawn from the study.
Section 6.1 Time and Events Table
Table 1
Footnote ‘o’ was revised as shown below:
o. Pregnancy testing will be conducted (women of child bearing potential only) on serum 
(S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of IP. Remind females of childbearing potential of the need to 


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avoid pregnancy while on study and adherence to the study’s contraception 
requirements.
Section 10 References
The following reference has been updated:
GlaxoSmithKline Document Number RM2007/00683/1011: GSK1349572 Clinical 
Investigator's Brochure, Version 11. October 20162017.
The following additional references were included:
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.
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th
edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.

SAP_003.pdf: 
Reporting and Analysis Plan 
Study ID:  200304 
Official Title of Study: Reporting and Analysis Plan Amendment for 200304: A Phase 
3b, randomised, open-label study of the antiviral activity and safety of dolutegravir 
compared to lopinavir/ritonavir both administered with dual nucleoside reverse 
transcriptase inhibitor therapy in HIV-1 infected adult subjects with treatment failure on 
first line therapy 
EudraCT: 2014-001057-17 
Date of Document: 31-Jan-2022 


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 0 3 0 4  
 
1  
Di visi o n  
: W orl d wi de  De vel o p me n t 
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
 
Title  
: Re p orti n g a n d A nal ysis Pla n A me n d me nt f or 2 0 0 3 0 4: A 
P hase 3 b, ra n d o mise d, o pe n -la bel st u d y of t he a nti viral 
acti vit y a n d s afet y of d ol ute gra vir c o m p are d t o 
l o pi na vir/rit o na vir b ot h a d mi nistere d wit h d ual n ucle osi de 
re vers e tra nscri ptase i n hi bit or t hera p y i n HI V-1 i nfecte d a d ult 
s u bjects wit h treat me nt f ail ure o n first li ne t hera p y 
C o m p o u n d N u m ber  : G S K 1 3 4 9 5 7 2  
Effecti ve D ate  
: Refer t o D oc u m e nt date  
 
Descri pti o n : 
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 0 0 3 0 4 . 
•  
T his R A P is i nte n de d t o descri be t he pl a n ne d effi cac y , safet y & t olera bilit y, vir ol o g y 
a n d healt h o utc o me  a nal ys es re q uire d f or t he st u d y.  
•  
T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of 
I D M C, t he Wee k 2 4 (i nteri m) a n d Wee k 4 8 (pri mar y ) Statistical A nal ysis C o m plete 
( S A C) d eli vera bles . 
•  
T his R A P is t o pr o vi de details of  pla n ne d a n al ys es a n d data dis pla ys  f or E n d of 
St u d y ( E o S) re p orti n g. T hese a nal ys es ma y be i ncl u de d i n re g ulat or y s u b missi o ns, 
st u d y re p orts a n d p u blicati o ns. 
 
 
A ut h or’s N a me a n d F u ncti o n al Are a:  
 
Se ni or Bi ostatisticia n  (Pare x el ) 
 
A p pr o ve d b y : 
A p pr o ver  
D ate  
Se ni or Ma na ger, Bi ostatistics  
 
 
 
C o p yri g ht 2 0 2 2  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d. s  
P P D
P P D


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS ......................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Hypotheses................................................................................. 12 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.1.1. 
Week 24 data cut ......................................................................... 12 
3.1.2. 
IDMC interim analyses ................................................................. 12 
3.2. 
Primary Analyses ........................................................................................ 13 
3.3. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 17 
6. 
STUDY POPULATION ANALYSES ....................................................................... 18 
6.1. 
Overview of Planned Analyses ................................................................... 18 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 21 
7.1. 
Efficacy Analyses ........................................................................................ 21 
7.1.1. 
Overview of Planned Efficacy Analyses ....................................... 21 
7.1.2. 
Planned Efficacy Statistical Analyses ........................................... 23 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 28 
8.1. 
Efficacy Analyses ........................................................................................ 28 
8.1.1. 
Overview of Planned Efficacy Analyses ....................................... 28 
8.1.2. 
Planned Efficacy Statistical Analyses ........................................... 30 
8.2. 
Safety Analyses .......................................................................................... 34 
8.2.1. 
Overview of Planned Analyses .................................................... 34 
8.2.2. 
Planned Safety Statistical Analyses ............................................. 38 
9. 
OTHER STATISTICAL ANALYSES ....................................................................... 40 
9.1. 
Health Outcomes Analyses ......................................................................... 40 
9.1.1. 
Overview of Planned Analyses .................................................... 40 
9.1.2. 
Planned Health Outcomes Statistical Analyses ............................ 41 
9.2. 
Virology Analyses ....................................................................................... 43 
9.2.1. 
Overview of Planned Analyses .................................................... 43 
10. REFERENCES ....................................................................................................... 45 
11. APPENDICES ........................................................................................................ 46 


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11.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 47 
11.1.1. 
Exclusions from Per Protocol Population ..................................... 47 
11.2. 
Appendix 2: Time & Events ......................................................................... 50 
11.2.1. 
Protocol Defined Time & Events .................................................. 50 
11.3. 
Appendix 3: Assessment Windows ............................................................. 52 
11.3.1. 
Definitions of Assessment Windows for Analyses ........................ 52 
11.4. 
Appendix 4: Treatment States and Phases ................................................. 54 
11.4.1. 
Study Phases .............................................................................. 54 
11.4.2. 
Treatment States ......................................................................... 54 
11.4.3. 
Post-treatment Assessments and Phases.................................... 57 
11.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 58 
11.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 58 
11.5.2. 
Baseline Definition & Derivations ................................................. 58 
11.5.3. 
Reporting Process & Standards ................................................... 59 
11.6. 
Appendix 6: Derived and Transformed Data ............................................... 61 
11.6.1. 
Week 24 cut off date .................................................................... 61 
11.6.2. 
General ........................................................................................ 61 
11.6.3. 
Study Population .......................................................................... 62 
11.6.4. 
Safety .......................................................................................... 64 
11.6.5. 
Efficacy ........................................................................................ 66 
11.6.6. 
Virology ....................................................................................... 71 
11.6.7. 
Health Outcomes ......................................................................... 75 
11.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ............... 79 
11.7.1. 
Premature Withdrawals ................................................................ 79 
11.7.2. 
Handling of Missing Data ............................................................. 79 
11.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 82 
11.9. 
Appendix 9: Multicenter Studies .................................................................. 83 
11.9.1. 
Methods for Handling Centres ..................................................... 83 
11.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata .......... 84 
11.10.1. Handling of Covariates, Subgroups & Other Strata ...................... 84 
11.11. Appendix 11: Handling of Multiple Comparisons & Multiplicity .................... 86 
11.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 87 
11.12.1. Statistical Analysis Assumptions .................................................. 87 
11.13. Appendix 13: Snapshot ............................................................................... 88 
11.14. Appendix 14 – Q2 Creatinine Assay Accuracy Issue .................................. 91 
11.14.1. Sensitivity Analyses ..................................................................... 91 
11.15. Appendix 15 – Abbreviations & Trade Marks .............................................. 92 
11.15.1. Abbreviations ............................................................................... 92 
11.15.2. Trademarks ................................................................................. 94 
11.16. Appendix 16 – Example SAS code for Additional Estimand 2 ..................... 95 
11.17. Appendix 17 – End of Study Analysis ......................................................... 98 
11.17.1. General considerations for data analyses .................................... 98 
11.17.2. Study Population ........................................................................ 102 
11.17.3. Efficacy Analysis ........................................................................ 103 
11.17.4. Safety Analysis .......................................................................... 103 
11.17.5. Virology analysis ........................................................................ 104 
11.17.6. COVID - 19 analysis .................................................................. 107 
11.17.7. Data Displays for End of Study Final Report .............................. 108 
11.17.8. Abbreviations and Trademarks .................................................. 119 
11.18. Appendix 18 –List of Data Displays........................................................... 132 


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11.18.1. Data Display Numbering ............................................................ 132 
11.18.2. Mock Example Shell Referencing .............................................. 132 
11.18.3. Deliverable ................................................................................. 133 
11.18.4. Study Population ........................................................................ 134 
11.18.5. Efficacy ...................................................................................... 144 
11.18.6. Safety ........................................................................................ 153 
11.18.7. Virology ..................................................................................... 164 
11.18.8. Health Outcomes ....................................................................... 166 
11.18.9. ICH Listings ............................................................................... 171 
11.18.10. Non-ICH Listings ........................................................................ 174 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
5  
 
Re visi o n  Hist or y : 
T he p ur p ose of t h e latest u p date ( R A P A me n d me nt 2 wit h E o S A nal ysis) is t o descri be 
t he a nal yses t o be i ncl u d e d i n t he E n d of St u d y Cli nical St u d y Re p ort base d o n St u d y 
2 0 0 3 0 4 pr ot oc ol a me n d me nt 3 ( 1 9 -J U N-2 0 1 8) - ( Gla x o S mit h Kli ne D oc u me nt N o.: 
2 0 1 3 N 1 7 2 6 7 2 _ 0 3).  
R e vi si o n C hr o n ol o g y:  
R A P  
3 0 -A pr -2 01 4  
R e p orti n g a nd An alysis Pl an f or St u dy MI D 2 0 03 04  
R A P A m e nd m e nt 1  
0 5 -Oct -2 01 5  
A m e n d m ent to R e porti n g an d An alysis Pl an f or St u dy 
MI D 2 0 0 30 4 ( HI V T S Q an d W e ek 4 8 S na ps hot)  
R A P A m e nd m e nt 2  
0 9 -A pr -2 01 7  
A m e n d m ent to R e p orti n g an d An alysis Pl an f or St u dy 
MI D 2 0 0 30 4 ( S witc h L P V/ R T V t o D T G ) 
R A P A m e nd m e nt 3  
wit h E o S A nalysis  
 
A m e n d m ent to R e porti n g an d An alysis Pl an wit h E n d of 
St u dy A nalysis f or Stu dy MI D 2 0 0 30 4 ( Ap pe n dix 1 1.1 7 
A d d ed)  
P P D


 
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1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP details all planned analyses and outputs required for the Week 24 
and Week 48 Clinical Study Reports (CSR) of study 200304.  
Protocol 
• 
This RAP is based on the protocol amendment No. 1 (Dated: 30-APR-2014) of 
study 200304 (GlaxoSmithKline Document No. : 2013N172672_01) and eCRF 
Version (Insert Version). 
Primary 
Objective  
• 
To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-
recommended standard of care regimen for second line treatment, LPV/RTV + 
two NRTIs, in HIV-1 infected patients failing first line therapy. 
Primary 
Endpoint 
• 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm (Missing, Switch or Discontinuation = Failure) for the intent-
to-treat exposed (ITT-E) population  
Study 
Design 
• 
Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel 
group, non-inferiority study 
• 
Approximately 612 adult patients with confirmed virologic failure (HIV-1 RNA 
400 c/mL on two occasions) on their first antiretroviral regimen consisting of 
one NNRTI + two NRTIs will be recruited. 
• 
Assuming a true response rate of 70% for both DTG and LPV/r arms, the study 
requires 306 subjects per arm to have 90% power with a 12% non-inferiority 
margin and a one-sided 2.5% significance level (see Section 8.2.1). 
• 
Subjects will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV 
(800/200 mg once daily or 400/100 mg twice daily, in accordance with 
investigator decision and local label), each added to an investigator selected 
background regimen consisting of two NRTIs with at least one fully active NRTI.  
In consultation with the medical monitor, 3TC may be added as a third NRTI to 
a dual-NRTI background regimen in subjects with chronic HBV infection and 
evidence of HIV resistance to 3TC (e.g. M184V) 
Planned 
Analyses 
• 
The primary analysis at Week 48 will take place after the last subject completes 
52 weeks on therapy (Day 1 to Week 48 plus a 4-week treatment extension). 
• 
An interim analysis and data cut will be conducted after the last subject 
completes 24 weeks on therapy, with the intent to provide an earlier 
assessment of efficacy to inform the Sponsor and clinicians.  
• 
An IDMC will be instituted to perform periodic reviews of the accumulating data 
to ensure that subjects are not being sub-optimally treated. 
Analysis 
Populations 
• 
The ‘Intent-to-Treat Exposed Population’ (ITT-E) consisting of all randomised 
subjects who receive at least one dose of study medication, assessed 
according to their randomised treatment regardless of the treatment they 
receive, will be the primary analysis population for evaluating efficacy. 


 
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Overview 
Key Elements of the RAP 
• 
The ‘Per-Protocol Population’ consisting of subjects in the ITT-E population with 
the exception of major protocol violators, e.g. violations that could affect the 
assessment of antiviral activity will be used for sensitivity analyses of the 
primary efficacy endpoint. 
• 
The ‘Safety Population’ consisting of all subjects who receive at least one dose 
of IP, assessed according to the actual treatment received, will be used for 
evaluating safety and tolerability.  Subjects will be analyzed according to the 
actual treatments received. 
• 
The ‘Intent-to-Treat Population’ consisting of all randomised subjects, assessed 
according to their randomised treatment even if no study treatment was taken 
or the wrong treatment was received, will be used for sensitivity analyses of the 
primary efficacy endpoint. 
Hypothesis 
• 
This study is designed to show that the antiviral effect of a regimen of DTG 
(administered once daily) + two NRTIs is non-inferior to LPV/RTV + two NRTIs; 
non-inferiority will be declared if the lower bound of the two-sided 95% CI for 
the difference in snapshot response rates (DTG – LPV/RTV) is greater than -
12%. The primary analysis will be based on the ITT-E population using the 
Snapshot dataset at Week 48. The primary comparison will be made at a one-
sided 2.5% level of significance.  
Primary 
Analyses 
• 
The primary endpoint will be analysed using a Cochran-Mantel-Haenszel 
stratified analysis, adjusting for baseline stratification factors.  A point estimate 
and corresponding 95% confidence interval will be constructed for the adjusted 
difference in response rates between DTG and LPV/RTV treatment groups. 
Secondary 
Analyses 
• 
Secondary analyses will be conducted for additional efficacy, safety, health 
outcomes, and virologic endpoints.  
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 1 (Dated: 30/APR/2014). 
The main changes included in RAP Amendment 1 are: 
• HIV TSQ 
The original RAP described analyses for the 10-item HIV TSQ, however the 14 
-item HIV TSQ is being used in this study.   
 
• Suspect Creatinine Samples 
An issue was identified with the creatinine testing at the central laboratory. 
Sensitivity analyses will be conducted excluding any suspect creatinine samples from 
laboratory summaries including creatinine.   
 
• Week 48 snapshot 
Including a summary of week 48 snapshot outcomes in the Week 24 interim. 
 
• Phenotype & genotype data for China subjects 
Phenotype data may not be available for all subjects in China at the time of the Week 
24 analyses. The China subjects may also have genotype data from Q2 and/or 
Monogram.  In the event that subjects have both Q2 and Monogram data at a 
timepoint, the Monogram data will be used.   
The main changes in RAP Amendment 2 are: 
Following Protocol Amendment 2 (Dated: 19/Apr/2017) additional analyses have been 
included to account for subjects that switch from LPV/RTV to DTG or withdraw from 
the study due to the IDMC recommendation.  
The planned summary by-visit CSSR has been replaced with the IDSL recommended 
summary. 
Other minor changes have been included. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To demonstrate non-inferior antiviral 
activity at 48 weeks of a DTG 
containing regimen (DTG 50 mg once 
daily + two NRTIs) compared to a 
WHO-recommended standard of care 
regimen for second line treatment, 
LPV/RTV + two NRTIs, in HIV-1 
• 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL 
at Week 48 using the Snapshot algorithm (Missing, 
Switch or Discontinuation = Failure) for the ITT-E 
population 


 
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9 
 
Objectives 
Endpoints 
infected patients failing first line 
therapy. 
Secondary Objectives 
Secondary Endpoints 
• 
To demonstrate non-inferior antiviral 
activity at 24 weeks of a DTG 
containing regimen (DTG 50 mg once 
daily + two NRTIs) compared to a 
recommended WHO standard of care 
regimen for second line treatment, 
LPV/RTV + two NRTIs, in HIV-1 
infected patients failing first line 
therapy 
• 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL 
at Week 24 using the Snapshot algorithm 
• 
To evaluate the antiviral and 
immunological activity and incidence 
of disease progression (HIV-
associated conditions, AIDS and 
death) of DTG compared to LPV/RTV 
over time 
• 
Proportion of subjects with plasma HIV-1 RNA <400 c/mL 
at Weeks 24 and 48 using the Snapshot algorithm; 
• 
Proportion of subjects without virologic or tolerability 
failure by Weeks 24 and 48, where failure equals 
treatment-related discontinuation (meeting confirmed 
virologic withdrawal criteria, treatment-related adverse 
event, safety stopping criteria, and lack of efficacy); 
• 
Time to viral suppression (HIV-1 RNA <50 c/mL); 
• 
Absolute values and changes from Baseline in CD4+ cell 
counts at Weeks 24 and 48; 
• 
Incidence of disease progression (HIV-associated 
conditions, AIDS and death). 
• 
To assess the development of viral 
resistance in subjects meeting 
confirmed virologic withdrawal criteria; 
• 
Incidence of treatment-emergent genotypic and 
phenotypic resistance to DTG, LPV/RTV and other on-
study ART in subjects meeting confirmed virologic 
withdrawal criteria. 
• 
To evaluate the safety, tolerability, 
and laboratory parameters of DTG 
compared to LPV/RTV over time 
• 
Incidence and severity of AEs and laboratory 
abnormalities;  
• 
Absolute values and changes over time in laboratory 
parameters; 
• 
The proportion of subjects who discontinue treatment due 
to AEs. 
• 
To compare the effects of DTG and 
LPV/RTV on fasting lipids over time 
• 
Change from Baseline in fasting LDL cholesterol at 
Weeks 24 and 48; 
• 
Change from Baseline in fasting TC/HDL ratio at Weeks 
24 and 48; 
• 
The incidence of maximum post-Baseline emergent 
Grade 2 or greater laboratory abnormalities in fasting LDL 
cholesterol by Weeks 24 and 48; 
• 
To compare the effects of DTG and 
LPV/RTV on the occurrence of 
gastrointestinal adverse events over 
time 
• 
The incidence of maximum post-Baseline emergent 
Grade 2 or greater drug-related diarrhoea by Weeks 24 
and 48 
• 
To compare the change in 
gastrointestinal symptom rating score 
for subjects treated with DTG and 
LPV/RTV over time 
• 
Change from Baseline, using the Gastrointestinal 
Symptom Rating Scale (GSRS), at Week 4, Week 24, 
and Week 48 
• 
To compare the satisfaction with 
• 
Change from Baseline in treatment satisfaction, using the 


 
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10 
 
Objectives 
Endpoints 
treatment of patients with DTG 
compared to the LPV/RTV over time 
HIV-Treatment Satisfaction Questionnaire (HIVTSQ), at 
Week 4, Week 24, and Week 48 
• 
To compare patients’ adherence with 
DTG compared to LPV/RTV over time 
• 
Change from Baseline in adherence with treatment, using 
the Morisky 8-Item Medication Adherence Scale (MMAS-
8), at Week 4, Week 24, and Week 48. 
• 
To evaluate the effect of patient 
demographics and baseline 
characteristics (e.g. demographic 
factors, HIV-1 subtype, baseline CD4+ 
cell count) on response to DTG 
compared to LPV/RTV over time 
• 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL 
at Weeks 24 and 48 using the Snapshot algorithm 
 


 
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11 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• Phase IIIb, randomised, open-label, active-controlled, multicentre, parallel 
group, non-inferiority study in HIV-1 infected adult subjects with treatment 
failure on first line therapy 
• The 4-week treatment extension up to Week 52 is designed  to collect a 
confirmatory viral load measurement at Week 52 in subjects presenting with 
HIV-1 RNA >50 c/mL at the Week 48 visit.  According to the FDA’s snapshot 
algorithm, which considers viral load measurements collected within a  6 
week window around the Week 48 visit (including data from the Week 52 visit), 
if the retest viral load is < 50 c/mL then the subject will be classified as a 
virologic success in the primary analysis. 
Dosing 
• DTG 50 mg once daily or LPV/RTV (800/200 mg once daily or 400/100 mg 
twice daily, in accordance with investigator decision and local label) 
Treatment 
Assignment 
• Approximately N=612 Subjects will be randomised 1:1 to receive DTG 50 mg 
once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in 
accordance with investigator decision and local label), each added to an 
investigator selected background regimen consisting of two NRTIs with at least 
one fully active NRTI.  In consultation with the medical monitor, 3TC may be 
added as a third NRTI to a dual-NRTI background regimen in subjects with 
chronic HBV infection and evidence of HIV resistance to 3TC (e.g. M184V). 
• GSK RandAll NG used to generate randomisation schedules, stratified by 
baseline HIV-1 RNA (Baseline plasma HIV-1 RNA ( vs. >100,000 c/mL) and 
Baseline Number of fully active background NRTIs (<2 vs. 2)). 
• Centralised randomisation using GSK RAMOS for treatment allocation 
• Following the IDMC recommendation to switch LPV/RTV subjects to DTG, 
some subjects randomised to LPV/RTV may receive DTG post switch. 
Interim 
Analysis 
• An interim analysis will be conducted when all subjects have completed their 
Week 24 visit in order to provide an earlier assessment of efficacy to inform the 
Sponsor and clinicians. 


 
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12 
 
Overview of Study Design and Key Features 
• An IDMC will be utilised in this study to ensure external objective medical 
and/or statistical review of safety and/or efficacy issues in order to protect the 
ethical and safety interests of subjects and to protect the scientific validity of 
the study.  Planned stopping guidelines and schedule for interim analyses are 
provided in Section 8.3.4.2 of the Protocol. 
2.4. 
Statistical Hypotheses 
This study is designed to show that the antiviral effect of a regimen of DTG 
(administered once daily) + two NRTIs is non-inferior to LPV/RTV + two NRTIs.  
If rd is the response rate on DTG + two NRTIs and ra is the response rate on LPV/RTV + 
two NRTIs then the hypotheses can be written as follows: 
H0: rd – ra ≤ -12%  
 
H1: rd – ra > -12%. 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The main analysis will be conducted to evaluate the primary objective of the protocol 
when all subjects have completed their Week 52 visit.   
3.1.1. 
Week 24 data cut 
An interim analysis will be conducted in order to provide an earlier assessment of 
efficacy to inform the Sponsor and clinicians after the following activities have been 
carried out: 
1. All subjects have completed their Week 24 visit.   
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3. Randomisation codes have been distributed according to RandAll NG procedures 
4. All criteria for unblinding the randomisation codes have been met.  
The analyses described in Section 7.1 and Section 8.1 will be performed with the sole 
difference being that the timepoint for these analyses will be Week 24 instead of Week 
48.   
No adjustment for multiplicity will be made for this analysis because the Week 24 
endpoints represent secondary objectives for the study which are subordinate to the 
primary analysis at Week 48.   
3.1.2. 
IDMC interim analyses 
An IDMC has been instituted to provide independent review of the accumulating data, 
primarily to ensure subjects are not being sub-optimally treated in either arm.  


 
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Three formal interim analyses are planned for review by the IDMC (Table 1). Additional 
details are provided in the protocol and IDMC charter. 
 
Table 1 
Timing of Planned IDMC Interim Analyses and Stopping Guidelines 
Interim 
Analysis 
Timing 
Endpoint 
Evaluation (guideline) 
#1 
Once 100 subjects (total) 
have completed their Week 
16 visit 
Proportion of subjects with 
HIV-1 RNA <50 c/mL 
 at Week 16 
(Snapshot algorithm) 
• Inferioritya (one-sided p<0.01) 
#2 
Once 300 subjects (total) 
have completed their Week 
24 visit 
Proportion of subjects with 
HIV-1 RNA <50 c/mL 
 at Week 24 
(Snapshot algorithm) 
• Inferioritya (one-sided p<0.01) 
#3 
Once all subjects have 
completed their Week 24 
visit 
Proportion of subjects with 
HIV-1 RNA <50 c/mL 
 at Week 48 
(Snapshot algorithm) 
• Inferioritya (one-sided p<0.01) 
• Superiorityb (one-sided p<0.0001) 
a. 
Inferiority: significantly lower response rate with DTG than LPV/r. 
b. 
Superiority: significantly higher response rate with DTG than LPV/r. 
 
At time of finalisation of Protocol Amendment 2, the IDMC had completed interim 
analyses #1 and #2.  Prior to interim analysis #3, the IDMC conducted an ad hoc review 
of trial data and observed significant, clinically relevant differences between treatment 
arms in favour of DTG.  The IDMC recommended to the sponsor that the LPV/RTV 
treatment arm be discontinued and subjects currently receiving LPV/RTV in the study be 
switched to a regimen with DTG as the third drug, if considered appropriate by the 
Investigator.  Interim analysis #3 will no longer take place. 
3.2. 
Primary Analyses 
The planned primary analyses will be performed after: 
1. All subjects have completed their Week 52 visit as defined in the protocol. 
2. All required database cleaning activities have been completed and database release 
and database freeze has been declared by Data Management. 
3.3. 
Final Analyses 
A final End-of-Study analysis will be conducted when all subjects have completed the 
study as defined in Section 3.1 of the Protocol. 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Subjects 
Screened 
• Comprised of all subjects screened for 
inclusion in the study.  
• Subjects may be re-screened once, for which 
they will receive a new subject number. 
• Only the latest re-screening data will be 
included in the screening population 
summaries/analyses but all screening data will 
be listed. 
• Study Population 
Intent-to-Treat 
Exposed (ITT-E) 
• Comprise of all randomised subjects who 
receive at least one dose of study medication. 
• Subjects will be assessed according to their 
randomised treatment, regardless of the 
treatment they receive 
• Efficacy 
• Health Outcome 
• Study population 
Safety 
• Comprise of all subjects who receive at least 
one dose of investigational product  
• Subjects will be analyzed according to the 
actual treatments received. 
• Safety 
Intent-To-Treat 
(ITT) 
• Comprise of all randomised subjects. 
• Subjects will be assessed according to their 
randomised treatment even if no study 
treatment was taken or the wrong treatment 
was received. 
• Sensitivity analyses 
of the primary 
efficacy endpoint 
Week 36 Intent-
to-Treat Exposed 
(MITT-E-36) 
• Comprise all subjects in the ITT-E population 
randomised at least 36 weeks prior to 18 Jan 
2017 (the last subject visit date for the Week 
24 study report), excluding subjects still on-
study in the randomised phase that had yet to 
provide a Week 36 HIV-1 RNA result by the 
Week 24 study report cutoff date. 
• Week 36 snapshot 
outcomes for Week 
24 study report. 
Week 48 Intent-
to-Treat Exposed 
(MITT-E-48) 
• Comprise all subjects in the ITT-E population 
randomised at least 48 weeks prior to 18 Jan 
2017 (the last subject visit date for the Week 
24 study report), excluding subjects still on-
study in the randomised phase that had yet to 
provide a Week 48 HIV-1 RNA result by the 
Week 24 study report cutoff date. 
• Week 48 snapshot 
outcomes for Week 
24 study report. 
Per-Protocol 
• Comprise of all subjects in the ITT-E 
population with the exception of major protocol 
violators, e.g. violations which could affect the 
• Sensitivity analyses 
of the primary 
efficacy endpoint 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
assessment of antiviral activity. 
• Protocol deviations that would exclude 
subjects from the PP population are defined in 
Section 4.1 (Protocol Deviations) and 
Appendix 1 (Protocol Deviation Management 
and Definition for Per-Protocol Population). 
• Only protocol deviations that occur duing the 
randomised phase and before the outcome of 
interest may lead to exclusion from the PP 
population. For example, a subject with  a 
protocol deviation between Week 24 and 
Week 48 would not be excluded from the 
Week 24 PP Population, due to this deviation, 
but would be excluded from the Week 48 PP 
Population 
Viral Genotypic  
• Comprise of all subjects in the ITT-E 
population with available On-treatment 
genotypic resistance data at the time 
confirmed virologic withdrawal criterion is met  
• Genotypic 
Viral Phenotypic 
• Comprise of all subjects in the ITT-E 
population with available On-treatment 
phenotypic resistance data at the time 
confirmed virologic withdrawal criterion is met 
• Phenotypic 
NOTES :  
• 
Please refer to Appendix 18  List of Data Displays which details the population to be used for each displays being 
generated. 
4.1. 
Protocol Deviations 
• 
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. 
• 
Important deviations which result in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population)]. 
• 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the per-
protocol analysis are captured and categorised on the protocol deviations dataset.  
This dataset will be the basis for the summaries and listings of protocol 
deviations. 


 
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• 
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
• 
There are planned examination of covariates and subgroups. 
• 
There are no planned adjustments made for multiple centres in this study. 
• 
There are no planned adjustments for multiple comparisons or multiplicity. 
• 
There are no PK analyses planned in this study. 
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 2 
Overview of Appendices 
Section 
Component 
Section 11.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
Section 11.2 
Appendix 2: Time & Events 
Section 11.3 
Appendix 3: Assessment Windows 
Section 11.4 
Appendix 4: Treatment States and Phases 
Section 11.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 11.6 
Appendix 6: Derived and Transformed Data 
Section 11.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
Section 11.8 
Appendix 8: Values of Potential Clinical Importance 
Section 11.9 
Appendix 9: Multicenter Studies 
Section 11.10 
Appendix 10: Examination of Covariates, Subgroups & Other Strata 
Section 11.11 
Appendix 11: Handling of Multiple Comparisons & Multiplicity 
Section 11.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Section 11.13 
Appendix 13: Snapshot 
Section 11.14 
Appendix 14: Q2 Creatinine Assay Accuracy Issue 
Section 11.15 
Appendix 15  Abbreviations & Trade Marks 
Section 11.16 
Appendix 16: Example SAS code for Additional Estimand 2  
Section 11.17 
Appendix 17: End of Study Analysis 
Section 11.18 
Appendix 18 : List of Data Displays 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
All displays are for the randomised phase only, unless specified otherwise. This means 
that the analysis will not be “windowed” at Week 24 ie all data collected up to the point 
of Database Freeze for Week 24will be included in summary statistics, which could be 
past week 24 for subjects enrolled early in the study. However, in the Week 48 report, the 
analysis will be “windowed”, ie summary statistics will include data up to Week 52 only 
for both arms. 
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 18  List of Data Displays. 
Table 3 
Overview of Planned Study Population Analyses 
Display Type 
Data Display’s Generated 
Figure 
Table 
Listing 
Randomisation 
Randomisation 
 
 
Y[1] 
Subject Disposition 
Study population[2] 
 
Y 
Y [3] 
Summary of Subjects Enrolled by Country and 
Investigator [2] 
 
Y 
Y 
Study recruitment by age (EMA) 
 
Y 
 
Reasons for Screening Failures [2] 
 
Y 
Y 
Subject  Accountability by Phase (Overall, 
Randomised Phase, Continuation Phase)[4] 
 
Y 
 
Reasons for Withdrawals by visit 
 
Y 
Y 
Study visit dates 
 
 
Y 
Important Protocol Deviations 
 
Y 
Y 
Deviations Leading to Exclusions from PP Population 
 
Y 
Y 
Inclusion and Exclusion Criteria Deviations 
 
Y 
Y 
Drug Accountability 
Investigational Product Accountability[5] 
 
 
Y 
Demography 
Demographics Characteristics[6] 
 
Y 
Y 
Race & Racial Combinations[7] 
 
Y x2 
Y 
CDC Classification of HIV Infection at Baseline 
 
Y 
Y 
Baseline Cardiovascular Risk Assessments 
 
Y 
Y 


 
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Display Type 
Data Display’s Generated 
Figure 
Table 
Listing 
Plasma HIV-1 RNA Results at Screening and 
Baseline 
 
Y 
 
CD4+ Cell Count Results at Screening and Baseline 
 
Y 
 
Hepatitis Status at Entry 
 
Y 
Y 
History of Cardiac Therapeutic Procedures 
 
 
Y 
Medical Condition & Concomitant  Medications 
Medical Conditions (Current/Past) 
 
Y  
Y[9] 
Medical Conditions: sub-conditions (Current/Past) 
 
Y  
Y 
Concomitant Medication (non ART) 
 
Yx3[10] 
Y[11,9] 
Prior Antiretroviral Therapy (including Duration) 
 
Yx4 
Y[11] 
Baseline Background Antiretroviral Therapy 
(including conART) 
 
Y 
Y[11] 
Lipid Modifying Agent Use (Starting Baseline/Post-
Baseline) 
 
Y 
Y 
Virology 
Summary of the Number of Baseline Major Mutations 
Associated with the Resistance to NRTI, NNRTI, and 
PI drug classes 
 
Yx2[8] 
 
Proportion of subjects without at least 1 fully active 
NRTI 
 
Y 
 
Summary of Baseline Major NNRTI and NRTI 
Mutations 
 
Y 
 
Summary of Stanford Baseline GSS to Background 
ART Regimen 
 
Y 
 
Summary of Monogram Baseline GSS to Background 
ART Regimen 
 
Y 
 
Summary of Baseline PSS to Background ART 
Regimen 
 
Y 
 
Summary of Baseline OSS (Net Assessment) to 
Background Therapy 
 
Y 
 
Summary of the Prevalence of HIV-1 Clades at 
Baseline by Frequency 
 
Y 
 
Summary of First Line Regimen and Expected Second 
Line Regimen Using the WHO Algorithm[12] 
 
Y 
 
Summary of Expected WHO Second Line vs. 
Background Regimen actually Taken[12] 
 
Y 
 
 
 


 
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NOTES: 
Y = Yes display generated, T = Tables, L = Listings, IP = Investigational Product. 
1. 
One listing of subjects randomised but not treated, and one listing of planned and actual treatment strata  
2. 
All subject screened population 
3. 
Listing of subjects excluded from any population will be generated only.   
4. 
Subjects who have not been recorded as either completing or withdrawing from the study will be categorised as 
“Ongoing at time of the analysis” for summary purposes. 
5. 
Dispensation information (dates and number of tablets dispensed and returned) 
6. 
Gender, age, ethnicity, weight and height collected at screening (Day 1 for height) 
7. 
The five high level FDA race categories and designated Asian subcategories will be summarised along with all 
combinations of high level categories which exist in the data. The nine race categories collected will be 
summarised along with categories for mixed race. A by-subject listing of race will also be produced. 
8. 
 Repeated for screening mutation for the Screen Failure population.   
9. 
Repeated for Mexican subjects who experienced an adverse event at the End of Study SAC. 
10. Three separate tables, summarised by Ingredient ATC Level 1, Ingredient combinations and Combination term 
ATC Level 1 (EG Includes single-ingredient medications with multi-ingredient medications labelled according to the 
sum of their ingredients, e.g., “TYLENOL Cold and Flu” would appear as “CHLORPHENAMINE MALEATE + 
DEXTROMETHORPHAN HYDROBROMIDE + PARACETAMOL +  PSEUDOEPHEDRINE HYDROCHLORIDE” 
under the ATC headings for “Nervous System” and “Respiratory System” (the combination’s ATC classifications).) 
11. One listing for concomitant non-ART medications, prior ART, background ART and one listing showing the 
relationship between verbatim text, ingredient and ATC Level 1. 
12. WHO First and Second Line Regimens are defined in Appendix 6. 
 
 


 
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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Efficacy Analyses 
7.1.1. 
Overview of Planned Efficacy Analyses 
The primary efficacy analyses will be based on the Intent-to-Treat Exposed population, 
unless otherwise specified. 
Summaries will be presented by treatment group with no total column. 
The primary estimand and additional estimands for the Week 48 deliverables is presented 
in Table 4 below. For all estimands, the population of interest (ITT-E population), 
variable (plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm), and 
summary measure (proportion of subjects with response) will be the same. All estimands 
will account for discontinuation (other than due to IDMC recommendation) and non-
permitted changes in background ART, as per the snapshot algorithm.  
Table 4 
Primary and Additional Estimands for the Week 48 Deliverable 
Type of 
Estimand 
Post-baseline Intervention of interest 
 
Primary 
No additional post baseline interventions considered. 
Subjects will be analysed according to their original treatment assignment 
regardless of treatment switch. 
Additional 
Additional Estimand 1 
In addition, accounting for subjects that switch from LPV/RTV to DTG or 
withdraw from the study due to the IDMC recommendation (and subsequent 
Protocol Amendment 2). HIV-1 RNA values collected after treatment 
switching or discontinuation will be excluded from the analyses.  
Additional 
Additional Estimand 2 
In addition, for subjects that switch from LPV/RTV to DTG or withdraw 
from the study due to the IDMC recommendation (and subsequent Protocol 
Amendment 2), their subsequent HIV-1 RNA values will be replaced with 
imputed values.  
 
Table 5 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 18 : List of Data Displays. 


 
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Table 5 
Overview of Planned Efficacy Analyses 
Endpoint 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Proportion of 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 48 using the 
Snapshot algorithm 
Y[1] 
 
 
Y[2]  
Y[] 
 
Y[2] 
Treatment 
Heterogeneity across 
randomisation strata 
Y 
 
 
 
 
 
 
Study Outcome 
based on the 
Snapshot  
 
 
 
Y[4] 
 
 
Y 
Study Outcome 
based on the 
Snapshot by number 
of fully active 
background NRTIs  
 
 
 
Y 
 
 
 
Proportion <50 c/mL 
at Week 48 by 
subgroup[5] 
 
 
 
Y 
Y[6] 
 
 
Summary of Study 
Outcomes based on 
the Snapshot at 
Week 48 by 
Subgroup 
 
 
 
Y 
 
 
 
Proportion of 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 48 using the 
Snapshot algorithm – 
Additional Estimand 
1 [7] 
Y[1] 
 
 
Y[2]  
 
 
 
Study Outcome 
based on the 
Snapshot – 
Additional Estimand 
1 [7] 
 
 
 
Y[4] 
 
 
 
Proportion of 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 48 using the 
Snapshot algorithm – 
Additional Estimand 
2 [7] 
Y[1] 
 
 
Y[2]  
 
 
 
Study Outcome 
 
 
 
Y[4] 
 
 
Y 


 
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Endpoint 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
based on the 
Snapshot – 
Additional Estimand 
2 [7] 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Statistical analysis displays will be generated using the ‘Intent-to-Treat Exposed’ (primary), ‘Per-Protocol’ and 
‘Intent-to-Treat’ (sensitivity) populations. 
2. 
Study outcomes (i.e., response below 50 c/mL, virologic failure or reason for no data in the window) based on the 
snapshot algorithm will be summarised and listed. 
3. 
Line plots, with 95% confidence intervals, for the proportion of subjects below 50 c/mL by treatment group at each 
visit will be produced. 
4. 
This summary will be produced for the week 24 study report. 
5. 
Baseline demography (age, gender, race, country, CDC), HIV-1 subtype, Baseline CD4 and Baseline viral load, 
background ART (ABC+3TC vs not ABC+3TC). 
6. 
Plot of 95% confidence intervals for the proportion of subjects below 50 c/mL by subgroup.  
7. 
This summary will be produced for the week 48 study report. 
 
7.1.2. 
Planned Efficacy Statistical Analyses 
Primary Statistical Analyses 
Endpoint(s) 
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm (Missing, Switch or Discontinuation = Failure) for the ITT-E population 
Snapshot Dataset 
• The Snapshot  algorithm treats all subjects without HIV-1 RNA data at the visit of interest (due 
to missing data or discontinuation of IP prior to the visit window) as non-responders, as well as 
subjects who switch their concomitant ART prior to the visit of interest in certain 
scenarios(Section 11.13). 
• Switch from 3TC to FTC (or vice versa) will not be considered a background NRTI change and 
will not incur a penalty as per the FDA’s Snapshot algorithm. 
• Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA 
assessment while the subject is On-treatment within the visit of interest analysis window (see 
Section 11.4.2) Full details of the Snapshot algorithm are in Section 11.13. 
• For subjects that switch from LPV/RTV to DTG, any subsequent HIV-1 RNA values will be left 
as is then virologic response or failure will be determined at Week 48 using snapshot 
algorithm, with subjects presented by their original randomised treatment.. 
•  
Model Specification 
• The primary endpoint will be analysed using a stratified analysis with Cochran-Mantel-
Haenszel (CMH) weights, adjusting for Baseline plasma HIV-1 RNA (  vs. >100,000 c/mL) 


 
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Primary Statistical Analyses 
and number of fully active background NRTIs in the background regimen (<2 vs. 2) at 
Baseline.   
• The CMH estimate of the adjusted treatment difference will be calculated as a weighted 
average of strata-specific estimates of the treatment difference calculated within each of the 
following four Baseline analysis strata: 
o Plasma HIV-1 RNA  100,000 c/mL AND <2 fully active background NRTIs 
o Plasma HIV-1 RNA  100,000 c/mL AND 2 fully active background NRTIs 
o Plasma HIV-1 RNA > 100,000 c/mL AND <2 fully active background NRTIs 
o Plasma HIV-1 RNA > 100,000 c/mL AND 2 fully active background NRTIs 
• If nk is the number of DTG treated subjects, mk is the number of LPV/RTV treated subjects, and 
Nk = nk + mk is the total number of subjects in the kth stratum, then the CMH estimate is given 
by 


=
k
k
k
cmh
W
d
W
d
ˆ
ˆ
 
• Where, 
 
k
k
k
k
N
m
n
W
=
  
are CMH weights and dk are estimates of the differences in response proportions between the 
two treatment arms, rd-ra, for the kth strata. 
• The corresponding two-sided 95% CI will be calculated as 
 
)
ˆ
r(
aˆ
v
96
.1
ˆ
cmh
cmh
d
d


 
using the variance estimator, var(dcmh), given by [Sato, 1989], which is consistent in both 
sparse data and large strata.  The full equation for this variance estimate is provided in the 
Appendix 6 (Section 11.6.5). 
• For analysis purposes, fully active NRTI is defined at Baseline by the genotypic resistance 
reports of the central laboratory (or a laboratory contracted by the central laboratory) showing 
no evidence of full or of partial genotypic resistance for a given NRTI.  If Baseline genotypic 
results are not available, then activity of the background regimen will be based on genotypic 
results at Screening. 
Model Results Presentation 
• Adjusted CMH estimate of the difference in the proportion of responders between each 
treatment group (DTG – LPV/RTV) and corresponding 95% confidence interval 
• Non-inferiority will be concluded if the lower bound of the two-sided 95% confidence interval 
(CI) for the CMH adjusted difference in the proportion of patients who respond in the DTG 
group minus the proportion of patients who respond in the LPV/RTV group is greater than -


 
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Primary Statistical Analyses 
12%.   
 
Sensitivity and Supportive Statistical Analyses 
• Treatment Heterogeneity across randomisation strata: 
• Randomization strata will be re-derived using Baseline values (Section 11.10.1). 
• The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to test for one-
way homogeneity across the levels of each categorical variable of the randomisation 
strata, with each categorical variable considered separately.  
• Following Lui and Kelly [Lui , 2000], ½ will be added to each cell in any strata for which the 
stratum-specific rate estimates of either rd or ra are zero or one, and tests will be one-
sided.  
• Any heterogeneity found to be statistically significant will be explored and if necessary 
results will be reported for each level of the categorical variable. Investigation of 
heterogeneity will be confined to the primary endpoint at week 24/48. Tests of 
homogeneity will be assessed at the one-sided 10% level of significance. 
• Per-protocol population analysis: 
• To assess the impact of major protocol deviations, statistical analysis will be repeated 
using the Per-protocol population and compared for consistency with the results from the 
primary ITT-E population analysis.  If both analyses show non-inferiority then the 
hypothesis that the antiviral effect of treatment with DTG + two NRTIs is superior to 
treatment with LPV/RTV + two NRTIs will be tested at the two-sided 5% level of 
significance.  Superiority will be declared if the lower end of the confidence internal is 
above 0% for the ITT-E population analysis. 
 
• Intent-to-Treat population analysis: 
• Statistical analysis will be repeated using the Intent-to-Treat population and compared for 
consistency with the results from the ITT-E and PP populations. 
• In this analysis, subjects randomised but not exposed to study treatment will be classified 
as non-responders, which therefore conservatively addresses any selection bias that may 
occur given the open-label study design.  
• Exploration of Subgroups: 
• A simple analysis for all the subgroups listed in Section 11.10.1 will be performed. This will 
show the proportion of subjects with plasma HIV-1 RNA <50 c/mL at the time of analysis 
(Week 24/48) based on the Snapshot algorithm will be presented by treatment group. 
• Unadjusted difference in proportions between treatment groups and corresponding two-
sided 95% CI will also be presented.by subgroup, and a 95% CI for the (unadjusted) 
treatment difference in each subgroup. These results will also be presented graphically.  
• If the basic summary suggests an interaction, then a corresponding summary of study 
outcomes (i.e., response below 50 c/mL, virologic failure or reason for no data in the 
window) by subgroup will be produced. 
Note: These subgroup analyses will be exploratory and likely underpowered so that 
interpretation may therefore focus on point estimates as well as the lower bounds of 95% CIs 
for the treatment differences and response rates. Additionally, multiple comparisons are being 


 
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Sensitivity and Supportive Statistical Analyses 
made which inflates the risk of false positive findings. Therefore, if consistent findings across 
the multiple comparisons were observed then these analyses would still be suggestive of a 
generalizable finding of non-inferiority. 
• Supportive analysis for the Week 48 deliverable: 
• Additional Estimand 1:  Following the IDMC recommendation (and subsequent Protocol 
Amendment 2), subjects may switch from LPV/RTV to DTG or withdraw from the study. 
Therefore, prior to the application of the Snapshot algorithm for the Week 48 deliverable, 
the following step will be undertaken: 
o For subjects that switch from LPV/RTV to DTG, any subsequent HIV-1 RNA 
values will be set to missing before the Snapshot algorithm is applied..  
o Note: for subjects that withdraw, the Snapshot algorithm will be applied as usual.  
• The population of interest (ITT-E population), variable (plasma HIV-1 RNA <50 c/mL at 
Week 48 using the Snapshot algorithm), and summary measure (proportion of subjects 
with response) will be the same as that used for the primary endpoint. 
• Additional Estimand 2: For subjects that switch from LPV/RTV to DTG or withdraw from the 
study due to the IDMC recommendation (and subsequent Protocol Amendment 2), their 
subsequent HIV-1 RNA values will be imputed prior to determination of virologic response 
or failure at Week 48 using snapshot algorithm. See below for more details.  
 
 
Additional Estimand 2 – Statistical Analyses 
Endpoint 
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm  
Covariates 
• Baseline Plasma HIV-1 RNA ( vs. >100,000 c/mL) 
• Baseline Number of Fully Active NRTIs in the Background Regimen (2 vs.<2) 
Input Dataset, Imputation, and Statistical Analysis  
• Select Log(HIV-1 RNA) samples and subset by treatment  
• For the LPV/RTV arm: 
o For subjects that switch from LPV/RTV to DTG or withdraw from the study due to 
the IDMC recommendation, set any subsequent HIV-1 RNA values to missing  
o Using Markov Chain Monte Carlo methods, simulate 100 datasets replacing Below 
Limit of Quantification (BLQ) values with those from a Log(Uniform(0, BLQ) 
distribution. The BLQ value used for this step should be slightly below the actual 
BLQ cut-off so that response is correctly attributed when applying the snapshot 
algorithm later.  
o The statistical model used for the MI data generation will be the Markov Chain 
Monte Carlo (MCMC) method with for the data (covariates and Log HIV-1 RNA at 
Baseline, Week 4, Week 8, Week 16, Week 24, Week 36, Week 48, and Week 52) 
to produce a monotone pattern first, and then the imputation will continue using 
the Regression (REG) method for the monotone pattern with the same set of 


 
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Additional Estimand 2 – Statistical Analyses 
covariates.   
▪ A seed of 200304 will be used in the SAS program.  
▪ One imputation is required for each of the monotone and mean matching 
steps 
▪ Since it is likely that subject discontinuation or switches treatment due to 
IDMC recommendation will be based on observed viral load counts, the 
missing at random (MAR) assumption is appropriate 
o For subjects that originally had missing HIV-1 RNA data within the Week 48 
window but did not discontinue or switch from LPV/RTV to DTG arms due to the 
IDMC recommendation, replace the imputed data with their original data. Data 
related to these subjects will be used only for the imputation of data for those that 
switch from LPV/RTV to DTG or withdraw from the study due to the IDMC 
recommendation  
• Log(HIV-1 RNA) data for subjects randomised to the DTG arm is merged back onto each 
imputed dataset.  
• Using Snapshot Algorithm, derive virologic response or failure at Week 48 using snapshot 
algorithm, as per Section 11.13, for each imputed dataset. 
• For each imputed dataset, the endpoint will be analysed using a stratified analysis with 
Cochran-Mantel-Haenszel (CMH) weights, adjusting for Baseline plasma HIV-1 RNA (  
vs. >100,000 c/mL) and number of fully active background NRTIs in the background 
regimen (<2 vs. 2) at Baseline. This will be the same model as used for the primary 
endpoint. 
• Wilson-Hilferty transformation will be applied to normalise the CMH statistic  
• PROC MIANALYZE in SAS will be used to combine the 1,000 estimated proportion of subjects 
with plasma HIV-1 RNA <50 c/mL and difference in proportions to produce one estimate with 
95% CI and associated p-value for the adjusted difference between each treatment group at 
Week 48 
 
See 11.16for example SAS code.  
 
 


 
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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Efficacy Analyses 
8.1.1. 
Overview of Planned Efficacy Analyses 
The secondary efficacy analyses will be based on the Intent-to-Treat Exposed population, 
unless otherwise specified. 
All displays are for the randomised phase only, unless specified otherwise. This means 
that the analysis other than “by-visit” summaries will not be windowed at Week 24 
(CVW, time to suppression). In other words, all data collected up to the point of DBF 
will be included in summary statistics, which could be past week 24 for subjects enrolled 
early in the study. However, at the Week 48 analysis, summary statistics will include data 
up to Week 52 for both arms. 
Table 6 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 18 : List of Data Displays. 
Table 6 
Overview of Planned Efficacy Analyses 
Endpoints 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL at Week 24- Snapshot 
Proportion of 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 24 using the 
Snapshot  
algorithm[1] 
Y 
 
 
Y  
Y 
 
Y[2] 
Treatment 
Heterogeneity across 
randomization strata 
Y 
 
 
 
 
 
 
Study Outcome 
based on the 
Snapshot by number 
of fully active 
background NRTIs  
 
 
 
Y 
 
 
 
Proportion <50 c/mL 
at Week 24 by 
subgroup[3] 
 
 
 
Y 
Y 
 
 
Proportion of Subjects 
with Plasma HIV-1 
RNA <50 c/mL by Visit 
and Subgroup - 
Snapshot 
 
 
 
Y 
 
 
 
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL at Week 36/48- Snapshot, at time of 
Week 24 interim analysis[7,8] 
Proportion of 
 
 
 
 
 
 
 


 
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Endpoints 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 36/48 using 
the Snapshot  
algorithm[1][9] 
Proportion of Subjects with Plasma HIV-1 RNA <400 & <50 copies/mL - Snapshot 
<50 c/mL by Visit 
 
 
 
Y 
 
 
 
<400 c/mL at 
analysis timepoint 
(Week 24/48) 
outcome 
 
 
 
Y 
 
 
Y 
<400 c/mL by Visit 
 
 
 
Y 
Y 
 
 
Virologic Failure endpoints 
Proportion of 
subjects without 
virologic or 
tolerability failure by 
analysis timepoint 
(Week 24/48) [4] 
Yx2 
 
 
Yx2 
Yx2 
 
Yx2 
Proportion of 
subjects without 
virologic or 
tolerability failure by 
analysis timepoint 
(Week 36/48) [5] 
Y 
 
 
Y 
Y 
 
Y 
Confirmed Virologic 
Withdrawal Criteria    
by Visit 
 
 
 
Yx2[6] 
 
 
Y 
Viral load for 
Confirmed Virologic 
Withdrawal Criteria  
 
 
 
Y 
 
 
 
Time to viral 
suppression (HIV-1 
RNA <50 c/mL) 
Y 
Y 
 
Y 
 
 
 
Proportion of Subjects 
With Detectable Viral 
Load Below the Limit 
of Quantification at 
Week 24/48 
 
 
 
Yx2[7] 
 
 
 
Disease Progression 
HIV Conditions 
including Recurrences 
 
 
 
Y 
 
 
Y 
HIV Conditions 
excluding Recurrences 
 
 
 
Y 
 
 
 
HIV Disease 
Progressions 
 
 
 
Y 
 
 
 


 
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Endpoints 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Exploratory Analysis 
Proportion of 
subjects with plasma 
HIV-1 RNA <50 c/mL 
at Week 48 using the 
Snapshot algorithm – 
Projected estimate 
Y[8] 
 
 
Y[2]  
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
See full description in Section 11.13. 
2. 
Study outcomes (i.e., response below 50 c/mL, virologic failure or reason for no data in the window) based on the 
snapshot algorithm will be summarised and listed. 
3. 
Baseline demography (age, gender, race, country, CDC), HIV-1 subtype, Baseline CD4+ and Baseline viral load, 
background ART (ABC+3TC vs not ABC+3TC). 
4. 
Outputs will be produced for TRD=F and ERD=F. 
5. 
Outputs will be produced for TRD=F only using the MITT-E-36 & MITT-E-48 populations 
6. 
The proportion of subjects with Confirmed Virologic Withdrawal Criteria will be summarised by visit, and also 
cumulatively by visit in terms of virologic non-response, virologic rebound and overall (see Appendix 6.) 
7. 
Repeat by Baseline Viral Load 
8. 
This summary will be produced for the week 24 study report 
9. 
Based on the MITT-E-36 and MITT-E-48 populations 
 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Immunologic 
CD4+ cell counts 
 
 
 
N 
 
 
Y 
 
 
 
Y 
Y 
 
 
Plasma HIV-1 RNA Over Time 
Observed 
 
 
 
N 
 
Y 
Yx
4[1]
[2] 
 
 
 
Y 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Include the interpretation of whether the virus is detected or not (‘Detected’ or ‘Not Detected’) by the assay. 
2. A Separate listing for Subjects with Virologic Failure (during randomised phase and separately during the 
continuation phase) or Last On-treatment VL >400 c/mL. Another listing of HIV-1 RNA and CD4 at baseline 
versus suspected and confirmed virologic failure. 
 
8.1.2. 
Planned Efficacy Statistical Analyses 
Statistical Analyses 
Endpoint(s) 


 
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Statistical Analyses 
• Proportion of subjects without virologic (ERDF) or virological and tolerability (TRDF) failure by 
analysis timepoint (Week 24/48) 
Model Specification/Analysis Methodology 
• Estimated using the Kaplan-Meier nonparametric method based on the time to Confirmed 
Virologic Withdrawal Criteria (CVWC) or treatment related/efficacy related discontinuation 
(i.e., drug-related AE, protocol defined safety stopping criteria, or lack of efficacy)  
• Subjects who have not met CVW criteria and are ongoing in the study, or who have 
discontinued for reasons other than those related to treatment, or switch from LPV/RTV to 
DTG, will be censored. 
• The estimate of the standard error used to derive confidence intervals for the difference in 
proportions between treatment groups will be based on Greenwood’s formula [Kalbfleisch, 
1980]. 
• Quartiles of time to viral failure (including median) will be summarised by treatment group.  
CIs will estimated using the Brookmeyer Crowley Method. 
• Cox proportional hazards model will also be used to estimate the hazard ratio (DTG vs. 
LPV/RTV) and 95% confidence interval.  
• The estimated proportion of subjects without confirmed virologic withdrawal criteria and not 
discontinued due to treatment related/efficacy related reasons at the time of analysis 
(Week 24/48) will be presented by treatment group, along with estimated difference in 
proportions between treatment groups and its associated two-sided 95% CI.  
o  
Model Results Presentation 
• Kaplan-Meier Plots for Time to Failure will be provided. The statistical analysis table will 
present: 
• Number and percentage of subjects with event or censored at week 24/36/48 
• Kaplan-Meier point estimate and 95% confidence intervals at week 24/36/48 
• Kaplan-Meier point estimate and 95% confidence interval of difference between groups at 
week 24/48 
Statistical Analyses 
Endpoint(s) 
• The time to viral suppression (i.e. first viral load value <50 copies/mL) 
Model Specification/Analysis Methodology 
• Culmulative incidence curves estimated using the Kaplan-Meier method 
o Subjects who withdraw for any reason or switch from LPV/RTV to DTG without 
having suppressed prior to the analysis will be censored 
o Quartiles of time to viral suppression (including median) will be summarised by 
treatment group.  CIs will estimated using the Brookmeyer Crowley Method. 
o Proportion of subjects with suppression at week 24/48 presented by treatment 
group.  
• The generalised Wilcoxon procedure will be used to estimate a p-value for detecting a 
difference in cumulative incidence curves between treatment groups. 
o Note: In general, the logrank test tends to be sensitive to distributional differences 
which are most evident late in time. In comparison, the generalised Wilcoxon test 
tends to be more powerful in detecting differences early in time (when the 
proportional hazard assumption are not met). 


 
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Statistical Analyses 
• Cox proportional hazards model will also be used to estimate the hazard ratio (DTG vs. 
LPV/RTV) and 95% confidence interval. 
• Kaplan-Meier Plots for time to viral suppression will be provided 
Model Results Presentation 
• Kaplan-Meier Plots for Time to Viral Suppression will be provided. 
• The statistical analysis table will present: 
o Number and percentage of subjects with event or censored at week 24/48 
o Quartiles of time to viral suppression (including median) and 95% confidence 
intervals  
o Proportion of subjects with suppression at week 24/48  
• Hazard ratio for viral suppression (DTG vs. LPV/RTV) and 95% confidence interval 
 
Exploratory Statistical Analyses 
The proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm will be estimated using the data collected at time of the Week 24 interim analysis. The 
purpose of this exploratory analysis is to explore the application of multiple imputation in predicting 
Week 48 response which may be useful for IDMC and futility analyses purposes in future.  
Subject data within the database at time of the Week 24 analysis should be considered into 3 
groups: 
[1] Subjects completed the study at Week 52 
[2] Subjects withdrawn from the study prior to the Week 24 data cut-off 
[3] Subjects ongoing within the study at time of the Week 24 data cut-off 
• Data for subjects in group 3 will be imputed using the methodology proposed below using all 
subject data from groups 1-3.  
Endpoint(s) 
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm – Projected Estimate  
Covariates 
• Baseline Plasma HIV-1 RNA ( vs. >100,000 c/mL) 
Baseline Number of Fully Active NRTIs in the Background Regimen (2 vs.<2) 
Model Specification/Analysis Methodology 
 
• Select Log(HIV-1 RNA) samples  
• Using Markov Chain Monte Carlo methods, simulate 100 datasets replacing BLQ with 
values with those from a Log(Uniform(0, BLQ) distribution. The BLQ value used for this 
step should be slightly below the actual BLQ cut-off so that response is correctly attributed 
when applying the snapshot algorithm later. 
• The statistical model used for the MI data generation will be the Markov Chain Monte Carlo 
(MCMC) method with for the data (covariates, randomised treatment group, and Log HIV-1 
RNA at Baseline, Week 4, Week 8, Week 16, Week 24, Week 36, and Week 48) to 
produce a monotone pattern first, and then the imputation will continue using the 
Regression with Predictive Mean Matching (REGPMM) method for the monotone pattern 
with the same set of covariates.   
o A seed of 200304 will be used in the SAS program.  
o One imputation is required for each of the monotone and mean matching steps 


 
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Statistical Analyses 
o For subjects that discontinued from the study prior to Week 24 data cut off, replace 
the imputed data with their original data. Data related to these subjects will be 
used only for the imputation of data for those that were ongoing at time of the 
Week 24 data cut off.  
o Week 52 HIV-1 RNA data for subjects that completed the study will not be 
included in the multiple imputation. Instead, the Week 52 data will be merged back 
onto the imputed datasets prior to the application of the snapshot algorithm.   
• Using Snapshot Algorithm, derive virologic response or failure at Week 48 using snapshot 
algorithm, as per Section 11.13, for each imputed dataset. 
• For each imputed dataset, the endpoint will be analysed using a stratified analysis with 
Cochran-Mantel-Haenszel (CMH) weights, adjusting for Baseline plasma HIV-1 RNA (  
vs. >100,000 c/mL) and number of fully active background NRTIs in the background 
regimen (<2 vs. 2) at Baseline. This will be the same model as used for the primary 
endpoint. 
• Wilson-Hilferty transformation will be applied to normalise the CMH statistic  
• PROC MIANALYZE in SAS will be used to combine the 1,000 estimated proportion of 
subjects with plasma HIV-1 RNA <50 c/mL and difference in proportions to produce one 
estimate with 95% CI and associated p-value for the adjusted difference between each 
treatment group at Week 48 
 
Model Results Presentation 
Adjusted CMH estimate of the difference in the proportion of responders between each treatment 
group (DTG – LPV/RTV) and corresponding 95% confidence interval 


 
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8.2. 
Safety Analyses 
8.2.1. 
Overview of Planned Analyses 
The safety analyses will be based on the Safety population, presented by treatment group 
with a total column and included in all reporting efforts unless otherwise specified. 
The observed case (OC) dataset will be used, which contains the data that is available at a 
particular timepoint, with no imputation for missing values, unless otherwise stated. All 
displays are for the randomised phase only, unless specified otherwise. This means that 
the analysis other than “by-visit” summaries will not be windowed at Week 24 (AEs, 
maximum post-baseline toxicities). In other words, all data collected up to the point of 
DBF will be included in summary statistics, which could be past week 24 for subjects 
enrolled early in the study. However, at the Week 48 analysis, summary statistics will 
include data up to Week 52 for both arms. 
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 18 : List of Data Displays. 
For the purposes of summarising AE data, unless stated otherwise, the summaries will 
include post-baseline data from the Randomised Phase of the study.  AEs are considered 
post-baseline if the onset date is on or after IP start date and before entering continuation 
phase. AE onset during the Continuation Phase will not be included in the Randomised 
Phase summaries unless it is specified in the title ie Randomised and Continuation Phase.  
Following the IDMC recommendation to switch subjects on the LPV/RTV treatment arm 
to a regimen with DTG as the third drug, in the Week 48 analysis, the summaries of AE 
and laboratory data will only include AEs/laboratory data prior to switch, and AEs/labs 
post switch will just be listed 
An issue was identified with the creatinine testing at the central laboratory. Sensitivity 
analyses will be conducted excluding any suspect creatinine samples from laboratory 
summaries including creatinine see Appendix 14. 


 
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Table 7 
Overview of Planned Safety Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Exposure 
Extent of Exposure 
 
 
 
Yx2[9] 
 
 
Y[10] 
 
 
 
 
 
 
 
Adverse Events [19] 
Grade 2 or greater 
Drug-Related 
Diarrhoea 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs by SOC [1]  
 
 
 
Y 
 
 
Y (x3) 
[11] 
 
 
 
 
 
 
 
All AEs by SOC by 
Toxicity Grade [12] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Common AEs by 
frequency[13]  
 
 
 
Y 
Y 
[15] 
 
 
 
 
 
 
 
 
 
Common grade 2-4 
AEs by frequency [13] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
All Grade 2-4 AEs by 
SOC 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
All Drug-Related AEs 
by SOC and toxicities 
[12]  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
All Drug-Related AEs 
by SOC[12] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Common Grade 2-4 
Drug-Related AEs by 
frequency [13] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
All Grade 2-4 Drug-
Related AEs by SOC 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Serious AEs 
 
 
 
Y[10] 
 
 
Y 
 
 
 
 
 
 
 
Reason for 
Considering as a 
Serious Adverse 
Event (FDA) 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Drug-Related Serious 
AEs 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Fatal AEs 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Non-Fatal Serious 
AEs 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
AEs leading to 
withdrawal 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Common non-
serious AEs 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 


 
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Endpoint 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
(FDAAA) 
Number of 
occurrences on Non-
serious AEs by SOC 
(EudraCT) 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Number of 
occurrences of SAEs, 
Drug-related SAEs, 
Fatal AEs, and Drug-
related SAEs 
(EudraCT) 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Non-serious AEs and 
SAE of Mexican 
Subjects[8] 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
SAEs of non-Mexican 
subjects (include 
drug-related as a 
column) [8] 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
CV events 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
PSRAE 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Summary of 
Cumulative Adverse 
Events 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Laboratory Values 
Fasting LDL 
Cholesterol 
 
 
 
 
 
 
 
Yx3 Y 
 
 
 
 
 
Fasting TC/HDL ratio 
 
 
 
 
 
 
 
Yx3 Y 
 
 
 
 
 
Fasting LDL 
Cholesterol 
Treatment 
Emergent 
Abnormalities of 
Grade 2 or 
Greater[7] 
 
 
 
 
 
 
 
Y[7] 
 
 
 
 
 
 
Clinical Chemistry  
 
 
 
 
 
 
Y[3] 
 
 
 
Yx3[2,3] 
 
 
 
Hematology  
 
 
 
 
 
 
Yx2[4] 
 
 
 
Yx2[2] 
 
 
 
Urinalysis (Dipstick) 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Liver chemistries[7][6] 
 
 
 
 
 
 
 
 
 
 
 
Y 
Y 
 
NCEP shifts in lipids 
[21][7] 
 
 
 
 
 
 
 
 
 
 
Yx4 
Yx4 
 
 
ECGs[5] 


 
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Endpoint 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
ECG Findings 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Vital Signs 
Vitals Values 
 
 
 
 
 
 
Y 
 
 
 
Y 
 
 
 
Other 
Abacavir HSR 
 
 
 
 
 
 
Y [16] 
 
 
 
 
 
 
 
Liver Assessment 
 
 
 
 
 
 
Y [17] 
 
 
 
 
 
 
 
Hepatobiliary 
Abnormality criteria – 
post baseline 
emergent 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Columbia suicidality 
 
 
 
Y 
 
 
Y [18] 
 
 
 
 
 
 
 
Subjects who became 
Pregnant 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Patient profiles 
 
 
 
 
 
 
Yx2 
[20] 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Listings will include subject’s numbers for individual AE’s & AE system organ classes, preferred terms and 
verbatim text. 
2. 
Chemistry & haematology summaries will include both changes from baseline & maximum post baseline emergent 
toxicities. Change from Baseline chemistry summaries will be repeated for Lipids and Glucose in Conventional 
Units. 
3. 
Clinical chemistry summaries will be re-run excluding subjects with suspect creatinine samples. 
4. 
Listing of Chemistry, haematology data for subjects with abnormalities of PCI will be listed.  
5. 
Only measured as part of CV assessment 
6. 
Scatter Plot of Maximum vs. Baseline for ALT, Scatter Plot of Maximum ALT  vs. Maximum Total Bilirubin 
7. 
Maximum Post-baseline 
8. 
Includes Continuation Phase and is only for the End of Study reporting effort. 
9. 
One for Randomisation Phase and one including the Continuation Phase. 
10. Repeated for Mexican subjects. Outputs for Mexican subjects include Continuation Phase and are only needed for 
the end of study reporting effort. 
11. One listing of all AEs including verbatim text and preferred term, one showing the relationship between verbatim 
text, preferred term and SOC and another giving subject numbers for individual all treatment emergent AEs. 
12. For AEs reported more than once by a subject, the most severe intensity will be included. 
13. Common AEs are those with >5% incidence in either treatment group summarised by frequency. 
14. Common AE by frequency graph description 
15. Plots of incidence rates and relative risk for DTG vs. LPV/RTV. 
16.  Separate listings for exposure to abacavir, history of drug allergies, family conditions, skin rash, symptoms, vital 
signs, individual symptoms and diagnostic category assignment. 
17.  Separate listings for time of event from trt, RUCAM score, biopsy, imaging, past/ current conditions & FU 
18. Listing but classed as a Table. Includes Baseline and lists all visits for a subject who reports any ideation or 
behaviour at any visit.. 
19. Adverse events will be coded using the MedDRA coding dictionary to give a preferred term and a system organ 
class. Summaries include only Post-baseline AEs with onset date up to cut-off date for reporting effort, listings 


 
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include all AEs including those with onset pre- or post-treatment. 
20. Patient profiles for subjects meeting protocol defined liver stopping criteria and for patients with virological failures. 
Patient profiles can also be provided for any other subjects, as necessary for medical review. 
21. One output will be created for each lipid parameter. Bar chart for LDL, HDL, TC, Trig and HDL/TC ratio 
8.2.2. 
Planned Safety Statistical Analyses 
Statistical Analyses 
Endpoints 
• Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48 
• Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48 
Lipids Last Observation Carried Forward (LOCF) Dataset 
• See Appendix 7 
Covariates 
• Baseline Plasma HIV-1 RNA ( vs. >100,000 c/mL) 
• Baseline Number of Fully Active NRTIs in the Background Regimen (2 vs.<2) 
• Age (<35, 35-<50, ≥50)  
Data Handling 
• If a subject is on lipid-lowering therapy from Baseline, they will be excluded from the analysis.  
• If a subject initiates lipid-lowering therapy during the study, all visits after that date will be set to 
missing.  
• All other data remains as is (observed or missing). 
• A multiple imputation technique will be used to deal with the missing data. 
 
Model Specification 
• Multiple imputations will be drawn from a multivariate normal model for the data (Fasted LDL, 
cholesterol and fasted TC/HDL measurements at Baseline, Week 16, Week 24 and Week 48 
(including covariates) with a Markov Chain Monte Carlo (MCMC) approach used to estimate 
posterior distributions.  A seed of 200304 will be used in the SAS program.  Where a subject 
has a monotone or non-monotone pattern of missingness, all of their missing observations can 
be imputed under this approach. The absolute value will be imputed before the change value is 
calculatedImputations will be drawn separately for subsets of subjects according to their 
treatment group, i.e., based on means and variance-covariances from the same treatment 
group (Missing At Random (MAR) approach) conditioning on observed covariates listed above.  
This will be known as the MAR method.  
• The imputations will be carried out 1,000 times. An ANOVA will be performed on each datasets 
produced adjusting for treatment, baseline value and the categorical covariates, regardless of 
their significance. PROC MIANALYZE in SAS will be used to combine the 1,000 estimated 
means and difference to produce one estimated mean with 95% CI and associated p-value for 
the adjusted mean difference between each treatment group at Week 24/48. 
• Interactions between treatment and each of the covariates will not be assessed. 
 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted means and corresponding standard error of means (SEs) will be presented for each 
treatment, together with estimated treatment difference (DTG – LPV/RTV) and corresponding 


 
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Statistical Analyses 
95% confidence interval and p-value.  
• Plots of LS means and 95% confidence intervals from the model will be generated for each 
treatment by time. 
Sensitivity Analyses 
Sensitivity analyses will be performed as follows: 
• using the standard Observed Case (OC) dataset, with no adjustment or imputation for 
withdrawing, initiating lipid-lowering agents or other missing data. An analysis of covariance 
(ANCOVA) model will be used with covariates (listed above), and baseline value as a 
covariate. 
• using the Lipid LOCF dataset, but also carrying forward the last observation to any missing 
visits, an ANCOVA model will be used with treatment, covariates (listed above), and baseline 
value as a covariate. 
   
 
 
Statistical Analyses 
Endpoints 
• The incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 24 and 48 
• The incidence of maximum post-Baseline emergent Grade 2 or greater drug-related diarrhoea 
by Weeks 24 and 48 
Dataset 
• The observed case (OC) dataset uses only the data that is available at a particular timepoint, 
with no imputation for missing values.  
Model Specification/Analysis Methodology 
• Endpoints will be statistically analysed for the comparison between DTG and LPV/RTV by 
Fisher’s exact test using the Safety Population  
Model Results Presentation 
• Incidence for each treatment group and a p-value for the difference in incidence between 
treatment groups. 


 
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9. 
OTHER STATISTICAL ANALYSES 
9.1. 
Health Outcomes Analyses 
9.1.1. 
Overview of Planned Analyses 
The Health Outcomes (HO) analyses will be based on the Intent-to-treat Exposed 
population, presented by treatment group with a total column and included in all 
reporting efforts unless otherwise specified. 
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 18 : List of Data Displays. 
Following the IDMC recommendation to switch subjects on the LPV/RTV treatment arm 
to a regimen with DTG as the third drug, the Week 48 summaries and analyses of HO 
data will only include HO data prior to switch, and HO post switch will just be listed.  
 
Table 8 
Overview of Planned Health Outcome Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats Analysis Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
HIVTSQs 
Individual Item 
Scores 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Treatment 
Satisfaction Score  
 
 
 
Y 
 
 
Y 
Yx2 
 
 
Y 
 
 
 
HIVTSQc 
Individual Item 
Scores (Change) 
Y[1] 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Treatment 
Satisfaction 
(Change) 
Y 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
MMAS-8 
Total Score 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Adherence Level 
Y 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Gastrointestinal Symptom Rating Scale (GSRS) 
Individual Item 
Scores 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Diarrhoea Syndrome 
Score 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 
Indigestion 
Syndrome Score 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 
Constipation Score 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 
Abdominal Score 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 
Reflux Score 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 


 
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Endpoint 
Absolute 
Change from Baseline 
Stats Analysis Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
HIVTSQ questionnaire included in Section 11.6.6 
Individual = Represents FL related to any displays of individual subject observed raw data 
9.1.2. 
Planned Health Outcomes Statistical Analyses 
Statistical Analyses 
HIVTSQs 
• 
Change from Baseline at Week 4, Week 24, and Week 48: 
o Treatment Satisfaction Score 
Model Specification 
• The MMRM will adjust for visit, Baseline Plasma HIV-1 RNA ( vs. >100,000 c/mL) and 
Baseline Number of Fully Active NRTIs in the Background Regimen (2 vs.<2). 
• The model will make no further assumptions about the correlations between a subject’s score 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (ie. a treatment*visit interaction will be included in the model), and separates estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline score can vary between visits (ie. baseline score*visit interactions will be 
included in the model). 
• Interactions between treatment and each of the covariates will not be assessed unless the 
exploratory subgroup analyses described in Section 7.1.2 on the primary endpoint highlights 
significant interactions. In this situation, the interaction(s) of interest will be assessed and, if 
necessary, results will be reported in the clinical study report. Interactions between treatment 
and the baseline score will be investigated but not included in the model.  If interactions are 
found to be significant, results might have to be presented separately by subgroup. 
Dataset 
• The observed case (OC) dataset uses only the data that is available at a particular timepoint, 
with no imputation for missing values in addition to the ones described in Section 11.6.7.  
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• The summaries will include the adjusted mean change from baseline and confidence interval 
for each treatment group across visits.   
• The interaction between treatment and the baseline score will be included in a footnote. 
 
Statistical Analyses 
HIVTSQc 
• 
Treatment Satisfaction Score (Change) at Week 48 
Model Specification 


 
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Statistical Analyses 
•   
• An analysis of covariance (ANCOVA) model will be used with covariates: treatment, Baseline 
Plasma HIV-1 RNA ( vs. >100,000 c/mL) and Baseline Number of Fully Active NRTIs in the 
Background Regimen (2 vs.<2). 
Dataset 
• The observed case (OC) dataset uses only the data that is available at a particular timepoint, 
with no imputation for missing values in addition to the ones described in Section 11.6.7. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted means and corresponding standard error of means (SEs) will be presented for each 
treatment, together with estimated treatment difference (DTG – LPV/RTV) and corresponding 
95% confidence interval and p-value.  
 
Statistical Analyses 
MMAS-8 
• Adherence level 
Model Specification/Analysis Methodology 
• Endpoints will be statistically analyzed for the comparison between DTG and LPV/RTV by 
Fisher’s exact test using the ITT(e) Population  
Dataset 
• The observed case (OC) dataset uses only the data that is available at a particular timepoint, 
with no imputation for missing values in addition to the ones described in Section 11.6.7. 
Model Results Presentation 
• Incidence for each treatment group and a p-value for the difference in incidence between 
treatment groups. 
 
Statistical Analyses 
Gastrointestinal Symptom Rating Scale (GSRS) 
• Change from Baseline at Week 4, Week 24, and Week 48: 
o Diarrhoea Syndrome Score 
o Indigestion Syndrome Score 
o Constipation Score 
o Abdominal Score 
o Reflux Score 
Model Specification 
•  
• A Wilcoxon rank sum test will be used to compare the change in gastrointestinal symptom 
rating score sub-items for subjects treated with DTG and LPV/RTV at each visit 


 
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Statistical Analyses 
Dataset 
• The observed case (OC) dataset uses only the data that is available at a particular timepoint, 
with no imputation for missing values in addition to the ones described in Section 11.6.7.  
Model Checking & Diagnostics 
•  
Model Results Presentation 
•  
9.2. 
Virology Analyses 
9.2.1. 
Overview of Planned Analyses 
The virology analyses will be based on the Viral Genotypic or Viral Phenotypic 
population, unless otherwise specified. 
Phenotype data may not be available for all subjects in China at the time of the Week 24 
analyses. The China subjects may also have genotype data from Q2 and/or Monogram.  
In the event that subjects have both Q2 and Monogram data at a timepoint, the 
Monogram data will be used.  Footnotes will be included in summaries indicating which 
subjects have Q2 data only or Q2 and Monogram. 
Table 9 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15 List of Data Displays. 
Table 9 
Overview of Planned Virology Analyses 
Endpoint 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, LPV/RTV and other 
on-study ART in subjects meeting confirmed virologic withdrawal criteria 
Genotype 
Summary of 
Genotypes Available 
 
 
 
Y 
 
 
 
Treatment Emergent 
Major Mutations of 
NRTI, NNRTI and PI 
Classes 
 
 
 
Y 
 
 
 
Pre-specified 
Treatment Emergent 
IN Substitutions at 
Time of Confirmed 
Virologic Withdrawal 
 
 
 
Y 
 
 
 


 
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Endpoint 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Changes in Genotypic 
Susceptibility (GSS) 
to Background ART 
Therapy at Time of 
Confirmed Virologic 
Withdrawal 
 
 
 
Y 
 
 
 
All Genotypic Data 
 
 
 
 
 
 
Y 
Phenotype 
Summary of 
Phenotypes Available 
 
 
 
Y 
 
 
 
Fold Change to DTG 
and LPV/RTV at 
Baseline and Time of 
Confirmed Virologic 
Withdrawal 
 
 
 
Y 
 
 
 
Changes in 
Phenotypic 
Resistance (PSSf) to 
Background ART 
Regimen at Time of 
Confirmed Virologic 
Withdrawal 
 
 
 
Y 
 
 
 
All Phenotypic Data 
 
 
 
 
 
 
Yx2[2] 
Net Assessment for Overall Susceptibility Score 
Overall Susceptibility 
Score (OSS) 
 
 
 
Y[3] 
 
 
 
Other 
Key Virologic Data  
 
 
 
 
 
 
Yx4[1] 
Virology Data at 
Confirmed Virologic 
Withdrawal 
 
 
 
Y 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
1. 
A Separate listing for Subjects with Virologic Failure (during randomisation phase and separately during the 
continuation phase) or Last On-treatment VL >400 c/mL.  
2. 
Include a separate listing for screening results from Quest. 
3. 
Produce for CVW resistance populations. 
4. 
This is a listing of subject data to be included as a Table. 
 


 
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10. 
REFERENCES 
Fleiss J.L. Statistical Methods for Rates and Proportions. 2nd ed. New York:John Wiley; 
1981.  
GlaxoSmithKline Document No.: 2013N172672_01A Phase 3b, randomised, open-label 
study of the antiviral activity and safety of dolutegravir compared to lopinavir/ritonavir 
both administered with dual nucleoside reverse transcriptase inhibitor therapy in HIV-1 
infected adult subjects with treatment failure on first line therapy Effective 30-Apr-14 
Grundy S.M., et al. Executive summary of the third report of the National Cholesterol 
Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of 
High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285 
(19):2486-2497.  
HIVTSQ user guidelines 
Kalbfleisch J.D., Prentice R.L. The Statistical Analysis of Failure Time Data. 1st ed. New 
York:John Wiley & Sons; 1980.  
Liu TF, Shafer RW. Web Resources for HIV type 1 Genotypic-Resistance Test 
Interpretation. Clin Infect Dis. 2006;42 (11):1608-1618. 
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, 
Biometrics, 2000;56:309-315. 
Ralph B. D’Agostino, Ramachandran S. Vasan, Michael J. Pencina, Philip A. Wolf, Mark 
Cobain, Joseph M. Massaro, William B. Kannel. 2008. General Cardiovascular Risk 
Profile for Use in Primary Care (The Framingham Heart Study). Circulation 2008; 117: 
743-753. 
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989;42:311-323.  
Wensing AM, Calvez V, Günthard HF et al. 2014 Update of Drug Resistance Mutations 
in HIV-1. Topics in Antiviral Medicine 2014; 22(3): 642-650. 
 
 


 
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11. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 11.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 11.2 
Appendix 2: Time and Events 
Section 11.3 
Appendix 3: Assessment Windows 
Section 11.4 
Appendix 4: Treatment States & Phases 
Section 11.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 11.6 
Appendix 6: Derived and Transformed Data 
• General, Study Population & Safety 
• Efficacy 
• Virology 
Section 11.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 11.8 
Appendix 8: Values of Potential Clinical Importance 
Section 11.9 
Appendix 9: Multicentre Studies 
Section 11.10 
Appendix 10: Examination of Covariates and Subgroups 
Section 11.11 
Appendix 11: Handling of Multiple Comparisons & Multiplicity 
Section 11.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Other RAP Appendices 
Section 11.13 
Appendix 13: Snapshot 
Section 11.14 
Appendix 14: Q2 Creatinine Assay Accuracy Issue 
Section 11.15 
Appendix 15  Abbreviations & Trade Marks 
Section 11.16 
Appendix 16: Example SAS code for Additional Estimand 2  
Section 11.17 
Appendix 17: End of Study Analysis 
Section 11.18 
Appendix 18 : List of Data Displays 
 
 


 
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11.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
11.1.1. 
Exclusions from Per Protocol Population 
Protocol deviations leading to exclusion from PP population are those deviations which  
• may directly impact the efficacy endpoint of HIV-1 RNA; or 
• lead to permanent discontinuation of IP/withdrawal and hence indirectly impact the 
efficacy endpoint by causing data to be missing. 
The following criteria define the protocol deviations which, if they occur prior to an 
analysis timepoint of interest, will lead to exclusion of a subject from the Per-Protocol 
population for that analysis. Potential protocol deviations leading to exclusion from PP 
population will be reviewed by the study team to confirm that they meet these criteria.  
This review will occur before the clinical database has been frozen for analysis.  
A subject meeting any of the following criteria prior to the timepoint of interest (eg week 
24 or 48) will be excluded from the Per Protocol population for the week 24 interim or 
week 48 respectively: 
Number 
Exclusion Description 
01 
Subject deviates from any inclusion or exclusion criteria, as recorded in the 
eCRF 
02 
Prohibited medications. 
 
There are several sub-categories for prohibited medication use: 
 
a) Subject receiving prohibited non-ART medications (See 
protocol) or receiving non-ART medication that would 
potentially impact exposure or response to therapy.  
Duration  of >2 consecutive weeks will be considered 
prohibited.  
 
• HIV immunotherapeutic vaccines 
• Other experimental agents 
• Antiretroviral drugs not otherwise specified in the protocol 
• Cytotoxic chemotherapy 
• Radiation therapy 
• Immunomodulators: 
• Calcineurin Inhibitors 
• Cyclosporine A, Pimecrolimus, Tacrolimus 
• Fluorouracil (including topical) 
• Interferon (rectal and transdermal routes are permitted) 
• mTor Kinase Inhibitors 


 
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Number 
Exclusion Description 
• Everolimus, Sirolimus 
• Methotrexate 
• Purine Analogues 
• Azathioprine, 6-Mercaptopurine 
• Targeted Immune Modulators (Biological Response Modifiers) 
• Abatacept, Adalimumab, Alefacept, Anakinra, Certolizumab, 
Efalizumab, Etanercept, Golimumab, Infliximab, Natalizumab, 
Rituximab, Tocilizumab, Ustekinumab 
• HCV therapy 
sofosbuvir (Sovaldi, Virunon),ledipasvir/sofosbuvir (Harvoni), 
paritaprevir/ritonavir/ombitasvir + dasabuvir (Viekira 
Pak),paritaprevir/ritonavir/ombitasvir (Viekirax), dasabuvir (Exviera), 
simeprevir (Olysio), telaprevir (Incivek, Incivo),  boceprevir (Victrelis), 
peginterferon alfa (e.g. Pegasys), interferon alfa (e.g. Intron A, 
Roferon-A), ribavirin (Copegus, Rebetol) 
 
b) Chronic use (>30 days) of systemic glucocorticoids  
• oral & iv routes are not permitted 
• topical & nasal routes are permitted 
 
c) Treatment dependent prohibited medications. 
Any duration is considered prohibited..   
 
For subjects randomised to DTG: 
• Carbamazepine 
• Dofetilide  
• Oxcarbamazepine 
• Phenobarbital 
• Phenytoin 
• Pilsicainide 
• Rifampicin 
•  rifapentine  
• St. John’s wort (Hypericum perforatum 
 
For subjects randomised to LPV/RTV: 
• Alfuzosin 
• Amiodarone 
• Antihistamines (astemizole, terfenadine) 
• Cisapride 
• Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, 
methylergonovine) 
• Fusidic acid (in dermatological infections) 
• HMG Co-A reductase inhibitors (specifically lovastatin, 
simvastatin) 


 
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Number 
Exclusion Description 
• Pimozide 
• Rifampicin 
• Sildenafil (when used for the treatment of pulmonary arterial 
hypertension) 
• Vardenafil 
• Avanafil 
• Midazolam (oral) 
• Triazolam 
• St John’s wort (Hypericum perforatum) 
 
As these deviations are treatment dependent it will not be possible to 
identify if they are deviations until treatment details are known post 
unblinding. 
 
d) Prohibited ART Medication Use 
Receiving ART medication other than that prescribed/allowed by the 
study for any duration 
 
03 
Non-permitted switch of background ART, specifically: On-treatment changes of 
background ART post the Week 4 visit window that  
• 
Are made for reasons other than toxicity or tolerability management, or  
• 
Introduce new agents which are not within class substitutions, or 
Result in a background regimen that consists of more than 2 NRTIs (or 3 NRTIs in 
the case of subjects receiving 3TC/FTC for treatment of hepatitis B. 
 
If a subject does not take an NRTI or a  fully active NRTI this will be considered a 
protocol deviation and lead to exclusion from the PP Population.  This will be 
considered as a non-permitted switch of background ART. 
  
04 
Subject took/received incorrect IP, i.e., other than the one to which they were 
randomised for greater than 10% of the total time On-treatment. It will not be 
possible to identify whether subjects received a different treatment to the one 
they were randomised to until post unblinding. 
 
05 
Interruption of IP for greater than 10% of the total time On-treatment, for 
reasons other than treatment-related adverse events/laboratory abnormalities, 
based on eCRF IP exposure forms.  This is mentioned in the PDMP but it is 
not listed as a PD category. 
 
06 
Permanent discontinuation of IP/withdrawal due to a reason of “Protocol 
Deviation” (as recorded in the eCRF).  This is stated in the PDMP but it is not 
listed as a PD category as the PD will be classified under one of the other PD 
categories.  
 
 


 
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11.2. 
Appendix 2: Time & Events 
11.2.1. 
Protocol Defined Time & Events 
 
 


 
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11.3. 
Appendix 3: Assessment Windows 
Laboratory data, vital signs, health outcomes assessments, and genotypic and phenotypic 
data will be assigned to assessment windows according to actual dates rather than the 
nominal visit labels as recorded on the eCRF or in the laboratory database. The CVW 
algorithm will be derived using nominal CRF visit rather than using the assessment 
window defined below. 
A window around a target Study Day will typically include all days from the midpoints 
between it and the target Study Days of the previous and the proceeding visits.  In 
general, the nominal target study day for week w is (7*w)+1. 
Based on the Study Day (see Section 11.6.1), assessments are assigned as shown in 
Section 11.3.1. 
11.3.1. 
Definitions of Assessment Windows for Analyses 
Analysis Set / 
Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
Snapshot 
(MSDF) 
endpoints 
-28 
-4 
-4 
Screen 
 
 
1 
-3  
1 
Day 1 
 
 
29 
2 
42 
Week 4 
 
 
57 
43 
84 
Week 8 
 
 
113 
85 
126 
Week 16 
 
 
169 
127 
210 
Week 24 
 
 
253 
211 
294 
Week 36 
 
 
337 
295 
378 
Week 48 
 
 
421 
379 
462 
Week 60 
 
 
7*w + 1 
(7*w – 41) 
 
(7*w + 42) 
Week w 
w = 72, 84, 
96, 
 
 
Study Day of last dose 
+ 28 
> (Study 
Day of last 
dose + 1) 
> (Study 
Day of last 
dose + 1) 
Follow-up 
 
 
 
 
 
 
Safety/Virology 
/Health 
Outcome  
 
-28 
-4 
-4 
Screen 
 
 
1 
-3  
1 
Day 1 
 
 
29 
2 
42 
Week 4 
 
 
57 
43 
84 
Week 8 
 
 
113 
85 
126 
Week 16 
 
 
169 
127 
210 
Week 24 
 
 
253 
211 
294 
Week 36 


 
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Analysis Set / 
Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
 
 
337 
295 
350 
Week 48 
 
 
365 
351 
392 
Week 52 
 
 
421 
393 
462 
Week 60 
 
 
7*w + 1 
(7*w – 41) 
 
(7*w + 42) 
Week w 
w = 72, 84, 
96, 
 
 
Study Day of last dose 
+ 28 
> (Study 
Day of last 
dose + 1) 
> (Study 
Day of last 
dose + 1) 
Follow-up 
NOTES : 
• 
For key timepoints at Week 24 and Week 48, the efficacy windows have been defined to cover  6 weeks, 
regardless of the midpoint between adjacent target Study Days.  The windows for the adjacent periods are 
adjusted accordingly. 
• 
For parameters that are not scheduled to be assessed at particular visits, the all-inclusive windows defined 
above will still be used; however, data summaries will only report scheduled visits. Assessments at 
unscheduled visits will be included for ‘any time On-treatment’ time points and in data listings, as well any 
algorithms that make use of additional data (e.g. snapshot). 
• 
See Section 11.6.1 for how to handle multiple assessments within a time window. 
 


 
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11.4. 
Appendix 4: Treatment States and Phases 
11.4.1. 
Study Phases 
All displays are for the randomised phase only, unless specified otherwise. This means 
that the analysis other than “by-visit” summaries will not be windowed at Week 24 (AEs, 
maximum post-baseline toxicities). In other words, all data collected up to the point of 
DBF will be included in summary statistics, which could be past week 24 for subjects 
enrolled early in the study. However, at the Week 48 analysis, summary statistics for the 
randomised phase will only include data up to Week 52 for both arms. 
For subjects entering the continuation phase, which phase an assessment or an event 
occurred in will be determined by comparing the event date with the week 52 visit date.  
The study phases are defined as follows: 
 
Phase 
Start 
End  
Randomised Phase 
IP start date 
Week 52 DOV, IP end date or 
Withdrawal date if on or before Week 
52 DOV 
Continuation Phase Week 52 DOV 
IP end date or Withdrawal date if post 
Week 52 DOV 
 
11.4.2. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment. 
11.4.2.1. 
Treatment States for HIV-1 RNA Data, Laboratory Data, HIV Associated 
Conditions, Vital Signs, , Health Outcomes assessments, and 
Genotypic and Phenotypic Data 
Treatment State 
Definition 
Pre-Treatment 
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date +1 
Post-Treatment 
Date > Study Treatment Stop Date +1 
NOTES:  
• 
If the study treatment stop date is missing then the assessment will be considered to be On-Treatment 
 


 
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11.4.2.2. 
Treatment States for AE Data 
For adverse events, a partial AE start date uses imputation as described in Section 11.7. 
 
Treatment State 
Definition 
Pre-Treatment 
AE Start Date < Study Treatment Start Date 
On-Treatment 
If AE onset date is on or after treatment start date & on or before treatment stop date. 
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date  
Post-Treatment 
If AE onset date is after the treatment stop date. 
AE Start Date > Study Treatment Stop Date  
Onset Time  
Since 1st Dose 
(Days) 
If Treatment Start Date ˃  AE Onset Date = AE Onset Date – Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date – Treatment Start Date +1 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing]. 
NOTES:  
• 
In the case of a completely missing start date, the event will be considered to have started On-treatment unless 
an end date for the AE is provided which is before start of investigational product; in such a case the AE is 
assigned as Pre-treatment. 
• 
If the IP Stop Date is missing, then any event with a start date on or after IP Start Date will be considered to be 
On-treatment. If the start date of the AE is after IP Stop Date but has been recorded as potentially related to IP, 
then it will be classified as On-treatment. 
11.4.2.3. 
Treatment States for Prior/Concomitant/Post-Therapy Medications Data 
• 
Prior medications are those taken (i.e., started) before the start date of 
investigational product.  
• 
Concomitant medications are those taken (i.e., started or continued) at any time 
between the start date and stop date of IP, inclusive. Prior medications that were 
continued during this period are also considered as concomitant medications.  
• 
Post-treatment medications are those started after the stop date of IP. 
Concomitant medications that were continued during this period are also 
considered as post-treatment medications. 
It will be assumed that medication has been taken on the date in which it is reported as 
started or stopped.  Also, for any medication starting on the same date as IP, it will be 
assumed that the medication was taken after the subject started taking IP. 
ART medications will also be classified as prior, concomitant and/or post-treatment 
according with the following modifications: 
• ART starting on study treatment stop date will be considered as only post-
treatment and not concomitant.  It is expected that after discontinuation of study 
treatment, a subject may immediately begin taking another ART.  (Note: this is 
different to concomitant medications which are considered concomitant and post-
treatment if they start on the IP stop date). 
• ART stopping on study treatment start date will only be considered as prior and 
not concomitant. (Note: this is different to concomitant medications which are 


 
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considered concomitant and post-treatment if they start on the IP stop date).Any 
ART entered on the Prior ART eCRF with partial end date will be assumed to 
have finished before Screening. 
Table 10 
Concomitant, and Post-treatment Classification of Medications 
 
Pre-
treatment 
On-treatment 
Post-treatment 
Prior 
Conco-
mitant 
Post 
(a) 
x⎯⎯⎯x 
IP Start Date 
 
IP Stop Date 
IP Stop Date+1 
 
Y 
N 
N 
(b) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯⎯x 
 
N 
Y 
N 
(e) 
 
x⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯⎯x 
N 
N 
Y 
(g) 
?⎯⎯⎯x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯⎯ 
⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
Y* 
Y* 
Y 
 
 
 
 
 
 
 
(j) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯ 
⎯⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯⎯⎯ 
⎯⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯⎯? 
N 
N 
Y 
(m) 
?⎯⎯⎯⎯ 
 
⎯⎯⎯⎯ 
 
 
⎯⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
 
 
 
 
 
 
 
 
 
 
(n) 
x⎯⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯⎯⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ 
⎯⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ 
⎯⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be assumed 
that the medication was ongoing from the Pre-treatment phase 
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then usage will be 
assumed to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from the Pre-
treatment phase to the Post-treatment phase 


 
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11.4.3. 
Post-treatment Assessments and Phases 
On-treatment and Post-treatment assessments and events will be classified as occurring 
during the Randomised Phase or the Continuation Phase of the study as follows: 
• 
If a subject did not enter the Continuation Phase, then any Post-treatment data will be 
assigned to the Randomised Phase.  
• 
For subjects who did enter the Continuation Phase, any Post-treatment data will be 
assigned to the Continuation Phase. 


 
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11.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
11.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Dolutegravir 50mg once daily  
DTG 
1 
B 
Lopinavir/ritonavir 800mg/200mg 
once daily or 400mg/100mg twice 
daily 
LPV/RTV 
2 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
11.5.2. 
Baseline Definition & Derivations 
11.5.2.1. 
Baseline Definitions 
For all endpoints (unless stated otherwise) the baseline value will be the latest pre-dose 
assessment. This is generally expected to be from the Day 1 visit, although such values 
may be missing or unscheduled assessments may be performed before treatment start. 
In the scenario where the treatment start date is more than 2 weeks after randomisation 
date, the randomisation date will be used as baseline for change from baseline. Therefore, 
for example, the week 12 visit data would be included in the week 12 visit summary 
rather than the week 8 visit summary.  All analyses will use this rule, except for 
resistance analyses; as the resistance test at or just before treatment start is more 
representative of a patient “baseline” rather than the randomisation date, since patients 
would have stayed on a failing regiment for longer than they should have. 
Example: 
A subject was randomised on 26Feb2016 but did not start IP until 18Mar2016.  Baseline 
will be 26Feb2016 for everything apart from resistance analyses where baseline will be 
18Mar2016. 
11.5.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline] 
Maximum Change from Baseline 
= Calculate the change from baseline at each given timepoint  
   and determine the maximum change 
 


 
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NOTES : 
• 
Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing. 
 
11.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software and TSCG will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Area 
: \ARPROD\GSK1349572\200304 
QC Spreadsheet 
: \ARPROD\GSK1349572\200304\(Week24, Week48 or Final)\Documents 
Analysis Datasets  
• Analysis datasets will be created according to according to CDISC standards (SDTM IG 
Version 3.1.3 & AdaM IG Version 1.0. 
• For creation of AdaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• RTF files will be generated for every reporting effort. 
 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
Formats 
• All data will be reported according to the actual treatment the subject received unless 
otherwise stated. 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Actual time relative to dosing will be used in figures, summaries, statistical analyses and 


 
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Reporting Standards 
calculation of any derived parameters, unless otherwise stated. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses. 
Unscheduled Visits 
• Unscheduled visits will be assigned to a study visit using the all-inclusive windows defined in 
Section 11.3.  
• However, data summaries will only report visits that are planned assessment time points for 
each parameter (according to the T&E table). 
• Assessments at unscheduled visits will be included for ‘any time On-treatment’ time points and 
in data listings, as well any algorithms that make use of additional data (e.g., Snapshot). 
Invalid Laboratory Assessments 
• Certain laboratory endpoints are required to be collected in a fasting state, i.e., glucose and 
lipids (triglycerides, total cholesterol, HDL, LDL). If these endpoints are collected in a non-
fasting state, then the results will be excluded from summaries; such results will be included in 
data listings with the fasting status noted. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
 


 
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11.6. 
Appendix 6: Derived and Transformed Data 
11.6.1. 
Week 24 cut off date 
For the week 24 interim it is necessary to define a cut-off for the purposes of defining 
prohibited medications and also for the calculation of total time on treatment during the  
Week 24 time period. 
To be considered prohibited the medication has to be taken before the date of Week 24 
viral load.  If the date of the Week 24 viral load is before the prohibited medication was 
taken then this does not impact the snapshot algorithm.   If the Week 24 viral load date is 
missing then the cut off date is defined as follows: 
• For subjects who have a Week 24 visit: 
use Week 24 date from Visit dataset (SV). 
• For subjects who have withdrawn (or last IP end date) before Week 24:visit 
use the minimum of : withdrawal date, disposition date, last visit date, last drug  
exposure date (while taking into account study drug interruptions) and last 
laboratory date. 
 
• For subjects who have not withdrawn but no IP stop date or week24 visit date yet: 
Cut-off= IP start date + week24studyday - 1   
where week24studyday could be 169 (the target date of wk24 window) or 210 
  
(upper bound of wk24 window). 
 
The last exposure data should use both EXSTDTC and EXENDTC in case the IP 
 was interrupted and re-started. 
 
This cut-off date also applies for the calculation of total on treatment during Week 
 24. 
 
A similar approach will be used for the Week 48 cut-off. 
11.6.2. 
General 
Multiple Measurements at One Time Point 
• If after window assignment (see Section 11.3), there are multiple valid assessments of a 
parameter within the same window, then the following hierarchy will be used to determine the 
value to be used for summary statistics of observed values: 
• the assessment closest to the window target Study Day; 
• if there are multiple assessments equidistant from the target Study Day, then the 
mean of these values will be used. For HIV-1 RNA, the geometric mean of the 
number of copies will be used as opposed to the arithmetic mean 
• Assessments not chosen for use in summary statistics by this algorithm will still appear in the 
associated listings. Also, such valid assessments will be used when determining values of 


 
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Multiple Measurements at One Time Point 
potential clinical concern for the ‘any time On-treatment’ time point, and for any algorithm that 
has specific rules for which observation to use (e.g., MSDF or LOCF). 
• In the event of laboratory re-tests being performed the last re-test in the visit window will be 
used.  For example: 
• If a subject had a week 24 viral load and then two re-tests (ie three viral loads 
labeled as week 24, unscheduled 1 unscheduled 2). and the first two viral loads 
were within the upper bound of the week 24 visit (Day 210) but the last re-test 
was slotted to week 36 then the last re-test would not be used for the week 24 
snapshot. 
• If a subject had a week 24 viral load but the re-test was performed on Day 220 
(week 36) then the re-test viral load would not be used for the week 24 snapshot. 
  
Study Day 
• Calculated as the number of days from the initial treatment start date : 
• Ref Date = Missing                       → Study Day = Missing  
• Ref Date < Treatment Start Date   → Study Day = Ref Date – Treatment Start Date     
• Ref Data ≥ Treatment Start Date   → Study Day = Ref Date – (Treatment Start Date) + 1     
 
Note that Treatment Start Date is considered to be on Study Day 1 and the day before this is Study 
Day -1; i.e., there is no Study Day 0. 
Post-baseline 
• Post-baseline refers to the combined time periods of On-treatment and Post-treatment (Section 
11.4.2). Post-baseline may be further specified according to phase of the study: Randomised 
or Continuation (Section 11.4.1). 
 
11.6.3. 
Study Population 
Demographics 
Age 
• Age, in whole years, will be calculated with respect to the subject’s Screening visit.   
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any subject with a missing day will have this imputed as day ‘15’.  
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
• Completely missing dates of birth will remain as missing, with no imputation applied. 
Consequently, the age of the subject will not be calculated and will remain missing. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)2 
Background ART 
• For purposes of calculating susceptibility scores (Section 11.6.6), a subject’s baseline 
background ART regimen is defined as the last full regimen received at the end of the Week 4 


 
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Demographics 
visit window.  This allows time to accommodate any early, protocol-permitted changes in 
background ART or for short, unexpected delays in implementing the chosen background NRTI 
regimen 
WHO First Line and Second Line Regimen 
First line combination regimen is defined as follows: 
 
TDF + 3TC + EFV                           
TDF + FTC + EFV 
AZT + 3TC + EFV 
AZT + FTC + EFV 
D4T + 3TC + EFV 
D4T + FTC + EFV 
AZT + 3TC + NPV 
AZT + FTC + NPV 
D4T + 3TC + NPV 
D4T + FTC + NPV 
TDF + 3TC + NVP 
TDF + FTC + NVP 
        
Second line combination regimen is defined as follows: 
AZT + 3TC + LPV/r 
TDF + 3TC + LPV/r 
TDF + FTC + LPV/r 
 
Framingham Risk Equation 
 
• The predicted probability, , of having a cardiovascular disease (CVD) within the 
next 10-years according to the Framingham formula [D’Agostino, 2008] is 
 
for females: 
F = 1 – S0(t)exp{ 2.32888 × log(age) + 1.20904 × log(TC) – 0.70833 × log(HDL) + 2.76157 × log(SBPu) + 2.82263 × log(SBPt) +  
0.52873 × Is + 0.69154 × Id – 26.1931}, 
 
for males: 
M = 1 – S0(t)exp{ 3.06117 × log(age) + 1.12370 × log(TC) – 0.93263 × log(HDL) + 1.93303 × log(SBPu) + 1.99881 × log(SBPt) +  
0.65451 × Is + 0.57367 × Id – 23.9802}, 
 
where 
S0(t) = 
 
TC = total serum cholesterol (mg/dL), 
HDL = serum HDL cholesterol (mg/dL), 
SBPu = systolic blood pressure (mmHg) if subject is not treated for high blood pressure 
(note that if a subject is treated for high blood pressure then log(SBPu) = 0) 
SBPt = systolic blood pressure (mmHg) if subject is treated for high blood pressure (note 
that if a subject is not treated for high blood pressure then log(SBPt) = 0) 


 
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Demographics 



=
otherwise
smo
current
Is
,0
ker
,1
 



=
otherwise
diabetic
Id
,0
,1
 
 
•  A subject will be considered as treated for high blood pressure if during screening it has 
specified that is suffering from hypertension. 
 
• A subject is classified as diabetic if current or past is indicated in the medical conditions 
eCRF for Type 1 or Type 2 diabetes mellitus, or if baseline fasting glucose 7.00 mmol/L 
(126 mg/dL).  
• Smoking status is collected in the eCRF on Day 1. A current smoker is defined as currently 
smoking/using tobacco or has smoked/used tobacco within the previous 6 months; a former 
smoker is defined as previously smoked/used tobacco products and has not smoked/used 
tobacco products within the previous 6 months. 
• This calculation will not be performed for subjects who have indicated current or past 
myocardial infarction conditions on the eCRF. These subjects will not be included in 
summary statistics of risk, but will be counted in the highest category of risk in the summary 
by category. 
11.6.4. 
Safety 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• Subjects who were randomised but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• Missing Treatment Stop Date will be imputed, for purposes of calculating exposure, as the date 
of last visit or the recorded date of withdrawal/completion, whichever is earlier. 
• An alternative calculation of exposure will be performed where the duration of any dosing 
interruptions based on eCRF data will be subtracted from the result above 
• 
The ratio (percentage) of the actual exposure to the overall exposure (i.e. study treatment  
stop date – study treatment start date+1) will be used to define protocol deviation leading to 
exclusion from PP Population due to study treatment interruption (i.e. >10%). 
ECG Parameters 
Not applicable as not routinely collected. 
 
Adverse Events 
AE Severity – DAIDS Grading 
• The DAIDS grading for severity of clinical adverse events will be performed. 
• See protocol for DAIDS grading criteria. 


 
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Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used 
to determine how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1 
Lab Toxicities – DAIDS Grading 
• Toxicities will be based on the Division of AIDS (DAIDS) grading system, as specified in the 
protocol.  
• Toxicity grades provided by the central laboratory do not distinguish between abnormally high 
or low criteria, when both are relevant for a particular parameter. 
• When summarising toxicity grades for such parameters, they will be categorised according to 
whether they are above or below the midpoint of normal range. 
Parameter 
Below Midpoint 
Above Midpoint 
Fasted glucose 
Hypoglycaemia 
Hyperglycaemia 
Sodium 
Hyponatremia 
Hypernatremia 
Potassium 
Hypokalemia 
Hyperkalemia 
National Cholesterol Education Program (NCEP) Lipid Categories 
• In addition to DAIDS toxicity scales (see protocol), lipid values will be categorised according to 
the 2001 NCEP Adult Lipid Guidelines [Grundy, 2001]. 
Parameter 
Value Range (mmol/L) 
Value Range (mg/dL) Category 
Triglycerides 
<1.70 
<150 
Normal 
1.70 to <2.26 
150 to <200 
Borderline High 
2.26 to <5.65 
200 to <500 
High 
5.65 
500 
Very High 
Total Cholesterol 
<5.18 
<200 
Desirable 
5.18 to <6.21 
200 to <240 
Borderline High 
6.21 
240 
High 
HDL Cholesterol 
<1.04 
<40 
Low 
1.04 to <1.56 
40 to <60 
Normal 
1.56 
60 
High 
LDL Cholesterol 
<2.59 
<100 
Optimal 
2.59 to <3.37 
100 to <130 
Near/Above Optimal 
3.37 to <4.14 
130 to <160 
Borderline High 
4.14 to <4.92 
160 to <190 
High 
4.92 
190 
Very High 
Total Cholesterol / HDL Cholesterol Ratio 
• When both total cholesterol and HDL cholesterol results are available from the same date for a 
subject, then the ratio will be calculated by dividing the total cholesterol result by the HDL 
cholesterol result. 
 


 
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Hepatitis Status 
 
• Hepatitis C status will be determined using antibody (anti-HCV) assessments performed during 
screening.  
• A subject will be considered chronically infected with hepatitis B virus (HBV) if they test HbsAg 
positive OR anti-HBc positive with HBV DNA present (HBV DNA is determined at Baseline for 
subjects who are tested HbsAg negative and anti-HBc positive at Screening). 
 
Other Safety Endpoints 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• Missing data will not have any imputation performed. 
• Incomplete calls: 
• when no complete call is databased on the same day, the incomplete data will be 
used 
• when a complete call is databased on the same day, the data from the complete 
call will be used in the summaries. 
• Duplicate calls: 
• If they occur on the same day, the latest entry will be used. 
• If they occur on different days, take the entry closest to the target visit date.  
 
11.6.5. 
Efficacy 
Efficacy 
Snapshot (Missing, Switch or Discontinuation=Failure) 
• The FDA’s “snapshot” algorithm is also known as the MSDF algorithm. It is intended to be 
primarily a virologic assessment of the endpoint, and as such follows a “virology first” hierarchy. 
• Virologic Success (e.g., <50 c/mL) or Virologic Failure within an analysis window (see Section 
11.3) is typically determined by the last available HIV-1 RNA measurement in that window while 
the subject is On-treatment. 
• When no HIV-1 RNA data is available within a window, a subject cannot be a Virologic 
Success.  Depending on the reason for lack of data, the subject will be classified as a Virologic 
Failure or reported as ‘No Virologic Data at Week X’; in the latter case, the algorithm further 
classifies the nature of the missing data. Typically, a subject withdrawn (i) due to AE or, (ii) for 
another reason yet was suppressed at the time, will be counted as ‘No Virologic Data at Week 
X’.  Should a subject withdraw for reasons other than AE and was not suppressed at the time, 
they will be a Virologic Failure. 
• A subject may also be considered a Virologic Failure if they make changes to their background 
regimen.  This includes: 
o background ART substitutions not permitted per protocol; 
o background ART substitutions permitted per protocol unless the decision to switch is 
documented as being before or at the first On-treatment visit where HIV-1 RNA is 
assessed. 
• For each scheduled assessment time, the MSDF (also known as snapshot) response rate for a 
given threshold (e.g., <50 c/mL) is defined as: 


 
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Efficacy 
population
 
analysis
 
in the
 
subjects
 
of
Number 
 window
analysis
in that 
 
responders
 
of
Number 
Rate
Snapshot 
=
 
• Full details of the algorithm, including the handling of special cases, are included in Section 
11.13. 
Treatment and Efficacy Related Discontinuation = Failure (TRDF and ERDF) 
• The analysis of time to confirmed virologic withdrawal criteria (CVWC) or discontinuation due to 
treatment related reasons (i.e., drug-related AE, protocol defined safety stopping criteria, or lack 
of efficacy) will censor subjects who have not met CVW criteria and are ongoing in the study, or 
who have discontinued for reasons other than those related to treatment. This will be the 
Treatment Related Discontinuation = Failure (TRDF) data. 
• Subjects who have not met CVW criteria and are ongoing in the study, or who have 
discontinued for reasons other than lack of efficacy, will be censored in the analysis of the 
Efficacy Related Discontinuation = Failure (ERDF) data. 
Plasma HIV-1 RNA 
• For summaries and analyses which use HIV-1 RNA level as a continuous measure, the 
logarithm to base 10 of the value will be used 
• HIV-1 RNA results may be provided as censored values, such as <40 or >9,999,999 c/mL. For 
the purposes of summary statistics, such values will be replaced by the next value beyond the 
limit of detection, e.g., 39 or 10,000,000 c/mL, respectively, for the given examples. Data 
listings will show the censored values as provided. 
Variance Estimator of Cochran Mantel-Haenszel Risk Difference 
• 
(
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(
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(
)
(
)
(
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−
=
 


 
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CVW Derivation 
There are 3 parts to the derivation of CVW.  All parts of the derivation need to use nominal visits 
(i.e. VISIT and VISITNUM). 
Virologic Non-response (Parts 1 &2) 
• 
A decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 16, with subsequent 
confirmation, unless plasma HIV-1 RNA is <400 c/mL. 
• 
Confirmed plasma HIV-1 RNA levels ≥400 c/mL on or after Week 24. 
Virologic Rebound (Part 3) 
• 
Confirmed rebound in plasma HIV-1 RNA levels to ≥400 c/mL after prior confirmed 
suppression to <400 c/mL. 
A patient can only be classified as CVW for the analyses if the patient is on-treatment at the time of 
the HIV-RNA value.  
Part 1.  A decrease in Plasma HIV-1 RNA of less than 1 log10 c/mL by week 16, with 
subsequent confirmation, unless Plasma HIV-1 RNA is <400 c/mL 
- 
This applies to Week 16 data only (where INT(VISITNUM)=80) 
- 
If there is a decrease < 1 log10 from Baseline at Week 16 and LBORRESN>=400, then -> 
suspected virologic withdrawal  
- 
If there is a confirmatory sample, then check if there is a decrease <1 log10 from Baseline 
and the LBORRESN>=400 then confirmed virologic withdrawal  
- 
The protocol states that the confirmatory sample needs to be taken within 1-4 weeks of 
initial sample, unless one of the extenuating circumstances outlined below apply: 
 
The following guidelines will be followed for scheduling confirmatory HIV-1 RNA testing in an 
effort to avoid false-positive results: 
• Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the subject should receive full dose of all IP. 
• Confirmatory testing should be scheduled at least 4 weeks following any immunisation, 
during which time the subject should receive full dose of IP. 
• If therapy is interrupted due to toxicity management, non-compliance, or other reasons, 
confirmatory testing should be scheduled 2 to 4 weeks following resumption of full dose of 
IP. 
• The subject should have received full doses of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA is done. 
 


 
C O N FI D E N TI A L  
 
 
 
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C o ns ec utiv e 
v al u e >4 0 0 
o n/ aft er we ek 
2 4  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 0  
 
P art 2: C o nfir m e d Pl a s m a HI V -1 R N A l e vel s > = 4 00 c/ m L o n or after W e ek 2 4  
- 
If p ati e nt is n ot alr e ady a confir me d V F d u e t o th e rul es i n P art 1, w e ca n t h en c o ntin u e t o 
c h eck th e r esults fr o m W e ek 2 4 o n w ar ds  
- 
Us e n o mi n al visits i .e. i nt(visit n u m) > = 1 0 0 
- 
If a p ati ent has a s a m pl e o n/ aft er Week 2 4 a n d th e r esult is > = 4 00 t he n -> sus p ect e d 
vir ol o gic wit h dr a w al. 
- 
If a p ati ent th e n h as a 2 n d co ns ecutiv e s a mpl e > = 4 0 0 th e n -> co nfir me d vir olo gic 
wit h dr a w al.  
 
P art 3: C o nfir m e d re b o u n d i n pl a s ma HI V -1 R N A l e vel s t o > =4 0 0 c/ m L after pri or c o nfir m e d 
s u p pr e s si o n t o < 4 00 c/ m L  
•  Vir ol o gic r e b o u nd c a n h a p pe n at any visit.  
•  P ati e nt m ust h av e 2 co ns ecutiv e v al ues <4 0 0, f oll o w ed by 2 co ns ecutiv e val u es > =4 0 0.  
•  O nc e a p ati e nt h as 2 co ns ec utiv e v al ues <4 0 0, if t he n ext v al u e is > = 4 00 this is a 
s us p ecte d r eb ou n d 
•  If a p ati ent th e n h as a 2 n d co ns ecutiv e s a mpl e > = 4 0 0 th e n t his is a co nfir me d r e b ou n d 
•  S u bj ect  
( ab ove) is cl assifi e d as vir ol ogic r e bo u nd, as t hey h av e  val u es <4 00 at W e eks 
4, 8, a nd 1 6, th e n c o nti n ues t o h av e 2 c o ns ec utiv e v alues > = 40 0. On 
 th e 
s u bj ect is a  ‘c onfir me d r e bou n d’. Als o s ee s u bj ect 
bel o w:  
 
N ot e th at t h er e is gr e at er tha n 1 -4 w e eks (
 fr o m s us p ecte d sa m pl e to c o nfir me d 
s a m pl e, h e nce t his r ule h as n ot b e en a p pli e d  
s u bj e ct 
n o mi n al 
vi sit 
vi sit d at e 
c/ m L 
l o g 1 0 
c/ m L 
l o g 1 0 
d e cr e a s e 
fr o m B L 
C V 
o ut c o m e  
c o m m e nt s  
B as eli ne  
3 0 3 0 0 7   
 
 
 
W e ek 4  
2 7 0 
2. 4 3  
3. 0 5   
  
W e ek 8  
1 4 0 
2. 1 5  
3. 3 3   
  
W e ek 1 6  
2 9 1 5 3  
4. 4 6  
1. 0 2 
S us p ecte d 
r e b o u n d 
2 c o nsec utiv e  
 v al u es < 4 00, 
 f oll o w e d by a n 
i niti al v al u e 
> = 4 0 0  
w e ek 1 6 
r et est 
4 5 4 
2. 6 6  
2. 8 2 
C o nfir m e d 
r e b o u n d 
2 c o nsec utiv e 
v al u es  < 4 00, 
f oll o w e d by 2 
c o ns ec utiv e 
v al u es > = 4 00 
Wit h dr a w al  
< 4 0  
1. 5 9  
3. 8 9   
  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 1  
 
1 1. 6. 6.  
Vir ol o g y  
G e n ot y p e  
A mi n o A ci d C h a n g e s  
•  A m ut atio n is c o nsi d er ed pres e nt w h en ev er th e e nco d ed a mi n o aci d r esi du e diff ers fr o m t h e 
a mi n o aci d t hat w oul d hav e b e en e nc o de d by t he wil d -typ e ( e.g., H X B 2, NL 4 3) co m p ar at or 
g e ne; e. g., Q 1 48 K.  
•  If t he e nc o de d a mi n o aci d is s e e n as a mixt ur e of wil d-ty p e an d m ut a nt a mi n o aci d, e. g., 
Q 1 4 8 Q/ K, t h e m ut ate d a mi no aci d is co nsi der e d pr es ent at th e co d on of i nt erest.  
•  If t he e nc o de d a mi n o aci d is s e e n as a mixt ur e of t w o or m or e a mi n o aci ds, whic h may or m ay 
n ot i nclu d e wil d ty p e, e.g., Q 1 8 4 K/ H or Q1 84 K/ H/ Q, et c., f or th e p ur p oses of c alc ul ati n g th e 
n u m b er of m utat e d a mi n o aci ds, o nly o n e m ut atio n is co nsi d er ed to b e pr ese nt at th e c o d on of 
i nt er est. 
R e pr e s e nt ati o n of A mi n o A ci d C h a n g e s  
M ut ati o n s  
A mi n o a ci d c h a n g e  
T 6 9 S  
Si n gl e m ut ati on fr o m a mi no aci d ‘T ’ (v e n dor r ef er enc e) to ‘S ’ (s a m pl e) at c o do n ‘6 9 ’  
Q 1 4 8 H/ K/ R  
Mixt ur e of a mi no aci d m ut ati o ns ‘ H’, ‘ K’ a nd ‘ R’ (s a m pl e) fr o m a mi n o aci d ‘ Q’ (v e n dor 
r ef er e nce) at co d on ‘ 14 8’ 
_ 6 9_ 1 T  
First i ns erti o n of a mi n o aci d ‘T ’ (s a m pl e) at c od o n ‘6 9 ’ 
_ 6 9_ 2 S  
S ec o nd i nserti o n of a mi no aci d ‘S ’ (s a m pl e) at co do n ‘69 ’ 
_ 6 9_ 3 S/ A  
T hir d i ns erti o n of a mixt ur e of a mi n o aci ds ‘S ’ a nd ‘A ’ (sa m pl e) at co d on ‘69 ’ 
L 7 4L/ - 
Mixt ur e of a mi no aci d ‘L ’ (s a m pl e) a n d a d el eti on at c odo n ‘74 ’ 
V 7 5 - 
Si n gl e d el etio n of a mi no acid (s a m pl e) at c o do n ‘7 5 ’ 
•  Tr e at m e nt -e m er ge nt g e n ot y pi c m ut ati o n s  ar e defi n ed as m utati ons t hat a p pe ar b et w ee n 
b as eli ne a nd a n On -tr e at m ent assess m e nt ( e. g., at ti m e of c onfir me d vir ol ogic wit h dr a w al 
crit eri a). 
R e si st a nc e A ss o ciat e d M ut ati o n s  
•  K n o w n I NI m utati o ns ass ociat e d wit h th e d ev el op m e nt of r esist anc e to R A L, E V G or D T G:  
 
A mi n o Aci ds i n 
HI V I nt e gr as e f or 
A n alysis  
H 5 1 Y,  T 6 6 A /I/K , L74 M , E 9 2 Q /V / G, Q9 5 K, T 9 7 A, G 1 1 8 R, F 12 1 Y, E 1 3 8 A/ K/ D, 
G 1 4 0 A/ C/ S,  Y 14 3 C/ H/ R/ K/ S/ G/ A,  P1 45 S , Q 1 4 6 P , S 1 47 G , Q1 48 H /K /R , 
V 1 5 1 I/L / A, S 15 3 F/ Y, N 1 5 5 H/ S/ T , E 1 5 7 Q, G1 6 3 R/ K, S 2 3 0 R, R 2 6 3 K,  
L 6 8 V/I*, L 7 4I*, E 1 38 T*, V 1 5 1I*, G 1 9 3 E*  
N O T E S:  
•  
Dr aft listi n g; m ay b e m o difi e d i n c as e of a d diti o n al s u bst a ntiv e d at a av ail a bility.  
•  
I NI m ut ati o ns list e d t ak e n fr o m St a nf or d HI V R esist a nc e D at a b as e ( htt ps:// hiv d b.st a nf or d. e d u/ hiv d b/ by -
m ut ati o ns/ htt p:// hiv d b .st a nf or d. e d u/ D R/c gi-bi n/r ul es _sc or es _ hiv d b.c gi ?cl ass =I NI cit e d  
 a n d 
acc ess e d o n 
 
•  
E ac h I NI m ut ati o n list e d h a d a sc or e of 1 5. I NI s u bstit ut i o ns list e d a b ov e i n b ol d h a d a sc or e of = 6 0. 
* D e n ot es a d diti o n al I NI m ut ati o ns a d d e d as t h ey w er e i d e ntifi e d d uri n g i n vitr o p ass a g e of D T G or s e e n i n a 
pr evi o us D T G st u dy i n I NI -ex p eri e nc e d s u bj ects (I N G 1 1 2 5 7 4).  
•  M aj or r esist a nc e m ut atio ns t o oth er cl asses (i. e., N R TI, N N R TI, PI) as d efi n ed by t he 
I nt er nati o nal A ntivir al S oci ety-U S A (I A S -U S A). T he m ost u p t o d ate I A S -U S A g ui d elin es 
av ail a bl e at th e ti m e of D B F will b e us ed i n th e a nalysis.  
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 2  
 
Cl a s s  
M ut ati o n s  
N R TIs  
M 4 1 L, A 6 2 V,  K 65 R/ E/ N , D67 N, 69 i ns ert,  K7 0 E/ R,  L 7 4 V,  V7 5I,  F 77 L,  Y1 15 F,  
F 1 1 6 Y,  Q 1 5 1 M, M 18 4 V/I, L2 1 0 W, T 21 5 Y/ F, K2 19 Q/ E  
N N R TIs  
L 1 00I, K 1 0 1 E/ P , K 1 03N /S, V 1 0 6 A/ M, V 1 08I,  E 13 8/ A/ G/ K/ Q / R, V179 L,  
Y 1 8 1 C/I/ V,  Y1 88 C/L/ H , G190 S/ A , H 22 1 Y, P 22 5 H , F 22 7 C, M 2 3 0I/L, 
P is 
D 3 0 N, V 32I , M 46I/L , I47 A/ V, G 4 8 V, I50 V / L, I 5 4M /L, Q 58 E,  T 7 4 P,  L 7 6 V,  
V 8 2 A/ T/ F/ L/ S, N83 D , I 84 V, N 8 8 S, L 9 0 M 
N ot e: List g e n er at e d fr o m W e nsi n g , 2 0 14  
S u s c e pti bilit y S c or e s  
St a nf or d G e n ot y pi c S u s ce pti bilit y Sc or e ( G S S)  
•  T o est a blis h g e noty pic s usce pti bility t o b ackgr o un d tre at m e nt, a g e n oty pic s ensitivity sc or e will 
b e c alcul at ed.  
•  G e n oty pic s ensitivity t o e ach dr u g will b e assess e d usin g th e HI Vd b, t he I nt e gr at e d G en otypic 
R esist a nc e I nter pr et ati o n Syst e m [ Li u , 2 00 6 ]. 
•  I n t he HI V d b syste m, eac h HI V -1 dr u g r esist a nce m utati o n is assi gn e d a dr u g p e nalty sc or e. 
T h e p e n alty sc or es for e ach dr u g r esista nc e m ut ati o n ar e av ail abl e at  
N N R TI: htt ps:// hiv db.st anf ord. e du/ dr -s u m m ary/ m ut-sc ores/ N N R TI/ 
N R TI:  htt ps:// hivd b.sta nfor d. e d u/ dr -s u m m ary/ m ut-sc ores/ N R TI/  
PI:  htt ps:// hiv db.sta nfor d. edu/ dr -s u m m ary/ m ut-sc or es/ PI/ 
I N S TI:   htt ps:// hiv db.sta nfor d. e du/ dr -s u m m ary/ m ut-sc ores/I N S TI/. Sc or es f or partic ul ar p att er ns 
of I N S TIs ar e also avail a bl e at htt ps:// hiv db.st anf or d. e du/ dr -s u m m ary/ p att er n-sc or es/I N S TI/ 
•  T h e dr ug r esist anc e esti m ate is o bt ai n e d by a ddi n g t oget h er th e p en alty scor es fr o m all 
m ut ati o ns ass ociat e d wit h resist a nc e t o t h at dr ug a n d th e n a n u m eric sc or e ( S -G S S) is a p pli ed 
f or e ach dr ug as sh o w n b elo w. T h e su m sc or es ar e titrat e d t o f all wit hi n th e f oll o win g r a ng es: 
s usc e pti ble, pot e nti al l o w-l ev el r esist a nce, l o w-l ev el r esist a nc e, i nt er medi at e r esist anc e, a n d 
hi g h -l ev el r esista nc e (s e e tabl e bel o w). 
 
 
•  F or a dr ug w hic h is n ot assess e d by HI Vd b ( e.g., e nfuvirti d e), t his dr ug will b e assi g n ed a 
n u m eric sc or e of 0 if
a nd 1 if 
(s e e Ta bl e  1 1 ). Mar avir oc will b e assi gn ed a sc or e of 0 if 
 an d 
1 if 
 
•  T h e HI V d b G S S will  t h e n b e c alc ul at e d for e ach s u bj ect d efi ne d as t he s u m of t h e r esist a nc e 
C CI
C CI
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 3  
 
sc or es f or eac h of th eir b ack gr o u nd dr ugs. 
M o n o gr a m G e n ot y pi c S u sc e pti bilit y S c or e ( G S S)  
•  G e n oty pic s ensitivity t o e ach dr u g will b e assess e d usin g th e M on o gr a m r esista nce sc or e for  
e ac h b ack gro u nd dr ug provi d e d in t he d at a b as e.  
S c or e  
S e n siti vit y  
 
•  T h e M o no gr a m G S S will t h e n b e c alc ulat e d f or e ac h su bj ect d efi ne d as th e su m of t h e 
r esist a nc e scor es for e ach of t h eir b ackgr o u nd dru gs. 
P h e n ot y pi c S us ce pti bilit y S c or e ( P S S)  
•  T o est a blis h s usce pti bility to b ack gr ou nd tr e at m e nt, a ph e noty pic s ensitivity sc or e will b e 
c alc ul at e d. Ph en otypic s usce pti bility t o e ach dr ug i n a su bj ect’s back gr ou n d r e gi men will b e 
d et er mi n e d by a pplyi n g dr ug -ass oci ate d cut offs as d efin e d by th e Ph en o S e ns e al gorit h m t o th e 
p h en otypic f ol d resist a nce to t hat dr ug at a cert ai n ti m e p oi nt ( e. g., Scr e eni n g or Bas eli n e). A 
n u m eric sc or e will b e assi gn e d t o e ac h b ackgr o un d drug usi ng t w o diff er ent m eth ods: on e wit h 
f ull s e nsitivity only ( P S Sf; Ta bl e 1 1 ) an d o n e wit h p arti al s e nsitivity i ncl u de d ( P S S p; T a bl e 1 2 ). 
 
T a bl e 1 1  
P S S wit h F ull S e n siti vit y O nl y ( P S Sf)  
F ol d C h a n g e  
S c or e  
I nt er pr et ati o n 
> cli nic al l o w er c utoff or bi olo gic c utoff  
 cli nic al l o w er c utoff or bi olo gic c utoff 
 
T a bl e 1 2  
P S S wit h P arti al S e n siti vit y I n cl u d e d ( P S S p)  
F ol d C h a n g e  
S c or e  
I nt er pr et ati o n 
> cli nic al hi g h er c utoff  
 cli nic al hi g h er c utoff a n d > cli nic al l o w er c utoff 
 cli nic al l o w er c utoff 
 
•  If o nly a bi olo gic al cut off is av ail a bl e, t he al gorit h m f or P S Sf will b e a ppli e d. M ar avir oc will 
b e assig n ed a scor e of 0 if th e 
 
, a n d 1 if th e 
. 
•  B ot h P S Sf an d  P S S p will b e c alc ul at e d s e p ar at ely f or eac h s u bj ect ed d efi ne d as t he s u m of 
t h e r esista nc e sc or es for e ac h b ackgr o un d dr u g. 
 
Dr u g  
A b br e vi ati o n  
Cl a s s  
P h e n o S e n se c ut off  
A b ac avir  
A B C  
N R TI  
( 4. 5 –  6. 5) a 
L a miv u di ne  
3 T C  
N R TI  
3. 5  a 
Di d a n osi ne  
d dI 
N R TI  
( 1. 3 –  2. 2)  a 
St av udi n e  
d 4 T 
N R TI  
1. 7  a 
Zi d ov u di ne  
A Z T ( Z D V)  
N R TI  
1. 9  
E mtricit a bi n e  
F T C  
N R TI  
3. 5  
C CI
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 4  
 
T e n ofovir  
T D F  
N R TI  
( 1. 4 –  4)  a 
D el avir di n e  
D L V  
N N R TI  
6. 2  
Ef avir e nz  
E F V  
N N R TI  
3  
N evir a pi n e  
N V P  
N N R TI  
4. 5  
Etr aviri n e  
E T R  
N N R TI  
( 2. 9-1 0)  a 
Ril piv ari n e  
R P V  
N N R TI  
2  
F os a m pr e n avir/r  
F P V/r  
PI  
( 4-1 1)  a 
At az an avir/r  
A T V/r  
PI  
5. 2  a 
I n di navir/r 
I D V/r 
PI  
1 0  a 
L o pi navir/r  
L P V/r  
PI  
( 9 –  55)  a 
N elfi n avir  
N F V  
PI  
3. 6  
S a q uin avir/r  
S Q V/r  
PI  
( 2. 3 –  1 2)  a 
Ti pr a n avir/r  
T P V/r  
PI  
( 2 –  8)  a 
D ar u n avir/r  
D R V/r  
PI  
( 1 0 –  9 0)  a 
Rit o n avir  
R T V  
PI  
2. 5  
E nf uvirti de  
T 2 0  
FI  
6. 4 8  
R alt e gr avir  
R A L  
I NI 
1. 5  
Elvit e gr avir  
E V G  
I NI 
2. 5   
D ol ut e gr avir  
D T G  
I NI 
( 4-1 3)  a 
a.  
cli nic al c ut off (l o w er c ut off –  hi g h er c ut off)  
 
N et A s s e ss m e nt f or O pti m i s e d S us ce pti bilit y Sc ori n g  
N et ass ess m ent is a n assess m e nt of a ntiviral activity of b ack gr ou n d A R Ts usi ng b oth g en otypic a nd 
p h en otypic t est res ults i nterpr et e d t hr ou gh a pr o prietary al g orit h m (fr o m M o n o gr a m Bi osci e nc es) 
a n d pr ovi d es t he over all s usc e pti bility of t he dr ug ( N ot e: p arti ally s e nsitiv e a nd r esista nt calls ar e 
c o nsi d er ed n ot fully activ e in t his a n alysis). F or det er mini n g ov er all s usce pti bility of b ack gr ou n d 
A R Ts ( O S S), a bi n ary scori n g syste m ( 0 = 
, 1 =  
 f or eac h antir etr ovir al 
a g ent w as us e d  a nd will b e pr ovi d e d i n th e M on o gra m d at as et . O S S will b e  calc ul ate d as t he s u m of 
t h e n et ass ess m ent sc or es of A R Ts c o m prisi n g t he s u bj ect b ackgr o un d A R T a nd cat e goris e d as 0, 
1, 2, or > 2.  
R e si st a nc e D at a fr o m C hi n a  
At t h e ti me of t h e W e ek 2 4 a n alysis n ot  all of th e p h en oty p e d ata m ay be avail a bl e fr o m M o n o gr a m 
f or s u bj ects i n C hin a.  T h e ge n otyp e d ata m ay b e a mixt ur e of Q 2 a n d M o n ogr a m dat a, a nd i n th e 
ev e nt t hat bot h Q 2 a n d M o no gr a m ar e av ail abl e at t h e sa m e ti me p oint th e M on o gra m d at a will be 
us e d.  
 
D ay 1 g e noty pic  an d p he n oty pic r esist a nce d at a for R T a n d P R O is pr ovi de d f or all s u bj ects by 
M o n o gr a m a n d will b e use d i n t he a n alysis. Su bj ects wit h C V W crit eria will als o have r esist a nce 
t esti n g p erfor me d by M o n ogr a m at S V W  ti m ep oi nts.  P S S is o nly pr ovi d ed by M on ogr am. T h e  
scr e e ni n g g en otyp e fr o m Q U E S T m ay be use d if M on ogr a m g en oty p e is missi n g.  
D efi niti o n of T A M S  
T A M S ar e thy mi di n e a n alo gu e m utati o ns a nd ar e a co m bi n ati on of t h e t hy mi di ne a nal o g ues A Z T 
( Z D V) m ut ati o ns a n d d 4 T mut ati ons i n R T (rev ers e tr a nscripit as e).  T hey c a n b e f ou n d at th e 
St a nfor d d ata b ase , det ails ar e i ncl u d ed i n t h e f oll o wi n g ta bl e:  
 
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 5  
 
 
T hy mi di n e An al og M ut ati o ns ( T A Ms)  
A mi n o aci d p ositi on i n R T  
4 1  
6 7  
7 0  
2 1 0  
2 1 5  
2 1 9  
Wil d ty p e  
M  
D  
K  
L  
T  
K  
M u ati o ns  
L  
N  
R  
W  
F Y  
Q E  
 
1 1. 6. 7.  
H e alt h O ut c o m e s  
HI V T S Q s  
Tr e at m e nt S atisf a cti o n S c or e  
•  It e ms 1-6, 7 a, 8, 9 b, 1 0 & 11  ar e  su m m e d to pr od uc e a sc or e wit h a p ossi bl e r an g e of 0 t o 6 6 .  
•  Hi g h er sc or es r epr es e nt great er tr eat m e nt s atisfacti o n as c o m p ar e d t o t h e p ast f e w w e eks.  
•  A m axi m u m of 5 it e ms c a n b e missi n g, whic h c an b e i m p ut e d t o refl ect th e me a n of t h e 
c o m pl et ed it e m sc or es. If 6 or m or e it e ms ar e missi n g, th e n t h e tr e at m ent satisf actio n sc ale 
sc or e s h oul d n ot b e co m p ute d a n d will r e m ai n missi n g.  
•  Fr e e t ext fi el d  
I n di vi d u al It e m Sc or e s 
•  It e ms ar e r at e d as 6 (
etc.) to 0 (
 
etc.).  
•  Hi g h er sc or es r epr es e nt great er s atisfacti on wit h e ac h as p ect of tr eat m e nt  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 6  
 
HI V T S Q c  
 
Tr e at m e nt S atisf a cti o n S c or e ( c h a n g e)  
•  It e ms 1-6, 7 a, 8, 9 a or 9b, 10 & 1 1 are s u m m e d t o pr o duc e a sc or e wit h a p ossi bl e r a n g e of -33 
t o 33  
•  T h e hi gh er th e scor e, th e gr e at er th e i mpr ove m e nt i n s atisf acti o n with tr eat m e nt; t h e l o w er t h e 
sc or e, t he gr eat er t h e d et eri or ati o n  in s atisfacti o n wit h tre at m e nt.  A sc or e of 0 r e pr es e nts 
 
.  
•  A m axi m u m of 5 it e ms c a n b e missi n g,  T h e missi n g scor es will b e i m p ute d with t h e m e a n of t h e 
c o m pl et ed it e m sc or es. If 6 or m or e it e ms ar e missi n g, th e n t h e ov er all tr eat m ent s atisf acti o n 
sc al e sc or e sh oul d not be co m p ut e d a n d will r e m ai n missi n g.  
I n di vi d u al Tre at m e nt C h a n g e It e m Sc or e s 
•  It e ms ar e r at e d as +3 
 
etc .) t o -3  (‘
 etc.).  
•  T h e hi gh er th e scor e, th e gr e at er th e i m pr ove m e nt i n s atisf acti o n with e ac h as p ect of tr e at m e nt 
a n d t h e l o w er t he sc or e, t h e gr e ater t he d et erior ati on i n s atisf acti on wit h e ac h as pect of 
tr e at m e nt. 
 
M M A S -8  
T ot al S c or e  
•  D eriv e d as th e su m m ati o n of t h e f oll o wi n g sc or es:  
•  It e ms 1,2, 3,4, 6, an d 7 ar e e ac h scor e d as 1 if a ns wer ed as ‘
’ a n d 0 if a ns w er ed 
as ‘ 
’;  
•   It e m 5 is scor e d as 1 if ans w er e d  as ‘ 
’ an d 0 if ans w er e d as ‘
’ (i.e., r eversin g 
t h e co d e r es p ons e in a p ositiv e directi on); 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 7  
 
•   It e m 8 is scor e d as th e val ue r e p orte d ( 0-4) divi d ed by 4 (i. e., sta nd ar dizi n g t he 5 -poi nt 
Lik ert Sc al e f or this it e m) . For t h e p ur pos es of s u m m arisi n g t he n ( %) of s u bj ects wit h 
e ac h scor e th e sta nd ar diz ed sc or e will b e r o u nd ed u p ie 0.5 will b e r ou n de d t o 1.  
•  T his r es ults i n a T otal Sc or e wit h a p ossi bl e ra n ge of 0 to 8.0 . 
•  7 5 % c o m pl eti o n is n ecess ary t o c alc ulat e t h e sc or e  (ie 6 o ut of 8 q u esti ons n e e d t o b e 
a ns w er e d).  
•  If 1 or 2 it e ms ar e missi n g, th e m e dia n val u es of th e ot h er 7 or 8 it e ms w oul d be s u bstit ute d for 
t h e missi n g ite m. 
A d h er e n c e Le v el  
•  
•  
•  
 
G S R S  
I n di vi d u al It e m Sc or e s 
•  E ac h of 15 Ite ms ar e r at e d usi n g a s ev en -gr a de d Lik ert sc al e, w her e 1 r e pr ese nts th e  
 
 opti on a n d 7 t he 
 o n e. 
Di arr h o e a S y n dr o m e S c ore  
•  M e a n v alu e for it e ms 1 1 (
 1 2 ( 
), 1 4 (
 
). 
•  T his d o m ai n scor e c an b e co m p ut e d if at l east 2 o ut of 3 it e ms ar e av ail abl e (i. e. less t h an 5 0 % 
of t h e it e m scor es wit hi n a di m e nsi o n ar e mis si n g); i n whic h c as e, t h e missi n g ite ms will b e 
i m p ut e d usi n g t he m e an scor e of t h e n on-missi n g it e m sc or es.  
I n di g e sti o n S y n dr o me S c or e 
•  M e a n v alu e for it e ms 6 ( 
), 7 (
), 8 ( 
), 9 ( 
 
). 
•  T his d o m ai n scor e c an b e co m p ut e d if at l east 2 o ut of 4 it e ms ar e av ail abl e (i. e. less t h an 5 0 % 
of t h e it e m scor es wit hi n a di m e nsi o n ar e missi n g); i n whic h c as e, t h e missi n g ite ms will b e 
i m p ut e d usi n g t he m e an scor e of t h e n on-missi n g it e m sc or es.  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
7 8  
 
C o n sti p ati o n S y n dr o m e Sc or e  
•  M e a n v alu e for it e ms 10 (
), 1 3 ( 
), 1 5 ( 
 
) 
•  T his d o m ai n scor e c an b e co m p ut e d if at l east 2 o ut of 3 it e ms ar e av ail abl e (i. e. less t h an 5 0 % 
of t h e it e m scor es wit hi n a di m e nsi o n ar e missi n g); i n whic h c as e, t h e missi n g ite ms will b e 
i m p ut e d usi n g t he m e an scor e of t h e n on-missi n g it e m sc or es.  
A b d o mi n al P ai n S y n dr o me S c ore  
•  M e a n v alu e for it e ms 1 (
), 4 (
), 5 (
) 
•  T his d o m ai n scor e c an b e co m p ut e d if at l east 2 o ut of 3 it e ms ar e av ail abl e (i. e. less t h an 5 0 % 
of t h e it e m scor es wit hi n a di m e nsi o n ar e missi n g); i n whic h c as e, t h e missi n g ite ms will b e 
i m p ut e d usi n g t he m e an scor e of t h e n on-missi n g it e m sc or es.  
R efl u x  S y n dr o me S c ore  
•  M e a n v alu e for it e ms 2 ( 
), 3 (
) 
•  T his d o m ai n scor e c an b e co m p ut e d if at l east 1 o ut of 2  it e ms ar e av ail abl e (i. e. less t h an 5 0 % 
of t h e it e m scor es wit hi n a di m e nsi o n ar e missi n g);  i n whic h c as e, t h e missi ng ite ms will b e 
i m p ut e d usi n g t he m e an scor e of t h e n on-missi n g it e m sc or es.  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
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11.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
11.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as: 
o Randomised to LPV/RTV + two NRTIs and completed the Randomised 
Phase including the Week 52 study visit; 
o Randomised to DTG + two NRTIs, completed the Randomised Phase 
including the Week 52 study visit, and did not enter the Continuation 
Phase; 
o Randomised to DTG + two NRTIs, completed the Randomised Phase, 
including the Week 52 study visit, entered and completed the 
Continuation Phase (defined as remaining on study until commercial 
supplies of DTG become locally available to patients [e.g. through 
public health services]). 
• Withdrawn subjects were not replaced in the study. 
• All available data from subjects who were withdrawn from the study will be 
listed. 
 
11.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument : 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
Health 
Outcome 
• See Section 11.6.7. 


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
 
8 0  
 
1 1. 7. 2. 1.  
H a n dli n g of Mi s si n g D at e s  
El e m e nt  
R e p orti n g D et ail  
G e n er al  
P arti al d at es will b e dis pl aye d as c a pt ur e d i n s u bj ect listi n g displ ays.  
A dv ers e Ev e nts  
•  T h e e C R F all o ws f or t he p ossi bility of p artial d ates (i. e., o nly m o nt h a n d 
y e ar) t o b e r ecor d e d f or A E st art a nd e n d d ates; th at is, t h e d ay of t h e 
m o nt h m ay b e missi n g. I n suc h a c as e, t he f oll o wi ng c o nv e ntio ns will b e 
a p pli ed f or calc ul ati ng t he ti m e t o o ns et a nd th e d ur ati on of t h e ev ent:  
o  M issi n g S t art D ay: First of th e m o nt h will b e us ed u nl ess t his is b ef or e 
t h e start dat e of stu dy tr e at m e nt; i n t his c ase t he stu dy tr e at m e nt st art 
d at e will b e use d a n d h enc e t h e ev ent is c onsi d er ed O n -tr e at m e nt as 
p er S ecti o n 1 1.4 . 
o  M issi n g S t o p D ay : L ast d ay of t h e m o nt h will b e us ed  ( ‘2 8/ 2 9/ 3 0/ 3 1 ’ 
d e pe n de nt o n t h e m o nth a nd y e ar) , u nl ess this is aft er th e sto p d at e of 
st u dy tr eat m e nt; i n t h
s c as e th e stu dy tre at m ent sto p d at e will b e 
us e d.  
•  C o m pl et ely missi n g start or e n d d ates will r e m ai n missi n g, wit h n o 
i m p ut ati on a p pli e d. C o nse qu e ntly, ti me t o o nset an d d ur ati o n of s uch 
ev e nts will b e missi n g.  
Pri or/ C o nc o mit ant 
M e dic ati o ns  
•  
P arti al d at es  for any prior/co nc o mit ant m e dicati o ns r ecor d e d in t he C R F 
will b e i m p ut e d usi ng t he foll o wi n g c o nv e ntio n:  
o  If t he p arti al d at e is a st art dat e, a ‘01 ’ will b e use d for t he d ay a nd 
‘J a n’ will b e use d for t he m ont h  
•  
If t he p arti al d at e is a st op d at e, a ‘28/ 2 9/ 3 0/ 3 1 ’ will b e us e d for t h e d ay 
( d e p en d ent o n th e m ont h a n d y e ar) a nd ‘D ec ’ will b e us e d for t h e m o nth.    
o  F or m e dic ati ons r ec or de d i n t h e e C R F as prior A R T, t he e arli er of t his 
i m p ut e d d ate or th e d ay b efor e I P st art will b e us ed. 
•  
T h e r ec or de d p arti a l d ate will b e dis pl aye d in listi n gs. 
•  
H a n dli n g of co m pl etely missi n g st art or e nd d at es is discuss e d in A pp en dix 
4 : Tr e at m ent St ates a n d P has es. 
 
P P D


 
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11.7.2.2. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
Snapshot 
(MSDF) 
• In the Snapshot dataset, subjects without HIV-1 RNA data in the assessment 
window for the visit of interest (due to missing data or discontinuation of IP prior 
to the visit window) are classified as non-responders in the derivation of the 
proportion of subjects with HIV-1 RNA < 50 c/mL (or <400 c/mL).  The nature of 
this missing data will be further classified in Snapshot summaries as either 
‘Virologic Failure’ or ‘No Virologic Data at Week X’. Full details of the Snapshot 
algorithm are in Section 11.13. 
• For the Week 48 deliverable, there will be 3 versions of the Snapshot dataset 
relative to the Primary Estimand and Additional Estimands 1 & 2. For the Week 
24 deliverable, there will only be one version of the dataset. 
•  
LOCF 
• In the LOCF dataset, missing values will be carried forward from the previous, 
non-missing available on-treatment assessment. 
HO 
• Missing data in the Health Outcome questionnaires are described in Section 
11.6.7. 
Lipids LOCF • If subjects initiate serum lipid-lowering agents Post-baseline, then the last 
available fasted On-treatment lipid values prior to the initiation will be used in 
place of future, observed On-treatment values.  
• Imputation will continue even if the subject discontinues the lipid-lowering agent.  
• Missing baseline assessments will not be imputed. Subjects on lipid-lowering 
agents at baseline will be excluded from this dataset.  
• This dataset will be used for all summaries and analyses of lipids data 
 


 
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11.8. 
Appendix 8: Values of Potential Clinical Importance 
 
Element 
Reporting Detail 
Laboratory 
Values and 
Adverse 
Events 
• The DAIDS grading for severity of laboratory toxicities and clinical adverse 
events is included in the protocol.  
• The central laboratory will flag lab parameter toxicities directly in the provided 
datasets. 


 
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11.9. 
Appendix 9: Multicenter Studies 
11.9.1. 
Methods for Handling Centres 
Data will be summarised for all centres combined. Country will be treated as an 
exploratory subgroup for analyses of the primary efficacy endpoint as described in 
Section 7.1.2. 
 


 
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11.10. 
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata 
11.10.1. 
Handling of Covariates, Subgroups & Other Strata 
• 
The following is a list of covariates that may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses (See 
Section 7.1.2 and Section 9.1 for further details).  
• 
Additional covariates of clinical interest may also be considered.  
• 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.   
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. 
Category 
Covariates and / or Subgroups 
Randomization Strata using 
Baseline Values 
• Baseline plasma HIV-1 RNA ( vs. >100,000 c/mL); 
• Number of fully active background NRTIs (<2 vs. 2) based 
on GSS at Baseline. 
 
For analysis purposes, randomization strata will be re-derived 
using Baseline values. In particular, fully active is defined at 
Baseline by the genotypic resistance reports of the central 
laboratory (or a laboratory contracted by the central laboratory) 
showing no evidence of full or of partial genotypic resistance for 
a given NRTI.  If Baseline genotypic results are not available, 
then activity of the background regimen will be based on 
genotypic results at Screening. 
 
All statistical analyses will adjust for the above baseline 
randomization strata, unless stated otherwise.  Treatment-by-
Strata interactions will be assessed as specified in the analysis 
Section 7.1 (primary endpoint) and Section 8.1 (secondary 
endpoint analyses) and Section 9.1 (health outcomes analyses).  
Background Regimen and 
Resistance Subgroups 
• WHO recommended public-heath approach second-line 
NRTI background regimen (yes vs. No ) (use definition in 
11.6.3) 
• Baseline PSS to background regimen: (<2 vs. 2) 
• Baseline GSS to background regimen: (<2 vs. 2) 
• ABC+3TC vs not ABC+3TC 
Demographic and Baseline 
Characteristic Subgroups 
• Age: <35, 35-<50, ≥50  
• Race: 
o White; Non-White 
o African American/African Heritage; Non-African 


 
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Category 
Covariates and / or Subgroups 
American/African Heritage 
• Sex: 
o Female 
o Male 
• Country 
• Baseline plasma HIV-1 RNA: 
o <1000; 1000 to <10,000; 10,000 to <50,000; 50,000 
to 100,000; >100,000 c/mL. 
o ≤100,000, >100,000 c/mL 
• HIV-1 subtype: 
o Subtype is found as part of the Monogram 
phenotype assay output.  It is also known as clade 
eg, clade B = subtype B. 
• Baseline CD4+ cell count: 
o Y cells/mm3 or >Y cells/mm3 (Y=cutoff closest to 
median); 
o <200, 200-<350, ≥350 cells/mm3 
• Baseline Centers for Disease Control and Prevention (CDC) 
category: 
o CDC Category A, 
o CDC Category B 
o CDC Category C); 
 
 
 


 
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11.11. 
Appendix 11: Handling of Multiple Comparisons & 
Multiplicity 
A pre-specified fixed sequence testing procedure is used to control for multiplicity: if the 
primary comparison is significant for NI at the 5% two-sided alpha level then testing for 
superiority will proceed at the 5% two-sided alpha level; otherwise testing of superiority 
will not be performed. 
The interim analysis schedule does not require an adjustment for multiplicity since the 
IDMC analyses do not inflate the type I error rate to any measurable degree (see protocol 
Section 8.3.4.2), and the Week 24 interim analysis is supportive to the primary Week 48 
analysis and will not be used to make definitive claims of a positive finding. 


 
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11.12. 
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses 
11.12.1. 
Statistical Analysis Assumptions 
Endpoint(s) • Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48 
• Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48 
• HIV-Treatment Satisfaction Questionnaire (treatment satisfaction score) 
• Gastrointestinal Symptom Rating Scale (Individual scores) 
Analysis 
• MMRM 
• 
Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. 
• 
The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• 
An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS.  
o Akaike’s Information Criteria (AIC) will be used to assist with the selection of 
covariance structure. 
• 
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 
• 
If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 


 
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11.13. 
Appendix 13: Snapshot 
 
➢ Consider an arbitrary visit window, Week X (see Section 11.3).  
➢ A subject’s response (i.e., ‘Virologic Success’, ‘Virologic Failure’, or ‘No Virologic Data 
at Week X’) in that window is determined as indicated below, in the order stated. 
 
1. If non-permitted change in background ART prior to Week X: Subject = Virologic Failure. 
2. If permitted change in background ART prior to Week X AND decision to make this change 
is after the first On-treatment HIV-1 RNA result AND the latest On-treatment HIV-1 RNA 
result prior to the date of decision to switch is ≥ 50 c/mL: Subject = Virologic Failure.  
3. If non-permitted change in background ART during Week X 
OR 
if permitted change in background ART during Week X AND decision to make this 
change is after the first On-treatment HIV-1 RNA result AND the latest On-treatment 
HIV-1 RNA result prior to the date of decision to switch is >=50 c/mL  
AND:  
• no HIV-1 RNA result is available during Week X prior to change: Subject = Virologic 
Failure; 
• there is at least one HIV-1 RNA result available during Week X prior to the 
change, then consider the latest such result: 
• 
If < 50 c/mL: Subject = Virologic Success 
• 
If ≥ 50 c/mL: Subject = Virologic Failure. 
4. If there is no change in background ART prior or during Week X 
OR 
a permitted change prior or during Week X is decided on before the first On-treatment 
HIV-1 RNA result, 
OR 
a permitted change prior or during Week X is decided on after the first On-treatment 
RNA result AND the latest On-treatment HIV-1 RNA result prior to the decision to switch 
is <50 c/mL, 
AND  
at least one HIV-1 RNA result is available during Week X, then consider the latest such 
result: 
• 
If < 50 c/mL: Subject = Virologic Success; 
• 
If ≥ 50 c/mL: Subject = Virologic Failure. 
5. If there is no change in background ART prior or during Week X 
OR 
a permitted change prior or during Week X is decided on before the first On-treatment 
HIV-1 RNA result 


 
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OR 
a permitted change prior or during Week X is decided on after the first On-treatment 
RNA result AND the latest On-treatment HIV-1 RNA result prior to the decision to switch 
is <50 c/mL, 
AND  
no HIV-1 RNA results are available during Week X: 
• If the subject has not withdrawn from the study prior to or during Week X: Subject = 
No Virologic Data at Week X, with a reason of ‘Missing data during window but on 
study’; 
• If the subject was withdrawn from the study prior to or during Week X due to AE or 
death: Subject = No Virologic Data at Week X, with a reason of ‘Discontinued due 
to AE or Death’; 
• Otherwise, consider the subject’s last available On-treatment HIV-1 RNA result: 
➢ If <50 c/mL or no result is available: Subject = No Virologic Data 
at Week X, with a reason of ‘Discontinued for Other Reasons’; 
➢ If ≥ 50 c/mL: Subject = Virologic Failure. 
 
Examples from FDA guidance 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window: 
• HIV-RNA = 580 copies/mL at Day 336, HIV-RNA below 50 copies/mL on Day 350. This 
should be categorized as HIV-RNA below 50 copies/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
• Any patient who discontinues because of an AE or death before the window should be 
classified as Discontinued due to AE or Death (as appropriate), regardless of the HIV-RNA 
result, even if the HIV-RNA is below 50 copies/mL at the time of discontinuation.  
• However, if a patient has an HIV-RNA value in the time window and also discontinues in the 
time window, the viral load data should be used to classify the patient’s response. This is 
the Virology First hierarchy: 
a. HIV-RNA below 50 copies/mL at Day 336 and discontinues because of AE or even 
dies on Day 360 — this person is categorized as having HIV-RNA below 50 
copies/mL.  
b. HIV-RNA is 552 copies/mL on Day 336 and the patient discontinues on Day 360, 
the patient is categorized as having HIV-RNA greater than or equal to 50 
copies/mL. 
Discontinued for Other Reasons: 
• Only patients who have achieved virologic suppression can be counted as Discontinued for 
Other Reasons. 
• If a patient discontinues the study before the time window because of lack of efficacy then 


 
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the patient should be included in the HIV-RNA greater than or equal to 50 row and not in 
the Discontinued for Other Reasons row. 
• If a patient discontinues because of subject withdrew consent and his or her HIV-1 RNA 
result at the time of discontinuation was equal to or above 50 copies/mL, then he or she 
should be categorized as HIV-RNA greater than or equal to 50 and NOT as Discontinued 
for Other Reasons.  
• If a patient discontinued because of Lost to Follow-Up and the last HIV-RNA result was 49 
copies/mL, then the patient can be categorized as Discontinued for Other Reasons. 
• If patients changed background treatment — not permitted by protocol— they should be 
considered an efficacy failure and captured in the HIV-RNA greater than or equal to 50 
copies/mL row. 
On study but missing data in window: 
• If there are no data during Days 294 to 377, but there is an HIV-RNA below 50 copies/mL 
on Day 380, this patient should be considered On Study but Missing Data in Window. 
• If there are no data during Days 294 to 377, but there is an HIV-RNA equal to or above 50 
copies/mL on Day 280, this patient also should be classified as On Study but Missing Data 
in Window. 
Optimized Background Therapy Substitutions After Randomisation 
• OBT substitutions (in-class or cross-class) permitted per protocol for documented toxicity 
reasons can be permitted on or before the first trial visit without penalty.  
If OBT substitutions for toxicity reasons occur after the first trial visit, then patients should be 
categorized as having HIV-RNA greater than or equal to 50 copies/mL if they have HIV-RNA above 
50 copies/mL at the time of switch. 
 
 


 
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11.14. 
Appendix 14 – Q2 Creatinine Assay Accuracy Issue 
11.14.1. 
Sensitivity Analyses 
The machine at the central laboratory had debris in the system which led to suspect samples for 
creatinine.  The impacted samples are indicated in the spreadsheet below. 
Sensitivity analyses will be conducted excluding the suspect creatinine samples from any 
laboratory summaries. The details of the samples to be excluded are in the excel spreadsheet 
Suspect Creatinine Samples Study 200304 (Reference: RAP-Amend1-200304-Appendix 14.xls). 


 
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11.15. 
Appendix 15 – Abbreviations & Trade Marks 
11.15.1. 
Abbreviations 
Abbreviation 
Description 
A&R 
Analysis and Reporting  
ABC 
Abacavir 
AdaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike’s Information Criteria 
ALT 
Alanine aminotransferase 
ART 
Antiretroviral Treatment 
ATC 
Anatomical Therapeutic Chemical 
ATV 
Atazanavir 
c/ml 
Copies per milliliter 
CD4+ 
Helper-inducer T-lymphocyte having surface antigen CD4 (cluster of 
differentiation 4) 
CDC 
Centers for Disease Control and Prevention 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTR 
Clinical Trial Register 
CV 
Cardiovascular 
CVWC 
Confirmed Virologic Withdrawal Criteria 
DAIDS 
Division of AIDS 
DBF 
Database Freeze 
DOB 
Date of Birth 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
ERDF 
Efficacy Related Discontinuation = Failure 
FC 
Fold change 
FDA 
Food and Drug Agency 
FDC 
Fixed Dose Combination 
FTC 
Emtricitabine 
FU 
Follow-up 
GFR 
Glomerular Filtration Rate 
GSK 
GlaxoSmithKline 
GSK 
GlaxoSmithKline 
GSRS 
Gastrointestinal Symptom Rating Scale 
GSS 
Genotypic Susceptibility Score 
GUI 
Guidance 


 
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Abbreviation 
Description 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
HIV(-1) 
Human immunodeficiency virus (type 1) 
HIVTSQ 
HIV Treatment Satisfaction Questionnaire 
HSR 
Hypersensitivity reaction 
IA 
Interim Analysis 
IAS-USA 
International Antiviral Society-USA 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IN(I) 
Integrase (Inhibitor) 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
ITT(e) 
Intent-To-Treat Exposed 
LDL 
Low density lipoprotein 
LOCF 
Last Observation Carries Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAS-8 
Morisky 8-Item Medication Adherence Scale 
MMRM 
Mixed Model Repeated Measures 
NCEP 
National Cholesterol Education Program 
NNRTI 
Non-nucleoside Reverse Transcript Inhibitor 
NRTI 
Nucleoside Reverse Transcript Inhibitor 
OC 
Observed Case 
OSS 
Optimised Susceptibility Scoring 
PCI 
Potential Clinical Importance  
PDMP 
Protocol Deviation Management Plan 
PI 
Protease Inhibitor 
PP 
Per Protocol 
PSRAE 
Possibly suicidality related Adverse Event 
PSS 
Phenotypic Susceptibility Score 
QC 
Quality Control 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAMOS 
Randomization & Medication Ordering System  
RAP 
Reporting & Analysis Plan 
RNA 
Ribonucleic acid 
RTV 
Ritonavir 
RUCAM 
Roussel Uclaf Causality Assessment Method 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 


 
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Abbreviation 
Description 
SOP 
Standard Operation Procedure 
SVW 
Suspected Virologic Withdrawal 
TA 
Therapeutic Area 
TC 
Total Cholesterol 
TDF/FTC 
Tenofovir/emtricitabine 
TFL 
Tables, Figures & Listings  
TRDF 
Treatment Related Discontinuation = Failure 
VF 
Virologic Failure 
WHO 
World Health Organisation 
 
11.15.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
DOLUTEGRAVIR 
 
Monogram Biosciences 
EPZICOM/KIVEXA 
 
Norvir 
 
 
Quest Diagnostics 
 
 
Reyataz 
 
 
SAS 
 
 
Truvada 
 
 
TSCG 
 
 
TYLENOL 
 
 
 
 


 
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11.16. 
Appendix 16 – Example SAS code for Additional Estimand 2 
*Presented below are excerpts of code that can be used for the multiple 
imputation steps for the Additional Estimand 2 methodology for the 
Primary Efficacy Endpoint at Week 48; 
*The code has not been extensively QC’ed therefore care must be taken 
when implementing;  
 
*Programming Steps:  
[1] Select LOG HIV-1 RNA data from ADLB 
[2] Subset data by Treatment group  
[3] Multiple Imputation on the Continuous scale 
[3a]For LPV/RTV arm: run a simulation replacing BLQ with values from 
U(0,BLQ) distribution; 
 
 
* 100 simulated datasets; 
data step3a ; 
  set step3a ; 
  do i=1 to 100; 
    if substr(LBSTRESC,1,1)="<" then aval2 = rand('uniform')*1.59;  
                   *i.e. 1.59 is slightly below log(50) hence BLQ; 
    else aval2=aval; 
 
_imputation_ = i; 
 
output; 
  end;   
  drop i; 
run; 
 
*Programming steps continued: 
[3b] Transpose datasets LPV/RTV & DTG datasets ready for MI 
[3c] For LPV/RTV subjects, PROC MI to create Monotone structure; 
 
 
*** Note: AVAL1 = Week 1 (baseline), to AVAL52 (Week 52); 
*** Programming Note: add stratification factors; 
proc mi data=step3c out=DATAIN_MONO nimpute=1 seed=200304; 
    by _imputation_; 
 
var AVAL1 AVAL4 AVAL8 AVAL16 AVAL24 AVAL36 AVAL48 AVAL52;  
 
mcmc impute=monotone; 
run; 
  
*Programming steps continued: 
[3d] Impute the remaining monotone missing values 
 
*** Assumption: MAR; 
data DATAIN_MONO (rename=(_Imputation_=Imputation)); 
  set DATAIN_MONO ; 
run; 
 
*** Programming Note: add stratification factors; 
proc mi data= DATAIN_MONO out= DATAIN_REG nimpute=1 seed=200304; 
 
by Imputation; 
 
var AVAL1 AVAL4 AVAL8 AVAL16 AVAL24 AVAL36 AVAL48 AVAL52; 
 
monotone regression;  
run; 
 


 
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data DATAIN_REG; 
  set DATAIN_REG; 
  rename Imputation = _impute_; 
run; 
 
*Programming steps continued: 
[4] Merge DTG to LPV/RTV imputed dataset. For DTG dataset, create 
duplicate rows (=number of imputed datasets) 
 
data step4dtg ; 
  set step4dtg; 
  _impute_=1; 
  do _impute_= 1 to 100; 
  output; 
  end; 
run;  
 
*Programming steps continued: 
[5a] Remove non-IDMC affected subjects from LPV/RTV imputed dataset.  
[5b] Merge original data of non-IDMC LPV/RTV subjects LPV/RTV imputed, 
replacing imputed data for these subjects with original observations. 
Do so by creating duplicate rows (=number of imputed datasets) 
[6] apply Snapshot algorithm  
[7a] Perform CMH test & obtain Mantel-Haenszel estimate of the common 
odds ratio & P-value; 
 
*programming note: need to add stratification factors; 
*take care when specifying tables statement; 
 
proc freq data=step7; 
  tables trt01p * snapresp /cmh riskdiff measures ;   
  by _impute_ ; 
  ODS OUTPUT CMH=cmh COMMONRELRISKS=comrrout CrossTabFreqs  = Freqout 
measures=measures_est riskdiffcol1=riskdiff_est; 
RUN; 
 
 
data Prop (keep= p SEp TREAT _impute_ ); 
  set riskdiff_est ; 
  p=1-risk; 
  SEp=ase; 
  if Row in("Row 1","Row 2"); 
       if Row="Row 1" then TREAT="DTG    "; 
  else if Row="Row 2" then TREAT="LPV/RTV"; 
run; 
 
proc sort data=PROP; 
  by TREAT ; 
run; 
 
*Programming steps continued: 
[7b] Combine results; 
PROC MIANALYZE DATA=prop ; 
  modeleffects p ; 
  stderr SEp; 
  by TREAT ; 
RUN; 


 
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*Programming steps continued: 
[7c] for the P-value, apply Wilson-Hilferty transformation to the CMH 
statistic and standardize the resulting normal variable; 
 
DATA cmh_wh;  
  SET cmh(WHERE=(AltHypothesis="General Association")); 
  cmh_value_wh=((VALUE/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF)); 
  cmh_sterr_wh = 1.0; 
RUN; 
 
*Programming steps continued: 
[7d] Combine results; 
PROC MIANALYZE DATA=cmh_wh; 
  ODS OUTPUT PARAMETERESTIMATES=mian_cmh_wh; 
  MODELEFFECTS cmh_value_wh; 
  STDERR cmh_sterr_wh; 
RUN; 
 
*Programming steps continued: 
[7e] Compute one-sided p-value; 
DATA mian_cmh_wh_p;  
  SET mian_cmh_wh; 
  IF tValue > 0 THEN Probt_upper = Probt/2; 
  ELSE Probt_upper = 1-Probt/2; 
RUN; 
 


 
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11.17. 
Appendix 17 – End of Study Analysis 
This appendix will provide the details of planned analyses and data displays for 
MID200304 End of Study (EoS) reporting. These analyses may be included for 
disclosure purposes. 
11.17.1. 
General considerations for data analyses 
This section is written specifically for the EoS analysis. Since the primary 
analyses have been completed, the present section is written to cover only 
analyses included in the final EoS reporting. Only those definitions and 
derivations that have changed since the previous interim analyses will be 
included in this section, i.e., for the derivation of analysis windowing, how to deal 
with missing dates, definition of concomitant medications, etc. refer to the 
previous corresponding RAP sections. The current section summarises only the 
key endpoints of interest for the final analysis and explains any deviations from 
the previous analysis. 
The details of the final EoS reporting and analysis are described below: 
1) The analyses for which the data have not been changed since the primary 
(Week 48/52) analysis will not be reported again to avoid redundancy. 
This includes the analyses of demographic, baseline characteristics and 
health outcomes. 
2) No subgroup analysis, hypotheses testing, or statistical analyses will be 
performed. 
3) All required disclosure outputs following the FDAAA and EudraCT 
guidelines will be produced.  
11.17.1.1. Study Phases 
In the previous analysis (primary Week 48 reporting), data were summarised for 
the Randomised Phase of the study. However, when data from the Continuation 
Phase were available, certain displays were repeated for the combined period of 
Randomised plus Continuation Phases. For the EoS reporting, data from both 
study phases (Randomised Phase plus Continuation Phase) will be tabulated in 
one summary table, unless specified otherwise, and this will be noted in the title 
of the output. Listings will contain all the data with a new column added to specify 
the phase of the study for each record. Randomised and Continuation Phases 
are defined as below: 
Phase 
Start 
End  
Randomised Phase 
IP start date 
Non-switch participants: Week 
52 DOV, IP end date or 
Withdrawal date if on or before 
Week 52 DOV;  
Switch participants: last 
LTV/RPV treatment date.   
Continuation Phase 
Non-switch participants: 
IP end date or Withdrawal 


 
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Phase 
Start 
End  
Week 52 DOV+1 day; 
Switch participants: last 
LTV/RPV treatment date+1 
day.   
date if post Week 52 DOV 
Note: Switch participants are participants that switched from LPV/RTV to DTG treatment between 
Week 48 and Week 52 visits (Please see Section 11.17.1.3).  
Note: A participant enters the Continuation Phase if they have at least one exposure to the 
Investigational Product after the end of Randomisation Phase. 
11.17.1.2. Analysis Population for the Continuation Phase 
In addition to the populations defined in Section 4 of the RAP amendment 2, the 
following populations were defined for the End of Study Analysis: 
Population  
Definition/ Criteria.  
Analysis Evaluated  
Safety Continuation  
 
Comprises all participants in the 
Safety Population who receive at 
least one dose of Investigational 
Product after entering the 
Continuation Phase.  
• 
Safety  
Intent-to-Treat Exposed (ITT-E) 
Continuation  
Comprises all participants in the 
ITT-E Population who continue into 
the Continuation Phase. 
• 
Efficacy  
• 
Study Population 
Viral Genotypic 
Comprises all participants in the 
ITT-E Population with available on-
treatment genotypic resistance data.
• 
Genotypic 
Viral Genotypic Continuation  
Comprises all participants in the 
ITT-E- Continuation Population with 
available on-treatment genotypic 
resistance data in the Continuation 
Phase.  
• 
Genotypic  
Viral Phenotypic 
Comprises all participants in the 
ITT-E Population with available on-
treatment phenotypic resistance 
data.  
• 
Phenotypic 
Viral Phenotypic Continuation  
Comprises all participants in the 
ITT-E- Continuation Population with 
available on-treatment phenotypic 
resistance data in the Continuation 
Phase.  
• 
Phenotypic  


 
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11.17.1.3. Participants that Switched from LPV/RTV to DTG Treatment (“Switch 
participants”) 
Following the IDMC’s recommendation and as per Protocol Amendment No. 2, 
there are two instances where participants continue to have access to DTG in the 
Continuation Phase. One is that participants randomised to receive DTG who 
successfully complete 52 weeks of treatment, the other is that participants 
originally randomised to receive LPV/RTV but switched to DTG prior to or at 
Week 52. Treatment arm “Switch from LPV/RTV to DTG” is added for switch 
treatment participants in the Continuation Phase.  
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Dolutegravir 50mg once daily  
DTG 
1 
B 
Lopinavir/ritonavir 800mg/200mg 
once daily or 400mg/100mg twice 
daily 
LPV/RTV 
2 
B/A 
Lopinavir/ritonavir 800mg/200mg 
once daily or 400mg/100mg twice 
daily / Dolutegravir 50mg once daily  
Switch from LPV/RTV to DTG 
3 
NOTES: 
Order represents treatments being presented in TFL, as appropriate. 
For EoS reporting, detailed information for both DTG and switch participants are 
included in the corresponding listings. Summary statistics are done according to 
below: 
Two treatment arms are to be reported for summary tables that cover both 
Randomization Phase and Continuation Phase, one for DTG and the other for 
LPV/RTV. For Safety summary tables, only data before the switch date are to be 
included for the switch participants in the LPV/RTV arm. A footnote, “Data on or 
after the switch date are not included for participants who switched from 
LPV/RTV to DTG”, will be added for these tables. For Efficacy or Study 
Population summary tables, all data for the LPV/RTV arm will be included for the 
table, no matter whether the participants switched treatment to DTG or not. 
For summary tables that only cover Continuation Phase, the switch participants 
are included in the table as a separate arm. Data are summarised for DTG 
treatment group, Switch treatment group and Total.  


 
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11.17.1.4. Decision tree for Monogram resistance data analyses 
Decision tree for Monogram resistance data analyses 
• We might have resistance data that come from mixed datasets: PSGT, PSIN, GSIN (primary assays) 
vs PSGT+IN (secondary assay) 
• If one of the primary assay does not work for a specific timepoint, we might report the secondary 
assay if data is available. If all primary assays for a specific timepoint work then we report primary. 
For example, for baseline if the same assay section (PSGT, PSIN, GSIN) worked then we report. If 
at least one of PSGT or PSIN or GSIN didn’t work then we report secondary PSGT+IN.  
• Secondary assay testing results might not always be available. 
• For examples please refer to decision tree below. 
Background :  
• PSGT - provides both geno and pheno data for PRO/RT (NRTI and NNRTI) only 
• PSIN - Provides pheno data on Integrase only  
• GSIN - Provides geno data on Integrase only  
• PSGT+IN - Secondary assay used if PSGT or GSIN assay fails; it provides both geno and pheno 
data on PRO, RT and Integrase  
 
Table Symbol Key: 
y = assay test successful 
n = assay test failure 
2nd  = back up test performed 
bold = assay to use for analysis 
 
How to make decisions:  
Scenario 1: if primary PSGT, PSIN and GSIN assays all work) for both baseline and CVW 
samples, then PSGT+IN assay will not be performed , no PSGT+IN data should be generated.  
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
y 
y 
GSIN  
y 
y 
 
Scenario 2: If PSGT works for baseline, but PSIN and GSIN fail, then secondary PSGT+IN assay 
will be performed on baseline sample; similarly, if PSGT works for CVW sample but PSIN and 
GSIN  fail to work, in this scenario, use data generated from PSGT+IN assay on both Baseline and 
CVW sample for analyses, regardless of obtained PSGT assay data.  
Assays  
Baseline  
CVW 


 
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PSGT 
y 
y 
PSIN 
n 
n 
GSIN  
n  
n 
2nd PSGT+IN  
Y 
Y 
 
Scenario 3:  If PSGT, PSIN and GSIN all work for baseline samples; PSGT works for CVW but 
PSIN and GSIN fail, while PSGT+IN on CVW sample works, then use CVW PSGT+IN (PR, RT 
and INSTI) to do comparison with PSGT, PSIN and GSIN baseline data (do not use PSGT at 
CVW data vs. PSGT at Baseline) 
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
y 
n 
GSIN  
y 
n 
2nd PSGT+IN 
- 
Y 
 
Scenario 4: If PSGT works but GSIN and PSIN both fail on baseline sample, then secondary 
PSGT+IN assay might be performed. And if PSGT, PSIN and GSIN all work for CVW sample, 
then use Baseline PSGT+IN data to do comparison with CVW Primary assay data, regardless of 
PSGT Baseline data. In other words, don’t use PSGT Baseline to do comparison of PSGT part of  
PSGT+IN assay data for CVW sample 
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
n 
y 
GSIN  
n  
y 
2nd PSGT+IN  
Y 
- 
 
11.17.2. 
Study Population  
The study population summaries and data listings will be based on the ITT-E or 
ITT-E Continuation Population, unless otherwise specified. Demographic and 
baseline characteristics will not be reported in EoS. Participant accountability 
summary will be produced for the overall study and separately for the 
Continuation Phase. 
Overview of the key planned study population endpoints: 
• Study Populations 
• Participant Accountability 
• Concomitant and Antiretroviral Medications. 
• Protocol deviation.  
Full details of the data displays are given in Section 11.17.7.1. 


 
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11.17.3. 
Efficacy Analysis  
The study efficacy summaries and data listings will be based on the ITT-E 
Population except for Table 2.16. Table 2.16 summarises plasma HIV-1 RNA 
results for participants meeting CVW criteria during the Continuation Phase and 
is based on the ITT-E Continuation Population. 
Overview of the key planned efficacy endpoints: 
• Proportion of Participants with Plasma HIV-1 RNA < 50 c/ mL – 
Observed Data 
• Proportion of Participants with Confirmed Virologic Withdrawal – 
(observed data)  
• Change from baseline CD4+ cell count over time  
• Incidence of disease progression and HIV-associated conditions 
Full details of data displays are given in Section 11.17.7.2. 
11.17.4. 
Safety Analysis 
All safety displays will be based on the Safety Population or the Safety 
Continuation Population.  
The core adverse event displays for the final report have been identified based 
on the IDSL library required tables. For the purposes of summarising the AE 
data, unless stated otherwise, the summaries will include only those AEs that 
occurred during the Continuation Phase. Common AEs are those with 2% 
(without rounding) incidence for any treatment.  
Summaries of AEs required for the FDAAA and EudraCT will be generated in this 
report. These summaries will include participants from both the Randomised and 
Continuation Phases. Common and/or serious AEs will be summarized for the 
Continuation Phase. SAEs and non-SAEs will be listed for Mexican participants 
only.  
Summaries of Maximum Post-Baseline Grade 3 or 4 Emergent Clinical Toxicities 
and Hepatobiliary Abnormality criteria will be reported only for the events that 
occurred during the Continuation Phase.  
A new figure of cumulative exposure showing the number of participants exposed 
to DTG and LPV/RTV over time will be added for EoS reporting. Missing 
Treatment stop date will be imputed as the last day of month or year if partial 
dates, the date of last visit or the recorded date of withdrawal/completion, 
whichever is earlier. 
Overview of the key planned safety endpoints: 
• Extent of Exposure 
• Adverse Events  
• Maximum Post-Baseline Emergent Clinical Chemistry/ Haematology 
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• Hepatobiliary Laboratory Abnormality Criteria 
• Liver Events Assessment 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Full details of data displays are given in Section 11.17.7.3. 
11.17.5. 
Virology analysis  
The virology summaries will be based on the Viral Genotypic and Viral 
Phenotypic Continuation Populations, unless otherwise specified.  Data listings 
will be presented for the ITT-E Population, unless otherwise specified. 
Virology summaries will focus on the Continuation Phase and be tabulated only 
for participants in the Viral Genotypic or Genotypic Continuation Population 
except table 4.2 and 4.3. Table 4.2 and 4.3 summarises emergent major 
mutations during Randomised Phase and is based on Viral Genotypic 
Population. Emergent Major Mutations of NRTI, NNRTI and PI Classes and 
Emergent Prespecified INSTI mutations are summarised both for the 
Randomised and the Continuation Phases in separate Tables.  
Prespecified lists of integrase substitutions have been modified since the 
previous interim analysis, hence an updated list of known INSTI mutations has 
been added in Error! Reference source not found. and IAS-USA major r
esistance associated mutations (RAMs) to other classes (i.e., NRTI, NNRTI, PI) 
are listed in Error! Reference source not found..  
Table 13 
Known INSTI mutations associated with the development of 
resistance to RAL, EVG or DTG  
Amino Acids 
in HIV 
Integrase for 
Analysis 
H51Y, T66A/I/K, L74M, E92Q/V/G, Q95K, T97A, G118R, 
F121Y, E138A/K, G140A/C/S, Y143C/H/R/K/S/G/A, P145S, 
Q146P, S147G, Q148N/H/K/R, V151I/L/A, S153F/Y, 
N155H/S/T, E157Q, G163R/K, S230R, R263K, L68V/I*, L74I*, 
E138T*, G193E* 
 
NOTES: 
• 
Current listing includes INSTI mutations identified via the Stanford HIV Resistance 
database, or identified during in vitro passage of DTG, or as seen in a previous DTG 
studies in INSTI-experienced participants (i.e. ING112574) and may be modified in case 
of additional substantive data availability.  
• 
INSTI mutations in bold have the maximum score of 60 and are for any INSTI drug in the 
Stanford database v8.9 (http://hivdb.stanford.edu/DR/cgi-
bin/rules_scores_hivdb.cgi?class=INSTI last updated on 25 OCT 2019 and accessed on 
17 FEB 2020); the rest have a maximum score <60.  
• 
The INSTI mutations listed are historically identified via the Stanford HIV Resistance 
database, and also include mutations identified during in vitro passage of DTG, or as 
seen in a previous DTG study in INI-experienced participants (ING112574).  
• 
This table is updated only by Virologists.  


 
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Table 14 
Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as 
defined by the International Antiviral Society-USA (IAS-USA).  
Class 
Mutations 
NRTIs 
M41L, K65R/E/N, D67N, 69 insert, K70E/R, L74V, Y115F, M184V/I, 
L210W, T215Y/F, K219Q/E; [A62V, V75I, F77L, F116Y, Q151M] 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138A/G/K/Q/R, 
V179L,Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, 
M230I/L 
PIs 
D30N,V32I , M46I/L, I47A/V, G48V, I50V/L, I54V/M/L, Q58E, T74P, 
L76V, V82A/T/F/L/S, N83D, I84V, N88S, L90M 
NOTES: 
• 
Updated to “2019 Resistance Mutations Update Volume 27 Issue 3, July/August 2019 
• 
The most up to date IAS-USA guidelines available at the time of DBF will be used in the 
analysis. 
• 
Q151M Complex: Q151M usually occurs in combination with two or more of the following 
four accessory NRTI mutations A62V, V75I, F77L, and F116Y However if any one of 
these mutations occur alone, they shall be considered as major mutation for the NRTI 
class.  
 
Clinical and Biological Cut-off Values for the PhenoSense HIV Drug Resistance 
Assay have changed since the previous interim analysis, hence for EoS 
phenotypic susceptibility will be categorised according to Fold Change as shown 
in Table 15 (based on Monogram PhenoSense assay). 


 
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Table 15 
Clinical and Biological Cutoff Values for the PhenoSense HIV Drug 
Resistance Assay 
Drug 
Abbreviation 
Class 
PhenoSense 
Cutoff 
Abacavir 
ABC 
NRTI 
(4.5 – 6.5)a 
Lamivudine 
3TC 
NRTI 
3.5 a 
Didanosine 
ddI 
NRTI 
(1.3 – 2.2) a 
Stavudine 
d4T 
NRTI 
1.7 a 
Zidovudine 
AZT (ZDV) 
NRTI 
1.9 
Emtricitabine 
FTC 
NRTI 
3.5 
Tenofovir 
TDF 
NRTI 
(1.4 – 4) a 
Delavirdine 
DLV 
NNRTI 
6.2 
Efavirenz 
EFV 
NNRTI 
3 
Nevirapine 
NVP 
NNRTI 
4.5 
Etravirine 
ETR 
NNRTI 
(2.9-10) a 
Rilpivirine 
RPV 
NNRTI 
2.5 
Fosamprenavir 
FPV 
PI 
2 a,c 
Fosamprenavir/r 
FPV/r 
PI 
(4-11) a 
Atazanavir 
ATV 
PI 
2.2 a, 
Atazanavir/r 
ATV/r 
PI 
5.2 a,c 
Indinavir/r 
IDV/r 
PI 
10 a 
Lopinavir/r 
LPV/r 
PI 
(9 – 55) a 
Nelfinavir 
NFV 
PI 
3.6 
Saquinavir 
SQV 
PI 
1.7 a,c 
Saquinavir/r 
SQV/r 
PI 
(2.3 – 12) a 
Tipranavir/r 
TPV/r 
PI 
(2 – 8) a 
Darunavir/r 
DRV/r 
PI 
(10 – 90) a 
Ritonavir 
RTV 
PI 
2.5 
Enfuvirtide 
T20 
FI 
6.48b 
Raltegravir 
RAL 
INSTI 
1.5 
Elvitegravir 
EVG 
INSTI 
2.5  
Dolutegravir 
DTG 
INSTI 
(4-13) a 
a: clinical cutoff (lower cutoff – higher cutoff) 
b: standard cut-off used by Monogram Inc. until clinical or biological cutoff have been 
determined  
c: Only the boosted cutoff shall be used to compute the PhenoSense sensitivity for 
Atazanavir, Fosamprenavir and Saquinavir except stated otherwise. 
 
Overview of the key planned virology endpoints: 
• Genotypic and Phenotypic Accountability  
• INSTI mutations  
• Major NRTI, NNRTI, PI mutations   
• Fold Change to DTG  


 
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Full details of data displays are given in Section 2.7.4. 
11.17.6. 
COVID - 19 analysis 
This study started in 2014 and continued during the COVID -19 pandemic. The 
information regarding the number of participants affected by COVID-19 and its 
symptoms will be reported according to GSK core standards. The visits impacted 
due to the pandemic outbreak will be reported. Protocol deviations or adverse 
events related to COVID-19 if any, will also be reported according to GSK core 
standards.  


 
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11.17.7. 
Data Displays for End of Study Final Report 
• Outputs that were not reported at Week 48 reporting are identified in Programming Notes as ‘New output’ 
11.17.7.1. Study Population  
Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Table 
1.1 
All Participants Screened  Summary of Study Populations 
  
Table 
1.2 
ITT-E 
Summary of Number of Participants by Study Visit  
New output (refer to the template 
provided) 
Table 
1.5 
ITT-E 
Summary of Participant Accountability: Study 
Conclusion Record by Relationship to COVID-19 
Pandemic 
FDAAA, EudraCT 
Have an overall and then split by 
COVID-19 relationship 
Table 
1.7 
ITT-E Continuation 
Summary of Participant Accountability: Continuation 
Phase Conclusion Record by Relationship to COVID-
19 Pandemic 
Have an overall and then split by 
COVID-19 relationship 
Table 
1.10 
ITT-E 
Summary of Important Protocol Deviations by 
Relationship to COVID-19 Pandemic 
Have an overall and then split by 
COVID-19 relationship 
Table 
1.26 
ITT-E 
Summary of Concomitant Medication by ATC Level 1 
and Ingredient  
Only non-ART medications  
Listing - ICH 
4 
 ITT-E  
Listing of Study Conclusions Reasons for Study 
Withdrawal 
  


 
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Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Listing - ICH 
8 
 ITT-E  
Listing of Important Protocol Deviations 
  
Listing - Other 
29 
All Participants Screened Listing of Study Populations 
  
Listing - Other 
31 
 ITT-E 
Listing of Visit Dates 
  
Listing - Other 
38 
 ITT-E 
Listing of Concomitant Medications 
  
Listing - Other 
39 
 ITT-E 
Listing of Relationship Between ATC Level 1, 
Ingredient and Verbatim Text 
  
Listing - Other 
41 
 ITT-E 
Listing of Concomitant and Post-treatment 
Antiretroviral Therapy 
  
Listing - Other 
43 
 ITT-E 
Listing of Relationship Between ATC Level 4, 
Ingredient and Verbatim Text for ART 
  
Listing - Other 
79 
 ITT-E 
All Non-Important COVID-19 Related Protocol 
Deviations 
New output (refer to Sailing EoS L.41) 
No figures for the Study Population.  


 
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11.17.7.2. Efficacy  
Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Table 
2.8 
ITT-E 
Summary of Proportion of Participants with Plasma 
HIV-1 RNA <50 c/mL by Visit -Observed Data  
Observed data calculates proportions 
using denominator of subjects with 
HIV RNA readings at visit week  
Table 
2.15 
ITT-E  
Proportion of Participants Meeting CVW Criteria by 
Visit by Type of Virologic Failure -Observed Data  
Proportion instead of 'Cumulative 
Proportion' comparing to w48 RE.  
Observed data calculates proportions 
using denominator of subjects with 
HIV RNA readings at visit week  
Table 
2.16 
ITT-E Continuation 
Distribution of Quantitative Plasma HIV-1 RNA 
Results at Suspected and Confirmation of Virologic 
Withdrawal Criteria for Participants with CVW During 
the Continuation Phase 
  
Table 
2.19 
ITT-E 
Summary of Post-Baseline HIV-1 Associated 
Conditions Including Recurrences 
  
Table 
2.20 
ITT-E 
Summary of Post-Baseline HIV-1 Associated 
Conditions Excluding Recurrences 
  
Table 
2.21 
ITT-E 
Summary of Post-Baseline HIV-1 Disease 
Progressions 
  


 
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Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Table 
2.22 
ITT-E 
Summary of Change from Baseline in CD4+ Cell 
Count (cells/mm^3) by Visit 
  
Table 
2.23 
ITT-E 
Summary of Change from Baseline in Plasma HIV-1 
RNA (log10 c/mL) by Visit 
  
Listing - ICH 
12 
ITT-E 
Listing of Quantitative Plasma HIV-1 RNA Data 
  
Listing - Other 
44 
ITT-E 
Listing of CD4+ Cell Count Data 
 
Listing - Other 
45 
ITT-E 
Listing of HIV-1 Associated Conditions 
  
Listing - Other 
47 
ITT-E 
Listing of Viral Load over time for Participants with 
CVW Criteria  
W48 RE only reported participants 
with CVW during continuation phase.  
Here please report all participants with 
CVW and group by phase.  
Figure 
2.8 
ITT-E 
Individual Plasma HIV-1 RNA and CD4+ Profiles by 
Visit for Participants with at least One Suspected 
Virologic Withdrawal Criteria Met  
Please use title and shell from F2.3 
gsk3515864/mid204861/primary_15 
 


 
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11.17.7.3. Safety  
Type 
Display 
Number 
Population  
Display Title 
Programming Notes 
Table 
3.1 
Safety Continuation  
Summary of Extent of Exposure to Investigational 
Product for Participants who Entered Continuation 
Phase 
  
Table 
3.2 
Safety  
Summary of Extent of Exposure to Investigational 
Product for All Participants in Randomised and 
Continuation Phase 
  
Table 
3.5 
Safety Continuation 
Summary of All Adverse Events by System Organ 
Class, Preferred Term and Maximum Toxicity - 
Continuation Phase 
  
Table 
3.6 
Safety Continuation 
Summary of Common (>=2%) Adverse Events by 
Preferred Term and Overall Frequency - Continuation 
Phase 
Common adverse events are those 
with >=2% (with rounding) incidence 
for any treatment. 
Table 
3.7 
Safety Continuation 
Summary of Common (>=2%) Grade 2-4 Adverse 
Events by Preferred Term and Overall Frequency - 
Continuation Phase 
Common adverse events are those 
with >=2% (with rounding) incidence 
for any treatment. 
Table 
3.9 
Safety Continuation 
Summary of All Drug-related Adverse Events by 
System Organ Class, Preferred Term and Maximum 
Toxicity - Continuation Phase 
  


 
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Type 
Display 
Number 
Population  
Display Title 
Programming Notes 
Table 
3.11 
Safety Continuation 
Summary of Common (>=2%) Drug-related Grade 2-4 
Adverse Events by Overall Frequency - Continuation 
Phase 
Common adverse events are those 
with >=2% (with rounding) incidence 
for any treatment. 
Table 
3.13 
Safety Continuation 
Summary of Serious Adverse Events by System 
Organ Class and Preferred Term - Continuation 
Phase 
  
Table 
3.18 
Safety Continuation 
Summary of Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Study 
Treatment by System Organ Class and Preferred 
Term - Continuation Phase 
  
Table 
3.20 
Safety  
Summary of Participants and Number of Occurrences 
of Common (>= 2%) Non-Serious Adverse Events by 
System Organ Class and Preferred Term - 
Randomised and Continuation Phases 
FDAAA, EudraCT 
Common adverse events are those 
with >=2% (without rounding) 
incidence for any treatment. 
Table 
3.21 
Safety  
Summary of Participants and Number of Occurrences 
of Serious Adverse Events by System Organ Class 
and Preferred Term - Randomised and Continuation 
Phases 
 FDAAA, EudraCT 
 
Table 
3.22 
Safety 
Summary of COVID-19 Assessment for Participants 
with COVID-19 Adverse Events 
New output. Please refer to Sailing 
EoS T8.26 


 
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Type 
Display 
Number 
Population  
Display Title 
Programming Notes 
Table 
3.23 
Safety 
Summary of COVID-19 Symptoms for Participants 
with COVID-19 Adverse Events 
New output. Please refer to Sailing 
EoS T8.27 
Table 
3.36 
Safety Continuation 
Summary of Maximum Post-Baseline Emergent 
Clinical Chemistry Toxicities - Continuation Phase 
 
Table 
3.38 
Safety Continuation 
Summary of Maximum Post-Baseline Emergent 
Hematology Toxicities - Continuation Phase 
 
Table 
3.45 
Safety Continuation 
Summary of Participants Meeting Hepatobiliary 
Laboratory Abnormality Criteria - Post-Baseline 
Emergent - Continuation Phase 
Abbreviated (see template provided) 
Table  
3.48 
Safety 
Summary of Participants with C-SSRS Suicidal 
Ideation or Behaviour during Treatment 
 
Listing - ICH 
15 
Safety 
Listing of Investigational Product Exposure Data 
Star * Switch participant and add 
footnote 
Listing - ICH 
18 
Safety 
Listing of All Adverse Events 
 Star * Switch participant and add 
footnote 
Listing - ICH 
21 
Safety 
Listing of Fatal Serious Adverse Events 
  
Listing - ICH 
22 
Safety 
Listing of Non-Fatal Serious Adverse Events 
  


 
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Type 
Display 
Number 
Population  
Display Title 
Programming Notes 
Listing - ICH 
23 
Safety 
Listing of Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Study 
Treatment 
  
Listing - ICH 
24 
 Safety 
Listing of Relationship of Adverse Event System 
Organ Class, Preferred Terms and Verbatim Text 
  
Listing - Other 
 25 
 Safety 
Listing of Non-Serious AEs of Mexican Participants 
 New output 
Listing - Other 
 26 
 Safety 
Listing of SAEs of Mexican Participants 
 New output 
Listing - Other 
 27 
 Safety 
Listing of SAEs of Non-Mexican Participants 
 New output 
Listing-Other 
28 
Safety 
Listing of COVID-19 Assessments and Symptoms 
New output 
Listing - Other 
53 
 Safety 
Listing of Participants Who Became Pregnant During 
the Study 
  
Listing - Other 
56 
 Safety 
Listing of Laboratory Data for Participants with Grade 
3 or 4 Post-Baseline Emergent Toxicities 
  
Listing - Other 
57 
Safety Continuation 
Listing of Post Baseline Maximum ALT and Maximum 
Bilirubin – Continuation Phase 
New output (Please refer to Sailing 
EoS L.30) 
Listing - Other 
58 
Safety Continuation 
Listing of Participants Meeting Hepatobiliary 
Laboratory Criteria -Continuation Phase 
 


 
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Type 
Display 
Number 
Population  
Display Title 
Programming Notes 
Listing - Other 
59 
Safety 
Listing of Liver Monitoring/Stopping Event Reporting 
  
Listing - Other 
86 
Safety 
Listing of Start and Stop Dates in the 
Continuation Phase 
New output. Please refer to Listing 86 
in Aria 
Listing - Other 
93 
Safety 
Listing of C-SSRS Suicidal Ideation and 
Behaviour Data 
 
Figure 
3.5 
 Safety Continuation 
Scatter Plot of Maximum Post-Baseline ALT vs. 
Maximum Post-Baseline Total Bilirubin - Continuation 
Phase 
  
Figure 
 3.6 
 Safety 
Plot of Cumulative Exposure to Investigational 
Product 
Please refer to Sailing EoS F8.27  
For switch subjects, only data before 
the switch date will be plotted 
 


 
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Virology 
Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Table 
4.1 
Viral Genotypic 
Continuation  
Summary of Participant Accountability: Genotypes 
Available - Continuation phase 
  
Table 
4.2 
Viral Genotypic 
Summary of Emergent Major Mutations of NRTI, 
NNRTI and PI Classes for Participants with CVW - 
Randomised Phase 
  
Table 
4.201 
Viral Genotypic 
Continuation  
Summary of Emergent Major Mutations of NRTI, 
NNRTI and PI Classes for Participants with CVW - 
Continuation phase 
  
Table 
4.3 
Viral Genotypic 
Summary of Pre-specified Treatment Emergent INSTI 
Substitutions at Time of Confirmed 
Virologic Withdrawal - Randomised Phase 
 
Table 
4.301 
Viral Genotypic 
Continuation  
Summary of Pre-specified Treatment Emergent INSTI 
Substitutions at Time of Confirmed 
Virologic Withdrawal - Continuation Phase 
 
Table 
4.5 
Viral Phenotypic 
Continuation  
Summary of Participant Accountability: Phenotype 
Available - Continuation phase 
  
Table 
4.8 
Viral Phenotypic 
Continuation  
Summary of Fold Change to DTG at Baseline and 
Time of CVW - Continuation Phase 
  
Listing Other 
77 
ITT-E 
Listing of All Genotypic Data 
  


 
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Type 
Display 
Number 
Population 
Display Title 
Programming Notes 
Listing Other 
78 
ITT-E 
Listing of All Phenotypic Data 
  
Listing Other 
80 
ITT-E 
Listing of Virology Data for Participants with CVW  
Please follow SAILING EoS L.37 
format  
Listing Other 
82 
ITT-E 
Listing of Virology Data for Participants with On-
Treatment Virology Results at Non-CVW timepoints 
Please follow SAILING EoS L.38 
format  
Listing Other 
83 
ITT-E 
Participant Level Summary of Key Virologic Data of 
Background Regimens for Participants with On-
Treatment Virology Results at CVW timepoints 
 
Listing Other 
84 
ITT-E 
Participant Level Summary of Key Virologic Data of 
Background Regimens for Participants with On-
Treatment Virology Results at Non-CVW timepoints  
New output, same format as L.83 
 
No figures for Virological Analysis


 
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11.17.8. 
Abbreviations and Trademarks  
11.17.8.1. Abbreviations 
ALT 
Alanine aminotransferase 
ART 
Antiretroviral Therapy 
BID 
Twice Daily 
DTG 
Dolutegravir 
EoS 
End of Study 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FDAAA 
Food and Drug Administration Amendment Act (2007) 
FI 
Fusion Inhibitor  
GSS 
Genotypic susceptibility score 
IAS-USA 
International Antiviral Society-USA 
INSTI  
Integrase Strand Transfer Inhibitor 
ITT-E 
Intent-to-Treat-Exposed 
mITT-E 
Modified Intent-to-Treat-Exposed 
NRTI 
Nucleoside reverse transcriptase inhibitor 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
CVW 
Confirmed Virologic Withdrawal 
PI 
Protease Inhibitor 
QD 
Once daily  
LPV/RTV 
Lopinavir/Ritonavir 
RAP 
Reporting and analysis plan 
RAM 
Resistance Associated Mutations  
TAM 
Thymidine Analogue-Associated Mutations 


 
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Example Mock Shells for Data Displays 
Table 2.15 Proportion of Participants Meeting CVW Criteria by Visit by Type of Virologic Failure 
Protocol: 200304                                                                                 Page 1 of 2 
Population: Intent-To-Treat Exposed 
                                                 Table 2.15 
           Proportion of Participants Meeting CVW Criteria by Visit by Type of Virologic Failure 
 
                                                   DTG                  LPV/RTV 
                Virologic Failure Type             (N=312)              (N=312) 
                --------------------------------------------------------------------------- 
                Any time                            296                  298                   
                 CVW                                 27   (X%)            31   (X%) 
                  Virologic non-response              4   (1%)            14   (5%) 
                  Rebound                            23   (8%)            17   (6%) 
 
                Week 16                             290                  296 
                 CVW                                 X   (X%)            X   (X%) 
                  Virologic non-response              1  (<1%)             0 
                  Rebound                             0                    1  (<1%) 
 
                Week 24                             293                   287  
                 CVW                                 xx   (X%)            xx   (X%) 
                  Virologic non-response              3   (1%)            11   (4%) 
                  Rebound                             2  (<1%)             6   (2%) 
                 .. 
                 .. 
                 .. 
               Week 216 
 
Note: The denominator for the proportion is the number of subjects with viral load data at visit week. 
Note: Subjects who switched treatment from LPV/RTV to DTG by Week 52 are included in their original treatment group, and 
all data from before and after switch dates are included in this summary table. 


 
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Table 3.13 Summary of Serious Adverse Events by System Organ Class and Preferred Term - Continuation Phase 
System Organ Class 
Preferred term 
DTG 
N=(XX) 
Switch from LPV/RTV to 
DTG 
(N=12) 
Total 
(N=XX) 
Any Event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Infections and infestations 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Any event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Nasopharyngitis 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 


 
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Table 4.1 
Viral Genotypic Continuation  
Summary of Participant Accountability: Genotypes Available - Continuation phase
 
  
Reference: Sailing Table 12.1 
 
Protocol: 200304                                                                              Page 1 of 1 
Population: Viral Genotypic Continuation 
                                                 Table 4.1 
                 Summary of Participant Accountability: Genotypes Available - Continuation phase 
 
                                                                 
               Genotype                                                 DTG            
                Assessment                                            (N=XX)           
               ------------------------------------------------------------------------------ 
               Integrase  
                 Screening Sample                                     XX (<1%)       
                 Baseline Sample                                      XX (XX%)      
                 On-Treatment CVW Sample                              XX (XX%)      
                 On-Treatment Non-CVW Sample                          XX (<1%)       
                 Baseline & On-Treatment CVW Sample                   XX (XX%)      
                 Baseline & On-Treatment Non-CVW Sample               XX (<1%)       
 
               Protease 
                 …… 
               Reverse Transcriptase 
                 …… 
 
 
Note: ’On-treatment CVW’ is at the time of confirmed virologic withdrawal. 
Note: Decision tree for Monogram resistance data has been used. 
Note: Baseline is set to latest pre-treatment assessment. If Day 1 sample is not available, 
screening sample will be used as baseline. 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 2 3  
 
Ta ble  4. 2  
Viral Ge n ot y pic  
 
S u m m a r y  o f  E m e r g e n t  M a j o r  M u t a t i o n s  o f  N R T I ,  N N R T I  a n d  P I  C l a s s e s  f o r  P a r t i c i p a n t s  w i t h  C V W  -  R a n d o m i s e d  P h a s e  
  
 
T a b l e  4 . 2 0 1  V i r a l  G e n o t y p i c  C o n t i n u a t i o n   
 
S u m m a r y  o f  E m e r g e n t  M a j o r  M u t a t i o n s  o f  N R T I ,  N N R T I  a n d  P I  C l a s s e s  f o r  P a r t i c i p a n t s  w i t h  C V W  -  C o n t i n u a t i o n  p h a s e    
R e f e r e n c e  S a i l i n g  1 2 . 1  
 
P r o t o c o l :  2 0 0 3 0 4                                                                               P a g e  1  o f  3  
P o p u l a t i o n :  V i r a l  G e n o t y p i c  
                                                 T a b l e  4 . 2  
                S u m m a r y  o f  E m e r g e n t  M a j o r  M u t a t i o n s  o f  N R T I ,  N N R T I  a n d  P I  C l a s s e s  f o r  P a r t i c i p a n t s  w i t h  C V W  -  R a n d o m i s e d   
P h a s e  
 
R e g i o n :  N R T I  
                                                                         D T G            L P V / R T V  
         C o d o n                            M u t a t i o n                         ( N = 1 1 )         ( N = 3 0 )  
         - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
         A n y                              A n y  M u t a t i o n                      1   ( 9 % )        3  ( 1 0 % )  
 
         D 6 7                              A n y  M u t a t i o n                      1   ( 9 % )        0  
                                          A n y  D 6 7 N                         1   ( 9 % )        0  
                                           D 6 7 N                            1   ( 9 % )        0  
 
         K 7 0                              A n y  M u t a t i o n                      0              2   ( 7 % )  
                                          A n y  K 7 0 R                         0              2   ( 7 % )  
                                           K 7 0 K / Q / R                        0              1   ( 3 % )  
                                           K 7 0 K / R                          0              1   ( 3 % )  
R e g i o n :  N N R T I  
R e g i o n :  P I     
 
N o t e :  D e c i s i o n  t r e e  f o r  M o n o g r a m  r e s i s t a n c e  d a t a  h a s  b e e n  u s e d  
N o t e :  S u b j e c t   
 w a s  r a n d o m i s e d  t o  L P V / R T V  b u t  a c t u a l l y  r e c e i v e d  D T G  t r e a t m e n t  a n d  i n c l u d e d  
i n  t h e  L P V / R T V  t r e a t m e n t  g r o u p .  
 
V i r a l  G e n o t y p i c                :  I T T E  +  a f t e r  b a s e l i n e  P F  d a t a ,   
 
V i r a l  G e n o t y p i c  C o n t i n u a t i o n   :  V i r a l  G e n o t y p i c  +  c o n t i n u a t i o n  p h a s e  P F  d a t a .  
 
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 2 4  
 
Ta ble  4. 3  
Viral Ge n ot y pic  
Pre -s pecifi e d Treat me nt E mer ge nt I N S TI S u bstit uti o ns at Ti me of C o nfir me d Vir ol o gic Wit h dra wal 
- Ra n d o mise d P hase  
 
T a b l e  4 . 3 0 1  V i r a l  G e n o t y p i c  C o n t i n u a t i o n   
P r e - s p e c i f i e d  T r e a t m e n t  E m e r g e n t  I N S T I  S u b s t i t u t i o n s  a t  T i m e  o f  C o n f i r m e d  
V i r o l o g i c  W i t h d r a w a l  -  C o n t i n u a t i o n  P h a s e  
 
 
P r o t o c o l :  2 0 0 3 0 4                                                                                  P a g e  1  o f  2  
P o p u l a t i o n :  V i r a l  G e n o t y p i c  
                                                 T a b l e  4 . 3  
            S u m m a r y  o f  E m e r g e n t  P r e - s p e c i f i e d  I N S T I  S u b s t i t u t i o n s  a t  T i m e  o f  C o n f i r m e d  
                            V i r o l o g i c  W i t h d r a w a l  D u r i n g  t h e  R a n d o m i s a t i o n  P h a s e  
 
R e g i o n :  I N S T I  
                                                               D T G            L P V / R T V  
                   C o d o n                  M u t a t i o n               ( N = X X )         ( N = X X )  
                   - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
                   A n y                    A n y  M u t a t i o n            X X  ( X X % )        X X   ( X X % )  
 
                   5 1                     n                       X X  ( X X % )        0  
                                         A n y  C h a n g e              X X  ( X X % )        0  
                                         H 5 1 H / Y                  X X  ( X X % )        0  
 
 
 
N o t e :  P r e - s p e c i f i e d  I N S T I  S u b s t i t u t i o n s  A s s o c i a t e d  w i t h  D e v e l o p m e n t  o f  R e s i s t a n c e  t o  I N S T I  C l a s s :  
H 5 1 Y ,  T 6 6 A ,  T 6 6 I ,  T 6 6 K ,  L 7 4 M ,  E 9 2 Q ,  E 9 2 V ,  E 9 2 G ,  Q 9 5 K ,  T 9 7 A ,  G 1 1 8 R ,  F 1 2 1 Y ,  E 1 3 8 A ,  E 1 3 8 K ,  
G 1 4 0 A ,  G 1 4 0 C ,  G 1 4 0 S ,  Y 1 4 3 C ,  Y 1 4 3 H ,  Y 1 4 3 R ,  Y 1 4 3 K ,  Y 1 4 3 S ,  Y 1 4 3 G ,  Y 1 4 3 A ,  P 1 4 5 S ,  Q 1 4 6 P ,  S 1 4 7 G ,  
Q 1 4 8 N ,  Q 1 4 8 H ,  Q 1 4 8 K ,  Q 1 4 8 R ,  V 1 5 1 I ,  V 1 5 1 L ,  V 1 5 1 A ,  S 1 5 3 F , S 1 5 3 Y ,  N 1 5 5 H ,  N 1 5 5 S ,  N 1 5 5 T ,  E 1 5 7 Q ,  G 1 6 3 R ,  
G 1 6 3 K ,  S 2 3 0 R ,  R 2 6 3 K ,  L 6 8 V * ,  L 6 8 I * ,  L 7 4 I * ,  E 1 3 8 T * ,  G 1 9 3 E *  
N o t e :  D e c i s i o n  t r e e  f o r  M o n o g r a m  r e s i s t a n c e  d a t a  h a s  b e e n  u s e d  
N o t e :  S u b j e c t   
 w a s  r a n d o m i s e d  t o  L P V / R T V  b u t  a c t u a l l y  r e c e i v e d  D T G  t r e a t m e n t  a n d  i n c l u d e d  
i n  t h e  L P V / R T V  t r e a t m e n t  g r o u p .  
P P D


 
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Table 4.5 
Viral Phenotypic Continuation  
 
Summary of Participant Accountability: Phenotype Available - Continuation phase   
 
Protocol: 200304                                                                              Page 1 of 2 
Population: Viral Phenotypic Continuation 
                                                 Table 4.5 
                 Summary of Participant Accountability: Phenotypes Available - Continuation phase 
 
               Phenotype                                           DTG            
                Assessment                                         (N=XX)        
               ------------------------------------------------------------------------------ 
               INSTI 
                 Screening Sample                                    XX (<1%)        
                 Baseline Sample                                     XX (XX%)       
                 On-Treatment CVW Sample                             XX (XX%)       
                 On-Treatment Non-CVW Sample                         XX (<1%)       
                 Baseline & On-Treatment CVW Sample                  XX (XX%)       
                 Baseline & On-Treatment Non-CVW Sample              XX (<1%)       
 
               NRTI 
                …… 
               PI 
                …… 
               NNRTI 
                …… 
 
 
Note: 'On-treatment CVW' is at the time of confirmed virologic withdrawal. 
Note: Decision tree for Monogram resistance data has been used 
Note: Baseline is set to latest pre-treatment assessment. If Day 1 sample is not available, 
screening sample will be used as baseline. 


 
CONFIDENTIAL 
 
 
 
200304 
126 
 
Table 4.8 
Viral Phenotypic Continuation  
Summary of Fold Change to DTG at Baseline and Time of CVW - Continuation 
Phase  Reference sailing table 12.8 
 
Protocol: 200304                                                                              Page 1 of 4 
Population: Viral Phenotypic Continuation 
                                                 Table 4.8 
          Summary of Fold Change to DTG at Baseline and Time of CVW  - Continuation Phase 
                                                                           DTG           LPV/RTV 
       Drug        Timepoint                                               (N=11)        (N=29) 
       ---------------------------------------------------------------------------------------------- 
       DTG         Baseline      Fold Change 
                                   n                                        11            27 
                                   <1                                        5 (45%)      17 (59%) 
                                   1-<2                                      6 (55%)      10 (34%) 
                                   2-<4                                      0             0 
                                   4-<8                                      0             0 
                                   >=8                                       0             0 
 
                                 Fold Change (class) 
                                   n                                        11            27 
                                   Geom. Mean                                0.99          0.94 
                                   CV(%)                                    20.180        24.976 
                                   Median                                    1.02          0.94 
                                   Q1                                        0.84          0.78 
                                   Q3                                        1.08          1.12 
                                   Min.                                      0.68          0.65 
                                   Max.                                      1.41          1.91 
 
       DTG         CVW           Fold Change 
                                  …… 
 
Note: CV (Coefficient of Variation) = 100*sqrt(exp((SD on log scale)^2)-1). 
Note: Decision tree for Monogram resistance data has been used 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 2 7  
 
Listi n g Ot her  7 7  
I T T-E  Listi n g of All Ge n ot y pic Data  
R e f e r e n c e  S a i l i n g  L i s t i n g   3 4  
 
-  
S h o w  a l l  a v a i l a b l e  P F G R P I D  t e s t  r e s u l t s ,  f o r  e x a m p l e  P S G T  A A ,  a n d  P S G T I N  A A  f o r  t h e  s a m e  v i s i t .  
 
P r o t o c o l :  2 0 0 3 0 4                                                                             P a g e  1  o f  x  
P o p u l a t i o n :  I T T - E  
                                                 L i s t i n g  7 7  
                                       L i s t i n g  o f  A l l  G e n o t y p i c  D a t a  
 
T r e a t m e n t :  D T G   
                 D a t e /  
                 S c h e d .  V i s i t /  
S i t e  I D . / U n i q u e   A c t u a l  V i s i t /                      R e v e r s e                                   I N        P R O / R T  
S u b j .             P h a s e             P r o t e a s e          T r a n s c r i p t a s e     I n t e g r a s e         C l a d e   a s s a y     A s s a y  
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
          W E E K  3 6 /          H 6 9 K ,  I 9 3 L ,       A 2 7 2 P ,  C 1 6 2 S ,     D 2 5 E ,  D 2 7 8 A ,      C       G S I N      P S G T  
2 0 0 3 0 4 . 
   W e e k  3 6 /          L 1 9 T ,  L 6 3 L / V ,     D 1 2 3 G ,  D 1 7 7 E ,     I 8 4 M ,  K 1 3 6 Q ,  
                 R a n d o m i s e d         L 8 9 M ,  M 3 6 I ,       E 2 9 1 D ,  E 3 6 E / A ,    K 1 7 3 R ,  K 2 1 9 Q ,  
                 P h a s e             R 4 1 K ,  T 7 4 S        I 1 3 5 V ,  I 1 5 9 I / V ,   L 1 0 1 I ,  S 2 8 3 S / G ,  
                                                   I 2 0 2 V ,            T 1 1 2 V ,  T 1 2 4 A ,  
                                                   * K 1 0 3 K / N ,         T 2 1 8 I ,  V 1 1 3 I ,  
                                                   K 1 2 2 E ,  K 1 7 3 A / T ,   V 2 0 1 I ,  V 2 3 4 I ,  
                                                   P 1 7 6 P / S ,  Q 1 0 2 K ,   V 3 1 I ,  V 7 2 I  
                                                   Q 1 7 4 K ,  Q 2 0 7 E ,  
                                                   R 2 1 1 R / K ,  
                                                   S 1 6 3 S / T ,  S 4 8 T ,  
                                                   T 1 6 5 T / I ,  T 2 0 0 A ,  
                                                   T 2 8 6 T / A ,  T 3 9 E ,  
                                                   V 2 4 5 Q ,  V 2 9 2 I ,  
                                                   V 3 5 T ,  V 6 0 I ,  
                                                   V 8 V / I N R =  N o t  R e p o r t e d .                     
 
     W E E K  3 6 /   
   N R           N R                                  N R       P S G T I N    P S G T I N  
               W e e k  3 6   
L 7 7 :  w h e r e  p a r c d  i n  ( " F O L D C H G " , " I C 5 0 " , " P S A S M " )  a n d  p a r c a t 1 = " P H E N O T Y P E "  a n d  P H E N F L = " Y "  ;  
L 7 8 :  w h e r e  p a r a m c d  = " A A "  a n d  d n a r e g  i n  ( " I N T E G R A S E " , " P R O T E A S E " , " R E V E R S E  T R A N S C R I P T A S E " )  a n d  G E N F L = " Y " ;  
' * '  T h e s e  r e p r e s e n t  t h e  k n o w n  I N S T I  m u t a t i o n s  a s  d e f i n e d  i n  t a b l e  1  a n d  m a j o r  m u t a t i o n s  f o r  P r o t e a s e  a n d  
R e v e r s e  T r a n s c r i p t a s e  a s  d e f i n e d  i n  t a b l e  2  f r o m  E O S  R A P .  
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 2 8  
 
 
 
L i s t i n g  O t h e r  7 8  
I T T - E  L i s t i n g  o f  A l l  P h e n o t y p i c  D a t a  
  
R e f e r e n c e  S a i l i n g  L i s t i n g  3 5  
 
P r o t o c o l :  2 0 0 3 0 4                                                                            P a g e  1  o f  2 3 1 4  
P o p u l a t i o n :  I T T - E  
                                                 L i s t i n g  7 8  
                                       L i s t i n g  o f  A l l  P h e n o t y p i c  D a t a  
 
T r e a t m e n t :  D T G   
 
 S i t e  I D . / U n i q u e   T i m e  P o i n t   D r u g     D r u g               I C 5 0       F o l d         S e n s i t i v i t y    P R O / R T     I N  
 S u b j .             P h a s e        C l a s s    D r u g  N a m e          ( N M O L / L )   C h a n g e       [ 1 ]            A s s a y      A s s a y  
 
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
 
          D A Y  1 /       I N I      D O L U T E G R A V I R       2 . 7 2 8      1 . 0 2         S e n s i t i v e                P S I N  
 2 0 0 3 0 4 . 
    D a y  1 /  
                  R a n d o m i s e d   
                                      E L V I T E G R A V I R       2 . 0 2       0 . 9 6         S e n s i t i v e               P S I N  
 
                                      R A L T E G R A V I R        4 . 9 6       0 . 8 1         S e n s i t i v e                P S I N  
 
 
                              N N R T I    D E L A V I R D I N E        >  5 0 0 0     > 1 2 0 . 5 2      R e s i s t a n t      P S G T  
 
/           D A Y  1 /       I N I      D O L U T E G R A V I R        N R      
 
         P S G T I N     P S G T I N  
 2 0 0 3 0 4 
   D a y  1 /  
 
 
 
N o t e :  S u b j e c t   
 w a s  r a n d o m i s e d  t o  L P V / R T V  b u t  a c t u a l l y  r e c e i v e d  D T G  t r e a t m e n t  a n d  i n c l u d e d  
i n  t h e  L P V / R T V  t r e a t m e n t  g r o u p .  
N o t e :  N R =  N o t  R e p o r t e d .  
 
 
P P D
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 2 9  
 
Listi n g Ot her  8 0  
I T T-E  Listi n g of Vir ol o g y Dat a f or Partici pa nts wit h C V W, Dis pla y data i n b ot h r a n d o mise d a n d c o nti n uati o n 
p hases, se parati n g b y p hases.  
L i s t i n g  O t h e r  8 2  
I T T - E  L i s t i n g  o f  V i r o l o g y  D a t a  f o r  P a r t i c i p a n t s  w i t h  O n - T r e a t m e n t  V i r o l o g y  R e s u l t s  a t  N o n - C V W  
t i m e p o i n t s   
-  
 P i c k  t e s t  r e s u l t s  w i t h  d e c i s i o n  t r e e  
 
P r o t o c o l :  2 0 0 3 0 4                                                                             P a g e  1  o f  1 1 0  
P o p u l a t i o n :  I n t e n t - t o - T r e a t  E x p o s e d  
                                                 L i s t i n g  8 0  
                       L i s t i n g  o f  V i r o l o g y  D a t a  f o r  P a r t i c i p a n t s  w i t h  C V W  
T r e a t m e n t :  D T G   
 
                       S u s c .    S u s c .  
                       S c o r e    S c o r e    S u s c .    S u s c .  
                       B k g d .    B k g d .    S c o r e    S c o r e  
  S i t e  I d .              A R T      A R T      D T G      D T G       
  U n i q u e                a t       a t       a t       a t        
  S u b j e c t  I d . /          B L       C V W      B L       C V W      I N S T I     P R / R T     I N S T I       M a j o r   M a j o r    M a j o r    
  C V W   V i s i t /           - - - - - - -  - - - - - - -  - - - - - - -  - - - - - - -  R C        R C        M u t a t i o n s   N R T I    N N R T I    P I      C l a d e     S w i t c h      
  C V W   D a t e /            P S S f /    P S S f /    P S S f /    P S S f /    - - - - - - - -  - - - - - - - -  - - - - - - - -                                   V i s i t         
  C V W   T y p e /            P S S p /    P S S p /    P S S p /    P S S p /    B L /       B L /        B L /        B L /     B L /      B L /  
  B k g d .  A R T             G S S      G S S      G S S      G S S      C V W       C V W        C V W        C V W     C V W      C V W  
  P h a s e  
  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
 
 
 
/               2 /       2 /       1 /       1 /       1 /       1 /       9 3 /       1 0 1 /    N A /    N A /     N A /    B          W e e k  5 2  
  2 0 0 3 0 4 . 0 0 0 0 X X /       2 /       2 /       1 /       1 /       1 /       1        1 0 8       1 3 6    N o n e   N o n e    A 1 2 3 C    
  W e e k  3 2 /              1 . 2 5     1 . 5      1        1        1        1  
  
/  
  R e b o u n d /  
  A T V / r , T D F  
  R a n d a m i z e d  p h a s e  
 
 
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 3 0  
 
Treat me nt: L P V/r  
                       S u s c .    S u s c .  
                       S c o r e    S c o r e    S u s c .    S u s c .  
                       B k g d .    B k g d .    S c o r e    S c o r e  
  S i t e  I d .              A R T      A R T      L P V / r      L P V / r  
  U n i q u e                a t       a t       a t       a t  
  S u b j e c t  I d . /          B L       C V W      B L       C V W      I N S T I     P R / R T     I N S T I       M a j o r   M a j o r    M a j o r    
  C V W   V i s i t /           - - - - - - -  - - - - - - -  - - - - - - -  - - - - - - -  R C        R C        M u t a t i o n s   N R T I    N N R T I    P I      C l a d e    S w i t c h  
  C V W   D a t e /            P S S f /    P S S f /    P S S f /    P S S f /    - - - - - - - -  - - - - - - - -  - - - - - - - -  - - - - - - - -                         V i s i t  
  C V W   T y p e /            P S S p /    P S S p /    P S S p /    P S S p /    B L /       B L /        B L /        B L /     B L /      B L /  
  B k g d .  A R T             G S S      G S S      G S S      G S S      C V W       C V W        C V W        C V W     C V W      C V W  
  P h a s e  
  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
 
/               2 /       2 /       1 /       1 /       9 3 /       1 0 1 /  
  2 0 0 3 0 4 . 
/       2 /       2 /       1 /       1 /       1 0 8       1 3 6  
  W e e k  3 2 /              1 . 2 5     1 . 5      1        1  
  
 
  R e b o u n d /  
  A T V / r , T D F  
  R a n d a m i z e d  p h a s e  
 
S V W    
C V W    
 w i t h i n  4  w e e k s .  
P F D T C  
  - - -  >  d a t a  i s s u e  ,  r i g h t  d a t e
 i s  s a m e  a s  S V W  d a t e .  
 
 
N o t e :  C V W  V i s i t  =  A c t u a l  v i s i t  w i n d o w  o f  t h e  i n i t i a l  s u s p e c t e d  v i r a l  l o a d  s a m p l e ,  w h i c h  w a s  
s u b s e q u e n t l y  c o n f i r m e d .  N R =  N o t  R e p o r t e d ,  F C  =  F o l d  C h a n g e  i n  I C 5 0  r e l a t i v e  t o  W i l d - T y p e ,  
R C  =  R e p l i c a t i o n  C a p a c i t y .  
N o t e :  I N S T I  m u t a t i o n s  i n c l u d e  t h e  s p e c i f i e d  k n o w n  I N S T I  m u t a t i o n s  l i s t e d  i n  E O S  R A P  T a b l e  1 .  
N o t e :  N A  i n d i c a t e s  e i t h e r  a s s a y  f a i l e d  o r  n o t  d o n e .  
N o t e :   *  i n d i c a t e  t h a t  t e s t s  r e s u l t s  a r e  p i c k e d  u s i n g  d e c i s i o n  t r e e .   
 
 
P P D
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 0 3 0 4  
1 3 1  
 
  
 
L i s t i n g  8 3 :   P a r t i c i p a n t  L e v e l  S u m m a r y  o f  K e y  V i r o l o g i c  D a t a  o f  B a c k g r o u n d  R e g i m e n s  f o r  P a r t i c i p a n t s  w i t h  O n - T r e a t m e n t  
V i r o l o g y  R e s u l t s  a t  C V W  T i m e p o i n t s    
L i s t i n g  8 4 :   P a r t i c i p a n t  L e v e l  S u m m a r y  o f  K e y  V i r o l o g i c  D a t a  o f  B a c k g r o u n d  R e g i m e n s  f o r  P a r t i c i p a n t s  w i t h  O n - T r e a t m e n t  
V i r o l o g y  R e s u l t s  a t  N o n - C V W  T i m e p o i n t s   
 
 
P r o t o c o l :  2 0 0 3 0 4                                                                             P a g e  1  o f  1 1 0  
P o p u l a t i o n :  I n t e n t - t o - T r e a t  E x p o s e d  
                                                 L i s t i n g  8 3  
                       P a r t i c i p a n t  l e v e l  s u m m a r y  o f  K e y  v i r o l o g i c  D a t a  o f  b a c k g r o u n d  r e g i m e n s  
                         f o r  P a r t i c i p a n t  w i t h  o n - t r e a t m e n t  V i r o l o g y  r e s u l t s  a t  C V W  t i m e p o i n t  
 
T r e a t m e n t :  D T G  
S i t e                              _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ B a c k g r o u n d  A R T _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _     
I d . /                                                                     S t a n f o r d  
U n i q u e   T i m e  p o i n t /    A c t u a l                                             S e n s . /  
S u b j e c t  C V W /           V i s i t /                                    F o l d      G e n o t y p i c    P h e n o t y p i c     N e t           S w i t c h  
I d .      P h a s e          V i s i t  d a t e  D r u g  N a m e      G S S * *   P S S *      c h a n g e    S e n s .        S e n s .          A s s e s s .       V i s i t  
 
 
 B a s e l i n e /      D a y  1 /      E M T R I C I T A B I N E    1      1       1 . 0 8      S e n s i t i v e /    S u s c e p t i b l e    S u s c e p t i b l e   Y                        
.                
                                       S e n s i t i v e  
                           T E N O F O V I R        1      1       0 . 9 6      S e n s i t i v e     S u s c e p t i b l e  
 
        C V W /           W e e k  3 6 /    E M T R I C I T A B I N E    1      1       0 . 8 9      S e n s i t i v e     S u s c e p t i b l e              Y  
        R a n d o m i s e d      
 
        T r e a t m e n t  
                                 T E N O F O V I R        1      1       0 . 7 9      S e n s i t i v e     S u s c e p t i b l e  
  
 
* :  i n d i v i d u a l  d r u g  s u s c e p t i b i l i t y  s c o r e  u s i n g  P S S F .  
N o t e :  N o t  p e r - p r o t o c o l  r e s i s t a n c e  t e s t i n g  ( g e n o t y p e  o n l y )  w a s  p e r f o r m e d  a t  Q 2  S o l u t i o n s  f o r  
S u b j e c t 
a f t e r  s u b j e c t  w i t h d r a w a l .  
 
P P D
P P D
P P D
P P D
P P D


 
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11.18. 
Appendix 18 –List of Data Displays 
11.18.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Pharmacodynamic and / or Biomarker 
5.1 to 5.n 
5.1 to 5.n 
Pharmacokinetic / Pharmacodynamic 
6.1 to 6.n 
6.1 to 6.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
 
11.18.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required an example mock-up displays provided in a separate document. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Virology 
VI_Fn 
VI _Tn 
VI _Ln 
Health Outcome 
HO_Fn 
HO_Tn 
HO_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as ‘[Non-Standard] + Reference.’ 


 
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11.18.3. 
Deliverable 
Delivery  
Description 
24 Week 
Interim Analysis Statistical Analysis Complete 
48 Week 
Primary Statistical Analysis Complete 
 
The following phases are defined:  R=Randomised Phase and RC=Randomised Phase and ContinuationPhase.  
 
Phase of the deliverable labelled as R/RC means that the output will initially be created based on the Randomised Phase only then repeated based on the 
Randomised Phase and Continuation Phase. Deliverables without a Phase are assumed to be for the Randomised phase only 
 


 
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11.18.4. 
Study Population 
11.18.4.1. Tables 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
Subject disposition 
1.1.  
All 
Subjects 
Screened  
SP1 
Summary of Study 
Populations 
CS CORE 
24wk, 48wk 
1.2.  
All 
Subjects 
Screened  
NS1 
Summary of Subjects by 
Country and Investigator 
CS CORE 
24wk, 48wk 
1.3.  ITT-E 
EudraCT age 
DM11 
Summary of Age 
Categories 
CS CORE 
24wk, 48wk 
1.4.  
All 
Subjects 
Screened 
ES6 
Summary of Reasons 
for Screen Failure 
CS CORE 
24wk, 48wk 
1.5.  
ITT-E 
ES1 
Summary of Subject 
Accountability: Study 
Conclusion Record 
 
24wk, 48wk 
1.6.  
ITT-E 
ES1 
Summary of Subject 
Accountability: 
Randomised Phase 
Conclusion Record 
 
24wk, 48wk 
1.7.  
ITT-E 
ES1 
Summary of Subject 
Accountability: 
Continuation Phase 
Conclusion Record 
 
24wk, 48wk 


 
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Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.8.  
ITT-E 
HIV_ES1 
Summary of Subject 
Accountability: 
Withdrawals by Visit 
 
24wk, 48wk 
1.9.  
ITT-E 
SD1 
Summary of Treatment 
Status 
 
 
1.10.
ITT-E 
DV1 
Summary of Important 
Protocol Deviations 
CS CORE 
24wk, 48wk 
1.11.
ITT-E 
SP2 
Summary of Protocol 
Deviations Leading to 
Exclusion from the Per-
Protocol Population 
CS CORE.  
Only deviations occurring in 
the period of interest can 
lead to exclusion from the PP 
Population. 
24wk, 48wk 
1.12.
ITT-E 
IE1 
Summary of 
Inclusion/Exclusion 
Criteria Deviations 
 
24wk, 48wk 
Demography 
1.13.
ITT-E 
DM1 
Summary of 
Demographic 
Characteristics 
CS CORE 
24wk, 48wk 
1.14.
ITT-E 
DM5 
Summary of Race and 
Racial Combinations 
CS CORE 
24wk, 48wk 
1.15.
ITT-E 
DM6 
Summary of Race and 
Racial Combinations 
Details 
CS CORE 
24wk, 48wk 
1.16.
ITT-E 
DM8 
Summary of All 
Indicated Races 
 
 
 


 
CONFIDENTIAL 
 
 
 
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Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.17.
ITT-E 
CDC1 
Summary of CDC 
Classification of HIV 
Infection at Baseline 
 
24wk, 48wk 
1.18.
ITT-E 
Shell POP_T1 
gsk2619619/ing117172/week48/drivers/cr_t_cvrf.sas  
Summary of Baseline 
Cardiovascular Risk 
Assessments 
 
24wk, 48wk 
1.19.
ITT-E 
Shell POP_T2 
gsk2619619/ing117172/week48/drivers/vl_t_scrnbl_hivrna.sas 
Distribution of 
Quantitative Plasma 
HIV-1 RNA Results at 
Screening and Baseline 
Include a category of viral 
load <400 especially for 
screening (ie to identify 
screening failure). Added 
<400 at baseline too. 
24wk, 48wk 
1.20.
ITT-E 
Shell POP_T3 
gsk2619619/ing117172/week48/drivers/vl_t_scrnbl_cd4.sas 
Distribution of CD4+ Cell 
Count (cells/mm^3) 
Results at Screening 
and Baseline 
 
24wk, 48wk 
1.21.
ITT-E 
Shell POP_T4 
gsk2619619/ing117172/week48/drivers/lb_t_hep.sas 
Summary of Hepatitis 
Status at Entry 
 
24wk, 48wk 
Medical Condition & Concomitant  Medications 
1.22.
ITT-E 
MH1 
Summary of Current 
Medical Conditions 
CS CORE 
24wk, 48wk 
1.23.
ITT-E 
MH1 
Summary of Past 
Medical Conditions 
CS CORE 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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137 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.24.
ITT-E 
MH4 
Summary of Current 
Cardiac, 
Gastrointestinal, 
Metabolism and 
Nutrition, Psychiatric, 
Renal and Urinary, and 
Nervous System 
Conditions 
 
24wk, 48wk 
1.25.
ITT-E 
MH4 
Summary of Past 
Cardiac, 
Gastrointestinal, 
Metabolism and 
Nutrition, Psychiatric, 
Renal and Urinary, and 
Nervous System 
Conditions 
 
24wk, 48wk 
1.26.
ITT-E 
CM1 
Summary of 
Concomitant Medication 
by Ingredient ATC Level 
1 
CS CORE 
24wk, 48wk 
1.27.
ITT-E 
CM8 
Summary of 
Concomitant Medication 
Ingredient Combinations 
 
24wk, 48wk 
1.28.
ITT-E 
CM1b 
Summary of 
Concomitant Medication 
by Combination Term 
ATC Level 1 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
138 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.29.
ITT-E 
Shell POP_T5 
gsk1349572/ing111762/week48/drivers/cm_t_prior.sas 
Summary of Prior 
Antiretroviral Therapy at  
the time of Screening 
 
24wk, 48wk 
1.30.
ITT-E 
Use shell for POP_T5 
Summary of Prior 
Antiretroviral  Therapy 
discontinued prior to 
Screening 
 
24wk, 48wk 
1.31.
ITT-E 
Shell POP_T6 
Summary of Prior 
Antiretroviral Therapy at 
the time of screening – 
First line combination 
New output 
24wk, 48wk 
1.32.
ITT-E 
Shell POP_T7 
/arenv/arprod/gsk1349572/ing111762/week48/drivers/cm_t_prinum.sas 
Summary of Prior 
Antiretroviral Therapy 
Classes at time of 
Screening 
Only create if we have more 
than 10 subjects with a prior 
ART other than 
NNRTI+NRTI. 
24wk, 48wk 
1.33.
ITT-E 
Shell POP_T8 
gsk1349572/ing111762/week48/drivers/cm_t_pridur.sas 
Summary of Duration of 
Prior Antiretroviral 
Therapy at time of 
Screening 
 
24wk, 48wk 
1.34.
ITT-E 
Shell POP_T9 gsk1349572/ing111762/week48/drivers/cm_t_day1.sas 
Summary of 
Background 
Antiretroviral Therapy 
Received at Time of IP 
Start by Agent 
Combination 
 
24wk, 48wk 
1.35.
ITT-E 
Shell POP_T10 
gsk1349572/ing111762/week48/drivers/cm_t_lipid_bl.sas 
Summary of Lipid 
Modifying Agent Use at 
Baseline 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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139 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.36.
ITT-E 
Shell POP_T11 
gsk1349572/ing111762/week48/drivers/cm_t_lipid_postbl.sas 
Summary of Lipid 
Modifying Agent Use 
Starting Post-Baseline 
 
24wk, 48wk 
Virology 
1.37.
ITT-E 
Shell POP_T12 
ing111762/week48/drivers/cm_t_classres.sas 
Summary of the Number 
of Baseline Major 
Mutations Associated 
with the Resistance to 
NRTI, NNRTI, and PI 
drug classes 
 
24wk, 48wk 
1.38.
ITT-E 
Shell POP_T13 
gsk1349572/ing111762/week48/drivers/mu_t_bl_maj_oth.sas 
Summary of the Number of 
Baseline Major 
Substitution to NRTI, 
NNRTI and PI Drug 
Classes 
 
 
1.39.
All 
Screened 
Subjects 
Shell POP_T14 
Proportion of subjects 
without at least 1 fully 
active NRTI 
 
24wk, 48wk 
1.40.
All 
Screened 
Subjects 
Shell POP_T15 
ing111762/week48/drivers/cm_t_classres.sas 
Summary of the Number 
of Screening Major 
Mutations Associated 
with the Resistance to 
NRTI, NNRTI, and PI 
drug classes 
Screening genotypic data is 
all from Q2. There may be 
some subtle differences to 
discuss with programmers 
compared with the 
Monogram data.  For Q2 if 
there is an insertion it may 
not be possible to  determine 
precise order. 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
140 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.41.
All 
Screened 
Subjects 
Shell POP_T16 
gsk1349572/ing111762/week48/drivers/mu_t_bl_maj_oth.sas 
Summary of the Number 
of Screening Major 
Substitution to NRTI, 
NNRTI and PI Drug 
Classes 
 
 
Screening genotypic data is 
all from Q2. There may be 
some subtle differences to 
discuss with programmers 
compared with the 
Monogram data.  For Q2 if 
there is an insertion it may 
not be possible to  determine 
precise order. 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
141 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.42.
ITT-E 
Shell POP_T17 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Baseline 
Major NNRTI and NRTI 
Mutations 
 
New table which includes: 
• 
Number of 
thymidine analogue-
associated 
mutations (TAMS): 
1, 2, >2 
• 
Prevalence of 
o  L65A or L70G 
o 69 insertion 
complex 
o 151 insertion 
complex 
o Other major 
NRTI mutations 
• 
Prevalence of 
o M184V only 
o M184V with any 
other major 
NRTI mutation 
[proposed new output to 
match that of the 
SECONDLINE Kirby 
manuscript] 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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142 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.43.
ITT-E 
Shell POP_T18 
gsk1349572/ing111762/week24/drivers/ph_t_bl_geno_gssd11.sas 
Summary of Stanford 
Baseline GSS to 
Background ART 
Regimen 
 
24wk, 48wk 
1.44.
ITT-E 
Shell POP_T19 
gsk1349572/ing111762/week24/drivers/ph_t_bl_geno_gssd11.sas 
Summary of Monogram 
Baseline GSS to 
Background ART 
Regimen 
New table.  Use summary of 
Stanford GSS summary as a 
shell. 
24wk, 48wk 
1.45.
ITT-E 
Shell POP_T20 
gsk1349572/ing112574/week48/drivers/ph_t_bossfbng_d8.sas 
Summary of Baseline 
OSS (Net Assessment) 
to Background Therapy 
Viking T12.71 
24wk, 48wk 
1.46.
ITT-E 
Shell POP_T21 
sk1349572/ing111762/week24/drivers/ph_t_basepss.sas 
Summary of Baseline 
PSS to Background 
ART Regimen 
 
24wk, 48wk 
1.47.
ITT-E 
Shell POP_T22 
gsk1349572/ing111762/week24/drivers/mu_t_hiv_clades.sas 
Summary of the 
Prevalence of HIV-1 
Clades at Baseline by 
Frequency 
Use Monogram Testing  
For W24, for China we will 
have mostly Q2 genotype 
and just a few Monogram 
testings of the samples that 
we were able to export for 
testing. 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
143 
 
Study Population Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
1.48.
ITT-E 
Shell POP_T23 
Summary of First Line 
Regimen and Expected 
Second Line Regimen 
Using the WHO 
Algorithm 
New table 
24 wk, 48 
wk 
1.49.
ITT-E 
Shell POP_T24 
Summary of Expected 
WHO Second Line vs. 
Background Regimen 
actually Taken 
New table 
24 wk, 48 
wk 
 
 


 
CONFIDENTIAL 
 
 
 
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144 
 
11.18.5. 
Efficacy 
11.18.5.1. Tables 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
Primary 
2.1.  
ITT-E  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 24/48 – Snapshot  
Analysis 
 
24wk, 48wk 
2.2.  
Per-
Protocol  
Shell EFF_T2 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 24/48 – Snapshot 
Analysis 
 
24wk48wk 
2.3.  
Intent to 
treat  
Shell EFF_T3 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 24/48 – Snapshot 
Analysis 
 
24wk, 48wk 
2.4.  
ITT-E 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 24/48 – 
Snapshot Analysis 
 
24wk, 48wk 
2.5.  
ITT-E 
Shell EFF_T6 
gsk2619619/ing117172/week48/drivers/t_snap_sum_prop_p.sas 
Treatment by Strata Tests of 
Homogeneity for the Proportion 
of Subjects with Plasma HIV-1 
RNA <50 c/mL at Week 24/48- 
Snapshot Analysis 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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145 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.6.  
ITT-E 
Shell EFF_T7 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 24/48 –  
by number of fully active 
background NRTIs 
 
24wk, 48wk 
2.7.  
ITT-E 
Shell EFF_T8 
gsk2619619/ing117172/week48/drivers/t_snap_sum_prop.sas 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 24/48by Subgroup - 
Snapshot Analysis 
Note: only present by 
ABC+3TC vs non 
ABC+3TC if more 
than 10 subjects took 
ABC+3TC 
24wk, 48wk 
2.8.  
ITT-E 
Shell EFF_T9 
gsk2619619/ing117172/week48/drivers/t_snap_prop_50.sas 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
by Visit - Snapshot Analysis 
 
24wk, 48wk 
2.9.  
ITT-E 
Shell EFF_T10 
gsk2619619/ing117172/week48/drivers/t_snap_prop_50.sas 
Proportion of Subjects with 
Plasma HIV-1 RNA<50 c/mL 
by Visit and Subgroup –
Snapshot Analysis  
Adapt program to 
include subgroups 
24wk, 48wk 
2.10.
ITT-E 
Shell EFF_T11 
gsk2619619/ing117172/week48/drivers/t_snap_prop_400.sas 
Proportion of Subjects with 
Plasma HIV-1 RNA <400 c/mL 
by Visit - Snapshot Analysis 
 
24wk, 48wk 
2.11.
ITT-E 
Shell EFF_T12 
gsk2619619/ing117172/week48/drivers/t_sn_studout_400.sas 
Summary of Study Outcomes 
(<400 c/mL) at Week X – 
Snapshot Analysis 
 
24wk, 48wk 
2.12.
ITT-E 
Shell EFF_T13 
gsk2619619/ing117172/week48/drivers/t_ef_km_trdf.sas 
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 48  
- Treatment Related 
Discontinuation = Failure  
TTE6 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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146 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.13.
ITT-E 
Shell EFF_T14 
gsk2619619/ing117172/week48/drivers/t_ef_km_erdf.sas  
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 48  
- Efficacy Related 
Discontinuation = Failure 
TTE6 
 
24wk, 48wk 
2.14.
ITT-E 
Shell EFF_T15 
/arenv/arprod/gsk1349572/ing114467/week48/drivers/ef_t_pdvf_vis.sas 
Proportion of Subjects Meeting 
Confirmed Virologic 
Withdrawal Criteria by Visit 
 
24wk, 48wk 
2.15.
ITT-E 
Shell EFF_T16 
/arenv/arprod/gsk1349572/ing111762/week48/drivers/ef_t_pdvf_vis.sas 
Cumulative Proportion of 
Subjects Meeting Confirmed 
Virologic Withdrawal Criteria by 
Visit by Type of Virologic 
Failure 
 
24wk, 48wk 
2.16.
ITT-E 
Shell EFF_T17 
gsk1349572/ing111762/week48/drivers/ef_t_pdvf_dist.sas 
Distribution of Quantitative 
Plasma HIV-1 RNA Results at 
Suspected and Confirmation of 
Virologic Withdrawal Criteria 
 
24wk, 48wk 
2.17.
ITT-E 
Shell EFF_T18 
gsk1349572/ing114915/week48/drivers/ef_t_km_timeto_sup50.sas  
Summary of Kaplan-Meier 
Estimates of Time to Viral 
Suppression (HIV-1 RNA <50 
c/mL)  
 
24wk, 48wk 
2.18.
ITT-E 
Shell EFF_T19 
Proportion of Subjects With 
Detectable Viral Load Below 
the Limit of Quantification at 
Week 24/48 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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147 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.19.
ITT-E 
HIV1 
Summary of Post-Baseline 
HIV-1 Associated Conditions 
Including Recurrences 
 
24wk, 48wk 
2.20.
ITT-E 
HIV1 
Summary of Post-Baseline 
HIV-1 Associated Conditions 
Excluding Recurrences 
 
24wk, 48wk 
2.21.
ITT-E 
HIV2 
Summary of Post-Baseline 
HIV-1 Disease Progressions 
 
24wk, 48wk 
2.22.
ITT-E 
Shell EFF_T19 
gsk2619619/ing117172/week48/drivers/ef_t_cd4_chg.sas 
Summary of Change from 
Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit 
 
24wk, 48wk 
2.23.
ITT-E 
Shell EFF_T20 
gsk2619619/ing117172/week48/drivers/t_ef_hv1rn_chg.sas 
Summary of Change from 
Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit 
 
24wk, 48wk 
2.24.
ITT-E 
Shell EFF_T21 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week X by 
[Subgroup] – Snapshot 
Analysis 
As Needed. Modify 
program to present 
by subgroups. 
24wk, 48wk 
2.25.
ITT-E  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 48 – Snapshot  
Analysis – Additional Estimand 
1 
 
48wk 
2.26.
ITT-E 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 48 – 
Snapshot Analysis – Additional 
Estimand 1 
 
48wk 


 
CONFIDENTIAL 
 
 
 
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148 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.27.
ITT-E  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 48 – Snapshot  
Analysis – Additional Estimand 
2 
 
48wk 
2.28.
ITT-E 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 48 – 
Snapshot Analysis – Additional 
Estimand 2 
 
48wk 
2.29. MITT-E-36  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 36 – Snapshot  
Analysis  
 
24wk 
2.30. MITT-E-36 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 36 – 
Snapshot Analysis  
 
24wk 
2.31. MITT-E-48  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 48 – Snapshot  
Analysis  
 
24wk 
2.32. MITT-E-48 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 48 – 
Snapshot Analysis  
 
24wk 


 
CONFIDENTIAL 
 
 
 
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149 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.33. MITT-E-36 
Shell EFF_T13 
gsk2619619/ing117172/week48/drivers/t_ef_km_trdf.sas 
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 36  
- Treatment Related 
Discontinuation = Failure  
TTE6 
24wk 
2.34. MITT-E-48 
Shell EFF_T13 
gsk2619619/ing117172/week48/drivers/t_ef_km_trdf.sas 
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 48  
- Treatment Related 
Discontinuation = Failure  
TTE6 
24wk 
2.35.
ITT-E 
Shell EFF_T13 
gsk2619619/ing117172/week48/drivers/t_ef_km_trdf.sas 
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 48  
- Treatment Related 
Discontinuation = Failure – 
Sensitvity Analysis  
TTE6 
48wk 


 
CONFIDENTIAL 
 
 
 
200304 
150 
 
Efficacy: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
2.36.
ITT-E 
Shell EFF_T14 
gsk2619619/ing117172/week48/drivers/t_ef_km_erdf.sas  
Summary of Kaplan-Meier 
Estimates of Proportion of 
Subjects Without Confirmed 
Virologic Withdrawal Criteria at 
Week 48  
- Efficacy Related 
Discontinuation = Failure – 
Sensitvity Analysis 
TTE6 
 
48wk 
2.37.
ITT-E  
 Shell EFF_T1 
gsk2619619/ing117172/week48/drivers/t_ef_analprop.sas 
Summary of Analysis of 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL 
at Week 48 – Snapshot  
Analysis – Projected Estimate 
 
24wk 
2.38.
ITT-E 
Shell EFF_T4 
gsk2619619/ing117172/week48/drivers/t_sn_studout.sas 
Summary of Study Outcomes 
(<50 c/mL) at Week 48 – 
Snapshot Analysis – Projected 
Estimate 
 
24wk 
 


 
CONFIDENTIAL 
 
 
 
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11.18.5.2. Efficacy Figures 
Efficacy: Figures 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
2.1.  
ITT-E 
Shell EFF_F1 
gsk2619619/ing117172/week48/drivers/ef_f_p50.sas 
Proportion (95% CI) of Subjects with HIV-
1 RNA <50 c/mL by Visit – Snapshot 
Analysis 
Week 24: Up to Week 24 
Data 
Week 48: Up to Week 48 
Data 
24wk, 48wk 
2.2.  
ITT-E 
Shell EFF_F2 
gsk2619619/ing117172/week48/drivers/ef_f_diffprop.sas  
Unadjusted Treatment Difference in 
Proportion (95%) of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week 24/48 by 
Subgroup – Snapshot Analysis 
 
24wk, 48wk 
2.3.  
ITT-E 
Shell EFF_F3 
gsk2619619/ing117172/week48/drivers/ef_f_p50.sas 
Proportion (95% CI) of Subjects with HIV-
1 RNA <400 c/mL by Visit – Snapshot 
Analysis 
Use <400 cut-off instead 
of <50 cut-off  
Week 24: Up to Week 24 
Data 
Week 48: Up to Week 48 
Data 
24wk, 48wk 
2.4.  
ITT-E 
Shell EFF_F4 
gsk1349572/ing111762/week48/drivers/ef_f_km_trdf.sas 
Kaplan-Meier Plot of Time to Failure by 
Week 24– Treatment Related 
Discontinuation = Failure 
 
24wk, 48wk 
2.5.  MITT-E-36 
Shell EFF_F4 
gsk1349572/ing111762/week48/drivers/ef_f_km_trdf.sas 
Kaplan-Meier Plot of Time to Failure by 
Week 36– Treatment Related 
Discontinuation = Failure 
 
24wk 
2.6.  MITT-E-48 
Shell EFF_F4 
gsk1349572/ing111762/week48/drivers/ef_f_km_trdf.sas 
Kaplan-Meier Plot of Time to Failure by 
Week 48 – Treatment Related 
Discontinuation = Failure 
 
24wk 
2.7.  
ITT-E 
Shell EFF_F5 
gsk1349572/ing111762/week48/drivers/ef_f_km_erdf.sas 
Kaplan-Meier Plot of Time to Failure –
Efficacy Related Discontinuation = Failure 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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152 
 
Efficacy: Figures 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
2.8.  
ITT-E 
Shell EFF_F6 
Individual Plasma HIV-1 RNA (log10 
c/mL) Profiles by Visit 
 
24wk, 48wk 
2.9.  
ITT-E 
Shell EFF_F7 
 
Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by visit 
New figure 
24wk, 48wk 
 


 
CONFIDENTIAL 
 
 
 
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153 
 
11.18.6. 
Safety 
11.18.6.1. Tables 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
Adverse Events 
3.1.  
Safety 
Shell SAFE_T1 
gsk2619619/ing117172/week48/drivers/ex_t_exposure_rand.sas 
Summary of Extent of Exposure to 
Investigational Product for the 
Randomised Phase 
CS Core 
24wk, 48wk 
3.2.  
Safety 
Shell SAFE_T2 
gsk2619619/ing117172/week48/drivers/ex_t_exposure.sas 
Summary of Extent of Exposure to 
Investigational Product for the 
Randomised and Continuation 
Phases 
 
24wk, 48wk 
3.3.  
Safety 
Shell SAFE_T3 
gsk1349572/ing114467/week48/drivers/ae_t_stats_neuro_psych.sas 
Statistical Analysis of Grade 2 or 
greater Drug-Related Diarrhoea 
New output.  
24wk, 48wk 
3.4.  
Safety 
AE1 
Summary of All Adverse Events 
by System Organ Class 
CS Core (optional) 
24wk, 48wk 
R, RC 
3.5.  
Safety 
AE5B 
Summary of All Adverse Events 
by System Organ Class and 
Maximum Toxicity 
CS Core 
24wk, 48wk 
R, RC 
3.6.  
Safety 
AE3 
Summary of Common (>=5%) 
Adverse Events by Overall 
Frequency 
CS Core 
24wk, 48wk 
3.7.  
Safety 
AE3 
Summary of Common (>=5%) 
Grade 2-4 Adverse Events by 
Overall Frequency 
CS Core 
24wk, 48wk 
3.8.  
Safety 
AE1 
Summary of All Grade 2-4 
Adverse Events by System Organ 
Class 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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154 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.9.  
Safety 
AE5B 
Summary of All Drug-Related 
Adverse Events by System Organ 
Class and Maximum Toxicity  
CS Core 
24wk, 48wk 
R, RC 
3.10.
Safety 
AE1 
Summary of All Drug-Related 
Adverse Events by System Organ 
Class 
CS Core 
24wk, 48wk 
3.11.
Safety 
AE3 
Summary of Common (>=5%) 
Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency 
CS Core 
24wk, 48wk 
3.12.
Safety 
AE1 
Summary of All Drug-Related 
Grade 2-4 Adverse Events by 
System Organ Class 
 
24wk, 48wk 
3.13.
Safety 
AE1 
Summary of Serious Adverse 
Events by System Organ Class 
CS Core 
24wk, 48wk 
R, RC 
3.14.
Safety 
AE3 
Summary of Drug-Related Fatal 
Serious Adverse Events 
 
24wk, 48 
wk 
3.15.
Safety 
AE1 
Summary of Drug-Related 
Serious Adverse Events by 
System Organ Class 
CS Core 
24wk, 48wk 
3.16.
Safety 
AE3  
Summary of Non-Fatal Serious 
AEs 
 
24wk, 48wk 
3.17.
Safety 
AE3 
Summary of Drug-Related Non-
Fatal Serious Adverse Events 
 
 
24wk, 48wk 
3.18.
Safety 
AE1 
Summary of Adverse Events 
Leading to Withdrawal/Permanent 
Discontinuation of Investigational 
Product 
CS Core 
24wk, 48wk 
R, RC 


 
CONFIDENTIAL 
 
 
 
200304 
155 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.19.
Safety 
AE1  
Summary of Common (>5%) Non-
Serious Adverse Events 
CS Core 
FDAAA 
 ‘Common’ to be 
defined by 
study/project team, 
in accordance with 
FDAAA 
requirements. 
Use >5% cut-off 
24wk, 48wk 
3.20.
Safety 
EudraCT Non-serious AE 
AE15 
Summary of Subjects and 
Number of Occurrences of 
Common Non-Serious Adverse 
Events by System Organ Class 
CS Core 
EudraCT 
 
For studies with 
very few 
events/subjects 
listing is sufficient. 
 
24wk, 48wk 
3.21.
Safety 
EudraCT SAE 
AE16 
Summary of Subjects and 
Number of Occurrences of 
Serious, Drug-Related Serious, 
Fatal, and Drug-Related Serious 
Adverse Events 
CS Core 
EudraCT 
 
For studies with 
very few 
SAEs/subjects 
listing is sufficient. 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
156 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.22.
Safety 
AE3 
Summary of Fatal Serious 
Adverse Events 
CS Core 
GSK CTR 
 
 For studies with 
very few fatal SAEs, 
listing is sufficient 
24wk, 48wk 
3.23.
Safety 
AE3 
Summary of Most Frequent  
Adverse Events by Overall 
Frequency 
 
24wk, 48wk 
3.24.
Safety 
Shell SAFE_T4 
gsk3365791/mid_dori_ph3/week48/drivers/t_ae_cum_er_srd1.sas 
Summary of Cumulative Adverse 
Events by Visit 
See DORI 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
157 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
Laboratory Values 
3.25.
Safety 
Shell SAFE_T5 
Use the non standard program in the ARIA study 
gsk2619619/ing117172/week48/drivers/t_stat_trig_mar.sas 
Statistical analysis of Change 
from Baseline in fasting LDL 
cholesterol at Weeks 24/48 
(Multiple imputations – MAR)  
 
 
24wk, 48wk 
3.26.
Safety 
Shell SAFE_T6 
From ARIA: 
gsk2619619/ing117172/week48/drivers/t_stat_trig_oc.sas 
Statistical analysis of Change 
from Baseline in fasting LDL 
cholesterol at Weeks 24/48 by 
Visit – ANCOVA – Observed 
Case 
 
24wk, 48wk 
3.27.
Safety 
Shell SAFE_T7 
From ARIA 
gsk2619619/ing117172/week48/drivers/t_stat_trig_locf.sas 
Statistical analysis of Change 
from Baseline in fasting LDL 
cholesterol at Weeks 24/48 by 
Visit – ANCOVA – LOCF 
 
24wk, 48wk 
3.28.
Safety 
Shell SAFE_T8 
Use the non standard program in the ARIA study 
gsk2619619/ing117172/week48/drivers/t_stat_trig_mar.sas  
Statistical analysis Change from 
Baseline in fasting TC/HDL ratio 
at Weeks 24/48 (Multiple 
imputations – MAR)   
 
Use Shell SAFE_T5 
24wk, 48wk 
3.29.
Safety 
Shell SAFE_T9 
From ARIA 
gsk2619619/ing117172/week48/drivers/t_stat_trig_oc.sas 
Statistical analysis Change from 
Baseline in fasting TC/HDL ratio 
at Weeks 24/48 by Visit - 
ANCOVA – Observed Case 
Use Shell SAFE_T6 
24wk, 48wk 
3.30.
Safety 
Shell SAFE_T10 
From ARIA 
gsk2619619/ing117172/week48/drivers/t_stat_trig_locf.sas 
Statistical analysis Change from 
Baseline in fasting TC/HDL ratio 
at Weeks 24/48 by Visit - 
ANCOVA – Lipids LOCF 
Use Shell SAFE_T7 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
158 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.31.
Safety 
Shell SAFE_T11 
(Famingo SAS code may be useful - 
gsk1349572/ing114915/week48/drivers/lb_t_stats_incid_grad2_ldl.sas) 
Statistical analysis of Maximum 
post-Baseline emergent Grade 2 
or greater laboratory 
abnormalities in fasting LDL 
cholesterol by Weeks 24/48 
New output 
24wk, 48wk 
3.32.
Safety 
LB1 
Summary of Chemistry Changes 
from Baseline by Visit 
CS Core 
24wk, 48wk 
3.33.
Safety 
LB1 
Summary of Chemistry Changes 
from Baseline by Visit – Sensitivity 
Analysis Excluding Suspect 
Creatinine Samples 
CS Core 
24wk, 48wk 
3.34.
Safety 
LB1 
Summary of Chemistry Changes 
from Baseline by Visit – Lipids 
and Glucose in Conventional 
Units 
 
24wk, 48wk 
3.35.
Safety 
LB1 
Summary of Hematology 
Changes From Baseline by Visit 
CS Core 
24wk, 48wk 
3.36.
Safety 
Shell SAFE_T12 
gsk2619619/ing117172/week48/drivers/lb_t_max_tox_rand.sas 
Summary of Maximum Post-
Baseline Emergent Chemistry 
Toxicities 
CS Core 
24wk, 48wk 
R, RC 
3.37.
Safety 
Repeat SAFE_T12 
Summary of Maximum Post-
Baseline Emergent Chemistry 
Toxicities - Sensitivity Analysis 
Excluding Suspect Creatinine 
Samples 
CS Core 
24wk, 48wk 
3.38.
Safety 
Shell SAFE_T13 
gsk2619619/ing117172/week48/drivers/lb_t_max_tox_haem_rand.sas 
Summary of Maximum Post-
Baseline Emergent Hematology 
Toxicities 
CS Core 
24wk, 48wk 
R, RC 


 
CONFIDENTIAL 
 
 
 
200304 
159 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.39.
Safety 
Shell SAFE_T14 
gsk2619619/ing117172/week48/drivers/lb_t_ncep_tri.sas 
Summary of Changes in NCEP 
Lipid Baseline Category to 
Maximum Post-Baseline Category 
- Triglycerides 
 
24wk, 48wk 
3.40.
Safety 
Shell SAFE_T15 
gsk2619619/ing117172/week48/drivers/lb_t_ncep_tot.sas 
Summary of Changes in NCEP 
Lipid Baseline Category to 
Maximum Post-Baseline Category 
– Total Cholesterol 
 
24wk, 48wk 
3.41.
Safety 
Shell SAFE_T16 
gsk2619619/ing117172/week48/drivers/lb_t_ncep_hdl.sas 
Summary of Changes in NCEP 
Lipid Baseline Category to 
Maximum Post-Baseline Category 
– HDL Cholesterol 
 
24wk, 48wk 
3.42.
Safety 
Shell SAFE_T17 
gsk2619619/ing117172/week48/drivers/lb_t_ncep_ldl.sas 
Summary of Changes in NCEP 
Lipid Baseline Category to 
Maximum Post-Baseline Category 
– LDL Cholesterol 
 
24wk, 48wk 
3.43.
Safety 
VS1 
Summary of Vital Signs 
 
24wk, 48wk 
3.44.
Safety 
VS1 
Summary of Change From 
Baseline in Vital Signs by Visit 
CS Core 
Will only be 
produced if post-
baseline data 
collected 
24wk, 48wk 
3.45.
Safety 
LIVER10 
Summary of Hepatobiliary 
Laboratory Abnormalities 
 
24wk, 48wk 
3.46.
Safety 
LIVER10 
Summary of Hepatobiliary 
Laboratory Abnormalities 
Including the Continuation phase 
 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
160 
 
Safety : Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
3.47.
Safety 
LIVER1 
Summary of Liver 
Monitoring/Stopping Event 
Reporting 
If a liver stopping 
event is reported 
24wk, 48wk 
3.48.
Safety 
Shell SAFE_T18 
gsk3365791/mid_dori_ph3/week48/drivers/t_cssrsib.sas  
Summary of C-SSRS Suicidal 
Ideation or Behaviour during 
Treatment Excluding Incomplete 
Calls  
Use DORI  
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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161 
 
11.18.6.2. Figures 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
3.1.  
Safety 
AE10 
Plot of Common Adverse Events and Relative Risk 
CS CORE 
24wk, 48wk 
3.2.  
Safety 
Shell SAFE_F1 
/arenv/arprod/g
sk1349572/ing1
14467/wk144/dr
ivers/ef_f_cd4cf
b_bywk.sas 
Line Plot of Adjusted Mean (95% CI) Change From Baseline in 
Fasting LDL Cholesterol (units) Over Time - Repeated Measure 
Mixed Model 
 
24wk, 48wk 
3.3.  
Safety 
Shell SAFE_F2 
/arenv/arprod/g
sk1349572/ing1
14467/wk144/dr
ivers/ef_f_cd4cf
b_bywk.sas 
Line Plot of Adjusted Mean (95% CI) Change From Baseline in 
Fasting TC/HDL ratio (units) Over Time - Repeated Measure 
Mixed Model 
 
24wk, 48wk 
3.4.  
Safety 
LIVER9 
Scatter Plot of Maximum vs. Baseline for ALT 
CS CORE. Add line of equality. 
24wk, 48wk 
3.5.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
CS CORE.  Lloyd would like to see 
theALT on the horizontal axis and 
Bilirubin on the vertical axis, is it 
possible to update the standard? 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
162 
 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
3.6.  
Safety 
Shell SAFE_F3 
/arenv/arprod/g
sk2619619/ing1
17172/wk48/dri
vers/sff_f_bar_t
rig.sas 
 
Bar Chart of Triglycerides (mmol/L) NCEP categories at Week 
24/48 vs Baseline  
Copy from ARIA 
24wk, 48wk 
3.7.  
Safety 
Shell SAFE_F4 
/arenv/arprod/g
sk2619619/ing1
17172/wk48/dri
vers/sff_f_bar_c
hol.sas 
 
Bar Chart of Total Cholesterol (mmol/L) NCEP categories at 
Week 24/48 vs Basline 
 
 
3.8.  
Safety 
Shell SAFE_F5 
/arenv/arprod/g
sk2619619/ing1
17172/wk48/dri
vers/sff_f_bar_
hdl.sas 
 
Bar Chart of HDL Cholesterol (mmol/L) NCEP categories at 
Week 24/48 vs Baseline 
 
 
 


 
CONFIDENTIAL 
 
 
 
200304 
163 
 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
3.9.  
Safety 
Shell SAFE_F6 
/arenv/arprod/g
sk2619619/ing1
17172/wk48/dri
vers/sff_f_bar_l
dl.sas 
 
Bar Chart of LDL Cholesterol (mmol/L) NCEP categories at 
Week 24/48 vs Baseline 
 
 
3.10. 
Safety 
Shell SAFE_F7 
/arenv/arprod/g
sk1349572/ing_
psap/trii_iss_m
ar/drivers/lb_f_lf
t_prof.sas 
Liver Chemistry Profile Plots for Subjects with Elevations at Any 
Post-Baseline Visit  
 
24wk, 48wk 
 


 
CONFIDENTIAL 
 
 
 
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11.18.7. 
Virology 
11.18.7.1. Tables 
Virology: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
Genotype 
4.1.  
ITT- E 
Shell VI_T1 
gsk1349572/ing111762/week48/drivers/mu_t_gen_acc_48.sas 
Summary of Subject 
Accountability: 
Genotypes Available 
We might want 
to note the China 
data in this 
dataset since is 
different assay 
 
 
24wk, 48wk 
4.2.  
CVW 
Genotypic  
Shell VI_T2 
/arenv/arprod/gsk1349572/ing114467/week48/drivers/mu_t_othmut_emrg.sas 
Summary of Treatment 
Emergent Major 
Mutations of NRTI, 
NNRTI and PI Classes 
 
24wk, 48wk 
4.3.  
CVW 
Genotypic 
Shell VI_T3 
/arenv/arprod/gsk1349572/ing111762/week48/drivers/mu_t_ini_te_pss48.sas 
Summary of Pre-
specified Treatment 
Emergent IN 
Substitutions at Time 
of Confirmed Virologic 
Withdrawal  
Replace 
columns: 
Baseline PSSf to 
Background 
Regimen with 
treatment arms 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
165 
 
Virology: Tables 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming 
Notes 
Deliverable 
& phase 
[Priority] 
4.4.  
CVW 
Genotypic 
Shell VI_T4 
/arenv/arprod/gsk1349572/ing111762/week48/drivers/ph_t_bl_geno_gsspdvf_48.sas 
Summary of Changes 
in Genotypic 
Susceptibility (GSS) to 
Background ART 
Therapy at Time of 
Confirmed Virologic 
Withdrawal 
 
24wk, 48wk 
Phenotype 
4.5.  
CVW 
Phenotypic 
Shell VI_T5 
Arenv/arprod/gsk1349572/ing111762/week48/drivers/mu_t_phen_acc_48.sas 
Summary of Subject 
Accountability: 
Phenotype Available 
 
24wk, 48wk 
4.6.  
CVW 
Phenotypic  
Shell VI_T6 
arenv/arprod/gsk1349572/ing114467/week48/drivers/ph_t_ot_sus_572ral.sas 
Summary of Fold 
Change to DTG and 
LPV/RTV at Baseline 
and Time of Confirmed 
Virologic Withdrawal 
 
24wk, 48wk 
4.7.  
CVW 
Phenotypic 
Shell VI_T7 
gsk1349572/ing111762/week48/drivers/ph_t_pss_shift_48.sas 
Summary of Changes 
in Phenotypic 
Resistance (PSSf) to 
Background ART 
Regimen at Time of 
Confirmed Virologic 
Withdrawal 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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166 
 
11.18.8. 
Health Outcomes 
11.18.8.1. Tables 
Health Outcome 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
HIV-Treatment Satisfaction Questionnaire 
ITT-E 
Shell HO_T1 
gsk2619619/ing117172/week48/drivers/t_qs_indiv_locf.sas 
Summary of HIV-Treatment Satisfaction 
Questionnaire Individual Item Scores 
Modify program to use OC 
rather than LOCF & 
include all items from 14-
item HIVTSQ. 
For Health Outcome 
SUMMARY tables use 
TU_FREQ 
24wk, 48wk 
ITT-E 
Shell HO_T2 
gsk2619619/ing117172/week48/drivers/t_qs_indiv_locf.sas 
Summary of HIV-Treatment Satisfaction 
Questionnaire Treatment Satisfaction 
Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T3 
gsk2619619/ing117172/week48/drivers/t_qs_indiv_locf.sas 
Summary of HIV-Treatment Satisfaction 
Questionnaire Pain/Discomfort 
Satisfaction Item Score 
Use Shell HO_T2.  This is 
item 12 only. 
24wk, 48wk 
ITT-E 
Shell HO_T4 
Summary of HIV-Treatment Satisfaction 
Questionnaire Change from Baseline in 
Individual Item Scores 
Use Shell HO_T2 
24wk, 48wk 
ITT-E 
Shell HO_T5 
Summary of HIV-Treatment Satisfaction 
Questionnaire Change from Baseline in 
Treatment Satisfaction Score 
Use Shell HO_T2 
24wk, 48wk 
ITT-E 
Shell HO_T6 
Summary of HIV-Treatment Satisfaction 
Questionnaire Change from Baseline in 
Pain/Discomfort Satisfaction Item Score 
Use Shell HO_T2 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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167 
 
Health Outcome 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
ITT-E 
Shell HO_T7 
Statistical Analysis of HIV-Treatment 
Satisfaction Questionnaire Change 
from Baseline in Treatment Satisfaction 
Score by visit – Repeated Measure 
Mixed Model Analysis 
 
 
24wk, 48wk 
ITT-E 
Shell HO_T8 
Statistical Analysis of HIV-Treatment 
Satisfaction 
Questionnaire 
Change 
from Baseline in Treatment Satisfaction 
Score at Week 24/48 - Repeated 
Measures Mixed Model Analysis 
 
 
24wk, 48wk 
ITT-E 
Shell HO_T9 
Summary of HIV-Treatment Satisfaction 
Questionnaire in Individual Item Scores 
Change 
Use Shell HO_T1 
48wk 
ITT-E 
Shell HO_T10 
Summary of HIV-Treatment Satisfaction 
Questionnaire in  Treatment 
Satisfaction Score Change 
Use Shell HO_T2 
48wk 
ITT-E 
Shell HO_T11 
Summary of HIV-Treatment Satisfaction 
Questionnaire in Pain/Discomfort Item 
Score Change 
Use Shell HO_T2 
48wk 
ITT-E 
Shell HO_T12 
Statistical Analysis of HIV-Treatment 
Satisfaction Questionnaire in Treatment 
Satisfaction Score Change at Week 48 
New output 
48wk   
Morisky Medication Adherence Scale – 8 
ITT-E 
Shell HO_T13 
Summary of the Morisky 8-Item 
Medication Adherence Scale - Total 
Score 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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168 
 
Health Outcome 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
ITT-E 
Shell HO_T14 
Summary of the Morisky 8-Item 
Medication Adherence Scale - 
Adherence Level 
 
24wk, 48wk 
ITT-E 
Shell HO_T15 
 
Statistical Analysis of the Morisky 8-
Item Medication Adherence Scale – 
Adherence Level 
New output 
24wk, 48wk 
Gastrointestinal Symptom Rating Scale 
ITT-E 
Shell HO_T16 
Summary of Gastrointestinal Symptom 
Rating Scale – Individual Item Scores 
 
24wk, 48wk 
ITT-E 
Shell HO_T17 
Summary of Gastrointestinal Symptom 
Rating Scale - Diarrhoea Syndrome 
Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T18 
Summary of Gastrointestinal Symptom 
Rating Scale – Indigestion Syndrome 
Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T19 
Summary of Gastrointestinal Symptom 
Rating Scale Constipation Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T20 
Summary of Gastrointestinal Symptom 
Rating Scale - Abdominal Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T21 
Summary of Gastrointestinal Symptom 
Rating Scale – Reflux Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T22 
Summary and Statistical Analysis of 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
- Diarrhoea Syndrome Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T23 
Summary and Statistical Analysis of 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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169 
 
Health Outcome 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
– Indigestion Syndrome Score 
ITT-E 
Shell HO_T24 
Summary and Statistical Analysis of 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
Constipation Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T25 
 
Summary and Statistical Analysis of 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
- Abdominal Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T26 
Summary and Statistical Analysis of of 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
– Reflux Score 
 
24wk, 48wk 
ITT-E 
Shell HO_T27 
Statistical Analysis of Change from 
Baseline in Gastrointestinal Symptom 
Rating Scale - Diarrhoea Syndrome 
Score at Week 24/48  
 
 
24wk, 48wk 
ITT-E 
Shell HO_T28 
Statistical Analysis of Change from 
Baseline in Gastrointestinal Symptom 
Rating Scale - Indigestion Syndrome 
Score at Week 24/48 
 
 
24wk, 48wk 
ITT-E 
Shell HO_T29 
Statistical Analysis of Change from 
Baseline in Gastrointestinal Symptom 
Rating Scale – Constipation Score at 
Week 24/48-  
 
24wk, 48wk 
ITT-E 
Shell HO_T30 
Statistical Analysis of Change from 
Baseline in Gastrointestinal  
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
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170 
 
Health Outcome 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
ITT-E 
Shell HO_T31 
Statistical Analysis of Change from 
Baseline in Gastrointestinal Symptom 
Rating Scale – Reflux Score at Week 
24/48  
 
24wk, 48wk 
 
 


 
CONFIDENTIAL 
 
 
 
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171 
 
11.18.9. 
ICH Listings 
ICH : Listings 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
Study Population 
1.  All Subjects 
Screened 
ES7 
Listing of Reasons for Screen 
Failure 
CS CORE 
24wk, 48wk 
2.  Randomised 
Shell POP_L1 
gsk2619619/ing117172/week48/drivers/sa_l_rand_notrt.sas 
Listing of Subjects Randomised 
But Not Treated 
CS CORE  
(related to ‘Listing for 
exclusion from any 
population) 
24wk, 48wk 
3.  Randomised TA1 
Listing of Randomised and Actual 
Strata and Treatment Assignment 
CS CORE 
 
24wk, 48wk 
4.  
ITT-E 
ES2 
Listing of Reasons for Study 
Withdrawal 
CS CORE 
  
24wk, 48wk 
5.  
ITT-E 
SD3 
Listing of Study Treatment 
Discontinuation Record 
 
 
6.  
ITT-E 
BL1 
Listing of Subjects for Whom the 
Treatment Blind Was Broken  
CS CORE 
24wk, 48wk 
7.  
ITT-E 
IE3 
Listing of Subjects with 
Inclusion/Exclusion Criteria 
Deviations 
CS CORE 
24wk, 48wk 
8.  
ITT-E 
DV2 
Listing of Important Protocol 
Deviations  
CS CORE 
24wk, 48wk 
9.  
ITT-E 
Shell POP_L2 
gsk2619619/ing117172/week48/drivers/pd_l_protdev_expp.sas 
Listing of Important Protocol 
Deviations Leading to Exclusion 
from the Per-Protocol Population 
CS CORE  
 
24wk, 48wk 
10.  
ITT-E 
DM2 
Listing of Demographic 
Characteristics 
CS CORE 
24wk, 48wk 
11.  
ITT-E 
DM9 
Listing of Race 
CS CORE 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
172 
 
ICH : Listings 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
Efficacy 
12.  
ITT-E 
Shell EFF_L1 
gsk2619619/ing117172/week48/drivers/l_eff_hivrna.sas 
Listing of Qualitative and 
Quantitative Plasma HIV-1 RNA 
Data 
Include the interpretation 
of whether the virus is 
detected or not 
(‘Detected’ or ‘Not 
Detected’) by the assay 
24wk, 48wk 
RC 
13.  
ITT-E 
Shell EFF_L2 
gsk2619619/ing117172/week48/drivers/l_so_01.sas 
Listing of Study Outcome (<50 
c/mL) at Week X – Snapshot 
Analysis 
 
24wk, 48wk 
14.  
ITT-E 
Shell EFF_L3 
gsk2619619/ing117172/week48/drivers/l_so_02.sas 
Listing of Study Outcome (<400 
c/mL) at Week X – Snapshot 
Analysis 
 
24wk, 48wk 
Safety 
15.  
Safety 
HIV_IP5 
Listing of Investigational Product 
Exposure Data 
CS CORE 
24wk, 48wk 
RC 
16.  
Safety 
HIV_IP5 
Listing of Investigational Product 
Exposure Data – Mexican 
Subjects 
CS CORE 
EOS 
RC 
17.  
Safety 
AE7 
Listing of Subject Numbers for 
Individual Adverse Events  
CS CORE 
24wk, 48wk 
RC 
18.  
Safety 
AE8 
Listing of All Adverse Events 
CS CORE 
24wk, 48wk 
RC 
19.  
Safety 
AE8 
Listing of Adverse Events 
Potentially Related to Torsades de 
Pointes 
 
24wk, 48wk 
RC 
20.  
Safety 
AE8 
Listing of Fatal Adverse Events 
CS CORE 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
173 
 
ICH : Listings 
No. Population 
IDSL / TST ID / Example Shell 
Title  
Programming Notes 
Deliverable 
& phase 
[Priority] 
21.  
Safety 
AE8 
Listing of Fatal Serious Adverse 
Events 
 
24wk, 48wk 
RC 
22.  
Safety 
AE8 
Listing of Non-Fatal Serious 
Adverse Events 
CS CORE 
24wk, 48wk 
RC 
23.  
Safety 
AE8 
Listing of Adverse Events Leading 
to Withdrawal/Permanent 
Discontinuation of Investigational 
Product 
CS CORE 
24wk, 48wk 
RC 
24.  
Safety 
AE2 
Listing of Relationship of Adverse 
Event System Organ Classes, 
Preferred Terms, and Verbatim 
Text 
CS CORE 
24wk, 48wk 
RC 
25.  
Safety 
SAE Reasons 
AE14 
Listing of Reasons for Considering 
as a Serious Adverse Event 
CS CORE 
FDA 
24wk, 48wk 
RC 
26.  
Safety 
LB5 
Listing of Clinical Chemistry 
Laboratory Data for Subjects with 
Laboratory Abnormalities of 
Potential Clinical Concern 
CS CORE  
24wk, 48wk 
RC 
27.  
Safety 
LB5 
Listing of Hematology Laboratory 
Data for Subjects with  Laboratory 
Abnormalities of Potential Clinical 
Concern 
CS CORE 
24wk, 48wk 
RC 
28.  
Safety 
UR2a 
Listing of Urinalysis Data for 
Subjects with Abnormalities of 
Potential Clinical Concern 
CS CORE 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
174 
 
11.18.10. Non-ICH Listings 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
Study Population 
29.  
All Subjects 
Screened 
Shell POP_L3 
gsk2619619/ing
117172/week48
/drivers/sa_l_po
p.sas 
Listing of Study Populations 
 
24wk, 48wk 
30.  
All Subjects 
Screened 
Shell POP_L4 
gsk2619619/ing
117172/week48
/drivers/l_subre
c_c.sas 
Listing of Subject Recruitment by Country and Site Number 
 
24wk, 48wk 
31.  
ITT-E 
Shell POP_L5 
gsk2619619/ing
117172/week48
/drivers/sa_l_vi
sits.sas 
Listing of Visit Dates 
 
24wk, 48wk 
RC 
32.  
ITT-E 
Shell POP_L6 
gsk2619619/ing
117172/week48
/drivers/lb_l_he
ptst.sas 
Listing of Hepatitis Test Results 
 
24wk, 48wk 
33.  
ITT-E 
CDC3 
Listing of CDC Classification of HIV Infection at Baseline 
 
24wk, 48wk 
34.  
ITT-E 
MH2 
Listing of Current and Past Medical Conditions at Baseline 
 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
175 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
35.  
ITT-E 
Shell POP_L7 
gsk2619619/ing
117172/week48
/drivers/l_card_
risk.sas 
Listing of Baseline Cardiovascular Risk Assessment Data 
 
24wk, 48wk 
36.  
ITT-E 
Shell POP_L8 
gsk2619619/ing
117172/week48
/drivers/l_hist_c
ardiac.sas 
Listing of History of Cardiac Therapeutic Procedures 
 
24wk, 48wk 
37.  
ITT-E 
Shell POP_L9 
gsk2619619/ing
117172/week48
/drivers/invp_l_
acct.sas 
Listing of Investigational Product Accountability 
 
24wk, 48wk 
RC 
38.  
ITT-E 
CM2 
Listing of Concomitant Medications 
CS CORE 
 
24wk, 48wk 
RC 
39.  
ITT-E 
CM6 
Listing of Relationship Between ATC Level 1, Ingredient and 
Verbatim Text 
 
24wk, 48wk 
RC 
40.  
ITT-E 
CA3 
Listing of Prior Antiretroviral Therapy 
 
24wk, 48wk 
41.  
ITT-E 
CA5 
Listing of Concomitant and Post-treatment Antiretroviral Therapy 
 
24wk, 48wk 
RC 
42.  
ITT-E 
CA5 
Listing of Subjects with Changes in Background Antiretroviral 
Therapy 
 
24wk, 48wk 
RC 
43.  
ITT-E 
CA7 
Listing of Relationship Between ATC Level 4, Combination, and 
Verbatim Text for ART 
 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
176 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
Efficacy 
44.  
ITT-E 
Shell EFF_L4 
gsk2619619/ing
117172/week48
/drivers/lb_cd4c
c.sas 
Listing of CD4+ Cell Count Data 
 
24wk, 48wk 
RC 
45.  
ITT-E 
HIV4 
Listing of HIV-1 Associated Conditions 
 
24wk, 48wk 
RC 
46.  
ITT-E 
Shell EFF_L5 
gsk1349572/ing
111762/week48
/drivers/ef_l_hv
1rn_olpdvf.s 
Listing of Viral Load over time for Subjects with Confirmed 
Virologic Withdrawal Criteria 
Other Listing 71 from SAILING 
24wk, 48wk 
 
47.  
ITT-E 
Shell EFF_L6 
gsk1349572/ing
111762/week48
/drivers/ef_l_hv
1rn_olpdvf.s 
Listing of Viral Load over time for Subjects with Confirmed 
Virologic Withdrawal Criteria During the Continuation Phase 
Other Listing 71 from SAILING 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
177 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
48.  
ITT-E 
Shell EFF_L7 
Listing 48 - 
gsk2619619/ing
117172/week48
/drivers/ef_l_cv
w.sas 
Listing 77 - 
gsk2619619/in
g117172/week
48/drivers/mu
_l_geno_resist
.sas 
Listing of Viral Load over time for Subjects with on-treatment 
virology results at non-CVWC  timepoints 
Use non-ICH listing 48 (for the 
format) and 77 (for the subjects to 
be included) 
24wk, 48wk 
RC? 
49.  
ITT-E 
Shell EFF_L8 
gsk1349572/ing
111762/week48
/drivers/mu_t_vl
cd4_pdvf.sas 
Plasma HIV-1 RNA and CD4+ Cell Count at Confirmed Virologic 
Withdrawal Criteria 
Use table 12.60, update as a listing, 
update population and program 
name 
24wk, 48wk 
RC? 


 
CONFIDENTIAL 
 
 
 
200304 
178 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
Safety 
50.  
Safety 
AE8 
Listing of Non-Serious AEs of Mexican Subjects 
 
EOS, RC 
51.  
Safety 
AE8 
Listing of SAEs of Mexican Subjects 
 
EOS, RC 
52.  
Safety 
AE8 
Listing of SAEs of non-Mexican Subjects 
 
EOS, RC 
53.  
Safety 
PREG1a 
Listing of Subjects Who Became Pregnant During the Study 
 
24wk, 48wk 
RC 
54.  
Safety 
LB5 
Listing of Clinical Chemistry Data 
 
24wk, 48wk 
RC 
55.  
Safety 
LB5 
Listing of Hematology Data 
 
24wk, 48wk 
RC 
56.  
Safety 
LB5 
Listing of Laboratory Data for Subjects with Grade 3 or 4 Post-
Baseline Emergent Toxicities 
See for the shell 
arenv/arprod/gsk1349572/ing11176
2/week48/drivers/lb_l_maxaltbil.sas 
24wk, 48wk 
RC 
57.  
Safety 
LB5 
Listing of Urinalysis Concentration Data 
 
24wk, 48wk 
RC 
58.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline 
 
 
24wk, 48wk 
RC 
59.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
If a liver stopping event is reported 
24wk, 48wk 
RC 
60.  
Safety 
Shell SAFE_L1 
gsk2619619/ing
117172/week48
/drivers/lb_l_ma
xaltbil.sas 
Listing of Post Baseline Maximum ALT and Maximum Bilirubin 
 
24wk, 48wk 
RC 
61.  
Safety 
EG5 
Listing of ECG Findings 
Only collected for CV events 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
179 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
62.  
Safety 
VS4 
Listing of Vital Signs 
 
24wk, 48wk 
RC 
63.  
Safety 
ABC_HSR 
_EXPO2 
Listing of Abacavir Hypersensitivity Reaction Record -  Exposure 
to Abacavir 
 
24wk, 48wk 
RC 
64.  
Safety 
ABC_HSR 
_DRUG2 
Listing of Abacavir Hypersensitivity Reaction Record -  Subject 
History of Drug Allergies 
 
24wk, 48wk 
RC 
65.  
Safety 
ABC_HSR 
COND2 
Listing of Abacavir Hypersensitivity Reaction Record -  Subject 
and Family Conditions 
 
24wk, 48wk 
RC 
66.  
Safety 
ABC_HSR 
_RASH2 
Listing of Abacavir Hypersensitivity Reaction Record -  Skin 
Rash Details 
 
24wk, 48wk 
RC 
67.  
Safety 
ABC_HSR 
_SYMP4 
Listing of Abacavir Hypersensitivity Reaction Record -  
Symptoms 
 
24wk, 48wk 
RC 
68.  
Safety 
VS4 
Listing of Abacavir Hypersensitivity Reaction Record -  Vital 
Signs 
 
24wk, 48wk 
RC 
69.  
Safety 
ABC_HSR 
_SYMP6 
Listing of Abacavir Hypersensitivity Reaction Record - Individual 
Symptoms and Diagnostic Category Assignments (Excluding 
Other Symptoms) 
 
24wk, 48wk 
RC 
70.  
Safety 
ABC_HSR 
_SYMP7 
Listing of Abacavir Hypersensitivity Reaction Record - Individual 
Symptoms and Diagnostic Category Assignments (Other 
Symptoms) 
 
24wk, 48wk 
RC 
71.  
Safety 
LIVER5 
Listing of Liver Event Results and Time of Event Relative to 
Treatment 
 
24wk, 48wk 
RC 
72.  
Safety 
LIVER6 
Listing of Liver Event Information for RUCAM Score 
 
24wk, 48wk 
RC 
73.  
Safety 
LIVER7 
Listing of Liver Biopsy Details 
 
24wk, 48wk 
RC 
74.  
Safety 
LIVER8 
Listing of Liver Imaging Details 
 
24wk, 48wk 
RC 


 
CONFIDENTIAL 
 
 
 
200304 
180 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
75.  
Safety 
MH2 
Listing of Past and Current Liver Disease Medical Conditions 
 
24wk, 48wk 
76.  
Safety 
LB5 
Listing of Laboratory Data from Liver Event Follow-Up 
 
24wk, 48wk 
RC 
Virology 
77.  
ITT-E 
 
Shell VI_L1 
gsk1349572/ing
111762/week48
/drivers/mu_l_g
eno_all.sas 
Listing of All Genotypic Data 
Baseline and on study genotypes 
are MAINLY Monogram, but 
some Q2 will be in there. We 
need to note when it is from Q2 
versus Monogram to assist with 
potential subtle differences in 
how the resistance data is 
annotated and provided 
24wk, 48wk 
RC 
78.  
ITT-E 
Shell VI_L2 
gsk1349572/ing
111762/week48
/drivers/ph_l_ph
eno_all.sas 
Listing of All Phenotypic Data 
 
24wk, 48wk 
RC 
79.  
All Subjects 
Screened 
Shell VI_L3 
gsk1349572
/ing111762
/week48/dr
ivers/mu_l
_geno_all.
sas 
Listing of All Screening Genotype Data from Quest 
New (study specific) 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
181 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
80.  
ITT-E 
Shell VI_L4 
gsk1349572/ing
111762/week48
/drivers/mu_t_vi
rology_pdvf 
Listing of Genotypic and Phenotypic Data for Subjects with 
Confirmed Virologic Withdrawal Criteria 
Use T12.59 from SAILING. Update 
as a listing and also title and 
population 
Potentially different 
assays,phenotypic assay for RT 
PRO and Integrase. Can we identify 
this in the listing 
24wk, 48wk 
RC 
81.  
ITT-E 
Shell VI_L5 
gsk1349572/ing
111762/week48
/drivers/mu_t_vi
rology_pdvf.sas 
Listing of Genotypic and Phenotypic Data for Subjects with 
Confirmed Virologic Withdrawal Criteria During the Continuation 
Phase 
Use T12.59 from SAILING. Update 
as a listing and also title and 
population 
24wk, 48wk 
C 
82.  
ITT-E 
Shell VI_L6 
gsk1349572/ing
111762/week48
/drivers/mu_t_vi
rology_last 
Listing of Genotypic and Phenotypic Data for Subjects with on-
treatment virology results at non-CVW timepoints  
Use T12.59 from SAILING. Update 
as a listing and also title and 
population 
24wk, 48wk 
RC 
83.  
ITT-E 
Shell VI_L7 
gsk1349572/ing
111762/week48
/drivers/ph_l_ph
eno_bg_pdvf.sa
s 
Subject Level Summary of Key Virologic Data for Subjects with 
Confirmed Virologic Withdrawal or Last On-treatment VL >400 
c/mL 
 As in Table 12.62 (SAILING) but 
add columns for DTG FC, LPV FC, 
IN substitutions, Major PI mutations, 
mutations, Major NRTI, Major 
NNRTI mutations; flag for CVW/Last 
VL >400. 
 


 
CONFIDENTIAL 
 
 
 
200304 
182 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
Health Outcome Listings 
84.  
ITT-E 
Shell HO_L1 
gsk2619619/ing
117172/week48
/drivers/l_hivtre
at_sat.sas 
Listing of HIV-Treatment Satisfaction Questionnaire  in Individual 
Item Scores and Treatment Satisfaction Score 
Use TU_LIST for all Health 
Outcome Listings 
Change SAS program to exclude 
Lifestyle Ease Score and General 
Satisfaction Clinical Score 
24wk, 48wk 
85.  
ITT-E 
Shell HO_L2 
gsk2619619/ing
117172/week48
/drivers/l_hivtre
at_sat.sas 
Listing of HIV-Treatment Satisfaction Questionnaire in Individual 
Item Scores Change and Treatment Satisfaction Score Change 
Modify program to use HIVTSQc 
48wk 
86.  
ITT-E 
Shell HO_L3 
Listing of Morisky 8-Item Medication Adherence Scale Individual 
Items, Total Score and Adherence Level  
New output but can use TSQ listing 
SAS code – Shell HO_L1 
24wk, 48wk 
87.  
ITT-E 
Shell HO_L4 
Listing of Gastrointestinal Symptom Rating Scale – Individual 
Item Scores 
New output but can use TSQ listing 
SAS code – Shell HO_L1 
24wk, 48wk 
88.  
ITT-E 
Shell HO_L5 
Listing of Gastrointestinal Symptom Rating Scale - Syndrome 
Scores 
New output but can use TSQ listing 
SAS code – Shell HO_L1 
24wk, 48wk 


 
CONFIDENTIAL 
 
 
 
200304 
183 
 
Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable & 
phase 
[Priority] 
89.  
 
 
Patient profiles for subjects meeting protocol defined liver 
stopping criteria, 
Example in 
/arenv/arprod/gsk1349572/ing_idmc
/interim1/drivers/dm_l_patproflist2.s
as or 
/arwork/…/<study>/profiles/profile.s
as 
Include: Investigator, country, tmt, 
sex, DOB, age, race, medical 
history, IP start and end date, 
reasons for discontinuation, AE, 
conmeds, prior ART, labs, viral 
loads, vital signs. 
24wk, 48wk 
90.  
 
 
Patient profiles for subjects with virological failures 
 
24wk, 48wk