Clinical trial NCT03441984
Conditions: HIV Infections
Keywords: Pediatric dispersible tablets Bioavailability
Sponsor: ViiV Healthcare
Start date: 2018-02-26; Completion date: 2018-04-28
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a 2-part, single-dose, open label, randomized 3-way cross-over study to compare BA of pediatric study drugs TRIUMEQ and (DTG/3TC) in healthy volunteers under fasted conditions. Study will be conducted in 2-parts. Each part 1 and part 2 will comprise of 3-treatment periods (TP) where Part 1, will assess BA, of pediatric TRIUMEQ dispersible tablets with an adult TRIUMEQ conventional tablet formulation and Part 2, will assess BA, of pediatric DTG/3TC dispersible tablets with adult DTG and 3TC conventional tablets formulation. Total duration of study is 9-weeks and will be conducted in approximately 36 subjects. The 2-parts, may be run in parallel as they are independent of each other. TRIUMEQ is a registered trademark of GlaxoSmithKline group of companies.

Detailed description:

Arms: arm 1: The subjects in Part 1 of the study, will receive a single dose of treatment A= adult TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 300 mg, 1 conventional tablet) administered as direct-to-mouth, in TP1; treatment B=Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 10 dispersible tablets) administered as a dispersion and taken immediately in TP2; and treatment C=Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 10 dispersible tablets) administered as direct-to-mouth in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 2: The subjects in Part 1 of the study, will receive treatment B in TP1, treatment C in TP2 and treatment A in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 3: The subjects in Part 1 of the study will receive a single dose each of, treatment C in TP1, treatment A in TP2 and treatment B in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 4: The subjects in Part 1 of the study will receive, treatment A in TP1, treatment C in TP2 and treatment B in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 5: The subjects in Part 1 of the study will receive a single dose each of, treatment B in TP1, treatment A in TP2 and treatment C in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 6: The subjects in Part 1 of the study will receive a single dose each of, treatment C in TP1, treatment B in TP2 and treatment A in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 7: The subjects in Part 2 of the study, will receive a single dose of treatment D= Adult DTG (50 mg, 1 conventional tablet) and adult 3TC (300 mg, 1 conventional tablet) administered as direct-to-mouth, in TP1; treatment E= Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets) administered as a dispersion and taken immediately in TP2; and treatment F= Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets) administered as direct-to-mouth in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 8: The subjects in Part 2 of the study, will receive a single dose respectively of treatment E in TP1, treatment F in TP2 and treatment D in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 9: The subjects in Part 2 of the study, will receive a single dose of treatment F in TP1, treatment D in TP2 and treatment E in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 10: The subjects in Part 2 of the study, will receive a single dose of treatment D in TP1, treatment F in TP2 and treatment E in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 11: The subjects in Part 2 of the study, will receive a single dose of treatment E in TP1, treatment D in TP2 and treatment F in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours. arm 12: The subjects in Part 2 of the study, will receive a single dose of treatment F in TP1, treatment E in TP2 and treatment D in TP3. Each treatment will be followed by a wash-out period of 7-days minus 4 hours.
Interventions: intervention 1: Treatment A intervention 2: Treatment B intervention 3: Treatment C intervention 4: Treatment D intervention 5: Treatment E intervention 6: Treatment F
Intervention descriptions: intervention 1: TRIUMEQ (Adult) administered as a, single dose, fixed dose combination (FDC) tablet - DTG 50 mg/ABC 600 mg/3TC 300 mg as 1 conventional tablet, orally as direct-to-mouth. intervention 2: TRIUMEQ (Pediatric) administered as a, single dose, FDC tablet - DTG 5 mg/ABC 60 mg/ 3TC 30 mg, orally as 10 dispersible tablets intervention 3: TRIUMEQ (Pediatric) administered as a, single dose, FDC tablet - DTG 5 mg/ABC 60 mg/3TC 30 mg, orally as direct-to-mouth. intervention 4: DTG and 3TC (Adult), administered as a, single dose, Single dose, 1 tablet DTG (50 mg) and

1 tablet 3TC (300 mg), orally as direct-to-mouth. intervention 5: DTG and 3TC (Pediatric) administered as a, single dose, FDC tablet single dose, FDC tablet - DTG 5 mg/3TC 30 mg, orally as 10 dispersible tablets. intervention 6: DTG and 3TC (Pediatric) administered as a, single dose, FDC tablet single dose, FDC tablet - DTG 5 mg/3TC 30 mg, orally as direct-to-mouth.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A 2-Part, Phase I, Single-Dose, 3-Period Crossover Relative 
Bioavailability Study of a Pediatric TRIUMEQ Dispersible Tablet and Pediatric 
Dolutegravir and Lamivudine (DTG/3TC) Fixed Dose Combination Dispersible Tablet 
Formulations as Compared With Adult Tablets in Healthy Volunteers
Protocol Number: 205894
Short Title: Relative Bioavailability of TRIUMEQ and DTG/3TC Pediatric Dispersible 
Tablet Formulations in Healthy Volunteers
Compound Numbers:
GSK2619619 (GSK1349572+GR109714+GI265235) and 
GSK3515864 (GSK1349572+GR109714)
This study is sponsored by ViiV Healthcare. PPD, Inc with GlaxoSmithKline is 
supporting ViiV Healthcare in the conduct of this study.
US IND Sponsor Name and Legal Registered Address: 
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, local law requires that the clinical trial sponsor is a local 
company legal entity. In these instances, the appropriate company to be identified as 
sponsor must be agreed with the global ViiV Healthcare clinical team and signed off 
by the Vice President, Global Medical Strategy
Medical Monitor Name and Contact Information:
 MD
Five Moore Drive
P.O. 13398
Research Triangle Park, NC
27709-3398, USA
SAE email: 
 and 
Back-up Medical Monitor:
 MD
Five Moore Drive
P.O. 13398
Research Triangle Park, NC
27709-3398, USA
Regulatory Agency Identifying Numbers: 114,820 (TRIUMEQ) and
127,475 (DTG/3TC)
Approval Date: 18-JAN-2018
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies. All 
rights reserved. Unauthorized copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
2.1.
Screening Assessments for Parts 1 and 2 ..................................................10
2.2.
Time and Events Table for Parts 1 and 2....................................................11
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................14
3.3.1.
Risk Assessment .........................................................................15
3.3.2.
Benefit Assessment.....................................................................17
3.3.3.
Overall Benefit:Risk Conclusion...................................................17
4.
OBJECTIVES AND ENDPOINTS...........................................................................18
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................21
5.3.
Participant and Study Completion...............................................................21
5.4.
Scientific Rationale for Study Design ..........................................................21
5.5.
Dose Justification........................................................................................21
6.
STUDY POPULATION...........................................................................................22
6.1.
Inclusion Criteria.........................................................................................22
6.2.
Exclusion Criteria........................................................................................23
6.3.
Lifestyle Restrictions...................................................................................25
6.3.1.
Meals and Dietary Restrictions ....................................................25
6.3.2.
Fasting Conditions.......................................................................25
6.3.3.
Fed Conditions ............................................................................26
6.3.4.
Caffeine, Alcohol, and Tobacco ...................................................26
6.3.5.
Activity .........................................................................................26
6.4.
Screen Failures...........................................................................................26
7.
TREATMENTS.......................................................................................................26
7.1.
Treatments Administered............................................................................27
7.1.1.
Dosing of Dispersible Tablets in Treatments B and E ..................27
7.1.2.
Dosing of Pediatric TRIUMEQ Tablets in Treatments C 
and F ...........................................................................................28
7.2.
Dose Modification .......................................................................................28
7.3.
Method of Treatment Assignment ...............................................................28
7.4.
Blinding.......................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability..............................................29
7.6.
Treatment Compliance................................................................................29
7.7.
Concomitant Therapy..................................................................................29
7.8.
Treatment after the End of the Study ..........................................................30
8.
DISCONTINUATION CRITERIA.............................................................................30
8.1.
Discontinuation of Study Treatment ............................................................30
 
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8.1.1.
Liver Chemistry Stopping Criteria ................................................30
8.1.2.
QTc Stopping Criteria ..................................................................31
8.2.
Withdrawal from the Study..........................................................................31
8.3.
Lost to Follow Up........................................................................................32
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................32
9.1.
Efficacy Assessments.................................................................................33
9.2.
Adverse Events...........................................................................................33
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................34
9.2.2.
Method of Detecting AEs and SAEs.............................................34
9.2.3.
Follow-up of AEs and SAEs.........................................................34
9.2.4.
Regulatory Reporting Requirements for SAEs .............................35
9.2.5.
Pregnancy ...................................................................................35
9.3.
Treatment of Overdose...............................................................................35
9.4.
Safety Assessments ...................................................................................36
9.4.1.
Physical Examinations.................................................................36
9.4.2.
Vital Signs....................................................................................36
9.4.3.
Electrocardiograms......................................................................36
9.4.4.
Clinical Safety Laboratory Assessments ......................................36
9.5.
Pharmacokinetics .......................................................................................37
9.5.1.
Blood Sample Collection..............................................................37
9.5.2.
Sample Analysis ..........................................................................37
9.6.
Formulation Palatability Assessment ..........................................................37
9.7.
Genetics .....................................................................................................37
10. STATISTICAL CONSIDERATIONS........................................................................38
10.1.
Sample Size Determination ........................................................................38
10.1.1.
Sample Size Assumptions ...........................................................38
10.1.2.
Sample Size Sensitivity................................................................38
10.2.
Populations for Analyses ............................................................................38
10.3.
Statistical Analyses.....................................................................................39
10.3.1.
Key Elements of Analysis Plan ....................................................39
10.3.2.
Pharmacokinetic Analyses...........................................................39
10.3.3.
Safety Analyses...........................................................................40
10.3.4.
Other Analyses ............................................................................40
10.3.5.
Interim Analyses ..........................................................................40
11. REFERENCES.......................................................................................................41
12. APPENDICES........................................................................................................42
12.1.
Appendix 1: Abbreviations and Trademarks................................................42
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................45
12.3.
Appendix 3: Study Governance Considerations..........................................46
12.4.
Appendix 4: Palatability Questionnaire........................................................50
12.5.
Appendix 5: Toxicity Management ..............................................................54
12.5.1.
Decline in Renal Function............................................................55
12.5.2.
Hypersensitivity Reaction.............................................................56
12.5.3.
Skin Reactions without Other Symptoms that are Typical 
of ABC HSR.................................................................................57
12.5.4.
Creatine Phosphokinase Elevation ..............................................58
12.5.5.
Anemia ........................................................................................59
 
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12.5.6.
Total Bilirubin Elevation ...............................................................60
12.5.7.
AST and ALT Elevation................................................................60
12.5.8.
Rash............................................................................................61
12.5.9.
Allergic Reaction..........................................................................62
12.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................64
12.7.
Appendix 7: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................68
12.8.
Appendix 8: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................70
12.9.
Appendix 9: Division Of AIDS Table For Grading The Severity Of 
Adult And Paediatric Adverse Events Version 2.0, November 2014............76
 
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1.
SYNOPSIS
Protocol Title: A 2-Part, Phase I, Single-Dose, 3-Period Crossover Relative 
Bioavailability Study of a Pediatric TRIUMEQ Dispersible Tablet and Pediatric 
Dolutegravir and Lamivudine (DTG/3TC) Fixed Dose Combination Dispersible Tablet 
Formulations as Compared With Adult Tablets in Healthy Volunteers
Short Title: Relative Bioavailability of TRIUMEQ and DTG/3TC Pediatric Dispersible 
Tablet Formulations in Healthy Volunteers
Rationale:
This study will compare the relative bioavailability (BA) of TRIUMEQ dispersible 
tablets developed for pediatric populations (dolutegravir [DTG] 5 mg/abacavir [ABC]
60 mg/lamivudine [3TC] 30 mg), when administered as direct-to-mouth and when
dispersed into purified water, with the adult TRIUMEQ conventional tablet (DTG 
50 mg/ABC 600 mg/3TC 300 mg) when administered as direct-to-mouth (reference). In 
addition, this study will compare the relative BA of DTG/3TC (DTG 5 mg/3TC 30 mg) 
dispersible tablets developed for pediatric populations, when administered as direct-to-
mouth and when dispersed into purified water, with the adult DTG (50 mg) and 3TC 
(300 mg) conventional tablets when administered as direct-to-mouth (reference).
 
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Objectives and Endpoints:
Objectives
Endpoints
Part 1
Primary

To compare the relative BA of DTG, ABC, 
and 3TC administered as pediatric 
TRIUMEQ dispersible tablets with the 
conventional adult TRIUMEQ tablet
(reference) administered as direct-to-mouth 
when:
o
Pediatric TRIUMEQ dispersible tablets
are administered as a dispersion and 
taken immediately 
o
Pediatric TRIUMEQ dispersible tablets
are administered as direct-to-mouth

Plasma DTG, ABC, and 3TC: 
o
Area under the plasma 
concentration-time curve (AUC) from 
time of dose extrapolated to infinity 
(AUC[0-∞])
o
AUC from time of dose to last 
measurable concentration (AUC[0-t])
o
Maximum observed concentration 
(Cmax)
Secondary

To compare the single-dose 
pharmacokinetics (PK) of DTG, ABC, and 
3TC administered as pediatric TRIUMEQ 
dispersible tablets with the conventional adult 
TRIUMEQ tablets (reference) administered 
as direct-to-mouth when:
o
Pediatric TRIUMEQ dispersible tablets
are administered as a dispersion and 
taken immediately 
o
Pediatric TRIUMEQ dispersible tablets
are administered as direct-to-mouth

Plasma DTG, ABC, and 3TC:
o
AUC from time of dose to 24 hours 
(AUC[0-24]) 
o
Time to maximum concentration 
(Tmax)
o
Time of last quantifiable concentration 
(Tlast)
o
Apparent oral clearance (CL/F)
o
Apparent volume of distribution (Vz/F)
o
Observed concentration at 24 hours
postdose (C24)
o
Last observed quantifiable 
concentration (Ct)
o
Terminal elimination phase half-life 
(t½)

Plasma DTG:
o
Lag time for absorption (tlag)

To evaluate the safety and tolerability of 
DTG, ABC, and 3TC administered as 
pediatric TRIUMEQ dispersible tablets as 
compared with conventional adult TRIUMEQ
tablet (reference) administered as direct-to-
mouth

Safety and tolerability parameters for 
adverse events (AE)/serious adverse 
events (SAE), observed and change from 
baseline clinical laboratory assessments, 
electrocardiogram (ECG), and vital signs
 
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Objectives
Endpoints
Part 2
Primary

To compare the relative BA of DTG and 3TC 
administered as pediatric DTG/3TC
dispersible tablets with the conventional adult 
DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and 
taken immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct-to-mouth

Plasma DTG and 3TC: 
o
AUC(0-∞)
o
AUC(0-t)
o
Cmax
Secondary

To compare the single-dose 
pharmacokinetics (PK) of DTG and 3TC 
administered as pediatric DTG/3TC
dispersible tablets, with the conventional 
adult DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and 
taken immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct-to-mouth

Plasma DTG and 3TC:
o
AUC(0-24) 
o
Tmax
o
Tlast
o
CL/F
o
Vz/F
o
C24
o
Ct
o
t½

Plasma DTG:
o
tlag

To evaluate the safety and tolerability of DTG
and 3TC administered as pediatric DTG/3TC
dispersible tablets as compared with the 
conventional adult DTG and 3TC tablets
(reference) administered as direct-to-mouth

Safety and tolerability parameters for AEs/
SAEs, observed and change from baseline 
clinical laboratory assessments, ECG, and 
vital signs
 
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Overall Design:
This is a 2-part, open-label, single-dose, 3-period, randomized, crossover study to 
compare the relative BA of pediatric TRIUMEQ dispersible tablets with an adult 
TRIUMEQ conventional tablet formulation (Part 1) and of pediatric DTG/3TC
dispersible tablets with adult DTG and 3TC conventional tablets formulation (Part 2) in 
healthy volunteers under fasted conditions. Prior to dosing on Day 1 of Period 1 in each 
part, participants will be randomized to 1 of 6 treatment sequences (ABC, BCA, CAB, 
ACB, BAC, or CBA in Part 1; DEF, EFD, FDE, DFE, EDF, or FED in Part 2) and will 
receive a single dose of each of the 3 treatments administered as 1 treatment per period.
Parts 1 and 2 of the study are independent of one another and may be run in parallel. 
Study assessments will be performed as indicated in the Schedule of Activities.
Number of Participants:
For each part, sufficient participants will be screened to achieve 18 randomized, each to 1
of 6 treatment sequences, to achieve approximately 12 evaluable participants that have 
completed all 3 treatment periods (2 evaluable participants per sequence).
Treatment Groups and Duration:
In each part, participants will receive a single dose of each of the following treatments,
administered as 1 treatment per period according to their assigned sequence:
Part 1:

Treatment A: Adult TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference).

Treatment B: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as a dispersion and taken immediately (test).

Treatment C: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as direct-to-mouth (test).
Part 2:

Treatment D: Adult DTG (50 mg, 1 conventional tablet) and adult 3TC (300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference).

Treatment E: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets)
administered as a dispersion and taken immediately (test).

Treatment F: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets)
administered as direct-to-mouth (test).
To ensure adequate washout, there will be at least 7 days between each dose of study 
drug, with an allowance window of 4 hours (i.e., 7 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic. In each of the 3 treatment 
periods, participants will be admitted to the clinic on Day −1 and will be discharged 
 
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following completion of the last study procedure on Day 4. Participants will return to the 
clinic for an outpatient follow-up visit 7 to 10 days after the last dose of study drug.
The total duration of participation in this study will be approximately 9 weeks, including
a screening visit within 30 days prior to the first dose of study drug, 3 treatment periods 
each with a single dose of study drug per treatment period, and a follow-up visit within 7
to 10 days after the last dose of study drug. 
2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening Assessments for Parts 1 and 2

Screening procedures may be done over more than one visit but must all be 
completed within 30 days prior to the first dose of study drug.

The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria.
Event
Notes
Informed Consent
Demographics
Medical History (includes substance use)
Inclusion/Exclusion
Human Immunodeficiency Virus, Hepatitis B and 
Hepatitis C Screen
HLA-B*5701
For Part 1 only.
Urine Drug/Alcohol/Cotinine Screen
Physical Examination
A brief physical examination is required at Screening.
Height, Weight & Body Mass Index
Vital Sign Measurement
12-lead Electrocardiogram (Single)
A single repeat evaluation is allowed for eligibility 
determination.
Follicle-stimulating Hormone and Estradiol (women)
Pregnancy Test (urine)
For women of child bearing potential (WOCBP) only.
Clinical Laboratory Tests (Chemistry, Hematology, 
and Urinalysis)
For clinical laboratory tests, see Appendix 2.
Concomitant Medication
 
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2.2.
Time and Events Table for Parts 1 and 2
Assessments
Periods 1-3
Follow-up
Notes
Day −1 of Periods 2 and 3 may be the same day as Day 6 of prior 
periods.
At Follow-up, male participants and female participants of non-
childbearing potential with no ongoing AEs or vital sign/clinical 
laboratory results of clinical concern may be followed up virtually 
by the site via telephone contact.
Day 
−1
Day
1
Day 
2
Day 
3
Day 
4
Predose
0
hr
Postdose
24 
hr
48 
hr
72 
hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
Follow-up visit will occur 7-10 days after last dose.
12-lead ECG (single)
X
Vital signs
X
X
At 4 hours postdose
X
X
Single vital sign measurements performed at all time points.
Vital signs at Follow-up are only necessary if participant had
ongoing AEs or a previous abnormal vital sign result of clinical 
concern. Only the abnormal value(s) need be re-assessed.
Brief Physical Examination
X
Physical examination required only on Day −1 of Period 1 and as 
needed based on AE assessment.
Urine Drug/Alcohol/Cotinine
X
Drug/Alcohol/Cotinine/pregnancy will be performed as per the 
standard practice of the site.
For clinical laboratory tests, see Appendix 2.
Clinical laboratory tests at Follow-up are only necessary if participant
had ongoing AEs or a previous abnormal clinical laboratory result of 
clinical concern. Only the abnormal value(s) need be re-assessed.
Pregnancy test (serum; WOCBP)
X
X
Clinical laboratory tests 
X
X
X
Dosing
X
Participants in Part 1 should be provided with an ABC HSR warning 
card and should be reminded to read it.
Palatability Assessment
Start within 10 minutes 
after dose
Complete for each dispersion treatment (Treatments B & E, see 
Appendix 4).
Pharmacokinetic Sampling
X
Collect at: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 
16, 24, 48 and 72 hours postdose before 
discharge at the end of each period
Predose is within 15 minutes prior to dosing (see Section 9.5.1).
Meals
Fasted from 10 hours prior to 
dosing to 4 hours postdose
Standard for the study centre
Adverse Events / SAE
X
======================X======================
X
Concomitant medications
X
======================X======================
X
 
 
 
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
The timing and number of planned study assessments, including safety, pharmacokinetic or other assessments may be altered 
during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by 
the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
 
 
 
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3.
INTRODUCTION
TRIUMEQ™ (GSK2619619) is a fixed-dose combination (FDC) that contains the 
integrase inhibitor (INI) dolutegravir (DTG [TIVICAY™, GSK1349572]) and 
2 nucleoside reverse transcriptase inhibitors, abacavir (ABC) and lamivudine (3TC).
GSK3515864 is an FDC in development that contains the INI DTG (TIVICAY, 
GSK1349572) and the nucleoside reverse transcriptase inhibitor 3TC.
3.1.
Study Rationale
An ABC/3TC conventional tablet is currently marketed worldwide for the treatment of 
human immunodeficiency virus (HIV) in adults and children (as EPZICOM™ in the 
United States [US] or as KIVEXA™ in the European Union [EU]). The TIVICAY 50 mg 
conventional tablet is for the treatment of HIV infection in adults and adolescents. 
Recently, 2 lower pediatric-strength conventional tablets (10 mg and 25 mg) were 
approved in the US and EU. A dispersible-tablet formulation (5-mg tablet for oral 
suspension) of TIVICAY has been developed for administration in younger pediatric 
populations.
This study will compare the relative bioavailability (BA) of TRIUMEQ dispersible 
tablets developed for pediatric populations (DTG 5 mg/ABC 60 mg/3TC 30 mg), when 
administered as direct-to-mouth and when dispersed into purified water, with the adult 
TRIUMEQ conventional tablet (DTG 50 mg/ABC 600 mg/3TC 300 mg) when 
administered as direct-to-mouth (reference). In addition, this study will compare the 
relative BA of DTG/3TC (DTG 5 mg/3TC 30 mg) dispersible tablets developed for 
pediatric populations, when administered as direct-to-mouth and when dispersed into 
purified water, with the adult DTG (50 mg) and 3TC (300 mg) conventional tablets when 
administered as direct-to-mouth (reference).
3.2.
Background
TIVICAY, as a DTG single-drug entity, was first approved in the US in August 2013 and 
is currently approved globally in more than 100 countries. DTG is a next-generation INI 
with low to moderate inter-participant pharmacokinetic (PK) variability, a predictable 
exposure-response relationship, and a 14-hour plasma half-life that supports once-daily 
dosing without the need for PK boosters. In addition, DTG lacks many of the associated 
drug interactions, specifically with oral contraceptives, statins, antidepressants, 
anxiolytics, anticoagulants, and other medications commonly taken by HIV-positive 
patients.
The TRIUMEQ FDC tablet was developed and approved for the treatment of HIV in 
adults and pediatric patients weighing at least 40 kg as a single-tablet regimen with or 
without food, or in combination with other antiretroviral therapies, to achieve convenient 
dosing and improve patient compliance. The TRIUMEQ conventional tablet (currently 
approved more than 50 countries) is bioequivalent to concurrent administration of DTG 
and ABC/3TC tablets (TRIUMEQ Prescribing Information, 2014). The DTG/3TC FDC 
tablet is currently being developed for treatment of HIV in adults. Alternate formulations 
 
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(e.g., dispersible tablets) and dosing strategies are being developed for pediatric patients 
less than 12 years old who may have difficulty swallowing conventional tablet 
formulations.
A detailed description of the chemistry, pharmacology, efficacy, and safety of DTG as a 
single entity, in combination with ABC/3TC as TRIUMEQ, and in combination with 3TC 
as DTG/3TC, is provided in the Investigator’s Brochure (IB) [GlaxoSmithKline 
Document Number RM2007/00683/11].
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of DTG, ABC, and 3TC may be found in the 
IB.
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG/ABC/3TC] Refer to IB for additional information on DTG and DTG/ABC/3TC
Refer to approved country product label for additional information on DTG and ABC/3TC
Hypersensitivity (including 
abacavir hypersensitivity 
reaction [ABC HSR]) and 
rash
A well characterized, idiosyncratic, drug-related HSR is the most important 
risk associated with ABC (Section 12.5.9). Exclusion of individuals found to 
carry the human leukocyte antigen (HLA)-B*5701 allele from ABC therapy 
reduces the risk of HSR. Rash, including Stevens-Johnson syndrome 
(SJS), toxic epidermal necrolysis (TEN), and erythema multiforme have 
been reported in patients taking ABC (Section 12.5.1).
HSR has been observed uncommonly with DTG. Rash was commonly 
reported in DTG Phase IIb/III clinical trials; episodes were generally mild to 
moderate in intensity; no episodes of severe rash, such as SJS, TEN, and 
erythema multiforme were reported. Data on HSR for DTG and 
DTG+ABC/3TC FDC suggest that there will not be additional risk from HSR 
in HLA-B*5701 negative participants receiving the DTG/ABC/3TC FDC.

Participants must be negative for HLA-B*5701 for inclusion in Part 
1 (Section 6.1). Additionally, participants with history of 
allergy/sensitivity to any of the study drugs are excluded 
(Section 6.2).

Specific/detailed toxicity management guidance is provided for 
suspected HSR with DTG or ABC (Appendix 5), and skin 
reactions without systemic involvement (Appendix 5).

The participant informed consent form includes information on this 
risk and the actions participants should take in the event of an 
HSR or associated signs and symptoms.

Participants in Part 1 will be provided with an ABC HSR warning 
card and are to be reminded to read it. 
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 antiretroviral therapy (ART) containing DTG regardless of dose or 
treatment population.
Current treatment guidelines [Guidelines 2016] do not recommend mono 
therapy with 3TC for patients with Hepatitis B virus (HBV) infection, which is 
what participants randomly assigned to DTG/ABC/3TC would effectively be 
receiving. Additionally, discontinuation of 3TC in HBV infected participants
can result in severe exacerbations of HBV.
Participants meeting either of the following criteria during the screening 
period are excluded from participating (Section 6.2).

Alanine aminotransferase (ALT) 1.5 times the upper limit of 
normal (ULN; isolated bilirubin >1.5 × ULN is acceptable if 
bilirubin is fractionated and direct bilirubin 35%).

Positive for HBV (hepatitis B virus surface antigen positive 
[+HBsAg]) or positive HCV (positive hepatitis C antibody test) 
within 3 months of the Day 1 study visit.
Specific/detailed liver chemistry stopping criteria (Section 8.1.1) and 
toxicity management guidance is provided for suspected DILI or other 
clinically significant liver chemistry elevations (Appendix 5).
Theoretical serious drug 
interaction with dofetilide
Co-administration of DTG may increase dofetilide plasma concentration via
inhibition of organic cation transporter (OCT) 2 transporter, resulting in 
Concomitant medications (e.g., dofetilide) are prohibited in the study
(Section 6.2 and Section 7.7).
 
 
 
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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy1
potentially life-threatening toxicity.
Gastrointestinal (GI) 
intolerance
Nonclinical studies showed upper and lower GI toxicity, including vomiting,
diarrhea, and gastric erosions observed in monkey toxicology studies 
(thought to be related to local and not systemic toxicity). 
Mild to moderate GI intolerance (mainly diarrhea and nausea) is associated 
with DTG treatment in a small proportion of participants; however there 
were no indications of an increased risk for peptic ulcers or serious 
erosions.
Routine monitoring of GI symptoms will be performed (Section 9.2 and 
Appendix 8).
Renal function
Mild elevations of creatinine have been observed with DTG that are related 
to a benign effect on creatinine secretion with blockade of the OCT-2 
receptor. DTG has been shown to have no significant effect on glomerular 
filtration rate (GFR) or effective renal plasma flow. Measurement of 
albumin/creatinine ratio confirmed there was no difference in the effect of 
DTG on albumin excretion compared with EFV or Raltegravir (RAL). 3TC is 
eliminated by renal excretion and exposure increases in patients with renal 
dysfunction.
Due to requirements for dose reduction of 3TC in patients with renal 
dysfunction, participants with a CrCl <90 mL/min are excluded
(Section 6.2).
Specific/detailed toxicity management guidance is provided for 
participants who develop a decline in renal function (Appendix 5).
Increases in serum creatinine are not expected to have any adverse 
effect and will reverse during the wash out period after each single 
dosing of DTG, and; therefore, do not require mitigation in this protocol 
for DTG.
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 
participants who develop Grade 3 to 4 CPK elevations (Appendix 5).
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 grading for HIV-infected patients [Appendix 9]). 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.
 
 
 
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3.3.2.
Benefit Assessment
This is a study in healthy participants and as such there is no expected benefit to 
administration of DTG, ABC, and 3TC. Participation in this study may contribute to the 
process of developing new therapies for HIV. There may be benefit to individual 
participants from the medical evaluations and assessments that could identify conditions 
that the participant was previously unaware of.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with DTG, ABC, and 3TC are low.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part 1
Primary

To compare the relative BA of DTG, ABC, 
and 3TC administered as pediatric 
TRIUMEQ dispersible tablets with the 
conventional adult TRIUMEQ tablet
(reference) administered as direct-to-mouth 
when:
o
Pediatric TRIUMEQ dispersible tablets
are administered as a dispersion and 
taken immediately 
o
Pediatric TRIUMEQ dispersible tablets
are administered as direct-to-mouth

Plasma DTG, ABC, and 3TC: 
o
Area under the plasma 
concentration-time curve (AUC) from 
time of dose extrapolated to infinity 
(AUC[0-∞])
o
AUC from time of dose to last 
measurable concentration (AUC[0-t])
o
Maximum observed concentration 
(Cmax)
Secondary

To compare the single-dose 
pharmacokinetics (PK) of DTG, ABC, and 
3TC administered as pediatric TRIUMEQ 
dispersible tablets with the conventional adult 
TRIUMEQ tablets (reference) administered 
as direct-to-mouth when:
o
Pediatric TRIUMEQ dispersible tablets
are administered as a dispersion and 
taken immediately 
o
Pediatric TRIUMEQ dispersible tablets
are administered as direct-to-mouth

Plasma DTG, ABC, and 3TC:
o
AUC from time of dose to 24 hours 
(AUC[0-24]) 
o
Time to maximum concentration 
(Tmax)
o
Time of last quantifiable concentration 
(Tlast)
o
Apparent oral clearance (CL/F)
o
Apparent volume of distribution (Vz/F)
o
Observed concentration at 24 hours
postdose (C24)
o
Last observed quantifiable 
concentration (Ct)
o
Terminal elimination phase half-life 
(t½)

Plasma DTG:
o
Lag time for absorption (tlag)

To evaluate the safety and tolerability of 
DTG, ABC, and 3TC administered as 
pediatric TRIUMEQ dispersible tablets as 
compared with conventional adult TRIUMEQ
tablet (reference) administered as direct-to-
mouth

Safety and tolerability parameters for 
adverse events (AE)/serious adverse 
events (SAE), observed and change from 
baseline clinical laboratory assessments, 
electrocardiogram (ECG), and vital signs
 
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Objectives
Endpoints
Part 2
Primary

To compare the relative BA of DTG and 3TC 
administered as pediatric DTG/3TC
dispersible tablets with the conventional adult 
DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and 
taken immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct-to-mouth

Plasma DTG and 3TC: 
o
AUC(0-∞)
o
AUC(0-t)
o
Cmax
Secondary

To compare the single-dose 
pharmacokinetics (PK) of DTG and 3TC 
administered as pediatric DTG/3TC
dispersible tablets, with the conventional 
adult DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and 
taken immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct-to-mouth

Plasma DTG and 3TC:
o
AUC(0-24) 
o
Tmax
o
Tlast
o
CL/F
o
Vz/F
o
C24
o
Ct
o
t½

Plasma DTG:
o
tlag

To evaluate the safety and tolerability of DTG
and 3TC administered as pediatric DTG/3TC
dispersible tablets as compared with the 
conventional adult DTG and 3TC tablets 
(reference) administered as direct-to-mouth

Safety and tolerability parameters for AEs/ 
SAEs, observed and change from baseline 
clinical laboratory assessments, ECG, and 
vital signs
Parts 1 and 2
Exploratory

To evaluate the palatability of the dispersible 
tablets

Palatability questionnaire
5.
STUDY DESIGN
5.1.
Overall Design
This is a 2-part, open-label, single-dose, 3-period, randomized, crossover study to 
compare the relative BA of pediatric TRIUMEQ dispersible tablets with an adult 
TRIUMEQ conventional tablet formulation (Part 1) and of pediatric DTG/3TC 
dispersible tablets with adult DTG and 3TC conventional tablets formulation (Part 2) in 
healthy volunteers under fasted conditions. A study design schematic is presented in 
Figure 1.
 
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Figure 1
Study Design Schematic
1.
Washout will be at least 7 days minus 4 hours.
Prior to dosing on Day 1 of Period 1 in each part, participants will be randomized to 1 of 
6 treatment sequences (ABC, BCA, CAB, ACB, BAC, or CBA in Part 1; DEF, EFD, 
FDE, DFE, EDF, or FED in Part 2) and will receive a single dose of each of the 
following treatments administered as 1 treatment per period:
Part 1:

Treatment A: Adult TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference).

Treatment B: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as a dispersion and taken immediately (test).

Treatment C: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as direct-to-mouth (test).
Part 2:

Treatment D: Adult DTG (50 mg, 1 conventional tablet) and adult 3TC (300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference).

Treatment E: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets)
administered as a dispersion and taken immediately (test).

Treatment F: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets)
administered as direct-to-mouth (test).
To ensure adequate washout, there will be at least 7 days between each dose of study 
drug, with an allowance window of 4 hours (i.e., 7 days minus 4 hours) to allow 
flexibility in scheduling participants for dosing at the clinic. In each of the 3 treatment 
periods, participants will be admitted to the clinic on Day −1 and will be discharged 
 
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following completion of the last study procedure on Day 4. Participants will return to the 
clinic for an outpatient follow-up visit 7 to 10 days after the last dose of study drug.
The total duration of participation in this study will be approximately 9 weeks. Each 
participant will have a screening visit within 30 days prior to the first dose of study drug, 
3 treatment periods with a single dose of study drug per treatment period, and a follow-up
visit within 7 to 10 days after the last dose of study drug.
Parts 1 and 2 of the study are independent of one another and may be run in parallel. 
Study assessments will be performed as indicated in the Schedule of Activities (SoA; 
Section 2).
5.2.
Number of Participants
For each part, sufficient participants will be screened to achieve 18 randomized, each to 1 
of 6 treatment sequences, to achieve approximately 12 evaluable participants that have 
completed all 3 treatment periods (2 evaluable participants per sequence; see Section 
10.1).
5.3.
Participant and Study Completion
A completed participant is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last participant’s last visit.
5.4.
Scientific Rationale for Study Design
The open-label crossover design of this study is well-established for evaluation of the 
relative BA of different oral dosage forms and random assignment to treatment sequences 
is an attempt to prevent bias. The washout of 7 days between dosing periods should 
eliminate the possibility of carryover of drug exposure from the previous dosing period. 
In each part of the study, there are appropriately named “test” and “reference” study 
treatments, which will be evaluated for the relative BA comparisons.
This study is participant to the appropriate regulatory approval and Ethics Committee 
approval, and will be listed on the website ClinicalTrials.gov. No blinding or placebo 
control will be used, as these are not necessary for the purposes of this study.
5.5.
Dose Justification
The US Food and Drug Administration (FDA)-approved dose of TRIUMEQ for the 
treatment of HIV infection in adults and pediatric patients weighing at least 40 kg is 
1 oral tablet, once daily, with or without food. TRIUMEQ is an FDC product containing 
600 mg of ABC, 50 mg of DTG, and 300 mg of 3TC. Oral solutions, adult scored tablets, 
and President’s Emergency Plan for AIDS Relief-approved dispersible and 
non-dispersible tablets of ABC and 3TC are available for use in pediatric patients, 
depending on their country of residence. In addition, the 10 mg DTG tablet was 
previously studied in study P1093 (ING112578) [GlaxoSmithKline Document Number 
 
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2015N235495_00]. The pediatric TRIUMEQ dispersible tablet consists of DTG 5 mg, 
ABC 60 mg, and 3TC 30 mg.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Between 18 and 65 years of age, inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Healthy, as determined by the investigator or medically qualified designee based on a 
medical evaluation, including medical history, physical examination, laboratory tests,
and cardiac evaluation (history and ECG).
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range for the 
population being studied may be included only if the investigator in consultation with the 
Medical Monitor agree and document that the finding is unlikely to introduce additional 
risk factors and will not interfere with the study.
WEIGHT
3. Body weight 50 kg for males and 45 kg for females and body mass index (BMI) 
within the range 18.5 – 31.0 kg/m2 (inclusive).
SEX
4. Male or female
i.
Male participants
A male participant must agree to use contraception as detailed in Appendix 6 of this 
protocol during the treatment period and for at least 2 weeks plus an additional 
90 days (a spermatogenesis cycle) after the last dose of study treatment and refrain 
from donating sperm during this period.
ii.
Female participants
A female participant is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin [hCG] test), not lactating, and at least 
1 of the following conditions applies:
a.
Non-reproductive potential, defined as:
 
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
Premenopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up
confirmation of bilateral tubal occlusion 

Documented hysterectomy

Documented bilateral oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone and estradiol levels consistent with menopause (refer to laboratory 
reference ranges for confirmatory levels)]. Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to 
use one of the highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Highly 
Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential
(see Appendix 6) from 30 days prior to the first dose of study medication and until 
2 weeks after dosing with study medication and completion of the follow-up visit.
c.
The investigator is responsible for ensuring that participants understand how to 
properly use these methods of contraception.
d.
All participants participating in the study should be counselled on safer sexual 
practices including the use and benefit/risk of effective barrier methods (e.g., male 
condom) and on the risk of HIV transmission to an uninfected partner.
INFORMED CONSENT
5. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
HISTORY/DIAGNOSTIC 
6. For participants in Part 1 only, documentation that the participant is negative for the 
human leukocyte antigen (HLA)-B*5701 allele.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1. ALT and bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if 
bilirubin is fractionated and direct bilirubin 35%).
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert’s syndrome or asymptomatic gallstones). 
 
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3. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart Rate
<45 and >100 bpm1
<50 and >100 bpm1
PR Interval
<120 and >220 msec
QRS Interval
<70 and >120 msec
QTcF Interval2
>450 msec
1. A heart rate from 100 to 110 bpm may be rechecked by ECG or vitals 
within 30 minutes to verify eligibility.
2.
The QTcF is the QT interval corrected for heart rate according to 
Fridericia’s formula, machine-read or manually over-read.

Evidence of previous myocardial infarction (does not include ST segment changes 
associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], Wolf-Parkinson-White
syndrome).

Sinus pauses >3 seconds.

Any significant arrhythmia which, in the opinion of the principal investigator or 
ViiV/GlaxoSmithKline (GSK) medical monitor, will interfere with the safety of 
the individual participant.

Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
NOTE:
For purposes of data analysis, only QTcF will be used as specified in the Reporting 
and Analysis Plan (RAP).
PRIOR/CONCOMITANT THERAPY
4. Unable to refrain from the use of prescription (e.g., dofetilide) or non-prescription
drugs, including vitamins, herbal and dietary supplements (including St John’s wort) 
within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 
(whichever is longer) prior to the first dose of study medication, unless in the opinion 
of the Investigator and ViiV Healthcare Medical Monitor the medication will not 
interfere with the study procedures or compromise participant safety.
RELEVANT HABITS
5. History of regular alcohol consumption within 6 months of the study, defined as an 
average weekly intake of >14 drinks for males or >7 drinks for females. One drink is 
equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of 
wine, or 1.5 ounces (45 mL) of 80 proof distilled spirits.
6. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 1 month prior to screening.
 
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CONTRAINDICATIONS
7. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation. The participant has participated in a 
clinical trial and has received an investigational product (IP) within the following 
time period prior to the first dosing day in the current study: 30 days, 5 half-lives or 
twice the duration of the biological effect of the IP (whichever is longer).
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
8. The participant has participated in a clinical trial and has received an IP within the 
following time period prior to the first dosing day in the current study: 30 days, 5 
half-lives or twice the duration of the biological effect of the IP (whichever is longer).
DIAGNOSTIC ASSESSMENTS
9. Creatinine clearance (CrCL) <90 mL/min
10. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at Screening or within 3 months prior to first dose of study treatment. 
11. A positive prestudy drug/alcohol/cotinine screen.
12. A positive test for HIV antibody.
13. Where participation in the study would result in donation of blood or blood product in 
excess of 500 mL within 60 days.
14. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants will refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 
7 days before the start of study treatment until after the final dose.
Participants will refrain from chewing or ingesting sugar-free gums, candies or other 
processed food/drink products that contain sugar alcohols (e.g., sorbitol, mannitol, 
xylitol, maltitol, isomalt) during the inpatient period of each dosing session (i.e., Day −1 
through 72 hours postdose).
Once in the clinical unit, participants will not be allowed to eat anything other than the 
food provided by the study centre.
6.3.2.
Fasting Conditions
During the overnight period from Day −1 to Day 1 of each dosing period:

An evening meal and/or snack will be provided by the unit (e.g., on Day −1).
 
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
From midnight, participants must then fast from all food and drink, except water
(approximately 10 hours predose and prior to any clinical laboratory evaluations, 
except repeat evaluations).

Water is permitted with dosing (approximately 240 mL total, including volume used 
for dispersing Treatments B and E) and at all times, except 1 hour predose through 
2 hours postdose. 

No food is allowed for at least 4 hours postdose.
6.3.3.
Fed Conditions
With the exception of the time period outlined for fasting conditions, participants will 
receive all other meals as defined as standard for the study centre.
6.3.4.
Caffeine, Alcohol, and Tobacco
During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours
before the start of dosing until after collection of the final PK sample at 72 hours 
postdose.
During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK sample at 72 hours postdose. 
Use of tobacco products is not allowed from 1 month prior to Screening and until after 
the final follow-up visit.
6.3.5.
Activity
Participants will abstain from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (e.g., watch television, read).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
 
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7.1.
Treatments Administered
Study Treatments
Product name:
TRIUMEQ (Adult)
TRIUMEQ (Pediatric)
DTG and 3TC (Adult)
DTG/3TC (Pediatric)
Dosage form:
1 Conventional tablet
10 Dispersible Tablets
1 Conventional tablet
of each
10 Dispersible Tablets
Unit dose 
strength(s)/
Dosage 
level(s):
Single dose, FDC 
tablet – DTG 50 
mg/ABC 600 mg/
3TC 300 mg
Single dose, FDC 
tablet – DTG 5
mg/ABC 60 mg/
3TC 30 mg
Single dose, 1 tablet 
DTG (50 mg) and 
1 tablet 3TC (300 mg)
Single dose, FDC 
tablet – DTG 5 mg/
3TC 30 mg
Route of 
Administration 
Oral
Oral 
Oral
Oral
Dosing 
instructions:
Treatment A:
Consume 1 tablet by 
taking directly into 
mouth with 240 mL of 
water
Treatment B:
Disperse 10 tablets in 
water as described in 
Section 7.1.1 (“Sterile 
Water for Irrigation, 
USP” is acceptable) 
and consume 
immediately (no more 
than 30 minutes after 
preparation)1
Treatment C:
Consume 10 tablets 
by taking them directly 
into mouth with 
240 mL of water1
Treatment D:
Consume 1 tablet of 
each by taking directly 
into mouth with 
240 mL of water
Treatment E:
Disperse 10 tablets in 
water as described in 
Section 7.1.1 (“Sterile 
Water for Irrigation, 
USP” is acceptable) 
and consume 
immediately (no more 
than 30 minutes after 
preparation)1
Treatment F:
Consume 10 tablets 
by taking them directly 
into mouth with 
240 mL of water1
Manufacturer:
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
Fasting 
instructions:
Administer in the AM 
under fasted 
conditions. Food will 
be unavailable until 
4 hours postdose and 
water until 2 hours
postdose.
Administer in the AM 
under fasted 
conditions. Food will 
be unavailable until 
4 hours postdose and 
water until 2 hours
postdose.
Administer in the AM 
under fasted 
conditions. Food will 
be unavailable until 
4 hours postdose and 
water until 2 hours
postdose.
Administer in the AM 
under fasted 
conditions. Food will 
be unavailable until 
4 hours postdose and 
water until 2 hours
postdose.
1.
The strawberry cream (PHS-132963) flavor of TRIUMEQ and DTG/3TC dispersible tablets contains no strawberry 
extracts and is therefore safe for use by people who are allergic to strawberries.
7.1.1.
Dosing of Dispersible Tablets in Treatments B and E
Each dispersible tablet for Treatment B contains DTG 5 mg/ABC 60 mg/3TC 30 mg; 
therefore, 10 tablets will be needed to achieve the DTG 50 mg/ABC 600 mg/3TC 300 mg
total dose. 
Each dispersible tablet for Treatment E contains DTG 5 mg/3TC 30 mg; therefore, 
10 tablets will be needed to achieve the DTG 50 mg/3TC 300 mg total dose.
1.
Place 50 mL of water in a 125-mL Nalgene container. A 60-mL syringe is 
appropriate to measure this volume. (Note: glass containers should not be used, as 
oxidation may occur.)
 
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2.
Place 10 tablets into the container and swirl/stir for 3 to 3.5 minutes. The tablets 
should be fully dispersed in approximately 90 seconds, but swirling/stirring for the 
full time will guarantee dispersion.
3.
Have the participant swallow the dispersion as swiftly as they can, preferably in 1 to 
2 swallows. 
4.
Rinse the container with 50 mL of water (a 60 mL syringe is appropriate to measure 
this volume) and have the participant swallow the rinse as swiftly as they can,
preferably in 1 to 2 swallows.
5.
Give the participant an additional 140 mL of water to swallow (Note: total volume of 
water given in Steps 1-5 should be 240 mL; additional water, if needed, will be 
documented).
Note the words “immediately dose” in the protocol mean within 30 minutes after 
completion of the 3- to 3.5-minute preparation. 
Anticipate that there will still be a limited amount of insoluble material visible in the 
dosing container after the dispersion has been dosed and rinsed; this is normal and will 
not affect the dose delivered.
7.1.2.
Dosing of Pediatric TRIUMEQ Tablets in Treatments C and F
Each dispersible tablet for Treatment C contains DTG 5 mg/ABC 60 mg/3TC 30 mg; 
therefore, 10 tablets will be needed to achieve the DTG 50 mg/ABC 600 mg/3TC 300 mg
total dose. 
Each dispersible tablet for Treatment F contains DTG 5 mg/3TC 30 mg; therefore, 
10 tablets will be needed to achieve the DTG 50 mg/3TC 300 mg total dose.
Participants will swallow 10 pediatric TRIUMEQ tablets for Treatment C, or 10 pediatric 
DTG/3TC tablets for Treatment F, with 240 mL of room-temperature tap water. 
Additional water, if needed to consume all 10 tablets, will be documented.
7.2.
Dose Modification
Not applicable.
7.3.
Method of Treatment Assignment
In each part, participants will be randomized to 1 of 6 treatment sequences (ABC, BCA, 
CAB, ACB, BAC, or CBA in Part 1; DEF, EFD, FDE, DFE, EDF, or FED in Part 2) in 
accordance with the randomization schedule generated by PPD prior to the start of the 
study and using validated software. Descriptions of the study treatments A, B, C, D, E, 
and F, and the respective treatment sequences are presented in Section 5.1 of this 
protocol.
7.4.
Blinding
This will be an open-label study.
 
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7.5.
Preparation/Handling/Storage/Accountability
The tablets are packaged in high-density polyethylene bottles. Each bottle will contain 
30 tablets. Tablets must be stored in the original package with the bottle tightly closed. 
The bottles contain a desiccant that must be kept in the bottle to protect tablets from 
moisture.
The contents of the label will be in accordance with all applicable regulatory 
requirements.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment, and only in 
accordance with the protocol. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Safety Data Sheet describing the occupational hazards and recommended handling 
precautions will be provided to site staff. Adequate precautions must be taken to 
avoid direct contact with the IP.
7.6.
Treatment Compliance
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
Study site personnel will examine each participant’s mouth to ensure that the study 
treatment was ingested.
7.7.
Concomitant Therapy
Participant must abstain from taking any other prescription (i.e. dofetilide) and 
nonprescription drugs, including vitamins, herbal, and dietary supplements (including 
St. John’s wort), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 
5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the 
 
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opinion of the investigator and ViiV Healthcare Medical Monitor the medication will not 
interfere with the study procedures or compromise participant safety.
Use of antacids, vitamins, and iron supplements are strictly prohibited within 7 days (or 
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
prior to the first dose of study medication and for the duration of the trial, including 
follow-up.
Acetaminophen, at doses of 2 grams/day, is permitted for use any time during the study
and should be noted in the electronic case report form (eCRF). Other concomitant 
medication may be considered on a case by case basis by the investigator in consultation 
with the ViiV Healthcare Medical Monitor.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from ViiV Healthcare after 
completion of the study because only healthy participants are eligible for study 
participation.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
NOTE: Although this is a single-dose study, please use the following as guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7.
8.1.2.
QTc Stopping Criteria
A participant that meets the following bulleted criterion will be withdrawn from the 
study:

QTcF > 500 msec
Notes:

QTcF should be used for all QTc data being collected for data analysis. Safety ECGs 
and other non-protocol specified ECGs are an exception.

The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5 to 10 minutes) recording period.
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons, including but not limited to:

Participant or investigator non-compliance
 
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
Participant requires concurrent medications after Screening that cannot be 
interrupted for 2 weeks prior to administration of IP and until completion of the 
study

Pregnancy

Positive urine drug or alcohol screen

Any clinically significant adverse even (AE) deemed to require discontinuation of IP
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. If a 
participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
Participants who withdraw, or are withdrawn from the study will not be replaced.
Refer to the SoA (Section 2) for data to be collected at the time of study discontinuation 
and follow-up, and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 2) and are the 
same for Parts 1 and 2. 
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 SoA, are essential and required for study conduct.
 
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Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. Vital signs
3. Blood draws
Note: Although PK calculations will be based on the actual time of collection, the 
timing of the assessments should allow the blood draw to occur at the exact nominal 
time noted in the SoA (Section 2).

The timing and number of planned study assessments, including safety, PK, or other 
assessments may be altered during the course of the study based on newly available 
data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File that is approved by the relevant ViiV 
Healthcare study team member and then archived in the study sponsor and site study 
files, but this will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme 
or amendment of the ICF. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 8.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 
 
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9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

Any SAE assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a ViiV 
Healthcare product will be recorded from the time of participant randomization up to 
and including any follow-up contact.

All AEs will be collected from the time of participant randomization until the follow-
up contact at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF, not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 8. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 8.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. Appropriate questions include the following:

“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?”
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and nonserious AEs of special 
interest, will be followed until the event is resolved, stabilized, otherwise explained, or 
the participant is lost to follow-up (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 8.
 
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9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate, according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in all female participants will be collected after the start of 
dosing and until the final postdose follow-up visit.

If a pregnancy is reported, the investigator should inform the sponsor within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 6.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, or ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
For this study, any dose of DTG, ABC, and/or 3TC greater than 50 mg, 600 mg, and/or 
300 mg, respectively, will be considered an overdose.
ViiV Healthcare does not recommend specific treatment for an overdose of DTG, ABC, 
and/or 3TC. The investigator will use clinical judgment to treat any overdose.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until DTG, 
ABC, and/or 3TC can no longer be detected systemically (at least 7 days).
3.
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
 
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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A brief physical examination (Screening and Day −1 of Period 1) will include, at a 
minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver 
and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in supine or semi-supine position after 5 minutes rest 
and will include temperature, systolic and diastolic blood pressure and pulse rate.
9.4.3.
Electrocardiograms

Twelve-lead ECGs will be performed with the participant in a supine or semi-supine 
position, having rested in this position for at least 10 minutes beforehand.

Single 12-lead ECGs will be obtained at Screening and on Day −1 as indicated in the 
SoA (Section 2) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTcF intervals. Refer to Section 8.1.2 for QTcF 
withdrawal criteria and additional QTcF readings that may be necessary.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency.

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).
 
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Laboratory requisition forms must be completed and samples must be clearly labelled 
with the participant number, protocol number, site/centre number, and visit date. Details 
for the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM (a.k.a., BioPacket). Reference ranges for all safety parameters will 
be provided to the site by the laboratory responsible for the assessments.
If additional nonprotocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE) the results must be 
recorded in the eCRF.
Refer to the BioPacket for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.
9.5.
Pharmacokinetics
9.5.1.
Blood Sample Collection
Whole blood samples of approximately 2 mL will be collected into K2EDTA tubes for 
measurement of plasma concentrations of DTG, ABC, and 3TC (in Part 1); and DTG and 
3TC (in Part 2) as specified in the SoA (Section 2). Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual date and time 
(24-hour clock time) of each sample will be recorded.
9.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology and Science 
(PTS), GlaxoSmithKline, the details of which will be included in the SRM
(BioPacket). Concentrations of DTG, ABC, and 3TC will be determined in plasma 
samples using the currently approved bioanalytical methodology. Raw data will be 
archived at the bioanalytical site (detailed in the BioPacket).
Once the plasma has been analyzed for drug concentrations any remaining plasma may 
be analyzed for other compound-related metabolites and the results reported under a 
separate PTS, ViiV Healthcare/GlaxoSmithKline protocol.
9.6.
Formulation Palatability Assessment
A palatability questionnaire (Appendix 4) will be administered to each participant within 
10 minutes following dosing of dispersion treatments only, as indicated in the SoA 
(Section 2). Participants will be given the questionnaire to read prior to receiving each 
unique dispersion dose.
9.7.
Genetics
(HLA)-B*5701 allele samples in Part 1 will be drawn at Screening for qualitative 
inclusion/exclusion only. There will be no quantitative analysis of these samples and they
will not be stored.
 
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10.
STATISTICAL CONSIDERATIONS
This study is designed to estimate the relative BA of each test treatment to the reference 
treatment (B vs. A and C vs. A in Part 1; E vs. D and F vs. D in Part 2) in the fasted state.
No formal hypotheses will be tested. For each primary PK endpoint in each part 
(AUC[0-], AUC[0-t], and Cmax), point estimates and corresponding 90% confidence 
intervals (CIs) will be constructed for the ratio of the geometric mean of the test 
treatment to the geometric mean of the reference treatment.
10.1.
Sample Size Determination
10.1.1.
Sample Size Assumptions
The PK of DTG is expected to have greater variability than ABC and 3TC; therefore, the 
sample size calculation is based upon estimates of DTG PK variability. Based on the 
results from a previous PK study of DTG granules administered to healthy volunteers, 
[GlaxoSmithKline Document Number 2011N124158_00], the within participant
variability (CVw%) of DTG AUC(0-∞) and Cmax ranged from 15.0% to 16.2%. 
Therefore, it is decided that 16.2% would be a conservative estimate on which the sample 
size calculation is based.
For each study part, with a sample size of 12 evaluable participants (2
participants/sequence), it is estimated that the precision (i.e. half-width of the 90% CI on 
the ratio scale) for the test: reference comparison will be within 12.5% of the point 
estimate for AUC(0-∞) and Cmax. Hence, if the point estimate of the ratio of geometric 
means is 1, then the 90% CI will be approximately (0.89, 1.13).
10.1.2.
Sample Size Sensitivity
For the sensitivity analysis, assuming a higher within-participant variability (24%), a 
sample size of 12 evaluable participants in each study part, it is estimated that the half 
width of the 90% CI for the ratio of treatment comparison (test: reference) would be 
within 19.0% of the point estimate for AUC(0-∞) and Cmax.
10.2.
Populations for Analyses
Participants excluded from any analyses will be fully documented and justified within the 
clinical study report (CSR). All analyses will be based on the actual treatment that each 
participant received. Any departures from the planned treatment according to the 
randomization schedule will be documented in the CSR.
For purposes of analysis, the following populations are defined for each part:
Population
Description
All Participants
All participants who receive at least 1 dose of study medication. This 
population will be used for all demographic and safety summaries.
 
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Population
Description
Pharmacokinetic (PK)
Participants in the ‘All Participants’ population for whom a PK
sample was obtained and who had evaluable PK assay results. 
Pharmacokinetic samples that may be affected by protocol 
deviations will be reviewed by the study team to determine whether 
or not the sample will be excluded. This population will be used for 
reporting of PK data.
10.3.
Statistical Analyses
10.3.1.
Key Elements of Analysis Plan
Final analyses will be performed after the completion of the study and final dataset 
authorization.
Data will be listed and summarized according to GSK reporting standards where 
applicable. Listings will be sorted by participant, period, day, and time, noting treatment. 
Summaries will be presented by treatment, day and time. 
Unless stated otherwise, descriptive summaries for continuous variables in each part will 
include n, mean, standard deviation (SD), coefficient of variation for the mean (%CV), 
median, minimum, and maximum. Categorical variables will be summarized with n and 
percent. Geometric mean with associated 95% CI and the between-participant CV 
(%CVb) for the geometric mean will be included for PK variables, where applicable.
Baseline or predose assessment will be the last available assessment prior to time of the 
first dose, unless noted otherwise. If there are multiple assessments collected on the same 
scheduled time, the average of these assessments will be used. For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
SAS Version 9.3 or higher will be used to analyze data, as well as to generate tables, 
listings, and figures.
10.3.2.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed under the supervision of the Clinical 
Pharmacology Modeling & Simulation department within GSK or their designee. For 
Part 1, plasma DTG, ABC, and 3TC; and, for Part 2, DTG and 3TC concentration-time 
data will be analyzed by noncompartmental methods with Phoenix WinNonlin
Version 6.4 or higher. Calculations will be based on the actual sampling times recorded 
during the study. From the plasma concentration-time data, the following PK parameters 
will be determined, as data permit: Cmax, Tmax, Tlast, AUC(0-t), AUC(0-24), AUC(0-
), t1/2, tlag, C24, Ct, Vz/F, and CL/F.
Pharmacokinetic data for each part will be listed and may be presented in graphical form,
and will be summarized descriptively. All PK data will be stored in the Archives, 
GlaxoSmithKline R&D. 
 
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Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Pharmacology, PPD.
The primary PK parameters for DTG, ABC, and 3TC in Part 1; and DTG and 3TC in 
Part 2 (AUC[0-], AUC[0-t], and Cmax) will be loge-transformed and separately 
analyzed using a mixed-effects model with fixed-effect terms for Period, Treatment, and 
Treatment Sequence for each treatment comparison. Participant will be nested within 
Treatment Sequence and treated as a random effect in the model. Point estimates and 
their associated 90% CIs will be constructed for the differences in PK parameter values 
between test and reference treatments. The point estimates and their associated 90% CIs 
will then be back-transformed to provide point estimates and 90% CIs for the ratios of 
PK parameters from test and reference treatments.
Further details will be provided in the RAP.
10.3.3.
Safety Analyses
Safety data for each part will be presented in tabular format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
No formal statistical analysis of the safety data will be conducted.
The details of the statistical analyses of safety will be provided in the RAP.
10.3.4.
Other Analyses
Palatability questionnaire variables for each part will be summarized descriptively. 
Further details will be provided in the RAP.
10.3.5.
Interim Analyses
There will be no formal interim analysis.
 
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11.
REFERENCES
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report. Pediatrics  Dec 2011,  128  (Supplement 5)  
S213-S256;  DOI: 10.1542/peds.2009-2107C.
GlaxoSmithKline Document Number 2011N124158_00. Study ID ING114556. Clinical 
Pharmacology Study Report: Relative Bioavailability Study of a Tablet Formulation vs. 
Pediatric Granule Formulation of Dolutegravir 50 mg and Effect of Different Types of 
Water Plus Infant Formula on the Pediatric Granule Formulation in Healthy Male and 
Female Volunteers (ING114556) .  13-February-2012.
GlaxoSmithKline Document Number 2015N235495_00 Study ID ING112578. CSR: A 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral 
Activity of GSK1349572, a Novel Integrase Inhibitor, in Combination Regimens in HIV1 
Infected Infants, Children and Adolescents. 03 April 2015.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, version 11. Oct 2017. 
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T et al. 
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. N Engl J 
Med 2012; 367(1):20-9. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et al. 
Pharmacokinetics of Acetaminophen-Adducts in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37(8):1779-84.
Kanis JA on behalf of the World Health Organization Scientific Group. Assessment of 
osteoporosis at the primary health-care level. Technical Report. World Health 
Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, 
UK. 2007: Printed by the University of Sheffield.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomažič J et al; Predict-1 Study 
Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008; 
358(6):568-79.
Post FA, Moyle GJ, Stellbrink HJ, Domingo P, Podzamczer D. Randomized comparison 
of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus 
tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-
infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 
2010; 55(1):49-57.
Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Sutherland-Phillips DH et al. 
Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-
boosted atazanavir in HIV-infected patients. HIV Clin Trials. 2010; 11(2):69-79.
TRIUMEQ Prescribing Information (abacavir, dolutegravir, and lamivudine) tablets, for 
oral use. August, 2014.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
%CV
Coefficient of variance
%CVb
Between participant coefficient of variation
3TC
Lamivudine
ABC
Abacavir
AE
Adverse event
AIDS
Acquired immune deficiency syndrome
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC(0-∞)
Area under the concentration-time curve from time zero extrapolated to 
infinity
AUC(0-24)
Area under the plasma concentration-time curve from time of dose to 24 
hours
AUC(0-t)
Area under the concentration-time curve from time zero to time of last 
observed quantifiable concentration calculated using the linear trapezoidal 
method when concentrations are increasing and the logarithmic 
trapezoidal method when concentrations are decreasing
BMI
Body mass index
CIOMS
Council for International Organizations of Medical Sciences
C24
Observed concentration at 24 hours after dose administration
CI
Confidence interval
CL/F
Apparent total clearance
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CSR
Clinical study report
Ct
Last observed quantifiable concentration
DAIDS
Division of AIDS
dL
Deciliter
DTG
Dolutegravir
ECG
Electrocardiogram
eCRF
Electronic case report form
EU
European Union
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
 
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GSK
GlaxoSmithKline
hCG
Human chorionic gonadotropin
HIPPA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HRT
Hormone replacement therapy
HSR
Hypersensitivity Reaction
IB
Investigator's Brochure
ICF
Informed consent form
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
INI
Integrase inhibitor
INR
International normalized ratio
IP
Investigational product(s)
IRB
Institutional Review Board
kg
Kilogram
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
Mol
Micromolar
MCH
Hemoglobin amount per red blood cell
MCV
Average red blood cell size
mg
Milligrams
mL
Milliliter
mmHg
Millimeters of mercury
PK
Pharmacokinetic(s)
PTS
Platform Technology and Science
QTc
Corrected QT interval
QTcF
Corrected QT interval according to Fridericia's formula
RAP
Reporting and analysis plan
RBC
Red blood cells
SAE
Serious adverse event
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SoA
Schedule of Activities
SRM
Study reference manual
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal elimination phase half-life
tlag
Plasma lag time for absorption
Tlast
Time of last quantifiable concentration taken directly from the 
concentration time profile
Tmax
Time to maximum observed concentration taken directly from the 
concentration time profile
ULN
Upper limit of normal
 
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US
United States
Vz/F
Apparent volume of distribution during the terminal phase following 
extravascular administration
WBC
White blood cells
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
KIVEXA/EPZICOM
Phoenix WinNonlin
TIVICAY
SAS
TRIUMEQ
TRIZIVIR
ZIAGEN
 
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12.2.
Appendix 2: Clinical Laboratory Tests
Hematology, clinical chemistry, urinalysis, and additional parameters to be tested are 
listed in Table 1.

The tests detailed in Table 1 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of this protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
Red Blood Cell (RBC) Indices:
White blood cell (WBC) 
count with Differential:
RBC Count
Mean corpuscular volume (MCV)
Neutrophils
Hemoglobin
Mean corpuscular haemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry 1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
aminotransferase (AST 
[SGOT])
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Creatine 
phosphokinase (CPK)
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol

Alcohol, cotinine, and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Urine Pregnancy test (for WOCBP)

HLA-B*5701 screening for Part 1

Creatine clearance (CrCL) for GFR estimation
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Section 8.1.1 Liver Chemistry Stopping Criteria
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
 
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ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicentre studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
 
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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

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 ViiV Healthcare site or 
other mutually-agreeable location.

ViiV Healthcare 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 
participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with ViiV 
Healthcare Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g.,
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
 
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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
Study and Site Closure
ViiV Healthcare or its designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of ViiV Healthcare. Study sites will 
be closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study-site closure visit has been 
performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Palatability Questionnaire
The following questionnaire will be administered to each participant within 10 minutes 
following any dose given as dispersion. Participants will be given the questionnaire to 
read prior to receiving this dose.
Participant #: _________________________   Date: __________   Treatment:______
1.
Please briefly describe the taste of the product in your own words (one word, short 
phrase descriptions are acceptable).
2.
Please rate the palatability (acceptability of taste) of the product by checking a rating 
below.
____1 = unacceptable (would not use product under any circumstances) 
____2 = neutral/acceptable
____3 = very good
3.
Please check all the descriptors that apply to the product.
______ Sweet
______ Sour/tart
______ Bitter
______ Fruity
______ Nutty
______ Chalky
______ Medicinal
4.
Please select the descriptor you most closely associate with the flavor of the product 
(i.e., select one).
______ Sweet
______ Sour/tart
______ Bitter
______ Fruity
______ Nutty
______ Chalky
______ Medicinal
______ Other (please specify)_____________________
 
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Participant #: _________________________   Date: __________   Treatment:______
5.
Please rate the mouth feel of the product by checking a rating below.
_____ 1= unacceptable (would not use product under any circumstances)
_____ 2= neutral/acceptable
_____ 3= very good
6.
Please rate the aroma of the product by checking a rating below.
____1 = unpleasant/unacceptable aroma
____2 = neutral/acceptable aroma
____3 = pleasant/desirable aroma
7.
Please rate the product aftertaste by checking a rating below.
____1 = unpleasant/unacceptable (e.g. need/desire to wash taste out of mouth)
____2 = neutral/acceptable
____3 = pleasant/desirable
 
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Participant #: _________________________   Date: __________   Treatment:______
8.
For each of the following attributes please circle the number that best describes your 
perception of each attribute. 
a.
Flavor intensity
Mild
Average
Strong
1
2
3
4
5
b. Aroma
Mild
Average
Strong
1
2
3
4
5
c.
Sweetness
Not Sweet
Sweet
Very Sweet
1
2
3
4
5
d. Sour/tartness
Mild
Average
Strong
1
2
3
4
5
e.
Consistency
Thin
Average
Thick
1
2
3
4
5
 
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Participant #: _________________________   Date: __________   Treatment:______
9.
Based on your response to #8, please circle the number on a scale of 1 to 5 that best 
describes your recommendation for modifying this product where:
1 = Reduce as much as possible
3 = Leave as is
5 = Increase as much as possible
f.
Flavor intensity
Reduce
Leave as is
Increase
1
2
3
4
5
g.
Aroma
1
2
3
4
5
h.
Sweetness
1
2
3
4
5
i.
Sour/tartness
1
2
3
4
5
j.
Consistency
1
2
3
4
5
10. Please rate the color of the product on a scale of 1 to 3, where:
____1 = unpleasant
____2 = neutral/acceptable
____3 = pleasant/desirable
11. Do you have any other suggestions for changing/improving the flavor of this 
product?
 
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12.5.
Appendix 5: Toxicity Management
Adverse events that occur during the trial should be evaluated by the investigator and 
graded according to the DAIDS toxicity scales (see Appendix 9). Additional information 
regarding detecting, documenting and reporting AEs and SAEs are available in 
Appendix 8.
Study drug may be interrupted at the discretion of the investigator and according to the 
severity of the AE. If one or more ART medication is held due to toxicity or AEs, all 
ART medications should be held to reduce the risk of development of resistance taking 
into account the length of the planned interruptions and the PK half-life of each ART of 
the regimen, in order to minimize the risk of development of resistance.
No toxicity-related dose reductions of study drugs will be allowed. Study drugs 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 study drugs or temporary interruption of one 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 participant management and study drug interruptions based on the 
severity of the AE for specific toxicities. All changes in study drug must be accurately 
recorded in the participant’s eCRF.
NOTE: In the event of a discontinuation of DTG/ABC/3TC FDC for any reason, 
re-initiation of this drug should be undertaken with caution. The investigator must obtain 
a complete history of the events surrounding the discontinuation of DTG/ABC/3TC FDC, 
evaluate for the possibility of a clinically suspected HSR, and initiate participant
management as outlined in the DTG IB, regardless of a participant’s HLA-B*5701 status.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study 
treatment at the discretion of the investigator. Participants who choose to withdraw from 
the study due to a Grade 1 or 2 AE should have study withdrawal and follow-up 
evaluations completed.
Grade 3 Toxicity/Adverse Event
Participants 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 study treatment, dosing may continue after discussion with the medical 
monitor.
Participants who develop a Grade 3 AE or toxicity that the investigator considers related 
or possibly related to the study drugs should have study treatment withheld and be 
rechecked each week until the AE returns to Grade 2. Once the AE is Grade ≤2, study 
treatment may be restarted. 
 
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Should the same Grade 3 AE recur within 28 days in the same participant, study 
treatment should be permanently discontinued and the participant withdrawn from study.
Participants experiencing Grade 3 AEs requiring permanent discontinuation of study 
treatment should be followed weekly until resolution of the AE and have withdrawal 
study evaluations completed. A Follow-up visit should be performed 4 weeks after the 
last dose of study drugs.
Participants with asymptomatic Grade 3 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue study drug if the investigator has compelling evidence that the 
toxicity is not related to study treatment.
Exceptions are noted for rash in Section 12.5.8.
Grade 4 Toxicity/Adverse Event
Participants who develop a Grade 4 AE or toxicity should have study treatment 
discontinued. However, if the investigator has compelling evidence that the AE is not 
causally related to the study drugs, dosing may continue after discussion with and assent 
from the medical monitor. Participants should be rechecked each week until the AE 
returns to Grade 2.
Participants experiencing Grade 4 AEs requiring permanent discontinuation of study 
treatment should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.
Participants with asymptomatic Grade 4 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 study treatment. An in-clinic Follow-Up visit will be conducted 
approximately 4 weeks after the last dose of study medication for participants with 
ongoing AEs, and SAEs and also any laboratory abnormalities that are considered to be 
AEs or potentially harmful to the participant, at the last on-study visit.
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to study treatment are provided below. 
Participants who permanently discontinue study treatment for reasons of toxicity should 
be followed weekly until resolution of the AE and encouraged to complete the 
withdrawal and Follow-up study evaluations (see Section 9.2.3).
12.5.1.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [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, serum cystatin C and an estimated GFR using the 
CKD-EPI cystatin C method [Inker, 2012] should also be done at this confirmatory visit 
(refer to the SPM for details on the collection and processing of these urine samples). If 
 
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the creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
12.5.2.
Hypersensitivity Reaction
Both ABC and DTG are associated with a risk for hypersensitivity reactions (HSR), and 
share some common features such as fever and/or rash with other symptoms indicating 
multi-organ involvement. Clinically it is not possible to determine whether a HSR with 
DTG/ABC/3TC FDC is caused by ABC or DTG. Hypersensitivity reactions have been 
observed more commonly with ABC, some of which have been life-threatening, and in 
rare cases fatal, when not managed appropriately. More detailed clinical descriptions of 
these reactions are included in the DTG/ABC/3TC IB [GlaxoSmithKline Document 
Number RM2007/00683/11].
The risk for ABC HSR to occur is significantly increased for patients who test positive 
for the HLA-B*5701 allele. However, ABC HSRs have been reported at a lower 
frequency in patients who do not carry this allele. In the prospective study CNA106030 
(PREDICT-1), the use of pre-therapy screening for the presence of HLA-B*5701 and 
subsequently avoiding ABC in HLA-B*5701 positive patients, significantly reduced the 
incidence of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803) 
(p<0.0001) [Mallal, 2008]. In clinical studies EPZ108859 (ARIES) and CNA109586 
(ASSERT), 0.8% (4/515) and 3.1% (6/192) of participants who were HLA-B*5701
negative and who received ABC developed a clinically suspected ABC HSR, respectively 
[Post, 2010; Squires, 2010]. 
With reference to the DTG/ABC/3TC IB and the ‘Participant Information and Consent 
Form’, Investigators must ensure that participants are fully informed regarding the risk of 
HSR prior to commencing ABC therapy. Each Participant should also be reminded of the 
importance of reading the Alert Card accompanying their study medication, and keeping 
it with them at all times.
The following should be adhered to in the management of Participants presenting 
with signs and symptoms suggesting a possible hypersensitivity reaction:

In any Participant treated with DTG/ABC/3TC, the clinical diagnosis of suspected 
hypersensitivity reaction must remain the basis of clinical decision making.

DTG/ABC/3TCmust be stopped without delay, even in the absence of the 
HLA-B*5701 allele, if a HSR is suspected. Delay in stopping treatment after the 
onset of hypersensitivity may result in a life-threatening reaction. Clinical status 
including liver aminotransferases and bilirubin should be monitored. 

Participants who have experienced a hypersensitivity reaction should be instructed to 
dispose of their remaining tablets, in order to avoid restarting ABC.

After stopping treatment with DTG/ABC/3TC for reasons of a suspected HSR, 
DTG/ABC/3TC or any other medicinal product containing ABC or DTG must 
never be re-initiated.
 
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
Restarting ABC- containing products following a suspected ABC HSR can 
result in a prompt return of symptoms within hours and may include life-
threatening hypotension and death.

If a hypersensitivity reaction is ruled out, Participants may restart 
DTG/ABC/3TC. Rarely, patients who have stopped ABC for reasons other than 
symptoms of HSR have also experienced life-threatening reactions within hours 
of re- initiating abacavir therapy. Participants must be made aware that HSR 
can occur with reintroduction of DTG/ABC/3TC or any other medicinal 
product containing abacavir and that reintroduction of DTG/ABC/3TC or any 
other medicinal product containing abacavir should be undertaken only if 
medical care can be readily accessed.
Reporting of Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC meets one of the International Conference 
on Harmonization (ICH)-E2A definitions of seriousness listed in Appendix 8 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.
12.5.3.
Skin Reactions without Other Symptoms that are Typical of ABC 
HSR
Including serious skin reactions such as Stevens-Johnson Syndrome, Toxic 
Epidermal Necrolysis, Erythema Multiforme or rash with significant liver 
dysfunction 
Participants should be instructed to contact the Investigator as soon as possible if they 
develop a rash while on study.
Participants who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as Stevens-Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN) or Erythema Multiforme. SJS, TEN and Erythema 
Multiforme have been reported very rarely in patients taking ABC-containing products.
These patients generally do not have the cluster of additional symptoms (e.g., 
gastrointestinal and respiratory) that characterize the ABC HSR, but they do have 
features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s) 
suspected in the Investigators causality assessment) should be discontinued, and the 
participant should not be re-challenged with any ABC-containing medicinal product (i.e., 
TRIUMEQ, ZIAGENTM, TRIZIVIRTM, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the participant is receiving should also be reviewed and 
discontinued as appropriate.
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 
 
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interruptions or discontinuations of therapy and tend to resolve within two to three weeks.
The index case of hypersensitivity with DTG involved a profuse, purpuric and coalescing 
leukocytoclastic vasculitis as well as clinically significant liver chemistry elevations.
Other than this case, no other instances of serious skin reaction, including SJS, TEN and 
erythema multiforme, have been reported for DTG in clinical trials.
The following guidance is provided for clinical management of participants who 
experience rash alone in the absence of accompanying diagnosis of ABC HSR, systemic 
or allergic symptoms or signs of mucosal or target lesions.
Participants with an isolated Grade 1 rash may continue IP and background ART at the 
Investigator’s discretion. The participant 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.
Participants may continue IP and background ART for an isolated Grade 2 rash. 
However, IP and background ART (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 8.1.1). The participant
should be advised to contact the physician immediately if rash fails to resolve (after more 
than two weeks), if there is any worsening of the rash, if any systemic signs or allergic 
symptoms develop, or if mucosal involvement develops.
Participants should permanently discontinue IP and background ART (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) for an 
isolated Grade 3 or 4 rash, and the participant should be withdrawn from the study. 
Participants should be treated as clinically appropriate and followed until resolution of 
the AE.
The rash and any associated symptoms should be reported as AEs (see Section 9.2) and 
appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
grading).
If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to 
a specific medical event or a concomitant non-study medication, routine management 
should be performed and documentation of the diagnosis provided.
12.5.4.
Creatine Phosphokinase 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 participant has 
abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the study drugs, study treatment should be 
discontinued and the participant withdrawn from the study.
 
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12.5.5.
Anemia
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
1.
peripheral blood smear
5.
indirect bilirubin (abnormal if increased >50% from baseline)
6.
haptoglobin (abnormal if 25 mg/dL)
7.
reticulocyte count (abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication. If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, participants will permanently discontinue study medication 
and be withdrawn from the trial. Participants should be followed up until resolution of 
anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1.
peripheral blood smear
2.
indirect bilirubin (abnormal if increased >50% from baseline)
3.
haptoglobin (abnormal if 25 mg/dL)
4.
reticulocyte count (abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication. If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, participants will permanently discontinue study medication 
and be withdrawn from the trial. Consultation with a Hematologist should be considered.
Participants should be followed up until resolution of anemia.
 
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Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
1.
peripheral blood smear
2.
indirect bilirubin
3.
haptoglobin
4.
reticulocyte count 
Participants will permanently discontinue study medication and be withdrawn from the 
trial. Consultation with a Hematologist should be considered. Participants should be 
followed up until resolution of anemia.
12.5.6.
Total Bilirubin Elevation
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate -
1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin). Participants may continue study medication. Participants 
should be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - >5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin). Participants will permanently discontinue study medication 
and be withdrawn from the trial. Participants should be followed up until resolution 
(return to baseline) of bilirubin elevation.
12.5.7.
AST and ALT Elevation
See Appendix 7.
 
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12.5.8.
Rash
Grade 1 rash (localized macular rash):
Participants with Grade 1 rash should be evaluated by the Investigator immediately. A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist. The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Lymphadenopathy
3.
Pharyngitis
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 rash may 
continue the study drug at the discretion of the Investigator. The participant 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 ulceration develops. If the rash is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the participant
may be treated symptomatically until the rash resolves. Antihistamines, topical 
corticosteroids or antipruritic agents may be prescribed. The participant should remain on 
the study to be followed for safety and PK as outlined in Section 9.2.3.
Grade 2 rash (diffuse macular, maculopapular, or morbilliform rash OR target 
lesions):
Participants with Grade 2 rash should be evaluated by the Investigator immediately.
Digital photographs should be obtained. A dermatologist may be consulted and a biopsy 
may be obtained if recommended by the dermatologist. The study drug should be 
permanently discontinued if the following signs or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Lymphadenopathy
3.
Pharyngitis
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 rash may 
continue the study drug at the discretion of the Investigator. It should be noted that oral 
mucosal erosions may be part of a Grade 2 rash. Any mucosal ulceration increases the 
severity of the rash to at least Grade 3. The participant 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 ulceration develops. If the rash is considered to be most 
likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the participant may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
 
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antipruritic agents may be prescribed. The participant should remain on the study to be 
followed for safety and PK as outlined in Section 9.2.3.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Participants with a Grade 3 rash will permanently discontinue the study medication. The 
participant should be evaluated in the physician’s office immediately and should be seen 
in the physician’s office or contacted by phone every 2 days until the rash resolves. A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained. Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator. The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops. The participant should remain on 
the study to be followed for safety and PK as outlined in Section 9.2.3.
Grade 4 rash (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)):
Participants with a Grade 4 rash will permanently discontinue the study medication. A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained. Sponsor and ViiV Healthcare Medical Monitor should be notified of this 
serious adverse event within 24hr via phone or fax. The participant should be closely 
followed every day until resolution of the reaction. The participant should remain on the 
study to be followed for safety and PK as outlined in Section 9.2.3.
12.5.9.
Allergic Reaction
Grade 1 allergic reaction (pruritus without rash):
Participants with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately. The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Eosinophilia
3.
Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the Investigator. The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic reaction 
is considered to be most likely due to concomitant illness or non-study medication, 
standard management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the participant
may be treated symptomatically until the rash resolves. Antihistamines, topical 
 
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corticosteroids or antipruritic agents may be prescribed. The participant should remain on 
the study to be followed for safety and PK as outlined in Section 9.2.3.
Grade 2 allergic reaction (localized urticaria):
Participants with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately. The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Eosinophilia
3.
Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the Investigator. The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic reaction 
is considered to be most likely due to concomitant illness or non-study medication, 
standard management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the participant
may be treated symptomatically until the rash resolves. Antihistamines, topical 
corticosteroids or antipruritic agents may be prescribed. The participant should remain on 
the study to be followed for safety and PK as outlined in Section 9.2.3.
Grade 3 allergic reaction (generalized urticaria or angioedema):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial. Participants will be treated as clinically appropriate. Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Grade 4 allergic reaction (anaphylaxis):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial. Participants will be treated as clinically appropriate. Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
 
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12.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 2 when having penile-vaginal 
intercourse with a woman of childbearing potential 
 
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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame 
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 2. 
Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and until the completion of the follow-up visit.
 
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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing should be performed prior to dosing in each cohort
during the treatment period and as required locally

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 10 mIU/mL will be performed [and assayed 
in a certified laboratory OR and assayed in the central laboratory OR using the test 
kit provided by the central laboratory/provided by the sponsor/approved by the 
sponsor and in accordance with instructions provided in its package insert
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to ViiV Healthcare within 24 hours of learning of the 
partner’s pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to ViiV 
Healthcare

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to ViiV 
Healthcare within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to ViiV Healthcare. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
 
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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to ViiV 
Healthcare as described in Appendix 8. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
treatment or be withdrawn from the study. 
 
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12.7.
Appendix 7: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, Report as an 
SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to ViiV Healthcare within 24 hours

Complete the liver event CRF, and complete an SAE 
data collection tool if the event also meets the criteria 
for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR >1.5

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within 24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR ≤1.5:

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within 24-72 hrs

Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) analysis, 
obtained within 72 hours of last dose.

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications.

Record alcohol use on the liver event alcohol intake 
case report form
If ALT≥3xULN AND bilirubin 2xULN or NR >1.5:

Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
liver injury in participants with definite or likely 
acetaminophen use in the preceding week [James, 
2009].

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.
 
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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
 
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12.8.
Appendix 8: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to ViiV Healthcare in lieu of completion of the ViiV Healthcare
/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by ViiV Healthcare. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to ViiV Healthcare.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
 
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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to ViiV Healthcare. However, it 
is very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to ViiV 
Healthcare.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
 
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by ViiV 
Healthcare to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide ViiV Healthcare with a copy of any post-
mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to ViiV Healthcare within 24 
hours of receipt of the information.
Reporting of SAE to ViiV Healthcare
SAE Reporting to ViiV Healthcare via Electronic Data Collection Tool

The primary mechanism for reporting SAE to ViiV Healthcare will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in Medical Monitor Name and Contact 
Information section of the Title Page of this protocol.
 
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SAE Reporting to ViiV Healthcare via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Medical Monitor Name and Contact 
Information section of the Title Page of this protocol.
 
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12.9.
Appendix 9: Division Of AIDS Table For Grading The 
Severity Of Adult And Paediatric Adverse Events Version 
2.0, November 2014
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated
Severe symptoms 
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
Arrhythmia
(by ECG or physical
examination)
Specify type, if
applicable
No symptoms 
AND No 
intervention 
indicated
No symptoms AND
non-urgent 
intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 
mmHg systolic 
OR 90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR ≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Heart Failure 
No symptoms 
AND Laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR 
Interval or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 
to < 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
DERMATOLOGIC
Alopecia (scalp only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 (without 
skin lesions) 
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 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
ENDOCRINE AND METABOLIC
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
Treatment
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms 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 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms 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) 
Lipoatrophy4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
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, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Bloating or 
Distension 
Report only one 
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 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea ≥ 1 year of 
age 
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 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with 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) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
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) 
MUSCULOSKELETAL
Arthralgia 
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 
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 
Myalgia 
(generalized) 
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 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6
≥ 30 years of age 
BMD t-score -2.5 
to -1 
NA 
NA 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 30 years of age 
BMD z-score -2 to 
-1 
NA
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
NEUROLOGIC
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
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 
Symptoms 
causing no or 
minimal
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
ataxia detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
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 
Developmental Delay 
< 18 years of age 
Specify type, if 
applicable 
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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83
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 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
decreased 
strength on 
examination 
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 (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory alteration 
on examination 
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 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 
5 minutes with < 
24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
 
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2017N330422_00
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205894
84
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
PREGNANCY, PUERPERIUM, AND PERINATAL
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant 
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, 
and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial or 
complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
 
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2017N330422_00
CONFIDENTIAL
205894
85
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
RESPIRATORY
Acute Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to ≥ 
70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to < 
70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to < 
50% OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities OR 
Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
SENSORY
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing loss 
at ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
 
2018N363263_00


2017N330422_00
CONFIDENTIAL
205894
86
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Uveitis 
No symptoms 
AND Detectable 
on examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
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 
Visual Changes 
(assessed 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) 
SYSTEMIC
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
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 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
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 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
 
2018N363263_00


2017N330422_00
CONFIDENTIAL
205894
87
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pain10 (not 
associated with study 
agent injections and 
not specified 
elsewhere) 
Specify location 
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 indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight12
> 5 to 19 years of 
age 
NA 
WHO BMI z-score < 
-2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score 
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score 
< -2 to ≤ -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
URINARY
Urinary Tract 
Obstruction 
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 
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain or 
Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
 
2018N363263_00


2017N330422_00
CONFIDENTIAL
205894
88
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Injection Site 
Erythema or 
Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 
surface area AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus 
Itching localized 
to the injection 
site that is 
relieved 
spontaneously or 
in < 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
LABORATORY VALUES Chemistries
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0
≥ 20 to < 30 
< 2.0 
< 20 
NA 
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences 
 
2018N363263_00


2017N330422_00
CONFIDENTIAL
205894
89
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) 
or Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age 
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
 
2018N363263_00


2017N330422_00
CONFIDENTIAL
205894
90
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
eGFR, Low 
Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2 OR 
10 to < 30% 
decrease from 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 OR ≥ 
30 to < 50% 
decrease from 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 OR ≥ 
50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 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 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 4.40 
to < 5.15 
200 to < 300 5.15 to 
< 7.77 
≥ 300 ≥ 7.77 
NA 
LDL, Fasting, High 
≥ 18 years of age 
130 to < 160 3.37 
to < 4.12 
160 to < 190 4.12 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
> 2 to < 18 years of 
age 
110 to < 130 2.85 
to < 3.34 
130 to < 190 3.34 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
HEMATOLOGY
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 x 109 to < 
0.650 x 109
500 to < 600 
0.500 x 109 to < 
0.600 x 109
350 to < 500 
0.350 x 109 to < 
0.500 x 109
< 350 
< 0.350 x 109
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109
600 to 799 
0.600 x 109 to 0.799 
x 109
400 to 599 
0.400 x 109 to 0.599 
x 109
< 400 
< 0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109
750 to 999 
0.750 x 109 to 0.999 
x 109
< 750 
< 0.750 x 109
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109
< 1,500 
< 1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 
0.75 to < 1.00 OR ≥ 
0.50 to < 0.75 x 
LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50 OR < 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x 
ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x ULN 
≥ 3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to < 
124,999 100.000 
x 109 to < 124.999 
x 109
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109
< 25,000 < 25.000 x 109
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 x 
ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2.499 x 109
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109
< 1,000 
< 1.000 x 109
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109
< 2,500 
< 2.500 x 109
URINALYSIS
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃  250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or 
on blood believed to 
be of menstrual 
origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
 
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1.
Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents [Pediatrics, 2011].  
2.
As per Bazett’s formula.  
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section 
(page 23).  
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
6.
BMD t and z scores can be found in: [Kanis, 2007].  
7.
Definition: A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
8.
Definition: A clinically recognized pregnancy occurring at < 20 weeks gestational age.  
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 
23).
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area. 
14. Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total 
bilirubin.  
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
17. Male and female sex are defined as sex at birth. 
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the 
result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.  
 
2018N363263_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205894
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
A 2-Part, Phase I, Single-Dose, 3-Period Crossover Relative 
Bioavailability Study of a Pediatric TRIUMEQ Dispersible 
Tablet and Pediatric Dolutegravir and Lamivudine 
(DTG/3TC) Fixed Dose Combination Dispersible Tablet 
Formulations as Compared With Adult Tablets in Healthy 
Volunteers
Compound Number
:
GSK1349572+GR109714+GI265235 (GSK2619619) and 
GSK1349572+GR109714 (GSK3515864)
Effective Date 
:
25-APR-2018
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205894.

This RAP is intended to describe the safety, tolerability, and pharmacokinetic (PK) 
analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
25-APR-2018
Biostatistician II (Biostatistics, Early Development Services, PPD)
25-APR-2018
Pharmacokineticist (Biostatistics, PPD)
Approved by: 
25-APR-2018
Principal Statistician (Clinical Statistics, GSK)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N363263_00
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CONFIDENTIAL
The GlaxoSmithKline group of companies
205894
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Approved by:
Approver
Date
Approval Method
Global Clinical Development Manager
18-APR-2018
e-mail
Director, Clinical Development 
19-APR-2018
e-mail
Director, Clinical Pharmacology
19-APR-2018
e-mail
SERM Manager
19-APR-2018
e-mail
Principal Programmer/Analyst
19-APR-2018
e-mail
Principal Data Manager
19-APR-2018
e-mail
 
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CONFIDENTIAL
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3
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Hypotheses.................................................................................12
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
7.
PRIMARY STATISTICAL ANALYSES....................................................................16
7.1.
Pharmacokinetic Analyses..........................................................................16
7.1.1.
Overview of Planned Pharmacokinetic Analyses .........................16
7.1.2.
Drug Concentration Measures .....................................................16
7.1.3.
Pharmacokinetic Parameters.......................................................16
7.1.3.1.
Deriving Pharmacokinetic Parameters........................16
7.1.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................17
7.1.4.
Interim Analysis ...........................................................................19
7.1.4.1.
Overview of Planned Analyses ...................................19
8.
SECONDARY STATISTICAL ANALYSES .............................................................20
8.1.
Safety Analyses..........................................................................................20
8.2.
Exploratory Analyses ..................................................................................21
9.
REFERENCES.......................................................................................................22
10. APPENDICES........................................................................................................23
10.1.
Appendix 1: Time & Events.........................................................................24
10.1.1.
Protocol Defined Screening Assessments for Parts 1 and 
2 ..................................................................................................24
10.1.2.
Protocol Defined Time and Events for Parts 1 and 2....................25
10.2.
Appendix 2: Treatment States and Phases.................................................27
10.2.1.
Treatment States .........................................................................27
10.2.1.1.
Treatment States for Safety Data ...............................27
10.2.1.2.
Treatment States for Event Data (e.g. AEs, 
Concomitant Medications) ..........................................27
10.3.
Appendix 3: Data Display Standards & Handling Conventions....................28
10.3.1.
Study Treatment & Sub-group Display Descriptors......................28
 
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10.3.2.
Baseline Definition & Derivations .................................................29
10.3.2.1.
Baseline Definitions....................................................29
10.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................29
10.3.3.
Reporting Process & Standards...................................................29
10.4.
Appendix 4: Derived and Transformed Data ...............................................32
10.4.1.
General........................................................................................32
10.4.2.
Study Population..........................................................................32
10.4.3.
Safety ..........................................................................................32
10.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............34
10.5.1.
Premature Withdrawals................................................................34
10.5.2.
Handling of Missing Data.............................................................34
10.5.2.1.
Handling of Missing Dates..........................................34
10.5.2.2.
Handling of Partial Dates............................................35
10.6.
Appendix 6: Values of Potential Clinical Importance ...................................36
10.6.1.
ECG.............................................................................................36
10.6.2.
Vital Signs....................................................................................36
10.7.
Appendix 7: Multiple Comparisons & Multiplicity .........................................37
10.7.1.
Handling of Multiple Comparisons & Multiplicity...........................37
10.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................38
10.9.
Appendix 9 – Abbreviations & Trade Marks ................................................39
10.9.1.
Abbreviations...............................................................................39
10.9.2.
Trademarks .................................................................................40
10.10. Appendix 10: List of Data Displays..............................................................41
10.10.1. Mock Example Shell Referencing ................................................41
10.10.2. Deliverable [Priority].....................................................................41
10.10.3. Study Population Tables..............................................................42
10.10.4. Safety Tables...............................................................................43
10.10.5. Pharmacokinetic Tables...............................................................45
10.10.6. Pharmacokinetic Figures .............................................................47
10.10.7. Exploratory Tables.......................................................................49
10.10.8. ICH Listings .................................................................................49
10.10.9. Other (non-ICH) Listings..............................................................53
10.11. Appendix 11: Example Mock Shells for Data Displays ................................54
 
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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe any 
planned analyses and output to be included in the clinical study report for 
Protocol 205894.
Protocol

This RAP is based on the original protocol (Dated: 18/JAN/2018) of study 
205894 (GlaxoSmithKline Document Number. 2017N330422_00).
Primary 
Objective

Part 1:

To compare the relative bioavailability (BA) of dolutegravir (DTG), abacavir 
(ABC), and lamivudine (3TC) administered as pediatric TRIUMEQ dispersible 
tablets with the conventional adult TRIUMEQ tablet (reference) administered as 
direct-to-mouth when:

Pediatric TRIUMEQ dispersible tablets are administered as a dispersion and 
taken immediately 

Pediatric TRIUMEQ dispersible tablets are administered as direct to-mouth.

Part 2:

To compare the relative BA of DTG and 3TC administered as pediatric 
DTG/3TC dispersible tablets with the conventional adult DTG and 3TC tablets 
(reference) administered as direct-to-mouth when:

Pediatric DTG/3TC dispersible tablets are administered as a dispersion and 
taken immediately

Pediatric DTG/3TC dispersible tablets are administered as direct-to-mouth
Primary
Endpoint

Parts 1 and 2: 

Plasma DTG, ABC (Part 1 only), and 3TC:

Area under the plasma concentration-time curve (AUC) from time of dose 
extrapolated to infinite [AUC(0-∞)], AUC from time of dose to last measurable 
concentration [AUC(0-t)], and maximum observed concentration (Cmax).
Secondary
Objectives

Part 1:

To compare the single-dose pharmacokinetics (PK) of DTG, ABC, and 3TC 
administered as pediatric TRIUMEQ dispersible tablets with the conventional 
adult TRIUMEQ tablets (reference) administered as direct-to-mouth when:

Pediatric TRIUMEQ dispersible tablets are administered as a dispersion and 
taken immediately 

Pediatric TRIUMEQ dispersible tablets are administered as direct to-mouth

To evaluate the safety and tolerability of DTG, ABC, and 3TC administered as 
pediatric TRIUMEQ dispersible tablets as compared with conventional adult 
TRIUMEQ tablet (reference) administered as direct-to-mouth
 
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Overview
Key Elements of the RAP

Part 2:

To compare the single-dose PK of DTG and 3TC administered as pediatric 
DTG/3TC dispersible tablets, with the conventional adult DTG and 3TC tablets 
(reference) administered as direct-to-mouth when:

Pediatric DTG/3TC dispersible tablets are administered as a dispersion and
taken immediately

Pediatric DTG/3TC dispersible tablets are administered as direct to-mouth

To evaluate the safety and tolerability of DTG and 3TC administered as 
pediatric DTG/3TC dispersible tablets as compared with the conventional adult 
DTG and 3TC tablets (reference) administered as direct-to-mouth
Secondary
Endpoints

Parts 1 and 2: 

Plasma DTG, ABC (Part 1 only) and 3TC:

AUC from time of dose to 24 hours [AUC(0-24)], time to maximum 
concentration (Tmax), time of last quantifiable concentration (Tlast), apparent 
oral clearance (CL/F), apparent volume of distribution (VZ/F), observed 
concentration at 24 hours postdose (C24), last observed quantifiable 
concentration (Ct), and terminal elimination phase half-life (t½), 

Plasma DTG: lag time for absorption (tlag)

Safety and tolerability parameters for adverse events (AEs)/serious adverse 
events (SAE), observed and change from baseline clinical laboratory 
assessments, electrocardiogram (ECG), and vital signs
Exploratory
Objective 

Parts 1 and 2: 

To evaluate the palatability of the dispersible tablets
Exploratory
Endpoint

Parts 1 and 2:

Palatability questionnaire
Study 
Design

This study will be conducted as a 2-part, open-label, single-dose, 3-period, 
randomized, crossover study to compare the relative BA of pediatric TRIUMEQ 
dispersible tablets with an adult TRIUMEQ conventional tablet formulation (Part 
1) and of pediatric DTG/3TC dispersible tablets with adult DTG and 3TC 
conventional tablets formulation (Part 2) in healthy volunteers under fasted 
conditions. Prior to dosing on Day 1 of Period 1 in each part, participants will be 
randomized to 1 of 6 treatment sequences (ABC, BCA, CAB, ACB, BAC, or 
CBA in Part 1; DEF, EFD, FDE, DFE, EDF, or FED in Part 2) and will receive a 
single dose of each of the 3 treatments administered as 1 treatment per period.
Parts 1 and 2 of the study are independent of one another and may be run in 
parallel.

Treatments are defined below:
 
2018N363263_00


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205894
7
Overview
Key Elements of the RAP

Part 1
o
Treatment A: Adult TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference)
o
Treatment B: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as a dispersion and taken immediately (test)
o
Treatment C: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered as direct-to-mouth (test).

Part 2
o
Treatment D: Adult DTG (50 mg, 1 conventional tablet) and adult 3TC (300 mg, 
1 conventional tablet) administered as direct-to-mouth (reference)
o
Treatment E: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets) 
administered as a dispersion and taken immediately (test)
o
Treatment F:  Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets) 
administered as direct-to-mouth (test)
Planned 
Analyses

Plasma DTG, ABC (Part 1 only), and 3TC concentration-time data will be 
analyzed by non-compartmental methods with Phoenix WinNonlin Version 6.4 
or higher. Calculations will be based on the actual sampling times recorded 
during the study. From the plasma concentration-time data, the following PK 
parameters will be determined, as data permit: Cmax, Tmax, Tlast, AUC(0-t), 
AUC24, AUC(0-∞), t1/2, tlag (DTG only), C24, Ct, Vz/F, and CL/F.

Pharmacokinetic data for each part will be listed and may be presented in 
graphical form, and will be summarized descriptively. All PK data will be stored 
in the Archives, GlaxoSmithKline R&D.

The primary PK parameters for DTG, ABC (Part 1 only), and 3TC in Part 1 
(AUC[0-∞], AUC[0-t], and Cmax) will be loge-transformed and separately 
analyzed using a mixed effects model with fixed-effect terms for Period, 
Treatment, and Treatment Sequence for each treatment comparison. 
Participant will be nested within Treatment Sequence and treated as a random 
effect in the model. Point estimates and their associated 90% CIs will be 
constructed for the differences in PK parameter values between test and 
reference treatments. The point estimates and their associated 90% CIs will 
then be back transformed to provide point estimates and 90% CIs for the ratios 
of PK parameters from test and reference treatments.

Safety data for each part will be presented in tabular format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards. No formal statistical analysis of the safety data will be conducted.

Palatability questionnaire variables for each part will be summarized 
descriptively.
Analysis 
Populations

All Participants Population: all participants who receive at least 1 dose of study 
medication. This population will be used for all demographic and safety 
 
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Overview
Key Elements of the RAP
summaries

PK Population: participants in the ‘All Participants’ population for whom a PK 
sample was obtained and who had evaluable PK assay results. PK samples 
that may be affected by protocol deviations will be reviewed by the study team 
to determine whether or not the sample will be excluded. This population will be 
used for reporting of PK data.
Hypothesis
This study is designed to estimate the relative BA of each test treatment to the 
reference treatment (B vs. A, C vs. A in Part 1; E vs. D, F vs. D in Part 2) in the 
fasted state. 

No formal hypothesis will be tested. For each primary pharmacokinetic endpoint 
(AUC[0-∞], AUC[0-t], and Cmax), point estimates and corresponding 90% CIs 
will be constructed for the ratio of the geometric mean of the test treatment to 
the geometric mean of the reference treatment, μ(test)/μ(reference).
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
An additional comparison between the two administration approaches of Pediatric 
TRIUMEQ in Part 1 and Pediatric DTG/3TC in Part 2, direct to mouth and dispersion (B 
vs. C, and E vs. F) will be included within the primary statistical analyses. The secondary 
PK parameter C24 will be included in the primary statistical analysis described in Section
7.1.3.2 of this document.
Screened and Enrolled populations have been defined as additional analysis populations.
There have been no other changes to the protocol defined statistical analysis plan.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Part 1

To compare the relative BA of DTG, ABC, 
and 3TC administered as pediatric 
TRIUMEQ dispersible tablets with the 
conventional adult TRIUMEQ tablet 
(reference) administered as direct-to-mouth 
when:
o
Pediatric TRIUMEQ dispersible tablets 
are administered as a dispersion and taken 
immediately 
o
Pediatric TRIUMEQ dispersible tablets 
are administered as direct to-mouth
Part 1

Plasma DTG, ABC, and 3TC:
AUC(0-∞), AUC(0-t), and Cmax.
Part 2

To compare the relative BA of DTG and 3TC 
administered as pediatric DTG/3TC 
dispersible tablets with the conventional 
adult DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and taken 
immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct-to-mouth
Part 2

Plasma DTG and 3TC:
AUC(0-∞), AUC(0-t), and Cmax.
 
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Objectives
Endpoints
Secondary Objectives
Secondary Endpoints
Part 1

To compare the single-dose 
pharmacokinetics (PK) of DTG, ABC, and 
3TC administered as pediatric TRIUMEQ 
dispersible tablets with the conventional 
adult TRIUMEQ tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric TRIUMEQ dispersible tablets 
are administered as a dispersion and taken 
immediately 
o
Pediatric TRIUMEQ dispersible tablets 
are administered as direct to-mouth

To evaluate the safety and tolerability of 
DTG, ABC, and 3TC administered as 
pediatric TRIUMEQ dispersible tablets as 
compared with conventional adult TRIUMEQ 
tablet (reference) administered as direct-to-
mouth.
Part 1

Plasma DTG, ABC, and 3TC: AUC(0-24), 
Tmax, Tlast, CL/F, Vz/F, C24, Ct, t½

Plasma DTG: tlag

Safety and tolerability parameters for AEs/ 
SAEs, observed and change from baseline 
clinical laboratory assessments, ECG, and 
vital signs.
Part 2

To compare the single-dose 
pharmacokinetics (PK) of DTG and 3TC 
administered as pediatric DTG/3TC 
dispersible tablets, with the conventional 
adult DTG and 3TC tablets (reference) 
administered as direct-to-mouth when:
o
Pediatric DTG/3TC dispersible tablets 
are administered as a dispersion and taken 
immediately
o
Pediatric DTG/3TC dispersible tablets 
are administered as direct to-mouth

To evaluate the safety and tolerability of 
DTG and 3TC administered as pediatric 
DTG/3TC dispersible tablets as compared 
with the conventional adult DTG and 3TC 
tablets (reference) administered as direct-to-
mouth
Part 2

Plasma DTG and 3TC: AUC(0-24), Tmax,
Tlast, CL/F, Vz/F, C24, Ct, t½

Plasma DTG: tlag

Safety and tolerability parameters for AEs/ 
SAEs, observed and change from baseline 
clinical laboratory assessments, ECG, and 
vital signs.
Exploratory Objectives
Exploratory Endpoints
Parts 1 and 2

To evaluate the palatability of the dispersible 
tablets.
Parts 1 and 2

Palatability questionnaire.
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

Phase I, 2-part, open-label, randomized, 3-period, cross-over study.

Part 1: Approximately 18 participants in a 3-period, cross-over study 
that will compare the relative BA of pediatric TRIUMEQ administered 
as a dispersion and taken immediately (Treatment B) or 
administered as direct-to-mouth (Treatment C) with adult TRIUMEQ 
administered direct-to-mouth (Treatment A). Each participant will 
receive all three treatments according to their assignment to one of 
the 6 treatment sequences (ABC, BCA, CAB, ACB, BAC, CBA).  
Each treatment sequence will be assigned to 3 participants.

Part 2: Approximately 18 participants in a 3-period, cross-over study 
that will compare the relative BA of pediatric DTG/3TC administered 
as a dispersion and taken immediately (Treatment E) or 
administered as direct-to-mouth (Treatment F) with adult DTG and 
adult 3TC administered direct-to-mouth (Treatment D). Each 
participant will receive all three treatments according to their 
assignment to one of the 6 treatment sequences (DEF, EFD, FDE, 
DFE, EDF, FED).  Each treatment sequence will be assigned to 3 
participants.
Dosing
Part 1:

Treatment A: Adult TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 
300 mg, 1 conventional tablet) administered as direct-to-mouth 
(reference).

Treatment B: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 
30 mg, 10 dispersible tablets) administered as a dispersion and 
taken immediately (test).

Treatment C: Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 
30 mg, 10 dispersible tablets) administered as direct-to-mouth (test).
 
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Overview of Study Design and Key Features
Part 2:

Treatment D: Adult DTG (50 mg, 1 conventional tablet) and adult 
3TC (300 mg, 1 conventional tablet) administered as direct-to-mouth 
(reference)

Treatment E: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 
10 dispersible tablets) administered as a dispersion and taken 
immediately (test).

Treatment F: Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 
10 dispersible tablets) administered as direct-to-mouth (test).
Treatment 
Assignment
Part 1:

On Period 1 Day 1, participants will be randomized to 1 of the 6
following treatment sequences: ABC, BCA, CAB, ACB, BAC, or CBA 
in accordance with the randomization schedule generated prior to 
the start of the study, using validated software.
Part 2:

On Period 1 Day 1, participants will be randomized to 1 of the 6 
following treatment sequences: DEF, EFD, FDE, DFE, EDF, or FED
in accordance with the randomization schedule generated prior to 
the start of the study, using validated software.
Interim Analysis

There will be no interim analysis.
2.4.
Statistical Hypotheses
This study is designed to estimate the relative BA of each test treatment to the reference 
treatment (B vs. A, C vs. A; E vs. D, F vs. D) in both study parts in the fasted state. 
Administration by either direct to mouth or dispersion will also be directly compared (B 
vs. C, and E vs. F) in both study parts.
No formal hypothesis will be tested. For each primary pharmacokinetic endpoint 
(AUC[0-∞], AUC[0-t], and Cmax), point estimates and corresponding 90% CIs will be 
constructed for the ratio of the geometric mean of the test treatment to the geometric 
mean of the reference treatment, μ(test)/μ(reference).
3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who signed an informed 
consent form.

Screen Failures

Protocol Deviations
Enrolled

All participants who were randomized

Study Populations
All Participants

All participants who receive at least one dose 
of study medication. This population 
corresponds to all participants enrolled.

Demographic

Safety

Exploratory
PK

Participants in the “All Participants” population 
for whom a PK sample was obtained and who 
had evaluable PK assay results.  PK samples 
that may be affected by protocol deviations will 
be reviewed by the study team to determine 
whether or not the sample will be excluded. 

PK
NOTES : 

Please refer to Appendix 10: List of Data Displays which details the population to be used for each display 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.

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 freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

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 electronic case report form (eCRF).
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Time & Events
10.2
Appendix 2: Treatment States and Phases
10.3
Appendix 3: Data Display Standards & Handling Conventions
10.4
Appendix 4: Derived and Transformed Data
10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data
10.6
Appendix 6: Values of Potential Clinical Importance
10.7
Appendix 7: Multiple Comparisons and Multiplicity
10.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
10.9
Appendix 9: Abbreviations and Trade Marks
10.10
Appendix 10: List of Data Displays
10.11
Appendix 11: Example Mock Shells for Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “All Participants” population, unless
otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Display’s Generated
Figure
Table
Listing
Enrollment
Number of Participants Enrolled by Country and Site 
ID
Y
Randomisation
Randomisation
Y
Participant Disposition
Participant Disposition
Y
Reasons for Screen Failures
Y
Y
Reasons for Withdrawals
Y
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography
Demographics Characteristics
Y
Y
Race and Racial Combinations
Y
Y
Age Ranges
Y
Study Populations
Y [1]
Concomitant  Medications
Concomitant Medications
Y
NOTES:

Y = Yes display generated.
1.
Listing includes only participants excluded from any population.
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Pharmacokinetic Analyses
7.1.1.
Overview of Planned Pharmacokinetic Analyses
The PK analyses will be based on the PK Population, unless otherwise specified.
Table 3 provides an overview of the planned analyses, with full details being presented in
Appendix 10: List of Data Displays. 
Table 3
Overview of Planned Pharmacokinetic Analyses
Display Type
Untransformed
Ln-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PK Concentrations
Y
Y[1] 
[2]
Y[1]
Y
Plasma PK 
Parameters
Y
Y
Y[1] 
[2]
Y
Y
Y
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 participant observed raw data.
1.
[1]       Linear and Semi-Logarithmic plots will be created on the same display.
2.
[2]       Separate mean and median plots will be generated.
7.1.2.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3
Reporting Process & Standards).
7.1.3.
Pharmacokinetic Parameters
7.1.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 3: Data Display Standards & Handling Conventions (Section
10.3.3 Reporting Process & Standards).

The PK parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin Version 6.4 or 
higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 4 will be determined from the plasma 
concentration-time data, as data permits.
 
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Table 4
Derived Plasma Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve (AUC) from time 0 (predose) to time of the 
last quantifiable concentration, to be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
AUC(0-24)
Area under the concentration-time curve (AUC) over time 0 (predose) to 24 hours 
after dose administration, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve from time 0 (predose) extrapolated to 
infinite time, calculated as: 
AUC(0-∞) = AUC(0-t) + Ct / λz
where Ct is the last observed quantifiable concentration.
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation (%AUCex) will be calculated 
as:
[AUC(0-∞) – AUC(0-t)] / AUC(0-∞) x 100
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data.
Ct
The last observed quantifiable concentration
C24
The observed concentration at 24 hours after dose administration
Tmax
Time to first occurrence of Cmax
Tlast
Time of last quantifiable concentration
tlag
Lag time before observation of drug concentrations in sampled matrix
t½
Terminal phase half-life will be calculated as: 
t½ = ln2 / λz
λz
Terminal-phase rate constant
CL/F
The apparent oral clearance
Vz/F
The apparent volume of distribution during the terminal phase
NOTES:

Additional parameters may be included as required.

tlag will be calculated for DTG only
7.1.3.2.
Statistical Analysis of Pharmacokinetic Parameters
The following PK statistical analyses will only be performed, if sufficient data are
available (i.e. if participants have well defined plasma profiles). 
 
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Pharmacokinetic Statistical Analyses
Endpoint(s)

Plasma primary PK endpoints include AUC(0-∞), AUC(0-t) and Cmax and the secondary 
endpoint C24 for DTG, ABC (only for Part 1), and 3TC, as data permit
Model Specification

In Part 1 of this study, the ln-transformed AUC(0-∞), AUC(0-t), Cmax, and C24 values for 
DTG, ABC, and 3TC will be analyzed separately using a mixed effects model, fitting fixed effect 
terms for period, treatment, and treatment sequence; and treating participant within treatment 
sequence as a random effect. Point estimates and 90% CIs will be constructed using the 
residual variance for the following differences of interest:
o
10 dispersible pediatric TRIUMEQ tablets [DTG 5 mg/ABC 60 mg/3TC 30 mg] 
administered as a dispersion and taken immediately [Treatment B, Test] and 
administered direct-to-mouth [Treatment C, Test] versus 1 conventional adult 
TRIUMEQ tablet [DTG 50 mg/ABC 600 mg/3TC 300 mg] administered direct-to-
mouth [Treatment A, Reference]
o
10 dispersible pediatric TRIUMEQ tablets [DTG 5 mg/ABC 60 mg/3TC 30 mg] 
administered as a dispersion and taken immediately [Treatment B, Test] versus 
10 dispersible pediatric TRIUMEQ tablets [DTG 5 mg/ABC 60 mg/3TC 30 mg]  
administered direct-to-mouth [Treatment C, Reference])

In Part 2 of this study, the ln-transformed AUC(0-∞), AUC(0-t), Cmax, and C24 values for DTG 
and 3TC will be analyzed separately using a mixed effects model, fitting fixed effect terms for 
period, treatment, and treatment sequence; and treating participant within treatment sequence 
as a random effect. Point estimates and 90% CIs will be constructed using the residual 
variance for the following differences of interest:
o
10 dispersible pediatric DTG/3TC tablets [DTG 5 mg/3TC 30 mg] administered as 
a dispersion and taken immediately [Treatment E, Test] and administered direct-
to-mouth [Treatment F, Test] versus 1 conventional adult DTG tablet [50mg] and 
1 conventional 3TC tablet [300 mg] administered direct-to-mouth [Treatment D, 
Reference]
o
10 dispersible pediatric DTG/3TC tablets [DTG 5 mg/3TC 30 mg] administered as 
a dispersion and taken immediately [Treatment E, Test] versus 10 dispersible 
pediatric DTG/3TC tablets [DTG 5 mg/3TC 30 mg] administered direct-to-mouth 
[Treatment F, Reference])
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Statistical analysis by ANOVA will be presented in tabular format with geometric mean ratios 
between TRIUMEQ dispersible pediatric tablets versus conventional adult tablets and 
TIRUMEQ dispersible pediatric tablets administered as a dispersion versus TRIUMEQ 
dispersible pediatric tablets administered as direct-to-mouth (Part 1) and DTG/3TC dispersible 
pediatric tablets versus conventional adult tablets and DTG/3TC dispersible pediatric tablets 
 
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Pharmacokinetic Statistical Analyses
administered as a dispersion versus DTG/3TC dispersible pediatric tablets administered as 
direct-to-mouth (Part 2), and 90% CIs for the ratios of AUC(0-∞), AUC(0-t), Cmax, and C24 for 
DTG, ABC (only for Part 1), and 3TC.
Part 1 Example SAS Code:
PROC MIXED;
CLASS USUBJID TRTA TRTSEQP APERIOD;
MODEL LOGPKPARM =TRTA TRTSEQP APERIOD /DDFM=KR;
RANDOM USUBJID(TRTSEQP);
LSMEANS TRTA;
ESTIMATE ‘B VS A’ TRTA -1 1 0/CL ALPHA=0.1;
ESTIMATE ‘C VS A’   TRTA -1 0  1/CL ALPHA=0.1;
ESTIMATE ‘B VS C’   TRTA 0 1 -1/CL ALPHA=0.1;
RUN;
Part 2 Example SAS Code:
PROC MIXED;
CLASS USUBJID TRTA TRTSEQP APERIOD;
MODEL LOGPKPARM =TRTA TRTSEQP APERIOD /DDFM=KR;
RANDOM USUBJID(TRTSEQP);
LSMEANS TRTA;
ESTIMATE ‘E VS D’  TRTA -1 1 0/CL ALPHA=0.1;
ESTIMATE ‘F VS D’   TRTA -1 0  1/CL ALPHA=0.1;
ESTIMATE ‘E VS F’   TRTA 0  1 -1/CL ALPHA=0.1;
RUN;
7.1.4.
Interim Analysis 
7.1.4.1.
Overview of Planned Analyses
No interim analysis is planned for this study.
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Safety Analyses
The safety analyses will be based on the “All Participants” population, unless otherwise
specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 5
Overview of Planned Safety Analyses
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Exposure Data
Y
Adverse Events
Relationship Between 
System Organ Class and 
Verbatim Term
Y
Subject Numbers for 
Individual AEs
Y
All AEs
Y
Y
All Drug-Related AEs
Y
Y
Common Non-serious 
AEs
Y
Serious AEs
Y
Y
AEs by Maximum Grade
Y
Withdrawal AEs
Y
Laboratory Values
Clinical Chemistry
Y
Y [2]
Y
Hematology
Y
Y [2]
Y
Urinalysis (Dipstick)
Y [5]
Y [2]
Electrocardiograms (ECGs)
ECG Findings
Y
Y [3]
ECG Values
Y
Y [4]
Vital Signs
Vital Signs
Y
Y [4]
Y
Liver
Liver Events [1]
Y
 
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NOTES :
1.
Conditional display, it will only be produced when an event has occurred.
2.
Displays contain only participants with DAIDS toxicities for HIV-infected patients of Grade 2 or higher
3.
Displays contain only participants with abnormal findings
4.
Displays contain only participants with values of potential clinical importance
5.
Displays contain only worst case results relative to baseline

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents TFL related to any displays of individual participant observed raw data.    
8.2.
Exploratory Analyses
The exploratory analyses will be based on the “All Participants” population, unless 
otherwise specified.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 6
Overview of Planned Exploratory Analyses
Display Type
Absolute
Summary
Individual
T
F
F
L
Palatability
Palatability Questionnaire Results
Y
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 participant observed raw data.
 
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9.
REFERENCES
GlaxoSmithKline Document Number 2017N330422_00 (Original – 18-JAN-2018): 2-
Part, Phase I, Single-Dose, 3-Period Crossover Relative Bioavailability Study of a 
Pediatric TRIUMEQ Dispersible Tablet and Pediatric Dolutegravir and Lamivudine 
(DTG/3TC) Fixed Dose Combination Dispersible Tablet Formulations as Compared 
With Adult Tablets in Healthy Volunteers (18-JAN-2018)
 
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10.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.1
Appendix 1: Time and Events
Section 10.2
Appendix 2: Treatment States & Phases
Section 10.3
Appendix 3: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.4
Appendix 4: Derived and Transformed Data

General, Study Population & Safety

Pharmacokinetic

Exploratory
Section 10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.6
Appendix 6: Values of Potential Clinical Importance
Section 10.7
Appendix 7: Multiple Comparisons and Multiplicity
Section 10.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.9
Appendix 9: Abbreviations & Trade Marks
Section 10.10
Appendix 10: List of Data Displays
Section 10.11
Appendix 11: Example Mock Shells for Data Displays
 
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10.1.
Appendix 1: Time & Events
10.1.1.
Protocol Defined Screening Assessments for Parts 1 and 2
Event
Notes
Informed Consent
Demographics
Medical History (includes substance use)
Inclusion/Exclusion
Human Immunodeficiency Virus, Hepatitis B and Hepatitis C Screen
HLA-B*5701
For Part 1 only.
Urine Drug/Alcohol/Cotinine Screen
Physical Examination
A brief physical examination is required at Screening.
Height, Weight & Body Mass Index
Vital Sign Measurement
12-lead Electrocardiogram (Single)
A single repeat evaluation is allowed for eligibility determination.
Follicle-stimulating Hormone and Estradiol (women)
Pregnancy Test (urine)
For women of child bearing potential (WOCBP) only.
Clinical Laboratory Tests (Chemistry, Hematology, and Urinalysis)
For clinical laboratory tests, see Appendix 2 in the protocol.
Concomitant Medication
 
 
 
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10.1.2.
Protocol Defined Time and Events for Parts 1 and 2
Assessments
Periods 1-3
Follow-up
Notes
Day −1 of Periods 2 and 3 may be the same day as Day 6 
of prior periods.
At Follow-up, male participants and female participants of 
non-childbearing potential with no ongoing AEs or vital 
sign/clinical laboratory results of clinical concern may be 
followed up virtually by the site via telephone contact.
Day 
−1
Day
1
Day 
2
Day 
3
Day 
4
Predose
0
hr
Postdose
24 
hr
48 
hr
72 
hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
Follow-up visit will occur 7-10 days after last dose.
12-lead ECG (single)
X
Vital signs
X
X
At 4 hours postdose
X
X
Single vital sign measurements performed at all time points.
Vital signs at Follow-up are only necessary if participant had 
ongoing AEs or a previous abnormal vital sign result of 
clinical concern. Only the abnormal value(s) need be 
re-assessed.
Brief Physical Examination
X
Physical examination required only on Day −1 of Period 1 and 
as needed based on AE assessment.
Urine Drug/Alcohol/Cotinine
X
Drug/Alcohol/Cotinine/pregnancy will be performed as per the 
standard practice of the site.
For clinical laboratory tests, see Appendix 2 in the protocol.
Clinical laboratory tests at Follow-up are only necessary if 
participant had ongoing AEs or a previous abnormal clinical 
laboratory result of clinical concern. Only the abnormal 
value(s) need be re-assessed.
Pregnancy test (serum; WOCBP)
X
X
Clinical laboratory tests 
X
X
X
Dosing
X
Participants in Part 1 should be provided with an ABC HSR 
warning card and should be reminded to read it.
Palatability Assessment
Start within 10 
minutes after dose
Complete for each dispersion treatment (Treatments B & E, see 
Appendix 4 in the protocol).
Pharmacokinetic Sampling
X
Collect at: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 
8, 12, 16, 24, 48 and 72 hours postdose 
before discharge at the end of each period
Predose is within 15 minutes prior to dosing (see Section 9.5.1 
in the protocol).
 
 
 
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Assessments
Periods 1-3
Follow-up
Notes
Day −1 of Periods 2 and 3 may be the same day as Day 6 
of prior periods.
At Follow-up, male participants and female participants of 
non-childbearing potential with no ongoing AEs or vital 
sign/clinical laboratory results of clinical concern may be 
followed up virtually by the site via telephone contact.
Day 
−1
Day
1
Day 
2
Day 
3
Day 
4
Predose
0
hr
Postdose
24 
hr
48 
hr
72 
hr
Meals
Fasted from 10 hours prior 
to dosing to 4 hours 
postdose
Standard for the study centre
Adverse Events / SAE
X
======================X======================
X
Concomitant medications
X
======================X======================
X
 
 
 
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10.2.
Appendix 2: Treatment States and Phases
10.2.1.
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.
10.2.1.1.
Treatment States for Safety Data
Treatment State
Definition
Pre-Treatment
Date/Time < Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time ≤Date/Time ≤ Study Treatment Stop Date/Time
+ 6 days
Post-Treatment
Date/Time > Study Treatment Stop Date/Time + 6 days
1.
NOTES: 

If the study treatment stop date is missing then the assessment will be considered to be On-Treatment
10.2.1.2.
Treatment States for Event Data (e.g. AEs, Concomitant Medications)
Treatment State
Definition
Pre-Treatment
Event Start Date/Time < Initial Study Treatment Date/Time
On-Treatment
If event onset date/time is on or after the initial treatment date/time & on or before the 
final treatment date/time with 7 days lag time.
Initial Study Treatment Date/Time ≤ Event Start Date/Time ≤ Final Study Treatment 
Date/Time + 6 days
Post-Treatment
If event onset date/time is after the final treatment date/time with 6 days lag time.
Event Start Date/Time > Final Study Treatment Date/Time + 6 days
Onset Time  
Since 1st Dose
(Days)
If Treatment Date/Time ˃ Event Onset Date/Time = Event Onset Date – Treatment 
Date/Time
If Treatment Date/Time ≤ Event Onset Date/Time = Event Onset Date/Time –
Treatment Date/Time +1
Missing otherwise.
Duration (Days) 
Event Resolution Date/Time – Event Onset Date/Time + 1
Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing.
NOTES: 

If the initial and final study treatment dates are missing then the event will be considered to be On-Treatment.
 
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10.3.
Appendix 3: Data Display Standards & Handling 
Conventions
10.3.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Study 
Part
Treatment Group 
Data Displays for Reporting 
Code
Description
Description[1]
Order [2]
1
A
Adult TRIUMEQ (DTG 50 mg/ABC 
600 mg/3TC 300 mg, 
1 conventional tablet) administered 
as direct-to-mouth (reference)
Treatment A
1
B
Pediatric TRIUMEQ (DTG 
5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered 
as a dispersion and taken 
immediately (test)
Treatment B
2
C
Pediatric TRIUMEQ (DTG 
5 mg/ABC 60 mg/3TC 30 mg, 
10 dispersible tablets) administered 
as direct-to-mouth (test)
Treatment C
3
2
D
Adult DTG (50 mg, 1 conventional
tablet) and adult 3TC (300 mg, 
1 conventional tablet) administered 
as direct-to-mouth (reference)
Treatment D
4
E
Pediatric DTG/3TC (DTG 
5 mg/3TC 30 mg, 10 dispersible
tablets) administered as a 
dispersion and taken immediately 
(test)
Treatment E
5
F
Pediatric DTG/3TC (DTG 
5 mg/3TC 30 mg, 10 dispersible
tablets) administered as direct-to-
mouth (test)
Treatment F
6
NOTES:
1.
The word “Treatment” may be omitted from displays in order to limit wrapping
2.
Order represents treatments being presented in TFL, as appropriate.

Where applicable, outputs will include a treatment footnote describing the treatments: “Treatment A = Adult 
TRIUMEQ (DTG 50 mg/ABC 600 mg/3TC 300 mg, 1 conventional tablet) administered as direct-to-mouth 
(reference); Treatment B = Pediatric TRIUMEQ (DTG 5 mg/ABC 60 mg/3TC 30 mg, 10 dispersible tablets) 
administered as a dispersion and taken immediately (test); Treatment C = Pediatric TRIUMEQ (DTG 5 mg/ABC 
60 mg/3TC 30 mg, 10 dispersible tablets) administered as direct-to-mouth (test); Treatment D = Adult DTG (50 
mg, 1 conventional tablet) and adult 3TC (300 mg, 1 conventional tablet) administered as direct-to-mouth 
(reference); Treatment E = Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible tablets) administered as a 
dispersion and taken immediately (test); Treatment F = Pediatric DTG/3TC (DTG 5 mg/3TC 30 mg, 10 dispersible 
tablets) administered as direct-to-mouth (test).”
 
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10.3.2.
Baseline Definition & Derivations
10.3.2.1.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
last available assessment prior to time of the first dose, unless noted otherwise. Baseline 
definitions are applicable to each period. For later periods, Day -1 may be the same day 
as Day 6 of the prior period.
Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Hematology
X
X
Day -1
Clinical Chemistry
X
X
Day -1
12-Lead ECG
X
X
Day -1
Vital Signs
X
X
X
Day 1 (Pre-Dose)
NOTES :

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.
10.3.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.3.2.1 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.

The baseline definition will be footnoted on all change from baseline displays.
10.3.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS 9.3 or higher and Phoenix WinNonlin software 6.4 or 
higher will be used.
Analysis Datasets 

Analysis datasets will be created according to CDISC standards SDTM IG Version 3.2 & 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 all reporting efforts described in the RAP.
 
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Reporting Standards
General

The current GSK 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 participant received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places 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:

Planned time relative to dosing will be used in figures (with the exception of individual PK 
concentration-time figures, where actual relative time will be used), summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

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 participant’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 not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1

NQs at the beginning of a participant profile (i.e. before the first 
incidence of a measurable concentration) are deemed to be zero as it is 
assumed that in this circumstance no drug is yet measurable in the 
blood.

For NQs at the end of the participant profile (i.e. after the last incidence 
of a measurable concentration);

for individual plots and pharmacokinetic analyses these are dropped 
(set to missing) as they do not provide any useful information (and 
can erroneously indicate that absolutely no drug is present)
 
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Reporting Standards

for summary statistics these are set to 0 (to avoid skewing of the 
summary statistics)

Individual NQs which fall between two measurable concentrations are 
set to missing (individual values of this nature are assumed to be an 
anomaly)

If two or more NQ values occur in succession between measurable 
concentrations, the profile will be deemed to have terminated at the last 
measurable concentration prior to these NQs. For the purpose of 
individual participant plots, these NQs will be set to 0, and the 
subsequent measurable concentrations will be retained. For the 
derivation of pharmacokinetic parameters, these NQs and any 
subsequent measurable concentrations will be omitted (set to missing).
Categorical Data
N (number of participants in subgroup), n (number of participants with 
evaluable data), frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Ln-Transformed)
N (number of participants in subgroup), n (number of participants with 
evaluable data), geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logged data and between geometric coefficient of variation
(CVb (%)) will be reported.
CVb (%) = square root of (exp(SD2) – 1) * 100
(SD = SD of ln-transformed data)
Parameters Not 
Being Ln-
Transformed
Tmax, Tlast, tlag, first point, last point, and number of points used in the 
determination of λz, %AUCex.
Summary Tables
The following PK parameters will not be summarised: first point, last point, 
and number of points used in the determination of λz and Rsq_adjusted.
Listings
Include the first point, last point and number of points used in the 
determination of λz. nd Rsq_adjusted for listings
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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10.4.
Appendix 4: Derived and Transformed Data
10.4.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from randomisation date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1 
10.4.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Only the year of birth will be collected.  The date and month will be imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
10.4.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:
[2] If QTcF is machine read and QTcB is not provided, then:

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
 
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ECG Parameters
collected value THEN do not derive.

Machine read values of RR should not be replaced with derived values.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 
Adverse Events
AEs of Special Interest

No analysis for AEs of Special Interest will be performed
 
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10.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
10.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as
completing all phases of the study including the follow-up visit.

Withdrawn participants may be replaced in the study.

All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.
10.5.2.
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 participant 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 participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.5.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in participant listing displays.
AEs

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
2: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
 
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Element
Reporting Detail

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
10.5.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
AEs

Any partial dates for AEs will be raised to data management. If the full date 
cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
 
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10.6.
Appendix 6: Values of Potential Clinical Importance
10.6.1.
ECG
ECG Parameter
Units
Potential Clinically Important Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450[1]
> 450[2]
≤ 479[2]
≥ 480[2]
≤ 499[2]
≥ 500[2]
Absolute PR Interval
msec
< 110[1]
> 220[1]
Absolute QRS Interval
msec
< 75[1]
> 110[1]
Change from Baseline
Increase from Baseline QTc
msec
≤ 30[2]
msec
> 30[1]
≤ 59[2]
msec
≥60[2]
NOTES:
1.
Represent standard ECG values of PCI for HV studies.
2.
Represent further subdivisions of ECG values for analysis.
10.6.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Potential Clinically Important Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
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10.7.
Appendix 7: Multiple Comparisons & Multiplicity
10.7.1.
Handling of Multiple Comparisons & Multiplicity
No adjustments for multiplicity will be made.
 
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10.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
10.8.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoints AUC(0-∞), AUC(0-t), Cmax, and C24
Analysis

Mixed Effects
Assumptions:

Model assumptions will be applied, but appropriate adjustments may be 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.
 
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10.9.
Appendix 9 – Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
3TC
Lamivudine
ABC
Abacavir
ADaM
Analysis Data Model
AE
Adverse Event
AUC
Area under the concentration-time curve
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time 
of the last quantifiable concentration
AUC(0-24)
Area under the concentration-time curve over time 0 (predose) to 24 
hours after dose administration
AUC(0-∞)
Area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation
BA
Bioavailability
BMI
Body Mass Index
C24
The observed concentration at 24 hours after dose administration
CDISC
Clinical Data Interchange Standards Consortium
CL/F
The apparent oral clearance
Cmax
Maximum observed concentration
CI
Confidence Interval
CPK
Creatine phosphokinase
Ct
The last observed quantifiable concentration
CV
Coefficient of variation
CVb 
Coefficient of variation (Between) 
DAIDS
Division of Acquired Immune Deficiency Syndrome
DTG
Dolutegravir
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
GSK
GlaxoSmithKline
HSR
Hypersensitivity reaction
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
kg
Kilograms
m
Meters
mg
Milligrams
msec
Milliseconds
PK
Pharmacokinetic
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
R&D
Research and Development
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
 
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Abbreviation
Description
SAS
Statistical Analysis Software
SD
Standard deviation
SDTM
Study Data Tabulation Model
TFL
Tables, Figures & Listings 
t½
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled matrix
Tlast
Time of last quantifiable concentration
Tmax
Time to first occurrence of Cmax
Vz/F
The apparent volume of distribution during the terminal phase
λz
terminal phase rate constant
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
TRIUMEQ
Phoenix WinNonlin
SAS
 
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10.10.
Appendix 10: List of Data Displays
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.7
NA
Safety
2.1 to 2.16
NA
Pharmacokinetic
3.1 to 3.14
3.1 to 3.21
Exploratory (Palatability)
4.1
NA
Section
Listings
ICH Listings
1 to 37
Other (non-ICH) Listings
38 to 45
10.10.1.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Exploratory (Palatability)
EXP_Fn
EXP_Tn
EXP_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.10.2.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
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10.10.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Participant Disposition and Populations
1.1
Enrolled
NS1
Summary of Number of Participants Enrolled by Country and Site ID
SAC [1]
1.2
All 
Participants
ES1A
Summary of Participant Disposition for the Participant Conclusion 
Record
SAC [1]
1.3
Screened
ES6
Summary of Screening Status and Reasons for Screen Failures
SAC [1]
1.4
Screened
DV1
Summary of Important Protocol Deviations
SAC [1]
Demographics
1.5
All 
Participants
DM3
Summary of Demographic Characteristics
SAC [1]
1.6
All 
Participants
DM5
Summary of Race and Racial Combinations
SAC [1]
1.7
All 
Participants
DM11
Summary of Age Ranges
SAC[1]
 
 
 
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10.10.4.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
2.1
All 
Participants
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
SAC [1]
2.2
All 
Participants
AE1CP
Summary of Drug-Related Adverse Events
SAC [1]
2.3
All 
Participants
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participants and 
Occurrences)
SAC [1]
2.4
All 
Participants
AE16
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences)
SAC[1]
2.5
All 
Participants
AE5A
Summary of Adverse Events by Maximum Grade by System Organ 
Class and Preferred Term
SAC [1]
Laboratory Values
2.6
All 
Participants
LB1
Summary of Clinical Chemistry Values
SAC [1]
2.7
All 
Participants
LB1
Summary of Clinical Chemistry Values Change from Baseline
SAC [1]
2.8
All 
Participants
BL
Summary of Clinical Chemistry Results by Maximum Grade Increase
Post-Baseline Relative to Baseline
SAC [1]
2.9
All 
Participants
LB1
Summary of Hematology Values
SAC [1]
2.10
All 
Participants
LB1
Summary of Hamatology Values Change from Baseline
SAC [1]
2.11
All 
Participants
LB16
Summary of Hematology Results by Maximum Grade Increase Post-
Baseline Relative to Baseline
SAC [1]
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12
All 
Participants
UR1
Summary of Worst Case Urinalysis Results Post-Baseline Relative to 
Baseline
SAC [1]
Electrocardiograms
2.13
All 
Participants
EG1
Summary of ECG Findings
SAC [1]
2.14
All 
Participants
EG2
Summary of ECG Values
SAC [1]
Vital Signs
2.15
All 
Participants
VS1
Summary of Values in Vital Signs
SAC[1]
2.16
All 
Participants
VS1
Summary of Change from Baseline in Vital Signs
SAC[1]
 
 
 
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10.10.5.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
3.1
PK 
PKCT1
Summary of DTG Plasma Pharmacokinetic Concentration-Time Data 
by Study Part and Treatment
SAC [1]
3.2
PK 
PKCT1
Summary of ABC Plasma Pharmacokinetic Concentration-Time Data 
by Treatment
Part 1 only
SAC [1]
3.3
PK 
PKCT1
Summary of 3TC Plasma Pharmacokinetic Concentration-Time Data 
by Study Part and Treatment
SAC [1]
PK Derived Parameters
3.4
PK 
PKPT4
Summary of Derived DTG Plasma Pharmacokinetic Parameters (Non-
Transformed) by Study Part and Treatment
Parameters with units 
SAC [1]
3.5
PK 
PKPT4
Summary of Derived DTG Plasma Pharmacokinetic Parameters (Ln-
Transformed) by Study Part and Treatment
Parameters with units 
SAC [1]
3.6
PK 
PKPT4
Summary of Derived ABC Plasma Pharmacokinetic Parameters (Non-
Transformed) by Treatment
Parameters with units; Part 1 only
SAC [1]
3.7
PK 
PKPT4
Summary of Derived ABC Plasma Pharmacokinetic Parameters (Ln-
Transformed) by Treatment
Parameters with units; Part 1 only
SAC [1]
3.8
PK 
PKPT4
Summary of Derived 3TC Plasma Pharmacokinetic Parameters (Non-
Transformed) by Study Part and Treatment
Parameters with units 
SAC [1]
3.9
PK 
PKPT4
Summary of Derived 3TC Plasma Pharmacokinetic Parameters (Ln-
Transformed) by Study Part and Treatment
Parameters with units 
SAC [1]
 
 
 
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Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Analysis Tables
3.10
PK
PKPT3
Statistical Analysis of DTG Plasma Pharmacokinetic Parameters, 
Study Part 1
AUC(0-t), AUC(0-∞), Cmax and C24
only by Treatment. Part 1 only.
SAC [1]
3.11
PK
PKPT3
Statistical Analysis of DTG Plasma Pharmacokinetic Parameters,
Study Part 2
AUC(0-t), AUC(0-∞), Cmax and C24 
only by Treatment. Part 2 only.
SAC [1]
3.12
PK
PKPT3
Statistical Analysis of ABC Plasma Pharmacokinetic Parameters, 
Study Part 1
AUC(0-t), AUC(0-∞), Cmax and C24 
only by Treatment. Part 1 only.
SAC [1]
3.13
PK
PKPT3
Statistical Analysis of 3TC Plasma Pharmacokinetic Parameters, 
Study Part 1
AUC(0-t), AUC(0-∞), Cmax and 
C24only by Treatment. Part 1 only.
SAC [1]
3.14
PK
PKPT3
Statistical Analysis of 3TC Plasma Pharmacokinetic Parameters,
Study Part 2
AUC(0-t), AUC(0-∞), Cmax and 
C24only by Treatment. Part 2 only.
SAC [1]
 
 
 
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10.10.6.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
3.1
PK
PKCF1X
Individual DTG Plasma Concentration-Time Plots by Participant
(Linear and Semi-Logarithmic)
Paginate by Participant
SAC [1]
3.2
PK
PKCF1X
Individual ABC Plasma Concentration-Time Plots by Participant
(Linear and Semi-Logarithmic)
Paginate by Participant; Part 1 only
SAC [1]
3.3
PK
PKCF1X
Individual 3TC Plasma Concentration-Time Plots by Participant
(Linear and Semi-Logarithmic)
Paginate by Participant
SAC [1]
Mean / Median Concentration Plots
3.4
PK
PKCF2
Mean DTG Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.5
PK
PKCF2
Median DTG Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.6
PK
PKCF2
Mean ABC Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.7
PK
PKCF3
Median ABC Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.8
PK
PKCF3
Mean 3TC Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.9
PK
PKCF3
Median 3TC Plasma Concentration-Time Plots by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
 
 
 
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Pharmacokinetic : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Analysis Plots
3.10
PK 
PKPF3
Comparative Plot of Individual DTG Plasma Cmax by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.11
PK 
PKPF3
Comparative Plot of Individual DTG Plasma AUC(0-t) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.12
PK 
PKPF3
Comparative Plot of Individual DTG Plasma AUC(0-∞) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.13
PK 
PKPF3
Comparative Plot of Individual DTG Plasma C24 by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.14
PK 
PKPF3
Comparative Plot of Individual ABC Plasma Cmax by Treatment 
(Linear and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.15
PK 
PKPF3
Comparative Plot of Individual ABC Plasma AUC(0-t) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.16
PK 
PKPF3
Comparative Plot of Individual ABC Plasma AUC(0-∞) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.17
PK 
PKPF3
Comparative Plot of Individual ABC Plasma C24 by Treatment (Linear 
and Semi-Logarithmic)
All treatments for Part 1 on one page
SAC [1]
3.18
PK 
PKPF3
Comparative Plot of Individual 3TC Plasma Cmax by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.19
PK 
PKPF3
Comparative Plot of Individual 3TC Plasma AUC(0-t) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.20
PK 
PKPF3
Comparative Plot of Individual 3TC Plasma AUC(0-∞) by Treatment 
(Linear and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
3.21
PK 
PKPF3
Comparative Plot of Individual 3TC Plasma C24 by Treatment (Linear 
and Semi-Logarithmic)
All treatments for each Part on one 
page
SAC [1]
 
 
 
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10.10.7.
Exploratory Tables
Exploratory : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Palatability
4.1
All 
Participants
EXP_T1
Summary of Palatability Questionnaire Results (Part 1, Treatment B 
and Part 2, Treatment E Only)
SAC[1]
10.10.8.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomisation
1
All 
Participants
CP_TA2
Listing of Randomized and Actual Treatment
SAC [1]
Participant Disposition
2
All 
Participants
ES3
Listing of Reasons for Study Withdrawal
SAC [1]
3
Screened
ES7
Listing of Reasons for Screen Failure
SAC [1]
4
Screened
DV2A
Listing of Important Protocol Deviations
SAC [1]
5
All 
Participants
IE4
Listing of Participants with Inclusion/Exclusion Criteria Deviations
SAC[1]
6
Enrolled
SP3
Listing of Participants Excluded from Any Population
SAC [1]
7
Enrolled
SAFE_L4
Listing of Participants in Previous Clinical Trial
SAC [1]
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographics
8
All 
Participants
DM4
Listing of Demographic Characteristics
SAC [1]
9
All 
Participants
DM10
Listing of Race
SAC [1]
Concomitant Medications
10
All 
Participants
CM4
Listing of Concomitant Medications
SAC[1]
Exposure
11
All 
Participants
SAFE_L1
Listing of Exposure Data
SAC[1]
Adverse Events
12
All 
Participants
AE2
Listing of Relationship Between System Organ Class and Verbatim 
Text
SAC[1]
13
All 
Participants
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC[1]
14
All 
Participants
AE9CP
Listing of All Adverse Events
SAC[1]
15
All 
Participants
AE9CP
Listing of Study Drug Related Adverse Events
SAC[1]
16
All 
Participants
SAFE_L2
Listing of Serious Adverse Events
SAC[1]
17
All 
Participants
AE9CP
Listing of Adverse Events Leading to Permanent Discontinuation of 
Study Treatment or Withdrawal from Study
SAC[1]
18
All 
Participants
SAFE_L3
Listing of Liver Adverse Events
SAC[1]
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19
All 
Participants
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC[1]
Laboratory Values
20
All 
Participants
LB6
Listing of Clinical Chemistry Toxicities of Grade 2 or Higher
SAC [1]
21
All 
Participants
LB6
Listing of All Clinical Chemistry Data for Participants with Toxicities of 
Grade 2 or Higher
SAC [1]
22
All 
Participants
LB6
Listing of Hematology Toxicities of Grade 2 or Higher
SAC [1]
23
All 
Participants
LB6
Listing of All Hematology Data for Participants with Toxicities of Grade 
2 or Higher
SAC [1]
24
All 
Participants
LB6
Listing of Urinalysis Toxicities of Grade 2 or Higher
SAC [1]
25
All 
Participants
LB6
Listing of All Urinalysis Data for Participants with Toxicities of Grade 2
or Higher
SAC [1]
Electrocardiograms
26
All 
Participants
EG6
Listing of Abnormal ECG Findings
SAC [1]
27
All 
Participants
EG6
Listing of All ECG Findings for Participants with an Abnormal Finding
SAC [1]
28
All 
Participants
EG4
Listing of ECG Values of Potential Clinical Importance
SAC [1]
29
All 
Participants
EG4
Listing of All ECG Values for Participants with any Value of Potential 
Clinical Importance
SAC[1]
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
30
All 
Participants
VS5
Listing of Vital Signs of Potential Clinical Importance
SAC [1]
31
All 
Participants
VS5
Listing of All Vital Signs for Participants with any Value of Potential 
Clinical Importance
SAC [1]
Liver Event
32
All 
Participants
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC[1]
33
All 
Participants
MH3
Listing of Medical Conditions for Participants with Liver Stopping 
Events
SAC[1]
34
All 
Participants
SAFE_L5
Listing of Alcohol Intake at Onset of Liver Event
SAC[1]
35
All 
Participants
PKCL1X
Listing of Plasma Concentration Data for Participants with Liver 
Stopping Events
SAC[1]
36
All 
Participants
LIVER7
Listing of Liver Biopsy Details
SAC[1]
37
All 
Participants
LIVER8
Listing of Liver Imaging Details
SAC[1]
 
 
 
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10.10.9.
Other (non-ICH) Listings
Other (non-ICH) : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
38
PK
PKCL1X
Listing of DTG Plasma Pharmacokinetic Concentration-Time Data by 
Treatment
Please list all the concentration data 
including unscheduled. Repeat for all 
treatments and Parts.
SAC [1]
39
PK
PKCL1X
Listing of ABC Plasma Pharmacokinetic Concentration-Time Data by 
Treatment
Please list all the concentration data 
including unscheduled. Repeat for all 
treatments of Part 1.
SAC [1]
40
PK
PKCL1X
Listing of 3TC Plasma Pharmacokinetic Concentration-Time Data by 
Treatment
Please list all the concentration data 
including unscheduled. Repeat for all 
treatments and Parts.
SAC [1]
41
PK
PKPL1X
Listing of Derived DTG Plasma Pharmacokinetic Parameters by 
Treatment
Repeat for all treatments and Parts.
SAC [1]
42
PK
PKPL1X
Listing of Derived ABC Plasma Pharmacokinetic Parameters by 
Treatment
Repeat for all treatments of Part 1.
SAC [1]
43
PK
PKPL1X
Listing of Derived 3TC Plasma Pharmacokinetic Parameters by 
Treatment
Repeat for all treatments and Parts.
SAC [1]
Exploratory
44
All 
Participants
EXP_L1
Listing of Palatability Questionnaire Results (Part 1, Treatment B 
Only)
SAC[1]
45
All 
Participants
EXP_L1
Listing of Palatability Questionnaire Results (Part 2, Treatment E 
Only)
SAC[1]
 
 
 
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10.11.
Appendix 11: Example Mock Shells for Data Displays
Available upon request
 
 
 
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