Conditions: HIV Infections
Keywords: Dispersible tablets Bioavailability Dolutegravir Healthy Conventional tablets
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 38
Healthy volunteers: yes

Brief summary:
The aim of this cross-over study is to compare the relative bioavailability and pharmacokinetic parameters of both 10 mg conventional tablets and 5 mg dispersible tablets of dolutegravir (DTG) with that of 25 mg or 50 mg conventional DTG tablets. The study will be carried out in 2 parts. Part 1 of the study will be open-label, 2 period designs with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 10 mg DTG tablets or one 50 mg DTG tablet in a crossover manner in the fasting state. Part 2 of the study will be a 3 period crossover design with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 5 mg DTG tablets (administered as dispersed with water or directly to mouth) or one 25 mg DTG tablet in a crossover manner in the fasting state. Subjects will have a follow-up visit 7-10 days post last dose of study treatment. Approximately 14 healthy subjects will participate in Part 1 and approximately 24 healthy subjects will participate in Part 2 of the study. The total duration of Part 1 will be approximately 7 to 8 weeks and that of part 2 will be approximately 8 to 9 weeks.

TIVICAY® is a trademark of the GlaxoSmithKline group of companies.

Detailed description:

Arms:
arm 1: Eligible subjects will be randomized in sequence A/B in Part 1 and will receive A: conventional 10 mg DTG tablet (5 tablets) in Period 1 and B: conventional 50 mg DTG tablet in Period 2, administered directly to mouth. arm 2: Eligible subjects will be randomized in sequence B/A in Part 1 and will receive B: conventional 50 mg DTG tablet in Period 1 and A: conventional 10 mg DTG tablet (5 tablets) in Period 2, administered directly to mouth. arm 3: Eligible subjects will be randomized in sequence C/D/E in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3. arm 4: Eligible subjects will be randomized in sequence D/E/C in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3. arm 5: Eligible subjects will be randomized in sequence E/C/D in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3. arm 6: Eligible subjects will be randomized in sequence C/E/D in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3. arm 7: Eligible subjects will be randomized in sequence D/C/E in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3. arm 8: Eligible subjects will be randomized in sequence E/D/C in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3.

Interventions: intervention 1: Conventional dolutegravir 10 mg tablet intervention 2: Conventional dolutegravir 50 mg tablet intervention 3: Dispersible dolutegravir 5 mg tablet intervention 4: Conventional dolutegravir 25 mg tablet
Intervention descriptions: intervention 1: Single dose of five 10 mg DTG tablets will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet. intervention 2: Single dose of one 50 mg tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet. intervention 3: Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet. intervention 4: Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A 2-Part, Phase I, Single Dose, Crossover Relative Bioavailability Study 
of Both TIVICAY 10 mg Conventional Tablets and 5 mg Dispersible Tablets Compared 
to Conventional TIVICAY Tablets in Healthy Adult Subjects
Protocol Number: 205893
Short Title: Relative Bioavailability Study of Pediatric Formulations in Healthy Adult 
Subjects
Compound Number:
GSK1349572
Sponsor Name and Legal Registered Address: 
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study.
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information
 M.D.
Five Moore Drive
P.O. 13398
Research Triangle Park, NC
27709-3398, USA
SAE email: 
 and 
Back-up Medical Monitor
 M.D.
1250 South Collegeville Road
Collegeville, PA 19426
Regulatory Agency Identifying Number(s): 75,382
Approval Date:  23-FEB-2017
Copyright 2017 the ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
Screening Assessments .............................................................................11
2.2.
Time and Events Table...............................................................................12
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................15
3.3.3.
Overall Benefit:Risk Conclusion...................................................15
4.
OBJECTIVES AND ENDPOINTS...........................................................................16
5.
STUDY DESIGN ....................................................................................................17
5.1.
Overall Design ............................................................................................17
5.2.
Treatment Groups and Duration .................................................................17
5.3.
Number of Participants ...............................................................................18
5.4.
Participant and Study Completion...............................................................19
5.5.
Scientific Rationale for Study Design ..........................................................19
5.6.
Dose Justification........................................................................................19
6.
STUDY POPULATION...........................................................................................20
6.1.
Inclusion Criteria.........................................................................................20
6.2.
Exclusion Criteria........................................................................................21
6.3.
Lifestyle Restrictions...................................................................................23
6.3.1.
Meals and Dietary Restrictions ....................................................23
6.3.2.
Fasting Conditions.......................................................................23
6.3.3.
Fed Conditions ............................................................................23
6.3.4.
Caffeine, Alcohol, and Tobacco ...................................................23
6.3.5.
Activity .........................................................................................23
6.4.
Screen Failures...........................................................................................23
7.
TREATMENTS.......................................................................................................24
7.1.
Treatments Administered............................................................................24
7.1.1.
Dosing Dispersible Tablets in Treatment C..................................25
7.2.
Blinding.......................................................................................................25
7.3.
Preparation/Handling/Storage/Accountability..............................................26
7.4.
Treatment Compliance................................................................................26
7.5.
Concomitant Therapy..................................................................................26
7.6.
Treatment at the End of the Study ..............................................................27
8.
DISCONTINUATION CRITERIA.............................................................................27
8.1.
Discontinuation of Study Treatment ............................................................27
8.1.1.
Liver Chemistry Stopping Criteria ................................................27
8.1.2.
QTc Stopping Criteria ..................................................................28
8.2.
Withdrawal from the Study..........................................................................29


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8.3.
Lost to Follow Up........................................................................................29
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30
9.1.
Adverse Events...........................................................................................31
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................31
9.1.2.
Method of Detecting AEs and SAEs.............................................31
9.1.3.
Follow-up of AEs and SAEs.........................................................32
9.1.4.
Regulatory Reporting Requirements for SAEs .............................32
9.1.5.
Pregnancy ...................................................................................32
9.2.
Treatment of Overdose...............................................................................32
9.3.
Safety Assessments ...................................................................................33
9.3.1.
Physical Examinations.................................................................33
9.3.2.
Vital Signs....................................................................................33
9.3.3.
Electrocardiograms......................................................................33
9.3.4.
Clinical Safety Laboratory Assessments ......................................33
9.4.
Pharmacokinetics .......................................................................................35
9.4.1.
Blood Sample Collection..............................................................35
9.4.2.
Sample Analysis ..........................................................................35
9.5.
Formulation Palatability Assessment ..........................................................35
10. STATISTICAL CONSIDERATIONS........................................................................35
10.1.
Hypotheses.................................................................................................35
10.2.
Sample Size Considerations.......................................................................36
10.2.1.
Sample Size Assumptions ...........................................................36
10.2.2.
Sample Size Sensitivity................................................................36
10.2.3.
Sample Size Re-estimation..........................................................36
10.2.4.
Analysis Populations....................................................................36
10.2.5.
Interim Analyses ..........................................................................37
10.3.
Key Elements of Analysis Plan ...................................................................37
10.3.1.
Primary Analyses.........................................................................37
10.3.1.1.
Pharmacokinetic Analyses..........................................37
10.3.1.2.
Safety Analyses..........................................................38
10.3.2.
Palatability Questionnaire ............................................................38
11. REFERENCES.......................................................................................................39
12. APPENDICES........................................................................................................40
12.1.
Appendix 1: Abbreviations and Trademarks................................................40
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................42
12.3.
Appendix 3: Study Governance Considerations..........................................44
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................48
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................53
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............53
12.5.2.
Collection of Pregnancy Information ............................................53
12.5.3.
Appendix 5 References................................................................54
12.6.
Appendix 6 - Division of AIDS Table For Grading The Severity Of 
Adult And Paediatric Averse Events Version 2.0, November 2014..............55


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12.7.
Appendix 7: Toxicity Management .............................................................74
12.7.1.
ANEMIA.......................................................................................74
12.7.2.
TOTAL BILIRUBIN ELEVATION..................................................75
12.7.3.
AST AND ALT ELEVATION.........................................................75
12.7.4.
RASH ..........................................................................................75
12.7.5.
ALLERGIC REACTION................................................................77
12.7.6.
CREATINE PHOSPHATE (CPK) ELEVATION ............................78
12.8.
Appendix 8: Palatability Questionnaire........................................................79


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1.
SYNOPSIS
Protocol Title: A 2-Part, Phase I, Single Dose, Crossover Relative Bioavailability Study 
of Both TIVICAY 10 mg Conventional Tablets and 5 mg Dispersible Tablets Compared 
to Conventional TIVICAY Tablets in Fasted Healthy Adult Subjects
Short Title: Pediatric Relative Bioavailability Study in Healthy Adult Subjects
Rationale
TIVICAY (dolutegravir [DTG], GSK1349572) 50mg conventional tablet is for the 
treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents. 
Recently two lower pediatric strength conventional tablets (10mg and 25mg) were 
approved in the United States (US) and received a positive opinion in the European 
Union (EU).  A dispersible tablet formulation (5 milligram [mg] tablet for oral 
suspension) of TIVICAY has been developed for administration in younger pediatric
populations. This study will be conducted in 2 separate parts with separate groups of 
fasted healthy adult subjects to investigate both 10 mg conventional tablets (Part 1) and 5 
mg dispersible tablets (Part 2).  Part 1 of the study will compare the relative 
bioavailability (BA) of five 10 mg conventional tablets (test) to that of one 50-mg 
conventional tablet (reference) in one group of subjects.  Part 2, will be a 
pharmacokinetic (PK) evaluation of 5 mg DTG dispersible tablets compared to the 
conventional 25 mg tablet of TIVICAY taken with water. The randomized cross-over 
treatments in Part 2 are:  1) 5 mg dispersible DTG tablet (5 tablets) administered as a 
dispersion and immediately taken (test 1), 2) 5 mg dispersible DTG tablet (5 tablets) 
administered as direct to mouth (test 2), and 3) the conventional 25-mg DTG tablet 
administered as direct to mouth (reference).
Objectives and Endpoints
Part 1
Objective
Endpoint
Primary
To evaluate the relative BA of DTG conventional 10 mg 
tablets (5 tablets) administered direct to mouth as 
compared to a conventional 50 mg tablet (reference) 
administered direct to mouth.
Plasma DTG AUC(0-∞), AUC(0-t), and Cmax
Secondary
To compare the single dose PK of DTG conventional 
10 mg tablets (5 tablets) administered direct to mouth 
as compared to a conventional 50 mg tablet (reference) 
administered direct to mouth.
To evaluate the safety and tolerability of DTG 
conventional 10 mg (5 tablets) administered direct to 
mouth as compared to the administration of a 
conventional 50 mg tablet (reference) administered 
direct to mouth.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), CL/F 
and Vz/F, Ct, and C24
Safety and tolerability parameters as assessed by 
change from baseline in number of subjects with 
adverse events and toxicity grading of clinical 
laboratory tests


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Part 2
Primary
To evaluate the relative BA of DTG dispersible 5 mg 
tablets (5 tablets) administered as “disperse and 
immediately take” and of DTG dispersible 5 mg tablets (5 
tablets) administered direct to mouth as compared to a 
conventional 25 mg tablet (reference) administered direct 
to mouth. 
Plasma DTG AUC(0-∞), AUC(0-t), and Cmax
Secondary
To compare the single dose PK of DTG dispersible 5 
mg tablets (5 tablets) administered as “disperse and 
immediately take” and of DTG dispersible 5-mg tablets 
(5 tablets) administered direct to mouth as compared to 
a conventional 25 mg tablet (reference) administered 
direct to mouth.
To evaluate the safety and tolerability of DTG 
dispersible 5-mg tablets (5 tablets) administered as 
“disperse and immediately take” and of DTG dispersible 
5-mg tablets (5 tablets) administered direct to mouth as 
compared to a conventional 25 mg tablet (reference) 
administered direct to mouth.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), CL/F 
and Vz/F, Ct, and C24
Safety and tolerability parameters as assessed by 
change from baseline in number of subjects with 
adverse events and toxicity grading of clinical 
laboratory tests
Exploratory
To evaluate the palatability of the dispersible tablets.  
Palatability Questionnaire
Study Design
This study will be conducted as a 2-part, open-label, randomized, cross-over design with 
one group of subjects in Part 1 of the study randomized to receive each of 2 study 
treatments (A and B) over 2 dosing periods, and another group of subjects in Part 2 of the 
study randomized to receive each of 3 study treatments (C, D, and E) over 3 dosing 
periods.  Subjects will participate in only one part of the study.  Parts 1 and 2 of the study 
may be conducted concurrently.  There will be a washout of at least 7 (-4 hours) days 
between doses of study medication.
Study Design – Part 1 of the Study
Screening 
(≤30 days)
Treatment Period 1
Treatment A: 
or
Treatment B:  
Washout of 7 days
Treatment Period 2
Treatment A: 
or
Treatment B: 
Follow-up (7-10 
days post last 
dose)


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Study Design – Part 2 of the Study
Treatment Period 1
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Treatment Period 2
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Treatment Period 3 
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Screening 
(≤30 days)
Washout of 7 days
Washout of 7 days
Follow-up (7-10 
days post last 
dose)
Treatment Groups and Duration
The study treatments to be administered in Part 1 of the study are:

Treatment A:  Conventional 10 mg DTG tablet (5 tablets, test) administered direct to 
mouth.

Treatment B:  Conventional 50 mg DTG tablet (reference) administered direct to 
mouth
Part 1 – Two-Period Crossover
Sequence (Total N=14)
Period 1
Period 2
1 (n=7)
A
B
2 (n=7)
B
A
The study treatments to be administered in Part 2 of the study are:

Treatment C:  5 mg dispersible DTG tablet (5 tablets) administered as a dispersion 
and immediately taken (test 1).

Treatment D:  5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth
(test 2).

Treatment E:  Conventional 25 mg DTG tablet administered as direct to mouth
(reference).
Part 2 – Three-Period Crossover
Sequence (Total N=24)
Period 1
Period 2
Period 3
1 (n=4)
C
D
E
2 (n=4)
D
E
C
3 (n=4)
E
C
D
4 (n=4)
C
E
D
5 (n=4)
D
C
E
6 (n=4)
E
D
C
The total duration of participation for a subject participating in Part 1 of the study will be 
approximately 7 to 8 weeks, and for a subject participating in Part 2 of the study, the total 
duration will be 8 to 9 weeks.


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Each participant will have a screening visit within 30 days prior to the first dose of study 
drug, two treatment periods each for a subject participating in Part 1 of the study and 
three treatment periods each for a subject participating in Part 2 of the study, with a 
single dose of study drug per treatment period and a follow-up visit within 7-10 days 
after the last dose of study drug.  At Follow-up, male subjects with no ongoing adverse 
events (AEs) or Vital Sign/Laboratory measures of clinical concern may be followed 
virtually by the site via telephone contact.
To ensure adequate washout, there will be at least 7 days between dosing periods, with an 
allowance window of 4 hrs (i.e., 7 days minus 4 hrs) to allow for flexibility in scheduling 
subjects to dose at the clinic.
PK samples will be collected for 72 hrs after each dose of study drug.
Number of Participants
Approximately 14 subjects (to achieve 12 completed subjects) will participate in Part 1 of 
the study, and approximately 24 subjects (to achieve 18 evaluable subjects) will 
participate in Part 2 of the study.  A subject will participate in only one part of the study.  
If participants prematurely discontinue the study for reasons other than AE, additional 
replacement participants may be assigned to the same treatment group sequence at the
discretion of the Sponsor in consultation with the investigator.
Analysis
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GSK or their designee.  Plasma DTG 
concentration-time data will be analyzed by non-compartmental methods with Phoenix 
WinNonlin.  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:  AUC(0-), area under the plasma concentration-time curve 
from time of dose to last measurable concentration (AUC(0-t)), area under the plasma 
concentration-time curve from time of dose to 24 hr (AUC0-24), maximum observed 
concentration (Cmax), plasma DTG lag time for absorption (tlag), time of occurrence of 
Cmax (tmax), t, terminal elimination phase half-life (t1/2), terminal rate constant (z), 
%AUCex, apparent oral clearance (CL/F) and apparent volume of distribution during
terminal phase (Vz/F), Ct, and concentration at 24 hours after dose administration (C24).
Pharmacokinetic data 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 
Research and Development (R&D) or their designee. 
The PK parameters (except for tmax and tlag) for DTG will be loge-transformed and 
separately analyzed using a mixed effects model with fixed effect terms for period and 
treatment for each treatment comparison.  Subject will be 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 


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estimates and 90% CIs for the ratios of PK parameters between test and reference 
treatments.
Safety data 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 will be summarized descriptively.


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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening Assessments
Screening procedures (Table 1) 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.
Table 1
Screening Assessments
Event
Notes
Informed Consent
Demographics
Medical history (includes substance usage )
Inclusion/Exclusion
HIV, Hep B and Hep C screen
Drug/alcohol screen
Brief Physical Exam
Height, Weight & BMI 
Vital Signs
12-lead ECG (single)
FSH and estradiol (women)
Pregnancy test (serum)
For Women of Child Bearing Potential (WCBP) only
Clinical Laboratory Tests (Chemistry, hematology, & 
urinalysis)
For Clinical laboratory Tests, see Section 9.3.4


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2.2.
Time and Events Table
Table 2
Treatment Period Time and Events
Assessments
All Study Periods (Parts 1 and 2)
Follow-up
Notes
Day -1 of Periods 2 -3 may be the same day as Day 6 
of prior periods
At Follow-up – Male subjects with no ongoing AEs or 
Vital Sign/Laboratory measures of clinical concern may 
be followed virtually by the site via telephone contact.
Day -1
Day 1
Day 2
Day 3
Day 4
Pre-dose
0 hr
Post Dose
24 hr
48 hr
72 hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
Follow-up visit will occur 7 to 10 days post last dose.
12-lead ECG (single)
X
Vital signs
X
X
X
X
X
Single vital sign measurements performed at all time points.
Brief Physical Exam
X
Drug/Alcohol/Cotinine/pregnancy will be performed per 
the standard practice of the site.
Clinical laboratory tests – see Table 5, Section 9.3.4.
*Clinical laboratory tests at follow-up are only necessary if 
subject had a previous abnormal lab value
Urine Drug/Alcohol/Cotinine
X
Pregnancy test (urine; WCBP)
X
X
Clinical laboratory tests 
X
X
X*
Dosing
X
See Section 7.1
Palatability Assessment
Start within 10 
min after dose
Complete for each dispersion treatment C (see Section 
12.8, Appendix 8)
PK Sampling
X
Collect at: 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 
16, 24, 48 and 72 hrs post-dose.
Pre-dose (within 15 minutes prior to dosing), Section 9.4
Meals
Fasted from 10 hrs prior to 
dosing to 4 hrs post-dose
Standard for the study center
See also Section 6.3.2 and Section 6.3.3
Adverse Events / SAE
X
======================X======================
X
Concomitant medications
X
======================X======================
X


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3.
INTRODUCTION
3.1.
Study Rationale
TIVICAY (dolutegravir [DTG], GSK1349572) 50mg conventional tablet is for the 
treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents. 
Recently two lower pediatric strength conventional tablets (10mg and 25mg) were 
approved in the United States (US) and received a positive opinion in the European 
Union (EU).  A dispersible tablet formulation (5 milligrams [mg] tablet for oral 
suspension) of TIVICAY has been developed for administration in younger pediatric
populations. This study will be conducted in 2 separate parts with separate groups of 
fasted healthy adult subjects to investigate both 10 mg conventional tablets (Part 1) and 5 
mg dispersible tablets (Part 2).  Part 1 of the study will compare the relative 
bioavailability (BA) of five 10 mg conventional tablets (test) to that of one 50-mg 
conventional tablet (reference) in one group of subjects.  Part 2, will be a 
pharmacokinetic (PK) evaluation of 5 mg DTG dispersible tablets compared to the 
conventional 25 mg tablet of TIVICAY taken with water. The randomized cross-over 
treatments in Part 2 are:  1) 5 mg dispersible DTG tablet (5 tablets) administered as a 
dispersion and immediately taken (test 1), 2) 5 mg dispersible DTG tablet (5 tablets) 
administered as direct to mouth (test 2), and 3) the conventional 25-mg DTG tablet 
administered as direct to mouth (reference).
3.2.
Background
TIVICAY (DTG) as a single drug entity was first approved in the US in August 2013 and 
is currently approved globally in more than 100 countries.  TIVICAY is a next generation 
integrase inhibitor with low to moderate inter-subject PK variability, a predictable 
exposure-response relationship, and a 14-hour plasma half-life that supports once-daily 
dosing without the need for the PK boosters. 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.  
Alternate formulations and dosing strategies (e.g., pediatric granules and dispersible 
tablets) are being developed for pediatric patients less than 12 years old who may have 
difficulty swallowing conventional tablet formulations.  Since the solubility of DTG is 
reduced when co-administered with divalent cation-containing products, the relative BA 
of DTG in dispersible tablets dispersed in either High Mineral Content (Contrex brand 
mineral water; contains high levels of calcium and magnesium) or Low Mineral Content 
Water (10% Contrex/90% Purified water) has been evaluated previously.  Mineral 
content had no effect on the relative bioavailability of dispersed tablets (Clinical 
Investigator's Brochure [GlaxoSmithKline Document Number RM2007/00683/10]).
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of DTG may be found in the Investigator’s Brochure.


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3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategya
Refer to Investigator Brochure (IB) for additional 
information
Hypersensitivity reaction 
(HSR) and rash
HSR has been observed uncommonly with DTG.  Rash 
was commonly reported in DTG Phase IIb/III clinical 
trials; episodes were generally mild to moderate in 
intensity; no episodes of severe rash, such as Stevens-
Johnson Syndrome (SJS), Toxic Epidermal Necrolysis 
(TEN) and erythema multiforme were reported.

Subjects with history of allergy/sensitivity to any of the study drugs are excluded 
(Section 6.2)

Specific/detailed toxicity management guidance is provided for HSR and rash 
(Section 12.7).

For Grade 3/4 rash, subjects must permanently discontinue study drug and be 
withdrawn from the study (Section 12.7.4)

The subject informed consent form includes information on this risk and the actions 
subjects should take in the event of an HSR or associated signs and symptoms. 
Drug induced liver injury 
(DILI) and other clinically 
significant liver chemistry 
elevations
Non-clinical data suggested a possible, albeit low, risk 
for hepatobiliary toxicity with DTG.  Drug-related hepatitis 
is considered an uncommon risk for antiretroviral therapy 
(ART) containing DTG regardless of dose or treatment 
population.  For subjects with hepatitis B virus (HBV) 
and/or hepatitis C virus (HCV) co-infection, 
improvements in immunosuppression as a result of HIV 
virologic and immunologic responses to DTG- containing 
ART, along with inadequate therapy for HBV co-infected 
subjects, likely contributed to significant elevations in 
liver chemistries.
Subjects meeting either of the following criteria during the screening period are excluded 
(Section 6.2).

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).

Alanine Aminotransferase (ALT) or bilirubin >1.5x upper limit of normal (ULN).

Subjects positive for HBV (hepatitis B virus surface antigen positive [+HBsAg] or
positive hepatitis B core antibody with a negative HBsAg), or HCV (positive hepatitis 
C antibody test) within 3 months of the Day 1 study visit.
Specific/detailed liver stopping criteria and toxicity management guidance is provided for 
suspected DILI or other clinically significant liver chemistry elevations (Section 12.2).
Renal functionb
Mild elevations of creatinine have been observed with 
DTG which are related to a likely benign effect on 
creatinine secretion with blockade of organic cation 
transporter 2 (OCT-2).  DTG has been shown to have no 
significant effect on glomerular filtration rate or effective 
renal plasma flow.
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 for this protocol in this respect of 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 subjects who develop 
Grade 3 to 4 CPK elevations (Section 12.7.6).
a.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). 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.
b.  Increases in creatinine of ~0.1 to 0.15mg/dL are expected and will reverse.


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3.3.2.
Benefit Assessment
This is a study in healthy subjects and as such there is no expected benefit to
administration of TIVICAY. Participation in this study may contribute to the process of 
developing new therapies for HIV. There may be benefit to individual subjects from the 
medical evaluations and assessments that could identify conditions that the subject was 
previously unaware of.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with TIVICAY are low.


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4.
OBJECTIVES AND ENDPOINTS
Part 1
Objective
Endpoint
Primary
To evaluate the relative BA of DTG conventional 10 mg 
tablets (5 tablets) administered direct to mouth as 
compared to a conventional 50 mg tablet (reference) 
administered direct to mouth.
Plasma DTG AUC(0-∞), AUC(0-t), and Cmax
Secondary
To compare the single dose PK of DTG conventional 
10 mg tablets (5 tablets) administered direct to mouth 
as compared to a conventional 50 mg tablet (reference) 
administered direct to mouth.
To evaluate the safety and tolerability of DTG 
conventional 10 mg (5 tablets) administered direct to 
mouth as compared to the administration of a 
conventional 50 mg tablet (reference) administered 
direct to mouth.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), CL/F 
and Vz/F, Ct, and C24
Safety and tolerability parameters as assessed by 
change from baseline in number of subjects with 
adverse events and toxicity grading of clinical 
laboratory tests
Part 2
Primary
To evaluate the relative BA of DTG dispersible 5 mg 
tablets (5 tablets) administered as “disperse and 
immediately take” and of DTG dispersible 5 mg tablets (5 
tablets) administered direct to mouth as compared to a 
conventional 25 mg tablet (reference) administered direct 
to mouth. 
Plasma DTG AUC(0-∞), AUC(0-t), and Cmax
Secondary
To compare the single dose PK of DTG dispersible 5 
mg tablets (5 tablets) administered as “disperse and 
immediately take” and of DTG dispersible 5-mg tablets 
(5 tablets) administered direct to mouth as compared to 
a conventional 25 mg tablet (reference) administered 
direct to mouth.
To evaluate the safety and tolerability of DTG 
dispersible 5-mg tablets (5 tablets) administered as 
“disperse and immediately take” and of DTG dispersible 
5-mg tablets (5 tablets) administered direct to mouth as 
compared to a conventional 25 mg tablet (reference) 
administered direct to mouth.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), CL/F 
and Vz/F, Ct, and C24
Safety and tolerability parameters as assessed by 
change from baseline in number of subjects with 
adverse events and toxicity grading of clinical 
laboratory tests
Exploratory
To evaluate the palatability of the dispersible tablets.  
Palatability Questionnaire


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5.
STUDY DESIGN
5.1.
Overall Design
This study will be conducted as a 2-part, open-label, randomized, cross-over design with
one group of subjects in Part 1 of the study randomized to receive each of 2 study 
treatments (A and B) over 2 dosing periods (see Figure 1), and another group of subjects 
in Part 2 of the study randomized to receive each of 3 study treatments (C, D, and E) over 
3 dosing periods (see Figure 2).  Subjects will participate in only one part of the study.  
Parts 1 and 2 of the study may be conducted concurrently.  There will be a washout of at 
least 7 (-4 hours) days between doses of study medication.
Note:  The -4 hours is an allowed tolerance window to the 7 day washout and is to allow 
the study site and subjects flexibility in scheduling admission and dosing for subsequent 
treatment periods (i.e., treatment periods 2 and/or 3).
Figure 1
Study Design – Part 1 of the Study
Screening 
(≤30 days)
Treatment Period 1
Treatment A: 
or
Treatment B:  
Washout of 7 days
Treatment Period 2
Treatment A: 
or
Treatment B: 
Follow-up (7-10 
days post last 
dose)
Figure 2
Study Design – Part 2 of the Study
Treatment Period 1
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Treatment Period 2
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Treatment Period 3 
Treatment C: 
or
Treatment D: 
or
Treatment E: 
Screening 
(≤30 days)
Washout of 7 days
Washout of 7 days
Follow-up (7-10 
days post last 
dose)
5.2.
Treatment Groups and Duration
The study treatments to be administered in Part 1 of the study are:

Treatment A:  Conventional 10-mg DTG tablet (5 tablets, test) administered direct to 
mouth.

Treatment B:  Conventional 50-mg DTG tablet (reference) administered direct to 
mouth.


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Table 3
Part 1 – Two-Period Crossover
Sequence (Total N=14)
Period 1
Period 2
1 (n=7)
A
B
2 (n=7)
B
A
The study treatments to be administered in Part 2 of the study are:

Treatment C:  5-mg dispersible DTG tablet (5 tablets) administered as a dispersion
and immediately taken (test 1).

Treatment D:  5-mg dispersible DTG tablet (5 tablets) administered as direct to mouth
(test 2).

Treatment E:  Conventional 25-mg DTG tablet administered as direct to mouth
(reference).
Table 4
Part 2 – Three-Period Crossover
Sequence (Total N=24)
Period 1
Period 2
Period 3
1 (n=4)
C
D
E
2 (n=4)
D
E
C
3 (n=4)
E
C
D
4 (n=4)
C
E
D
5 (n=4)
D
C
E
6 (n=4)
E
D
C
The total duration of participation for a subject participating in Part 1 of the study will be 
approximately 7 to 8 weeks, and for a subject participating in Part 2 of the study, the total 
duration will be 8 to 9 weeks.
Each participant will have a screening visit within 30 days prior to the first dose of study 
drug, two treatment periods each for a subject participating in Part 1 of the study and 
three treatment periods each for a subject participating in Part 2 of the study, with a 
single dose of study drug per treatment period and a follow-up visit within 7-10 days 
after the last dose of study drug.  At Follow-up, male subjects with no ongoing adverse 
events (AEs) or Vital Sign/Laboratory measures of clinical concern may be followed 
virtually by the site via telephone contact.
To ensure adequate washout, there will be at least 7 days between dosing periods, with an 
allowance window of 4 hrs (i.e., 7 days minus 4 hrs) to allow for flexibility in scheduling 
subjects to dose at the clinic.
PK samples will be collected for 72 hrs after each dose of study drug.
5.3.
Number of Participants
Approximately 14 healthy subjects (to achieve 12 completed subjects) will participate in 
Part 1 of the study, and approximately 24 subjects (to achieve 18 evaluable subjects) will 
participate in Part 2 of the study.  A subject will participate in only one part of the study.  
If participants prematurely discontinue the study for reasons other than AE, additional 


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replacement participants may be assigned to the same treatment group sequence at the
discretion of the Sponsor in consultation with the investigator.
5.4.
Participant and Study Completion
A completed subject 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 subject’s last visit.
5.5.
Scientific Rationale for Study Design
This open-label, randomized, cross-over design is well-established for the evaluation of 
relative bioavailability of different oral dosage forms.  Randomization of the 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 bioavailability comparisons.  
The study is subject 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.
5.6.
Dose Justification
The US Food and Drug Administration (FDA)-approved dose of DTG for treatment-
naive HIV-infected adult and pediatric patients 12 years and older (and 40 kilogram 
[kg]) is 50 mg once daily.  The adult dose is given as 1x50 mg tablet once daily.
Part 1 of the study will compare relative BA of five 10-mg conventional tablets (test) to 
that of one 50-mg conventional tablet (reference). For part 1, the approved adult dose of 
50 mg DTG conventional tablet is used as a reference to benchmark exposures with
paediatric formulations to what is safe and effective in adults. 
Part 2 of the study will compare relative BA of five 5 mg dispersible tablets administered 
as “disperse and immediately take” and of dispersible 5 mg tablets to be administered as 
“direct to mouth” to that of a single 25 mg conventional tablet (reference) administered 
direct to mouth.  The 25 mg dose of DTG control dose used in Part 2 of this study will 
accommodate the relative BA assessment of the two pediatric dosage forms and will 
require a dosing of only five (5) 5 mg tablets, as opposed to 10 tablets that would have 
been necessary if the 50 mg DTG control dose would have been chosen for evaluation in 
Part 2 of the study. With respect to reference dose in Part 2 of this study, the 25 mg tablet 
is quantitatively proportional to the 50 mg tablet and hence two 25mg tablets are 
equivalent to 50 mg tablet.  However, the 25 mg tablet was chosen as a comparator for 
this part so as to decrease the burden on the subjects to consume 10 x 5 mg tablets 
directly to mouth as well as to minimize any associated variability.


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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.  
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare investigational product or other 
study treatment that may impact subject eligibility is provided in the Investigator’s 
Brochure (see GlaxoSmithKline Document Number RM2007/00683/10).
6.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare investigational product or other 
study treatment that may impact subject eligibility is provided in the Investigator’s 
Brochure [GlaxoSmithKline Document Number RM2007/00683/10]. 
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 SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
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 electrocardiogram [ECG]).
A subject 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 procedures. 
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
a.
Non-reproductive potential defined as:


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Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) 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 Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 5 [Section 12.5]) 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.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
5. Capable of giving signed informed consent as described in Section 12.3, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QT DURATION CORRECTED FOR HEART RATE [QTc]
INTERVAL) 
1. ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN 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). 
3. QT correction using Fridericia Formula (QTcF) >450 Milliseconds (msec)
NOTES:

The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), machine-read or manually over-read.


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
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.
For purposes of data analysis, QTcF, will be used as specified in the Reporting 
and Analysis Plan (RAP).
CONCOMITANT MEDICATIONS
4. Unable to refrain from the use of prescription (i.e., 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 Medical Monitor the medication will not interfere with 
the study procedures or compromise subject 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 milliliters [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.
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.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
8. Creatinine clearance (CrCL) <90 mL/min
9. A positive hepatitis B surface antigen (HBsAg) or a positive hepatitis B core antibody 
with a negative hepatitis B surface antibody, positive hepatitis C antibody test result 
at screening or within 3 months prior to first dose of study treatment.
10. A positive pre-study drug/alcohol screen.
11. A positive test for HIV antibody.
12. Where participation in the study would result in donation of blood or blood product in 
excess of 500 mL within 56 days.
13. The subject has participated in a clinical trial and has received an investigational 
product 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 
investigational product (whichever is longer).
14. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.


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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
[and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days prior 
to the first dose of study medication until after the final dose.
Once in the clinical unit, subjects will not be allowed to eat anything other than the food 
provided by the study center.
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).

Subjects must then fast from all food and drink (except water) for 10 hrs pre-dose and 
prior to any clinical laboratory evaluations (except repeat evaluations).

Water is permitted with dosing (200-250 mL) for all Treatments except Treatment C 
and at all times except 1 hour (hr) pre-dose through 2-hrs post-dose. 

No food is allowed for at least 4 hrs post-dose.
6.3.3.
Fed Conditions
With the exception of the time period outlined for fasting conditions, subjects will receive 
all other meals as defined as standard for the study center.
6.3.4.
Caffeine, Alcohol, and Tobacco
During each treatment period, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 hrs prior to the 
start of dosing until collection of the final PK and or pharmacodynamic sample during 
each session. 
During each dosing session, subjects will abstain from alcohol for 24 hrs prior to the start 
of dosing until collection of the final pharmacokinetic and or pharmacodynamic sample 
during each session. 
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
Subjects will abstain from strenuous exercise for 48 hrs prior to each blood collection for 
clinical laboratory tests.  Subjects 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 randomized/entered in the study. A minimal set of screen failure 


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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 serious adverse 
events (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.
7.1.
Treatments Administered
Subjects in Part 1 of the study will be randomized to one of the 2 following treatment 
sequences: AB or BA in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated software.  
Subjects in Part 2 of the study will be randomized to one of the 6 following treatment 
sequences:  CDE, DEC, ECD, CED, DCE, or EDC in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated
software. 
Descriptions of the study treatments A and B in Part 1 of the study, and study treatments 
C, D, and E in Part 2 of the study, and the respective treatment sequences are as described 
in Section 5.1 of this protocol.
Study Treatments in Part 1 of the Study
Product name:
TIVICAY (DTG)
TIVICAY (DTG)
Dosage form:
Conventional 10 mg DTG Tablet
Conventional 50 mg DTG Tablet
Unit dose strength(s)/Dosage 
level(s):
Single dose of five (5) 10 mg DTG 
tablets 
Single dose of one (1) 50 mg DTG 
tablet
Route of Administration
Oral
Oral 
Dosing instructions:
Treatment A: Take five (5) 10 mg 
DTG tablets direct to mouth with 240 
mL of water 
Treatment B: Take one (1) 50 mg DTG 
tablet direct to mouth with 240 mL of 
water
Physical description:
DTG (10 mg) tablets – White, round, 
biconvex tablets
DTG (50 mg) tablets – White, round, 
biconvex tablets
Manufacturer:
GlaxoSmithKline
GlaxoSmithKline
Fasting instructions:
Administer in the AM on an empty 
stomach.  Food will be unavailable 
until 4h after dose and water until 2h 
after dose.
Administer in the AM on an empty 
stomach.  Food will be unavailable until 
4h after dose and water until 2h after 
dose.


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Study Treatments in Part 2 of the Study
Product name:
TIVICAY (DTG)
TIVICAY (DTG)
Dosage form:
5 mg Dispersible DTG Tablet
Conventional 25 mg DTG Tablet
Unit dose strength(s)/Dosage 
level(s):
Single dose of five (5) 5 mg DTG 
tablets 
Single dose of one (1) 25 mg DTG 
tablet
Route of Administration
Oral
Oral 
Dosing instructions:
Treatment C: Immediately take five (5) 
5 mg Dispersible DTG tablets 
administered as Dispersed in water
Treatment D:  Take five (5) 5 mg 
Dispersible DTG tablets with 240 mL of 
water direct to mouth
Treatment E: Take one (1) 25 mg DTG 
tablet with 240 mL of water direct to 
mouth
Physical description:
DTG (5 mg) tablets – White, round, 
biconvex tablets
DTG (25 mg) tablets – White, round, 
biconvex tablets
Manufacturer:
GlaxoSmithKline
GlaxoSmithKline
Fasting instructions:
Administer in the AM on an empty 
stomach.  Food will be unavailable 
until 4h after dose and water until 2h 
after dose.
Administer in the AM on an empty 
stomach.  Food will be unavailable until 
4h after dose and water until 2h after 
dose.
7.1.1.
Dosing Dispersible Tablets in Treatment C
Each dispersible tablet for Treatment C contains DTG 5 mg in strength; therefore, 
5 tablets will be needed to achieve the 25 mg total dose.
1. Place 25 mL of purified water in a small beaker / container.  A 100 mL beaker or a 
similar-sized vessel works well.  A 50 mL syringe is appropriate to measure this 
volume.
2. Preparation - Place 5 tablets into the beaker and swirl / stir for 3 – 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 volunteer swallow the dispersion as swiftly as they can, preferably in 1 to
2 swallows. 
4. Rinse the beaker with 25 mL of purified water, a 50 mL syringe is appropriate to 
measure this volume, and have the volunteer swallow this as swiftly as they are able,
preferably in 1 to 2 swallows.
5. Give the volunteer an additional 190 mL of purified water to swallow.
NOTE: The words “immediately dose” in this protocol mean within one minute after 
completion of the 3 minute preparation. 
Anticipate that there will still be a limited amount of insoluble material visible in the 
beaker after the dispersion has been dosed and rinsed; this is normal and will not affect 
the dose delivered.
7.2.
Blinding
This is an open-label study; potential bias will be reduced by a randomization of 
treatments provided to the site pharmacist.


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7.3.
Preparation/Handling/Storage/Accountability
The tablets are packaged into high-density polyethylene (HDPE) bottles.  Each bottle of 
DTG 50 mg, 25 mg, and 10 mg will contain 30 tablets, and each bottle of DTG 5 mg will 
contain 60 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 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 subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled 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 final disposition of unused study treatment are 
provided in the Study Reference Manual.

TIVICAY tablets are to be stored at 15-30C and protected from light.  Maintenance 
of a temperature log (manual or automated) is required.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.4.
Treatment Compliance
When subjects 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 subject 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 subject’s mouth to ensure that the study treatment 
was ingested.
7.5.
Concomitant Therapy
Subjects must abstain from taking any other prescription and 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 until completion of the follow-up visit, 


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unless in the opinion of the Investigator and Medical Monitor the medication will not 
interfere with the study procedures or compromise subject 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.  
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the ViiV Medical Monitor.
7.6.
Treatment at the End of the Study
This is a single dose study, there will be no treatment at the end of the study.
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 subject 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 subject 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 2 (Section 12.2).
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.1.2.
QTc Stopping Criteria
A subject that meets the following bulleted criterion below will be withdrawn from the 
study.  

QTcF >500 msec
NOTES:

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF must 
be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for 
data analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.  


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
The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5-10 minute) 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 or Sponsor for safety, 
behavioral, compliance or administrative reasons.

If after screening, the subject requires concurrent medications that cannot be 
interrupted for 2 weeks prior to administration of investigational product and until 
completion of the study.

Pregnancy

Positive urine drug or alcohol screen.

Any clinically significant AE deemed to require discontinuation of investigational 
product.

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.

Refer to the Table 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. 


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9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in Table 2. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. 
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.
Adherence to the study design requirements, including those specified in Table 2, are
essential and required for study conduct.
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. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of informed consent form (ICF) may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria 
and was performed within the time frame defined in Table 2.
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: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

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 which is approved by the relevant GSK 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 Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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). 
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in Table 2 (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 electronic case report form (eCRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. 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 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 


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9.1.3.
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 non-serious AEs, 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 4 (Section 12.4).
9.1.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a 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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (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 a SAE or other 
specific safety information, e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure (GlaxoSmithKline 
Document Number RM2007/00683/10) and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.1.5.
Pregnancy
Details of all pregnancies in all female subjects will be collected after the start of dosing 
and until the final post-dose follow-up visit.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Section 12.5.2 of 
Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
In Part 1 of this study, any single dose of DTG >50 mg will be considered an overdose.  
In Part 2 of this study, any single dose of DTG>25 mg will be considered an overdose.
ViiV does not recommend specific treatment for an overdose of DTG. 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


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2. Closely monitor the subject for AEs)/ SAEs and laboratory abnormalities until DTG 
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.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in Table 2.
9.3.1.
Physical Examinations

A full physical examination, if needed, will include, at a minimum, assessments of 
the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, 
abdomen (liver and spleen), lymph nodes and extremities. Height and weight will also 
be measured and recorded. 

A brief physical examination 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
9.3.2.
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 (BP) and pulse 
rate.
9.3.3.
Electrocardiograms

12-lead ECGs will be performed with the subject in a supine or semi-supine position 
having rested in this position for at least 5 minutes beforehand

Single 12-lead ECGs will be obtained at screening and on Day -1 as indicated in the 
Time and Events Table using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTcF intervals.  If a subject experiences a 
QTcF >500 msec, refer to Section 8.1.2 for QTcF withdrawal criteria and repeat 2 
ECG recordings over a brief (e.g., 5-10 minute) period (i.e., additional QTcF readings
that may be necessary).
9.3.4.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 5, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule in the 
SoA for the timing and frequency. Laboratory requisition forms must be completed and 
samples must be clearly labelled with the subject number, protocol number, site/centre 
number, and visit date. Reference ranges for all safety parameters will be provided to the 
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If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the Study Reference Manual (SRM)/BioPacket for appropriate processing and 
handling of samples to avoid duplicate and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 5.
Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices
White blood cell (WBC) count with 
Differential:
Hematocrit
Mean corpuscular 
hemoglobin (MCH)
Mean corpuscular 
volume (MCV)
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Red blood cell Count (RBC) 
WBC Count (absolute)
Clinical 
Chemistrya
Blood urea nitrogen 
(BUN)
Potassium
AST (serum glutamic 
oxaloacetic 
transaminase [SGOT])
Total and direct bilirubin
Creatinine 
Sodium
ALT (serum glutamic 
pyruvic transaminase 
[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 
and/or Additional 
Tests (see
Section 2 for 
timing of these 
Assessments)

HIV

Hepatitis B (HBsAg)

Hepatitis B core antibody 

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing potential only)

Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines)b

Cotinine

Creatinine clearance (CrCL) for glomerular filtration rate (GFR) estimation 

Serum or urine human chorionic gonadotropin hCG Pregnancy test (as needed for women 
of child bearing potential)b

The results of each test must be entered into the eCRF.
NOTES :
a 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 and Section 12.2.
b  Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.


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All laboratory tests with values that are 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 (at the discretion of the 
Investigator and Medical Monitor).  If such values do not return to normal within a period 
judged reasonable by the investigator, the etiology should be identified and the Sponsor 
notified.
9.4.
Pharmacokinetics
9.4.1.
Blood Sample Collection
Blood samples for PK analysis of DTG will be collected at the time points indicated in
the Time and Events Table.  The actual date and time of each blood sample collection 
will be recorded.  Blood specimens (2 mL) will be collected into K2
ethylenediaminetetraacetic acid (EDTA) tubes. 
Details of PK blood sample collection, Windows of Allowance, processing, storage and 
shipping procedures are provided in the site provided SRM/BioPacket.
9.4.2.
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 Study Reference 
Manual (BioPacket). Concentrations of DTG will be determined in plasma samples 
using the currently approved bioanalytical methodology. Raw data will be archived at 
the bioanalytical site (detailed in the SRM/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, GlaxoSmithKline protocol.
9.5.
Formulation Palatability Assessment
A palatability questionnaire will be administered to each subject in Treatment Arm C
within 10 minutes following dosing of dispersion treatments only, see Appendix 8
(Section 12.8).  Subjects will be given the questionnaire to read prior to receiving each 
unique dispersion dose.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
This study is designed to estimate the relative bioavailability of each test treatment to the 
reference treatment (A vs. B; C vs. E and D vs. E) in both study parts in the fasted state.
No formal hypothesis will be tested. For each pharmacokinetic endpoint (except for time 
of occurrence of Cmax [tmax] and tlag), point estimates and corresponding 90% confidence 
intervals 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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10.2.
Sample Size Considerations
10.2.1.
Sample Size Assumptions
Based on the results from a previous PK study of dolutegravir granules administered to 
healthy volunteers, [GlaxoSmithKline Document Number 2011N124158_00], the within-
subject variability (CVw%) of dolutegravir area under the plasma concentration-time 
curve from time of dose extrapolated to infinity(AUC(0-)) and maximum observed 
concentration (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 Part 1, with a sample size of 12 evaluable subjects (6 subjects/sequence), it is 
estimated that the precision (i.e. half-width of the 90% confidence interval (CI) on the 
ratio scale) for the test: reference comparison will be within 13% 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% confidence interval (CI) will be approximately (0.89, 1.13).
For Part 2, with a sample size of 18 subjects (at least 3 subjects/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 10% 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 
(0.91, 1.10).
10.2.2.
Sample Size Sensitivity
For the sensitivity analysis, assuming a higher within-subject variability (24%), a sample 
size of 12 evaluable subjects in Part 1, it is estimated that the half width of the 90% CI for 
the ratio of treatment comparison (test : reference) would be within 19% of the point 
estimate for AUC(0-) and Cmax.  A sample size of 18 evaluable subjects in Part 2, it is 
estimated that the half width of the 90% CI for the ratio of treatment comparison 
(test:reference) would be within 14% of the point estimate for AUC(0-∞) and Cmax. 
10.2.3.
Sample Size Re-estimation
No sample size re-estimation will be performed.
10.2.4.
Analysis Populations
Subjects excluded from any analyses will be fully documented and justified within the 
clinical study report. All analyses will be based on the actual treatment that each subject 
received. Any departures from the planned treatment according to the randomization 
schedule will be documented in the clinical study report.
The following populations will be used for the analysis and reporting of data:


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All Subjects Population
The ‘All Subjects Population’ is defined as all subjects who receive at least one dose of 
study medication. This population will be used for all demographic and safety 
summaries.
Pharmacokinetic (PK) Population
The ‘PK Population' is defined as subjects in the ‘All Subjects’ population for whom a 
PK sample was obtained and 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.
10.2.5.
Interim Analyses
There will be no formal interim analysis.
10.3.
Key Elements of Analysis Plan
Final analyses will be performed after the completion of the study and final database 
authorization.  
Data will be listed and summarized according to GlaxoSmithKline reporting standards 
where applicable. Listings will be sorted by subject, period, day, and time, noting 
treatment. Summaries will be presented by treatment, day and time. 
Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), median, minimum, maximum; whereas, n and percent 
will be used as summary statistics for categorical variable. Geometric mean with 
associated 95% CI, and the between-subject coefficient of variance (CV) (%CVb) for the 
geometric mean will be included for PK variables, where applicable.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified 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.
Version 9.4 or higher of the Statistical Analysis Software (SAS) system will be used to 
analyze data as well as to generate tables, listings, and figures.
10.3.1.
Primary Analyses
10.3.1.1.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GSK or their designee.  Plasma DTG 
concentration-time data will be analyzed by non-compartmental methods with Phoenix 
WinNonlin.  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:  AUC(0-), area under the plasma concentration-time curve 


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from time of dose to last measurable concentration (AUC(0-t)), area under the plasma 
concentration-time curve from time of dose to 24 hr (AUC0-24), Cmax, plasma DTG lag 
time for absorption (tlag), time of occurrence of Cmax (tmax), terminal elimination phase 
half-life (t1/2), terminal rate constant (z), % of AUC(0-∞) that was extrapolated
(%AUCex), apparent oral clearance (CL/F) and apparent volume of distribution during
terminal phase (Vz/F), last quantifiable concentration (Ct), and concentration at 24 hours 
after dose administration (C24).
Pharmacokinetic data 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 
Research and Development (R&D). 
The PK parameters (except for tmax and tlag) for DTG will be loge-transformed and 
separately analyzed using a mixed effects model with fixed effect terms for period and 
treatment for each treatment comparison.  Subject will be 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 between test and reference 
treatments.
Further details will be provided in the Regulatory Analysis Plan (RAP).
10.3.1.2.
Safety Analyses
Safety data 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 and PK data will be provided in the RAP.
10.3.2.
Palatability Questionnaire
Palatability questionnaire variables will be summarized descriptively. Further details will 
be provided in the RAP.


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11.
REFERENCES
GlaxoSmithKline Document Number RM2007/00683/10: GSK1349572 Clinical 
Investigator's Brochure. 10 October 2016
GlaxoSmithKline Document Number 2011N124158_00.  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); February 2012.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALT
Alanine aminotransferase (SGPT)
ART
Antiretroviral Therapy
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
AUC(0-t)
Area under the plasma concentration-time curve from time of dose to last measurable 
concentration
AUC(0-)
Area under the plasma concentration-time curve from time of dose extrapolated to infinity
AUC(0-24)
Area under the plasma concentration-time curve from time of dose to 24 hr
%AUCex
% of AUC(0-∞) that was extrapolated
BA
Bioavailability
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C24
Concentration at 24 hours after dose administration
CI
Confidence Interval
CL/F
Apparent oral clearance
Cmax
Maximum observed concentration 
C24
Observed concentration at 24h post-dose
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CrCL
Creatinine Clearance
CRF
Case Report Form
CV
Coefficient of variance
CVb
Between subject coefficient of variation
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug-Induced Liver Injury
DTG
Dolutegravir
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EU
European Union
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HRT
Hormone Replacement Therapy
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure


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ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
kg
Kilogram
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
OCT
Organic cation transporter
PK
Pharmacokinetic(s)
PTS
Platform Technology and Science
QTc
QT duration corrected for heart rate
QTcF
QT correction using FridericiaFormula
R&D
Research and Development
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SJS
Stevens-Johnson syndrome
SOP
Standard Operating Procedure
SRM
Study Reference Manual
t½
Terminal elimination phase half-life
TEN
Toxic epidermal necrolysis
tlag
Plasma DTG lag time for absorption
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
UK
United Kingdom
US / USA
United States (of America)
WBC
White blood cells
WCBP
Women of Child Bearing Potential
Vz/F
Apparent Volume of Distribution During Terminal Phase
z
Terminal Rate Constant
Trademark Information
Trademarks of the ViiV group of companies
Trademarks not owned by the ViiV group of 
companies
TIVICAY
WinNonlin
SAS


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject 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  International Normalized 
Ratio (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 GSK within 24 hours

Complete the liver event eCRF, 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 subject 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 subjects 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 subjects 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 subjects 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 eCRF 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 subject 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 subjects 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 
Appendix 2 - References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al.. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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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 International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, 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. 


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
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, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 

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. 

Participants who are rescreened are required to sign a new ICF.
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 multi-center studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Dissemination of Clinical Study Data
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 (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 

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 eCRF 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. 
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 eCRF 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
GSK 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 GSK. 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.


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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: 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 (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, 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.
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 (eg, 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 


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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 (eg, 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.
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.


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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 (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
The investigator will then record all relevant AE/SAE information in the eCRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE eCRF page.
There may be instances when copies of medical records for certain cases are requested by 
GSK. 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 GSK.
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.
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 


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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 GSK. 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 GSK.
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.
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 GSK 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 GSK with a copy of any post-mortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information.
Reporting of SAE to GSK/ViiV
SAE Reporting to GSK via Electronic Data Collection Tool
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).
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 


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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 the Medical Monitor Name and Contact 
Information section of the Title Page of this protocol.


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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception [Hatcher, 2011].
1.
Contraceptive subdermal implant
1.
Intrauterine device or intrauterine system
2.
Combined estrogen and progestogen oral contraceptive 
3.
Injectable progestogen
4.
Contraceptive vaginal ring
5.
Percutaneous contraceptive patches
6.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject. The 
documentation on male sterility can come from the site personnel’s: review of 
subject’s medical records, medical examination and/or semen analysis, or medical 
history interview provided by her or her partner.
7.
Male condom plus partner use of one of the contraceptive options below that meets 
the standard operating procedure (SOP) effectiveness criteria including a <1% rate of 
failure per year, as stated in the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive

Injectable progestogen

Contraceptive vaginal ring

Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study


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Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  
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.
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 GSK as described in 
Section 9.1.5. 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 subject who becomes pregnant while participating will discontinue study 
medication or be withdrawn from the study.
12.5.3.
Appendix 5 References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.


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12.6.
Appendix 6 - Division of AIDS Table For Grading The 
Severity Of Adult And Paediatric Averse 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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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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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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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 


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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 


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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 


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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 


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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 


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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 
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];128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C. 
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]JA on behalf of the World Health Organization Scientific Group 
(2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization 


2016N302761_00
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73
Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of 
Sheffield.
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.  
Appendix 6 References
Kanis JA on behalf of the World Health Organization Scientific Group (2007) 
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.
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.


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12.7.
Appendix 7:  Toxicity Management
12.7.1.
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
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, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects 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, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects should be followed up until resolution of anemia.
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
Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects should be followed up 
until resolution of anemia.


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12.7.2.
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).  Subjects may continue study medication.  Subjects 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).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial. Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
12.7.3.
AST AND ALT ELEVATION
See Section 12.2.
12.7.4.
RASH
Grade 1 rash (Localized macular rash):
Subjects 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, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal 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 subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 9.1 and Section 9.3.


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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target 
lesions):
Subjects 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, subjects 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 subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal 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 subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 9.1 and Section 9.3.
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):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject 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 subject 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 subject should remain on the 
study to be followed for safety and PK as outlined in Section 9.1 and Section 9.3.
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)):
Subjects 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 Medical Monitor should be notified of this serious adverse 
event within 24hr via phone or fax.  The subject should be closely followed every day 


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until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined Section 9.1 and Section 9.3.
12.7.5.
ALLERGIC REACTION
Grade 1 allergic reaction (Pruitis without rash):
Subjects 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, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject 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 subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined Section 9.1 and Section 9.3.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug will 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, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject 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 subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 9.1 and Section 9.3.


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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects 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
12.7.6.
CREATINE PHOSPHATE (CPK) ELEVATION
Grade 3 or higher:
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 4 
weeks to ensure the result is transient or due to exercise and will not require a change in 
study treatment. A history regarding use of drugs known to cause increase of CPK (such 
as statins) physical activity or exercise preceding the CPK evaluation should be obtained.
Grade 4 elevations in CPK should have a repeat assessment after the subject has 
abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the study drug, study drug should be 
discontinued and the subject withdrawn from the study.


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12.8.
Appendix 8: Palatability Questionnaire
The following questionnaire will be administered to each subject within 10 minutes 
following any dose of the DTG where it is given as a dispersion.  Subjects will be given 
the questionnaire to read prior to receiving this dose.
Subject #: _________________________   Date: __________   Treatment:______
Page 1 of 4
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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Subject #: _________________________   Date: __________   Treatment:______
Page 2 of 4
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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Subject #: _________________________   Date: __________   Treatment:______
Page 3 of 4
8.
For each of the following attributes please circle the number that best describes your 
perception of each attribute. 
g.
Flavor intensity
Mild
Average
Strong
1
2
3
4
5
h. Aroma
Mild
Average
Strong
1
2
3
4
5
i.
Sweetness
Not Sweet
Sweet
Very Sweet
1
2
3
4
5
j.
Sour/tartness
Mild
Average
Strong
1
2
3
4
5
k. Consistency
Thin
Average
Thick
1
2
3
4
5


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Subject #: _________________________   Date: __________   Treatment:______
Page 4 of 4
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
l.
Flavor intensity
Reduce
Leave as is
Increase
1
2
3
4
5
m. Aroma
1
2
3
4
5
n.
Sweetness
1
2
3
4
5
o.
Sour/tartness
1
2
3
4
5
p.
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?

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205893 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for Study 205893: A 2-Part 
Phase I, Single Dose, Crossover Relative Bioavailability 
Study of Both TIVICAY 10 mg Conventional Tablets and 5 
mg Dispersible Tablets Compared to Conventional TIVICAY 
Tablets in Healthy Adult Subjects 
Compound Number  
: GSK1349572 
Effective Date  
: 19-JUN-2017 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205893. 
• 
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-JUN-2017 
Biostatistician II (Biostatistics, Early Development Services, PPD) 
 
25-JUN-2017 
Pharmacokineticist (Biostatistics, PPD) 
 
Approved by:  
 
25-JUN-2017 
Manager (Statistics, Programming and Data Strategy, GSK) 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS .......................................................... 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ................................................... 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s) ................................................................ 7 
2.3. 
Study Design .................................................................................................. 9 
2.4. 
Statistical Hypotheses .................................................................................. 10 
3. 
PLANNED ANALYSES ............................................................................................ 10 
3.1. 
Final Analyses .............................................................................................. 10 
4. 
ANALYSIS POPULATIONS ..................................................................................... 10 
4.1. 
Protocol Deviations ...................................................................................... 11 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ....................................................................................................... 12 
6. 
STUDY POPULATION ANALYSES ......................................................................... 13 
6.1. 
Overview of Planned Analyses..................................................................... 13 
7. 
PRIMARY STATISTICAL ANALYSES ..................................................................... 14 
7.1. 
Pharmacokinetic Analyses ........................................................................... 14 
7.1.1. 
Overview of Planned Pharmacokinetic Analyses .......................... 14 
7.1.2. 
Drug Concentration Measures ...................................................... 14 
7.1.3. 
Pharmacokinetic Parameters ........................................................ 14 
7.1.3.1. 
Deriving Pharmacokinetic Parameters ........................ 14 
7.1.3.2. 
Statistical Analysis of Pharmacokinetic 
Parameters .................................................................. 15 
7.1.4. 
Interim Analysis ............................................................................. 16 
7.1.4.1. 
Overview of Planned Analyses .................................... 16 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................... 17 
8.1. 
Safety Analyses ........................................................................................... 17 
8.2. 
Exploratory Analyses.................................................................................... 17 
9. 
REFERENCES ........................................................................................................ 19 
10. APPENDICES .......................................................................................................... 20 
10.1. 
Appendix 1: Time & Events .......................................................................... 21 
10.1.1. 
Protocol Defined Time & Events ................................................... 21 
10.2. 
Appendix 2: Treatment States and Phases .................................................. 22 
10.2.1. 
Treatment States .......................................................................... 22 
10.2.1.1. Treatment States for Safety Data ................................ 22 
10.2.1.2. Treatment States for AE Data ..................................... 22 
10.3. 
Appendix 3: Data Display Standards & Handling Conventions .................... 23 
10.3.1. 
Study Treatment & Sub-group Display Descriptors ...................... 23 
10.3.2. 
Baseline Definition & Derivations .................................................. 23 
10.3.2.1. Baseline Definitions ..................................................... 23 
 
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10.3.2.2. Derivations and Handling of Missing Baseline 
Data ............................................................................. 24 
10.3.3. 
Reporting Process & Standards .................................................... 24 
10.4. 
Appendix 4: Derived and Transformed Data ................................................ 27 
10.4.1. 
General ......................................................................................... 27 
10.4.2. 
Study Population ........................................................................... 27 
10.4.3. 
Safety ............................................................................................ 27 
10.5. 
Appendix 5: Premature Withdrawals & Handling of Missing Data ................ 29 
10.5.1. 
Premature Withdrawals ................................................................. 29 
10.5.2. 
Handling of Missing Data .............................................................. 29 
10.5.2.1. Handling of Missing Dates ........................................... 29 
10.5.2.2. Handling of Partial Dates ............................................. 30 
10.6. 
Appendix 6: Values of Potential Clinical Importance .................................... 31 
10.6.1. 
ECG .............................................................................................. 31 
10.6.2. 
Vital Signs ..................................................................................... 31 
10.7. 
Appendix 7: Multiple Comparisons & Multiplicity .......................................... 32 
10.7.1. 
Handling of Multiple Comparisons & Multiplicity ........................... 32 
10.8. 
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses ....................................................................................................... 33 
10.9. 
Appendix 9 – Abbreviations & Trade Marks ................................................. 34 
10.9.1. 
Abbreviations ................................................................................ 34 
10.9.2. 
Trademarks ................................................................................... 35 
10.10. Appendix 10: List of Data Displays ............................................................... 36 
10.10.1. Mock Example Shell Referencing ................................................. 36 
10.10.2. Deliverable [Priority] ...................................................................... 36 
10.10.3. Study Population Tables ............................................................... 37 
10.10.4. Safety Tables ................................................................................ 38 
10.10.5. Pharmacokinetic Tables ................................................................ 39 
10.10.6. Pharmacokinetic Figures .............................................................. 40 
10.10.7. Exploratory Tables ........................................................................ 41 
10.10.8. ICH Listings ................................................................................... 41 
 
 
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1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
Overview 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
6 
 
Overview 
Key Elements of the RAP 
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μK<JKμI<=<I<E:<
 
2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
7 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The parameter “t” in the list of secondary endpoints in the protocol has been excluded as 
this does not represent an actual PK parameter and may be a typographical error in the 
protocol text.  There were no other changes to or deviations from the originally planned 
statistical analysis specified in the protocol (Dated: 23/FEB/2017). 
Listings of clinical laboratory data above a certain DAIDs toxicity grading are included 
in the outputs.  Section 3.3.1 of the protocol indicated that these listings contain toxicities 
of grade 3 or higher; however, the listings will instead contain toxicities of grade 2 or 
higher. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives
Primary Endpoints
Part 1 
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Secondary Objectives 
Primary Objectives 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
8 
 
Objectives 
Endpoints 
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Exploratory Objectives 
Exploratory Endpoints 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
9 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
Part 1: 
 
Part 2: 
Design 
Features 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
10 
 
Overview of Study Design and Key Features 
• /I<8KD<EK
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Treatment 
Assignment 
Part 1: 
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Part 2: 
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Interim 
Analysis 
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2.4. 
Statistical Hypotheses 
This study is designed to estimate the relative BA of each test treatment to the reference 
treatment (A vs. B; C vs. E and D vs. E) in both study parts in the fasted state.  
No formal hypothesis will be tested. For each pharmacokinetic endpoint (except for time 
of occurrence of Cmax [tmax] and tlag), 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 subjects 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. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
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• +&
 
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Population 
Definition / Criteria 
Analyses Evaluated 
N?<K?<IFIEFKK?<J8DGC<N@CC9<<O:CL;<;
NOTES :  
• 
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><E<I8K<;
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 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the “All Subjects” 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 
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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 

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• 
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• 
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• 
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• 
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7.1.2. 
Drug Concentration Measures 
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 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 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 
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NOTES: 
• 
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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 subjects have well defined plasma profiles).  
Pharmacokinetic Statistical Analyses 
Endpoint(s) 
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Pharmacokinetic Statistical Analyses 
KI<8KD<EK	8E;KI<8K@E>JL9A<:K8J8I8E;FD<==<:K+F@EK<JK@D8K<J8E;$J=FIK?<
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Model Results Presentation 
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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 Subjects” 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 
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• 
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• 
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• 
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8.2. 
Exploratory Analyses 
The exploratory analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
 
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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 
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• 
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• 
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• 
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• 
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9. 
REFERENCES 
GlaxoSmithKline Document Number 2016N302761_00 (Original – 23-FEB-2017): A 
2-Part Phase I, Single Dose, Crossover Relative Bioavailability Study of Both TIVICAY 
10 mg Conventional Tablets and 5 mg Dispersible Tablets Compared to Conventional 
TIVICAY Tablets in Healthy Adult Subjects (23-FEB-2017) 
 
 
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10. 
APPENDICES 
Section 
Appendix 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
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• #8E;C@E>F=(@JJ@E>8K8
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Other RAP Appendices 
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10.1.  
Appendix 1: Time & Events 
10.1.1.  Protocol  
Defined Time & Events 
Assessments
All Study
 Periods (Parts 1 and 2)
Follow-up
Notes
• Day -1 of Per
iods 2 -3 may be the same day as Day 
6 of pr
ior per
iods
• At Fo
l
low-up – Ma
le sub
jects w
ith no ongo
ing AEs or 
V
ita
l S
ign/Laboratory measures of c
l
in
ica
l concern may 
be fo
l
lowed v
irtua
l
ly by the s
ite v
ia te
lephone contact.
Day -1
Day 1
Day 2
Day 3 Day 4
Pre-dose 0 hr
Post Dose
24 hr
48 hr 
72 hr
Fo
l
low-upv
is
it w
i
l
l occur 7 to 10 dayspost
 
last dose.
S
ing
le v
ita
l s
ign measurementsperformedat a
l
l t
imepo
ints.
• Drug/A
lcoho
l/Cot
in
ine/pregnancy w
i
l
l be performed per the 
standard pract
ice of the s
ite. 
• C
l
in
ica
l 
laboratory tests – see Protoco
l Tab
le 5, Sect
ion 9.3.4. 
• C
l
in
ica
l
 
laboratory
 tests
 at
 fo
l
low-up
 are
 on
ly
 necessary
 
if
 
sub
ject had a prev
ious abnorma
l 
lab va
lue
Dosing
X
See Protoco
l
 Sect
ion 7.1
Comp
lete
 for
 each
 d
ispers
ion
 treatment
 C
 (see
 Protoco
l
 Sect
ion
 
12.8, Append
ix 8)
Pre-dose
 (w
ith
in
 15
 m
inutes
 pr
ior to
 dos
ing),
 Pro
toco
l
 Sect
ion
 9.4
See a
lso Protoco
l
 Sect
ion 6.3.2 and Sect
ion 6.3.3
 
 
 
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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 
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NOTES:  
• 
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/I<8KD<EK
 
10.2.1.2. 
Treatment States for AE Data 
Treatment State 
Definition 
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NOTES:  
• 
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/I<8KD<EK
 
 
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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] 
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8;D@E@JK<I<;;@I<:KKFDFLK?
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NOTES: 
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 
*I;<II<GI<J<EKJKI<8KD<EKJ9<@E>GI<J<EK<;@E/!'	8J8GGIFGI@8K<
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 
latest pre-dose assessment. Baseline definitions are applicable to each period. 
Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Safety
#<D8KFCF>P
3
3

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3
3

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
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3
3

8P

1@K8C.@>EJ
3
3
3
8P+I<
FJ<
NOTES : 
 
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Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
• 
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K?8KK@D<GF@EK
10.3.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
?8E><=IFD8J<C@E<
 +FJK
FJ<1@J@K18CL<V8J<C@E<
NOTES : 
• 
0EC<JJFK?<IN@J<JG<:@=@<;	K?<98J<C@E<;<=@E@K@FEJJG<:@=@<;@E.<:K@FE8J<C@E<<=@E@K@FEJN@CC9<LJ<;
=FI;<I@M8K@FEJ=FI<E;GF@EKJG8I8D<K<IJ8E;@E;@:8K<;FEJLDD8I@<J8E;C@JK@E>J
• 
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• 
/?<98J<C@E<;<=@E@K@FEN@CC9<=FFKEFK<;FE8CC:?8E><=IFD98J<C@E<;@JGC8PJ
 
10.3.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• /?<:LII<EKCPJLGGFIK<;M<IJ@FEJF=..8E;+?F<E@O2@E)FEC@EJF=KN8I<N@CC9<LJ<;
Analysis Datasets  
• E8CPJ@J;8K8J<KJN@CC9<:I<8K<;8::FI;@E>KF$.JK8E;8I;J./($"1<IJ@FE
;8($"1<IJ@FE
• !FI:I<8K@FEF=;8(;8K8J<KJ( 	K?<J8D<M<IJ@FEF=;@:K@FE8IP;8K8J<KJN@CC9<
@DGC<D<EK<;=FI:FEM<IJ@FE=IFD.$KF./(
Generation of RTF Files 
• -/!=@C<JN@CC9<><E<I8K<;=FI8CCI<GFIK@E><==FIKJ;<J:I@9<;@EK?<-+
 
Reporting Standards 
General 
• /?<:LII<EK".&$.'N@CC9<8GGC@<;=FII<GFIK@E>	LEC<JJFK?<IN@J<JK8K<;
o KF"<E<I8C+I@E:@GC<J
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o KF+I@E:@GC<J-<C8K<;KF"I8G?@:J
Formats 
• CC;8K8N@CC9<I<GFIK<;8::FI;@E>KFK?<8:KL8CKI<8KD<EKK?<JL9A<:KI<:<@M<;LEC<JJ
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• ".&$.'.K8K@JK@:8C+I@E:@GC<J=FI;<:@D8CGC8:<JN@CC9<8;FGK<;=FII<GFIK@E>
F=;8K898J<;FEK?<I8N;8K8:FCC<:K<;
• )LD<I@:;8K8N@CC9<I<GFIK<;8KK?<GI<:@J@FE:FCC<:K<;FEK?<<-!
• /?<I<GFIK<;GI<:@J@FE=IFDEFE<-!JFLI:<JN@CC=FCCFNK?<$.'JK8K@JK@:8CGI@E:@GC<J9LK
D8P9<8;ALJK<;KF8:C@E@:8CCP@EK<IGI<K89C<ELD9<IF=+SJ
Planned and Actual Time 
 
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Reporting Standards 
• -<GFIK@E>=FIK89C<J	=@>LI<J8E;=FID8CJK8K@JK@:8C8E8CPJ<J
• +C8EE<;K@D<I<C8K@M<KF;FJ@E>N@CC9<LJ<;@E=@>LI<J	JLDD8I@<J	JK8K@JK@:8C8E8CPJ<J8E;
:8C:LC8K@FEF=8EP;<I@M<;G8I8D<K<IJ	LEC<JJFK?<IN@J<JK8K<;
• /?<@DG8:KF=8EPD8AFI;<M@8K@FE=IFDK?<GC8EE<;8JJ<JJD<EKK@D<J8E;FIJ:?<;LC<;
M@J@K;8PJFEK?<8E8CPJ<J8E;@EK<IGI<K8K@FEF=K?<I<JLCKJN@CC9<8JJ<JJ<;8J8GGIFGI@8K<
• -<GFIK@E>=FI8K8'@JK@E>J
• +C8EE<;8E;8:KL8CK@D<I<C8K@M<KFJKL;P;IL>;FJ@E>N@CC9<J?FNE@EC@JK@E>J-<=<IKF
$.'.K8K@JK@:8C+I@E:@GC<
• 0EJ:?<;LC<;FILEGC8EE<;I<8;@E>JN@CC9<GI<J<EK<;N@K?@EK?<JL9A<:KSJC@JK@E>J
• 1@J@KJFLKJ@;<K?<GIFKF:FC;<=@E<;K@D<
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Unscheduled Visits 
• 0EJ:?<;LC<;M@J@KJN@CCEFK9<@E:CL;<;@EJLDD8IPK89C<J
• 0EJ:?<;LC<;M@J@KJN@CCEFK9<@E:CL;<;@E=@>LI<J
• CCLEJ:?<;LC<;M@J@KJN@CC9<@E:CL;<;@EC@JK@E>J
Descriptive Summary Statistics 
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• ),J8KK?<9<>@EE@E>F=8JL9A<:KGIF=@C<@<9<=FI<K?<=@IJK@E:@;<E:<F=
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• !FI),J8KK?<<E;F=K?<JL9A<:KGIF=@C<@<8=K<IK?<C8JK@E:@;<E:<F=8
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• =FI@E;@M@;L8CGCFKJ8E;G?8ID8:FB@E<K@:8E8CPJ<JK?<J<8I<;IFGG<;
J<KKFD@JJ@E>8JK?<P;FEFKGIFM@;<8EPLJ<=LC@E=FID8K@FE8E;
:8E<IIFE<FLJCP@E;@:8K<K?8K89JFCLK<CPEF;IL>@JGI<J<EK
• =FIJLDD8IPJK8K@JK@:JK?<J<8I<J<KKFKF8MF@;JB<N@E>F=K?<
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• $E;@M@;L8C),JN?@:?=8CC9<KN<<EKNFD<8JLI89C<:FE:<EKI8K@FEJ8I<
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8EFD8CP
• $=KNFFIDFI<),M8CL<JF::LI@EJL::<JJ@FE9<KN<<ED<8JLI89C<
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;8K8	=I<HL<E:P	
Reporting of Pharmacokinetic Concentration Data
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Reporting of Pharmacokinetic Parameters 
 
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Reporting Standards 
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'@JK@E>J
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;<K<ID@E8K@FEF=λQ
Graphical Displays 
• -<=<IKF$.'.K8K@JK@:8C+I@E:@G8CJKF
 
 
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10.4. 
Appendix 4: Derived and Transformed Data 
10.4.1. 
General 
Multiple Measurements at One Time Point 
• (<8EF=K?<D<8JLI<D<EKJN@CC9<:8C:LC8K<;8E;LJ<;@E8EP;<I@M8K@FEF=JLDD8IPJK8K@JK@:J
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• $=K?<I<8I<KNFM8CL<JN@K?@E8K@D<N@E;FNK?<M8CL<:CFJ<JKKFK?<K8I><K;8P=FIK?8KN@E;FN
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• .L9A<:KJ?8M@E>9FK?#@>?8E;'FNM8CL<J=FI)FID8C-8E><J8K8EPGFJK
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C@E@:8C$DGFIK8E:<JLDD8IPK89C<J
Study Day 
• 8C:LC8K<;8JK?<ELD9<IF=;8PJ=IFDI8E;FD@J8K@FE;8K<
• -<=8K<(@JJ@E>→.KL;P8P(@JJ@E>
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• -<=8K8≥-8E;FD@J8K@FE8K<→.KL;P8P-<=8K<V-8E;FD@J8K@FE8K<
10.4.2. 
Study Population 
Demographics 
Age 
• ".&JK8E;8I;$.'8C>FI@K?DJN@CC9<LJ<;=FI:8C:LC8K@E>8><N?<I<9@IK?;8K<N@CC9<@DGLK<;
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• @IK?;8K<N@CC9<GI<J<EK<;@EC@JK@E>J8JR4444S
Body Mass Index (BMI) 
• 8C:LC8K<;8JWeight (kg) / [Height (m)2] 
 
10.4.3. 
Safety 
ECG Parameters 
RR Interval 
• $!--@EK<IM8CDJ<:@JEFKGIFM@;<;;@I<:KCP	K?<E--:8E9<;<I@M<;8J
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56 $=,/:!@JD8:?@E<I<8;8E;,/:@JEFKGIFM@;<;	K?<E
 
• $= "J8I<D8EL8CCPI<8;	K?<--M8CL<GI<:<;@E>K?<D<8JLI<D<EK,/@EK<IM8CJ?FLC;9<8
:FCC<:K<;M8CL</# );FEFK;<I@M<
 
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ECG Parameters 
• (8:?@E<I<8;M8CL<JF=--J?FLC;EFK9<I<GC8:<;N@K?;<I@M<;M8CL<J
Corrected QT Intervals 
• 2?<EEFK<EK<I<;;@I<:KCP@EK?<<-!	:FII<:K<;,/@EK<IM8CJ9P8Q<KKSJ,/:8E;
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• $!--@EK<IM8CDJ<:@JGIFM@;<;K?<ED@JJ@E>,/:8E;FI,/:!N@CC9<;<I@M<;8J


 
AEs 
AEs OF Special Interest 
• #PG<IJ<EJ@K@M@KPI<8:K@FE#.-8E;I8J?
• '@M<I M<EKJ
• -<E8C!LE:K@FE
• I<8K@E<+?FJG?FB@E8J<+&<C<M8K@FEJ
 
 
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10.5. 
Appendix 5: Premature Withdrawals & Handling of Missing 
Data 
10.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
"<E<I8C
• .L9A<:KJKL;P:FDGC<K@FE@<8JJG<:@=@<;@EK?<GIFKF:FCN8J;<=@E<;8J
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LGM@J@K
• 2@K?;I8NEJL9A<:KJD8P9<I<GC8:<;@EK?<JKL;P
• CC8M8@C89C<;8K8=IFDJL9A<:KJN?FN<I<N@K?;I8NE=IFDK?<JKL;PN@CC9<C@JK<;
8E;8CC8M8@C89C<GC8EE<;;8K8N@CC9<@E:CL;<;@EJLDD8IPK89C<J8E;=@>LI<J	
LEC<JJFK?<IN@J<JG<:@=@<;
 
10.5.2. 
Handling of Missing Data 
Element 
Reporting Detail 
"<E<I8C
• (@JJ@E>;8K8F::LIJN?<E8EPI<HL<JK<;;8K8@JEFKGIFM@;<;	C<8;@E>KF9C8EB
=@<C;JFEK?<:FCC<:K@FE@EJKILD<EK
o /?<J<;8K8N@CC9<@E;@:8K<;9PK?<LJ<F=8T9C8EBU@EJL9A<:KC@JK@E>
;@JGC8PJ0EC<JJ8CC;8K8=FI8JG<:@=@:M@J@K8I<D@JJ@E>@EN?@:?:8J<K?<
;8K8@J<O:CL;<;=IFDK?<K89C<
o EJN<IJJL:?8JT)FK8GGC@:89C<U8E;T)FK<M8CL89C<U8I<EFK:FEJ@;<I<;KF
9<D@JJ@E>;8K88E;J?FLC;9<;@JGC8P<;8JJL:?
*LKC@<IJ
• EPJL9A<:KJ<O:CL;<;=IFDK?<JLDD8I@<J8E;FIJK8K@JK@:8C8E8CPJ<JN@CC9<
;F:LD<EK<;8CFE>N@K?K?<I<8JFE=FI<O:CLJ@FE@EK?<:C@E@:8CJKL;PI<GFIK
10.5.2.1. 
Handling of Missing Dates 
Element 
Reporting Detail 
"<E<I8C
+8IK@8C;8K<JN@CC9<;@JGC8P<;8J:8GKLI<;@EJL9A<:KC@JK@E>;@JGC8PJ
 J
• /?<<-!8CCFNJ=FIK?<GFJJ@9@C@KPF=G8IK@8C;8K<J@<	FECPDFEK?8E;P<8IKF
9<I<:FI;<;=FI JK8IK8E;<E;;8K<JK?8K@J	K?<;8PF=K?<DFEK?D8P9<
D@JJ@E>$EJL:?8:8J<	K?<=FCCFN@E>:FEM<EK@FEJN@CC9<8GGC@<;=FI:8C:LC8K@E>
K?<K@D<KFFEJ<K8E;K?<;LI8K@FEF=K?<<M<EK
o (@JJ@E>.K8IK8P!@IJKF=K?<DFEK?N@CC9<LJ<;LEC<JJK?@J@J9<=FI<K?<
JK8IK;8K<F=JKL;PKI<8KD<EK@EK?@J:8J<K?<JKL;PKI<8KD<EKJK8IK;8K<N@CC
9<LJ<;8E;?<E:<K?<<M<EK@J:FEJ@;<I<;*E
KI<8KD<EK8JG<IGG<E;@O
/I<8KD<EK.K8K<J8E;+?8J<J
o (@JJ@E>.KFG8P'8JK;8PF=K?<DFEK?N@CC9<LJ<;	LEC<JJK?@J@J8=K<IK?<
JKFG;8K<F=JKL;PKI<8KD<EK@EK?@J:8J<K?<JKL;PKI<8KD<EKJKFG;8K<N@CC
9<LJ<;
• FDGC<K<CPD@JJ@E>JK8IKFI<E;;8K<JN@CCI<D8@ED@JJ@E>	N@K?EF@DGLK8K@FE
8GGC@<;FEJ<HL<EKCP	K@D<KFFEJ<K8E;;LI8K@FEF=JL:?<M<EKJN@CC9<
D@JJ@E>
 
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Element 
Reporting Detail 
• .K8IKFI<E;;8K<JN?@:?8I<:FDGC<K<CPD@JJ@E>@<EFP<8IJG<:@=@<;N@CC
I<D8@ED@JJ@E>	N@K?EF@DGLK8K@FE8GGC@<;
 
10.5.2.2. 
Handling of Partial Dates 
Element 
Reporting Detail 
FE:FD@K8EK
(<;@:8K@FEJ
• +8IK@8C;8K<J=FI8EP:FE:FD@K8EKD<;@:8K@FEJI<:FI;<;@EK?<<-!N@CC9<
@DGLK<;LJ@E>K?<=FCCFN@E>:FEM<EK@FE
o $=K?<G8IK@8C;8K<@J8JK8IK;8K<	8RSN@CC9<LJ<;=FIK?<;8P8E;R%8ESN@CC
9<LJ<;=FIK?<DFEK?
o $=K?<G8IK@8C;8K<@J8JKFG;8K<	8RSN@CC9<LJ<;=FIK?<;8P
;<G<E;<EKFEK?<DFEK?8E;P<8I8E;R<:SN@CC9<LJ<;=FIK?<DFEK?
• /?<I<:FI;<;G8IK@8C;8K<N@CC9<;@JGC8P<;@EC@JK@E>J
 J
• EPG8IK@8C;8K<J=FI JN@CC9<I8@J<;KF;8K8D8E8><D<EK$=K?<=LCC;8K<
:8EEFK9<8J:<IK8@E<;	K?<=FCCFN@E>8JJLDGK@FEJN@CC9<D8;<
o $=K?<G8IK@8C;8K<@J8JK8IK;8K<	8RSN@CC9<LJ<;=FIK?<;8P8E;R%8ESN@CC
9<LJ<;=FIK?<DFEK?
o #FN<M<I	@=K?<J<I<JLCKJ@E8;8K<GI@FIKF2<<B8P8E;K?<<M<EK
:FLC;GFJJ@9CP?8M<F::LII<;;LI@E>KI<8KD<EK=IFDK?<G8IK@8C@E=FID8K@FE	
K?<EK?<2<<B8P;8K<N@CC9<8JJLD<;KF9<K?<JK8IK;8K<
o /?< N@CCK?<E9<:FEJ@;<I<;KFJK8IKFE
KI<8KD<EKNFIJK:8J<
o $=K?<G8IK@8C;8K<@J8JKFG;8K<	8RSN@CC9<LJ<;=FIK?<;8P
;<G<E;<EKFEK?<DFEK?8E;P<8I8E;R<:SN@CC9<LJ<;=FIK?<DFEK?
• /?<I<:FI;<;G8IK@8C;8K<N@CC9<;@JGC8P<;@EC@JK@E>J
 
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Element 
Reporting Detail 
10.6. 
Appendix 6: Values of Potential Clinical Importance 
10.6.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
9JFCLK<,/:$EK<IM8C
DJ<:
56

56
≤56
≥56
≤56
≥56

9JFCLK<+-$EK<IM8C
DJ<:
56
56
9JFCLK<,-.$EK<IM8C
DJ<:
56
56
Change from Baseline 
$E:I<8J<=IFD8J<C@E<,/:
DJ<:
≤56

DJ<:
56
≤56
DJ<:
≥56

NOTES: 
 
-<GI<J<EKJK8E;8I; "M8CL<JF=+$=FI#1JKL;@<J
 
-<GI<J<EK=LIK?<IJL9;@M@J@FEJF= "M8CL<J=FI8E8CPJ@J
 
10.6.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
.PJKFC@:CFF;+I<JJLI<
DD#>


@8JKFC@:CFF;+I<JJLI<
DD#>


#<8IK-8K<
9GD


 
 
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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) 
• +&<E;GF@EKJ0
∞	0
K8E;D8O
Analysis 
• (@O<; ==<:KJ
Assumptions: 
• (F;<C8JJLDGK@FEJN@CC9<8GGC@<;	9LK8GGIFGI@8K<8;ALJKD<EKJD8P9<D8;<98J<;FEK?<
;8K8
• /?<&<EN8I;8E;-F><ID<K?F;=FI8GGIFO@D8K@E>K?<;<EFD@E8KFI;<>I<<JF==I<<;FD8E;
:FII<:K@E>=FI9@8J@EK?<<JK@D8K<;M8I@8E:<
:FM8I@8E:<F=K?<=@O<;<==<:KJN@CC9<LJ<;
 
 
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10.9. 
Appendix 9 – Abbreviations & Trade Marks 
10.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AUC(0-t) 
Area under the concentration-time curve (AUC) from time 0 (predose) 
to time of the last quantifiable concentration 
AUC0-24 
Area under the concentration-time curve (AUC) 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 
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 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
TFL 
Tables, Figures & Listings  
 
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Abbreviation 
Description 
t½ 
Terminal phase half-life 
tlag 
Lag time before observation of drug concentrations in sampled matrix 
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 
TIVICAY 
 
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 
.KL;P+FGLC8K@FE
KF
)
.8=<KP
KF
)
+?8ID8:FB@E<K@:
KF
KF
 OGCFI8KFIP+8C8K89@C@KP

)
Section 
Listings 
$#'@JK@E>J
KF
 
10.10.1. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated. 
Section 
Figure 
Table 
Listing 
.KL;P+FGLC8K@FE
+*+7!E
+*+7/E
+*+7'E
.8=<KP
.! 7!E
.! 7/E
.! 7'E
+?8ID8:FB@E<K@:
+&7!E
+&7/E
+&7'E
 OGCFI8KFIP+8C8K89@C@KP
 3+7!E
 3+7/E
 3+7'E
NOTES:  
• 
)FE
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R5)FE
.K8E;8I;6-<=<I<E:<S
 
10.10.2. 
Deliverable [Priority] 
Delivery [Priority] [1] 
Description 
.536
!@E8C.K8K@JK@:8CE8CPJ@JFDGC<K<
NOTES:  
 
$E;@:8K<JGI@FI@KP@<FI;<I@EN?@:?;@JGC8PJN@CC9<><E<I8K<;=FIK?<I<GFIK@E><==FIK
 
 
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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] 
Subject Disposition and Analysis Sets 
 
CC.L9A<:KJ
).
.LDD8IPF=)LD9<IF=.L9A<:KJ EIFCC<;9PFLEKIP8E;.@K<$

.56
 
CC.L9A<:KJ
 .
.LDD8IPF=.L9A<:K@JGFJ@K@FE

.56
 
.:I<<E<;
 .
.LDD8IPF=-<8JFEJ=FI.:I<<E@E>!8@CLI<J

.56
 
.:I<<E<;
1
.LDD8IPF=$DGFIK8EK+IFKF:FC<M@8K@FEJ

.56
Demographics 
 
CC.L9A<:KJ
(
.LDD8IPF=<DF>I8G?@:?8I8:K<I@JK@:J

.56
 
CC.L9A<:KJ
(
.LDD8IPF=-8:<8E;-8:@8CFD9@E8K@FEJ

.56
 
CC.L9A<:KJ
(
.LDD8IPF=-8:<8E;-8:@8CFD9@E8K@FEJ<K8@CJ

.56
 
CC.L9A<:KJ
(
.LDD8IPF=><-8E><J

.56
 
 
 
 
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10.10.4. 
Safety Tables 
Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
AEs 
 
CC.L9A<:KJ
 
.LDD8IPF=CC;M<IJ< M<EKJ

.56
 
CC.L9A<:KJ
 
.LDD8IPF=CCIL>
-<C8K<;;M<IJ< M<EKJ

.56
 
CC.L9A<:KJ
 
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J<I@FLJ;M<IJ< M<EKJ9P
.PJK<D*I>8EC8JJ8E;+I<=<II<;/<ID

.56
 
CC.L9A<:KJ
 
.LDD8IPF=.<I@FLJ;M<IJ< M<EKJ9P.PJK<D*I>8EC8JJ
8E;+I<=<II<;/<ID

.56
Laboratory Values 
 
CC.L9A<:KJ
'
.LDD8IPF=C@E@:8C?<D@JKIP18CL<J?8E><=IFD8J<C@E<

.56
 
CC.L9A<:KJ
'
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.56
 
CC.L9A<:KJ
0-
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.56
Electrocardiograms 
 
CC.L9A<:KJ
 "
.LDD8IPF= "!@E;@E>J

.56
Vital Signs 
 
CC.L9A<:KJ
1.
.LDD8IPF=?8E><=IFD8J<C@E<@E1@K8C.@>EJ

.56
 
 
 
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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 
 
+&
+&/
.LDD8IPF=/"+C8JD8+?8ID8:FB@E<K@:FE:<EKI8K@FE
/@D<
8K89P.KL;P+8IK8E;/I<8KD<EK

.56
PK Derived Parameters 
 
+&
+&+/
.LDD8IPF=<I@M<;/"+C8JD8+?8ID8:FB@E<K@:+8I8D<K<IJ
)FE
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+8I8D<K<IJN@K?LE@KJ
.56
 
+&
+&+/
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'E
/I8EJ=FID<;9P.KL;P+8IK8E;/I<8KD<EK
+8I8D<K<IJN@K?LE@KJ
.56
PK Analysis Tables 
 
+&
+&+/
.K8K@JK@:8CE8CPJ@JF=/"+C8JD8+?8ID8:FB@E<K@:
+8I8D<K<IJ	.KL;P+8IK
0
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∞	8E;D8O
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.56
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+8I8D<K<IJ	.KL;P+8IK
0
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∞	8E;D8O
FECP9P/I<8KD<EK+8IKFECP
.56
 
 
 
 
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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
$E;@M@;L8C/"+C8JD8FE:<EKI8K@FE
/@D<+CFKJ9P.L9A<:K
'@E<8I8E;.<D@
'F>8I@K?D@:
+8>@E8K<9P.L9A<:K
.56
Mean / Median Concentration Plots 
 
+&
+&!
(<8E/"+C8JD8FE:<EKI8K@FE
/@D<+CFKJ9P/I<8KD<EK
'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><

.56
 
+&
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(<;@8E/"+C8JD8FE:<EKI8K@FE
/@D<+CFKJ9P/I<8KD<EK
'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><

.56
PK Analysis Plots 
 
+&
+&+!
FDG8I8K@M<+CFKF=$E;@M@;L8C/"+C8JD8D8O9P/I<8KD<EK
'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><
.56
 
+&
+&+!
FDG8I8K@M<+CFKF=$E;@M@;L8C/"+C8JD80
K9P
/I<8KD<EK'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><
.56
 
+&
+&+!
FDG8I8K@M<+CFKF=$E;@M@;L8C/"+C8JD80
∞9P
/I<8KD<EK'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><
.56
 
+&
+&+!
FDG8I8K@M<+CFKF=$E;@M@;L8C/"+C8JD89P/I<8KD<EK
'@E<8I8E;.<D@
'F>8I@K?D@:
CCKI<8KD<EKJ=FI<8:?+8IKFEFE<
G8><
.56
 
 
 
 
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10.10.7. 
Exploratory Tables 
Exploratory : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Palatability 
 
CC.L9A<:KJ
 3+7/
.LDD8IPF=+8C8K89@C@KP,L<JK@FEE8@I<-<JLCKJ+8IK	
/I<8KD<EK*ECP

.56
 
10.10.8. 
ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Randomisation 
 

CC.L9A<:KJ
+7/
'@JK@E>F=-8E;FD@J<;8E;:KL8C/I<8KD<EK

.56
Subject Disposition 
 

CC.L9A<:KJ
 .
'@JK@E>F=-<8JFEJ=FI.KL;P2@K?;I8N8C

.56
 

.:I<<E<;
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
42 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Concomitant Medications 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
43 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory Values 
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2017N324595_00


 
CONFIDENTIAL 
 
 
 
205893 
 
44 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
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2017N324595_00