Clinical trial NCT03078556
Conditions: Infection, Human Immunodeficiency Virus
Keywords: FDC Lamivudine Bio-equivalence Dolutegravir HIV
Sponsor: ViiV Healthcare
Start date: 2017-03-27; Completion date: 2017-08-18
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study aims to compare the bioequivalence of two experimental fixed dose combination (FDC) tablets versus single entity products of dolutegravir (DTG) and lamivudine (3TC) in healthy adult subjects. The study will be carried out in two parts. Part 1 of the study will be open label, up to 3 periods design with a wash out period of at least 7 days between treatment periods. Subjects will be randomized to receive either single entities or formulation 1 FDC of DTG and 3TC in a crossover manner in first 2 periods. The first 16 subjects who complete the first two treatment periods and consent to continue will receive a single dose of FDC formulation 1 tablet administered with a high fat meal for a third treatment period. In Part 2 of the study, subjects will be randomized to receive either single entities or formulation 2 FDC of DTG and 3TC in a crossover manner in first 2 periods. Similarly the first 16 subjects will then receive FDC formulation 2 tablets with high fat meal in treatment period 3. Subjects will have a follow-up visit within 7-14 days after the last dose of study drug. Approximately 76 healthy subjects will be included in Part 1 of the study and if Part 2 of the study is conducted, another 76 healthy subjects will be included. The total duration will be approximately 11 weeks.

Detailed description:

Arms: arm 1: Eligible subjects will be randomized in sequence A/B and will receive A: DTG 50 milligram (mg) and 3TC 300 mg single entities in Period 1, B: DTG 3TC FDC formulation 1 tablet in Period 2. arm 2: Eligible subjects will be randomized in sequence B/A and will receive B: DTG 3TC FDC formulation 1 tablet in Period 1 and A: DTG 50 mg and 3TC 300 mg single entities in Period 2. arm 3: Eligible subjects will be administered single dose of DTG 3TC FDC formulation 1 tablet with high fat meal in Period 3 to study the effect of food on tablet. arm 4: Eligible subjects will be randomized in sequence A/B and will receive A: DTG 50 mg and 3TC 300 mg single entities in Period 1 and C: DTG 3TC FDC formulation 2 tablet in Period 2. arm 5: Eligible subjects will be randomized in sequence C/A and will receive C: DTG 3TC FDC formulation 2 tablet in Period 1 and A: DTG 50 milligram (mg) and 3TC 300 mg single entities in Period 2. arm 6: Eligible subjects will be administered single dose of DTG 3TC FDC formulation 2 tablet with high fat meal in Period 3 to study the effect of food on tablet.
Interventions: intervention 1: Dolutegravir intervention 2: Lamivudine intervention 3: Dolutegravir + Lamivudine FDC Formulation 1 intervention 4: Dolutegravir + Lamivudine FDC Formulation 2
Intervention descriptions: intervention 1: Single dose of DTG 50 mg tablet along with 3TC (EPIVIR) tablet will be given to randomized subjects in parts 1 and 2 with 240 mL of room temperature water. DTG will be a white, film coated, round tablet engraved with SV 572 on one side and 50 on the other side. intervention 2: Single dose 3TC (commercial name: EPIVIR) 300 mg tablet along with DTG tablet will be given to randomized subjects in parts 1 and 2 with 240 mL of room temperature water.\<br\>3TC will be gray, diamond shaped tablet, engraved "GX EJ7" on one side and plain on the other side. intervention 3: Single dose of DTG 50 mg combined with 3TC 300 mg in a FDC formulation 1 tablet will be administered to randomized subjects in treatment periods 1 and 2 (under fasted state) of Part 1 and the first 16 subjects in treatment period 3 (under fed) of Part 1 with 240 mL of room temperature water. \&lt;br\&gt;FDC formulation 1 tablets will be oval, biconvex, white, film coated tablet engraved 'SV H7I' on one face. intervention 4: Single dose of DTG 50 mg combined with 3TC 300 mg in a FDC formulation 2 tablet will be administered to randomized subjects in treatment periods 1 and 2 (under fasted state) and the first 16 subjects in treatment period 3 (under fed) of Part 2 with 240 mL of room temperature water. \&lt;br\&gt;FDC formulation 2 tablets will be oval, biconvex, white, film coated tablet engraved 'SV 13N' on one face.

Protocol documents:
Prot_000.pdf: 
2016N286215_01
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
204994
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An Open-label, Randomized, Single dose, Crossover, Pivotal 
Bioequivalence Study of Fixed-dose Combination Tablet(s) of 
Dolutegravir and Lamivudine versus Dolutegravir and 
Lamivudine single entities and Food Effect Assessment in 
Healthy Volunteers
Compound Number:
GSK3515864 (GSK1349572+GR109714)
Development Phase:
I
Effective Date:
07-FEB-2017
Protocol Amendment Number:  1
Author (s):
Clinical Statistics (PAREXEL)
Clinical Pharmacology Modelling & Simulation
Platform Technologies and Sciences
Infectious Diseases Medicines Discovery and Development
Research and Development, ViiV Healthcare
Clinical Pharmacology Science and Study Operations
Clinical Pharmacology Science and Study Operations
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N286215_00
2017-JAN-12
Original
2016N286215_01
2017-FEB-07
Amendment No. 1
Amendment 1 allows for an evaluation of a monolayer FDC tablet bioequivalence in Part 
1 of the study and, if available, an evaluation of a bilayer FDC tablet bioequivalence in 
Part 2.  The original protocol combined these bioequivalence evaluations into a single 3-
way cross over design versus reference.
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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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
 MD
ViiV Healthcare
5 Moore Drive,
Research 
Triangle, NC 
27709
Secondary 
Medical 
Monitor
 MD
1250 South 
Collegeville 
Road, 
Collegeville, 
PA 19426
SAE contact  
information 
Email:
Medical Monitor as 
above
Sponsor Legal Registered Address: 
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study.
ViiV Registered Address
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Regulatory Agency Identifying Number(s):  IND Number:  127475
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204994
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204994........................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.1.1.
Part 1: Bioequivalence and Food Effect with a FDC 
monolayer tablet ..........................................................................18
4.1.2.
Part 2 – Bioequivalence and Food Effect with an FDC 
bilayer tablet ................................................................................19
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................20
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................23
4.6.3.
Overall Benefit:Risk Conclusion...................................................23
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............23
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................25
5.3.
Screening/Baseline/Run-in Failures............................................................26
5.4.
Withdrawal/Stopping Criteria.......................................................................26
5.4.1.
Liver Chemistry Stopping Criteria ................................................27
5.4.2.
QTc Stopping Criteria ..................................................................27
5.4.3.
Rash............................................................................................28
5.5.
Subject and Study Completion....................................................................28
6.
STUDY TREATMENT ............................................................................................28
6.1.
Investigational Product and Other Study Treatment....................................28
6.2.
Treatment Assignment................................................................................29
6.3.
Planned Dose Adjustments.........................................................................30
6.4.
Blinding.......................................................................................................30
6.5.
Packaging and Labeling..............................................................................30
6.6.
Preparation/Handling/Storage/Accountability..............................................30
6.7.
Compliance with Study Treatment Administration.......................................31
6.8.
Treatment of Study Treatment Overdose....................................................31
6.9.
Treatment after the End of the Study ..........................................................32
6.10.
Lifestyle and/or Dietary Restrictions............................................................32
6.10.1.
Meals and Dietary Restrictions ....................................................32
6.10.1.1.
Fasting Conditions......................................................32
6.10.1.2.
Fed Conditions (Period 3 only) ...................................32
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................33


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6.10.3.
Activity .........................................................................................33
6.11.
Concomitant Medications and Non-Drug Therapies....................................33
6.11.1.
Permitted Medications and Non-Drug Therapies..........................33
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
7.1.
Time and Events Table...............................................................................35
7.2.
Screening and Critical Baseline Assessments ............................................37
7.3.
Safety .........................................................................................................37
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........37
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................37
7.3.1.2.
Method of Detecting AEs and SAEs ...........................38
7.3.1.3.
Follow-up of AEs and SAEs........................................38
7.3.1.4.
Regulatory Reporting Requirements for SAEs............38
7.3.2.
Pregnancy ...................................................................................38
7.3.3.
Physical Exams ...........................................................................39
7.3.4.
Vital Signs....................................................................................39
7.3.5.
Electrocardiogram (ECG).............................................................39
7.3.6.
Clinical Safety Laboratory Assessments ......................................39
7.4.
Pharmacokinetics .......................................................................................40
7.4.1.
Blood Sample Collection..............................................................41
7.4.2.
Sample Processing Procedures...................................................41
7.4.3.
Sample Storage Conditions .........................................................41
7.4.4.
Sample Analysis ..........................................................................41
8.
DATA MANAGEMENT ...........................................................................................42
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................42
9.1.
Hypotheses.................................................................................................42
9.2.
Sample Size Considerations.......................................................................43
9.2.1.
Sample Size Assumptions ...........................................................43
9.2.2.
Sample Size Sensitivity................................................................43
9.2.3.
Sample Size Re-estimation or Adjustment...................................44
9.3.
Data Analysis Considerations .....................................................................45
9.3.1.
Analysis Populations....................................................................45
9.3.2.
Interim Analysis ...........................................................................46
9.4.
Key Elements of Analysis Plan ...................................................................46
9.4.1.
Primary and Secondary Analyses ................................................46
9.4.2.
Pharmacokinetic Analyses...........................................................47
9.4.3.
Safety Analyses...........................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................48
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............48
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................49
10.4.
Quality Assurance.......................................................................................49
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................50
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50


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11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................53
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................53
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................56
12.3.
Appendix 3:  Handling of Clinical Testing Samples in Pivotal 
Bioequivalence Studies...............................................................................58
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................60
12.4.1.
Definition of Adverse Events........................................................60
12.4.2.
Definition of Serious Adverse Events...........................................61
12.4.3.
Recording of AEs and SAEs ........................................................62
12.4.4.
Evaluating AEs and SAEs............................................................62
12.4.5.
Reporting of SAEs to GSK/ViiV....................................................64
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................65
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............65
12.5.2.
Collection of Pregnancy Information ............................................65
12.5.3.
References ..................................................................................66
12.6.
Appendix 6 - Division of AIDS Table for Grading The Severity Of 
Adult And Pediatric Averse Events Version 2.0, November 2014................68
12.7.
Appendix 7: Toxicity Management ..............................................................87
12.8.
Appendix 8 - Country Specific Requirements..............................................92


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1.
PROTOCOL SYNOPSIS FOR STUDY 204994
Rationale
Treatment of human immunodeficiency virus (HIV) infection requires daily oral 
administration of a combination of at least three potent antiretroviral (ARV) drugs to 
reduce the patient’s HIV levels.  Lifelong adherence to these treatments is key to their 
success in decreasing HIV-related mortality and morbidity.  Fixed dose combinations of 
these drugs have led to increase patient adherence and consequently reduce the likelihood 
of virological failure and viral resistance. However, since these regimens will need to be 
taken life-long, there is growing concern about their long-term toxicities and cost.  Two-
drug antiretroviral regimens may maintain virologic suppression while minimizing the 
adverse effects from cumulative drug exposure and reducing drug-related healthcare 
costs.
A combination of two potent, well-characterized and well-tolerated ARVs, dolutegravir 
(DTG, TIVICAY™), a HIV-1 integrase inhibitor (INI) and lamivudine (3TC; GR109714, 
EPIVIR™), a nucleoside analogue, may provide effective long-term antiviral suppression
while limiting the risk of adverse reactions associated with ARV’s. DTG and 3TC are 
indicated in combination with other antiretroviral agents for treatment in adults and 
children, and are each approved in the United States, European Union, and other 
countries for the treatment of HIV-1 infection.  Two Phase 3 studies are ongoing to 
evaluate the safety and effectiveness of the co-administration of DTG and 3TC for the 
treatment of HIV-1 infection in antiretroviral-naive adult patients.  Although the Phase 3 
studies are being conducted with the individual entity products, the goal is to develop a 
fixed-dose combination (FDC) tablet of DTG and 3TC which can be taken once daily.  
The purpose of the present study is to evaluate the bioequivalence of experimental FDC 
tablet(s) of DTG and 3TC relative to co-administration of the single entity products in 
healthy adult subjects.  A monolayer FDC formulation was chosen based on the results 
from study 204993.  In addition, a bilayer FDC tablet is being developed and will be 
included for Part 2, if available.  This study will also assess the effect of food on these 
FDC formulation(s). 


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Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To evaluate the bioequivalence of FDC tablet 
formulation(s) of DTG 50 mg and 3TC 300 mg versus 
co-administration of the separate tablet formulations of 
DTG 50 mg plus 3TC 300 mg, in the fasted state.
Plasma DTG and 3TC AUC(0-∞), AUC(0-t), and Cmax.
Secondary

To characterize the PK profile of single dose FDC 
tablet formulation(s) of DTG 50 mg and 3TC 
300 mg versus co-administration of the separate 
tablet formulations of DTG 50 mg plus 3TC 
300 mg, in the fasted state

To evaluate the food effect on FDC tablet 
formulation(s) of DTG 50 mg and 3TC 300 mg 

To assess the safety and tolerability from single-
dose administration of the combination of DTG 
50 mg, 3TC 300 mg in healthy volunteers either 
fasted or with a high fat meal.

Plasma DTG and 3TC tlag, tmax, t, t½, z, %AUCex, 
AUC(0-24), CL/F and Vz/F, Ct, and C24

Plasma DTG and 3TC AUC(0-∞), AUC(0-t), Cmax, 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 vital signs (BP and HR), 
number of subjects with adverse events and 
toxicity grading of clinical laboratory tests
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞) = area under the plasma concentration time curve from time zero to infinity
AUC(0-24) = area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
tmax = time of maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration
PK = Pharmacokinetic 
t = time of last quantifiable concentration
tlag = absorption lag time
z=apparent elimination rate constant
t1/2 =the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution
Overall Design
This is a single-center, open-label, randomized, two-part study.    
There will be a washout of at least 7 days between treatment periods and all subjects will 
return for a follow-up visit 7 to 14 days after the last dose of study drug. A 4-hour 
tolerance limit to the washout period will be permitted prior to dosing (i.e., -4 hours) to 
allow flexibility at the study site in scheduling subject return visits for subsequent periods 
2 and 3.
Part 1 – Bioequivalence and Food Effect with an FDC monolayer tablet
Part 1 of the study will be a randomized, open-label, 2-period, single-dose, crossover 
study in 76 healthy adult subjects to achieve at least 70 evaluable subjects. 


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The first 16 subjects who complete the first two dosing periods, and consent to continue, 
will return for a third treatment period and receive a single dose of the FDC tablet 
formulation administered with a high fat meal.
The purpose of Part 1 is to evaluate the bioequivalence (first two treatment periods) of 
oral DTG 50 mg/3TC 300 mg FDC tablet formulation (monolayer with Product Code 
AH) proposed for commercial use compared to co-administration of the separate tablet 
formulations of DTG 50 mg (clinical trial material image) and 3TC 300 mg (EPIVIR)
and food effect (treatment period 3). For treatment periods 1 and 2, each treatment will 
be administered in the fasted state after at least 10 hours of fasting. 
Figure 1
Study Design: Part 1, Bioequivalence and Food Effect with 
monolayer FDC tablet
Part 2 – Bioequivalence and Food Effect with an FDC bilayer tablet (Product Code TBD)
If another FDC formulation is available, Part 2 of the study will be conducted, similar to 
Part 1. 
Figure 2
Study Design: Part 2, Bioequivalence and Food Effect with bilayer 
FDC tablet
Treatment Arms and Duration
Each subject will have a screening visit within 30 days prior to the first dose of study 
drug, three treatment periods each with a single dose of study drug and a follow-up visit 
within 7-14 days after the last dose of study drug.  There will be a washout of at least 7 
days (-4 hours) between each dose of study drug.  The total duration of participation of a 
subject in this study will be approximately 11 weeks.
Randomization N=76
Treatment Period 1
A: Reference treatment 
DTG + 3TC
Or
B: FDC formulation
Washout ≥ 7 days
Treatment Period 2
A: Reference treatment 
DTG + 3TC
Or
B: FDC formulation  
Treatment Period 3 
B: FDC formulation
(N=16)
With high fat meal
Washout ≥ 7 days
Randomization N=76
Treatment Period 1
A: Reference treatment 
DTG + 3TC
Or
C: FDC formulation
Washout ≥ 7 days
Treatment Period 2
A: Reference treatment 
DTG + 3TC
Or
C: FDC formulation  
Treatment Period 3 
C: FDC formulation
(N=16)
With high fat meal
Washout ≥ 7 days


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Type and Number of Subjects
A minimum of 76 healthy adult subjects will be randomized such that a minimum of 
approximately 70 evaluable subjects complete treatment periods 1 and 2 of Part 1 of the 
study.  A total of 16 subjects, who complete treatment periods 1 and 2 and provide 
consent will continue and participate in period 3 of the study, in Part 1.
If Part 2 of the study is conducted, another 76 healthy adult subjects will be randomized 
such that a minimum of approximately 70 evaluable subjects complete treatment periods 
1 and 2 of Part 2 of the study.  A total of 16 subjects who complete treatment periods 1 
and 2 and provide consent will continue and participate in period 3 of the study, in Part 2.
Analysis
Interim Analysis
Following completion of Part 1, preliminary PK data from Part 1 will be analyzed. The 
point estimates and corresponding 90% CIs will be constructed for the ratio of the 
geometric mean of the test treatment (monolayer) to the geometric mean of the reference 
treatments, μ(test)/μ(reference) for AUC(0-∞), AUC(0-t), and Cmax for both DTG and 3TC. 
The result will be used for planning a future Phase III study. 
An independent statistical and programming team will perform the preliminary PK 
analysis. As the PK data are analysed separately for each part of the study, there will be 
no adjustments for multiplicity.
Final Analysis
Final analyses will be performed after the completion of the study and final database
authorization.  
Primary and Secondary Analyses
PK analyses will be the responsibility of the Clinical Pharmacology Modeling & 
Simulation department within GSK or their designee.  Plasma DTG and 3TC 
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 pharmacokinetic 
parameters will be determined, as data permit:  Cmax, Tmax, AUC(0-t), AUC(0-), AUC(0-24),
t1/2, tlag, Ct, C24, z, %AUCex, Vz/F, t and CL/F.
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline or their designee.
The PK parameters for DTG and 3TC (except tmax and tlag) will be loge-transformed and 
separately analyzed using a mixed effects model. For the analysis of bioequivalence, the 
model will include fixed effect terms for period and treatment.  Subject will be treated as 
a random effect in the model.  For the analysis of food effect, the model will include a 
fixed effect term for treatment (fed versus fasted) and a random effect term for subject. 


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Point estimates and their associated 90% confidence intervals (CIs) will be constructed 
for the differences in PK parameter values between test and reference treatments for the 
treatment comparisons. 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.
Tmax and Tlag of DTG and 3TC will be separately analyzed with the non-parametric 
Wilcoxon matched pair method to compute point estimates and associated 90% 
confidence intervals for the median differences 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.


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2.
INTRODUCTION
2.1.
Study Rationale
Treatment of human immunodeficiency virus (HIV) infection requires daily oral 
administration of a combination of at least three potent antiretroviral (ARV) drugs to 
reduce the patient’s HIV levels.  Lifelong adherence to these treatments is key to their 
success in decreasing HIV-related mortality and morbidity.  Fixed dose combinations of 
these drugs have led to increase patient adherence and consequently reduce the likelihood 
of virological failure and viral resistance. However, since these regimens will need to be 
taken life-long, there is growing concern about their long-term toxicities and cost.  Two-
drug antiretroviral regimens may maintain virologic suppression while minimizing the 
adverse effects from cumulative drug exposure and reducing drug-related healthcare 
costs.
A combination of two potent, well-characterized and well-tolerated ARVs, dolutegravir 
(DTG, TIVICAY™), a HIV-1 integrase inhibitor (INI) and lamivudine (3TC; GR109714, 
EPIVIR™), a nucleoside analogue, may provide effective long-term antiviral suppression
while limiting the risk of adverse reactions associated with ARV’s. DTG and 3TC are 
indicated in combination with other antiretroviral agents for treatment in adults and 
children, and are each approved in the United States, European Union, and other 
countries for the treatment of HIV-1 infection.  Two Phase 3 studies are ongoing to 
evaluate the safety and effectiveness of the co-administration of DTG and 3TC for the 
treatment of HIV-1 infection in antiretroviral-naive adult patients.  Although the Phase 3 
studies are being conducted with the individual entity products, the goal is to develop a 
fixed-dose combination (FDC) tablet of DTG and 3TC which can be taken once daily.  
The purpose of the present study is to evaluate the bioequivalence of experimental FDC 
tablet(s) of DTG and 3TC relative to co-administration of the single entity products in 
healthy adult subjects.  The monolayer FDC formulation was chosen based on the results 
from study 204993 (GlaxoSmithKline Document Number 2015N258080_00.  In 
addition, a bilayer FDC tablet is being developed and will be included, if available.  This 
study will also assess the effect of food on the FDC formulation(s). 
2.2.
Brief Background
DTG is an HIV-1 integrase inhibitor with low to moderate inter-subject pharmacokinetic 
(PK) variability, a predictable exposure-response relationship, and a 14 hour plasma 
half-life.  Although co-administration of DTG with low-, moderate-, and high-fat meals 
in Study ING113674 (GlaxoSmithKline Document Number 2010N105142_00) increased 
DTG exposures (area under the plasma concentration-time curve from time 0 to infinity 
AUC(0-∞)) by 33%, 41%, and 66%, respectively, the TIVICAY product label states that 
the approved dose regimen is 50 mg once daily taken with or without food based on 
efficacy and safety results of Phase 3 trials where DTG was taken without regard to 
mealtimes.  DTG is available as the single entity product TIVICAY and as a component 
of the FDC product TRIUMEQ (DTG/abacavir (ABC)/lamivudine (3TC). 
Bioequivalence was demonstrated between DTG/ABC/3TC (TRIUMEQ) and the 
separate co-administered tablet formulations of TIVICAY plus ABC/3TC FDC 


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(EPZICOM) in the pivotal bioequivalence and food effect study for TRIUMEQ in Study 
ING114580 (GlaxoSmithKline Document Number 2012N145882_00).  The effect of 
food on DTG when administered as DTG/ABC/3TC FDC (TRIUMEQ) in study 
ING114580 was similar to the effect of food on a 50 mg DTG (ING113674) dose and 
was not considered clinically significant.  More information on the efficacy, PK, safety 
and drug interaction potential of DTG based on an extensive program of Phase I to III 
clinical trials can be found in the Investigator Brochure (IB) [GlaxoSmithKline 
Document Number RM2007/00683/07]).
Lamivudine (3TC) is an approved synthetic nucleoside reverse transcriptase inhibitor 
(NRTI) with activity against HIV and hepatitis B (HBV).  Intracellularly, 3TC is 
phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (L-TP). 
The principal mode of action of L-TP is the inhibition of HIV-1 reverse transcriptase via 
deoxyribonucleic acid (DNA) chain termination after incorporation of the nucleoside 
analogue into viral DNA.  3TC is well absorbed from the gastrointestinal tract with an 
absolute oral bioavailability in adults of 86% to 88% for liquid and solid dosage forms 
with Time to observed maximal drug concentration (Tmax)of approximately 1 hour.  3TC 
may be administered with or without food.  3TC exhibits dose-proportional PK at steady 
state following repeat doses of 0.25 to 10 mg/kg twice daily.  3TC is available as the 
single entity product EPIVIR and as a component of the following FDC products:  
COMBIVIR (zidovudine/3TC), EPZICOM/KIVEXA (ABC/3TC), TRIZIVIR 
(ABC/3TC/zidovudine), TRIUMEQ (DTG/ABC/3TC).
No significant food effect was observed for 3TC when administered as 3TC alone (study 
NUCA1001), as DTG/ABC/3TC (TRIUMEQ) in study ING114580, or as ABC/3TC 
FDC (EPZICOM) in study CAL10001 (GlaxoSmithKline Document Number
RM2002/00116/00).  
In a relative bioavailability study conducted in the fasted state, 204993, two experimental 
monolayer FDC tablet formulations of DTG/3TC were evaluated and compared to co-
administration of the separate formulations of DTG 50 mg clinical image and a single 
EPIVIRTM 300 mg tablet, in healthy volunteers 18 to 65 years of age.  All formulations of 
DTG/ 3TC were well-tolerated in this study. No deaths, serious adverse events (SAEs), 
or adverse events (AEs) leading to withdrawal from the study occurred. No clinically 
significant changes in clinical laboratory values, vital signs, or ECGs were observed 
during the study. The results for the primary endpoints of this study showed are shown in 
Table 1.


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Table 1
Statistical Comparisons of DTG and 3TC AUC(0-) and Cmax 
Following Administration of two FDC Tablets (Product Code AA and 
AB) versus Reference (Co-administration of the Separate 
Formulations of DTG 50 mg Clinical Image and a Single EPIVIRTM 300 
mg)
PK 
Parameters
DTG
3TC
Ratio of Geometric Least Squares Means (90% Confidence Interval)
Product Code AA (n=29) 
vs. Reference (n=30)
Product Code AB (n=29)
vs. Reference (n=30)
Product Code AA
(*n=29) vs. 
Reference (*n=30)
Product Code AB
(*n=29) vs. 
Reference (*n=30)
AUC(0-)
(h.ug/mL)
1.122
(1.005, 1.252)
1.015 
(0.909, 1.132)
1.033 
(0.991, 1.078)
1.030 
(0.988, 1.074)
Cmax (g/mL)
1.145 
(1.025, 1.278)
1.020 
(0.913, 1.140)
1.178
(1.080, 1.284)
1.231 
(1.129, 1.342)
DTG=Dolutegravir; 3TC=Lamivudine; AUC(0-)=AUC from time 0 extrapolated to infinity; Cmax=maximum 
observed concentrations; 
*For 3TC, AUC(0-): n=28 for reference, n=26 for product code AA, n=27 for product code AB. AUC(0-)for 5 
subjects was excluded because the duration for the calculation of z (apparent terminal slope) was <2x the 
calculated zand/or the R squared adjusted was < 0.85.
In brief, for the monolayer FDC tablet code AA, the DTG Cmax and AUC(0-) were 
approximately 14.5% and 12.2% higher than those following the reference treatment 
(DTG 50 mg tablet (clinical image) plus EPIVIR 300 mg tablet).  The 3TC AUC(0-) was 
similar to the reference treatment however, the 3TC Cmax was 17.8% higher than that for 
the reference treatment.  For the monolayer FDC tablet code AB, the DTG Cmax and 
AUC(0-), and the 3TC AUC(0-) were similar to those from the reference; however, the 
3TC Cmax was 23.1% higher than that from the reference.
The DTG/3TC FDC monolayer tablets used in study 204993 are similar in formulation 
with the approved TRIUMEQ formulation, minus the ABC component, which was 
shown to be bioequivalent to the separate co-administered tablet formulations of 
TIVICAY plus ABC/3TC FDC (EPZICOM) in Study ING114580.  A comprehensive 
analysis of the study conduct, inclusion/exclusion criteria, dissolution characteristics and 
impact of the demographic characteristics on the PK profiles and variability was unable 
to provide a clear explanation of the observed differences between the test and reference 
formulations.
In study 204993, product codes AA and AB contained the same quantitative composition 
and varied in the processing conditions used to manufacture the DTG granule. The
proposed study will use product code AH which has the same quantitative composition 
with the dolutegravir granule manufactured at the 300L commercial scale, which results 
in an in vitro dissolution profile for dolutegravir that falls between what was observed for 
product codes AA and AB in study 204993.
In addition, to the monolayer tablet FDC (product code AH), a bilayer FDC tablet is 
being developed.  The monolayer formulation is the preferred formulation for 
commercial development due to the lower complexity of manufacturing.  


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A flexible study design is proposed due to the uncertainty of whether or not a robust 
formulation for the bilayer tablet can be developed.  Part 2 of the study, incorporating the 
bilayer FDC formulation, will only be conducted if a suitable formulation is available.
Part 1:
Treatment periods 1 and 2 are a single-dose, crossover pivotal bioequivalence evaluation 
of the DTG/3TC FDC monolayer formulation tablet.  The reference formulation will be 
the 50 mg DTG clinical image and 3TC 300 mg tablet (EPIVIR).
Period 3 will evaluate the effect of a high fat meal on the FDC monolayer tablet
formulation.  As an increase in exposure has been previously shown when DTG was co-
administered with a high fat meal (ING113674), this portion of the study is not powered 
to demonstrate bioequivalence.  These data will be used to assess whether a similar food 
effect is observed with the FDC tablet as is seen with the single DTG entity.  A high fat 
meal was selected as this has shown the largest increase in DTG exposure compared with 
low- and moderate- fat meals. 
Part 2:
Treatment periods 1 and 2 will be conducted with the identical design as in Part 1, and 
evaluate the bioequivalence of a bilayer DTG/3TC FDC formulation tablet. The single 
entity reference formulations mentioned above will also be used in Part 2 (treatment 
periods 1 and 2). The food effect of the bilayer FDC tablet will be evaluated in Period 3 
of Part 2. 


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
To evaluate the bioequivalence of FDC tablet 
formulation(s) of DTG 50 mg and 3TC 300 mg versus 
co-administration of the separate tablet formulations of 
DTG 50 mg plus 3TC 300 mg, in the fasted state.
Plasma DTG and 3TC AUC(0-∞), AUC(0-t), and Cmax.
Secondary

To characterize the PK profile of single dose of 
FDC tablet formulation(s) of DTG 50 mg and 3TC 
300 mg versus co-administration of the separate 
tablet formulations of DTG 50 mg plus 3TC 
300 mg, in the fasted state

To evaluate the food effect on FDC tablet 
formulation(s) of DTG 50 mg and 3TC 300 mg 

To assess the safety and tolerability from single-
dose administration of the combination of DTG 
50 mg, 3TC 300 mg in healthy volunteers either 
fasted or with a high fat meal.

Plasma DTG and 3TC tlag, tmax, t, t½, z, %AUCex, 
AUC(0-24), CL/F and Vz/F, Ct, and C24

Plasma DTG and 3TC AUC(0-∞), AUC(0-t), Cmax, 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 vital signs (BP and HR), 
number of subjects with adverse events and 
toxicity grading of clinical laboratory tests
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞) = area under the plasma concentration time curve from time zero to infinity
AUC(0-24) = area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
tmax = time of maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
PK = Pharmacokinetic 
t = time of last quantifiable concentration
tlag = absorption lag time
z=apparent elimination rate constant
t1/2 =the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution


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4.
STUDY DESIGN
4.1.
Overall Design
This is a single-center, open-label, randomized, two-part study.    
There will be a washout of at least 7 days between treatment periods and all subjects will 
return for a follow-up visit 7 to 14 days after the last dose of study drug. A 4-hour 
tolerance limit to the washout period will be permitted prior to dosing (i.e., -4 hours) to 
allow flexibility at the study site in scheduling subject return visits for subsequent periods
2 and 3.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.
4.1.1.
Part 1: Bioequivalence and Food Effect with a FDC monolayer 
tablet 
Part 1 of the study will be a randomized, open-label, 2-period, single-dose, crossover 
study in 76 healthy adult subjects to achieve at least 70 evaluable subjects.  The first 16
subjects who complete the first two dosing periods, and consent to continue, will return 
for a third treatment period and receive a single dose of the FDC tablet formulation 
administered with a high fat meal.
The purpose of Part 1 is to evaluate the bioequivalence (first two treatment periods) of 
oral DTG 50 mg/3TC 300 mg FDC tablet formulation (monolayer with Product Code 
AH) proposed for commercial use compared to co-administration of the separate tablet 
formulations of DTG 50 mg (clinical trial material image) and 3TC 300 mg (EPIVIR)
and food effect (treatment period 3). For treatment periods 1 and 2, each treatment will 
be administered in the fasted state after at least 10 hours of fasting. 
Figure 3
Study Design: Part 1, Bioequivalence and Food Effect with 
monolayer FDC tablet
Randomization N=76
Treatment Period 1
A: Reference treatment 
DTG + 3TC
Or
B: FDC formulation
Washout ≥ 7 days
Treatment Period 2
A: Reference treatment 
DTG + 3TC
Or
B: FDC formulation  
Treatment Period 3 
B: FDC formulation
(N=16)
With high fat meal
Washout ≥ 7 days


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4.1.2.
Part 2 – Bioequivalence and Food Effect with an FDC bilayer 
tablet 
Part 2 of the study, incorporating the bilayer FDC formulation, will only be conducted if 
a suitable formulation is available.
Figure 4
Study Design – Part 2, Bioequivalence and Food Effect with bilayer 
FDC formulation (if conducted)
4.2.
Treatment Arms and Duration
Each subject will have a screening visit within 30 days prior to the first dose of study 
drug, up to three treatment periods each with a single dose of study drug and a follow-up 
visit within 7-14 days after the last dose of study drug.  There will be a washout of at 
least 7 days (-4 hours) between each dose of study drug.  The total duration of 
participation of a subject in this study will be approximately 11 weeks.
4.3.
Type and Number of Subjects
A minimum of 76 healthy adult subjects will be randomized such that a minimum of 
approximately 70 evaluable subjects complete treatment periods 1 and 2 of Part 1 of the 
study. A total of 16 subjects who complete treatment periods 1 and 2 and provide consent 
will continue and participate in period 3 of the study, in Part 1.
If Part 2 of the study is conducted, another 76 healthy adult subjects will be randomized
such that a minimum of approximately 70 evaluable subjects complete treatment periods 
1 and 2 of Part 2 of the study.  A total of 16 subjects who complete treatment periods 1 
and 2 and provide consent will continue and participate in period 3 of the study, in Part 2.
Evaluable subjects are defined as all subjects who provide sufficient concentration-time 
profiles to calculate valid PK parameters for both analytes for Period 1 and Period 2
without important protocol violation. Data from subjects who vomit within 4 hours of 
study drug administration will not be considered as evaluable.
If subjects prematurely discontinue the study for reasons other than adverse event (AE), 
additional replacement subjects may be randomized and assigned to the same treatment 
sequence at the discretion of the Sponsor in consultation with the investigator.
4.4.
Design Justification
This primary objective of this study is to evaluate the bioequivalence of DTG and 3TC
when administered as a FDC tablet compared to the co-administration of the 2 single 
Randomization N=76
Treatment Period 1
A: Reference treatment 
DTG + 3TC
Or
C: FDC formulation
Washout ≥ 7 days
Treatment Period 2
A: Reference treatment 
DTG + 3TC
Or
C: FDC formulation  
Treatment Period 3 
C: FDC formulation
(N=16)
With high fat meal
Washout ≥ 7 days


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entity products in the fasted state.  Two FDC formulations will be tested (a monolayer 
[preferred formulation] and a bilayer formulation, if available).  In addition, an evaluation 
of the effect of food on the FDC formulation(s) will be conducted.
A cross-over design was selected for this study so that within subject comparisons can be 
utilized to reduce the number of subjects required for the study.  The half-life of DTG
and 3TC requires at least a 7-day washout between DTG and 3TC doses and a 72-hour
PK sampling period to ensure that pre-dose concentrations are negligible and that PK 
parameters are well-estimated.
4.5.
Dose Justification
The United States Food and Drug Administration (US FDA)-approved adult dose of DTG 
for treatment-naive and non-INI resistant treatment-experienced HIV-infected patients is 
50 mg once daily, in combination with other antiretroviral drugs. 
The US FDA-approved recommended adult dose of 3TC for treatment naive 
HIV-infected patients is 300 mg once daily, in combination with other antiretroviral 
drugs. 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DTG
or DTG in combination with 3TC can be found in the Investigator’s Brochure 
(GlaxoSmithKline Document Number RM2007/00683/07) and product labels for DTG 
and 3TC.  The following section outlines the risk assessment and mitigation strategy for 
this protocol. Of note, the events noted in the table below were observed with the 
repeated doses of DTG and 3TC. The risk of these events would be significantly lower 
for the single doses being used in this protocol. 


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4.6.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to IB for additional information
DTG: Hypersensitivity 
reaction (HSR) and rash
DTG: 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 5.2)

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 5.4.3)

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. 
DTG & 3TC: Drug induced 
liver injury (DILI) and other 
clinically significant liver 
chemistry elevations
DTG: 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.  
3TC:  Current treatment guidelines Department of Health and Human 
Services, 2013 and European AIDS Clinical Society, 2012) do not recommend 
monotheraphy with 3TC for patients with HBV infection.  Additionally, 
discontinuation of 3TC in HBV coinfected subjects can result in severe 
exacerbations of HBV.
Subjects meeting either of the following criteria during the screening 
period are excluded (Section 5.2).

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).
DTG and 3TC: Renal 
function
DTG:  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 (GFR) 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. 

Due to requirements for dose reduction of 3TC in patients with 


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to IB for additional information
3TC is eliminated by renal excretion and exposure increases in patients with 
renal dysfunction.
renal dysfunction, only healthy volunteers will be enrolled and 
subjects with a creatinine clearance (CrCL) <90 mL/min will be 
excluded in this study.
DTG: Creatine 
Phosphokinase (CPK) 
elevations
DTG:  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).
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.  


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4.6.2.
Benefit Assessment
This is a study in healthy subjects and as such there is no expected benefit to 
administration of DTG or 3TC.  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.
4.6.3.
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 DTG and 3TC are justified by the 
anticipated benefits that may be afforded to subjects with HIV.  The events noted in 
Section 4.6.1 were observed with the repeated doses of DTG and 3TC.  The risk of these 
events would be significantly lower for the single doses being used in this protocol. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL 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 respective IBs and 
product labels.
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.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 55 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, electrocardiogram [ECG]).
3. 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 if required, agree and document that the finding is unlikely 


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to introduce additional risk factors and will not interfere with the study procedures. 
4. Subject must be able to swallow 2 tablets at the same time (Reference tablets only).
WEIGHT
5. Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive)
SEX
6. Male or Female
Female subject: is eligible to participate if she is not pregnant (as confirmed by a 
negative serum or urine human chorionic gonadotrophin [hCG] test), not lactating, 
and at least one of the following conditions applies:
a. Non-reproductive potential defined as: 

Pre-menopausal females with one of the following:
o
Documented tubal ligation
o
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion
o
Hysterectomy
o
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 Section 12.5) from 30 days prior to the first dose of study 
medication and until at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer after the last dose of 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
7. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply ply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND 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 interval corrected for heart rate according to Fridericia’s formula (QTcF) > 
450msec.
NOTES:

The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), machine-read or manually over-read.

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, QT interval corrected for heart rate according to 
Bazett’s formula (QTcB), QTcF, another QT correction formula, or a composite of 
available values of QTc will be used as specified in the Reporting and Analysis Plan 
(RAP).
CONCOMITANT MEDICATIONS
4. Unable to refrain from the use of prescription 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 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.


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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.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and if necessary a certified letter to the subject’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 


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destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
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 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 subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
A subject that meets the criterion below will be withdrawn from the study.  

QTcF > 500 msec


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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.  
The QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period.   
5.4.3.
Rash
If subject develops Grade 3/4 rash, subject must permanently discontinue study drug and 
will be withdrawn from the study. Specific/detailed toxicity management guidance is 
provided for rash in Section 12.7.
5.5.
Subject 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.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may;
therefore, refer to the individual study treatments or the combination of those study 
treatments.


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Study Treatment
Reference Treatment
Test:  FDC Monolayer 
Tablet
Test:  FDC Bi-layer 
Tablet (if conducted)
Product name:
Dolutegravir
Lamivudine 
(EPIVIR)
Dolutegravir/Lamivudine 
Tablets, 50 mg/300 mg 
Item Code DP277482 
Product Code AH
Dolutegravir/Lamivudine 
Tablets, 50 mg/300 mg 
Item Code TBD Product 
Code TBD
Formulation 
components:
Dolutegravir, 
D-mannitol, 
microcrystalline 
cellulose, 
povidone, 
sodium starch
glycolate, 
sodium stearyl 
fumarate, 
Opadry II white 
85F48011
Lamivudine, 
Microcrystalline 
cellulose, 
sodium starch 
glycolate, 
magnesium 
stearate, 
Opadry Gray 
YS—1-17506A
Dolutegravir, Lamivudine
D-mannitol, 
microcrystalline cellulose, 
povidone, sodium starch 
glycolate, sodium stearyl 
fumarate, Aquarias film 
coat white BP18237
Dolutegravir, Lamivudine
D-mannitol, 
microcrystalline cellulose, 
povidone, sodium starch 
glycolate, sodium stearyl 
fumarate, magnesium 
stearate, Aquarias film 
coat white BP18237
Formulation 
Description
Clinical image 
dolutegravir 
tablet
Commercial 
EPIVIR Tablet
Commercial dolutegravir 
granules made at set 
point conditions combined 
with extragranular 
lamivudine and excipients
Information forthcoming
Dosage form:
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
Dolutegravir 50 mg, Lamivudine 300 mg
Route of 
Administration
Oral
Dosing 
instructions:
One or both, tablet(s) to be taken at the same time with 240 mL of room temperature water
Physical 
description:
A white, film-
coated, round 
tablet debossed 
with SV 572 on 
one side and 50 
on the other 
side.
Gray, diamond-
shaped tablet, 
engraved 
“GX EJ7” on 
one side and 
plain on the 
other side.
Oval, biconvex, white, film 
coated tablet deembossed 
‘SV H7I’ on one face 
Oval, biconvex, white, 
film coated tablet 
deembossed ‘SV 13N’ 
on one face 
Method for 
individualizing 
dosage:
One tablet
6.2.
Treatment Assignment
Subjects will be randomized to one of the following two sequences in Part 1 and Part 2, if 
conducted, in accordance with the randomization schedule generated by GSK Clinical 
Statistics or designee, prior to the start of the study, using validated internal software.
A description of each regimen is provided in Table 2:


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Table 2
Treatment Assignments
Sequences
Period 1
Period 2
Period 3
Bioequivalence, 2 Period-
Crossover Design
Food effecta
Part 1
A/B, n=38
A
B
B Fed
(n=16)
B/A, n=38
B
A
Part 2 (if conducted)
A/C, n=38
A
C
C Fed
(n=16)
C/A, n=38
C
A
Treatment A = DTG 50 mg tablet (clinical image) plus a single EPIVIR 300 mg tablet
Treatment B = DTG 50 mg/3TC 300 mg FDC monolayer formulation (Product code AH)
Treatment C = DTG 50 mg/3TC 300 mg FDC bilayer formulation (Product code TBD)
a. first 16 subjects who complete the two treatment periods, and consent to continue to 
complete period 3 in each part
6.3.
Planned Dose Adjustments
This study will be conducted using single doses of investigational product.  There will be 
no dose adjustments.
6.4.
Blinding
This will be an open-label, randomized, study.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

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 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.

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).  Information 
on the Handling of Clinical Testing Samples for Pivotal Bioequivalence Studies is 
provided in Section 12.3.


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
Further guidance and information for final disposition of unused study treatment are 
provided in the Dispensing plan provided by the site.

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 
ViiV Healthcare.
6.7.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
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.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of dolutegravir >50 mg or lamivudine >300 mg within a 24 hour 
time period 1 hour will be considered an overdose.
ViiV Healthcare does not recommend specific treatment for an overdose. The 
investigator will use clinical judgment to treat any overdose.
In the event of an overdose the investigator or treating physician should:
1. Contact the Medical Monitor immediately
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until DTG and 3TC can no longer be detected 
systemically (at least 7 days)
3. Obtain a plasma sample for pharmacokinetic (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 case report form (CRF).
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.


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6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from ViiV Healthcare after completion 
of the study because only healthy volunteers are eligible for study participation.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
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 collection of the final pharmacokinetic 
sample after the final dose.
Subjects will refrain from chewing or ingesting sugar-free gums, candies or other 
processed food/drink products that containing sugar alcohols (e.g., sorbitol, mannitol, 
xylitol, maltitol, isomalt) during the inpatient period of each dosing session (i.e., Day -1 
through 48 hours post-dose).
Once in the clinical unit subjects will not be allowed to eat anything other than the food 
provided by the study center.
6.10.1.1.
Fasting Conditions
In treatment periods 1 and 2 of each part of the study during the overnight period from 
Day -1 to Day 1:

An evening meal and/or snack, identical across each period, will be provided by the 
unit (e.g. on Day -1).

Subjects must then fast from all food and drink (except water) for 10 hours pre-dose 
and prior to any clinical laboratory evaluations (except repeat evaluations).

No food is allowed for at least 4 hours post-dose.

Room temperature water will be provided with dosing (~240 mL, 8 fluid ounces) and 
at all times except 1 hour pre-dose through 2-hours post-dose.  The full 240 mL must 
be consumed at dosing.
6.10.1.2.
Fed Conditions (Period 3 only)
In Period 3 of each part of the study, subjects will receive study medication following a 
standard high fat breakfast similar to what is defined in FDA Guidance, 2002.  Following 
an overnight fast of at least 10 hours, subjects will start the recommended meal 30 
minutes prior to dosing.  Study subjects will eat this meal in 25 minutes or less and 
dosing will be administered 30 minutes after the start of the meal.  Identical breakfasts 
will be served for this period on the dosing day and the entire meal must be consumed.  
Dosing will occur with 240 mL (8 fluid ounces) of room temperature water.  No food 
should be allowed for at least 4 hours post-dose.  Water can be allowed as desired except 
1 hour pre-dose through 2-hours post-dose.  


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An example high-fat meal would be:

two eggs fried in butter,

two strips of bacon,

two slices of toast with butter,

four ounces of hash brown potatoes and 

eight ounces of whole milk. 
Substitutions to the test meal can be made as long as the meal provides a similar amount 
of calories from protein, carbohydrate, and fat and has comparable meal volume and 
viscosity (approximately 150, 250, and 500-600 calories from protein, carbohydrate, and 
fat, respectively). At all other times, subjects will receive standardized meals scheduled 
at the same time in each period of the study.
6.10.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 
hours prior to the start of dosing until collection of the final pharmacokinetic sample 
during each dosing session. 

During each dosing session, subjects will abstain from alcohol for 24 hours 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 until after 
the final follow-up visit.
6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests (e.g., screening, Day -1, and follow-up). Subjects will 
maintain upright position (sitting, walking, or propped upright in bed) for 4 hours post-
dose.  Subjects may participate in light recreational activities during studies (e.g., watch 
television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Acetaminophen, at doses 2 grams/day, is permitted for use at any time during the study.  
Other concomitant medications may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor if required.
6.11.2.
Prohibited Medications and Non-Drug Therapies
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.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
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, and 
pharmacokinetic 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/ViiV
study team member and then archived in the study sponsor and site study files, but 
this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the 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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7.1.
Time and Events Table
Table 3
Screening Assessments
Visit Window (relative to Day 1)
Day -30 to -2
Notes
Informed Consent
X
Demographics
X
Physical examination height, weight and BMI
X
Medical/medication/ history
X
Medical/medication/drug and alcohol history will 
be recorded at screening, and updated at 
admission.
Urine drug / Cotinine and Breathalyzer 
screening
X
12-lead ECG and Vital Signs
X
Serum or urine hCG test (female subjects only)
X
See inclusion criterion #6.
Performed at site standard procedure.
FSH and estradiol (women)
X
HIV, Hep B and Hep C Screen
X
Hematology/Chemistry/Urinalysis tests
X


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Table 4
Treatment Period Assessments
Assessments
All Dosing Periods
Follow-up
Notes
Day -1 of Periods 2 to 3 may be the same day as Day 6 
of prior periods
Day -1
Day 1
Day 
2
Day 
3
Day 
4
Pre-
dose
0 hr
Post Dose
-
48 hr
72 hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
X
Follow-up visit will occur 7 to 14 days post last dose.
12-lead ECG
X
Single ECGs will be collected at Screening and on Day-1 of 
Period 1 only. Additional ECGs may be performed at the 
discretion of the investigator.
Vital signs
X
X
At 4 hours post-dose
X
X
X
X
Single measurements performed at all time points.
Brief Physical Exam
X
Brief examinations may be made full examinations and 
laboratory procedures may be repeated, if needed, at the 
discretion of the Investigator.
Illicit Drug/Alcohol/Cotinine/pregnancy screening will be 
performed in accordance with the sites’ standard practice.
Clinical laboratory tests – see Table 5.
Urine Drug/ Cotinine and 
Breathalyzer
X
Pregnancy test
X
X
Clinical laboratory tests 
X
X
Dosing
X
Subject will be dosed while in the seated position.
Pharmacokinetic Sampling
X
Collect at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 5, 6, 8, 12, 16, 24, and 48 hours post-
dose
X
Pre-dose (within 15 minutes prior to dosing). 
4 hour post dose sample must be taken prior to provision of 
food.
Permitted window for the collection of PK sample at each 
time point will be specified in BioPacket. 
Meals – (Treatment periods 
1 and 2)
Fasted from 10 hours prior to 
dosing to 4 hours post-dose
Standard for the study center
See also Section 6.10.1.1
Meals - Treatment Period 3
(Fed Conditions only)
Fasted from 10 hours prior to 
test meal and dosing then 
through 4 hours post-dose
Standard for the study center
Entire meal to be consumed in 25 minutes or less and 
dosing will be administered 30 minutes after the start of the 
meal.  See also Section 6.10.1.2
Adverse Events
X
=======================X=======================
X
Concomitant medications
X
=======================X=======================
X


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7.2.
Screening and Critical Baseline Assessments
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 listed in Section 5.  
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Additional time points for safety tests (e.g., vital signs, physical exams and 
laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4 (see Section 12.4).
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
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/ViiV
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 Study Treatment until the follow-up contact 
(see Section 7.3.1.1), at the timepoints specified in the Time and Events Table 
(Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the CRF.

All SAEs will be recorded and reported to GSK/ViiV within 24 hours, as indicated in 
Section 12.4.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator must promptly 
notify GSK/ViiV.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK/ViiV are provided 
in Section 12.4


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7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Section 12.4.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK/ViiV of SAEs related to study treatment 
(even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product 
under clinical investigation are met. 
GSK/ViiV has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  
GSK/ViiV will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK/ViiV policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK/ViiV will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
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/ViiV within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Section 12.5.


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7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height
(screening only) and weight will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.3.4.
Vital Signs
Vital signs will be measured in the supine or semi-supine position after 5 minutes rest 
and will include temperature, systolic and diastolic blood pressure (BP) and pulse rate.
7.3.5.
Electrocardiogram (ECG)
12-lead ECGs will be performed with the subject in a supine or semi-supine position 
having rested in this position for at least 10 minutes beforehand.
Single 12-lead ECGs will be obtained at each time point during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTcF intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.
7.3.6.
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.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the BioPacket. Reference ranges for all safety parameters will be provided to 
the site by the laboratory responsible for the assessments.
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 CRF.
Refer to the BioPacket for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.


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Refer to the site provided 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 Chemistry1
Blood urea nitrogen 
(BUN)
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine 
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Creatine 
phosphokinase 
(CPK)
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
and/or Additional 
Tests

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)

Cotinine

Creatinine clearance (CrCL) for GFR estimation 

Serum or urine hCG Pregnancy test (as needed for women of child bearing potential)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2, Appendix 2.
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.  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.
7.4.
Pharmacokinetics
Further information on the Handling of Clinical Testing Samples in Pivotal 
Bioequivalence Studies in provided in Section 12.3.


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7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of DTG and 3TC will be collected at 
the time points indicated in Section 7.1 Time and Events Table. The 4-hour post-dose 
sample must be drawn prior to the subjects’ first post-dose meal.  The actual date and 
time of each blood sample collection will be recorded.  
For each time point identified in Section 7.1, Time and Events Table, 2 mL of blood will 
be collected into di-potassium ethylenediaminetetraacetic acid (K2EDTA) tubes.  Details 
of PK blood sample collection, processing, storage and shipping procedures are provided 
in the site provided BioPacket.
7.4.2.
Sample Processing Procedures
If a cannula is used, the cannula will be inserted into an arm vein within sufficient time 
prior to dosing, will be kept patent with normal saline, and will be removed after the last 
blood sample is collected or earlier if the subject requests.  To avoid artificial dilution of 
the PK samples by saline, 1 mL of whole blood will be collected and discarded before 
each whole blood sample is collected.
Collect each serial whole blood PK sample as close as possible to the planned time 
relative to dosing detailed in the protocol.  Collect a whole blood (2 mL) sample into a 
properly labelled K2EDTA evacuated blood collection tube.  Record the date and exact 
time that each sample is collected in the CRF.
7.4.3.
Sample Storage Conditions
Immediately after collection, gently invert (DO NOT SHAKE) the blood collection tube 
8-10 times to mix the K2EDTA anti-coagulants with the whole blood and place the 
samples at room temperature.  Within 45 minutes of sample collection, centrifuge for 10 
minutes, at 1500 - 2000 G, in 4°C.  Within 30 minutes of centrifugation, using a 
polyethylene pipette, transfer plasma into separate, single, and appropriately labelled 
2 mL Amber Sarstedt tubes.  Immediately freeze the storage tubes in an upright position 
at -20°C.
7.4.4.
Sample Analysis
Dolutegravir will be extracted from plasma using protein precipitation followed by ultra 
performance liquid chromatography triple quadrapole mass spectrometry (UPLC-
MS/MS) using the previously validated method, Quantitation of GSK1349572 in Human 
Plasma via UPLC with MS/MS Detection (PPD method number, P1170.02; 
GlaxoSmithKline Document Number 2012N147635_00.  The analysis will be performed 
by PPD, 3230 Deming Way, Middleton, WI, USA. The DTG sample analysis will be 
under the management of Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, 
GlaxoSmithKline.  Raw data will be archived at the bioanalytical site.
Lamivudine will be extracted from plasma using protein precipitation followed by high
performance liquid chromatography triple quadrapole mass spectrometry (HPLC-
MS/MS) using the previously validated method, Quantitation of  Abacavir and 


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Lamivudine in Human Plasma via UHLC with MS/MS Detection (PPD method number, 
P1165; GlaxoSmithKline Document Number 2012N147635_00). The analysis will be 
performed by PPD, 3230 Deming Way, Middleton, WI, USA. The lamivudine sample 
analysis will be under the management of Bioanalysis, Immunogenicity and Biomarkers 
(BIB), PTS, GlaxoSmithKline.  Raw data will be archived at the bioanalytical site.
8.
DATA MANAGEMENT

For this study subject data will be entered into a Site defined and GSK validated eDC 
system (TrialOne), transmitted electronically to GSK and combined with data 
provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK/ViiV policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The first two treatment periods of each part of this study are designed to test the 
bioequivalence of FDC tablets of DTG and 3TC (test treatment) relative to co-
administered DTG plus 3TC (reference treatment) all under fasting conditions. The null 
hypothesis is that the true ratio of the geometric mean of the test treatment to the 
geometric mean of the reference treatment, μ(test)/μ(reference), for each primary PK 
endpoint, is either less than 0.800 or greater than 1.250.  The alternate hypothesis is that 
the true ratio of the test treatment geometric mean to the reference treatment geometric 
mean is greater than or equal to 0.800 and less than or equal to 1.250. Symbolically, this 
is expressed as follows: H(0): μ(test)/μ(reference) < 0.800 or μ(test)/μ(reference) > 1.250, 
i.e., treatments are not bioequivalent versus H(1): 0.800 ≤μ(test)/μ(reference) ≤1.250
i.e., treatments are bioequivalent. For each PK parameter designated as a primary 
endpoint (see Section 3), a two one-sided t-test (TOST) procedure (Schiurmann, 1987) 
with α=0.05 for each one-sided test will be used to test this set of hypotheses.  This is 
equivalent to requiring that a 90% interval for the true ratio of test to reference geometric 
means falls entirely within the range of 0.800 to 1.250.  To declare bioequivalence of 
FDC tablet DTG and 3TC to co-administered DTG plus 3TC, the primary PK endpoints 
for both analytes should demonstrate bioequivalence.
For the food effect portions, no formal hypothesis will be tested and an estimation 
approach will be used to evaluate the effect of food on the FDC tablet.  


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
For the bioequivalence portions, geometric mean ratio and within subject variability from 
the PK analysis of a similar FDC formulation in study 204993 (GlaxoSmithKline 
Document Number 2015N258080_00 are shown in Table 6.
Estimates of the likely CVw% and true GLS means ratio were based on the results of 
study 204993 (GlaxoSmithKline Document Number 2015N258080_00) and 
consideration of in vitro dissolution properties for DTG.  Based on the largest CVw
estimate of 26% (SD=0.256) and the following assumptions, a sample size of 70 
statistically evaluable subjects will provide 90% power to demonstrate bioequivalence for 
the FDC compared to co-administration of DTG and 3TC:

a true ratio of 1.10,

the within-subject variability from the current study will not be larger than that used 
in the sample size calculations,

data are log-normally distributed, and each one sided t-test is made at the 5% level.
Table 6
Ratio of Geometric Least Squares Means and CVw% for DTG and 
3TC in Study 204993
PK Parameters
DTG
3TC
Product Code AA 
vs. Reference
Product Code AB
vs. Reference
Product Code AA
vs. Reference
Product Code AB
vs. Reference
AUC(0-t) (h.µg/mL)
1.126 (25.6)
1.014 (25.6)
1.024 (9.6)
1.042 (9.6)
AUC(0-) (h. µg/mL)
1.122 (25.4)
1.015 (25.4)
1.033 (9.0)
1.030 (9.0)
Cmax (g/mL)
1.145 (25.7)
1.020 (25.7)
1.178 (19.9)
1.231 (19.9)
For the food effect portions, based on a CVw of 26% and a sample size of 14 evaluable 
subjects for food effect assessment, it is estimated that the precision (i.e., half width of 
the 90% confidence interval on the log scale) for the treatment difference will be within 
17.2% of the point estimate for AUC(0-∞), AUC(0-t), and Cmax, for food effect assessment. 
9.2.2.
Sample Size Sensitivity
A sensitivity analysis was conducted in the event that the variability will be greater than 
estimated or the GLS means ratio deviates from assumptions for the bioequivalence 
portions.  The effects on the power of declaring bioequivalence in the face of either a 
change of magnitude in the within subject variation or a shift in the expected ratio of the 
means are examined and presented in Table 7 for both DTG and 3TC.  A sample size of 
70 evaluable subjects will provide approximately 79% or 52% power to demonstrate 
bioequivalence in 3TC Cmax for the FDC compared to co-administration of DTG and 
3TC, if CVw is 20% and the true ratio is as high as 1.15 or 1.18; respectively, in 3TC 
Cmax.  This higher 3TC Cmax is not considered clinically significant and does not represent 
a safety concern.


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Table 7
Within-Subject Variability and Changes in Expected True Ratio of 
Test: Reference on Power with the Targeted Sample
Analyte
Target Sample 
Size
Within Subject 
Variability (CVw%)
True Ratio
Power (%)
DTG
70
26
0.95
98.9
1.02
99.9
1.05
99.1
1.10
90.0
1.15
60.4
70
30
0.95
96.3
1.02
99.1
1.05
96.7
1.10
81.8
1.15
50.8
60
26
0.95
97.7
1.02
99.6
1.05
98.0
1.10
85.6
1.15
54.8
60
30
0.95
93.6
1.02
98.0
1.05
94.1
1.10
76.2
1.15
45.7
3TC
70
20
1.10
98.4
1.15
79.4
1.18
52.4
70
25
1.10
91.9
1.15
63.3
1.18
39.2
60
20
1.10
96.8
1.15
73.7
1.18
47.2
60
25
1.10
87.8
1.15
57.5
1.18
35.3
For the food effect portions, a higher within-subject CVw of 30% will be assumed.  With 
14 evaluable subjects, it is estimated that the half width of the 90% confidence interval 
for the treatment difference on the log scale will be within 19.8% of the point estimate for 
AUC(0-∞), AUC(0-t) and Cmax. 
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.


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9.3.
Data Analysis Considerations
9.3.1.
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:
Screening Population
All subjects who signed the consent form will be included in this population. This
population will be used to present the date of first subject first screened, and numbers of
subjects screened and enrolled.
Safety Population
All subjects who enrolled in the study and received at least one dose of study drug will be
included in the Safety Population. This will be the population for the safety analyses and
for summarization of baseline/demographic characteristics.
Pharmacokinetic Plasma Concentration Population
The PK Plasma Concentration Population will include all subjects who undergo plasma 
PK sampling and have evaluable PK assay results for DTG or 3TC.  This population will 
be used for Listing the PK concentrations, calculating PK parameters, and plotting of the 
individual concentration-time profiles for DTG and 3TC.  Data from subjects who vomit 
within 4 hours of study drug administration will be excluded from pharmacokinetic 
concentration summary, pharmacokinetic parameter summary, and statistical 
comparisons, but will be included in the Listings.
Pharmacokinetic Parameter Summary Population
The PK Parameter BE Summary Population will include all subjects who have evaluable 
PK parameters for both analytes and for both Period 1 and Period 2. Data from subjects 
who vomit within 4 hours of study drug administration will not be considered as 
evaluable. This population will be used for the statistical analysis of parameter data, the 
PK concentration summary, and the PK parameter summary and figures for DTG and 
3TC for bioequivalence assessment. Excluded subjects will be included in footnotes for 
summary tables.
The PK Parameter Food Effect Summary Population will include subjects who 
participate in the food effect part of study, and have evaluable PK parameters for both fed 
and fasted administration of the FDC tablet formulation.  Data from subjects who vomit 
within 4 hours of study drug administration will not be considered as evaluable. This 
population will be used for summary and analysis of PK parameter data for food effect 
assessment.


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9.3.2.
Interim Analysis
Following completion of Part 1, preliminary PK data from Part 1 will be analyzed. The 
point estimates and corresponding 90% CIs will be constructed for the ratio of the 
geometric mean of the test treatment (monolayer) to the geometric mean of the reference 
treatments, μ(test)/μ(reference) for AUC(0-∞), AUC(0-t), and Cmax for both DTG and 3TC. 
The result will be used for planning a future Phase III study. 
An independent statistical and programming team will perform the preliminary PK 
analysis. As the PK data are analyzed separately for each part of the study, there will be 
no adjustments for multiplicity.
9.4.
Key Elements of Analysis Plan
Final analyses will be performed after the completion of the study and final datasets
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 variables; Geometric mean with 
associated 95% confidence interval (CI), and the between-subject CV (%CVb) for the 
geometric mean will be included for the 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 9.3 or higher of the Statistical Analysis Software (SAS) system will be used to 
analyze data as well as to generate tables, listings, and figures. Complete details will be 
documented in the RAP.
9.4.1.
Primary and Secondary Analyses
Comparisons will be made for the single dose PK parameters of DTG and 3TC, as 
described in Table 8. 
Table 8
Primary and Selected Secondary Comparisons of Interest
DTG or 3TC 
PK Parameter
Test
Reference
Assessment
Primary
AUC(0-), AUC(0-t), Cmax,
Treatment B
Treatment A
Bioequivalence
Treatment C 
(if Part 2 is 
conducted)
Treatment A
Secondary
CL/F, AUC(0-24), C24, t1/2
Treatment B
Treatment A
Bioequivalence


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DTG or 3TC 
PK Parameter
Test
Reference
Assessment
Treatment C
(if Part 2 is 
conducted)
Treatment A
AUC(0-), AUC(0-t), Cmax, 
CL/F, AUC(0-24), C24, t1/2
Treatment B 
Fed
Treatment B 
Fasted
Food Effect
Treatment C 
Fed
(if Part 2 is 
conducted)
Treatment C 
Fasted
9.4.2.
Pharmacokinetic Analyses
PK analyses will be the responsibility of the Clinical Pharmacology Modeling & 
Simulation department within GSK or their designee.  Plasma DTG and 3TC 
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 pharmacokinetic 
parameters will be determined, as data permit:  Cmax, Tmax, AUC(0-t), AUC(0-), AUC(0-24),
t1/2, tlag, C24, z, %AUCex, Vz/F, t and CL/F.
PK 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 R& D. 
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline or their designee.
The PK parameters for DTG and 3TC (except tmax and tlag) will be loge-transformed and 
separately analyzed using a mixed effects model. For the analysis of bioequivalence, the 
model will include fixed effect terms for period and treatment.  Subject will be treated as 
a random effect in the model.  For the analysis of food effect, the model will include a 
fixed effect term for treatment (fed versus fasted) and a random effect term for subject. 
Point estimates and their associated 90% CIs will be constructed for the differences in PK 
parameter values between test and reference treatments for the treatment comparisons 
specified in Section 9.4.1.  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.
Tmax and Tlag of DTG and 3TC will be separately analyzed with the non-parametric 
Wilcoxon matched pair method to compute point estimates and associated 90% 
confidence intervals for the median differences between test and reference treatments.
9.4.3.
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.


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The details of the statistical analyses of safety and PK data will be provided in the 
Reporting and Analysis Plan.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK/ViiV will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK/ViiV policy.
The study will also be conducted in accordance with International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) Good Clinical Practice (GCP), all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 


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being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff 
the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, 
GSK/ViiV may conduct a quality assurance assessment and/or audit of the site 
records, and the regulatory agencies may conduct a regulatory inspection at any time 
during or after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK/ViiV reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicenter studies, this can occur at one or more or at all 
sites.  

If GSK/ViiV determines such action is needed, GSK/ViiV will discuss the reasons for 
taking such action with the investigator or the head of the medical institution (where 


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applicable).  When feasible, GSK/ViiV will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the impending 
action.

If the study is suspended or prematurely discontinued for safety reasons, GSK/ViiV
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK/ViiV will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
for a GSK/ViiV audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  

The investigator must notify GSK/ViiV of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of 
the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 


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opportunity to review the complete study results at a GSK/ViiV site or other mutually-
agreeable location.
GSK/ViiV will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK/ViiV
Policy.


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11.
REFERENCES
FDA Guidance for Industry Food-Effect Bioavailability and Fed Bioequivalence Studies. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 2002.
GlaxoSmithKline Document Number 2010N105142_00. “Relative Bioavailability Study 
of Three Different Tablet Formulations of GSK1349572 50 mg and the Dose 
Proportionality of and Effect of Food on the Selected Formulation in Healthy Male and 
Female Volunteers” Effective Date Oct 2010.
GlaxoSmithKline Document Number 2012N145882_00. “Study ING114580 - An 
Evaluation of the Bioequivalence of a Combined Formulated Tablet 
(50mg/600mg/300mg dolutegravir/abacavir/lamivudine) Compared to One Dolutegravir 
50mg Tablet and One EPZICOM (600mg/300mg abacavir/lamivudine) Tablet 
Administered Concurrently and the Effect of Food on Bioavailability of the Combined 
Formulation in Healthy Adult Subjects.”  Effective Date May 2013.
GlaxoSmithKline Document Number 2012N147635_00 Quantitation of GSK1349572 in 
Human Plasma via UPLC with MS/MS Detection Compound: GSK1349572. Effective 
Date 2012
GlaxoSmithKline Document Number 2012N150069_02: Quantitation of Abacavir and 
Lamivudine in Human Plasma. Effective Date 2012
GlaxoSmithKline Document Number 2015N258080_00 “Study 204993 - A Phase I, 
relative oral bioavailability study of different fixed dose combinations of dolutegravir and 
lamivudine in healthy subjects”. Effective Date 2015
GlaxoSmithKline Document Number RM2002/00116/00. An Evaluation of the 
bioequivalence of a Combined Formulated Tablet (600 mg /300 mg abacavir/lamivudine) 
Compared to ZIAGEN† (abacavir) 2 X 300mg Tablets and EPIVIR† (lamivudine) 2 X 
150mg Tablets Administered Concurrently and the Effect of Food on Absorption of the 
Combined Formulation in Healthy Adult Subjects. Effective Date June 2002.
GlaxoSmithKline Document Number RM2007/00683/07: GSK1349572 Clinical 
Investigator's Brochure. 9 October 2015
Schiurmann DJ.  A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability.  J Pharmacokinetics 
Biopharm 1987;15:657-679.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR TM
ACTG
AIDS Clinical Trials Group
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALT (SGPT)
Alanine Aminotransferase (serum glutamic pyruvic transaminase)
ANC
Absolute neutrophil count
ART
Antiretroviral Therapy
ARV
Antiretroviral
AST (SGOT)
Aspartate Aminotransferase (serum glutamic oxaloacetic transaminase)
AUC(0-24)
Area under the concentration-time curve from time 0 to 24 hours
AUC(0-t)
Area under the concentration-time curve from time 0 to the last measurable timepoint
AUC(0-)
Area under the concentration-time curve from time 0 extrapolated to infinity
BMD
Bone mineral density
BMI
Body mass index
BP
Blood Pressure
BPAP
Bilevel positive airway pressure
BUN
Blood urea nitrogen
Ct
Last measurable drug concentration 
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 (cluster of differentiation 4)
CI
Confidence interval
CL/F
Apparent oral clearance
Cmax
Maximal drug concentration
CNS
Central nervous system
C24
Drug concentration at 24 hours post-dose
CONSORT
Consolidated Standards of Reporting Trials
CPAP
Continuous positive airway pressure
CPK
Creatine Phosphokinase
CRF
Case report form
CrCl
Creatinine Clearance
CV
Coefficient of Variation
DAIDS
Division of Acquired Immunodeficiency Syndrome 
DILI
Drug Induced Liver Injury
dL
Decilitre
DNA
Deoxyribonucleic acid
DTG
Dolutegravir, TIVICAYTM
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
FDA
Food and Drug Administration
FDC
Fixed dose combination
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GLS
Geometric least square
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen


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HBV
Hepatitis B Virus
hCG
Human chorionic gonadotrophin
HCV
Hepatitis C Virus
HIV-1
Human Immunodeficiency Virus type 1
HPLC
High-performance liquid chromatography
HRT
Hormone replacement therapy
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
Ig
Immunoglobulin
INI
Integrase inhibitor
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IEC
Independent Ethics Committee
K2EDTA
Di-potassium ethylenediaminetetraacetic acid
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LLN
Lower limit of normal
L-TP
Lamivudine triphosphate
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Millilitre
MSDS
Material Safety Data Sheet
NRTI
Nucleoside reverse transcriptase inhibitor
OCT-2
Organic Cation Trasporter-2
PICTS
Phase I Clinical Trial System 
PK
Pharmacokinetic
PT
Prothrombin Time
PTT
Partial thromboplastin time
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RAP
Reporting Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SD
Standard Deviation
SJS
Stevens-Johnson Syndrome
SRM
Study Reference Manual
t
Time of last measurable concentration
t1/2
Half-life
tlag
Absorption lag time
Tmax
Time to observed maximal drug concentration
TEN
Toxic Epidermal Necrolysis
g
Microgram
ULN
Upper Limit of Normal
UPLC-
MS/MS
Ultra performance liquid chromatography triple quadrapole mass spectrometry


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US
United States
WBC
White Blood Cell
WHO
World Health Organization
ViiV Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
MedDRA
EPZICOM
SAS
TIVICAY
WinNonlin
TRIUMEQ
TRIZIVIR


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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

Report the event to GSK/ViiV within 24 hours

Complete the liver event CRF, and complete an SAE 
data collection tool if the event also meets the criteria 
for an SAE2

Perform liver event follow up assessments

Monitor the 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, Aspartate 
Aminotransferase (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 INR >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 High-performance 
liquid chromatography (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 CRF forms.


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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that 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 
Ribonucleic Acid (RNA); Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
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:  Handling of Clinical Testing Samples in Pivotal 
Bioequivalence Studies
The follow are responsibilities of the Investigator of the Study Site:

Ensure that a quantity of the clinical testing samples (e.g., study drug product and 
study drugs to be retained as reserve samples), sufficient to conduct the study, is 
randomly (nonsystematically) selected from the drug shipment.  The remaining 
testing study drugs must be retained as reserve samples.

Ensure that an adequate record is maintained of the receipt and distribution of all 
testing samples on the Drug Accountability forms.

Storage of the study drugs to be retained as reserve samples is the responsibility of 
the Investigator and under no conditions can the reserve samples be returned to the 
Sponsor for storage.

Ensure that the study drugs to be retained as reserve samples are stored in the original 
primary packaging and outer cartons.  The carton must be closed using tamper-
evident tape, and an additional label affixed to the outer carton indicating “Reserve 
Sample for ViiV/GlaxoSmithKline Study 204994.”  The label should have an area for 
the Investigator or pharmacist to sign and date it and the label must not be placed over 
any existing label(s).

Store all study drugs to be retained as reserve samples under the appropriate 
environmental conditions.  For products requiring refrigeration or freezing, and for 
sites located in areas with extreme climate, the temperature must be controlled and a 
weekly temperature log must be maintained.  The storage area must be segregated 
from the area where the clinical study was conducted and should be limited to access 
by authorized personnel only.

Ensure that the reserve samples are retained for a period of at least 5 years following 
the date on which the application or supplemental application is approved.  In the 
case of non-approval, the retention period is at least 5 years following the date of 
completion of the corresponding study.

Consult with the Sponsor if the storage of the study drugs to be retained as reserve 
samples presents problems.

Contract with an independent third party to provide storage for study drugs to be 
retained as reserve samples if storage at the study site is not possible.  Before the 
transfer of the study drugs to be retained as reserve samples, the Sponsor must assess 
and approve the facilities of the third party.

The independent third party must store the study drugs to be retained as reserve 
samples under the appropriate environmental conditions.  For products requiring 
refrigeration or freezing, and for sites located in areas with extreme climate, the 
temperature must be controlled and a weekly temperature log must be maintained.


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
Transfer the study drugs to be retained as reserve samples to an independent third 
party for storage if the Investigator or study site ceases business.

When an independent third party stores reserve samples, provide the Sponsor with the 
name and address of the facility and a contact name and telephone number.  Provide 
the independent third party with a contact name and number for the Sponsor.

Upon request from the United States Food and Drug Administration (FDA), release 
the study drugs retained as reserve samples to the FDA and provide the FDA with a 
written assurance that the reserve samples came from the same supplies used to 
conduct the specific bioavailability or bioequivalence study.


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.

Only laboratory abnormalities that are clinically significant need to be graded as 
AEs/SAEs. Clinically significant laboratory abnormalities captured as AEs should be 
graded as per the clinical AE grade criteria, rather than by laboratory grade.  
Otherwise, laboratory abnormalities that are assessed by the site as not clinically 
significant (Section 7.3.6) should not be captured as AEs, and are to be graded by the 
central laboratory or central statistical analysis group using DAIDS laboratory 
grading criteria (Section 12.5.1).
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 
subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).


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Events NOT meeting definition of an AE include:

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.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the 
CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK/ViiV in lieu of completion of the GSK/ViiV, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK/ViiV.  In this instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK/ViiV.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 


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Assessment of Intensity
outcomes as described in the definition of an SAE.
IMPORTANT – PLEASE NOTE THE FOLLOWING STATEMENT:
For this study the above criteria regarding mild, moderate and severe will be used in 
combination with the Modified Division of Acquired immune deficiency syndrome
(AIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004 
(Section 12.5.1).
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK/ViiV.  However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to GSK/ViiV.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK/ViiV
to elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK/ViiV with a copy of any post-mortem 


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Follow-up of AEs and SAEs
findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK/ViiV within the 
designated reporting time frames.
12.4.5.
Reporting of SAEs to GSK/ViiV
SAE reporting to GSK/ViiV via electronic data collection tool

Primary mechanism for reporting SAEs to GSK/ViiV will be the electronic data 
collection tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax/email it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the Electronic Case Report Form (eCRF) page. 

After the study is completed at a given site, the electronic data collection tool (e.g., 
Phase I Clinical Trial System (PICTS)) 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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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.
1.
Intrauterine device or intrauterine system
2.
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 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
3.
Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository)
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

Information will be recorded on the appropriate form and submitted to GSK/ViiV
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/ViiV.  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 


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GSK/ViiV as described in 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 and be withdrawn from the study
12.5.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
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.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.


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International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.6.
Appendix 6 - Division of AIDS Table for Grading The 
Severity Of Adult And Pediatric 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 
regimen 
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 
Bone mineral 
density (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 Central 
nervous system 
(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 


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


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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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., 
Continuous positive 
airway pressure [CPAP], 
Bilevel positive airway 
pressure [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) 


2016N286215_01
CONFIDENTIAL
204994
78
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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) 


2016N286215_01
CONFIDENTIAL
204994
79
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 
World Health 
Organization 
(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 


2016N286215_01
CONFIDENTIAL
204994
80
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 < Lower 
limit of normal 
(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 


2016N286215_01
CONFIDENTIAL
204994
81
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 


2016N286215_01
CONFIDENTIAL
204994
82
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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
Estimated 
glomerular filtration 
rate (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 


2016N286215_01
CONFIDENTIAL
204994
83
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
Low Density 
Lipoprotein (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 
> 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 


2016N286215_01
CONFIDENTIAL
204994
84
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Absolute cluster of 
differentiation 4 
(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
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 


2016N286215_01
CONFIDENTIAL
204994
85
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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% 
Partial 
thromboplastin 
time (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
Prothrombin time 
(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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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.  
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.
Bone mineral density (BMD) t and z scores can be found in: 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.  
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.
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 sexes 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.  


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12.7.
Appendix 7: Toxicity Management
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


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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.
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.
AST AND ALT ELEVATION
See Section 12.2.
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 7.3.


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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 7.3.
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 7.3.
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 Healthcare Medical Monitor should be notified of this 
serious adverse event within 24hr via phone or fax.  The subject should be closely 
followed every day until resolution of the reaction.  The subject should remain on the 
study to be followed for safety and PK as outlined in Section 7.3.


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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis 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 in Section 7.3.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature > 38.5°C
2. Eosinophilia
3. Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, 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 7.3.


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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 AIDS Clinical Trials Group 
(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
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 - Country Specific Requirements
No country-specific requirements exist.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204994
1
Division
:
Worldwide Development
Information Type     
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan Amendment 1 for An Open-
label, Randomized, Single dose, Crossover, Pivotal
Bioequivalence Study of Fixed-dose Combination Tablets of 
Dolutegravir and Lamivudine versus Dolutegravir and
Lamivudine single entities and Food Effect Assessment in
Healthy Volunteers
Compound Number
:
GSK3515864 (GSK1349572+GR109714)
Effective Date 
:
28-AUG-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 204994

This RAP is intended to describe the safety, pharmacokinetics (PK), and tolerability 
analyses required for the study. 

This version of the RAP includes amendment 1 to the originally approved RAP.

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: 
 (Clinical Statistics, PAREXEL)
22-AUG-2017
The Clinical Statistician (or designee) will give final approval:
 (Clinical Statistics, GSK)
23-AUG-2017
Revision Chronology
Date
Version
26-JUL-2017
Original
28-AUG-2017
Amendment No. 1
Amendment 1 provides clarity that a similar preliminary PK analysis as was conducted 
following Part 1, will also be performed for Part 2.
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................4
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSIS..............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Analyses ...................................................................12
7.
PRIMARY STATISTICAL ANALYSES....................................................................12
7.1.
Pharmacokinetic Analyses..........................................................................12
7.1.1.
Overview of Planned Pharmacokinetic Analyses .........................13
7.1.2.
Drug Concentration Measures .....................................................13
7.1.3.
Pharmacokinetic Parameters.......................................................14
7.1.3.1.
Deriving Pharmacokinetic Parameters........................14
7.1.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................15
8.
SECONDARY STATISTICAL ANALYSES .............................................................16
8.1.
Safety Analyses..........................................................................................16
8.1.1.
Overview of Planned Analyses ....................................................16
9.
REFERENCES.......................................................................................................18
10. APPENDICES........................................................................................................19
10.1.
Appendix 1: Protocol Deviation Management .............................................20
10.2.
Appendix 2: Data Management...................................................................21
10.3.
Appendix 3: Time & Events.........................................................................22
10.4.
Appendix 4: Treatment States and Phases.................................................24
10.4.1.
Treatment Phases .......................................................................24
10.4.2.
Treatment States .........................................................................24
10.4.2.1.
Treatment States for AE Data.....................................24
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................25
10.5.1.
Study Treatment & Sub-group Display Descriptors......................25
10.5.2.
Baseline Definition & Derivations .................................................25
10.5.2.1.
Baseline Definitions....................................................25


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10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................26
10.5.3.
Reporting Process & Standards...................................................26
10.6.
Appendix 6: Derived and Transformed Data ...............................................29
10.6.1.
General........................................................................................29
10.6.2.
Study Population..........................................................................29
10.6.3.
Safety ..........................................................................................30
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............31
10.7.1.
Premature Withdrawals................................................................31
10.7.2.
Handling of Missing Data.............................................................31
10.7.2.1.
Handling of Missing Dates..........................................31
10.7.2.2.
Handling of PK Concentration Data............................32
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................33
10.8.1.
Laboratory Values........................................................................33
10.8.2.
ECG.............................................................................................33
10.8.3.
Vital Signs....................................................................................33
10.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................34
10.9.1.
Statistical Analysis Assumptions..................................................34
10.10. Appendix 10 - Abbreviations & Trade Marks...............................................35
10.10.1. Abbreviations...............................................................................35
10.10.2. Trademarks .................................................................................36
10.11. Appendix 11: List of Data Displays..............................................................37
10.11.1. Data Display Numbering..............................................................37
10.11.2. Mock Example Referencing .........................................................37
10.11.3. Study Population Tables..............................................................38
10.11.4. Pharmacokinetic Tables...............................................................39
10.11.5. Pharmacokinetic Figures .............................................................51
10.11.6. Safety Tables...............................................................................60
10.11.7. ICH Listings .................................................................................62
10.11.8. Non-ICH Listings..........................................................................65
10.12. Appendix 12: Example Mock Shells for Data Displays ................................68


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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the Reporting and Analysis Plan 
Purpose
The purpose of this reporting and analysis plan (RAP) is to describe the 
planned analyses and output to be included in the Clinical Pharmacology 
Study Report for Protocol 204994
Protocol
This RAP is based on the original protocol (Dated: 12-JAN-2017) of study 
GSK204994 (GSK Document No.: 2016N286215_00) and protocol 
amendment 1 (Dated: 07-FEB-2017) of study GSK204994 (GSK 
Document No.: 2016N286215_01)
Primary 
Objective
To evaluate the bioequivalence (BE) of fixed-dose combination (FDC) 
tablet formulation(s) of DTG 50 mg and 3TC 300 mg versus co-
administration of the separate tablet formulations of DTG 50 mg plus 3TC 
300 mg, in the fasted state.
Primary 
Endpoint
Plasma DTG and 3TC AUC(0-∞), AUC(0-t), and Cmax.
Study 
Design
This is a single-center, open-label, randomized, two-part study (if Part 2 is 
conducted)
Part 1, Bioequivalence and Food Effect (FD) with Monolayer FDC Tablet
Part 1 of the study will be a randomized, open-label, 2-period, single-dose, 
crossover study in 76 healthy adult subjects to achieve at least 70 evaluable 
subjects. The first 16 subjects who complete the first two treatment periods, 
and consent to continue, will return for a third treatment period and receive 
a single dose of the FDC tablet formulation administered with a high fat 
meal.
Part 2, Bioequivalence and Food Effect with Bilayer FDC Tablet
Part 2 of the study, incorporating the bilayer FDC formulation, will only be 
conducted if a suitable formulation is available. Part 2 of the study will be 
conducted, similarly to Part 1.
Planned 
Analyses

Interim analyses are detailed within Section 3.1.

The final planned analyses will be performed after the completion of 
the study and final datasets authorization, i.e. when database freeze 


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Overview
Key Elements of the Reporting and Analysis Plan 
(DBF) is declared.
Analysis 
Population

Screening Population

Safety Population

PK Plasma Concentration Population

PK Parameter BE Summary Population 

PK Parameter FD Summary Population 
Hypothesis
The first two treatment periods of each part of this study are designed to 
test the BE of FDC tablets of DTG and 3TC (test treatment) relative to co-
administered DTG plus 3TC (reference treatment) all under fasting 
condition: 

H(0): μ(test)/μ(reference) < 0.800 or μ(test)/μ(reference) > 1.250, i.e., 
treatments are not bioequivalent.
Versus 

H(1): 0.800 ≤ μ(test)/μ(reference) ≤1.250 i.e., treatments are 
bioequivalent. 
Food Effect: 
No formal hypothesis will be tested and an estimation approach will be 
used to evaluate the effect of food on the FDC tablet(s).  
Primary 
Analyses
Following loge-transformation, AUC(0-∞), AUC(0-t), Cmax from the first two 
treatment periods for BE will be separately analyzed for each analyte using 
a mixed effects model. Point estimates and their associated 90% confidence 
intervals (CIs) will be provided for the ratios of PK parameters between
test and reference treatments on the original scale.
Secondary 
Analyses

PK data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  

Following loge-transformation, AUC(0-24), C24, CL/F and t1/2  from the 
first two treatment periods for BE, and AUC(0-∞), AUC(0-t), Cmax, CL/F, 
AUC(0-24), C24, t1/2 from the third treatment period (food effect) will be 
analysed similarly using a mixed effects model.

Tmax and tlag of DTG and 3TC will be separately analyzed with the non-
parametric Wilcoxon matched pair method to compute point estimates 
and associated 90% CIs for the median differences.

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.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Except for the addition of a similar preliminary PK analysis for Part 2 as was conducted
for Part 1, there were no changes or deviations to the originally planned statistical 
analysis specified in the protocol amendment 1 [Dated: 07-FEB-2017].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To evaluate the bioequivalence of FDC 
tablet formulation(s) of DTG 50 mg and 
3TC 300 mg versus co-administration of the 
separate tablet formulations of
DTG 50 mg plus 3TC 300 mg, in the fasted 
state.
Plasma DTG and 3TC AUC(0-∞), 
AUC(0-t), and Cmax.
Secondary Objectives
Secondary Endpoints

To characterize the PK profile of single 
dose of FDC tablet formulation(s) of 
DTG 50 mg and 3TC 300 mg versus co-
administration of the separate tablet 
formulations of DTG 50 mg plus 3TC 
300 mg, in the fasted state

To evaluate the food effect on FDC 
tablet formulation(s) of DTG 50 mg and 
3TC 300 mg

To assess the safety and tolerability 
from single dose administration of the 
combination of DTG 50 mg, 3TC 300 
mg in healthy volunteers either fasted or 
with a high fat meal.

Plasma DTG and 3TC tlag, tmax, t, 
t½, z, %AUCex, AUC(0-24), CL/F 
and Vz/F, Ct, and C24

Plasma DTG and 3TC AUC(0-∞), 
AUC(0-t), Cmax, 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 vital signs (BP and HR),
number of subjects with adverse 
events and toxicity grading of 
clinical laboratory tests
AUC(0-t)= area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞)= area under the plasma concentration time curve from time zero to infinity
AUC(0-24)= area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax= maximum observed concentration
tmax= time of maximum observed concentration
C24= concentration at 24h post-dose
Ct = last quantifiable concentration
PK = Pharmacokinetic
t = time of last quantifiable concentration
tlag= absorption lag time
z=apparent elimination rate constant
t1/2 = the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution


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2.3.
Study Design
Overview of Study Design and Key Features
Part 1, Bioequivalence and Food Effect with Monolayer FDC Tablet
Part 2, Bioequivalence and Food Effect with Bilayer FDC Tablet
Design 
Features
In both Part 1 and Part 2 (if conducted), the first two treatment periods will be 
randomized, open-label, 2-period, single-dose, crossover. In each study part, 
the first 16 subjects who complete the first two treatment periods, and consent 
to continue, will return for a third treatment period and receive a single dose 
of the FDC tablet formulation (monolayer in Part 1, bilayer in Part 2) 
administered with a high fat meal.
Dosing

In the first two treatment periods (BE), each subject will be randomized to 
either receive an oral reference treatment DTG (50 mg) plus EPIVIR(300 
mg); or an oral FDC (DTG 50mg/3TC 300mg) formulation (monolayer in 
Part 1, bilayer in Part 2) in two periods per the two sequences specified 
below under fasted state.

The first 16 subjects who complete the first two treatment periods in each 
part, and consent to continue, will return for a third treatment period and 
receive an oral FDC (DTG 50mg/3TC 300mg) formulation (monolayer in 
Part 1, bilayer in Part 2) administered with a high fat meal.

Total duration for each subject (from screening to follow-up) will be a 
minimum of 5 weeks, with a maximum of up to 9 weeks, depending on 
the screening period and whether a subject participates the third period.


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Overview of Study Design and Key Features
Treatment 
Assignment
Subjects will be randomized to one of the following two sequences in Part 1 
and Part 2, if conducted.
Subjects will be administered the 1st treatment in the sequence in the 1st
period; the 2nd treatment in the sequence in the 2nd period; 

Each treatment will be administered in the fasted state after at least 10 
hours of fasting in the first two treatment periods. 

Each treatment will be administered with a high fat meal in the third 
treatment period.
Interim 
Analysis
Following completion of Part 1, preliminary PK data from Part 1 will be 
analyzed. The point estimates and corresponding 90% CIs will be constructed 
for the ratio of the geometric mean of the test treatment (monolayer) to the 
geometric mean of the reference treatments, μ(test)/μ(reference) for AUC(0-∞), 
AUC(0-t), and Cmax for both DTG and 3TC.
A similar preliminary PK analysis as was conducted following Part 1, will 
also be performed for Part 2.The result will be used for planning a future 
Phase III study. An independent statistics and programming team will 
perform the preliminary PK analyses for both parts. 
2.4.
Statistical Hypotheses
The first two treatment periods of each part of this study are designed to test the
bioequivalence of FDC tablets of DTG and 3TC (test treatment) relative to co-
administered DTG plus 3TC (reference treatment) all under fasting condition. The null
hypothesis is that the true ratio of the geometric mean of the test treatment to the
geometric mean of the reference treatment, μ(test)/μ(reference), for each primary PK
endpoint, is either less than 0.800 or greater than 1.250. The alternate hypothesis is that
the true ratio of the test treatment geometric mean to the reference treatment geometric
mean is greater than or equal to 0.800 and less than or equal to 1.250. Symbolically, this


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is expressed as follows: 

H(0): μ(test)/μ(reference) < 0.800 or μ(test)/μ(reference) > 1.250, i.e., treatments 
are not bioequivalent versus 

H(1): 0.800 ≤ μ(test)/μ(reference) ≤1.250 i.e., treatments are bioequivalent. 
For each PK parameter designated as a primary endpoint (see Section 2.2), a two one-
sided t-test (TOST) procedure (Schiurmann, 1987) with α=0.05 for each one-sided test 
will be used to test this set of hypotheses. This is equivalent to requiring that a 90% 
interval for the true ratio of test to reference geometric means falls entirely within the 
range of 0.800 to 1.250. To declare bioequivalence of FDC tablet DTG and 3TC to co-
administered DTG plus 3TC, the primary PK endpoints for both analytes should 
demonstrate bioequivalence.
For the food effect portion(s), no formal hypothesis will be tested and an estimation
approach will be used to evaluate the effect of food on the FDC tablet.
3.
PLANNED ANALYSIS
3.1.
Interim Analyses
Following completion of Part 1, preliminary PK data from Part 1 will be analyzed. The 
point estimates and corresponding 90% CIs will be constructed for the ratio of the 
geometric mean of the test treatment (monolayer) to the geometric mean of the reference 
treatments, μ(test)/μ(reference) for AUC(0-∞), AUC(0-t), and Cmax for both DTG and 3TC.
A similar preliminary PK analysis as was conducted following Part 1, will also be 
performed for Part 2. This is simply bringing forward a part of the planned end of study 
analysis to pre-DBF, but after all subjects have completed the trial, in order to expedite 
decision making. The PK parameter data for the preliminary analysis will be based on the 
nominal sampling times.
The result will be used for planning a future Phase III study. An independent statistics 
and programming team will perform the preliminary PK analyses for both part1. As the 
PK data are analyzed separately for each part of the study, there will be no adjustments 
for multiplicity.
3.2.
Final Analyses
Analysis
Details
Final Analyses 
Final analyses will be performed after the completion of the study 
and final database authorization.
The final planned 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.


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3. All criteria for unblinding the randomisation codes have been met. 
4. Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screening 
Population
All subjects who signed the 
consent form will be included in 
this population.  

Subject Disposition
Safety 
Population
All subjects who enrolled in the 
study and received at least one 
dose of study drug will be
included in the Safety 
Population.  

Study Population

Safety
Pharmacokinetic 
(PK) Plasma 
Concentration
The PK Plasma Concentration 
Population will include all 
subjects who undergo plasma PK 
sampling and have evaluable PK 
assay results for DTG or 3TC.  

PK concentration listings, 

calculating PK parameters,

PK parameter listings

plotting of the individual 
concentration-time profiles
Pharmacokinetic
(PK) Parameter 
BE Summary
The PK Parameter BE Summary 
Population will include all 
subjects who have evaluable PK 
parameters for both analytes and 
for both Period 1 and Period 2. 
Data from subjects who vomit 
within 4 hours of study drug 
administration will not be 
considered as evaluable. 

PK concentration summary

PK parameter summary and 
figure 

Statistical analysis of 
parameter data

Excluded subjects will be 
included in footnotes for 
summary tables
Pharmacokinetic
(PK) Parameter 
FD Summary
The PK Parameter FD Summary 
Population will include subjects 
who participate in the food effect 
part of study, and have evaluable 
PK parameters for both fed and 
fasted administration of the FDC 
tablet formulation.  Data from 
subjects who vomit within 4 
hours of study drug 
administration will not be 
considered as evaluable.  

PK concentration summary

PK parameter summary and 
figure 

Statistical analysis of 
parameter data 

Excluded subjects will be 
included in footnotes for 
summary tables
NOTES : 

Please refer to Appendix 11 which details the population to be used for each display being generated.

Additional PK concentration and parameter summary tables will be provided by using the PK plasma concentration 
population if there are subjects with only 1 period PK data or subjects who vomit. 


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4.1.
Protocol Deviations

All protocol deviations will be listed with flags to indicate whether a PD is important 
and results in exclusion from the analysis population.

Important deviations will also be summarized, reported in the study report (Please 
refer to Appendix 1: Protocol Deviation Management).

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised in the protocol deviations dataset. 
o
This dataset will be the basis for the listings of protocol deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management 
10.2
Appendix 2: Data Management
10.3
Appendix 3: Time & Events
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
10.10
Appendix 10: Abbreviations and Trade Marks
10.11
Appendix 11: List of Data Displays
10.12
Appendix 12: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” 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 11: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Figure
Table
Listing
Randomization
Randomization
Y
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failures
Y[1]
Reasons for Withdrawals
Y
Important[3] Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Subjects Excluded from Analysis Populations
Y[2]
Demography
Demographics Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Concomitant  Medications
Concomitant Medication
Y
NOTES:

Y = Yes display generated.
1.
Conditional displays, if data is available listing will be generated.
2.
Listing of subjects excluded from any population will be generated only.
3.
All protocol deviations will be listed, with important protocol deviations summarized.
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Pharmacokinetic Analyses
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Sciences and Study 
Operations (CPSSO) data management, GlaxoSmithKline. 
The merge of PK concentration data, randomization and CRF data will be performed by
Study Data Tabulation Model (SDTM) programmer at Quintiles and the analysis PK 


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concentration dataset and WinNonLin files will be created by statistics and programming, 
PAREXEL, under the direct auspices of statistics and programming, Quantitative 
Sciences (QSci), GlaxoSmithKline.   
Derivation of pharmacokinetic parameters will be performed by Clinical Pharmacology 
Modelling & Simulation (CPMS), QSci, GlaxoSmithKline.
Statistical Analysis of pharmacokinetic parameters will be performed by statistics and 
programming, PAREXEL, under the direct auspices of statistics and programming, QSci, 
GlaxoSmithKline.    
7.1.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “PK Plasma Concentration” or 
“PK Parameter BE or FD Summary’ populations, unless otherwise specified.
Table 3 provides an overview of the planned analyses, with full details being presented in 
Appendix 11: List of Data Displays.
Table 3
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Loge-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma  Drug 
Concentrations
Y [1] [2]
Y
Y [1]
Y
Derived PK Parameters
Y
Y[3]
Y
Y[4]
Y
Y
Statistical Analysis PK 
Parameters
Y[ 5]
Y
Y[6]
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.   

Tmax and tlag are not log transformed.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Mean (+SD) and Median plots will be generated.
3.
Comparative Plot of Individual DTG and 3TC Plasma PK Parameter versus treatments
4.
Treatment Comparative Plot of adjusted geometric mean (95% CI) with Individual Subject Plasma PK 
Parameters will be generated.
5.
Geometric Mean Treatment Ratio and 90% CI of DTG and 3TC Plasma PK Parameters will be 
generated.
6.
Supportive SAS Output from Statistical Analysis of  Loge-transformed DTG and 3TC Plasma PK
Parameters
7.1.2.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).


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7.1.3.
Pharmacokinetic Parameters
7.1.3.1.
Deriving Pharmacokinetic Parameters

PK analyses will be the responsibility of the CPMS department within GSK or their 
designee.  Plasma DTG and 3TC concentration-time data will be analyzed by non-
compartmental methods according to current working practices and using Phoenix 
WinNonlin 6.3 or higher.  Calculations will be based on the actual sampling times 
recorded during the study and based on nominal sampling times.  From the plasma 
concentration-time data, the following PK parameters will be determined, as data 
permit:  Cmax, Tmax, AUC(0-t), AUC(0-∞), AUC(0-24), t1/2, tlag, C24, Ct, z, %AUCex, Vz/F, 
t and CL/F.

Refer to Appendix 5: Data Display Standards & Handling Conventions 
(Section 10.5.3 Reporting Process & Standards). 

Non-compartmental analysis will be performed in accordance with GSK PK 
Guidance document GUI_51487.

Two sets of PK parameters will be derived for each subject, analyte and treatment: 
one set based on actual sampling times and one set based on nominal times.

Pharmacokinetic parameters described in Table 4 will be determined from plasma 
concentration-time data, as data permit. 
Refer Appendix 7 Section 10.7.2.2 for handling of PK Concentration data.
Table 4
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-∞)
Area under the concentration-time curve from time zero extrapolated to 
infinity
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (Ct) will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid.
AUCt(%)
Percent of the area measured by AUC(0-t) relative to the extrapolated 
AUC(0-)
AUC(0-24)
Area under the plasma concentration time curve from time zero to 24 
hours
%AUCex
% of AUC(0-∞) that was extrapolated
C24
Drug concentration at 24 hours post-dose
Cmax
Maximum observed concentration, determined directly from the 
concentration-time data.
Ct 
last quantifiable concentration
t
time of last quantifiable concentration
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
tlag
Lag time before observation of drug concentrations in sampled matrix


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Parameter
Parameter Description
z
Apparent elimination rate constant
t½
Apparent terminal half-life will be calculated as: t½ = ln2 / Lambda_z
(NOTE: Lambda_z is the terminal phase rate constant).
CL/F
The apparent oral clearance (CL/F) will be calculated as CL/F = 
Dose/AUC(0-∞)
Vz/F
Apparent oral volume of distribution
7.1.3.2.
Statistical Analysis of Pharmacokinetic Parameters
Two sets of bioequivalence assessments and food effect will be performed based on:

PK parameters derived based on actual sampling times

PK parameters derived based on nominal sampling times
For each of the parameters AUC(0-∞), AUC(0-t), AUC(0-24), Cmax, C24, Ct, CL/F and t1/2, the 
following summary statistics will be calculated and tabulated by treatment (dose): 

Untransformed Data : N, n, arithmetic mean, %CV, 95% confidence interval (CI) 
for the arithmetic mean, SD, median, minimum, and maximum.

Loge-transformed Data:  Geometric mean, 95% CI for the geometric mean, SD of 
loge-transformed data and %CVb
For %AUCex, Tmax, tlag, z, t, and Vz/F, the summary statistics specified for 
untransformed data above will be generated.
PK 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 R& D. 
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline or their designee.
The PK parameters for DTG and 3TC (except Tmax and tlag) will be loge-transformed and 
separately analyzed using a mixed effects model. For the analysis of bioequivalence, the
model will include fixed effect terms for period and treatment. Subject will be treated as
a random effect in the model. For the analysis of food effect, the model will include a
fixed effect term for treatment (fed versus fasted) and a random effect term for subject.
Point estimates and their associated 90% CIs will be constructed for the differences in PK
parameter values between test and reference treatments for the treatment comparisons. 
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.
Tmax and tlag of DTG and 3TC will be separately analyzed with the non-parametric 
Wilcoxon matched pair method to compute point estimates and associated 90% 
confidence intervals for the median differences between test and reference treatments.


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Primary and Secondary Comparisons of Interest
DTG or 3TC 
PK Parameter
Test
Reference
Assessment
Primary
AUC(0-), AUC(0-t), Cmax,
Treatment B
Treatment A
Bioequivalence
Treatment C 
(if Part 2 is conducted)
Treatment A
Secondary
CL/F, AUC(0-24), C24, t1/2
Treatment B
Treatment A
Bioequivalence
Treatment C
(if Part 2 is conducted) 
Treatment A
AUC(0-), AUC(0-t), Cmax, 
CL/F, AUC(0-24), C24, t1/2
Treatment B Fed
Treatment B 
Fasted
Food Effect
Treatment C Fed
(if Part 2 is conducted) 
Treatment C 
Fasted
Estimates of within-subject variability for AUC(0-∞), AUC(0-t), Cmax, CL/F, AUC(0-24), C24, 
t1/2 will also be provided, where CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the 
residual mean squared error from the model. CVw represents a pooled measure of within-
subject variability across the treatments A and B or A and C (if Part 2 is conducted).
Comparative Plot of Individual subject DTG and 3TC Plasma PK Parameter Versus 
Treatment will be generated.
Treatment Comparative Plots of adjusted geometric mean (95% CI) with Individual 
Subject Plasma PK Parameters AUC(0-∞), AUC(0-t), Cmax, CL/F, AUC(0-24), C24, t1/2 will be 
generated.
Plots will also be provided showing the adjusted geometric mean ratio of test to reference 
treatment for AUC(0-∞), AUC(0-t), Cmax, CL/F, AUC(0-24), C24, t1/2 with 90% CIs.
The SAS output from the statistical models and the assessment of assumptions underlying 
the models will be included in a listing of supportive SAS output.
Additional PK displays for Canada specific submission requirements will also be 
provided. 
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Safety Analyses
The safety analyses will be based on the “Safety” population, unless otherwise specified.
8.1.1.
Overview of Planned Analyses
Table 5 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 11: List of Data Displays.


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Table 5
Overview of Planned Safety Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Exposure
Y
Adverse Events
All AE’s
Y
Y
Serious AE’s
Y
Y
Drug Related AEs
Y
Y
Withdrawal AE’s
Y
Y
Relationship Between 
System Organ Class And 
Verbatim Text
    Y
Subject Numbers for 
Individual AEs
Y
Laboratory Values 
Clinical Chemistry 
Y
Y
Hematology 
Y
Y
Abnormal Clinical 
Chemistry 
Y
Abnormal Hematology 
Y
Abnormal Urinalysis
Y
ECG’s
ECG Findings
Y
ECG Values
Y
ECG Values Outside the 
PCI Range
Y
All ECG Values for 
Subjects with a Value of 
PCI
Y
Abnormal ECG Findings
Y
Vital Signs
Vitals Values
Y
Y
Vital Signs Measurements 
Outside the PCI Range
Y
Y
All Vital Signs for Subjects 
with Values of PCI
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.     


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9.
REFERENCES
GlaxoSmithKline Document Number 2016N286215_00: An Open-label, Randomized, 
Single dose, Crossover, Pivotal Bioequivalence Study of Fixed-dose Combination 
Tablets of Dolutegravir and Lamivudine versus Dolutegravir and Lamivudine single 
entities and Food Effect Assessment in Healthy Volunteers. Effective Date: 12-JAN-2017
GlaxoSmithKline Document Number 2016N286215_01: An Open-label, Randomized, 
Single dose, Crossover, Pivotal Bioequivalence Study of Fixed-dose Combination 
Tablet(s) of Dolutegravir and Lamivudine versus Dolutegravir and Lamivudine single 
entities and Food Effect Assessment in Healthy Volunteers Effective Date: 07-FEB-2107
Schiurmann DJ. A comparison of the two one-sided tests procedure and the power
approach for assessing the equivalence of average bioavailability. J Pharmacokinetics
Biopharm 1987; 15:657-679.


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10.
APPENDICES
Section
Appendix
RAP Section 4: Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management 
RAP Section 5 : General Considerations for Data Analyses & Data Handling 
Conventions
Section 10.2
Appendix 2: Data Management
Section 10.3
Appendix 3: Time and Events
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General

Study Population

Safety

Pharmacokinetic
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

General

Study Population & Safety
Section 10.8
Appendix 8: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Section 10.9
Appendix 9: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.10
Appendix 10: Abbreviations & Trade Marks
Section 10.11
Appendix 11: List of Data Displays
Section 10.12
Appendix 12: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management
A subject meeting any of the following criteria will be excluded from the PK Parameter 
BE and/or FD Summary Population:
Number
Exclusion Description
01
Failure of any inclusion/exclusion criteria, but subject is still enrolled
02
A subject with emesis occurring within 4 hours of the dose


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10.2.
Appendix 2: Data Management
Data Type
Source 
Format 
of Data
Planned Date of 
Final File1
Responsibility
Safety
Database
SDTM
DBF
CPSSO
PK 
Concentration
SMS2000 data files
dat file
DBF
BIB/BESM
PK 
Concentration 
(ADPC), 
WNL File
PK concentration 
data (SDTM PC), 
exposure (EX) and 
demography (DM)
datasets2
ADaM, 
CSV file
DBF + 5 Days1
QSci
PK 
Parameters
WNL file
CSV file
PK Concentration, 
WNL file + 5 
Days
CPMS
1.
Provided SDTM PC, EX and DM are in time and clean
2.
PK concentration data is released via SMS2000 by Bioanalysis, Immunogenicity and Biomarkers 
(BIB)/Bioanalytical External Study Monitors (BESM) and the SDTM PC contains date/times and PK 
sample ID


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10.3.
Appendix 3: Time & Events
Screening Assessments
Visit Window (relative to Day 1)
Day -30 to -2
Notes
Informed Consent
X
Demographics
X
Physical examination height, weight and BMI
X
Medical/medication/ history
X
Medical/medication/drug and alcohol history will be recorded at screening, and 
updated at admission.
Urine drug / Cotinine and Breathalyzer screening
X
12-lead ECG and Vital Signs
X
Serum or urine hCG test (female subjects only)
X
See inclusion Protocol criterion #6.
Performed at site standard procedure.
FSH and estradiol (women)
X
HIV, Hep B and Hep C Screen
X
Hematology/Chemistry/Urinalysis tests
X


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Treatment Period Assessments
Assessments
All Dosing Periods
Follow-up
Notes
Day -1 of Periods 2 to 3 may be the same day as Day 6 
of prior periods
Day -1
Day 1
Day 
2
Day 
3
Day 
4
Pre-
dose
0 hr
Post Dose
-
48 hr
72 hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
X
Follow-up visit will occur 7 to 14 days post last dose.
12-lead ECG
X
Single ECGs will be collected at Screening and on Day-1 of 
Period 1 only. Additional ECGs may be performed at the 
discretion of the investigator.
Vital signs
X
X
At 4 hours post-dose
X
X
X
X
Single measurements performed at all time points.
Brief Physical Exam
X
Brief examinations may be made full examinations and 
laboratory procedures may be repeated, if needed, at the 
discretion of the Investigator.
Illicit Drug/Alcohol/Cotinine/pregnancy screening will be 
performed in accordance with the sites’ standard practice.
Clinical laboratory tests – see Protocol Table 5.
Urine Drug/ Cotinine and 
Breathalyzer
X
Pregnancy test
X
X
Clinical laboratory tests 
X
X
Dosing
X
Subject will be dosed while in the seated position.
Pharmacokinetic Sampling
X
Collect at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 5, 6, 8, 12, 16, 24, and 48 hours post-
dose
X
Pre-dose (within 15 minutes prior to dosing). 
4 hour post dose sample must be taken prior to provision of 
food.
Permitted window for the collection of PK sample at each 
time point will be specified in BioPacket. 
Meals – (Treatment periods 
1 and 2)
Fasted from 10 hours prior to 
dosing to 4 hours post-dose
Standard for the study center
See also Protocol Section 6.10.1.1
Meals - Treatment Period 3 
(Fed Conditions only)
Fasted from 10 hours prior to 
test meal and dosing then 
through 4 hours post-dose
Standard for the study center
Entire meal to be consumed in 25 minutes or less and 
dosing will be administered 30 minutes after the start of the 
meal.  See also Protocol Section 6.10.1.2
Adverse Events
X
=======================X=======================
X
Concomitant medications
X
=======================X=======================
X


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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop date/time of the study treatment.
Treatment 
Phase
Definition
Pre-Treatment 
Date/Time ≤ Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time < Date/Time ≤[Study Treatment Stop Date/Time + 3 
Days] 
Post-Treatment
Date/Time > [Study Treatment Stop Date/Time + 3 Days]
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date/time of the study treatment.
10.4.2.1.
Treatment States for AE Data
Treatment 
State
Definition
Pre-Treatment
AE Start Date/Time < Study Treatment Start Date/Time
On-Treatment
If AE onset date/time is on or after treatment start date/time & 3 or fewer days 
after the treatment stop date/time
Study Treatment Start Date/Time ≤ AE Start Date/Time ≤ [Study Treatment 
Stop Date/Time + 3]
Post-
Treatment
If AE onset date/time is more than 3 days after the treatment stop date/time
AE Start Date/Time > [Study Treatment Stop Date/Time + 3]
Onset Time
Since First 
Dose
(Days)
If Treatment Start Date/Time > AE Onset Date/Time = AE Onset Date -
Treatment Start Date
If Treatment Start Date/Time ≤ AE Onset Date/Time = AE Onset Date -
Treatment Start Date +1
Missing otherwise
Duration 
(Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF 
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for 
Reporting 
Code
Description
Description
A
DTG 50mg plus EPIVIR 300mg 
A
B
DTG 50mg and 3TC 300mg FDC monolayer
B
C
DTG 50mg and 3TC 300mg FDC bilayer
C
B_Fed[1]
DTG 50mg and 3TC 300mg FDC monolayer fed
B_Fed
C_Fed[1]
DTG 50mg and 3TC 300mg FDC bilayer fed
C_Fed
[1] Treatments B_Fed and C_Fed are assigned.
NOTES: Add the following footnote for treatment description.
A: DTG 50mg plus EPIVIR 300mg
B: DTG 50mg and 3TC 300mg FDC monolayer
C: DTG 50mg and 3TC 300mg FDC bilayer
B_Fed: DTG 50mg and 3TC 300mg FDC monolayer fed
C_Fed: DTG 50mg and 3TC 300mg FDC bilayer fed
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints (except as noted in the table) the baseline value will be the latest pre-
dose assessment. 
Table 6
Baseline Definitions
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 
(Pre-Dose)
Safety
Lab
X
X
Day -1
Vital Signs (blood 
pressure, and pulse rate)
X
X
X
Day 1 (Pre-Dose) for 
each Period


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10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions 
will be used for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to 
missing.

The baseline definition will be footnoted on all change from baseline displays.
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and S-Plus software will be used.
Reporting Area
HARP Server
: US1SALX00259-HARP PROD-US
HARP Area
: \ARPROD\GSK1349572\mid204994\Final
QC Spreadsheet
: \ARWORK\GSK1349572\mid204994\Final\Documents
Analysis Datasets 

Analysis datasets will be created according to Clinical Data Interchange Standards 
Consortium (CDISC) standards (SDTM IG Version 3.1.3 & Analysis Data Model 
(ADaM) Implementation Guide (ADaM IG) Version 1.0 or higher dataset 
standards)
Generation of Rich Text Format (RTF) Files

RTF files will be generated for summary displays.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.


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Reporting Standards

The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :
o
Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.
o
The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.

Reporting for Data Listings: 
o
Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).
o
Unscheduled or unplanned readings will be presented within the subject’s listings. 
o
Visits outside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings but omitted from figures, summaries and 
statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further 
details)
Reporting of Pharmacokinetic Parameters
Descriptive Summary 
Statistics.                      
(Un-Transformed)   
N, n, arithmetic mean, 95% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum and CV(%)

CV(%)=(SD/mean)*100
Descriptive Summary 
Statistics.                      
(Loge Transformed)   
N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logged data and between-subject geometric 
coefficient of variation (CVb (%)) will be reported.

Geometric mean = exp (mean on loge scale)

CVb (%) = √ (exp(SD2) - 1) * 100 [NOTE: SD = SD of loge
transformed data]
Parameters Not Being 
Loge Transformed  
%AUCex, Tmax, tlag, t, z, Vz/F
Listings
Include PK Parameters AUC(0-∞), AUC(0-t), AUC(0-24), %AUCex, 
Cmax, C24, Ct, t, Tmax, z, t1/2, tlag, CL/F, Vz/F, ratios (test: 


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Reporting Standards
reference) for AUC(0-∞), AUC(0-t), AUC(0-24), C24 and Cmax; and 
the ratio of AUC(0-t)/AUC(0-∞) (AUCt(%)) for Canada specific 
submission requirement.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for 
that window will be used. If values are the same distance from the target then the 
mean will be taken.
Study Day

Calculated as the number of days from Treatment start date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Treatment start Date   → Study Day = Ref Date – Treatment start Date  

Ref Data ≥ Treatment start Date   → Study Day = (Ref Date – Treatment start 
Date) + 1    
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age using date of the 
screening visit relative to birth date, where birth date is imputed as:

Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2


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10.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
RR = [(QT/QTcB)^(2) ]*1000
[2] If QTcF is machine read and QTcB is not provided, then: 
RR = [(QT/QTcF)^(3) ]*1000
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals using Bazett’s (QTcB) 
and Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the 
availability of other measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as 
: 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is 
missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field) is present, the number of significant 
digits in the observed values will be used to determine how much to add or subtract in 
order to impute the corresponding numeric value. 

Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01

Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1

Example 3: 0 Significant Digits = ‘< x’ becomes x – 1


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

All subjects who withdraw prematurely from the study/study drug will 
be documented and the reason for their withdrawal recorded in the final 
Clinical Pharmacology Study Report (CPSR).  

All available data collected up until the point of withdrawal, and the 
follow-up visits will be used in the analyses and will be listed and all 
available planned data will be included in the summaries according to 
the populations defined in Section 4.

Any data collected up until the point of withdrawal, and the follow-up 
visits will be used in the analyses.

In the event that the study is prematurely discontinued, all available 
data will be listed and a review carried out by the study team to assess 
which statistical analyses are still considered appropriate.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
Outliers

Any subjects excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical 
study report.
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.


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10.7.2.2.
Handling of PK Concentration Data
Element
Reporting Detail
General

The PK Plasma Concentration Population will include all subjects who 
undergo plasma PK sampling and have evaluable PK assay results for 
DTG or 3TC. 

Data from subjects who vomit within 4 hours of study drug 
administration or who have major protocol deviations will be excluded 
from PK concentration summary, PK parameter summary and statistical 
comparisons but will be included in the Listing and flagged.

This population will be used for listing PK concentrations, parameters, 
calculating PK parameters and plotting of individual concentration-time 
files.

If the pre-dose concentration is ≤ 5% of Cmax value in a subject, the 
concentration data for that subject without any adjustments will be 
included in PK and statistical analysis. If the pre-dose concentration is > 
5% of Cmax value in a subject, then the concentration data for that 
subject will not be included in PK and statistical analysis and only the 
concentration data of that subject(s) will be presented

If during clinical phase, 3 consecutive samples in any phase i.e. 
(Absorption, Distribution and Metabolism / Excretion) are found to be 
missing then data for  that subject will not be included in PK and 
statistical analysis and only the concentration data of that subject(s) will 
be presented


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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Division of AIDS (DAIDS, Version 2.0, November 2014) AE grade 2 and above of lab 
abnormalities will be listed by subject, period/treatment, visit, and actual date and time.
10.8.2.
ECG
ECG Values of Potential Clinical Importance (Healthy Volunteers)
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>450
msec
PR Interval
<110 and >220
msec
QRS Interval
<75 and >110
msec
10.8.3.
Vital Signs
Vital Signs Values of Potential Clinical Importance (Healthy Volunteers)
VS Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure
<85 and >160
mmHg
Diastolic Blood Pressure
<45 and >100
mmHg
Heart Rate
<40 and >110
bpm
Vital Signs change from Baseline Flagging Range
VS Parameter
Flagging Criteria
Unit
Systolic Blood Pressure 
(Change from Baseline)
Increase ≥20
mmHg
Increase ≥40
Decrease ≥ 20
Decrease≥40
Diastolic Blood Pressure  
(Change from Baseline)
Increase  ≥ 10
mmHg
Increase≥20
Decrease ≥ 10
Decrease≥20
Heart Rate
(Change from Baseline)
Increase ≥ 15
bpm
Increase ≥ 30
Decrease ≥ 15
Decrease ≥ 30


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10.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses
10.9.1.
Statistical Analysis Assumptions
Endpoint(s)

AUC(0-), AUC(0-t), Cmax, CL/F, AUC(0-24), C24, t1/2
Analysis

Linear Mixed Model
Assumptions:

For the Linear Mixed Model, model assumptions will be applied, but appropriate 
adjustments may be applied based on the data.

The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.

An unstructured covariance structure for the G matrix will be used by specifying 
‘type=UN’ on the RANDOM line. 
o
In the event that this model fails to converge, alternative covariance structures 
may be considered such as VC or CS. 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.

Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 

Sensitivity analysis will be performed if the normality assumptions are violated due to 
presence of outliers.


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10.10.
Appendix 10 - Abbreviations & Trade Marks
10.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
ADaM IG
Analysis Data Model Implementation Guide
AE
Adverse Event
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration 
AUC(0-24)
Area under the plasma concentration time curve from time zero to 24 
hours
%AUCex
% of AUC(0-∞) that was extrapolated
AUCt(%)
Percent of the area measured by AUC(0-t) relative to the extrapolated 
AUC(0-)
BE
Bioequivalence
BESM
Bioanalytical External Study Monitors
BIB
Bioanalysis, Immunogenicity and Biomarkers
C24
Drug concentration at 24 hours post-dose
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
The apparent oral clearance
Cmax
Maximum observed concentration 
CP
Clinical Programming
CPMS
Clinical Pharmacology Modelling & Simulation
CPSSO
Clinical Pharmacology Sciences and Study Operations
CRF
Case record form
CS
Clinical Statistics
Ct 
last quantifiable concentration
CV
Coefficient of Variation
CVb/CVw
Coefficient of Variation (Between)/Coefficient of Variation (Within)
DAIDS
Division of Acquired Immune Deficiency Syndrome
DBF
Database Freeze
DBR
Database Release
DTG
Dolutegravir 
FD
Food Effect
GSK
GlaxoSmithKline
HARP
Harmonized Analysis and  Reporting Process
IDSL
Integrated Data Standards Library
z
Terminal phase rate constant
LLQ
Lower limit of quantification
NC
Not Calculable


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NQ
Non-quantifiable concentration measured as below LLQ
PK
Pharmacokinetic
QSci
Quantitative Sciences
RAP
Reporting and Analysis Plan
RTF
Rich Text Format
3TC
Lamivudine, EPIVIRTM
SAS
Statistical Analysis System
SD
Standard deviation
SDTM
Study Data Tabulation Model
SRP
Statistics Resourcing and Programming
t
time of last quantifiable concentration
t½
Terminal phase half-life
tlag
Absorption lag time
Tmax
Time of occurrence of Cmax
z
Apparent elimination rate constant
Vz/F
Apparent oral volume of distribution
10.10.2.
Trademarks
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
MedDRA
EPZICOM
SAS
TIVICAY
WinNonlin
TRIUMEQ
TRIZIVIR


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10.11.
Appendix 11: List of Data Displays
10.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.05
N/A
Pharmacokinetic
2.01 to 2.78*
*If Part 2 is conducted, same set 
of tables will be provided as 
2.101 to 2.178 with Part 1 and 
Part 2 indication in the titles
2.01 to 2.44*
*If Part 2 is conducted, same set 
of figures will be provided as 
2.101 to 2.144 with Part 1 and 
Part 2 indication in the titles
Safety
3.01 to 3.13*
*If Part 2 is conducted, same set 
of tables will be provided as 
3.101 to 3.113 with Part 1 and 
Part 2 indication in the titles
N/A
Section
Listings*
*If Part 2 is conducted, same set of listings will be provided as 101 
to 148 with Part 1 and Part 2 indication in the titles
ICH Listings
1 to 25
Other Listings
26 to 48
10.11.2.
Mock Example Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 12: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
N/A
N/A
N/A
Pharmacokinetic
PK_F1, PK_F2
PK_T1, PK_T2, 
PK_T3, PK_T4, PK_T5
N/A
Safety
N/A
SAFE_T1
SAFE_L1
NOTES: 

Indicate display is Non-Standard in the ‘IDSL/TST ID / Example Shell’ or ‘Programming Notes’ 
column.


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10.11.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable
[Priority]
Subject Disposition 
1.01
Safety
CP_ES1 
(XO)
Summary of Subject Disposition
Include Part 2 and Total (if Part 2 is 
conducted)
SAC
Demographics
1.02
Safety
DM3 (XO)
Summary of Demographic characteristics
Include BMI, Race detail
Include Part 2 and Total (if Part 2 is 
conducted)
SAC
1.03
Safety
DM5
Summary of Race and Racial 
Combinations
Include Part 2 and Total (if Part 2 is 
conducted)
SAC
1.04
Safety
DM6
Summary of Race and Racial 
Combinations Details
Include Part 2 and Total (if Part 2 is 
conducted)
SAC
1.05
Safety 
DV1
Summary of Important Protocol 
Deviations 
Include Part 2 and Total (if Part 2 is 
conducted)
SAC


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10.11.4.
Pharmacokinetic Tables
If Part 2 is conducted, same set of tables will be provided as 2.101 to 2.178 with Part 1 and Part 2 indication in the titles
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data 
2.01
PK Parameter 
BE  Summary
pkct1
Summary of DTG Plasma Concentration-time 
Data (unit) by Treatment - Bioequivalence
Assessment
Treatments A, B only
SAC
2.02
PK Parameter 
BE Summary
pkct1
Summary of 3TC Plasma Concentration-time 
Data (unit) by Treatment - Bioequivalence 
Assessment
Treatments A, B only 
SAC
2.03
PK Parameter 
FD  Summary
pkct1
Summary of DTG Plasma Concentration-time 
Data (unit) by Treatment - Food Effect
Treatments B, B_Fed only
SAC
2.04
PK Parameter 
FD Summary
pkct1
Summary of 3TC Plasma Concentration-time 
Data (unit) by Treatment – Food Effect
Treatments B, B_Fed only
SAC
2.05
PK Plasma 
Concentration
pkct1
Summary of DTG Plasma Concentration-time 
Data (unit) by Treatment
All 3 treatments in the 
same table
SAC
2.06
PK Plasma 
Concentration
pkct1
Summary of 3TC Plasma Concentration-time 
Data (unit) by Treatment
All 3 treatments in the 
same table
SAC


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Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Derived Parameters based on Actual Sampling Time
2.07
PK Parameter 
BE  Summary
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.08
PK Parameter 
BE Summary
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.09
PK Parameter 
BE Summary
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
Treatments A, B only
SAC
2.10
PK Parameter 
BE Summary
pkpt3
Summary of Loge-transformed 3TC Plasma PK
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
Treatments A, B only
SAC
2.11
PK Parameter 
FD Summary
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based on Actual Sampling Time -
Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC
2.12
PK Parameter 
FD Summary
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based on Actual Sampling Time -
Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC


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Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13
PK Parameter 
FD Summary
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Actual Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
Treatments B, B_Fed only
SAC
2.14
PK Parameter 
FD Summary
pkpt3
Summary of Loge-transformed 3TC Plasma PK
Parameters based on Actual Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
Treatments B, B_Fed only
SAC
2.15
PK Plasma 
Concentration
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based
on Actual Sampling Time
All parameters with units;
All treatments
SAC
2.16
PK Plasma 
Concentration
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based
on Actual Sampling Time
All parameters with units;
All treatments
SAC
2.17
PK Plasma 
Concentration
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Actual Sampling Time
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
All treatments
SAC
2.18
PK Plasma 
Concentration
pkpt3
Summary of Loge-transformed 3TC Plasma PK 
Parameters based on Actual Sampling Time
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;
All treatments
SAC


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Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Statistical Analysis Table based on Actual Sampling Time
2.19
PK Parameter 
BE Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based 
on Actual Sampling Time - Bioequivalence 
Assessment 
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
SAC
2.20
PK Parameter 
BE Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Actual Sampling Time - Bioequivalence 
Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
SAC
2.21
PK Parameter 
BE Summary
PK_T2
Summary of Statistical Analysis of 
Untransformed DTG Plasma PK Parameters 
based on Actual Sampling Time - Bioequivalence 
Assessment
Parameters tlag and Tmax
with units; Treatments A, B 
only
SAC
2.22
PK Parameter 
BE Summary
PK_T2
Summary of Statistical Analysis of
Untransformed 3TC Plasma PK Parameters based 
on Actual Sampling Time - Bioequivalence 
Assessment
Parameters tlag and Tmax
with units; Treatments A, B 
only
SAC
2.23
PK Parameter 
BE Summary
MID201676, 
Table 2.17
Summary of Type 3 Tests of Fixed Effects for 
Loge-transformed PK Parameters based on Actual 
Sampling Time - Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
SAC
2.24
PK Parameter 
BE Summary
MID201676, 
Table 2.18
Summary of Variance Estimates Effects for PK 
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
SAC


CONFIDENTIAL
204994
43
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.25
PK Parameter 
FD Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based 
on Actual Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed
only
SAC
2.26
PK Parameter 
FD Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Actual Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
SAC
2.27
PK Parameter 
FD Summary
PK_T2
Summary of Statistical Analysis of 
Untransformed DTG Plasma PK Parameters 
based on Actual Sampling Time – Food Effect
Parameters tlag and Tmax
with units; Treatments B, 
B_Fed only
SAC
2.28
PK Parameter 
FD Summary
PK_T2
Summary of Statistical Analysis of
Untransformed 3TC Plasma PK Parameters based 
on Actual Sampling Time – Food Effect
Parameters tlag and Tmax
with units; Treatments B, 
B_Fed only
SAC
2.29
PK Parameter 
FD Summary
MID201676, 
Table 2.17
Summary of Type 3 Tests of Fixed Effects for 
Loge-transformed PK Parameters based on Actual 
Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed
only
SAC
2.30
PK Parameter 
FD Summary
MID201676, 
Table 2.18
Summary of Variance Estimates Effects for PK 
Parameters based on Actual Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
SAC


CONFIDENTIAL
204994
44
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Derived Parameters based on Nominal Sampling Time
2.31
PK Parameter 
BE Summary
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.32
PK Parameter 
BE Summary
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.33
PK Parameter 
BE Summary
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units; Treatments A, B only
SAC
2.34
PK Parameter 
BE Summary
pkpt3
Summary of Loge-transformed 3TC Plasma PK
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;Treatments A, B only 
SAC
2.35
PK Parameter 
FD Summary
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based on Nominal Sampling Time -
Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC
2.36
PK Parameter 
FD Summary
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based on Nominal Sampling Time -
Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC
2.37
PK Parameter 
FD Summary
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Nominal Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units;Treatments B, B_Fed 
only
SAC


CONFIDENTIAL
204994
45
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.38
PK Parameter 
FD Summary
pkpt3
Summary of Loge-transformed 3TC Plasma PK
Parameters based on Nominal Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
SAC
2.39
PK Plasma 
Concentration
pkpt1
Summary of Untransformed DTG Plasma PK
Parameters based on Nominal Sampling Time
All parameters with units; 
All treatments
SAC
2.40
PK Plasma
Concentration
pkpt1
Summary of Untransformed 3TC Plasma PK
Parameters based on Nominal Sampling Time
All parameters with units; 
All treatments
SAC
2.41
PK Plasma 
Concentration
pkpt3
Summary of Loge-transformed DTG Plasma PK
Parameters based on Nominal Sampling Time
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units; All treatments
SAC
2.42
PK Plasma 
Concentration
pkpt3
Summary of Loge-transformed 3TC Plasma PK 
Parameters based on Nominal Sampling Time
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, Ct, CL/F and t1/2 with 
units; All treatments 
SAC
Statistical Analysis Table based on Nominal Sampling Time
2.43
PK Parameter 
BE Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based 
on Nominal Sampling Time - Bioequivalence 
Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
IA (only 
AUC(0-∞), 
AUC(0-t), 
Cmax) 
SAC


CONFIDENTIAL
204994
46
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.44
PK Parameter 
BE Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Nominal Sampling Time - Bioequivalence 
Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
IA (only 
AUC(0-∞), 
AUC(0-t), 
Cmax) 
SAC
2.45
PK Parameter 
BE Summary
PK_T2
Summary of Statistical Analysis of
Untransformed DTG Plasma PK Parameters
based on Nominal Sampling Time -
Bioequivalence Assessment
Parameters tlag and Tmax 
with units; Treatments A, B 
only
SAC
2.46
PK Parameter 
BE Summary
PK_T2
Summary of Statistical Analysis of
Untransformed 3TC Plasma PK Parameters based 
on Nominal Sampling Time - Bioequivalence 
Assessment
Parameters tlag and Tmax 
with units; Treatments A, B 
only
SAC
2.47
PK Parameter 
BE Summary
MID201676, 
Table 2.17
Summary of Type 3 Tests of Fixed Effects for 
Loge-transformed PK Parameters based on 
Nominal Sampling Time - Bioequivalence 
Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units;Treatments A, B only
SAC
2.48
PK Parameter 
BE Summary
MID201676, 
Table 2.18
Summary of Variance Estimates Effects for PK 
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments A, B only
SAC
2.49
PK Parameter 
FD Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based 
on Nominal Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
IA (only 
AUC(0-∞), 
AUC(0-t), 
Cmax) 
SAC


CONFIDENTIAL
204994
47
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.50
PK Parameter 
FD Summary
PK_T1
Summary of Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Nominal Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
IA (only 
AUC(0-∞), 
AUC(0-t), 
Cmax) 
SAC
2.51
PK Parameter 
FD Summary
PK_T2
Summary of Statistical Analysis of
Untransformed DTG Plasma PK Parameters
based on Nominal Sampling Time – Food Effect
Parameters tlag and Tmax 
with units; Treatments B, 
B_Fed only
SAC
2.52
PK Parameter 
FD Summary
PK_T2
Summary of Statistical Analysis of
Untransformed 3TC Plasma PK Parameters based 
on Nominal Sampling Time – Food Effect
Parameters tlag and Tmax
with units; Treatments B, 
B_Fed only
SAC
2.53
PK Parameter 
FD Summary
ING114580, 
Table 3.10
Summary of Type 3 Tests of Fixed Effects for 
Loge-transformed PK Parameters based on 
Nominal Sampling Time - Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
SAC
2.54
PK Parameter 
FD Summary
ING114580, 
Table 3.11
Summary of Variance Estimates Effects for PK 
Parameters based on Nominal Sampling Time -
Food Effect
Parameters AUC(0-∞), 
AUC(0-t), AUC(0-24), Cmax, 
C24, CL/F and t1/2 with 
units; Treatments B, B_Fed 
only
SAC
Canada Specific PK Tables
PK Concentration Data 
2.55
PK Plasma 
Concentration
PK_T3
DTG Drug Concentration (unit) for the Test 
Formulation B
SAC


CONFIDENTIAL
204994
48
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.56
PK Plasma 
Concentration
PK_T3
DTG Drug Concentration (unit) for the Test 
Formulation B_Fed
SAC
2.57
PK Plasma 
Concentration
PK_T3
DTG Drug Concentration (unit) for the Reference 
Formulation A
SAC
2.58
PK Plasma 
Concentration
PK_T3
3TC Drug Concentration (unit) for the Test 
Formulation B
SAC
2.59
PK Plasma 
Concentration
PK_T3
3TC Drug Concentration (unit) for the Test 
Formulation B_Fed
SAC
2.60
PK Plasma 
Concentration
PK_T3
3TC Drug Concentration (unit) for the Reference 
Formulation A
SAC
PK Derived Parameters based on Actual Sampling Time
2.61
PK Plasma 
Concentration
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation B
All parameters with units
SAC
2.62
PK Plasma 
Concentration
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation 
B_Fed
All parameters with units
SAC
2.63
PK Plasma 
Concentration
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Reference 
Formulation A
All parameters with units
SAC
2.64
PK Plasma 
Concentration
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation B
All parameters with units
SAC
2.65
PK Plasma 
Concentration
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation 
B_Fed
All parameters with units
SAC
2.66
PK Plasma 
Concentration
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Reference 
Formulation A
All parameters with units
SAC


CONFIDENTIAL
204994
49
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.67
PK Parameter 
BE Summary
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation B -
Bioequivalence Assessment
All parameters with units
SAC
2.68
PK Parameter 
BE Summary
PK_T4
DTG Parameter Estimates based on Actual Time
for Each Subject Given the Reference
Formulation A - Bioequivalence Assessment
All parameters with units
SAC
2.69
PK Parameter 
BE Summary
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation B -
Bioequivalence Assessment
All parameters with units
SAC
2.70
PK Parameter 
BE Summary
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Reference 
Formulation A - Bioequivalence Assessment
All parameters with units
SAC
2.71
PK Parameter 
BE Summary 
PK_T5
DTG Parameter Analysis – Data based on Actual 
Time - Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.72
PK Parameter 
BE Summary 
PK_T5
3TC Parameter Analysis – Data based on Actual 
Time - Bioequivalence Assessment
All parameters with units; 
Treatments A, B only
SAC
2.73
PK Parameter 
FD Summary
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation 
B_Fed – Food Effect
All parameters with units
SAC
2.74
PK Parameter 
FD Summary
PK_T4
DTG Parameter Estimates based on Actual Time 
for Each Subject Given the Reference 
Formulation A – Food Effect
All parameters with units
SAC
2.75
PK Parameter 
FD Summary
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Test Formulation 
B_Fed – Food Effect
All parameters with units
SAC


CONFIDENTIAL
204994
50
Pharmacokinetic Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.76
PK Parameter 
FD Summary
PK_T4
3TC Parameter Estimates based on Actual Time 
for Each Subject Given the Reference 
Formulation A – Food Effect
All parameters with units
SAC
2.77
PK Parameter 
FD Summary
PK_T5
DTG Parameter Analysis – Data based on Actual 
Time - Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC
2.78
PK Parameter 
FD Summary 
PK_T5
3TC Parameter Analysis – Data based on Actual 
Time - Food Effect
All parameters with units; 
Treatments B, B_Fed only
SAC


CONFIDENTIAL
204994
51
10.11.5.
Pharmacokinetic Figures
If Part 2 is conducted, same set of figures will be provided as 2.101 to 2.144 with Part 1 and Part 2 indication in the titles
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
2.01
PK Plasma 
Concentration
pkcf1x
Individual Subject DTG Plasma Concentration-
time Plot (Linear and Semi-log) by Subject
Paged by Subject
SAC
2.02
PK Plasma 
Concentration
pkcf1x
Individual Subject 3TC Plasma Concentration-
time Plot (Linear and Semi-log) by Subject
Paged by Subject
SAC
2.03
PK Plasma 
Concentration
pkcf6
Individual Subject DTG Plasma Concentration-
time Plot (Linear and Semi-log) by Treatment
Paged by Treatment 
SAC
2.04
PK Plasma 
Concentration
pkcf6
Individual Subject 3TC Plasma Concentration-
time Plot (Linear and Semi-log) by Treatment
Paged by Treatment
SAC


CONFIDENTIAL
204994
52
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Mean / Median Concentration Plots
2.05
PK Parameter 
BE Summary
pkcf4
Arithmetic Mean (+SD) DTG Plasma 
Concentration-time Plot (Linear and Semi-log)
- Bioequivalence Assessment
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
A, B only
SAC
2.06
PK Parameter 
BE Summary
pkcf4
Arithmetic Mean (+SD) 3TC Plasma 
Concentration-time Plot (Linear and Semi-log)
- Bioequivalence Assessment
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
A, B only
SAC
2.07
PK Parameter 
BE Summary
pkcf5
Median (range) DTG Plasma Concentration-
time Plot (Linear and Semi-log) -
Bioequivalence Assessment
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
A, B only
SAC
2.08
PK Parameter 
BE Summary
pkcf5
Median (range) 3TC Plasma Concentration-
time Plot (Linear and Semi-log) -
Bioequivalence Assessment
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
A, B only
SAC
2.09
PK Parameter 
BE Summary
pkcf4
Arithmetic Mean DTG Plasma Concentration-
time Plot (Linear and Semi-log) -
Bioequivalence Assessment
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
A, B only
SAC
2.10
PK Parameter 
BE Summary
pkcf4
Arithmetic Mean 3TC Plasma Concentration-
time Plot (Linear and Semi-log) -
Bioequivalence Assessment
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
A, B only
SAC


CONFIDENTIAL
204994
53
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11
PK Parameter
BE Summary
pkcf5
Median DTG Plasma Concentration-time Plot 
(Linear and Semi-log) - Bioequivalence 
Assessment
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
A, B only
SAC
2.12
PK Parameter 
BE Summary
pkcf5
Median 3TC Plasma Concentration-time Plot 
(Linear and Semi-log)- Bioequivalence 
Assessment
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
A, B only
SAC
2.13
PK Parameter 
FD Summary
pkcf4
Arithmetic Mean (+SD) DTG Plasma 
Concentration-time Plot (Linear and Semi-log)
- Food Effect
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
B, B_Fed only
SAC
2.14
PK Parameter 
FD Summary
pkcf4
Arithmetic Mean (+SD) 3TC Plasma 
Concentration-time Plot (Linear and Semi-log)
- Food Effect
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
B, B_Fed only
SAC
2.15
PK Parameter 
FD Summary
pkcf5
Median (range) DTG Plasma Concentration-
time Plot (Linear and Semi-log) - Food Effect
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
B, B_Fed only
SAC
2.16
PK Parameter 
FD Summary
pkcf5
Median (range) 3TC Plasma Concentration-
time Plot (Linear and Semi-log) - Food Effect
Use nominal times in X Axis, 
Paged by Treatment. Treatments 
B, B_Fed only
SAC


CONFIDENTIAL
204994
54
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.17
PK Parameter 
FD Summary
pkcf4
Arithmetic Mean DTG Plasma Concentration-
time Plot (Linear and Semi-log) - Food Effect
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
B, B_Fed only
SAC
2.18
PK Parameter 
FD Summary
pkcf4
Arithmetic Mean 3TC Plasma Concentration-
time Plot (Linear and Semi-log) - Food Effect
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
B, B_Fed only
SAC
2.19
PK Parameter
FD Summary
pkcf5
Median DTG Plasma Concentration-time Plot 
(Linear and Semi-log) - Food Effect
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
B, B_Fed only
SAC
2.20
PK Parameter
FD Summary
pkcf5
Median 3TC Plasma Concentration-time Plot 
(Linear and Semi-log) - Food Effect
Use nominal times in X Axis. 
Keep all the treatments in one 
plot. Use different colours for 
different treatments. Treatments 
B, B_Fed only
SAC
Comparative PK Parameters Plots based on Actual Sampling Time
2.21
PK Parameter 
BE Summary
pkpf3
Comparative Plot of Individual Subject  DTG 
Plasma Pharmacokinetic Parameter based on 
Actual Sampling Time Versus Treatment -
Bioequivalence Assessment
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC


CONFIDENTIAL
204994
55
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.22
PK Parameter 
BE Summary
pkpf3
Comparative Plot of Individual Subject 3TC 
Plasma Pharmacokinetic Parameter based on 
Actual Sampling Time Versus Treatment -
Bioequivalence Assessment
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.23
PK Parameter 
BE Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects DTG Plasma Pharmacokinetic  
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.24
PK Parameter 
BE Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects 3TC Plasma Pharmacokinetic  
Parameters based on Actual Sampling Time -
Bioequivalence Assessment
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.25
PK Parameter 
FD Summary
pkpf3
Comparative Plot of Individual Subject  DTG 
Plasma Pharmacokinetic Parameter based on 
Actual Sampling Time Versus Treatment –
Food Effect
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
2.26
PK Parameter 
FD Summary
pkpf3
Comparative Plot of Individual Subject 3TC 
Plasma Pharmacokinetic Parameter based on 
Actual Sampling Time Versus Treatment –
Food Effect
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC


CONFIDENTIAL
204994
56
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27
PK Parameter 
FD Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects DTG Plasma Pharmacokinetic  
Parameters based on Actual Sampling Time –
Food Effect
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
2.28
PK Parameter 
FD Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects 3TC Plasma Pharmacokinetic  
Parameters based on Actual Sampling Time –
Food Effect
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
Statistical Analysis Plots based on Actual Sampling Time
2.29
PK Parameter 
BE Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of DTG Plasma Pharmacokinetic Parameters
based on Actual Sampling Time -
Bioequivalence Assessment
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments A, B only
SAC
2.30
PK Parameter 
BE Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of 3TC Plasma Pharmacokinetic Parameters
based on Actual Sampling Time -
Bioequivalence Assessment
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments A, B only
SAC
2.31
PK Parameter 
FD Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of DTG Plasma Pharmacokinetic Parameters
based on Actual Sampling Time – Food Effect
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments B, B_Fed only
SAC


CONFIDENTIAL
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Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.32
PK Parameter 
FD Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of 3TC Plasma Pharmacokinetic Parameters
based on Actual Sampling Time – Food Effect
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments B, B_Fed only
SAC
Comparative PK Parameters Plots based on Nominal Sampling Time
2.33
PK Parameter 
BE Summary
pkpf3
Comparative Plot of Individual Subject  DTG 
Plasma Pharmacokinetic Parameter based on 
Nominal Sampling Time Versus Treatment -
Bioequivalence Assessment
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.34
PK Parameter 
BE Summary
pkpf3
Comparative Plot of Individual Subject 3TC 
Plasma Pharmacokinetic Parameter based on 
Nominal Sampling Time Versus Treatment -
Bioequivalence Assessment
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.35
PK Parameter 
BE Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects DTG Plasma Pharmacokinetic  
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC
2.36
PK Parameter 
BE Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects 3TC Plasma Pharmacokinetic  
Parameters based on Nominal Sampling Time -
Bioequivalence Assessment
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments A, B 
only
SAC


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Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.37
PK Parameter 
FD Summary
pkpf3
Comparative Plot of Individual Subject  DTG 
Plasma Pharmacokinetic Parameter based on 
Nominal Sampling Time Versus Treatment –
Food Effect
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
2.38
PK Parameter 
FD Summary
pkpf3
Comparative Plot of Individual Subject 3TC 
Plasma Pharmacokinetic Parameter based on 
Nominal Sampling Time Versus Treatment –
Food Effect
Parameters AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
2.39
PK Parameter 
FD Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects DTG Plasma Pharmacokinetic  
Parameters based on Nominal Sampling Time –
Food Effect
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
2.40
PK Parameter 
FD Summary
PK_F1
Treatment Comparative Plot of Adjusted 
Geometric Mean (95% CI) with Individual 
Subjects 3TC Plasma Pharmacokinetic  
Parameters based on Nominal Sampling Time –
Food Effect
Paged by AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2 with units; Treatments B, 
B_Fed only
SAC
Statistical Analysis Plots based on Nominal Sampling Time
2.41
PK Parameter 
BE Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of DTG Plasma Pharmacokinetic Parameters
based on Nominal Sampling Time -
Bioequivalence Assessment
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments A, B only
SAC


CONFIDENTIAL
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Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.42
PK Parameter 
BE Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of 3TC Plasma Pharmacokinetic Parameters
based on Nominal Sampling Time -
Bioequivalence Assessment
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments A, B only
SAC
2.43
PK Parameter 
FD Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of DTG Plasma Pharmacokinetic Parameters
based on Nominal Sampling Time – Food 
Effect
Produce for AUC(0-∞), AUC(0-t), 
AUC(0-24), Cmax, C24, CL/F and
t1/2, all parameters on one plot. 
Treatments B, B_Fed only
SAC
2.44
PK Parameter 
FD Summary
PK_F2
Geometric Mean Treatment Ratio and 90% CI 
of 3TC Plasma Pharmacokinetic Parameters
based on Nominal Sampling Time – Food 
Effect
Produce for AUC(0-∞), AUC(0-t),
AUC(0-24), Cmax, C24, CL/F and 
t1/2, all parameters on one plot. 
Treatments B, B_Fed only
SAC


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10.11.6.
Safety Tables
If Part 2 is conducted, same set of tables will be provided as 3.101 to 3.113 with Part 1 and Part 2 indication in the titles
Safety Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.01
Safety
CP_AE1x 
(xo)
Summary of All Adverse Events
SAC
3.02
Safety
CP_AE1x 
(xo)
Summary of Drug-Related Adverse Events
SAC
3.03
Safety
CP_AE1x 
(xo)
Summary of Serious Adverse Events
SAC
3.04
Safety
CP_AE1x 
(xo)
Summary of AEs Leading to Permanent 
Discontinuation of Study Drug or Withdrawal 
from Study
SAC
Labs
3.05
Safety
LB1
Summary of Chemistry Laboratory Values
SAC
3.06
Safety
LB1
Summary of Change from Baseline for 
Chemistry Laboratory Values
SAC
3.07
Safety
LB1
Summary of Hematology Laboratory Values
SAC
3.08
Safety
LB1
Summary of Change from Baseline for 
Hematology Laboratory Values
SAC
ECGs
3.09
Safety
EG1
Summary of ECG Findings 
SAC
3.10
Safety
EG2
Summary of ECG Values 
SAC
Vital Signs 
3.11
Safety
VS1
Summary of Vital Signs 
Include BP, HR
SAC


CONFIDENTIAL
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Safety Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.12
Safety
VS1
Summary of Change From Baseline for Vital 
Signs 
Include BP, HR
SAC
3.13
Safety
SAFE_T1
Frequency of Subjects with Vital Signs 
Measurements Outside the Potential Clinical 
Concern Range
SAC


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10.11.7.
ICH Listings
If Part 2 is conducted, same set of listings will be provided as 101 to 148 with Part 1 and Part 2 indication in the titles
ICH Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomisation
1
Safety
CP_RA1x
(XO)
Listing of Randomized and Actual 
Treatments
Add randomization date
SAC
Subject Disposition
2
Screening
ES7
Listing of Reasons for Screening Failures
Include Age and Sex. Concatenate with 
Subjid 
SAC
3
Safety
CP_ES10x 
(XO)
Listing of Reasons for Withdrawal
SAC
4
Safety
DV2
Listing of Protocol Deviations
SAC
5
Screening
SAFE_L1
Listing of Subjects Excluded from 
Analysis Populations
SAC
6
Safety
IE4 (XO)
Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations
SAC
Demographics
7
Safety
DM4 (XO)
Listing of Demographic Characteristics
SAC
8
Safety
DM10 (XO)
Listing of Race
SAC
Concomitant Medication
9
Safety
CP_CM4
(XO)
Listing of Concomitant Medications by 
Generic Term
SAC
Exposure
10
Safety
EX4 (XO)
Listing of Exposure Data
SAC


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ICH Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
11
Safety
AE7
Listing of Subject Numbers for Individual 
Adverse Events
SAC
12
Safety
CP_AE9 
(XO)
Listing of All Adverse Events
SAC
13
Safety
CP_AE9 
(XO)
Listing of Drug Related Adverse Events
SAC
14
Safety
CP_AE9a 
(xo)
Listing of Serious Adverse Events
SAC
15
Safety
CP_AE9 
(xo)
Listing of Adverse Events Leading to 
Permanent Discontinuation of Study 
Treatment or Withdrawal from Study
SAC
LABS
16
Safety
CP_LB6 
(xo) 
Listing of Clinical Chemistry with Grade 2 
or Higher Lab Abnormalities
Include all tests in which we have 
DAIDS criteria.
SAC
17
Safety
CP_LB6 
(xo) 
Listing of All Clinical Chemistry 
Laboratory Data for Subjects with Grade 2 
or Higher Lab Abnormalities
Include all tests in which we have 
DAIDS criteria.
SAC
18
Safety
CP_LB6 
(xo) 
Listing of Hematology with Grade 2 or 
Higher Lab Abnormalities
Include all tests in which we have 
DAIDS criteria.
SAC
19
Safety
CP_LB6 
(xo) 
Listing of All Hematology Laboratory 
Data for Subjects with Grade 2 or Higher 
Lab Abnormalities
Include all tests in which we have 
DAIDS criteria.
SAC
20
Safety
UR2b
Listing of Urinalysis Data for Subjects 
with Positive Dipstick or Microscopic 
Results
SAC


CONFIDENTIAL
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64
ICH Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ECGs
21
Safety
CP_EG4 
(xo)
Listing of ECG Values of Potential 
Clinical Importance
SAC
22
Safety
CP_EG4 
(xo)
Listing of All ECG Values for Subjects 
with any Value of Potential Clinical 
Importance
SAC
23
Safety
CP_EG6 
(xo)
Listing of Abnormal ECG findings
SAC
Vital Signs
24
Safety
CP_VS5 
(XO)
Listing of Vital Signs of Potential Clinical 
Importance
SAC
25
Safety
CP_VS5 
(XO)
Listing of All Vital Signs for Subjects 
with any Value of Potential Clinical 
Importance
SAC


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10.11.8.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
AE
26
Safety
AE2
Relationship between System Organ Class and 
Verbatim Text 
SAC
PK
27
PK Plasma 
Concentration
pkcl1x
Listing of DTG Plasma Concentration-time Data
SAC
28
PK Plasma 
Concentration
pkcl1x
Listing of 3TC Plasma Concentration-time Data
SAC
29
PK Plasma 
Concentration
pkpl1x
Listing of DTC Plasma PK Parameters based on Actual 
Sampling Time
SAC
30
PK Plasma 
Concentration
pkpl1x
Listing of 3TC Plasma PK Parameters based on Actual 
Sampling Time
SAC
31
PK Plasma 
Concentration
pkpl1x
Listing of DTC Plasma PK Parameters based on 
Nominal Sampling Time
SAC
32
PK Plasma 
Concentration
pkpl1x
Listing of 3TC Plasma PK Parameters based on 
Nominal Sampling Time
SAC
33
PK Parameter
BE Summary
mid20167, 
listing 33
Listing of Individual DTG Plasma PK Parameter 
Treatment Ratios based on Actual Sampling Time -
Bioequivalence Assessment
SAC
34
PK Parameter 
BE Summary
mid20167, 
listing 33
Listing of Individual 3TC Plasma PK Parameter 
Treatment Ratios based on Actual Sampling Time -
Bioequivalence Assessment
SAC


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66
Non-ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
35
PK Parameter 
FD Summary
mid20167, 
listing 33
Listing of Individual DTG Plasma PK Parameter 
Treatment Ratios based on Actual Sampling Time –
Food Effect
SAC
36
PK Parameter 
FD Summary
mid20167, 
listing 33 
Listing of Individual 3TC Plasma PK Parameter 
Treatment Ratios based on Actual Sampling Time –
Food Effect
SAC
37
PK Parameter 
BE Summary
mid20167, 
listing 33
Listing of Individual DTG Plasma PK Parameter 
Treatment Ratios based on Nominal Sampling Time -
Bioequivalence Assessment
SAC
38
PK Parameter 
BE Summary
mid20167, 
listing 33 
Listing of Individual 3TC Plasma PK Parameter 
Treatment Ratios based on Nominal Sampling Time -
Bioequivalence Assessment
SAC
39
PK Parameter 
FD Summary
mid20167, 
listing 33
Listing of Individual DTG Plasma PK Parameter 
Treatment Ratios based on Nominal Sampling Time –
Food Effect
SAC
40
PK Parameter 
FD Summary
mid20167, 
listing 33 
Listing of Individual 3TC Plasma PK Parameter 
Treatment Ratios based on Nominal Sampling Time –
Food Effect
SAC
41
PK Parameter 
BE Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based on 
Actual Sampling Time - Bioequivalence Assessment
SAC
42
PK Parameter 
BE Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Actual Sampling Time - Bioequivalence Assessment
SAC


CONFIDENTIAL
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67
Non-ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
43
PK Parameter 
FD Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based on 
Actual Sampling Time - Food Effect
SAC
44
PK Parameter 
FD Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Actual Sampling Time - Food Effect
SAC
45
PK Parameter 
BE Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based on 
Nominal Sampling Time - Bioequivalence Assessment
SAC
46
PK Parameter 
BE Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Nominal Sampling Time - Bioequivalence Assessment
SAC
47
PK Parameter 
FD Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed DTG Plasma PK Parameters based on 
Nominal Sampling Time - Food Effect
SAC
48
PK Parameter 
FD Summary
N/A
RAW SAS Output from Statistical Analysis of Loge-
transformed 3TC Plasma PK Parameters based on 
Nominal Sampling Time - Food Effect
SAC


CONFIDENTIAL
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10.12.
Appendix 12: Example Mock Shells for Data Displays
Example 
: PK_T1
                                         
Protocol
: 204994                                                                                                                                               Page 1 of n
Population
: PK Parameter BE Summary (programming note: ‘PK Parameter BE (or FD) Summary’ depending each display in TOC)
Table xx.xx
Summary of Statistical Analysis of Loge-transformed DTG Plasma Pharmacokinetic Parameters based on Actual Sampling Time
Parameter
   Comparison
       Adjusted Geometric Mean
  Ratio
90% Confidence
%CVw
  Test vs Reference
n    Test          n    Ref          (Test/Ref)          Interval for Ratio
-----------------------------------------------------------------------------------------------------------
Cmax(units)         [Test treatment description] vs       x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)             xx.x
  [Reference treatment description]
AUC(0-t)(units)     [Test treatment description] vs        x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)             xx.x
   [Reference treatment description]
AUC(0-∞)(units)   [Test treatment description] vs
  x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)             xx.x
   [Reference treatment description]
C24(units)          [Test treatment description] vs
  x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)             xx.x
[Reference treatment description]


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Example 
: PK_T2
                                                           
Protocol
: 204994                                                                                                                                               Page 1 of n
Population
: PK Parameter BE Summary
Table xx.xx
Summary of Statistical Analysis of Median Difference and Confidence Interval for DTG Pharmacokinetic Parameters based on Actual 
Sampling Time
Parameter
Comparison
       
  Median                                 Estimated 
                                                                                                                                   Median Diff        90% Confidence
Test vs Reference
n    Test          n    Ref           (Test - Ref)          Interval for Diff
-----------------------------------------------------------------------------------------------------------
Tlag(units)          [Test treatment description] vs       x   xx.xx          x  xx.xx             x.xxxx
(x.xxxx, x.xxxx)             
  [Reference treatment description]
Tmax)(units)      [Test treatment description] vs        x   xx.xx          x  xx.xx             x.xxxx
(x.xxxx, x.xxxx)             
[Reference treatment description]


CONFIDENTIAL
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70
Example 
: PK_F1
                         Page 1 of n
Protocol
: 204994
Population
: PK Parameter BE Summary
                                                                      Figure xx.xx
                 Treatment Comparative Plot of Adjusted Geometric Mean (95% CI) with Individual Subjects
                                              DTG Plasma Pharmacokinetic Parameters
                                 
Programming note: add footnote for treatment A, B.


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71
Example 
: PK_F2
                 Page 1 of n
Protocol
: 204994
Population
: PK Parameter BE Summary
                                                                         Figure xx.xx
           Geometric Mean Treatment Ratio and 90% CI of DTG Plasma Pharmacokinetic Parameters
                                                                                                     A vs B
Note: The reference lines at ratios of 0.80, 1.25 represent BE criterion.
Programming note: add footnote for treatment A, B.


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72
Example: SAFE_T1
Protocol: 204994                                                                         Page 1 of n
Population: Safety
                                                 Table xx.xx
Number of Subjects with Change from Baseline Vital Signs Category
                                          Subject                            Test         Reference
VSTEST                    Pl. Time        Position     Flagging category    (N=XX)          (N=XX)
-----------------------------------------------------------------------------------------------------------
Diastolic Blood Pressure   Time 1
     Supine       n                    XX              XX
(mmHg)                    
                                                       Increase >=20        0               XX(XX%)
                                                       Increase >=40        XX(XX%)          0
                                                       Decrease >=20        0               XX(XX%)
                                                       Decrease >=40        XX(XX%)          0
                           Time 2
     Supine       n                    XX              XX
                          
                                                      Increase >=20        0               XX(XX%)
                                                       Increase >=40        XX(XX%)          0
                                                       Decrease >=20        0               XX(XX%)
                                                       Decrease >=40        XX(XX%)          0


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73
Example: SAFE_L1
Protocol: 204994                                                                         Page 1 of n
Population: Screening
Listing X
Listing of Subjects Excluded from Analysis Populations
                  No. of
                                   No. of     Subjects
  Population                      Subjects   Excluded   Subject numbers
  ------------------------------------------------------------------------
  Screening                       xxx        xx   xxx, xxx, xxx, xxx.
  
   Safety                          xx          0
  PK Plasma Concentration          xx         xx   xxx
  
   PK Parameter BE Summary          xx         xx   xxx
   PK Parameter Food Effect Summary xx         xx   xxx


CONFIDENTIAL
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74
Example: PK_T3
Protocol: 204994                                                                         Page 1 of n
Population: PK Plasma Concentration 
Table x.xx
DTG Drug Concentration (unit) for the Test Formulation B


CONFIDENTIAL
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Example: PK_T4
Protocol: 204994                                                                         Page 1 of n
Population: PK Plasma Concentration
Table x.xx
DTG Parameter Estimates based on Actual Time for Each Subject Given the Test Formulation B


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76
Example: PK_T5
Protocol: 204994                                                                         Page 1 of n
Population: PK Parameter BE Summary
Table x.xx
DTG Parameter Analysis – Data based on Actual Time - Bioequivalence Assessment