A Phase I, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of Dolutegravir + Rilpivirine (JULUCA™) 50 mg/25 mg Tablets in Healthy Participants of Japanese Descent
Phase: PHASE1
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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TITLE PAGE
Protocol Title: A Phase I, Open-label, Single-dose Study to Investigate the 
Pharmacokinetics, Safety and Tolerability of Dolutegravir + Rilpivirine (JULUCA™) 50 
mg/25 mg tablets in healthy participants of Japanese descent
Protocol Number: 212312
Compound Number:
GSK3365791
Study Phase: Phase 1 
Short Title: Study to Evaluate Pharmacokinetics, Safety and Tolerability of Dolutegravir 
and Rilpivirine (JULUCA™) 50 mg/25 mg tablets in healthy participants of Japanese 
descent
US IND Sponsor Name and Legal Registered Address: 
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as Sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the Vice President, Global Research and Medical Strategy. 
This study is sponsored by ViiV Healthcare.  Parexel with GlaxoSmithKline are 
supporting ViiV Healthcare in the conduct of this study. 
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND Number 123306
Approval Date: 04-APR-2019
Copyright 2019 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schedule of Activities (SoA)..........................................................................8
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Background ................................................................................................11
2.3.
Benefit/Risk Assessment ............................................................................12
2.3.1.
Risk Assessment .........................................................................13
Benefit Assessment....................................................................................15
2.3.2.
Overall Benefit: Risk Conclusion..................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Scientific Rationale for Study Design ..........................................................16
4.3.
Justification for Dose ..................................................................................16
4.4.
End of Study Definition ...............................................................................16
5.
STUDY POPULATION...........................................................................................16
5.1.
Inclusion Criteria.........................................................................................17
5.2.
Exclusion Criteria........................................................................................18
5.3.
Lifestyle Considerations..............................................................................20
5.3.1.
Meals and Dietary Restrictions ....................................................20
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................20
5.3.3.
Activity .........................................................................................21
5.4.
Screen Failures...........................................................................................21
6.
STUDY INTERVENTION........................................................................................21
6.1.
Study Intervention(s) Administered .............................................................22
6.2.
Preparation/Handling/Storage/Accountability..............................................22
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................22
6.4.
Study Intervention Compliance ...................................................................22
6.5.
Concomitant Therapy..................................................................................23
6.6.
Dose Modification .......................................................................................23
6.7.
Intervention after the End of the Study........................................................23
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................23
7.1.
Discontinuation of Study Intervention..........................................................23
7.1.1.
Liver Chemistry Follow Up Criteria...............................................24
7.1.2.
QTc Stopping Criteria ..................................................................24
7.1.3.
Temporary Discontinuation ..........................................................24
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................24
7.3.
Lost to Follow Up........................................................................................24
 
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8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................25
8.1.
Efficacy Assessments.................................................................................26
8.2.
Safety Assessments ...................................................................................26
8.2.1.
Physical Examinations.................................................................26
8.2.2.
Vital Signs....................................................................................26
8.2.3.
Electrocardiograms......................................................................26
8.2.4.
Clinical Safety Laboratory Assessments ......................................26
8.2.5.
Suicidal Ideation and Behaviour Risk Monitoring .........................27
8.3.
Adverse Events and Serious Adverse Events.............................................27
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................27
8.3.2.
Method of Detecting AEs and SAEs.............................................28
8.3.3.
Follow-up of AEs and SAEs.........................................................28
8.3.4.
Regulatory Reporting Requirements for SAEs .............................28
8.3.5.
Pregnancy ...................................................................................28
8.3.6.
Cardiovascular and Death Events................................................29
8.3.7.
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs................................................................29
8.3.8.
Medical Device Incidents (Including Malfunctions).......................29
8.4.
Treatment of Overdose...............................................................................29
8.5.
Pharmacokinetics .......................................................................................29
8.5.1.
Blood Sample Collection..............................................................29
8.5.1.1.
Sample Processing Procedures..................................30
8.5.2.
Sample Analysis ..........................................................................31
8.6.
Pharmacodynamics ....................................................................................31
8.7.
Genetics .....................................................................................................31
8.8.
Biomarkers .................................................................................................31
9.
STATISTICAL CONSIDERATIONS........................................................................31
9.1.
Statistical Hypotheses.................................................................................31
9.2.
Sample Size Determination ........................................................................32
9.2.1.
Sample Size Assumptions ...........................................................32
9.2.2.
Sample Size Sensitivity................................................................32
9.3.
Populations for Analyses ............................................................................32
9.4.
Statistical Analyses.....................................................................................32
9.4.1.
Efficacy Analyses.........................................................................33
9.4.2.
Safety Analyses...........................................................................33
9.4.3.
Pharmacokinetic Analysis............................................................33
9.4.4.
Data Monitoring Committee (DMC)..............................................33
9.5.
Interim Analysis ..........................................................................................34
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................35
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........35
10.1.1.
Regulatory and Ethical Considerations ........................................35
10.1.2.
Financial Disclosure.....................................................................35
10.1.3.
Informed Consent Process ..........................................................36
10.1.4.
Data Protection............................................................................36
10.1.5.
Committees Structure ..................................................................36
 
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10.1.6.
Dissemination of Clinical Study Data ...........................................37
10.1.7.
Data Quality Assurance ...............................................................37
10.1.8.
Source Documents ......................................................................38
10.1.9.
Study and Site Closure ................................................................38
10.1.10. Publication Policy.........................................................................39
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................40
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................42
10.3.1.
Definition of Adverse Event (AE)..................................................42
10.3.2.
Definition of Serious Adverse Event (SAE) ..................................43
10.3.3.
Recording and Follow-Up of AE and SAE....................................44
10.3.4.
Reporting of SAE to GSK.............................................................46
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................47
10.4.1.
Definitions:...................................................................................47
10.4.2.
Collection of Pregnancy Information: ...........................................47
10.5.
Appendix 5: Genetics..................................................................................49
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................50
10.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................52
10.8.
Appendix 8: Country-specific requirements.................................................53
10.9.
Appendix 9: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, July 2017 .................................54
10.10. Appendix 10: Abbreviations and Trademarks..............................................55
11. REFERENCES.......................................................................................................58
 
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Phase I, Open-label, Single-dose Study to Investigate the 
Pharmacokinetics, Safety and Tolerability of Dolutegravir + Rilpivirine (JULUCA™) 50 
mg/25 mg tablets in healthy participants of Japanese descent
Short Title: Study to Evaluate Pharmacokinetics, Safety and Tolerability of Dolutegravir
+ Rilpivirine (JULUCA™) 50 mg/25 mg tablets in healthy participants of Japanese 
descent
Rationale:
Dolutegravir (DTG), a human immunodeficiency virus (HIV)-1 integrase inhibitor (INI), 
and rilpivirine (RPV), a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), 
are each approved in the United States (US), European Union, and other countries for the 
treatment of HIV-1 infection, in combination with other antiretrovirals (ARVs).  JULUCA
is a fixed-dose single tablet containing dolutegravir and rilpivirine approved by the US 
Food and Drug Administration in 2017 and the European Commission and Japan Ministry 
of Health Labor & Welfare (MHLW) in 2018.  JULUCA is a complete regimen indicated 
for the treatment of HIV-1 infection in ARV-experienced adult patients who are switching 
from their current ARV regimen to the 2-drug regimen while their viral load is suppressed 
to <50 copies/milliliter (c/mL).  
Although, the pharmacokinetics (PK), safety and tolerability of DTG/RPV (50 mg/25mg) 
fixed-dose combination (FDC) tablets have been extensively studied in participants not of 
Japanese heritage, these parameters have not been assessed exclusively in Japanese 
participants.  To support a post-approval commitment for DTG/RPV 50 mg/25 mg FDC in 
Japan, this study will characterize the PK, safety and tolerability of a single dose 
DTG/RPV 50 mg/25 mg FDC in a healthy adult Japanese population.  This study will be 
conducted under fed conditions to maintain alignment with the JULUCA product label.
 
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Objectives and Endpoints:
Objectives
Endpoints
Primary 
To evaluate the PK of DTG and RPV following 
a single oral dose of DTG/RPV 50 mg/25 mg 
FDC in healthy, adult Japanese participants.
Plasma DTG and RPV AUC(0-∞), AUC(0-t),  
Cmax, tlag, tmax, t, t½, z, %AUCex, AUC(0-24), 
AUC(0-72), CL/F and Vz/F, Ct, and C24  
following a single oral dose of DTG/RPV 50 
mg/25 mg FDC in healthy adult Japanese 
participants. 
Secondary
To evaluate the safety and tolerability of 
DTG/RPV FDC in healthy, adult Japanese 
participants.
Safety and tolerability parameters, adverse 
event (AE)/serious adverse events (SAE), 
observed and change from baseline clinical 
laboratory values, and vital sign assessments.
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
AUC(0-72) = area under the plasma concentration time curve from time zero to 72 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
t = time of last quantifiable concentration
tlag = absorption lag time
tmax = time of maximum observed concentration
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 will be a single-center, single dose, open-label study in adult Japanese healthy 
participants to evaluate the PK, safety and tolerability of the DTG/RPV 50 mg/25mg FDC
tablet.  The study will consist of screening, treatment and follow-up phases.  Participants 
will have a screening visit within 28 days prior to receiving the study intervention.  
Enrolled participants will receive a single oral dose of the DTG/RPV 50 mg/25 mg FDC
tablet in a fed state.  Safety assessments including, clinical laboratory safety tests and 
adverse event reports will be performed throughout the study. Serial PK samples will be 
collected pre-dose through 264 hours post-dose.  All participants will have a follow-up 
visit within 12-17 days after the last dose of study intervention. 
Disclosure Statement: This is a single group, single arm study that has no masking.
 
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Number of Participants:
A maximum of 16 healthy adult Japanese subjects will be enrolled such that a minimum of 
approximately 13 evaluable subjects complete the study with at least 3 participants of each 
gender enrolled.  
Intervention Groups and Duration:
Each subject will have a screening visit within 28 days prior to the one treatment period 
with a single dose of study drug and a follow-up visit up within 12-17 days after the single 
dose of study intervention.  The total duration of participation of a subject in this study 
will be approximately 45 days.
Data Monitoring Committee: No
1.2.
Schedule of Activities (SoA)
Table 1
Screening Visit
Procedure
Screening (up to 28 days before Day 1)
Informed Consent
X
Inclusion and exclusion criteria
X
Demographics
X
Brief physical examination including height, 
weight and body mass index (BMI)1
X
Medical history including substance (Drug, 
Alcohol, Tobacco and Caffeine) usage 
X
Urine drug / serum alcohol / Cotinine screening
X
Triplicate 12-Lead Electrocardiogram (ECG)4
X
Vital Sign (VS) measurements4
X
Serum or urine pregnancy test (WOCBP only)
X
Follicle-stimulating hormone (as needed, to 
confirm postmenopausal status)
X
HIV, Hep B and Hep C Screening2
X
Clinical laboratory assessments (hematology, 
chemistry, urinalysis, including liver 
chemistries)3,4
X
1 A brief physical examination will include at a minimum, assessments of the skin, cardiovascular, and respiratory.
2 If test otherwise performed within 3 months prior to first dose of study intervention, testing at screening is not required
3 Glucose non-fasting at screening.
4 VS, Clinical laboratory assessments, ECG can be repeated once. 
 
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Table 2
Study Intervention Period Assessments
Procedure
Day -1
Study Intervention Period 
Follow-Up
(12 -17
days post 
last dose)
2,3
Notes
Day 
1
2
3
4
6
8
10
12
Pre
Dose
0 
hr
Post Dose
24 hr
48 hr
~72 
hr
~120 
hr
~168
hr
~216 
hr
~264 
hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
X
X
X
X
X
Brief Physical Exam1
X
Pregnancy test (urine or serum)
X
X
Urine/Drug/Alcohol/Cotinine
X
Illicit Drug/Alcohol/Cotinine 
performed at the standard practice 
of the site.
12-Lead ECG
X
Single ECGs will be collected
Vital Signs (VS) measurements
X
X
X
Single VS measurements will be 
performed at all time points.
Safety lab assessments 
(Hematology,Chemistry)
X
X
Glucose fasting is required 
approximately 10 hours prior to 
dosing on Day -1 and at least 6 
hours at Day 3 post dose. 
DTG/RPV FDC Dosing
X
1.
Subjects will fast for ~10 hours 
and receive the dose ~30 minutes
(5 minutes) after the start of a 
standardized moderate fat breakfast
Pharmacokinetic Sampling
X
Collected at 0.5, 1, 1.5, 2, 2.5, 
3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 
24, and 48 hours post-dose
X
X
X
X
X
1.
Subjects should be scheduled 
to provide PK samples in the 
morning on Days 4, 6, 8, 10, and 
12; Days 8, 10, and 12 are for RPV 
sampling only.
2.
The 4-hour post-dose sample 
must be drawn prior to the subjects’ 
first post-dose meal
 
 
 
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Procedure
Day -1
Study Intervention Period 
Follow-Up
(12 -17
days post 
last dose)
2,3
Notes
Day 
1
2
3
4
6
8
10
12
Pre
Dose
0 
hr
Post Dose
24 hr
48 hr
~72 
hr
~120 
hr
~168
hr
~216 
hr
~264 
hr
Serious Adverse Event (SAE)
Review
X
==========================X===========================
X
Adverse Event (AE) Review
==========================X===========================
X
Concomitant medication review
X
==========================X===========================
X
1 Brief examinations may be made full examinations and laboratory procedures may be repeated, if needed, at the discretion of the investigator.
2 If withdrawal is after Day 3, but before Follow Up procedure, please perform all Follow Up study procedures.
3 Follow up study procedures can be performed on Day 12. 

The timing and number of planned study assessments, including safety and PK assessments may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging pharmacokinetic data 
from this study must be documented and approved by the relevant study team member and then archived in the sponsor and site study 
files, but will not constitute a protocol amendment.The Competent Authority (CA) and ethics committee (EC) will be informed of any 
safety issues that constitute a substantial amendment and require alteration of the safety monitoring scheme or amendment of the 
informed consent form (ICF). The changes will be approved by the CA and the EC before implementation.
 
 
 
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2.
INTRODUCTION
2.1.
Study Rationale
Dolutegravir (DTG), a human immunodeficiency virus (HIV)-1 integrase inhibitor (INI), 
and rilpivirine (RPV), a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), 
are each approved in the US, European Union, and other countries for the treatment of 
HIV-1 infection, in combination with other antiretrovirals (ARVs).  JULUCA is a fixed-
dose single tablet containing dolutegravir and rilpivirine approved by the US Food and 
Drug Administration (FDA) in 2017 and the European Commission and Japan Ministry 
of Health Labor & Welfare (MHLW) in 2018.  JULUCA is a complete regimen indicated 
for the treatment of HIV-1 infection in ARV-experienced adult patients who are 
switching from their current ARV regimen to the 2-drug regimen while their viral load is 
suppressed to <50 copies/milliliter (c/mL).  For more details, please reference the current 
JULUCA Prescribing Information [Juluca USPI, 2017].  
Although, the pharmacokinetics (PK), safety and tolerability of DTG/RPV 50 mg/25 mg 
fixed-dose combination (FDC) tablet have been extensively studied in participants not of 
Japanese heritage, these parameters have not been assessed exclusively in Japanese 
participants.  To support a post-approval commitment for the DTG/RPV 50 mg/25 mg
FDC tablet in Japan, this study will characterize the PK, safety and tolerability of a single 
dose of the DTG/RPV 50 mg/25 mg FDC tablet in a healthy adult Japanese population.  
This study will be conducted under fed conditions to maintain alignment with the 
JULUCA Prescribing Information [Juluca USPI, 2017].
2.2.
Background
TIVICAY (dolutegravir) was first approved in the United States in 2013 and is currently 
approved globally in more than 100 countries including, the Japanese Pharmaceuticals 
and Medical Devices Agency in 2014. DTG is an INI with low to moderate inter-subject 
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 
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 results of Phase 3 trials in treatment-naive or treatment-experienced, 
INI-naive patients who took DTG without regard to mealtimes [TIVICAY USPI, 2015] .  
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 RM2007/00683/09].
EDURANT (rilpivirine), an NNRTI with in vitro activity against wild type virus and a 
broad range of NNRTI-resistant viruses, is approved in multiple countries including the 
US, Europe, Canada and Japan for the treatment of antiretroviral drug- naive patients 
(with viral load 100,000 c/mL) at a dose of 25 mg once daily. RPV is primarily 
metabolized by CYP450 3A and has a half-life of approximately 50 h.  The long half-life 
of RPV requires a lengthy PK sampling period of RPV to adequately characterize the 
terminal elimination phase and ensure that PK parameters are well-estimated. More 
 
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detailed information about efficacy, safety, and clinical pharmacology from an extensive 
program of Phase I-III clinical trials can be found in the RPV Investigator’s Brochure
[Janssen EDMS Number EDMS-ERI-3713711, 15.0., 2018].
JULUCA (dolutegravir and rilpivirine) is a fixed-dose single tablet containing a two-drug 
combination of dolutegravir and rilpivirine.  JULUCA is indicated for the treatment of 
HIV-1 infection in ARV-experienced adult patients who are switching from their current 
ARV regimen to the 2-drug regimen while their viral load is suppressed to <50 
copies/milliliter (c/mL).  For more details, please reference the current JULUCA
Prescribing Information [Juluca USPI, 2017].
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks, reasonably 
expected adverse events, and summaries of findings from both clinical and non-clinical 
studies conducted with DTG and RPV may be found in the product label for JULUCA
[Juluca USPI, 2017], and the Investigator’s Brochure and product labels for DTG             
[GlaxoSmithKline Document Number RM2007/00683/09] [TIVICAY, 2015] and RPV     
[Janssen EDMS Number EDMS-ERI-3713711, 12.0.] [EDURANT, 2015].  The 
following section outlines the risk assessment and mitigation strategy for this protocol.  
 
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2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and RPV] [GSK3365791]
Refer to IBs for additional information
DTG - Hypersensitivity reaction (HSR) 
and rash
RPV - 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. 
RPV:  Rash is a recognized risk for the NNRTI class; however, the severe 
rash defined above that are labelled for efavirenz and nevirapine were not 
seen with RPV in clinical trials.  In Phase III clinical trials, skin events of 
interest were reported at a lower incidence and grades, and resulted in 
fewer subject withdrawals, in the RPV group than in the efavirenz group and 
were mostly driven by the individual preferred term Rash. 
Since this is a single dose study, discontinuation of study 
intervention for suspected HSR and rash will not be 
applicable for participants.
Subjects with history of allergy/sensitivity to any of the 
study drugs are excluded (Section 5.2).
In the event of a HSR, participants should be evaluated by 
the Investigator immediately.  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.  Subjects will be 
treated as clinically appropriate.  Subjects should be 
followed up until resolution of the adverse event and 
standard management should be undertaken.
The subject informed consent form includes information on 
this risk and the actions subjects should take in the event 
of: 1) an HSR or associated signs and symptoms; or 2) 
developing any type of rash or skin abnormality. 
The rash and any associated symptoms should be 
reported as adverse events and appropriate toxicity ratings 
should be used to grade the events (based on DAIDS 
toxicity gradings).
If the etiology of the rash can be definitively diagnosed as 
being unrelated to IP and due to a specific medical event 
or a concomitant non-study medication, routine 
management should be performed and documentation of 
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
the diagnosis provided.
DTG and RPV - 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 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.  
RPV: Hepatic events have been reported in patients receiving a RPV 
containing regimen.  Patients with underlying HBV or HCV, or marked 
elevations in transaminases prior to treatment may be at increased risk for 
worsening or development of transaminase elevations with use of RPV. A 
few cases of hepatic toxicity have been reported in patients receiving a RPV 
containing regimen who had no pre-existing hepatic disease or other 
identifiable risk factors.
Subjects meeting either of the following criteria during the
screening period are excluded (Section 5.2).
•
A positive pre-study Hepatitis B surface antigen or 
positive Hepatitis C antibody result at screening.
•
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 >1.5xULN.
Since this is a single dose study, discontinuation of study 
intervention for suspected DILI and if the liver chemistry 
stopping criteria are met will not be applicable for 
participants. 
DTG - Renal function
Mild elevations of creatinine have been observed with DTG which are 
related to a likely benign effect on creatinine secretion with blockade of 
OCT-2.  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; therefore, do not require mitigation 
for this protocol. 
Subjects with Creatinine clearance (CrCL) <60 mL/min will 
be excluded from the study.
RPV - Corrected QT interval (QTc) 
prolongation
In healthy subjects, supratherapeutic doses of RPV (75 mg once daily and 
300 mg once daily) have been shown to prolong the QTc interval of the 
electrocardiogram (ECG). RPV at the recommended dose of 25 mg 
administered once daily is not associated with a clinically relevant effect on 
QTc.
Screening ECG to identify those with pre-existing 
prolonged QT interval.
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 gradings for HIV-infected patients). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of 
investigational product (IP), and will be followed to resolution as per Sponsor’s standard medical monitoring practices.  
 
 
 
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Benefit Assessment
This is a study in healthy participants, as such there is no expected benefit to
administration of DTG/RPV 50 mg/25 mg FDC tablets. There may be benefit to 
individual participants from the medical evaluations and assessments that could identify 
conditions that the participant was previously unaware of.
2.3.2.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, please refer to the current JULUCA label [Juluca USPI, 2017] for the potential 
risks identified in association with the DTG/RPV 50 mg/25 mg FDC tablet.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the PK of DTG and RPV 
following a single oral dose of DTG/RPV 
50 mg/25 mg FDC in healthy, adult 
Japanese participants.
Plasma DTG and RPV AUC(0-∞), AUC(0-t), Cmax, 
tlag, tmax, t, t½, z, %AUCex, AUC(0-24), AUC(0-72), 
CL/F and Vz/F, Ct, and C24  following a single
oral dose of DTG/RPV 50 mg/25 mg FDC in 
healthy adult Japanese participants.
Secondary
To evaluate the safety and tolerability of
DTG/RPV FDC in healthy, adult Japanese 
participants.
Safety and tolerability parameters, adverse
event (AE) /serious adverse events (SAE),
observed and change from baseline clinical
laboratory values, and vital sign
assessments.
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
AUC(0-72) = area under the plasma concentration time curve from time zero to 72 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
t = time of last quantifiable concentration
tlag = absorption lag time
tmax = time of maximum observed concentration
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 will be a single dose, open-label study in adult Japanese healthy participants to 
evaluate the PK, safety and tolerability of DTG/RPV 50 mg/25 mg FDC tablets.  The 
study will consist of screening, treatment and follow-up phases.  Participants will have a 
screening visit within 28 days prior to receiving the treatment.  Enrolled participants will 
receive the DTG/RPV 50 mg/25 mg FDC tablet as a single oral dose in a fed state.  
Safety assessments including, clinical laboratory safety tests and adverse event reports 
will be performed throughout the study.  Serial PK samples will be collected pre-dose 
through approximately 264 hours post-dose. All participants will have a follow-up visit 
within 12-17 days after the last dose of study intervention. 
4.2.
Scientific Rationale for Study Design
Prior population PK analyses have shown that the PK of DTG and RPV are similar in 
healthy and HIV-infected participants and race/ethnicity was not identified as a clinically 
relevant covariate to affect DTG and RPV PK. Therefore, the PK of the DTG/RPV 50 
mg/25 mg FDC tablet is expected to be similar in Japanese healthy subjects and HIV-
infected Japanese patients and the result from this study in healthy Japanese subjects can 
be applied to HIV-infected Japanese patients.
4.3.
Justification for Dose
JULUCA, a two-drug regimen of DTG/RPV, is indicated as a complete regimen for the 
treatment of HIV-1 in adults who are virologically suppressed.  The approved adult dose 
of JULUCA (DTG/RPV) is 50 mg/25 mg taken orally once daily with a meal.  Since 
race/ethnicity was not identified as a significant covariate to affect DTG and RPV PK in 
prior population PK analyses, no differences in PK are expected with the approved 50 
mg/25 mg FDC tablet to be administered to healthy, Japanese adults in this study.  In 
addition, both products as single agents and as JULUCA, and as part of other fixed dose 
combinations are approved at the same dosages in Japan.    
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Activities.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the Schedule of Activities (SoA) for the last 
participant in the trial globally.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
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The adherence to the study design requirements, including those specified in the SoA, are 
essential and required for study conduct.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare investigational product or other 
study treatment that may impact subject eligibility is provided in the respective IBs 
and/or product labels.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics:
2. Participants who were born in Japan with 4 ethnic Japanese grandparents.  
Participants who have not lived outside Japan for more than 10 years and who are
Japanese passport holders (current or expired).
3. Participants who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and cardiac 
monitoring (history and ECG).
Weight
4. 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
5. Male and female
a) Male Participants: No restrictions
b) Female Participants:
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in 
Appendix 4. Additional requirements for pregnancy testing during and after study 
intervention are located in Appendix 2 .
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
 
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Informed Consent
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History or presence of/significant history of or current cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; constituting a risk when taking the study intervention or 
interfering with the interpretation of data.
2. Abnormal blood pressure [as determined by the investigator]
3. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)
4. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
5. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones).
6.
QTcF >460 msec; [Based on the average of the 12 Lead ECG triplicate readings 
obtained at Screening]
NOTES:

The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), and/or another method, 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.
Prior/Concomitant Therapy
7. Past or intended use of over-the-counter or prescription medication including 
herbal medications within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) prior to dosing, see Section 6.5. 
Acetaminophen, as listed in Section 6.5, is allowed.    
Prior/Concurrent Clinical Study Experience
8. Participation in the study would result in loss of blood or blood products in excess 
of 500mL within 56 days.
 
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9. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
10. Current enrollment or past participation within the last 30 days before signing of 
consent in any other clinical study involving an investigational study intervention 
or any other type of medical research
Diagnostic assessments
11. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention.
12. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
first dose of study intervention.
NOTE: 

Subjects with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
13. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention
NOTE: 

Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing.
14. Positive pre-study drug/alcohol screen.
15. Positive human immunodeficiency virus (HIV) antibody test.
16. Regular use of known drugs of abuse.
17. Creatinine clearance (CrCL) <60 mL/min.
Other Exclusions
18. Employment with Janssen, ViiV, GlaxoSmithKline(GSK), or with the 
Investigator or study site, with direct involvement in the proposed study or other 
studies under the direction of that Investigator or study site, as well as family 
members of the employees or the Investigator.
19. Urinary cotinine levels indicative of smoking or history or regular use of tobacco-
or nicotine-containing products (e.g. nicotine patches or vaporizing devices) 
within 6 months prior to screening.
20. Regular alcohol consumption within 6 months prior to the study defined as: 
An average weekly intake of > 14 units for males or >7 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits.
21. Sensitivity to heparin or heparin-induced thrombocytopenia.
22. Sensitivity to any of the study interventions, or components thereof, or drug or 
other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study.
 
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5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Once in the clinical unit subjects will not be allowed to eat anything other than the 
food provided by the study centre.

At all times subjects will refrain from consumption of red wine, Seville oranges, 
grapefruit or grapefruit juice, grapefruit hybrids, pomelos, exotic citrus fruits, 
quinine, mustard greens and poppy seeds from 7 days prior to the first dose of study 
medication until after the final PK sample.

Subjects will fast (except water) from approximately 10 hours prior to dosing and 
will receive a standardized moderate fat breakfast approximately 30 minutes prior to 
dosing.  Subjects will consume this entire meal steadily over 25 minutes.    Dose 
administration will occur approximately 30 minutes after the start of meal 
consumption (so as to allow approximately 5 minutes for dose preparation).  Subjects 
will not receive any further food until 4 hours post-dose.  Other than the 240 mL of 
water consumed at dosing, subjects will not be permitted water between 2 hours 
prior to dosing to 2 hours post dose.  The moderate fat meal consists of 
(approximately 625 total calories: 125 calories from protein, 300 calories from 
carbohydrate, and 200 calories from fat):
1 English muffin
1 hard cooked egg
1 slice (0.5oz) American cheese
1 sausage link or patty (1 oz)
1 cup red seedless grapes
6 fl oz cranberry juice
8 fl oz skim/nonfat milk.

At all other times during inpatient treatment, subjects will receive meals as specified 
by the site standards.
5.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) sample.

During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample. 

Use of tobacco products will not be allowed from screening until after the final 
follow-up visit. As per SOA, a negative cotinine test is required at screening. 
 
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5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants will be assigned the same participant number 
as for the initial screening.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.  
 
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6.1.
Study Intervention(s) Administered
Table 3
Study Intervention
Intervention Name
JULUCA (Dolutegravir and Rilpivirine) 50 mg/25 mg FDC tablet
Type 
Drug
Dose Formulation
Tablet
Unit Dose Strength(s)
Dolutegravir 50 mg, Rilpivirine 25 mg
Dosage Level(s)
Single dose – 50 mg/ 25 mg tablet single dose
Route of Administration
Oral
IMP and NIMP
NIMP
Sourcing
Purchased by the Investigator 
6.2.
Preparation/Handling/Storage/Accountability
No special preparation of the study intervention is required for this study.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).  

Further guidance and information for the final disposition of unused study
intervention are provided in the Study Reference Manual provided by the site.

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label, single center, single dose study. 
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision.  The date and time of 
 
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each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Use of H2-blockers, proton-pump inhibitors, antacids, vitamins, calcium or iron 
supplements are strictly prohibited within 7 days prior to the first dose of study 
medication until 12 hours post-dose.  In addition to these drugs, participants must abstain 
from taking prescription or non-prescription drugs (including vitamins and dietary or 
herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) 
or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study. 
Acetaminophen, at doses of 2 grams/day, is permitted for use any time during the 
study. 
6.6.
Dose Modification
As this is a single dose study in healthy participants, there are no planned dose 
modifications.
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment after completion of the study 
because only healthy volunteers are eligible for study participation. 
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
As this is a single dose study, the permanent discontinuation of study intervention for a 
participant is non-applicable. 
 
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7.1.1.
Liver Chemistry Follow Up Criteria
Liver chemistry follow up assessments and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
Since this is a single dose study, discontinuation of study intervention if the liver 
chemistry stopping criteria is met will not be applicable for participants. Therefore, 
increased monitoring criteria indicated in liver safety required actions and follow up 
assessments, as outlined in Appendix 6, Section 10.6, will be employed.
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
QTc Stopping Criteria
This section is not applicable in this study.
7.1.3.
Temporary Discontinuation
This Section is not applicable to this study.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons. This is expected to be 
uncommon.

If withdrawal is after Day 3, but before Follow Up procedure, please perform 
all Follow Up procedures as per SoA.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
 
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
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. Vital Signs
2. Blood Draws
NOTE: The timing of the assessments should allow the blood draw to occur as close 
as possible to the exact nominal time.
 
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8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Additional time 
points for safety tests (such as 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.
8.2.1.
Physical Examinations

A brief physical examination will include, at a minimum, assessments of the 
skin, respiratory and cardiovascular system.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Temperature, pulse rate, and blood pressure (collected as standard for the site) 
and will be assessed.

Blood pressure and pulse measurements will be assessed in the supine position
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).
8.2.3.
Electrocardiograms

Single 12-lead ECG will be obtained, in supine or semi-supine position after 5 
minutes rest at Day-1 as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 

Triplicate ECG are required at Screening at which 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 
2 minutes apart. The full set of triplicates should be completed in less than 4 
minutes.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
 
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are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 17 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal (grade 2 or lower) by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Suicidal Ideation and Behaviour Risk Monitoring
Not applicable.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA.  However, any SAEs assessed as related 
to study participation (e.g., study intervention, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be 
recorded from the time a participant consents to participate in the study.

All AEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA.

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
 
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including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 2.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy
Not applicable for this study.
 
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8.3.6.
Cardiovascular and Death Events
Not applicable for a healthy volunteer study
8.3.7.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Not applicable for this study.
8.3.8.
Medical Device Incidents (Including Malfunctions)
Not applicable for this study.
8.4.
Treatment of Overdose
For this study, any dose of greater than 1 FDC tablet of DTG 50 mg / RPV 25 mg within 
a 24-hour time period will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 25 days).
3.
Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study intervention 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 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 
participant.
8.5.
Pharmacokinetics
8.5.1.
Blood Sample Collection  

Blood samples for pharmacokinetic analysis of DTG and RPV will be collected 
at the time points indicated in SoA. 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 DTG PK sample, 2 mL of blood will be collected into di-potassium 
ethylenediaminetetraacetic acid (K2EDTA) tubes for DTG quantification and 
protected from light.
 
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
For each RPV PK sample, 2 mL of blood will be collected into sodium heparin 
tubes for RPV quantification and protected from light.

Processing, storage and shipping procedures are provided in the Study Reference 
Manual provided by the site or other equivalent document.  Please pay special 
attention to the light protection procedures for both DTG and RPV 
collections and processing.
8.5.1.1.
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 for DTG and a properly 
labelled sodium heparin tube for RPV.  Record the date and exact time that each 
sample is collected in the CRF.  All samples should be protected from light at all 
times by putting them in closed boxes, wrapping with aluminium foil or handling 
under yellow light.
8.5.1.2 
Sample Storage Conditions
For DTG PK samples, 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 protected from light.  For RPV PK 
samples, immediately after collection, gently invert (do not shake) the blood collection 
tube 8-10 times to mix the sodium heparin anti-coagulants with the whole blood and 
place the samples at room temperature protected from light. 

All samples must be protected from light at all times by putting them in closed 
boxes, wrapping with aluminium foil or handling under yellow light.

Within 45 minutes of sample collection for both DTG and RPV, 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/Brown Sarstedt tubes. 

Immediately freeze the storage tubes in an upright position at -20°C.
DTG and RPV are photosensitive so all plasma sample manipulation procedures (sample 
collection and analytical steps) will be performed protecting samples from light.  Limit 
the time between centrifugation and transfer of the plasma to amber/brown tubes as much 
as possible, with care to close the centrifuge lid between the different actions.  If it is not 
possible to transfer the blood to plasma immediately; the centrifuged tubes should remain 
protected from light at all times (boxes or foil).  
 
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8.5.2.
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 2015N231443_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.
Rilpivirine will be extracted from plasma using protein precipitation followed by
UPLC-MS/MS using the previously validated method, validation of a method for the
determination of JNJ-16150108 (PRA-NL-SML-2159/JJP110EL-181103-C/BA13223).
The potential conversion of rilpivirine to the Z-isomer will be evaluated as part of the 
rilpivirine sample analysis. The analyses will be performed by PRAHS, Amerikaweg 18, 
9407 TK Assen, The Netherlands.  The RPV sample analysis will be under the 
management of Janssen.  Raw data will be archived at the bioanalytical site. 
Dolutegravir and rilpivirine sample analyses will be performed under light 
protection procedures.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
This study will seek to characterize the pharmacokinetics of DTG and RPV following a
single oral dose of DTG/RPV 50 mg/25 mg FDC in healthy, adult Japanese
subjects. Also, this study will seek to assess the safety and tolerability of DTG/RPV
50 mg/25 mg FDC in healthy, adult Japanese participants. No formal statistical 
hypothesis will be tested.
 
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9.2.
Sample Size Determination
Approximately 16 participants will be enrolled and assigned to study intervention such 
that 13 evaluable participants complete the study.
There was no formal calculation of power or sample size for this study.
9.2.1.
Sample Size Assumptions
Based on the previous DTG and RPV BE study (Study 201676) [GlaxoSmithKline 
Document Number 2015N243078_01], the intersubject coefficients of variation (CVs) 
for AUC0-t, AUC0-inf and Cmax of a single dose of DTG+RPV (given as either single 
components or a fixed dose combination formulation) in a fed state were estimated to be 
less than or equal to 43.66% in healthy non-Japanese adult subjects. Using a conservative 
estimate of 43.66% for intersubject CV and a sample size of 13 subjects, the true mean
AUC0-t, AUC0-inf and Cmax of DTG+RPV FDC were estimated to be within 80% to 
125% of the observed geometric means with 95% confidence.
9.2.2.
Sample Size Sensitivity
Not applicable.
9.3.
Populations for Analyses
All of the data that is databased will be presented in subject listings and where
appropriate presented in summary tables. 
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants who sign the ICF
Safety
All participants who enrolled in the study and received at 
least one dose of study drug.
Pharmacokinetic (PK)
All participants in the Safety population for whom a PK 
sample was obtained and had evaluable PK assay results.
9.4.
Statistical Analyses
Final analyses will be performed after the completion of the study and final dataset
authorization.
Data will be listed and summarized according to GlaxoSmithKline reporting standards
where applicable. 
Unless stated otherwise, descriptive summaries for continuous variables will include n,
mean, standard deviation (SD), median, minimum, maximum; whereas, n and percent
will be used as summary statistics for categorical variable. Geometric mean with
 
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associated 95% CI, and the between-subject coefficient of variance (CV) (%CVb) for the
geometric mean will be included for PK variables, where applicable.
Baseline or pre-dose assessment is the last available assessment prior to time of the first
dose unless it is specified otherwise. If there are multiple assessments collected on the
same scheduled time, the average of these assessments will be used. For tabulated safety
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.4 or higher of the Statistical Analysis Software (SAS) system will be used to
analyze data as well as to generate tables, listings, and figures.
Complete details will be documented in the Reporting and Analysis Plan (RAP).
9.4.1.
Efficacy Analyses
Not Applicable.
9.4.2.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. No formal statistical analysis 
of the safety data will be conducted. All safety data will be listed. 
Full details will be provided in the Reporting and Analysis Plan.
All safety analyses will be performed on the Safety Population. 
9.4.3.
Pharmacokinetic Analysis
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling & Simulation department within GlaxoSmithKline, or its designee.
Plasma DTG and RPV concentration-time data will be analyzed by non-compartmental 
methods with Phoenix WinNonlin version 6.3 or higher. Calculations will be based on 
the actual sampling times recorded during the study.
From the plasma concentration-time data, please refer Objectives and Endpoints (Section 
3), for the pharmacokinetic parameters that will be determined, as data permit.
Pharmacokinetic data will be listed and may be presented in graphical form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. Statistical analyses of the pharmacokinetic 
parameter data will be the responsibility of Clinical Statistics, GlaxoSmithKline.
Full PK analyses will be described in the reporting and analysis plan. 
9.4.4.
Data Monitoring Committee (DMC)
Not applicable for this study.
 
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9.5.
Interim Analysis
Not applicable for this study
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
 
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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
 
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as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.
 
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
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in Study Reference 
Manual.
10.1.9.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
 
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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.10.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 below will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the timepoints indicated in the SoA.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.

Reference ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose2
Calcium
Alkaline 
phosphatase
 
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

FSH (as needed in women of probable non-child bearing potential only)

Creatinine Clearance

[Serum or urine] [alcohol, cotinine, and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Highly sensitive [Serum or urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)3

HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody 
NOTES :
1.
Details of liver chemistry criteria and required actions and follow-up assessments after liver stopping or monitoring 
event are given in Section 7.1 and Appendix 6. All events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 
× ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).
2.
As noted in the SoA, Glucose fasting is required approximately 10 hours prior to dosing on Day -1 and at least 6 
hours at Day 3 post dose.  At all other timepoints, glucose will be non-fasting (i.e, at Screening).
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of Adverse Event (AE)
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2.
Definition of Serious Adverse Event (SAE)
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
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and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
 
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severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
IMPORTANT – PLEASE NOTE THE FOLLOWING STATEMENT:
For this study the above criteria regarding mild, moderate and severe will be used in 
combination with the Division of AIDS (DAIDS) Table for Grading Severity of Adult 
and Pediatric Adverse Events, Version 2.1, July 2017 (Appendix 9).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. The 
investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.
 
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
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Study Reference Manual.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Study Reference Manual.
 
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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement (>40 IU/L or mIU/mL) is required. 

Females on HRT and whose menopausal status is in doubt will be excluded 
from the study.
10.4.2.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
 
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in this study. This applies only to male participants who receive the study 
intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) 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 intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will be withdrawn from the study.
 
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10.5.
Appendix 5: Genetics
Not Applicable
 
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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I Liver chemistry follow up criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance). In this study, this guidance is for following any subject who has these 
elevated values post-dosing. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry criteria and required follow up assessments
Liver Chemistry Follow Up Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 

Viral hepatitis serology3

Obtain international normalized ratio (INR) 
and recheck with each liver chemistry 
assessment until the transaminases values 
show downward trend

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, 
 
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Liver Chemistry Follow Up Criteria 
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 INR) and 
perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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.

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.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention 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, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody or Hepatitis E RNA
 
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10.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Not Applicable
 
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10.8.
Appendix 8: Country-specific requirements
Not Applicable
 
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10.9.
Appendix 9: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, July 2017
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for AE reporting.  A grading (severity) scale is provided for each AE term. Please refer to 
the DAIDS grading table Version 2.1, July 2017 (https://rsc.tech-res.com/docs/default-
source/safety/daidsgradingcorrecetedv21.pdf) for more information.
 
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10.10.
Appendix 10: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALT (SGPT)
Alanine Aminotransferase (serum glutamic pyruvic 
transaminase)
AST (SGOT)
Aspartate Aminotransferase (serum glutamic oxaloacetic 
transaminase)
ART
Antiretroviral Treatment
ARV
Antiretroviral
AUC0-24
Area under the concentration-time curve from time 0 to 24 
hours
AUC0-t
Area under the concentration-time curve from time 0 to the 
last measurable timepoint
AUC0-
Area under the concentration-time curve from time 0 
extrapolated to infinity
BMI
Body mass index
BP
Blood Pressure
BUN
Blood urea nitrogen
CA
Competent Authority
CIOMS
Council for International Organizations of Medical Sciences
Ct
Last quantifiable drug concentration 
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
CPK
Creatine Phosphokinase
CRF
Case report form
CrCl
Creatinine Clearance
CSR
Clinical Study Report
Ct
Last quantifiable concentration
CVw%
Coefficients of variation
DAIDS
Division of Acquired Immunodeficiency Syndrome 
DILI
Drug Induced Liver Injury
dL
Decilitre
DMC
Data Monitoring Committee
DTG
Dolutegravir
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
FDA
Food and Drug Administration
FDC
Fixed Dose Combination
 
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FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GSK
GlaxoSmithKline
h
Hours
HBsAg
hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human chorionic gonadotrophin
HCV
Hepatitis C Virus
HIPPA
Health Insurance Portability and Accountability Act
HIV-1
Human Immunodeficiency Virus type 1
HPLC
High-performance liquid chromatography
HR
Heart Rate
HRT
Hormone replacement therapy
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IND
Investigational New Drug
INI
Integrase inhibitor
INR
International Normalized Ratio
IP
Investigational Product
IU
International Units
IRB
Institutional Review Board
K2EDTA
Di-potassium ethylenediaminetetraacetic acid
Kg
Kilograms
Lbs
Pounds
LDH
Lactate Dehydrogenase
m
Meters
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
mg
Milligrams
MHLW
European Commission and Japan Ministry of Health Labor 
& Welfare
mL
Millilitre
MSDS
Material Safety Data Sheet
NRTI
Nucleoside reverse transcriptase inhibitor
PK
Pharmacokinetic
QTc
Corrected QT interval
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
 
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RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic Acid
RPV
Rilpivirine
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SD
Standard Deviation
SJS
Stevens-Johnson syndrome
SUSAR
Suspected unexpected serious adverse reactions
t
Time of last quantifiable 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
US
United States
USPI
United States Prescribing Information
VS
Vital Signs
Vz/F
Apparent oral volume of distribution
WBC
White Blood Cell
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
JULUCA
DAIDS
TIVICAY
EDURANT
Phoenix WinNonlin
SAS
 
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11.
REFERENCES
EDURANT (rilpivirine) Product Information. May, 2015.
GlaxoSmithKline Document Number 2015N231443_00; Supplement Validation Data 6, 
P1170, Project AGTR2.  Quantitiation of GSK1349572 in Human Plasma via UPLC with 
MS/MS Detection.  19-October-2015.
GlaxoSmithKline Document Number 2015N243078_01, Study 201676. An Open-label, 
Randomized, Two-way Crossover, Single dose, Pivotal Bioequivalence Study of a Fixed-
dose Combination of Dolutegravir and Rilpivirine in Healthy Volunteers. 26 April 2016.
GlaxoSmithKline Document Number RM2007/00683/09: DTG Clinical Investigator's 
Brochure. October 2015.
Janssen EDMS Number EDMS-ERI-3713711, 15.0.  Investigator's Brochure TMC278 
(rilpivirine, oral [EDURANT] and parenteral), July 2018. 
Juluca (dolutegravir and rilpivirine) US Prescribing Info, 2017.
TIVICAY (dolutegravir) Product Information. May, 2015.
 
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