Clinical trial NCT03921723
Conditions: HIV Infections
Keywords: Dolutegravir Human immunodeficiency virus Sequential study Dispersible tablet Suspension Liquid solution
Sponsor: ViiV Healthcare
Start date: 2019-05-07; Completion date: 2019-07-25
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open-label, single-center, single dose, non-randomized, sequential, fixed-sequence study, which will evaluate pharmacokinetics (PK) of dolutegravir (DTG) in healthy adult subjects. The study will contain 6 periods with five prototype liquid formulations for evaluation in fasted state. In period 1, 2 and 3 single reference dose of 2 dispersible tablets of 5 milligram DTG will be administered and at least 2 liquid prototype DTG formulations (containing a target total dose of 10mg DTG). There will be a wash-out period of 7 days between each period. In period 4 through 6, there would be options to evaluate additional prototype liquid formulations. The total duration of study will be up to 17 weeks. DTG has been found to be safe and effective in adults infected with human immunodeficiency virus (HIV). DTG dispersible tablets have been developed primarily for use in children from 4 weeks to 6 years of age, and a DTG liquid formulation are is being developed to study the appropriate dose needed for the HIV-exposed and infected neonatal population in the first four weeks of life. Approximately 18 subjects will be enrolled in this study.

Detailed description:

Arms: arm 1: Subject will receive a prototype equivalent to DTG 10 mg liquid formulation in period 1, a prototype equivalent to DTG 10 mg liquid formulation in period 2, a DTG 10 mg dispersible tablet in Period 3, each period will be separated by washout period of \>= 7 days, if required a prototype equivalent to DTG 10 mg liquid formulation in period 4, a prototype equivalent to DTG 10 mg liquid formulation in period 5, and a prototype equivalent to DTG 10 mg liquid formulation in period 6 will be evaluated.
Interventions: intervention 1: Dolutegravir dispersible tablet intervention 2: Dolutegravir oral suspension intervention 3: Dolutegravir oral solution
Intervention descriptions: intervention 1: DTG will be available as an oral tablet with dosing strength of 5 mg 2 tablet will be dispersed in water will be administered orally for prescribed regimen. intervention 2: DTG will be available as an oral suspension with dosing strength of 5 mg per milliliter (ml) or 2 mg per ml with miglyol 812N or ethyl cellulose in miglyol 812N as vehicle for suspension administered orally for prescribed regimen. intervention 3: DTG will be available as an oral solution with dosing strength of 2 mg per ml will be administered orally for prescribed regimen.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: Non-randomized, sequential, fixed-sequence evaluation of prototype 
dolutegravir liquid formulations versus 5mg dolutegravir dispersible tablets following 
single-dose fasted-state administrations to normal healthy adult participants
Protocol Number: 209354 / 1
Compound Number:
GSK1349572
Study Phase: Phase 1 
Short Title: Dolutegravir Paediatric Liquid Formulation Study
Sponsor Name and Legal Registered Address: (excluding US):
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
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:
 
Medical Monitor Name and Contact Information
FCP, MSc
Director, Clinical Development Research and Development, ViiV Healthcare
980 Great West Road
Brentford, Middlesex, TW 9GS United Kingdom
Regulatory Agency Identifying Number(s): EudraCT - 2018-003613-18
Approval Date: 27-FEB-2019
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as Sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the Vice President, Global Medical Strategy
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline and Quotient Clinical are
supporting ViiV Healthcare in the conduct of this study.  
Copyright 2019 ViiV Healthcare group of companies All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 1
27-FEB-2019
2018N379348_01
Original Protocol
29-OCT-2018
2018N379348_00
Amendment 01 27-February-2019
Overall Rationale for the Amendment: The original protocol was written assuming that
a greater number of prototype formulations would possibly have been tested in the study.  
Pre-clinical testing yielded only 2 prototypes suitable to take forward clinically.  This 
amendment clarifies the study design for only 2 test formulations.
The US IND number was removed from the cover page as this study will be conducted in 
the UK.
Some additional copy changes may have been made to text (e.g., Table 3, changed 
formulation from 1 and 2, to A and B).  These were administrative change not affecting 
participants.
Section # and Name
Description of Change
Brief Rationale
Cover Page
IND number removed
The study is not occurring in the United 
States, the presence of an IND number is 
not warranted.
Section 1.1 - Synopsis,
Section 1.2 - Schema,
Section 1.3-Schedule of Activities, Table 2
Section 2 - Introduction,
Section 4.1 – Overall Design,
Section 4.2 – Formulation Decision,
Section 4.4 – Justification for Dose,
Section 6.1 – Study Intervention(s) 
Administered,
Section 7 – Discontinuation of Study 
Intervention,
Section 9.1 – Statistical Hypothesis,
Section 9.4.1 – Primary and Secondary 
Analyses,
Section 9.5 – Preliminary Analyses
All changes were made 
to reflect the reduction 
in study design from up 
to 5 to only 2 test 
formulations, including, 
but not limited to, the 
removal of a need for 
interim dosing reviews 
as these will no longer 
be necessary.
Pre-clinical testing yielded only 2 
prototypes suitable to take forward 
clinically into this study.  These changes 
reflect the reduction in study design from 
up to 5 to only 2 test formulations.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................7
1.1.
Synopsis.......................................................................................................7
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................9
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Background ................................................................................................11
2.3.
Benefit/Risk Assessment ............................................................................12
2.3.1.
Risk Assessment .........................................................................13
2.3.2.
Benefit Assessment.....................................................................15
2.3.3.
Overall Benefit: Risk Conclusion..................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Formulation Decision ..................................................................................17
4.3.
Scientific Rationale for Study Design ..........................................................18
4.4.
Justification for Dose ..................................................................................18
4.5.
Discontinuation / Stopping Study ................................................................18
4.6.
End of Study Definition ...............................................................................19
5.
STUDY POPULATION...........................................................................................19
5.1.
Inclusion Criteria.........................................................................................19
5.2.
Exclusion Criteria........................................................................................20
5.3.
Lifestyle Considerations..............................................................................22
5.3.1.
Meals and Dietary Restrictions ....................................................22
5.3.1.1.
Fasting Conditions......................................................22
5.3.1.2.
Fed Conditions ...........................................................22
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................22
5.3.3.
Activity .........................................................................................23
5.4.
Screen Failures...........................................................................................23
6.
STUDY INTERVENTION........................................................................................23
6.1.
Study Intervention(s) Administered .............................................................24
6.2.
Preparation/Handling/Storage/Accountability..............................................25
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................25
6.4.
Study Intervention Compliance ...................................................................25
6.5.
Concomitant Therapy..................................................................................25
6.6.
Dose Modification .......................................................................................26
6.7.
Intervention after the End of the Study........................................................26
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................26
7.1.
Discontinuation of Study Intervention..........................................................26


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7.1.1.
Liver Chemistry Stopping Criteria ................................................27
7.1.2.
QTc Stopping Criteria ..................................................................28
7.1.3.
Temporary Discontinuation ..........................................................28
7.1.4.
Study Termination........................................................................28
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................29
7.3.
Lost to Follow Up........................................................................................29
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30
8.1.
Efficacy Assessments.................................................................................31
8.2.
Safety Assessments ...................................................................................31
8.2.1.
Physical Examinations.................................................................31
8.2.2.
Vital Signs....................................................................................31
8.2.3.
Electrocardiograms......................................................................32
8.2.4.
Clinical Safety Laboratory Assessments ......................................32
8.3.
Adverse Events and Serious Adverse Events.............................................33
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................33
8.3.2.
Method of Detecting AEs and SAEs.............................................33
8.3.3.
Follow-up of AEs and SAEs.........................................................34
8.3.4.
Regulatory Reporting Requirements for SAEs .............................34
8.3.5.
Pregnancy ...................................................................................34
8.4.
Treatment of Overdose...............................................................................34
8.5.
Pharmacokinetics .......................................................................................35
8.5.1.
Blood Sample Collection..............................................................35
8.5.2.
Sample Processing Procedures...................................................35
8.5.3.
Sample Storage Conditions .........................................................36
8.5.4.
Sample Analysis ..........................................................................36
8.6.
Pharmacodynamics ....................................................................................36
8.7.
Genetics .....................................................................................................36
8.8.
Biomarkers .................................................................................................36
8.9.
Medical Resource Utilization and Health Economics ..................................36
9.
STATISTICAL CONSIDERATIONS........................................................................37
9.1.
Statistical Hypotheses.................................................................................37
9.2.
Sample Size Determination ........................................................................37
9.2.1.
Sample Size Assumptions ...........................................................37
9.2.2.
Sample Size Sensitivity................................................................37
9.3.
Populations for Analyses ............................................................................38
9.4.
Statistical Analyses.....................................................................................38
9.4.1.
Primary and Secondary Analyses ................................................39
9.4.2.
Pharmacokinetic Analyses...........................................................39
9.4.3.
Safety Analyses...........................................................................40
9.5.
Preliminary Analyses ..................................................................................40
10. REFERENCES.......................................................................................................41
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................42
11.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................42
11.1.1.
Regulatory and Ethical Considerations ........................................42
11.1.2.
Protocol Amendments..................................................................42


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11.1.3.
Protocol Deviations......................................................................43
11.1.4.
Financial Disclosure.....................................................................43
11.1.5.
Informed Consent Process ..........................................................43
11.1.6.
Data Protection............................................................................44
11.1.7.
Publication Policy.........................................................................44
11.1.8.
Dissemination of Clinical Study Data ...........................................44
11.1.9.
Data Quality Assurance ...............................................................45
11.1.10. Source Documents ......................................................................45
11.1.11. Study and Site Closure ................................................................46
11.1.12. Publication Policy.........................................................................46
11.2.
Appendix 2: Clinical Laboratory Tests.........................................................47
11.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................48
11.3.1.
Definition of AE............................................................................48
11.3.2.
Definition of SAE..........................................................................49
11.3.3.
Recording and Follow-Up of AE and SAE....................................50
11.3.4.
Reporting of SAE to ViiV Healthcare/GSK ...................................52
11.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................53
11.4.1.
Definitions:...................................................................................53
11.4.2.
Collection of Pregnancy Information: ...........................................53
11.5.
Appendix 5: Division of AIDS Table For Grading The Severity Of 
Adult And Paediatric Averse Events Version 2.1, March 2017 ....................55
11.6.
Appendix 6: Toxicity Management ..............................................................56
11.6.1.
ANEMIA.......................................................................................56
11.6.2.
TOTAL BILIRUBIN ELEVATION..................................................57
11.6.3.
AST AND ALT ELEVATION.........................................................57
11.6.4.
RASH ..........................................................................................57
11.6.5.
ALLERGIC REACTION................................................................59
11.6.6.
Decline in Renal Function ............................................................60
11.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................61
11.8.
Appendix 8: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................62
11.9.
Appendix 9: Abbreviations and Trademarks................................................64
11.10. Appendix 10: Protocol Amendment History.................................................67


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: Non-randomized, sequential, fixed-sequence evaluation of prototype 
dolutegravir liquid formulations versus 5mg dolutegravir dispersible tablets following 
single-dose fasted-state administrations to normal healthy adult participants
Short Title: Dolutegravir (DTG) Paediatric liquid formulation study
Rationale: Dolutegravir (DTG) has been shown to be safe and effective in adults who 
are infected with human immunodeficiency virus (HIV).  Dosage forms for paediatric 
patients are in development and under investigation for safety and efficacy.  This study 
will evaluate the pharmacokinetics (PK), via relative bioavailability, of single dose 
prototype liquid formulations containing 10 mg equivalent DTG compared to 2 x 5mg 
dispersible DTG tablets dispersed in water.  These DTG liquid formulations are being 
developed to support future efficacy and safety studies for the treatment of HIV-infected 
new-borns of up to approximately 6 weeks of age.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of equivalent 
doses of single dose prototype liquid formulations 
containing 10mg equivalent DTG compared to a 
single dose of 2 x 5mg dispersible DTG tablet 
dispersed in water.
Plasma DTG AUC(0-t), AUC(0-), Cmax
Secondary
To characterize the pharmacokinetics of equivalent 
doses of a single dose of prototype liquid 
formulations containing 10mg equivalent DTG and 
a single dose of 2 x 5mg dispersible DTG tablet 
dispersed in water.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), AUC(0-72), 
CL/F and Vz/F, Ct, and C24 of each formulation
To assess the safety and tolerability from single-
dose administration of prototype liquid formulations 
containing 10mg equivalent DTG in healthy 
participants in a fasted state.
Safety and tolerability parameters as assessed by change from 
baseline in vital signs (BP and HR), number of participants with 
adverse events and toxicity grading of clinical laboratory tests.
BP = Blood Pressure
HR = Heart rate
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞) = area under the plasma concentration time curve from time zero to infinity
AUC(0-24) = area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
tmax = time of maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
PK = Pharmacokinetic 
t = time of last quantifiable concentration
tlag = absorption lag time


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z=apparent elimination rate constant
t1/2 = the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution
Overall Design: This is an open-label, single-centre, single dose study in healthy male 
and female participants to assess prototype liquid formulations containing 10 mg 
equivalent DTG.  
Disclosure Statement: This is an Intervention study with 2 prototype liquid formulations 
of DTG versus a reference dose of 2 x 5mg dispersible DTG (TIVICAY) tablet dispersed 
in water.
Number of Participants:  A maximum of 18 participants will be enrolled to receive 
study intervention such that approximately 16 evaluable participants complete the study.
An evaluable participant will have completed the planned safety and PK assessments up 
to 72 hours after dosing.  An evaluable participant must also have received the relevant 
prototype and reference formulations for the comparisons of interest (e.g. a prototype
formulation and the reference).
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the Sponsor in consultation with the investigator.
Intervention Groups and Duration:  This is an open-label single dose study, please see 
the study schema (Figure 1) below.
Data Monitoring Committee: No
1.2.
Schema
Figure 1
Study Design Schematic
W = Washout ≥7 days (-4 hours)
Reference formulation = 2 x 5mg DTG dispersible tablets taken as dispersed in water.
Prototype formulations = liquid formulation containing 10 mg equivalent DTG
Period 1 
Prototype A 
Period 2 
Prototype B
Period 3 
Reference
Screening 
(≤30 days)
Follow-up
(7-14 
days post 
last dose)
N=18
Prototype Formulations
W
W


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1.3.
Schedule of Activities (SoA)
Table 1
Screening Assessments
Visit Window (relative to Day 1)
Day -30 
to -2
Notes
Informed Consent
X
Demographics
X
Physical examination height, weight and BMI
X
Medical/medication/ history
X
Medical/medication/drug and alcohol history will 
be recorded at screening and updated at 
admission.
Urine drug / Cotinine and Breathalyzer screening
X
12-lead ECG and Vital Signs
X
Serum or urine hCG test (female participants only)
X
See inclusion criterion for female participants.
Performed at site standard procedure.
FSH and estradiol (women)
X
HIV, Hep B and Hep C Screen
X
Hematology/Chemistry/Urinalysis tests
X
BMI: Body mass index, ECG: Electrocardiogram, hCG: Human chorionic gonadotropin, FSH: Follicle stimulating 
hormone; HIV: Human immunodeficiency virus, Hep B: Hepatitis B; Hep C: Hepatitis C

The timing and number of planned study assessments, including safety or 
pharmacokinetic assessments may be altered during the course of the study based on 
newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 

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.

There are times where it is required for more than one procedure to be completed at 
the same time point. In these instances, the following will apply to post-dose time 
points:
PK samples take priority over other procedures scheduled at the same time point. As 
guidance, the preferred order of assessments is:
ECGs
(if needed)
Vital Signs
PK blood sampling
(nominal time)
Other assessments eg 
physical exams,

Electrocardiograms (ECGs) will be taken prior to vital signs when both 
measurements are scheduled at the same time point.  Other assessments, e.g. physical 
examinations etc, will be performed within the required time windows.  All safety 
assessments will be timed and performed relative to the start of dosing.


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Table 2
Treatment Period Assessments
Assessments
All Dosing Periods
Follow-up
Notes

Day -1 of Periods 2 and 3 may be the same day as Day 6 
of prior periods 

At Follow-up – Participants with no ongoing AEs or Vital 
Sign/Laboratory measures of clinical concern may be 
followed virtually by the site via telephone contact.

Follow-up assessments should be completed in the event 
of an early participant termination.
Day -1
Day 1
Day 2
Day 3
Day 4
Pre-
dose
0 hr
Post Dose
-
48 hr
72 hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
X
Follow-up visit will occur 7 to 14 days post last dose.
12-lead ECG
X
Single ECGs will be collected at Screening and on Day-1 of 
Period 1 only. Additional ECGs may be performed at the 
discretion of the investigator.
Vital signs
X
X
X
Single measurements performed at all time points.
Brief Physical Exam
X
Brief examinations may be made full examinations and 
laboratory procedures may be repeated, if needed, at the 
discretion of the Investigator.
Illicit Drug/Alcohol/Cotinine screening will be performed in 
accordance with the sites’ standard practice.
Clinical laboratory tests – see Table 6
*Clinical laboratory tests at follow-up are only necessary if 
participant had a previous abnormal lab value
Urine Drug / Cotinine and 
Breathalyzer
X
Clinical laboratory tests 
X
X*
Dosing
X
Participant will be dosed while in the seated position.
Meals
X
Post 4-hour PK sample
Per standard at the clinic
Participants will fast from 10hrs pre-dose to 4-hours post-dose.
Pharmacokinetic Sampling
X
Collect at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 5, 6, 8, 12, 16, 24, and 48-hours 
post-dose
X

Pre-dose (within 15 minutes prior to dosing). 

4-hour post dose sample must be taken prior to provision 
of food.

Permitted window for the collection of PK sample at each 
time point is specified in Section 8.5.1.
Adverse Events/SAEs
X
=======================X=======================
X
Concomitant medications
X
=======================X=======================
X


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
The timing and number of planned study assessments, including safety or 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 PK 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.
2.
INTRODUCTION
The purpose of the present study is to evaluate the relative bioavailability of two
prototype liquid formulations containing 10 mg equivalent DTG in healthy adult 
participants versus single doses of 2 x 5 mg dispersible tablets dispersed in water.
2.1.
Study Rationale
Dolutegravir (DTG) has been shown to be safe and effective in adults who are infected 
with HIV.  Dosage forms for paediatric patients are in development and under 
investigation for safety and efficacy.  This study will evaluate the pharmacokinetics, via 
relative bioavailability, of single dose prototype liquid formulations containing 10 mg 
equivalent DTG compared to 5mg dispersible DTG tablets dispersed in water.  These 
DTG liquid formulations are being developed to support future efficacy and safety 
studies for the treatment of HIV-infected new-borns of up to approximately 6 weeks of 
age.
2.2.
Background
The safety and efficacy of DTG (TIVICAY) is already established in adults.  For younger 
children aged 4 weeks to <12 years of age, the evaluation of once daily dosing of DTG 
will be supported by data from paediatric efficacy and safety studies of DTG alone and in 
combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs; lamivudine and 
abacavir) and current labelling for the individual components of the FDC in paediatric 
patients.  It is the Sponsor’s intention to develop both a dispersible tablet (DT) paediatric 
formulation of DTG and a liquid formulation of DTG that would optimize the dose 
through achieving drug exposures similar to that of approved adult formulations. Under 
the assumption that these paediatric formulations are feasible, the DTG PK data from this 
study in healthy adult participants will be compared to drug exposures obtained 
historically in adults receiving DTG at approved/recommended paediatric and adult 
doses.  Such data will be used to determine the final composition and weight band-based 
doses of the FDC product to be used in paediatric populations.  More information on the 
efficacy, PK, safety and drug interaction potential of DTG based on an extensive program 


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of Phase I to III clinical trials can be found in the Investigator Brochure (IB) and 
supplement [GlaxoSmithKline Document Number RM2007/00683/11 and 
GlaxoSmithKline Document Number 2017N352880_00).
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of DTG may be found in the Investigator’s Brochure 
[GlaxoSmithKline Document Number RM2007/00683/11] and Supplement to DTG 
Investigator’s Brochure [GlaxoSmithKline Document Number 2017N352880_00].  The 
following section outlines the risk assessment and mitigation strategy for this protocol.  
Of note, the events noted in the table below were observed with the repeated doses of 
DTG at 50 mg.  The risk of these events would be significantly lower for the single doses 
(2 x 5 mg dispersible tablets dispersed in water) being used in this protocol.


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2.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB and IB Supplement for additional information
Hypersensitivity reaction 
(HSR) and rash
HSR has been observed uncommonly with DTG.  Rash was commonly reported 
in DTG Phase IIb/III clinical trials; episodes were generally mild to moderate in 
intensity; no episodes of severe rash, such as Stevens-Johnson Syndrome 
(SJS), Toxic Epidermal Necrolysis (TEN) and erythema multiforme were 
reported.

Participants with history of allergy/sensitivity to any of the 
study drugs are excluded (Section 5.2)

Specific/detailed toxicity management guidance is provided 
for HSR and rash (Section 11.6).

For Grade 3/4 rash, participants must permanently 
discontinue study drug and be withdrawn from the study 
(Section 7.1)

The participant informed consent form includes information on 
this risk and the actions participants should take in the event 
of an HSR or associated signs and symptoms. 
Neural tube defects
In one observational study in Botswana, preliminary results show that among 
women who were taking DTG when they became pregnant, approximately 0.9% 
had babies with neural tube defects compared to a background rate of 0.1%.
Women of childbearing potential cannot participate in the study.
Drug induced liver injury 
(DILI) and other clinically 
significant liver chemistry 
elevations
Non-clinical data suggested a possible, albeit low, risk for hepatobiliary toxicity 
with DTG.  Drug-related hepatitis is considered an uncommon risk for 
antiretroviral therapy (ART) containing DTG regardless of dose or treatment 
population.  A review of post-marketing data found that the number of cases 
reporting particularly severe liver dysfunction was found to be very low in the 
context of exposure to DTG and DTG/ABC/3TC. The reported cases of severe 
liver dysfunction (including acute hepatic failure) are complex with potential 
confounding factors but in a very small number of cases, drug-induced liver 
injury is likely and the role of DTG containing regimens cannot be ruled out 
particularly in those involving DTG with ABC/3TC or DTG/ABC/3TC.
Participants meeting either of the following criteria during the 
screening period are excluded (Section 5.2).

Current or chronic history of liver disease or known hepatic or 
biliary abnormalities (with the exception of Gilbert's syndrome 
or asymptomatic gallstones).

Alanine Aminotransferase (ALT) or bilirubin >1.5x upper limit 
of normal (ULN).
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically 
significant liver chemistry elevations (Section 11.6, Appendix 6).


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB and IB Supplement for additional information
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 organic cation 
transporter 2 (OCT-2).  DTG has been shown to have no significant effect on 
glomerular filtration rate (GFR) or effective renal plasma flow.
Increases in serum creatinine due to DTG are not expected to 
have any adverse effect and will reverse during the wash out 
period after each single dosing of DTG, and; therefore, do not 
require mitigation for this protocol. 
Risks Associated with Study Procedures
Cannulation
During cannulation more than one attempt may be needed to insert the cannula 
in a vein of a participant and it is possible that bruising and/or inflammation may 
be experienced at the site of cannulation.

A vein assessment will be conducted at screening to ensure 
only volunteers with veins suitable for multiple venepuncture 
and cannulation are enrolled.

Cannulation and/or venepuncture will only be performed by 
staff who are trained in these procedures
ECG Collection
Electrocardiogram stickers on the participants’ chests and limbs may cause 
some local irritation and may be uncomfortable to remove.

Participants will be monitored to ensure any local irritation 
does not persist.

Up to 2.5% hydrocortisone cream is permitted to relieve 
irritation from ECG leads.
a.
Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired Immune 
Deficiency Syndrome [DAIDS] toxicity grading for HIV-infected patients). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of 
investigational product (IP), and will be followed to resolution as per Sponsor’s standard medical monitoring practices.  


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2.3.2.
Benefit Assessment
This is a study in healthy participants and as such there is no expected benefit to 
administration of DTG.  Participation in this study may contribute to the process of 
developing new therapies for HIV.  There may be benefit to participants from the medical 
evaluations and assessments that could identify conditions that the participant was 
previously unaware.
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with DTG are justified by the anticipated benefits 
that may be afforded to paediatric patients with HIV.  The events noted in Section 2.3.1
were observed with the repeated doses of DTG.  The risk of these events would be 
significantly lower for the single doses being used in this protocol.


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of equivalent 
doses of single dose prototype liquid formulations 
containing 10mg equivalent DTG compared to a single 
dose of 2 x 5mg dispersible DTG tablet dispersed in 
water.
Plasma DTG AUC(0-t), AUC(0-), Cmax
Secondary
To characterize the pharmacokinetics of equivalent 
doses of a single dose of prototype liquid formulations 
containing 10mg equivalent DTG and a single dose of 
2 x 5mg dispersible DTG tablet dispersed in water.
Plasma DTG tlag, tmax, t, t½, z, %AUCex, AUC(0-24), 
AUC(0-72), CL/F, Vz/F, Ct, and C24 of each formulation
To assess the safety and tolerability from single-dose 
administration of prototype liquid formulations 
containing 10mg equivalent DTG in healthy participants 
in a fasted state.
Safety and tolerability parameters as assessed by 
change from baseline in vital signs (BP and HR), 
number of participants with adverse events and toxicity 
grading of clinical laboratory tests
BP = Blood pressure 
HR = Heart rate
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞) = area under the plasma concentration time curve from time zero to infinity
AUC(0-24) = area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
tmax = time of maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
PK = Pharmacokinetic 
t = time of last quantifiable concentration
tlag = absorption lag time
z=apparent elimination rate constant
t1/2 =the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution
4.
STUDY DESIGN
4.1.
Overall Design
This is an open-label, single-centre, single dose study in healthy adult participates to 
assess prototype liquid formulations with 2 x 5mg DTG Dispersible tablet as reference.  
The study is a non-randomized 3-period, sequential, 3-way fixed-sequence design in 
which 2 prototype liquid formulations will be evaluated following single-dose 
administrations in the fasted state.  Periods 1, 2 and 3 will evaluate a single reference 
dose (2 x 5mg dispersible DTG tablet dispersed in water) and 2 liquid prototype DTG 
formulations (containing a target total dose of 10mg DTG).  
Participants will be admitted to the clinic the morning before dosing (i.e. Day -1) of each 
inpatient period. Each inpatient period will consist of 48 hours of post-dose assessments.  


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There will be one outpatient visit per Period for PK assessment at approximately 72 hours 
post dose. This will be followed by a washout of at least 7 (-4 hours) days between doses 
of study medication. The total length of study participation may be up to 8 weeks 
including screening, 3 dosing sessions, and follow-up.  The follow-up visit will occur 7 to 
14 days after the last dose of study drug. Participants will receive a single oral dose of
study treatment during each inpatient period.  At Follow-up, participants with no ongoing 
adverse events (AEs) or Vital Sign/Laboratory measures of clinical concern may be 
followed virtually by the site via telephone contact.
Note:  The -4 hours is an allowed tolerance window to the 7-day washout and is to enable
the study site and participants flexibility in scheduling admission and dosing for 
subsequent dosing periods (i.e., treatment periods 2 and/or 3).
4.2.
Formulation Decision
Following the Dosing Periods, a preliminary data review will be conducted.  The 
preliminary review will utilize data from Dosing Periods 1, 2, and 3 (i.e., single reference 
dose and 2 liquid prototype DTG formulations).  For the preliminary formulation 
decision, data must be available from a minimum of 16 participants who have completed 
the planned safety and PK assessments up to 72 hours after dosing.  An evaluable 
participant must also have received the relevant prototype and reference formulation(s)
for the comparisons of interest (e.g., a prototype formulation(s) and the reference).  If full 
data, as described below, are not available for 16 participants, the principal investigator 
(PI), scientific lead and Sponsor will take a decision as to whether the data available are 
sufficient to support the formulation selection decision.  If data in fewer than 16
participants are used in the decision process, additional participants will not be dosed to 
increase the number of participants in the completed regimen.
The following data will be available to the Sponsor and the site:
•
Plasma concentrations of DTG.
•
Nominal time PK parameter estimates of DTG AUC(0-), AUC(0-t), AUC(0-24), tmax, 
Cmax and t1/2.
In evaluating a prototype formulation for success, the Sponsor and the site will consider 
the above listed data within the context of the geometric mean ratios (GMR) and 90% CIs 
for DTG (see Table 4 in Section 9.2.2).  If the nominal time PK estimates for a prototype 
fall within the GMR and 90% CI limits defined in Section 9.2.2. 
The decision on formulation selection will be made by the site’s study team (i.e., PI, 
scientific lead and pharmacokineticist) and Sponsor study team (at a minimum the 
Sponsor’s Medical Monitor, Clinical Pharmacokinetics Modelling and Simulation 
[CPMS] and Medicinal Product Development Lead).  The decision will be documented 
and signed by the PI as per the site’s current standard operating procedure.  Evidence of 
the decision will be retained in the Investigator Site File and GSK Trial Master File.
See also Section 9.4.2.


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4.3.
Scientific Rationale for Study Design
Human Immunodeficiency Virus (HIV) is a retrovirus that infects primarily cluster of 
differentiation 4 (CD4) + T lymphocytes where it establishes latency. HIV-1 infection is 
associated with a progressive decrease in CD4+ T lymphocytes and an increase in viral 
load resulting in the destruction of the immune system and leading to the acquired 
immunodeficiency syndrome (AIDS) defined by the presence of one or more 
opportunistic infections. In the absence of treatment, HIV/AIDS is associated with 
serious morbidity and mortality. Combination antiretroviral therapy has demonstrated 
significant improvement in AIDS-related morbidity and mortality.
As the treatment of HIV in paediatric patients is a life-long endeavour, the development 
of new agents remains essential for overcoming drug resistance and toxicity, improving 
treatment compliance, and providing new options in cases where a lack of paediatric 
formulations or cross-resistance within a class limit the options available for children. A 
liquid formulation of DTG would provide a new option for new borns of up to 
approximately 6 weeks of age who have acquired or been born with HIV.  
The purpose of the present study is to evaluate the relative bioavailability of experimental 
liquid formulations of DTG relative to administration of a 2 x 5 mg DTG dispersible 
tablets dispersed in water, in healthy adult participants.  
4.4.
Justification for Dose
The European Medicines Agency (EMEA)-approved adult dose of DTG for treatment-
naive and non-INI resistant treatment-experienced HIV-infected patients is 50 mg once 
daily, alone or in combination with other antiretroviral drugs. 
This relative bioavailability study intends to test 2 neonatal formulations with different 
strengths currently under development in a sequential design in healthy adult subjects. 
Paediatric dispersible tablet (5mg) will be used as reference. Selection of the reference 
dose (2 x 5 mg DTG dispersible tablets dispersed in water) will be based on the neonatal 
formulation strength to compare similar doses of the two formulations. Relative 
bioavailability of the previous 5 mg dispersible tablet (5x5mg) was studied in study 
205893 against 25mg film coated tablet. This study will be used to bridge the neonatal 
formulation bioavailability with the 50mg film coated tablets currently being used in 
adults.
4.5.
Discontinuation / Stopping Study
The study will be halted, and the risk to other participants evaluated, prior to a decision as 
to whether to terminate the study if any of the following criteria are met: 
•
The occurrence of an SAE considered at least possibly related to DTG administration 
in one participant.
•
The occurrence of severe, non-serious AEs considered at least possibly related to 
DTG administration in 2 participants.


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Relatedness will be determined by the investigator.  If the study is halted, a temporary 
halt will be submitted to the Medicines and Healthcare products Regulatory Agency 
(MHRA) and ethics committee (EC) in the form of a substantial amendment. The study 
will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC
4.6.
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 for the last 
participant in the trial globally.
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, clearly 
explaining the reasons for the termination.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
The site will have a full medical history from each participant’s general practitioner 
within the last 12 months, prior to enrolment in the study. Participants will be recruited 
from the site panel or by direct advertising to the public.
Before participants are admitted to the clinic, The Over Volunteering Prevention System 
will be checked to ensure that each participant has not participated in a study at another 
site within at least 3 months of the dosing date.
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 are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac evaluation. 


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Weight
3. 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
4. Male and/or female

Male Participates: No restrictions

Female Participants: - A female participant is eligible to participate if she is not
pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP; 
see Appendix 4, Section 11.4) 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing, if needed, 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.
Informed Consent
5. 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 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. QT correction using Fridericia Formula (QTcF) >450 msec


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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 participant (Fridericia’s) is determined prior to 
initiation of the study. Several different formulae cannot be used to calculate the 
QTc for an individual participant and then the lowest QTc value used to include 
or discontinue the participant from the trial.
Prior/Concomitant Therapy
7. Past or intended use of over-the-counter or prescription medication (including herbal 
medications) within 7 days prior to dosing. Paracetamol, as listed in Section 6.5, is
allowed.
8. History of allergy or sensitivity to DTG.
Prior/Concurrent Clinical Study Experience
9. Participation in the study would result in loss of blood or blood products in excess of
500 mL within 56 days.
10. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
11. Current enrollment or past participation within the last 30 days before signing of
consent in this or any other clinical study involving an investigational study 
intervention or any other type of medical research.
Diagnostic assessments
12. Presence of Hepatitis B surface antigen (HBsAg), or a positive hepatitis B core 
antibody with a negative hepatitis B surface antibody at screening
13. Positive Hepatitis C antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
15. Positive pre-study drug/alcohol screen.
16. Positive human immunodeficiency virus (HIV) antibody test.
17. Regular use of known drugs of abuse.
Other Exclusions
18. Regular alcohol consumption within one month prior to the study defined as: 

For the United Kingdom an average weekly intake of >14 units for males or 
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. 


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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.
To assess any potential impact on participant eligibility with regard to safety, the 
investigator must refer to the IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions, 
contraindications, AEs, drug interactions, and other significant data pertaining to the 
study drugs.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
[and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days 
prior to the first dose of study medication until after the final dose.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK 
sample in that period.

Once in the clinical unit, participants will not be allowed to eat anything other than 
the food provided by the study centre.
5.3.1.1.
Fasting Conditions
During the overnight period from Day -1 to Day 1 of each dosing period:

An evening meal and/or snack will be provided by the unit (e.g. on Day -1).

Participants must then fast from all food and drink (except water) for 10 hrs pre-dose 
and prior to any clinical laboratory evaluations (except repeat evaluations).

Water is permitted with dosing (240 mL) for all Treatments and at all times except 
1 hour pre-dose through 2-hours post-dose. 

No food is allowed for at least 4 hours post-dose.
5.3.1.2.
Fed Conditions
With the exception of the period outlined in Section 5.3.1.1, participants will receive all 
other meals as defined as standard for the study centre.
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) and/or 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 and/or sample. 


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
Use of tobacco products will not be allowed from screening until after the final 
follow-up visit.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 72 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 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants will be assigned a new participant number.
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 Interventions
Study Treatment
Arm Name
Reference Treatment
Possible Prototype (Test) Liquid Formulations
Ingredient:
A
B
Intervention name:
Dolutegravir (TIVICAY), 5 
mg
Dolutegravir Sodium
0.526
0.211
Ethylcellulose (Ethocel 
Standard 20 Premium)
Miglyol 812N (Excipient 
Grade – (Triglycerides, 
Medium Chain Ph Eur, 
USP-NF, JPE))
to 100.000
Glycerol (Ph Eur)
to 100.000
Formula Description
Suspension
Solution/liquid
Type
Drug
Dose Formulation 
components:
D-Mannitol, 
Microcrystalline Cellulose, 
Povidone, Sodium Starch 
Glycolate, Silicified 
Microcrystalline Cellulose, 
Crospovidone, Calcium 
Sulfate Dihydrate, 
Sucralose, Strawberry 
Cream Flavour, Sodium 
Stearyl Fumarate, White 
film coat (Contains: 
Hypromellose, 
Polyethylene Glycol and 
Titanium Dioxide)
Refer to IMPD for prototype
No non-pharmacopoeial nor novel excipients will be used
TBD (see above)
Formulation 
Description
Dispersible tablets
Oral Suspension / Oral Liquid (see below)
Unit dose 
strength(s)/Dosage 
level(s):
2 x 5 mg DTG dispersible 
tablets dispersed in water
5mg/mL 
Dolutegravir (as 
Dolutegravir 
Sodium), in 
miglyol 812N 
vehicle (oral 
suspension)
2mg/mL 
Dolutegravir (as 
Dolutegravir 
Sodium) (glycerol 
vehicle) (oral 
liquid)
Route of 
Administration
Oral
IMP
Yes
Sourcing
Provided centrally by 
Sponsor
Manufacture on site by Quotient Sciences
Physical 
description:
White, round, film coated 
tablets debossed with ‘SV 
H7S’ on one side and ‘5’ 
on the other side.
See above
Method for 
individualizing 
dosage:
Oral via dosing cup
TBC (Oral via dosing syringe)


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6.2.
Preparation/Handling/Storage/Accountability

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.

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-centre study.
6.4.
Study Intervention Compliance
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 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 
enrolment 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


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The Medical Monitor will be contacted if there are any questions regarding concomitant 
or prior therapy.
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. 
Paracetamol at doses of 2 grams/day, is permitted for use any time during the study.
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor if required.
Hydrocortisone cream (2.5%) is permitted to relieve irritation from ECG leads.
6.6.
Dose Modification
This is a single dose study in healthy participants, there are no planned dose 
modifications.
6.7.
Intervention after the End of the Study
There will be no intervention available to participants following the study.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the Sponsor in consultation with the investigator.
Replacement participants enrolled will be dosed with the next planned treatment of the 
withdrawn participant, and they will not receive any treatment that the withdrawn 
participants already received with the exception of the need to increase participant 
numbers to obtain the minimum number of evaluable participants required for the
preliminary decision, and to obtain data in any other treatment that is required for a valid 
comparison.  Replacement participants will receive the required treatments as planned for 
the original participant and the minimum washout period will be respected with regard to 
the timing of dosing.
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not 
remain in the study to be evaluated for future pharmacokinetic measures. See the SOA 
for data to be collected at the time of discontinuation of study intervention.
Participants must be discontinued from the study for any of the following reasons:


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
Liver toxicity where stopping criteria specified in Section 7.1.1 are met and no 
compelling alternate cause is identified;

Allergic reaction or Rash criteria as described in Appendix 6 Section 11.6 are met and 
no compelling alternate cause is identified.

Renal toxicity as specified in Appendix 6 Section 11.6 are met and no compelling 
alternate cause is identified;

Grade 4 clinical AE considered causally related to study drug; 

QTcF >500msec or change from baseline:  QTc >60msec (Section 7.1.2).

Pregnancy (intrauterine), regardless of termination status of pregnancy.
(NOTE: Women of child bearing potential are not allowed to participate in this 
study).
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7, Section 11.7.
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.


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7.1.2.
QTc Stopping Criteria
A participant that meets the bulleted criterion based on the average of triplicate ECG
readings will be withdrawn from study intervention.  There are no planned ECG 
collections post-dose in this study; however, additional ECGs may be performed during 
the study at the discretion of the investigator.

QTcF > 500msec,

Change from baseline:  QTc >60msec.
NOTES:

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  

The QTc will be based on the average of triplicate ECG readings obtained over a 
brief (e.g., 5-10 minute) recording period.  
See the SoA for data to be collected at the time of intervention discontinuation or follow-
up for any further evaluations that need to be completed.
7.1.3.
Temporary Discontinuation
This Section is not applicable to this study.
7.1.4.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the Sponsor and investigator without consultation with the MHRA 
and EC.  The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is terminated, clearly explaining the reasons.  A 
description of follow up measures taken for safety reasons if applicable, will also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the principal 
investigator (PI) or Sponsor must notify the end of trial to the EC and MHRA by letter 
outlining the reasons for abandonment of the trial.
Once exposure to DTG has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study.

The occurrence of serious or severe AE(s), as defined in Appendix 4 (Section 11.4), if 
considered to be related to study treatment.


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
New information regarding the safety of the study treatment that indicates a change in 
the risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises participant safety.
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 2.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable.  In these circumstances 
termination can only take place with the agreement of the investigator and Sponsor.  The 
MHRA and EC will be informed of study termination.
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and Sponsor.
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
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, behavioural, 
compliance or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation or follow-up for any further evaluations that need to be 
completed.

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 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 
500mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 48 hours post-dose providing that:
o
No AEs have been reported during the study visit
o
The participant responds positively when asked “How are you feeling?”


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
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorisation of the investigator or appropriately 
qualified delegate.
8.1.
Efficacy Assessments
This Section is not applicable to this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height
(screening only) and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2.
Vital Signs

Temperature (collected as standard for the site), pulse rate, and systolic and diastolic 
blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.

Blood pressure \ vital signs 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) and will be measured in a supine position and will include temperature, 
systolic and diastolic blood pressure, and pulse.

The acceptable deviations from the nominal vital signs measurement time points are:
o
Discharge vital signs measurements will be taken ±1 hour from the nominal time 
point.

If a participant shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the investigator.

Any clinically significant abnormality, including changes from baseline (pre-dose 
Day 1), must be reported as an AE.


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8.2.3.
Electrocardiograms

12-lead ECGs will be performed with the participant in a supine position having 
rested in this position for at least 10 minutes beforehand.

Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTcF intervals. Refer to Section 7 for QTc withdrawal criteria and additional 
QTc readings that may be necessary.
The acceptable deviations from the nominal ECG measurement time points are:
o
Discharge ECG measurements will be taken ±1 hour from the nominal time point.

If a participant shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required.  Additional 
measurements may be taken as deemed necessary by the investigator.

Any clinically significant abnormality, including changes from baseline (pre-dose 
Day 1), will be reported as an AE.
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. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
o
The pre-dose blood sample will be taken ≤2 hours before dosing

The acceptable deviations from the nominal urine sampling time points for urinalysis 
are:
o
The pre-dose urine sample will be taken ≤3 hours before dosing or the first void 
of the day

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 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study intervention
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period-of-time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.


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
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
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 (Section 1.3).  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 ViiV product 
will be recorded from the time a participant gives consent 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 (Section 1.3).

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 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, 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. 


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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, 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
Women of child bearing potential are not permitted to participate in this study.
8.4.
Treatment of Overdose
For this study, any dose of dolutegravir greater than 50 mg within a 24-hour period 4
hours will be considered an overdose.
ViiV Healthcare 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 
dolutegravir can no longer be detected systemically (at least 7 days).
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).


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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 (PK) analysis of DTG will be collected at the time 
points indicated in the SoA via venepuncture and/or cannulation, Section 1.3.  The 4-hour 
post-dose sample must be drawn prior to the participants’ first post-dose meal.  
Instructions for the collection and handling of biological samples are provided below.  
The actual date and time of each blood sample collection will be recorded.  
For each time point identified in the SoA, Section 1.3 , 2 mL of blood will be collected 
into di-potassium ethylenediaminetetraacetic acid (K2EDTA) tubes.  Details of PK blood 
sample collection, processing, storage and shipping procedures are provided in the site 
provided SRM.
The acceptable deviations from the nominal post-dose blood sampling times are as 
follows:

The pre-dose blood sample will be taken ≤1hour before dosing. 

Post-dose samples from >0 to 4 hours post-dose will be taken within ±2 minutes of 
the nominal post-dose sampling time.

Post-dose samples from >4 to 12 hours post-dose will be taken within ±5 minutes of 
the nominal post-dose sampling time.

Post-dose samples from >12 to 48 hours will be taken within ±15 minutes of the 
nominal post-dose sampling time.

Post-dose samples for 72 hours will be taken within ±2 hours of the nominal post-
dose sampling time.
8.5.2.
Sample Processing Procedures
If a cannula is used, the cannula will be inserted into an arm vein within sufficient time 
prior to dosing, will be kept patent with normal saline, and will be removed after the last 
blood sample is collected or earlier if the participant requests.  To avoid artificial dilution 
of the PK samples by saline, 0.5 mL of whole blood will be collected and discarded 
before each whole blood sample is collected.
Collect each serial whole blood PK sample as close as possible to the planned time 
relative to dosing detailed in the protocol.  Collect a whole blood (2 mL) sample into a 
properly labelled K2EDTA evacuated blood collection tube.  Record the date and exact 
time that each sample is collected in the CRF.


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Samples will be used to evaluate the PK of dolutegravir. Each sample will be divided 
into 2 aliquots. Samples collected for analyses of dolutegravir whole blood concentration 
may also be used to evaluate safety or efficacy aspects related to concerns arising during 
or after the study.
8.5.3.
Sample Storage Conditions
Immediately after collection, gently invert (DO NOT SHAKE) the blood collection tube
8-10 times to mix the K2EDTA anti-coagulants with the whole blood and place the 
samples at room temperature.  Within 45 minutes of sample collection, centrifuge for 
10 minutes, at 1500 - 2000 G, in 4°C.  Within 30 minutes of centrifugation, using a 
polyethylene pipette, transfer plasma into separate, single, and appropriately labelled 
2 mL Amber Sarstedt tubes.  Immediately freeze the storage tubes in an upright position 
at -20°C.
8.5.4.
Sample Analysis
DTG will be extracted from plasma using protein precipitation followed by ultra-
performance liquid chromatography triple quadrupole mass spectrometry (UPLC-
MS/MS) using the previously validated method, Quantitation of GSK1349572 in Human 
Plasma via UPLC with MS/MS Detection (PPD method number, P1170.02; 
GlaxoSmithKline Document Number 2012N147635_00).  The analysis will be performed 
by PPD, 3230 Deming Way, Middleton, WI, USA. The DTG sample analysis will be 
under the management of Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, 
GlaxoSmithKline.  Raw data will be archived at the bioanalytical site.
Genetic analyses will not be performed on these whole blood samples. Participant 
confidentiality will be maintained. 
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.
8.9.
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
This study is designed to estimate the relative bioavailability of 2 experimental liquid
formulations of DTG relative to DTG dispersible tablets dispersed in water and dosed in 
the fasted state. 
No formal hypotheses will be tested.
For each pharmacokinetic endpoint (except tmax and tlag), point estimates of the geometric 
mean of the prototype treatment and Reference Treatment are estimated. The ratio of the 
two estimates (GMR), (prototype)/(reference), and its corresponding 90% confidence 
interval will be constructed.
9.2.
Sample Size Determination
9.2.1.
Sample Size Assumptions
A maximum of 18 participants will be enrolled to receive study intervention such that 
approximately 16 evaluable participants complete the study.  Precision estimates for both 
the mean treatment ratios and variability for the primary objectives of the study based on 
16 participants completing the study have been calculated.
The within subject coefficient of variation (CVw%) for the PK parameters in the GSK 
study 205893 following 5-mg dispersible DTG tablet was not available in the Clinical 
Pharmacology Study Report; therefore, the within subject coefficient of variation for the 
PK parameters was calculated using mixed model with treatment and period as fixed 
effects and subject as random effect on loge-transformed parameters. The estimates of 
within subject coefficient of variation (CVw %) are 16.7% for AUC(0-∞) and AUC(0-t) and 
20.8% for Cmax. A CVw% of 20.8% is a conservative estimate on which the sample size 
calculation was based.
For a sample size of 16 evaluable participants, it is estimated that for a point estimate of 
the ratio of geometric means (prototype: reference) of 1.00 the 90% CI would be 
approximately (0.88, 1.14) for the AUC(0-∞), AUC(0-t), and Cmax parameters.  
9.2.2.
Sample Size Sensitivity
Using estimates of parameter (any PK parameter, e.g., AUC, Cmax) variability [16.7%, 
23.5% and 27.5%] and point estimate of geometric mean ratio of 0.90, 0.95, 1.00, 1.05,
1.10, and 1.15,  the 90% CI for 16 evaluable participants has been calculated (Table 4).


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Table 4
Precision Estimate of the Mean for DTG
Within Subject variability CVw (%)
Geometric Mean Ratio
(90% Confidence Interval)
16.7
0.90
(0.81, 1.00)
0.95
(0.86, 1.05)
1.00
(0.90, 1.11)
1.05
(0.95, 1.16)
1.10
(0.99, 1.22)
1.15
(1.04, 1.27)
23.5
0.90
(0.78, 1.04)
0.95
(0.82, 1.10)
1.00
(0.87, 1.15)
1.05
(0.91, 1.21)
1.10
(0.95, 1.27)
1.15
(1.00, 1.33)
27.5
0.90
(0.76, 1.06)
0.95
(0.80, 1.12)
1.00
(0.85, 1.18)
1.05
(0.89. 1.24)
1.10
(0.93, 1.30)
1.15
(0.97, 1.36)
For example, based upon the estimate of variability (CVw%) of 27.5% for DTG and a 
point estimate of the ratio of geometric means of 1.05; it is estimated that the 90% CI for 
the means of the PK parameter (e.g., AUCs, Cmax) will be (0.89, 1.24).
9.3.
Populations for Analyses
An evaluable participant will have completed the planned safety and PK assessments up 
to 72 hours after dosing.  An evaluable participant must also have received the relevant 
prototype and reference formulations for the comparisons of interest (e.g. a prototype
formulation and the reference).
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants who sign the ICF
All Participants
All participants who receive at least one dose of study medication. This population will 
be used for the study population and safety displays.
Pharmacokinetic (PK)
Participants in the ‘All Participants’ population for whom a pharmacokinetic sample 
was obtained and had evaluable PK assay results. PK population will be the 
population for reporting of PK data.
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. Listings will be sorted by participant, period, day, and time, noting 
treatment. Summaries will be presented by treatment, day and time. 
Unless stated otherwise, descriptive summaries for continuous variables will include n,


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mean, standard deviation (SD), median, minimum, maximum; whereas, n and percent
will be used as summary statistics for categorical variable. Geometric mean with
associated 95% CI, and the between-subject coefficient of variance (CV) (%CVb) for the
geometric mean will be included for PK variables, where applicable.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected on the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.3 or higher of the Statistical Analysis Software (SAS) system will be used to 
analyze data as well as to generate tables, listings, and figures.
Complete details will be documented in the Reporting and Analysis Plan (RAP).
9.4.1.
Primary and Secondary Analyses
Comparisons will be made for the single dose PK parameters of DTG, as described in 
Table 5.  For preliminary formulation decision see Section 4.2.
Table 5
Primary and Secondary Comparisons of Interest
DTG 
PK Parameter
Prototype
Reference
Assessment
AUC(0-), AUC(0-t), Cmax, CL/F, 
AUC(0-24), C24, t1/2
Prototype Treatments A 
and B
Reference Treatment
Relative bioavailability
9.4.2.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modelling & Simulation department within GSK or their designee.  Plasma DTG 
concentration-time data will be analyzed by non-compartmental methods with Phoenix 
WinNonlin.  Calculations will be based on the actual sampling times recorded during the 
study.  From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit:  Cmax, tmax, AUC(0-t), AUC(0-), AUC(0-24), 
AUC(0-72), t1/2, tlag, C24, CL/F, tmax, t, λz, %AUCex, Vz/F and Ct.
Pharmacokinetic data will be listed and may be presented in graphical form and will be
summarized descriptively.  All PK data will be stored in the Archives, GlaxoSmithKline 
R& D. 
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline.
The PK parameters for DTG (except tmax and tlag) will be loge-transformed and separately 
analysed using a mixed effects model with fixed effect terms for treatment for each 
treatment comparison specified in Section 9.4.1.  Participant will be treated as a random 
effect in the model.  Point estimates and their associated 90% CIs will be constructed for 
the differences in PK parameter values between prototype and reference treatments.  The 
point estimates and their associated 90% CIs will then be back-transformed to provide 


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point estimates and 90% CIs for the ratios of PK parameters from prototype and reference 
treatments.
The tmax will be analysed using the non-parametric Wilcoxon matched pair method to 
calculate point estimates and associated 90% confidence intervals for the median 
differences between test and reference treatments.
Further details will be provided in the RAP.
9.4.3.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.  No formal statistical 
analysis of the safety data will be conducted.
The details of the statistical analyses of safety and PK data will be provided in the 
Reporting and Analysis Plan.
All safety analyses will be performed on the All Participants Population. 
9.5.
Preliminary Analyses
There will be no formal interim analyses.  However, an analyses of nominal time PK data 
will be performed after the final dosing session of the study (see Section 4.2).  .  
Treatment and period information may be used in the analyses.


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10.
REFERENCES
GlaxoSmithKline Document Number 2012N147635_00.  Quantitation of GSK1349572 
in Human Plasma via UPLC with MS/MS Detection. 14-August-2012.
GlaxoSmithKline Document Number 2017N352880_00: Supplement to DTG 
Investigator's Brochure. 11-December-2017.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure. 13-October-2017.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
11.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
11.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o Applicable International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines
o 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. 

The study must be approved by the Competent Authority (CA) prior to initiation.

Any substantial amendments to the protocol will require IEC/IRB and CA 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:
o
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
o
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures
o
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
11.1.2.
Protocol Amendments
After the protocol has been submitted to the MHRA and/or EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented.
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations.


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If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled participants 
and must be provided to additional participants prior to their entry into the study.
11.1.3.
Protocol Deviations
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances will be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol.
Protocol waivers are not acceptable.
Deviations from the protocol will be recorded in the source workbook as noted by the 
clinical staff.  If necessary, the Sponsor will be informed of the deviation.
Any protocol deviations assessed as major will be discussed with the Sponsor in order to 
determine if the withdrawal criteria stated in Section 8 have been met.
11.1.4.
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.
11.1.5.
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 centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 

Participants who are rescreened are required to sign a new ICF.


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11.1.6.
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.
11.1.7.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multi-centre 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.
11.1.8.
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/ViiV Healthcare will also provide the investigator with the full summary of the 
study results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

The procedures and timing for public disclosure of the 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 


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by trial participants are used to maximum effect in the creation of knowledge and 
understanding
11.1.9.
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.

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. 
11.1.10.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the Monitoring Plan.


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11.1.11.
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

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
11.1.12.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multi-centre 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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11.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by The Doctors Laboratory, except for
routine urinalysis, urine pregnancy test, urine drug screen and cotinine tests, and 
alcohol breath tests. These tests will be performed on-site according to site SOPs. 

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 
o
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.
o Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the standard procedure for the site during the study and according to 
the Schedule of Assessments.
o 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 during the participant's participation in the study.
Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
(MCH)
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (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
Glucose (fasted)
Calcium
Alkaline phosphatase
Creatine Kinase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
(all tests to be 
conducted as 
standard for the 
study site)

Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines)]

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody)

Hepatitis C RNA (when participant has a history of treated hepatitis C)

Creatinine clearance (or estimation of GFR using CKD-EPIcreatinine)
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Appendix 7 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).


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11.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
11.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study 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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 


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Events NOT Meeting the AE Definition 
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.
11.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:

Results in death
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, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.


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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.
11.3.3.
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
Every AE and SAE reported during the trial should be evaluated by the investigator and 
graded in the eCRF according to the DAIDS toxicity scales (see Appendix 5, Section
11.5 for a link to DAIDS toxicity). 
Note: Grade 4 DAIDS toxicity grades for laboratory parameters that are asymptomatic 
would not necessarily be considered SAEs, a clinical correlation would be necessary.
Where a DAIDS toxicity scale is not available for a particular event or parameter, then 
the investigator will instead make an assessment of intensity using one 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 is sufficiently discomforting to interfere with normal 
everyday activities.


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
Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
Note: An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
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. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.


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
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.
11.3.4.
Reporting of SAE to ViiV Healthcare/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 are:
Primary Medical Monitor
; FCP, MSc
Director, Clinical Development Research and Development, ViiV Healthcare
980 Great West Road
Brentford, Middlesex, TW 9GS United Kingdom
Back-up Medical Monitor
, M.D.
Director, Clinical Development Research and Development, ViiV Healthcare
Five Moore Drive, P.O. 13398
Research Triangle Park, NC  27709-3398, USA
All SAEs to SAE emails (use both addresses below): 


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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11.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
11.4.1.
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). 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
11.4.2.
Collection of Pregnancy Information:
Women of child bearing potential are not allowed to participate in this study.


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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 will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study 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 discontinue study 
intervention or be withdrawn from the study


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11.5.
Appendix 5: Division of AIDS Table For Grading The 
Severity Of Adult And Paediatric Averse Events Version 2.1, 
March 2017
VERSION 2.1, March 2017
The Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The table in the link below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as Grade 5.
Reference
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events, 
Version 2.1. [March 2017].
Available at: https://rsc.tech-res.com/docs/default-source/safety/daids-ae-grading-table-
mar2017.pdf MAR-2017).  


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11.6.
Appendix 6: Toxicity Management
11.6.1.
ANEMIA
Grade 1 (mild) haemoglobin decrease:
Any haemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
1. peripheral blood smear
2. indirect bilirubin
(abnormal if increased >50% from baseline)
3. haptoglobin (abnormal if 25 mg/dL)
4. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of 
haemolytic anaemia as specified above, participants will permanently discontinue study 
medication and be withdrawn from the trial.  Participants should be followed up until 
resolution of anaemia.
Grade 2 (moderate) haemoglobin decrease:
Any haemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1. peripheral blood smear
2. indirect bilirubin
(abnormal if increased >50% from baseline)
3. haptoglobin
(abnormal if 25 mg/dL)
4. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of 
haemolytic anaemia as specified above, participants will permanently discontinue study 
medication and be withdrawn from the trial.  Consultation with a Haematologist should 
be considered.  Participants should be followed up until resolution of anaemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
1. peripheral blood smear
2. indirect bilirubin
3. haptoglobin
4. reticulocyte count 
Participants will permanently discontinue study medication and be withdrawn from the 
trial.  Consultation with a Haematologist should be considered.  Participants should be 
followed up until resolution of anaemia.


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11.6.2.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate - 1.6-
2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects may continue study medication.  Subjects should 
be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the ULN must be repeated and fractionated (direct and indirect 
bilirubin).  Subjects will permanently discontinue study medication and be withdrawn 
from the trial.  Subjects should be followed up until resolution (return to baseline) of 
bilirubin elevation.
11.6.3.
AST AND ALT ELEVATION
See Appendix 7 [Section 11.7].
11.6.4.
RASH
Grade 1 rash (Localized macular rash):
Participants with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature >38.5°C
2. Lymphadenopathy
3. Pharyngitis
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 rash may 
continue the study drug at the discretion of the Investigator.  The participant should be 
advised to contact the Investigator immediately if there is any worsening of the rash, if
any systemic signs or symptoms worsen, or if mucosal ulceration develops. If the rash is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the participant
may be treated symptomatically until the rash resolves. Antihistamines, topical 
corticosteroids or antipruritic agents may be prescribed.  
Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target 
lesions):
Participants with Grade 2 rash should be evaluated by the Investigator immediately.  
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may be obtained if recommended by the dermatologist.  The study drug should be 
permanently discontinued if the following signs or symptoms are noted at any time:
1. Temperature >38.5°C
2. Lymphadenopathy
3. Pharyngitis
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 rash may 
continue the study drug at the discretion of the Investigator.  It should be noted that oral 
mucosal erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the 
severity of the rash to at least Grade 3.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms worsen, or if mucosal ulceration develops. If the rash is considered to be most 
likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the participant may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The participant should remain on the study to be 
followed for safety and PK as outlined in Section 11.3 (Appendix 3).
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Participants with a Grade 3 rash will permanently discontinue the study medication.  The 
participant should be evaluated in the physician’s office immediately and should be seen 
in the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The participant should remain on 
the study to be followed for safety and PK as outlined in Section 11.3 (Appendix 3).
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Participants with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and GSK Medical Monitor should be notified of this serious adverse 
event within 24hr via phone or fax.  The participant should be closely followed everyday 
until resolution of the reaction.  The participant should remain on the study to be 
followed for safety and PK as outlined in Section 11.3 (Appendix 3).


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11.6.5.
ALLERGIC REACTION
Grade 1 allergic reaction (Pruitis without rash):
Participants with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature > 38.5°C
2. Eosinophilia
3. Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the Investigator.  The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK as outlined in 
Section 11.3 (Appendix 3).
Grade 2 allergic reaction (Localized urticaria):
Participants with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature > 38.5°C
2. Eosinophilia
3. Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the Investigator.  The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK as outlined in 
Section 7.1.1 and Appendix 7, Section 11.7.
Grade 3 allergic reaction (Generalized urticaria or angioedema):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 


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followed up until resolution of the adverse event and standard management should be 
undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
11.6.6.
Decline in Renal Function
Participants who experience an increase in serum creatinine from baseline of 
45 micromoles/liter (micromol/L) (or 0.5 milligrams/deciliter [mg/dL]) or greater should 
have a confirmatory assessment. A urinalysis, urine albumin/creatinine and urine total 
protein/albumin ratios, serum cystatin C and an estimated GFR using the CKD-EPI 
(cystatin C) [Inker, 2012] should also be done at this confirmatory visit. If the creatinine 
increase is confirmed, the investigator should contact the study medical monitor to 
discuss additional follow-up and medical management. 
References
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T et. al. 
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. N Engl J 
Med 2012; 367(1):20-9.


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11.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Table 7
Phase I liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping 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/ViiV within 24 hours

Complete the liver event CRF, and complete an SAE 
data collection tool if the event also meets the criteria 
for an SAE2

Perform liver event follow up assessments 

Monitor the 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 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR ≤1.5:

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin and INR) and perform liver 
event follow up assessments within 24-72 hrs

Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology3

Obtain international normalized ratio (INR) and 
recheck with each liver chemistry assessment until 
the transaminases values show downward trend

Obtain blood sample for pharmacokinetic (PK) 
analysis, 72 hours of last dose4 

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications.

Record alcohol use on the liver event alcohol intake 
case report form
If ALT≥3xULN AND bilirubin 2xULN or INR >1.5:

Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG) or gamma 
globulins.

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 participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to participants 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 


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11.8.
Appendix 8: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.  In addition to 
SUSARs, other safety issues may qualify for expedited reporting where they might 
materially alter the current benefit-risk assessment of a study treatment or that would be 
sufficient to consider changes in the study treatments administration or in the overall 
conduct of the study, for instance:

An increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

New events related to the conduct of the study or the development of the study 
treatments and likely to affect the safety of the participants, such as:
o
An SAE which could be associated with the study procedures and which could 
modify the conduct of the study
o
A major safety finding from a newly completed animal study (such as 
carcinogenicity)
o
Any anticipated end or temporary halt of a study for safety reasons and conducted 
with the same study treatments in another country by the same sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the Sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the Sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures will be followed.
Fatal or life-threatening SUSARs:

It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility will be delegated to the 
pharmacovigilance provider (GSK/ViiV).

The investigator is required to notify the EC of any SUSAR as soon as possible, but 
no later than 7 calendar days after they first became aware of the reaction.

Any additional relevant information will be sent within 8 days of the report.
Other SUSARs:

It is the responsibility of the Sponsor to report other SUSARs to the MHRA and 
EMA as soon as possible, but no later than 15 calendar days after they first became 


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aware of the reaction. This responsibility will be delegated to the pharmacovigilance 
provider (GSK/ViiV).

The investigator is required to notify the EC of other SUSARs as soon as possible, 
but no later than 15 calendar days after they first became aware of the reaction.
Urgent Safety Measures
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as:

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health.
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and to safeguard the health or safety of 
individuals, Quotient Sciences may take urgent safety measures before informing the 
sponsor, but the sponsor must be informed immediately after the hazard has resolved.
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC.
Reporting of Urgent Safety Issues
Quotient Sciences is required to inform the appropriate competent authorities and the EC 
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the Sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study.
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.


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11.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
ABC
Abacavir
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALT
Alanine aminotransferase (SGPT)
ART
Antiretroviral Therapy
ARV
Antiretroviral
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
AUC(0-t)
Area under the plasma concentration-time curve from time of dose to last 
measurable concentration
AUC(0-)
Area under the plasma concentration-time curve from time of dose 
extrapolated to infinity
AUC(0-24)
Area under the plasma concentration-time curve from time of dose to 24 hr
AUC (0-72)
Area under the plasma concentration-time curve from time of dose to 72 hr
%AUCex
% of AUC(0-∞) that was extrapolated
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C24
Concentration at 24 hours after dose administration
CA
Competent Authority
CI
Confidence Interval
CL/F
Apparent oral clearance
Cmax
Maximum observed concentration 
C24
Observed concentration at 24h post-dose
CD4
Cluster of differentiation 4
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CRF
Case Report Form
Ct
Last quantifiable concentration
CV
Coefficient of variance
CVb
Between subject coefficient of variation
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic acid
DT
Dispersible tablet
DTG
Dolutegravir
EC
Ethics committee
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMEA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration


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FDC
Fixed-dose combination
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMR
Geometric Mean Ratio
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HRT
Hormone Replacement Therapy
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
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
IgG
Immunoglobulin G
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
kg
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MHRA
Medicines and Healthcare products Regulatory Agency
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
NRTI
Nucleoside reverse transcriptase inhibitors
OCT
Organic cation transporter
PI
Principal investigator
PK
Pharmacokinetic(s)
PTS
Platform Technology and Science
QTc
QT duration corrected for heart rate
QTcF
QT correction using Fridericia Formula
R&D
Research and Development
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software


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SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SJS
Stevens-Johnson syndrome
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reactions
t
Time of last quantifiable concentration
t½
Terminal elimination phase half-life
TEN
Toxic epidermal necrolysis
tlag
Plasma DTG lag time for absorption
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
UK
United Kingdom
UPLC-
MS/MS
Ultra-performance liquid chromatography triple quadrapole mass 
spectrometry
US / USA
United States (of America)
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
Vz/F
Apparent Volume of Distribution During Terminal Phase
z
Terminal Rate Constant
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
TIVICAY
SAS


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11.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).

SAP_001.pdf: 
CONFIDENTIAL
Viiv Healthcare group of companies
209354
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a non-randomized, 
sequential, fixed-sequence evaluation of prototype 
dolutegravir liquid formulations versus 5mg dolutegravir
dispersible tablets following single-dose fasted-state 
administrations to normal healthy adult participants
Compound Number 
:
GSK1349572
Effective Date 
:
17-Apr-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 209354.

This RAP is intended to describe the final analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
17-Apr-2019.
Senior Statistician (Infectious Diseases, Clinical Statistics)
Copyright 2019 the ViiV Healthcare group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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RAP Team Review Confirmations (Method: E-mail):
Reviewer
Date
14-Apr-2019
Programming Manager (Infectious Diseases, Clinical 
Programming)
12-Apr-2019
Global Clinical Development Director (Infectious Diseases, 
R&D PCPS GCSD)
, FCP MSc
12-Apr-2019
Director (Clinical Development, Research and Development, 
ViiV Healthcare)
12-Apr-2019
Director (Clinical Pharmacology, ViiV Healthcare)
15-Apr-2019
Director (Clinical Pharmacology Modelling and Simulation)
15-Apr-2019
Principal Statistician (Dolutegravir Statistics)
Clinical Statistics and Clinical Programming Line Approvals (Method: Pharma 
TMF eSignature and Email):
Approver
Date
17-Apr-2019
Statistics Director (Infectious Diseases, Clinical Statistics)
[pharma TMF e-Signature]
16-Apr-2019
Programming Director (Infectious Diseases, Clinical 
Programming) [email approval]
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................6
2.4.
Statistical Hypotheses...................................................................................7
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................8
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................10
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
6.2.
Details of Planned Study Population Summaries ........................................12
7.
SAFETY ANALYSES .............................................................................................14
7.1.
Adverse Events Analyses ...........................................................................14
7.1.1.
Details of Planned Adverse Event Summaries.............................14
7.2.
Clinical Laboratory Analyses.......................................................................15
7.2.1.
Details of Planned Laboratory Summaries...................................15
7.3.
Other Safety Analyses ................................................................................16
8.
PHARMACOKINETIC ANALYSES.........................................................................17
8.1.
Primary Pharmacokinetic Analyses.............................................................17
8.1.1.
Endpoint / Variables.....................................................................17
8.1.1.1.
Drug Concentration Measures....................................17
8.1.1.2.
Derived Pharmacokinetic Parameters.........................17
8.1.2.
Summary Measure ......................................................................17
8.1.3.
Population of Interest...................................................................17
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................18
8.1.5.
Statistical Analyses / Methods .....................................................18
8.1.5.1.
Statistical Methodology Specification..........................18
8.1.6.
Details of Planned Pharmacokinetic Displays ..............................19
8.2.
Secondary Pharmacokinetic Analyses........................................................19
8.2.1.
Endpoint / Variables.....................................................................19
8.2.1.1.
Drug Concentration Measures....................................19
8.2.1.2.
Derived Pharmacokinetic Parameters.........................19


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8.2.2.
Summary Measure ......................................................................20
8.2.3.
Population of Interest...................................................................21
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
8.2.5.
Statistical Analyses / Methods .....................................................21
8.2.5.1.
Statistical Methodology Specification..........................21
8.2.6.
Details of Planned Pharmacokinetic Displays ..............................21
9.
REFERENCES.......................................................................................................23
10. APPENDICES........................................................................................................24
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................24
10.2.
Appendix 2: Schedule of Activities ..............................................................25
10.2.1.
Protocol Defined Schedule of Events...........................................25
10.2.1.1.
Screening Assessments .............................................25
10.2.1.2.
Treatment Period Assessments..................................26
10.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................27
10.3.1.
Study Phases ..............................................................................27
10.3.1.1.
Study Phases for Concomitant Medication .................27
10.3.2.
Treatment Emergent Flag for Adverse Events .............................28
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................29
10.4.1.
Reporting Process .......................................................................29
10.4.2.
Reporting Standards....................................................................29
10.4.3.
Reporting Standards for Pharmacokinetic....................................30
10.5.
Appendix 5: Derived and Transformed Data ...............................................31
10.5.1.
General........................................................................................31
10.5.2.
Study Population..........................................................................31
10.6.
Appendix 6: Reporting Standards for Missing Data.....................................32
10.6.1.
Premature Withdrawals................................................................32
10.6.2.
Handling of Missing Data.............................................................32
10.6.2.1.
Handling of Missing and Partial Dates ........................32
10.7.
Appendix 7: Values of Potential Clinical Importance ...................................33
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................34
10.8.1.
Abbreviations...............................................................................34
10.8.2.
Trademarks .................................................................................35
10.9.
Appendix 9: List of Data Displays ...............................................................36
10.9.1.
Data Display Numbering..............................................................36
10.9.2.
Mock Example Shell Referencing ................................................36
10.9.3.
Deliverables.................................................................................36
10.9.4.
Study Population Tables..............................................................37
10.9.5.
Safety Tables...............................................................................39
10.9.6.
Pharmacokinetic Tables...............................................................42
10.9.7.
Pharmacokinetic Figures .............................................................43
10.9.8.
ICH Listings .................................................................................44
10.10. Appendix 10: Example Mock Shells for Data Displays ................................48


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2018N379348_00
29-Oct-2018
Original
2018N379348_01
27-Feb-2019
The original protocol was written assuming that a greater 
number of prototype formulations would possibly have been 
tested in the study.  Pre-clinical testing yielded only 2 
prototypes suitable to take forward clinically.  This amendment 
clarifies the study design for only 2 test formulations.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 01 [(Dated: 27/Feb/2019)].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To evaluate the relative bioavailability of 
equivalent doses of single dose prototype 
liquid formulations containing 10mg 
equivalent DTG compared to a single dose 
of 2 x 5mg dispersible DTG tablet 
dispersed in water.
Plasma DTG

AUC(0-t)

AUC(0-)

Cmax
Secondary Objectives
Secondary Endpoints
To characterize the pharmacokinetics of 
equivalent doses of a single dose of 
prototype liquid formulations containing 
10mg equivalent DTG and a single dose of 
2 x 5mg dispersible DTG tablet dispersed 
in water.
Plasma DTG

tlag

tmax

tlast

t½

z

%AUCex

AUC(0-24)

AUC(0-72)

CL/F and Vz/F

Ct

C24
of each formulation
To assess the safety and tolerability from 
single-dose administration of prototype 
liquid formulations containing 10mg 
equivalent DTG in healthy participants in a 
fasted state.
Safety and tolerability parameters as assessed by change 
from baseline in vital signs (BP and HR), number of 
participants with adverse events and toxicity grading of clinical 
laboratory tests.


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BP = Blood Pressure
HR = Heart rate
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable time point
AUC(0-∞) = area under the plasma concentration time curve from time zero to infinity
AUC(0-24) = area under the plasma concentration time curve from time zero to 24 hours
%AUCex=% of AUC(0-∞) that was extrapolated
Cmax = maximum observed concentration
tmax = time of maximum observed concentration
C24 = concentration at 24h post-dose
Ct = last quantifiable concentration 
PK = Pharmacokinetic 
t = time of last quantifiable concentration
tlag = absorption lag time
z=apparent elimination rate constant
t1/2 =the elimination half-life
CL/F = apparent oral clearance
Vz/F= apparent oral volume of distribution
2.3.
Study Design
Overview of Study Design and Key Features
W = Washout ≥7 days (-4 hours)
Reference formulation = 2 x 5mg DTG dispersible tablets taken as dispersed in water.
Prototype formulations = liquid formulation containing 10 mg equivalent DTG
Period 1 
Prototype A 
Period 2 
Prototype B
Period 3 
Reference
Screening 
(≤30 days)
Follow-up
(7-14 
days post 
last dose)
N=18
Prototype Formulations
W
W
Design
Features

This is an open-label, single-centre, single dose study in healthy adult participants to 
assess prototype liquid formulations with 2 x 5mg DTG Dispersible tablet as reference.

The study is a non-randomized 3-period, sequential, 3-way fixed-sequence design in 
which 2 prototype liquid formulations will be evaluated following single-dose 
administrations in the fasted state.
Dosing
Periods 1, 2 and 3 will evaluate a single reference dose (2 x 5mg dispersible DTG tablet 
dispersed in water) and 2 liquid prototype DTG formulations (containing a target total dose 
of 10mg DTG).
Time & 
Events
Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment
This is an open-label, non-randomized study wherein all the subjects will be part of Period 
1, 2 and 3.
Interim 
Analysis
There will be no formal interim analyses.  However, an analyses of nominal time PK data 
will be performed after the final dosing session of the study. Treatment and period 
information will be used in the analyses.


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2.4.
Statistical Hypotheses
This study is designed to estimate the relative bioavailability of two experimental liquid 
formulations of DTG relative to DTG dispersible tablets dispersed in water and dosed in 
the fasted state. 
No formal hypotheses will be tested.
For each pharmacokinetic endpoint (except tmax and tlag), point estimates of the geometric 
mean of each prototype treatment and Reference Treatment are estimated.  The ratio of 
the two estimates (GMR), (prototype)/(reference), and its corresponding 90% 
confidence interval will be constructed.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
There will be no formal interim analyses.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
The study has a non-randomised open label design; however, for internal study 
reporting, subjects will be assigned randomisation numbers. Therefore, the formal 
process for unblinding the randomization codes is required.
4.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who sign the ICF
Screen Failures
Enrolled

All participants who passed screening and entered the 
study.

Note screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study.
Study Population
(Selected Outputs)
All 
Participants/Safet
y

All participants who were randomized and received at 
least one dose of study medication.

This population will be used for the study population and 
safety displays.

Study Population

Safety
Pharmacokinetic
(PK)

Participants in the ‘All Participants’ population for whom 
a pharmacokinetic sample was obtained and had 
evaluable PK assay results.

PK population will be the population for reporting of PK 
data.
PK
Refer to Appendix 9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.


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Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised in the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
Prototype A
Prototype A
1
B
Prototype B
Prototype B
2
R
2x5mg DTG Dispersible Tablets
dispersed in water
DTG Ref
3
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
Prototype A vs DTG Reference Treatment
2.
Prototype B vs DTG Reference Treatment
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
last pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Vital Signs
X
Day -1
Clinical Laboratory
X
Day -1
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.


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5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Reporting Standards for Missing Data
10.7
Appendix 7: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “All Participants” population, unless 
otherwise specified. Screen failures will be summarised or listed based on the “Screened” 
population.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 9: List of Data Displays.
6.2.
Details of Planned Study Population Summaries
Participant Disposition
Participant Disposition for the Subject Conclusion Record
The number and percentage of participants who completed the study as well as 
participants who withdrew from the study will be summarized. Reason for withdrawal 
will also be summarized for participants who withdrew from the study. Only the total 
column will appear.
Treatment Status and Reasons for Discontinuation of Study Treatment
A summary of the number and percentage of subjects who completed the study treatment 
as planned as well as subjects who stopped study treatment prematurely will be produced.
Only the total column will appear.
Screening Status and Reasons for Screen Failure
This will be based on Screened population. The number and percentage of subjects who 
passed screening and who failed screening will be summarized along with the reasons for 
screen failure. Only the total column will appear.
Number of Subjects Enrolled by Country and Site ID
This will be based on Enrolled population. The number of subjects summarized by 
Country, Site ID and Investigator name will be presented. Only the total column will 
appear.
Protocol Deviations
Important Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined as 
part of the protocol deviation management plan for the study, will be summarized. Only 
the total column will appear.


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Demographic and Baseline Characteristics
Demographic Characteristics
The number and percentage of subjects or summary statistics will be provided for each 
demographic characteristic and only the total column will appear: Sex, Age (years), Age 
Group (years), Ethnicity, Race detail, Height, Weight, and Body Mass Index. Age Group 
(years) will be categorized into three ('18', '19-55', '56'). Each demographic 
characteristic will be summarized using the minimum set of summary statistics.
Age Ranges
This will be based on Enrolled population. The number and percentage of subjects within 
each age range category will be provided. Only the total column will appear. Only age 
ranges that are applicable to the study will be included (i.e., only ‘18-55 years’). This is 
based on the standard of EMA clinical trial results disclosure requirements.
Race and Racial Combinations
The five high level FDA race categories and designated Asian subcategories will be 
summarised along with all combinations of high level categories which exist in the data.
Only the total column will appear.
Prior and Concomitant Medications
All prior and concomitant medications will be summarized based on the definition 
specified in Appendix 3 later in the document.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “All Participants” population, unless otherwise 
specified. No formal statistical analysis of the safety data will be conducted.
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.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. Tables will present 
AEs in the treatment phase.  Listings will present all AEs. The details of the planned 
displays are provided in Appendix 9: List of Data Displays.
7.1.1.
Details of Planned Adverse Event Summaries
Summaries will be provided by Period (Prototype A, Prototype B, DTG Reference 
Treatment) unless otherwise specified.
Adverse Events (AEs)
All AEs by SOC and PT
The number and percentage of subjects with all relevant adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group 
and total. The counting of events and the percentages will be based on the number of 
subjects on each treatment, so subjects may appear in more than one treatment category.
All AEs by Maximum Grade by SOC and PT
The number and percentage of subjects with adverse events by grade will be summarized 
by MedDRA System Organ Class and Preferred Term by treatment group and total. The 
counting of events and the percentages will be based on the number of subjects on each 
treatment, so subjects may appear in more than one treatment category.
Drug-related AEs by SOC and PT
The number and percentage of subjects with all drug-related adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group 
and total. The counting of events and the percentages will be based on the number of 
subjects on each treatment, so subjects may appear in more than one treatment category.
Drug-related AEs by Maximum Grade by SOC and PT
The number and percentage of subjects with drug-related adverse events by grade will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group 


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and total. The counting of events and the percentages will be based on the number of 
subjects on each treatment, so subjects may appear in more than one treatment category.
Common AEs
Summaries of the number and percentage of subjects with common (incidence greater 
than five percent) adverse events by overall frequency will be displayed for grade 2-4 
events, non-serious events by SOC and PT, and drug related grade 2-4 events. The 
counting of events and the percentages will be based on the number of subjects on each 
treatment, so subjects may appear in more than one treatment category.
Serious Adverse Events
Serious AEs by SOC and PT
The number and percentage of subjects with serious adverse events will be summarized 
by MedDRA System Organ Class and Preferred Term by treatment group and total. The 
counting of events and the percentages will be based on the number of subjects on each 
treatment, so subjects may appear in more than one treatment category.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. All laboratory data will be summarized and listed. The details of the planned
displays are in Appendix 9: List of Data Displays.
7.2.1.
Details of Planned Laboratory Summaries
Changes from Baseline
Changes in value from baseline for each quantitative laboratory test will be summarised 
at every assessed time point using descriptive statistics defined above.
Worst Case Laboratory Results by PCI Criteria Post-Baseline Relative to Baseline
The number of subjects with worst case laboratory results relative potential clinical 
importance (PCI) criteria which are post-baseline relative to baseline will be summarized 
by laboratory test and category.
Laboratory Results by Maximum Grade Increases Post-Baseline Relative to Baseline
The number of subjects with laboratory results will be summarized by laboratory test, 
term (e.g. CTCAE term), maximum grade increase (e.g., Increase to Grade 1, Increase to 
Grade 2, Increase to Grade 3, Increase to Grade 4) and maximum grade increase subtotals 
(e.g., Increase to Grades 1 to 4, Increase to Grades 2 to 4, Increase to Grades 3 to 4).
Hepatobiliary results will also be summarized.


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7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. Change from baseline in 
vital signs will be summarized descriptively. All ECG and vital signs data will be listed.
The details of the planned displays are presented in Appendix 9: List of Data Displays.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 10.4.3
Reporting Standards for Pharmacokinetic)
8.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters of DTG will be calculated by standard non-compartmental 
analysis according to current working practices and using the currently supported version 
of WinNonlin 6.3 or higher. All calculations of non-compartmental parameters will be 
based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits.
Parameter
Parameter Description
AUC(0-t)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) to the time of last
quantifiable concentration (AUC(0-t)) will be calculated by a combination of linear and
logarithmic trapezoidal methods. The linear trapezoidal method will be employed for all
incremental trapezoids arising from increasing concentrations and the logarithmic
trapezoidal method will be used for those arising from decreasing concentrations (i.e.,
Linear Up/Log Down calculation method in Phoenix WinNonlin Professional).
AUC(0-inf)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) extrapolated to
infinite time (AUC(0-inf)) will be calculated as follows:
AUC(0-inf) = AUC(0-t) + Ct / z
Cmax (ng/mL)
Maximum observed plasma concentration following each dose will be obtained directly from 
the concentration-time data.
NOTES:

Additional parameters may be included as required.

Ct is the last observed quantifiable concentration.

z is the first order rate constant associated with the terminal (log-linear) portion of the curve.
8.1.2.
Summary Measure
The ratio of geometric means for AUC(0-t), AUC(0-inf) and Cmax of DTG between each of 
the prototypes and DTG reference treatment will be used for the comparison between 
Prototype A vs. DTG Reference Treatment, and Prototype B vs. DTG Reference 
Treatment.
8.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic”
population, unless otherwise specified.


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8.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events which may affect the evaluation of bioequivalence and food effect are 
not anticipated.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
8.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
Endpoint / Variables
Derived PK parameters of DTG:

AUC(0-t)

AUC(0-inf)

Cmax
Model Specification

To evaluate the relative bioavailability of equivalent doses of single dose prototype liquid 
formulations containing 10mg equivalent DTG (Prototypes A and B) compared to a single dose 
of 2 x 5mg dispersible DTG tablet dispersed in water (DTG Reference Treatment), the PK 
parameters will be analysed using a mixed effect model as described below:
loge (PK parameter) = 0 +i + j + εij
where,
0: intercept
i: random effect for ith participant, following N(0, b2)
j: treatment effect (j = Prototype A or Prototype B or DTG Reference Treatment)
εij: random error for participant i, treatment effect j, following N(0, w2).

The model parameters will be estimated using Restricted Maximum Likelihood with the 
Newton-Raphson algorithm.

The Kenward-Roger degree of freedom approach will be used.

Given the random effect for subject “i", the random error is assumed to be independently 
distributed within the subject.

The least square means for each treatment formulation (Prototype A, Prototype B and DTG 
Reference Treatment) will be estimated based on the fitted model. The mean difference 
between the treatment formulations (Prototype A vs. DTG Reference Treatment, and Prototype 
B vs. DTG Reference Treatment) and its 90% CIs will be also estimated using the within-
subject variance.

The estimates of least square means for each treatment formulation, the treatment difference 
between treatment formulations and the 90% CIs will be exponentially back-transformed to 
obtain the estimates of geometric means of AUC(0-t), AUC(0-inf) and Cmax for each treatment 


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formulation, the ratio of geometric means (Prototype A/DTG Reference, Prototype B/DTG 
Reference) and its 90% CIs, respectively.

Within-subject variability (%CVw) for the PK parameters will be estimated using within-subject 
variance from the analysis model as follows:
%CVw (%) = [exp(w2) – 1]1/2 x 100
Model Checking & Diagnostics
In case there is a problem with model convergence, the arithmetic means for loge-transformed 
AUC(0-t) and Cmax and the treatment differences (Prototype A vs. DTG Reference, Prototype B vs. 
DTG Reference) within each participant will be calculated using only data from the participants who 
have completed both the periods for Prototype A and DTG Reference (and Prototype B and DTG 
Reference, for the second comparison).The mean treatment difference and paired-t test based 
90% CIs for treatment difference in loge scale will be estimated. The results will be provided in an 
exponentially back-transformed scale.
Model Results Presentation
Based on the relative bioavailability, the bioequivalence between Prototypes A, B and DTG 
Reference Treatment will be evaluated as follows: 

The bioequivalence is established when the 90% CI of the ratio for AUC(0-t), AUC(0-inf) and 
Cmax between treatment formulations (Prototype A vs. DTG Reference Treatment, and 
Prototype B vs. DTG Reference Treatment) are within the range of 0.80 to 1.25.

Even if the 90% CI doesn’t meet the above criteria, the bioequivalence is established when 
the point estimate of the ratio for AUC(0-t), AUC(0-inf) and Cmax between treatment 
formulations are within the range of 0.90 to 1.11.
8.1.6.
Details of Planned Pharmacokinetic Displays
Analysis of relative bioavailability of Prototypes A and B vs. DTG Reference Treatment 
for AUC(0-t), AUC(0-inf) and Cmax
The analysis results will be presented as described in Section 8.1.5.1 - Model Results 
Presentation.
8.2.
Secondary Pharmacokinetic Analyses
8.2.1.
Endpoint / Variables
8.2.1.1.
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 10.4.3
Reporting Standards for Pharmacokinetic)
8.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters of DTG will be calculated by standard non-compartmental 
analysis according to current working practices and using the currently supported version 
of WinNonlin 6.3 or higher. All calculations of non-compartmental parameters will be 


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based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits.
Parameter
Parameter Description
AUC(0-t)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) to the time of last
quantifiable concentration (AUC(0-t)) will be calculated by a combination of linear and
logarithmic trapezoidal methods. The linear trapezoidal method will be employed for all
incremental trapezoids arising from increasing concentrations and the logarithmic
trapezoidal method will be used for those arising from decreasing concentrations (i.e.,
Linear Up/Log Down calculation method in Phoenix WinNonlin Professional).
AUC(0-inf)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) extrapolated to
infinite time (AUC(0-inf)) will be calculated as follows:
AUC(0-inf) = AUC(0-t) + Ct / z
AUC(0-24)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) to 24 hours post-
dose.
AUC(0-72)
(h*ng/mL)
The area under the concentration-time curve from zero time (pre-dose) to 72 hours post-
dose.
Cmax (ng/mL)
Maximum observed plasma concentration following each dose will be obtained directly from 
the concentration-time data.
C24 (ng/mL)
The observed concentration at 24h post-dose.
Ct (ng/mL)
The last observed quantifiable concentration.
tmax (h)
The time to maximum observed plasma drug concentration following each dose will be 
obtained directly from the concentration-time data.
t1/2 (h)
Terminal half-life will be calculated as follows:
t1/2 = ln2 / z
tlag (h)
Absorption lag time.
t (h)
The time of last quantifiable concentration.
%AUCex (%)
The percentage of AUC(0-inf) obtained by extrapolation (%AUCex) will be calculated as 
follows:
%AUCex = (AUC(0-inf) – AUC(0-t)) / AUC(0-inf) x 100
CL/F
(mL/h)
Apparent clearance following oral dosing will be calculated as follows:
CL/F = Dose / AUC(0-inf)
Vz/F
(mL)
Apparent volume of distribution after oral administration will be calculated as follows:
Vz/F = Dose / (z x AUC(0-inf))
z (/h)
The first order rate constant associated with the terminal (log-linear) portion of the curve.
NOTES:

Additional parameters may be included as required.
8.2.2.
Summary Measure
Descriptive summaries of the above defined parameters except tmax will be presented. 
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.
For the tmax, point estimates and associated 90% confidence intervals for the median 
differences between treatment formulations (Prototype A, Prototype B) and DTG 
Reference Treatment will be presented.
8.2.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent events which may affect the evaluation of bioequivalence and food effect are 
not anticipated.
8.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

tmax
Model Specification

A non-parametric analysis of this endpoint will be performed by using Wilcoxon matched pair 
test.
Model Results Presentation

Point estimates and associated 90% confidence intervals for the median differences between 
treatment formulations (Prototypes A and B) and DTG Reference Treatment will be presented.
8.2.6.
Details of Planned Pharmacokinetic Displays
Summaries will be provided by treatment formulations (Prototype A, Prototype B and 
DTG Reference Treatment), unless otherwise specified.
DTG Plasma Concentration-Time Data
DTG plasma concentrations at every scheduled time point will be summarized using n, 
mean, standard deviation, median, minimum, and maximum.


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Derived DTG Plasma Pharmacokinetic Parameters (non-transformed)
DTG plasma pharmacokinetic parameters defined in Section 8.2.1 will be summarized 
using n, mean, 95% CI, standard deviation, median, minimum, and maximum.
Derived DTG Plasma Pharmacokinetic Parameters (log-transformed)
For each pharmacokinetic parameter with a log-normal distribution (AUC(0-t), AUC(0-inf), 
Cmax, t1/2, %AUCex, CL/F, Vz/F, z), the log-transformed parameters will be summarized 
using n, geometric mean, 95% CI of geometric mean, standard deviation of log-
transformed data and between subject coefficient of variation (%CVb).
Non-Parametric Analysis of the Pharmacokinetic Parameter tmax
For tmax, point estimates of the treatment differences in median along with its 90% CI will 
be presented. Also, the individual estimates of median of each treatment formulations 
(Prototypes A and B) and DTG Reference Treatment will be presented along with the n 
of each group.


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9.
REFERENCES
GlaxoSmithKline Document Number 2018N379348_01 Study ID 209354. A non-
randomized, sequential, fixed-sequence evaluation of prototype dolutegravir liquid 
formulations versus 5mg dolutegravir dispersible tablets following single-dose fasted-
state administrations to normal healthy adult participants. 2019.


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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Not applicable, as there is no Per Protocol Population defined for this study.


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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
10.2.1.1.
Screening Assessments
Visit Window (relative to Day 1)
Day -30 
to -2
Notes
Informed Consent
X
Demographics
X
Physical examination height, weight and BMI
X
Medical/medication/ history
X
Medical/medication/drug and alcohol history will 
be recorded at screening and updated at 
admission.
Urine drug / Cotinine and Breathalyzer screening
X
12-lead ECG and Vital Signs
X
Serum or urine hCG test (female participants only)
X
See inclusion criterion for female participants.
Performed at site standard procedure.
FSH and estradiol (women)
X
HIV, Hep B and Hep C Screen
X
Hematology/Chemistry/Urinalysis tests
X
BMI: Body mass index, ECG: Electrocardiogram, hCG: Human chorionic gonadotropin, FSH: Follicle stimulating 
hormone; HIV: Human immunodeficiency virus, Hep B: Hepatitis B; Hep C: Hepatitis C


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10.2.1.2.
Treatment Period Assessments
Assessments
All Dosing Periods
Follow-up
Notes

Day -1 of Periods 2 and 3 may be the same day as Day 6 
of prior periods 

At Follow-up – Participants with no ongoing AEs or Vital 
Sign/Laboratory measures of clinical concern may be 
followed virtually by the site via telephone contact.

Follow-up assessments should be completed in the event 
of an early participant termination.
Day -
1
Day 1
Day 2
Day 3
Day 4
Pre-
dose
0 
hr
Post Dose
-
48 hr
72 hr
Admission to Unit
X
Discharge
X
Outpatient Visit
X
X
Follow-up visit will occur 7 to 14days post last dose.
12-lead ECG
X
Single ECGs will be collected at Screening and on Day-1 of 
Period 1 only. Additional ECGs may be performed at the 
discretion of the investigator.
Vital signs
X
X
X
Single measurements performed at all time points.
Brief Physical Exam
X
Brief examinations may be made full examinations and 
laboratory procedures may be repeated, if needed, at the 
discretion of the Investigator.
Illicit Drug/Alcohol/Cotinine screening will be performed in 
accordance with the sites’ standard practice.
Clinical laboratory tests – see Table 6 of Study Protocol.
*Clinical laboratory tests at follow-up are only necessary if 
participant had a previous abnormal lab value
Urine Drug / Cotinine and 
Breathalyzer
X
Clinical laboratory tests 
X
X*
Dosing
X
Participant will be dosed while in the seated position.
Meals
X
Post 4-hour PK sample
Per standard at the clinic
Participants will fast from 10hrs pre-dose to 4-hours post-dose.
Pharmacokinetic Sampling
X
Collect at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 5, 6, 8, 12, 16, 24, and 48-hours 
post-dose
X

Pre-dose (within 15 minutes prior to dosing). 

4-hour post dose sample must be taken prior to provision of 
food.

Permitted window for the collection of PK sample at each 
time point is specified in Section 8.5.1. of Study Protocol.
Adverse Events/SAEs
X
=======================X=======================
X
Concomitant medications
X
=======================X=======================
X


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10.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
10.3.1.
Study Phases
Assessments and events (e.g., study withdrawal) will be classified according to the time 
of occurrence relative to dosing start Date and Time by Period.
Study Phase
Definition
Pre-Treatment 
Reference Day Previous Day of Dosing Start Date in Period 1
Period 1
Previous Day of Dosing Start Date in Period 1 < Reference Day Previous Day of 
Dosing Start Date in Period 2 
Period 2
Previous Day of Dosing Start Date in Period 2 < Reference Day Previous Day of 
Dosing Start Date in Period 3
Period 3
Previous Day of Dosing Start Date in Period 3 < Reference Day Dosing Start Date in 
Period 3 + 4 Days
Post-Treatment
Reference Day > Dosing Start Date in Period 3 + 4 Days
10.3.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 7 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


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10.3.2.
Treatment Emergent Flag for Adverse Events
Study Phase
Definition
Pre-Treatment
AE Onset Date and Time < Study First Dosing Start Date and Time
Period 1
Study First Dosing Start Date and Time AE Onset Date and Time < Dosing Start 
Date and Time in Period 2
Period 2
Dosing Start Date and Time in Period 2 AE Onset Date and Time < Dosing Start 
Date and Time in Period 3
Period 3
Dosing Start Date and Time in Period 3 AE Onset Date and Time Dosing Start 
Date and Time in Period 3 + 4 Days
Post-Treatment
AE Onset Date and Time > Dosing Start Date in Period 3 + 4 Days
Time since Study
First Dose (min)
If study phase of the event is pre-treatment,
AE Onset Date and Time - Study First Dosing Start Date and Time
otherwise
AE Onset Date and Time – Study First Dosing Start Date and Time + 1 min
Time since Period 
First Dose (min)
If study phase of the AE is Pre-Treatment, set to missing
If study phase of the AE is Period 1,
AE Onset Date and Time – Dosing Start Date and Time in Period 1 + 1 min
If study phase of the AE is Period 2,
AE Onset Date and Time – Dosing Start Date and Time in Period 2 + 1 min
If study phase of the AE is Period 3,
AE Onset Date and Time – Dosing Start Date and Time in Period 3 + 1 min
If study phase of the AE is Post-Treatment,
AE Onset Date and Time – (Dosing Start Date in Period 3 + 4 Days) + 1 min
Duration (min)
AE Resolution Date and Time – AE Onset Date and Time + 1 min
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be treatment emergent.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Reporting Process
Software

The currently supported versions of SAS software 9.4 will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Compound
: \ARPROD\GSK1349572\MID209354\
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1].
Generation of RTF Files

RTF files will be generated.
10.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1


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Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
10.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
No PK parameters derived by programmer are planned
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters in GUI_51487.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards: Standards for the Transfer and Reporting of 
PK Data using HARP


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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Period Day

Calculated as the number of days from Dosing Date in Period 1 or Period 2 or Period 3.

If Study Phase of Ref Assessment or Event = Pre-Treatment or Missing
→ Period Day = Missing 

If Study Phase of Ref Assessment or Event = Period 1
→ If Ref Date is on or after Dosing Date in Period 1, Period Day = Ref Date – Dosing Date in 
Period 1 + 1 day

If Study Phase of Ref Assessment or Event = Period 2
→ If Ref Date is on or after Dosing Date in Period 2, Period Day = Ref Date – Dosing Date in 
Period 2 + 1 day

If Study Phase of Ref Assessment or Event = Period 3
→ If Ref Date is on or after Dosing Date in Period 3, Period Day = Ref Date – Dosing Date in 
Period 2 + 1 day

If Study Phase of Ref Assessment or Event = Post-Treatment
→ If Ref Date is after Dosing Date in Period 3 + 4 Days, Period Day = Ref Date – (Dosing Date in 
Period 3 + 4 Days) + 1 day
10.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug for each period will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were enrolled but did not report a treatment start date will be categorised as having 
zero days of exposure.
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
A date and month will be imputed as ‘30th June’ as it will not be captured.

Date of Informed Consent will be used as reference date of calculation.


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10.6.
Appendix 6: Reporting Standards for Missing Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as completion of 
all phases of the study including the follow up visit.

Withdrawn participants may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
10.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF does not allow for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month will not be 
missing.

The eCRF allows for the possibility of missing times to be recorded for AE start and end 
dates. Missing times will be imputed using the following convention:
o
If the missing time is a start time, a '00:00' will be used for the time.
o
If the missing time is a stop time, a '23:59' will be used for the time.

The recorded missing time will be displayed in listings without imputed values.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The eCRF allows for the possibility of missing times to be recorded for concomitant 
medications start and end dates. Missing times will be imputed using the following 
convention:
o
If the missing time is a start time, a '00:00' will be used for the time.
o
If the missing time is a stop time, a '23:59' will be used for the time.

The recorded partial date and missing time will be displayed in listings without imputed 
values.


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10.7.
Appendix 7: Values of Potential Clinical Importance
Any DAIDS Grade 2 or above event will be treated as an event of potential clinical 
importance.
Please refer to the link below for more details:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf


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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTC
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 


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Abbreviation
Description
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TMF
Trial Master File
10.8.2.
Trademarks
Trademarks of the ViiV Healthcare Group 
of Companies
Trademarks not owned by the ViiV 
Healthcare Group of Companies
None
SAS
WinNonlin


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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.12
Not Applicable
Safety
3.1 to 3.21
Not Applicable
Pharmacokinetic
4.1 to 4.5
4.1 to 4.5
Section
Listings
ICH Listings
1 to 33
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
PK_Fn
PK_Tn
Not Applicable
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.9.3.
Deliverables
Delivery
Description
SAC
Final Statistical Analysis Complete


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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All 
Participants
ES1A
Summary of Participant Disposition for the Participant
Conclusion Record
Only “Total” column will appear
Please refer to mock shell DM1 in 
Appendix 10 for an idea of how a 
typical study population display would 
look like.
SAC
1.2.
All 
Participants
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
Only “Total” column will appear
SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Only “Total” column will appear
SAC
1.4.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
Only “Total” column will appear
SAC
Protocol Deviation
1.5.
All 
Participants
DV1
Summary of Important Protocol Deviations
Only “Total” column will appear
SAC
Population Analysed
1.6.
Enrolled
SP1
Summary of Study Populations 
SAC
Demographic and Baseline Characteristics
1.7.
All 
Participants
DM3
Summary of Demographic Characteristics
Only “Total” column will appear
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
Enrolled
DM11
Summary of Age Ranges
Only “Total” column will appear
SAC
1.9.
All 
Participants
DM5
Summary of Race and Racial Combinations
Only “Total” column will appear
SAC
Prior and Concomitant Medications
1.10.
All 
Participants
MH1
Summary of Past Medical Conditions
Only “Total” column will appear
SAC
1.11.
All 
Participants
MH1
Summary of Current Medical Conditions
Only “Total” column will appear
SAC
1.12.
All 
Participants
CM1
Summary of Concomitant Medications
Only “Total” column will appear
SAC


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10.9.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
All 
Participants
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
Include “Total” column
Please refer to mock shell AE1CP in 
Appendix 10 for an idea of how a typical 
safety display would look like.
SAC
3.2.
All 
Participants
AE5B
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term
Include “Total” column
SAC
3.3.
All 
Participants
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
Include “Total” column
SAC
3.4.
All 
Participants
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events by 
Overall Frequency
Include “Total” column
SAC
3.5.
All 
Participants
AE1CP
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
Include “Total” column
SAC
3.6.
All 
Participants
AE5B
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Grade
Include “Total” column
SAC
3.7.
All 
Participants
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
Include “Total” column
SAC
3.8.
All 
Participants
AE3
Summary of Common (>=5%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency
Include “Total” column
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
3.9.
All 
Participants
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
Include “Total” column
SAC
Laboratory: Chemistry 
3.10.
All 
Participants
LB1
Summary of Chemistry Changes from Baseline 
Include “Total” column
SAC
3.11.
All 
Participants
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline
Include “Total” column
SAC
3.12.
All 
Participants
LB16
Summary of Worst Case Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline
Include “Total” column
SAC
Laboratory: Hematology
3.13.
All 
Participants
LB1
Summary of Hematology Changes from Baseline
Include “Total” column
SAC
3.14.
All 
Participants
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
Include “Total” column
SAC
3.15.
All 
Participants
LB16
Summary of Worst Case Hematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline
Include “Total” column
SAC
Laboratory: Urinalysis
3.16.
All 
Participants
LB1
Summary of Urine Concentration Changes from Baseline
Include “Total” column
SAC
3.17.
All 
Participants
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
Include “Total” column
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hepatobiliary (Liver)
3.18.
All 
Participants
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
Include “Total” column
SAC
3.19.
All 
Participants
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
Include “Total” column
SAC
Vital Signs
3.20.
All 
Participants
VS1
Summary of Change from Baseline in Vital Signs
Only “Total” column will appear
SAC
3.21.
All 
Participants
VS3
Summary of Worst Case Vital Signs Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline
Only “Total” column will appear
SAC


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10.9.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK01
Summary of DTG Plasma Concentration-Time Data
SAC
4.2.
PK
PK03
Summary of Derived DTG Plasma Pharmacokinetic Parameters 
(non-transformed)
SAC
4.3.
PK
PK05
Summary of Derived DTG Plasma Pharmacokinetic Parameters 
(log-transformed)
SAC
4.4.
PK
PK_T1
Non-parametric Analysis of tmax
Refer to example shell
SAC
4.5.
PK
PK_T2
Analysis of Relative Bioavailability of Prototype Formulations vs. 
DTG Reference Treatment for Cmax, AUC(0-t), and AUC(0-inf)
Refer to example shell
SAC


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10.9.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK16b
Individual DTG Plasma Concentration-Time Plots by Participant
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
4.2.
PK
PK16b
Individual DTG Plasma Concentration-Time Plots by Treatment
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
4.3.
PK
PK17
Mean (+SD) DTG Plasma Concentration-Time Plots
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
4.4.
PK
PK18
Median DTG Plasma Concentration-Time Plots
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
4.5.
PK
PK_F1
Plot of Individual DTG Plasma Cmax, AUC(0-t), and AUC(0-inf) 
by Treatment
Refer to example shell
SAC


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10.9.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
All 
Participants
ES3
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
All 
Participants
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4.
All 
Participants
TA2
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
5.
All 
Participants
DV2A
Listing of Important Protocol Deviations 
ICH E3
SAC
6.
All 
Participants
IE4
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Populations Analysed
7.
All 
Participants
SP3a
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
8.
All 
Participants
DM4
Listing of Demographic Characteristics
ICH E3
SAC
9.
All 
Participants
DM10
Listing of Race
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
10.
All 
Participants
CM5
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
11.
All 
Participants
EX4
Listing of Exposure Data
ICH E3
SAC
Adverse Events
12.
All 
Participants
AE9CP
Listing of All Adverse Events
ICH E3
SAC
13.
All 
Participants
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
14.
All 
Participants
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
15.
All 
Participants
AE9CPa
Listing of Fatal Serious Adverse Events
ICH E3
SAC
16.
All 
Participants
AE9CPa
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
17.
All 
Participants
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
18.
All 
Participants
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
19.
All 
Participants
AE8 / AECP8 / 
AE9 / AE9CP
Listing of Other Significant Adverse Events
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Hepatobiliary (Liver)
20.
All 
Participants
MH3
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
21.
All 
Participants
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
SAC
All Laboratory
22.
All 
Participants
LB6
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
23.
All 
Participants
LB6
Listing of Laboratory Values of Potential Clinical Importance
SAC
24.
All 
Participants
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
25.
All 
Participants
UR2B
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
ECG
26.
All 
Participants
EG4
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
27.
All 
Participants
EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
28.
All 
Participants
EG6
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
IDSL
SAC
29.
All 
Participants
EG6
Listing of Abnormal ECG Findings
IDSL
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
30.
All 
Participants
VS5
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
31.
All 
Participants
VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
PK
32.
All 
Participants
PK08
Listing of DTG Plasma Pharmacokinetic Concentration-Time 
Data
IDSL
SAC
33.
All 
Participants
PK14
Listing of Derived DTG Plasma Pharmacokinetic Parameters
IDSL
SAC


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10.10.
Appendix 10: Example Mock Shells for Data Displays
Example DM1
Protocol: 209354                                                                             Page 1 of 3
Population: All Patients
Table X
Summary of Demographic Characteristics
Total
(N=200)
Sex
 n
 200
 F
 100  (50%)
 M
 100  (50%)
Age (YEARS)[1]
 n
 200
 Mean
  50.0
 SD
  10.00
 Median
  50.0
 Min.
  18
 Max.
  65
Age Group(YEARS)[1]
  <=18
    5   (3%)
  19-64
  100  (50%)
  >=65
  95  (48%)
[1] Age is imputed when full date of birth is not provided.


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Example AE1CP
Protocol: 209354                                                                      Page 1 of n
Population: All Patients
                                                  Table X
Summary of Adverse Events by System Organ Class and Preferred Term
                     System Organ Class             Prototype A  Prototype B
DTG Reference  Total
                       Preferred Term                (N=78)      (N=78)        (N=78)     (N=78)
                     ------------------------------------------------------------------------------
                     ANY EVENT                         58 (74%)    64 (82%)    64 (85%)    65 (83%)
                     Gastrointestinal disorders
                       Any event                       28 (36%)    34 (44%)    22 (29%)    34 (44%)
                       Dyspepsia                        9 (12%)    11 (14%)     5  (7%)    15 (19%)
                       Nausea                           6  (8%)     8 (10%)     4  (5%)    11 (14%)
                       Vomiting Nos                     3  (4%)    10 (13%)     3  (4%)    10 (13%)
                       Constipation                     6  (8%)     6  (8%)     3  (4%)     7  (9%)
                       Diarrhoea Nos                    2  (3%)     4  (5%)     2  (3%)     6  (8%)
                       Toothache                        3  (4%)     1  (1%)     3  (4%)     5  (6%)
                       Abdominal Pain Upper             1  (1%)     2  (3%)     2  (3%)     5  (6%)
                       Dry Mouth                        0           1  (1%)     4  (5%)     5  (6%)
                       Flatulence                       1  (1%)     3  (4%)     1  (1%)     4  (5%)
                       Gastrointestinal Upset           0           1  (1%)     3  (4%)     3  (4%)
                       Haemorrhoids                     3  (4%)     0           0           3  (4%)
                       Salivary Hypersecretion          0           2  (3%)     1  (1%)     2  (3%)
                       Abdominal Tenderness             0           2  (3%)     0           2  (3%)
                       Hyperacidity                     0           1  (1%)     1  (1%)     2  (3%)
                       Loose Stools                     0           2  (3%)     0           2  (3%)
                       Abdominal Pain Nos               1  (1%)     0           0           1  (1%)
                       Faecal Incontinence              0           1  (1%)     0           1  (1%)
                       Gastritis Nos                    0           1  (1%)     0           1  (1%)
                       Lip Disorder Nos                 0           0           1  (1%)     1  (1%)
                       Lip Dry                          0           0           1  (1%)     1  (1%)
                       Stomach Discomfort               0           0           1  (1%)     1  (1%)
                     Nervous system disorders
                       Any event                       28 (36%)    28 (36%)    27 (36%)    30 (38%)
                       Headache                        15 (19%)    11 (14%)    14 (19%)    27  (35%)
                       Dizziness                        3  (4%)     8 (10%)     3  (4%)    11  (14%)
                       Extrapyramidal Disorder          4  (5%)     4  (5%)     5  (7%)    10  (13%)


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Example: PK_T1
Page 1 of n
Protocol: 209354
Population: PK
Table X
Analysis of Relative Bioavailability of Prototype Formulations vs. DTG Reference Treatment for Cmax, AUC(0-t), 
and AUC(0-inf)
Parameter
Treatment
Comparison
Adjusted Geom Mean
Ratio 
(trt2/trt1)
90% CI
%CVw[1]
n
Test
n
Ref
Cmax (unit)
trt1 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
AUC(0-t)(unit)
trt1 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
AUC(0-inf) (unit)
trt1 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
trt2 vs 
ref
xx
xx.xxx
xx
xx.xxx
x.xxx
(x.xxx, x.xxx)
x.xxx
[1] Within-subject variability of each PK parameter
trt1 = “Prototype A”, trt2 = “Prototype B” trt3 = “DTG Reference”


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Example: PK_F1
Page 1 of n
Protocol: 209354
Population: PK
Table X
Plot of Individual DTG Plasma Cmax, AUC(0-t), and AUC(0-inf) by Treatment
Note: Geometric mean and 95% CI 
Programming notes: 
Add three treatments – trt1 = “Prototype A”, trt2 = “Prototype B” trt3 = “DTG Reference”
Figures will be presented in left (Cmax), center (AUC(0-t), and right (AUC(0-inf).