Conditions: Leishmaniasis
Keywords: Dose escalation phase First time in human Single ascending dose Multiple ascending dose GSK3186899
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 25
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.

Detailed description:

Arms:
arm 1: Subjects will receive 3 single ascending oral doses (SAD) of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 1 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period. arm 2: Subjects will receive 3 SAD of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 2 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period. arm 3: Subjects will receive GSK3186899 orally, under fasted condition and fed conditions on Day 1 of cohort 3 in each of the two treatment periods. There will be a wash out period of at least 10 days between each treatment period. A dose level will be determined based on the effect of food on the safety, tolerability and PK of a single dose of GSK3186899, with dose level selected from Cohorts 1 and 2. arm 4: Subjects will receive GSK3186899, orally, twice daily (BID) on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A. arm 5: Subjects will receive placebo, orally, BID on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.

Interventions: intervention 1: GSK3186899 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3186899 will be available as white to slightly colored, spray dried powder in a bottle to be administered orally along with mixture of propylene glycol and water. intervention 2: Placebo will be available as white to slightly colored, blend powder in a bottle to be administered orally along with mixture of propylene glycol and water.

Protocol document:
Prot_000.pdf: 
2018N385133_01
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TITLE PAGE
Protocol Title: A randomized, double-blind (sponsor unblinded), placebo-controlled, 
first time in human study to evaluate the safety, tolerability and pharmacokinetics of 
single (in both fed and fasted states) and repeat doses of GSK3186899 in healthy 
participants
Protocol Number :208436/Amendment 01
Version: 01
Compound Number:
GSK3186899
Study Phase: Phase 1 
Short Title: Safety, tolerability and pharmacokinetics investigation of GSK3186899 in 
healthy participants.
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT  2018-004642-42
Approval Date: 19-MAR-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1 (version 01)
19-MAR-2019
2018N385133_01
Original Protocol (version 00)
09-JAN-2019
2018N385133_00
Amendment 1 19-MAR-2019
Overall Rationale for the Amendment: To amend the protocol with required changes 
from the Medicines and Healthcare products Regulatory Agency, UK
Section # and 
Name
Description of Change
Brief Rationale
3.3.1 Risk 
Assessment
&
6.2 Exclusion 
Criteria
The exclusion criterion on renal function has been 
amended to an age appropriate GFR (CKD-EPI) of
≤ 90 (ml/min/1.73m2). 
In alignment with this change, the mitigation 
strategy in the risk assessment table has also been 
updated. 
MHRA requested changes 
to exclusion criterion.
6.2 Exclusion 
Criteria
An additional criterion has been added to exclude 
participants with abnormally low blood pressure, as 
determined by the Principal Investigator.
MHRA requested changes 
to add an additional 
exclusion criterion.
7.3 Measure to 
Minimize Bias: 
Randomization 
and Blinding
Additional wording has been added to include 
information on general and emergency unblinding.
To correct an omission in 
the original protocol, as 
identified by the MHRA.
8.1.2 Dose 
Escalation / 
Study 
Progression 
Stopping 
Criteria
One criterion has been updated to remove 
reference to two or more participants on active 
treatment experiencing the same / medically similar 
AE. This wording has now been updated to:
“Two or more participants in the same cohort 
experience a severe non-serious adverse reaction 
(i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP 
administration), independent of within or not within 
the same system-organ-class.”
MHRA requested changes 
to the stopping criterion.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................7
1.1.
Synopsis.......................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
PART A (Cohorts 1-3).................................................................................13
2.2.
PART B (Cohorts 4-6).................................................................................16
3.
INTRODUCTION....................................................................................................22
3.1.
Study Rationale ..........................................................................................22
3.2.
Background ................................................................................................22
3.3.
Benefit/Risk Assessment ............................................................................22
3.3.1.
Risk Assessment .........................................................................24
3.3.2.
Benefit Assessment.....................................................................29
3.3.3.
Overall Benefit: Risk Conclusion..................................................29
4.
OBJECTIVES AND ENDPOINTS...........................................................................29
5.
STUDY DESIGN ....................................................................................................30
5.1.
Overall Design ............................................................................................30
5.2.
Number of Participants ...............................................................................34
5.3.
End of Study Definition ...............................................................................34
5.4.
Scientific Rationale for Study Design ..........................................................34
5.5.
Justification for Dose ..................................................................................36
5.5.1.
Human Predicted Pharmacokinetics ............................................36
5.5.1.1.
Background on Pharmacology for Human Dose 
Selection ....................................................................36
5.5.1.2.
Human Starting Dose Determination ..........................39
5.5.1.3.
Human Anticipated Therapeutic Dose 
Determination.............................................................40
5.5.2.
Maximum SAD Dose Determination.............................................40
5.5.3.
Dose Escalation Plan...................................................................41
5.5.4.
Safety Margins.............................................................................41
5.5.5.
Multiple Ascending Dose (MAD) ..................................................42
5.6.
Dose Escalation..........................................................................................42
5.6.1.
Dose Escalation Committee.........................................................43
5.6.2.
Part A ..........................................................................................43
5.6.3.
Part B ..........................................................................................43
6.
STUDY POPULATION...........................................................................................44
6.1.
Inclusion Criteria.........................................................................................44
6.2.
Exclusion Criteria........................................................................................45
6.3.
Lifestyle Considerations..............................................................................47
6.3.1.
Meals and Dietary Restrictions ....................................................47
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................47
6.3.3.
Activity and Travel .......................................................................48


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6.4.
Screen Failures...........................................................................................48
7.
STUDY TREATMENT ............................................................................................48
7.1.
Study Treatment(s) Administered ...............................................................49
7.2.
Preparation/Handling/Storage/Accountability..............................................49
7.3.
Measures to Minimize Bias: Randomization and Blinding ...........................50
7.3.1.
Randomization.............................................................................50
7.3.2.
Blinding........................................................................................50
7.4.
Study Treatment Compliance......................................................................51
7.5.
Concomitant Therapy..................................................................................51
7.6.
Treatment after the End of the Study ..........................................................52
8.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................52
8.1.
Discontinuation of Study Treatment ............................................................52
8.1.1.
Dose Adjustment/Stopping Pharmacokinetic Criteria ...................52
8.1.2.
Dose Escalation / Study Progression Stopping Criteria................53
8.1.3.
Renal Withdrawal Criteria ............................................................53
8.1.4.
Adrenal Withdrawal Criteria (Part B only).....................................54
8.1.5.
Liver Chemistry Stopping Criteria ................................................54
8.1.6.
QTc Stopping Criteria ..................................................................54
8.1.7.
Individual Safety Stopping / Withdrawal Criteria...........................55
8.1.8.
Group Safety Stopping Criteria ....................................................55
8.1.9.
Study Treatment Restart or Rechallenge .....................................56
8.2.
Participant Discontinuation/Withdrawal from the Study ...............................56
8.3.
Lost to Follow Up........................................................................................56
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
9.1.
Safety Assessments ...................................................................................57
9.1.1.
Physical Examinations.................................................................57
9.1.2.
Vital Signs....................................................................................57
9.1.3.
Electrocardiograms......................................................................58
9.1.4.
Holter Monitoring .........................................................................58
9.1.5.
Clinical Safety Laboratory Assessments ......................................58
9.2.
Adverse Events and Serious Adverse Events.............................................59
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................59
9.2.2.
Method of Detecting AEs and SAEs.............................................59
9.2.3.
Follow-up of AEs and SAEs.........................................................60
9.2.4.
Regulatory Reporting Requirements for SAEs .............................60
9.2.5.
Pregnancy ...................................................................................60
9.3.
Treatment of Overdose...............................................................................61
9.4.
Pharmacokinetics .......................................................................................61
9.4.1.
Blood Sample Collection..............................................................61
9.4.2.
Urine Sample Collection ..............................................................61
9.4.3.
Entero-test: Bile Sample Collection..............................................62
9.5.
Pharmacodynamics ....................................................................................62
9.6.
Genetics .....................................................................................................62
9.7.
Pharmacological Biomarkers ......................................................................62
9.8.
Health Economics / Medical Resource Utilization and Health 
Economics..................................................................................................62


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10. STATISTICAL CONSIDERATIONS........................................................................62
10.1.
Statistical Hypotheses.................................................................................62
10.2.
Sample Size Determination ........................................................................63
10.3.
Sample Size Sensitivity...............................................................................63
10.4.
Populations for Analyses ............................................................................64
10.5.
Statistical Analyses.....................................................................................65
10.5.1.
Safety Analyses...........................................................................65
10.5.2.
Pharmacokinetic (PK) Analyses...................................................65
10.6.
Interim Analyses .........................................................................................67
10.7.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................68
10.7.1.
Regulatory and Ethical Considerations ........................................68
10.7.2.
Financial Disclosure.....................................................................68
10.7.3.
Informed Consent Process ..........................................................68
10.7.4.
Data Protection............................................................................69
10.7.5.
Publication Policy.........................................................................69
10.7.6.
Dissemination of Clinical Study Data ...........................................70
10.7.7.
Data Quality Assurance ...............................................................70
10.7.8.
Source Documents ......................................................................71
10.7.9.
Study and Site Closure ................................................................71
10.7.10. Publication Policy.........................................................................72
10.8.
Appendix 2: Clinical Laboratory Tests.........................................................73
10.9.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................75
10.9.1.
Definition of AE............................................................................75
10.9.2.
Definition of SAE..........................................................................76
10.9.3.
Recording and Follow-Up of AE and SAE....................................77
10.9.4.
Reporting of SAE to GSK.............................................................79
10.10. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................80
10.10.1. Definitions:...................................................................................80
10.10.2. Contraception Guidance: .............................................................81
10.10.3. Collection of Pregnancy Information: ...........................................82
10.11. Appendix 5: Part B Assessments Based on an Alternative Dosing 
Regimen .....................................................................................................84
10.12. Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................87
10.13. Appendix 7: Abbreviations and Trademarks................................................89
10.14. Appendix 8: Protocol Amendment History...................................................92
11. REFERENCES.......................................................................................................93


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A randomized, double-blind (sponsor unblinded), placebo-controlled, 
first time in human study to evaluate the safety, tolerability and pharmacokinetics of 
single (in both fed and fasted states) and repeat doses of GSK3186899 in healthy 
participants.
Short Title: Safety, tolerability and pharmacokinetics investigation of GSK3186899 in 
healthy participants.
Rationale: Visceral leishmaniasis (VL) is a parasitic disease caused by obligate 
intracellular protozoan parasites, particularly by the species Leishmania donovani and 
Leishmania infantum/chagasi. If left untreated, cases of VL are typically fatal. While 
therapies are available to treat the disease, none are ideal for use (due to toxicity, route of 
administration and cost) in resource poor settings where the disease is endemic. As such 
there is a real unmet medical need for new, short course oral drugs for the treatment of 
this disease. 
The Phase 1 program will comprise a First Time in Human (FTIH) study of single and 
repeat ascending doses in healthy participants, incorporating a food effect component to 
investigate the influence of food on the pharmacokinetics (PK) of GSK3186899. The 
study will evaluate the safety, tolerability and PK profile of single and repeat ascending 
doses of GSK3186899. Results of this study are intended to be used to identify 
appropriate and well tolerated doses of GSK3186899 to be used in further studies. This 
study will be conducted at a single centre.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
single and repeat doses of GSK3186899
in healthy participants

Adverse event reporting, clinical laboratory 
safety data, vital signs, 12 lead 
electrocardiogram (ECGs), 24 hours (hr)
telemetry.
Secondary

To evaluate the systemic PK profile of 
single (fasted and fed) and repeat 
doses of GSK3186899 in healthy 
participants

Plasma concentrations of GSK3186899 plus 
derived parameters, as data allow.
For single ascending dose (SAD) part:  
Derived PK parameters for GSK3186899
following single dose (fasted and fed)
including area under the plasma drug 
concentration versus time curve (AUC(0-t), 
AUC(0-∞), maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(Tmax),trough plasma concentration (Ctau) and 


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Objectives
Endpoints

To examine dose proportionality 
following single and multiple doses of 
GSK3186899

To assess accumulation and time-
invariance ratios of GSK3186899 after 
multiple doses
apparent terminal half-life (T1/2) as data allow.
Predicted accumulation Ratio (ARpred)# will be 
calculated.
For multiple ascending dose (MAD) part: 
AUC(0-t), AUC(0-∞), AUC(0-tau), Cmax, Tmax 
and T1/2.

Dose-proportionality assessment using 
derived PK parameters, as data allow:
For SAD part: AUC(0-∞), Cmax
For MAD part: AUC(0-tau), Cmax, Ctau

Accumulation ratios assessment*, where 
data allow: RAUC(0-tau), RCmax, RCtau.
Time-invariance ratio calculation as AUC(0-
12) on day 10 to AUC(0-∞) on day 1.
Exploratory

To collect residual plasma following  
GSK3186899 analysis, and urine 
samples, for analysis of metabolites of 
GSK3186899

To collect bile samples for analysis of 
metabolites of GSK3186899 (Part A 
Cohort 3 only)

Metabolites of GSK3186899 in plasma and 
urine. These analyses will be run and 
reported separately from this protocol.

Metabolites of GSK3186899 in bile. These 
analyses will be run and reported separately 
from this protocol.
* Accumulation ratios calculated as the ratio of last dose to first dose PK parameters: RAUC(0-tau) = AUC(0-tau)on last 
dose to AUC(0-tau) on first dose, RCmax = Cmax on last dose to Cmax on first dose, RCtau= Ctau on last dose to Ctau 
on first dose. # ARpred = 1/(1-e^(k*tau)) where k is elimination rate constant following the single dose and tau is 
the dosing interval for the intended repeat dosing.
Overall Design: This study will be a randomized, double-blind (sponsor unblinded), 
placebo-controlled, 2-part study of the oral administration of GSK3186899 in healthy 
participants. As this will be the first time GSK3186899 is administered to humans, the 
study design may change based on emerging data as the study progresses. 


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This study is planned to include approximately 54 participants and will consist of 2 parts:

Part A will include a single-ascending, sequential crossover design in up to 3 cohorts 
of participants (Cohorts 1, 2 and 3). Part A Cohorts 1-2 will comprise of a 4-way 
crossover which includes 4 dosing regimens under fasted conditions. Part A Cohort 3 
will comprise of a 2-way crossover which includes 1 dosing regimen under fasted 
conditions and 1 regimen under fed conditions. The fed conditions regimen will 
investigate the effect on safety, tolerability and PK of a single dose of GSK3186899
following food administration. 

Part B will be a twice-daily (BID) 10-day repeat dose design in up to 3 parallel 
cohorts of participants (Cohorts 4, 5 and 6), although the dosing regimen may be 
altered depending on emerging data (Appendix 5). Part B may include drug 
administration after either fed or fasted conditions; this will be dependent on the 
interim results from Part A. If under fasted conditions, participants will be required to 
fast at least 2 hours before and after drug administration.
All participants in the study will attend a screening visit within 28 days prior to their first 
dose and a follow-up visit within 14-21 days after their final dose. If required, additional 
follow-up visits may be scheduled.
Disclosure Statement: This is a sequential cross-over (Part A) and parallel (Part B) 
treatment study with 6 arms that is participant and investigator blinded.
Number of Participants: A sufficient number of participants will be screened to ensure 
that a planned minimum of 54 are eligible to be randomized (Part A: 8 participants into 
each of Cohorts 1-2 and up to 14 participants for Cohort 3; Part B: 8 participants into 
each of Cohorts 4-6). A participant is considered evaluable if they complete both 
screening and at least one treatment period in Part A, or the 10-day treatment period in 
Part B. Participants that take part in Part A of the study cannot take part in Part B. 
If participants prematurely discontinue the study, then additional replacement participants 
may be recruited and assigned to the same treatment sequence, at the discretion of the 
Sponsor in consultation with the Principal Investigator in both Parts A and B.
Treatment Groups and Duration:
Part A
For the dose escalation phase in Part A, up to 3 cohorts may be used (Cohorts 1-3). 
Cohorts 1 and 2 will consist of 8 healthy participants each. Cohort 3 will consist of up to 
14 healthy participants.
Cohorts 1 and 2 will each comprise of 4 treatment periods. Each participant will receive a 
maximum of 3 ascending oral doses of GSK3186899 and 1 placebo dose under fasted 
conditions. At each dose level, GSK3186899 and placebo will be administered in a 3:1 
ratio, within each period, according to the randomization schedule in a blinded manner. 
Up to a maximum of 7 dose levels will be studied in Part A.
Cohort 3 will comprise of 2 treatment periods and investigate the effect of food on the 
safety, tolerability and PK of a single dose of GSK3186899, with a dose level (DLX) 


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previously selected from Cohorts 1-2. Dose selection will be based on in silico 
modelling, where the maximum exposure would not be exceeded following fed 
administration. The decision on the dose level of GSK3186899 to be administered will be 
made by the dose escalation committee (DEC).  Each participant will receive a maximum 
of 2 oral doses of GSK3186899 under fasted and fed conditions. Bile samples will be 
collected under both fed and fasted conditions for the analysis of GSK3186899 and any 
metabolites.
Study Duration of Cohorts 1-3
Screening
All screening assessments to be completed within 28 days prior to 
first-dose. 
Treatment Period
Cohorts 1 and 2 will comprise of 4 treatment periods, investigating 4 
dosing regimens under fasted conditions. Cohort 3 will comprise of 2 
treatment periods, investigating 2 dosing regimens under fasted and 
fed conditions. 
Each regimen will consist of a single dose given on Day 1, with 
participants in-house for 4 nights and 5 days. Participants will be 
admitted to the unit the day before dosing (Day -1) and will remain in 
the unit overnight until Day 4, when they will be discharged after 
completion of all assessments. 
Washout Period
At least 10 days between each dose for an individual participant.
Follow-up
At least 14 days and no greater than 21 days after last study drug 
administration. If warranted, additional follow-up visits may be 
scheduled.
Total duration
Cohorts 1 and 2 will be approximately 11-12 weeks each
Cohort 3 will be approximately 8-9 weeks 
Part B
For the repeat dose escalation phase in Part B, there will be up to 3 cohorts (Cohorts 4, 5 
and 6), each cohort will consist of 8 healthy participants. Participants will only participate 
in one cohort. In each cohort, participants will be randomized to receive repeat doses of 
either GSK3186899 or placebo, administered in a 3:1 ratio according to the 
randomization schedule in a blinded manner. For BID dosing, GSK3186899 or placebo 
will be administered using a 12hr dosing interval. If another dosing regimen is selected 
for Part B based on emerging data, the interval between doses is outlined in Appendix 5.
Participants will receive each dose after either fed or fasted conditions, dependent upon 
the interim results from Part A. If under fasted conditions, participants will be required to 
fast at least 2 hours before and after drug administration. Up to a maximum of 3 dose 
levels will be studied in Part B.


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Study Duration of Cohort 4-6
Screening
All screening assessments to be completed within 28 days prior to 
first-dose. 
Treatment Period
Each Cohort will consist of a 10-day treatment duration (Days 1-10), 
with participants in-house for 14 nights and 15 days. Participants will 
be admitted to the unit the day before dosing (Day -2) and will remain 
in the unit overnight until Day 13, when they will be discharged after 
completion of all assessments. 
Follow-up
At least 14 days and no greater than 21 days after last study drug 
administration. If warranted, additional follow-up visits may be 
scheduled. 
Total duration
Approximately 8-9 weeks 
Data Monitoring Committee: No
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities (SoA) tables (Section 2.1 and Section 2.2), are 
essential and required for study conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the Study Reference Manual (SRM). The SRM will provide the site 
personnel with administrative and detailed technical information that does not impact 
participant safety.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoA tables (Section 2.1 and Section 2.2).
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-Lead ECG
2. Vital Signs
3. Blood Draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or other assessments may be altered during the course of the 
study based on newly available data (e.g. to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring.


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
The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File, which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM.


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2.1.
PART A (Cohorts 1-3)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
======X======
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams can be 
made into full exams, by the Investigator, as deemed necessary (e.g. 
where safety or laboratory findings indicate). Tests will be conducted 
within site specified standards.
Brief Physical Examination
X
X
X
X
Drug/Alcohol/Smoking Screen
X
X
Tests include alcohol breath test, smoking breath test and urine drug 
screen.
Medical/Medication/Drug/Alcohol 
History
X
Human immunodeficiency virus 
(HIV), Hepatitis B and C Screening
X
Follicle stimulating hormone (FSH)
+ Oestradiol
X
Females only, if required
Holter Monitoring (48 hours)
X
Haematology/ Clinical Chemistry 
/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
If trace protein in urine is detected, a repeat test can be performed
(within 24 hours). If tests are considered abnormal, further 
quantification is required.
Non-fasted samples can be collected on Day -1 and the Follow-Up 
Visit. All other samples to be collected in a fasted state.
Urine Sampling (metabolism)
X
X
A urine sample will be taken pre-dose (approx. 20mL) All urine from 
each participant will be collected from 0-24 hrs post dosing. Details of 
urine collection and processing are described in the SRM.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Safety biomarkers (KIM1, NGAL, 
Urinary albumin)
X
X
First urine sample of the morning to be collected (Day 1 sample 
collection should be pre-dose). 
Additional samples may be collected, as deemed necessary by the 
Investigator (e.g. where safety or laboratory findings indicate).
PK Blood Sampling
X
X
PK blood samples to be taken pre-dose on Day 1 and then at the 
following time points post first-dose:  10min, 30min, 1hr, 1.5hr, 2hr,
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, 12hr; 24hr. 
The time points stated may be modified depending on emerging SAD 
PK information as appropriate.
Blood volumes to be collected include 2 mL for all time-points from pre-
dose to 10hrs, and 5 mL for time-points 12hr and 24 hr.
12-Lead ECG
X
X
T
X
X
Vital signs to include heart rate (HR), blood pressure (BP), 
temperature and respiration rate. BP will be conducted in both a supine 
and standing position if participant develops any signs/symptoms 
which in the investigator’s opinion are suggestive of adrenal 
insufficiency.
12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose 
on Day 1 and then at the subsequent time points post-dose: 
30 min, 1hr, 1.5hr, 2hr, 2.5hr, 4hr, 8hs, 12hr, 24hr, 48hr
Timings will be reviewed as cohorts progress and may be adjusted to
ensure appropriate measurements relative to peak concentrations for
subsequent cohorts.
T = Triplicate (for all assessments, except temperature and respiratory 
rate).
If any abnormal ECG reading is recorded, refer to Section 8.1.6 for 
appropriate action. 
Vital Signs
X
X
T
X
X
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Telemetry
X
Continuous at least 24hr post-dose. Initiate at least 15 min. prior to 
dosing.
Meals
X
X
X
X
X
Fasting regimen: On Day 1, participants will have fasted 8hr overnight 
prior to dosing. An adapted standard breakfast will be served 
approximately 3hrs after dosing.
Fed regimen: On Day 1, participants will fast 8hr overnight and an 
adapted standard breakfast will be served approximately 30 mins prior 
to dosing. 
Meals will be served as per the site schedule on Days -1, 2, 3 and 4.
Water permitted on an ad lib basis up to 1hr before dosing. No water 
to be taken in the hour prior to dosing except for the liquid part of the
adapted standard breakfast for the Fed regimen. At least 8 fl oz 
(240ml) to be taken 1hr after dosing. No water to be taken in the hour 
after dosing except for the rinse of the dose.
Bile Sampling (Entero-test)
X
Cohort 3 only. Entero-test bile string swallowed 2hr post-dose, after 
5hr the bile string will be removed.
Randomization
X
Study Treatment
X
Adverse event (AE) Review
=======X=======
X
Serious adverse event (SAE)
Review
X
=======X=======
X
Concomitant Medication Review
X
=======X=======
X


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2.2.
PART B (Cohorts 4-6)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Outpatient Visit
X
X
Admission to 
Clinical Unit
X
Inpatient Stay at 
Clinical Unit
=========================X=========================
Discharge from 
Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and 
Exclusion Criteria
X
Demography
X
Full Physical 
Examination
X
Additional exams/screens may be 
performed, or brief exams can be made 
into full exams, by the Investigator, as 
deemed necessary (e.g. where safety or 
laboratory findings indicate). Tests will be 
conducted within site specified standards.
Brief Physical 
Examination
X
X
X
X
X
Drug/Alcohol/Smoki
ng Screen
X
X
Tests include alcohol breath test, smoking 
breath test and urine drug screen.
Medical/Medication/
Drug/Alcohol 
History
X
HIV, Hepatitis B 
and C Screening
X
FSH + Oestradiol 
X
Females only, if required
Holter Monitoring 
(48 hour)
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Haematology/
Clinical Chemistry 
/Urinalysis Test 
X
X
X
X
X
X
X
X
X
X
If trace protein is detected, a repeat test 
can be performed.
Sample to be drawn pre-dose on Days 2, 
4, 6, 8 and 10.
Non-fasted samples can be collected on 
Day -1 and Follow-Up Visit. All other 
samples to be collected in fasted state.
Cortisol Test
X
X
Tests to be performed in the early 
morning on Day -1 and Day 11. 
If levels are <420 nmol/L, then a
adrenocorticotropic hormone (ACTH)
stimulation test will be performed to 
assess hypothalamic pituitary adrenal 
(HPA) axis.
Safety biomarkers 
(KIM1, NGAL, 
Urinary albumin)
X
X
First urine sample of the morning to be 
collected (pre-dose). 
Additional samples may be collected, as 
deemed necessary by the Investigator 
(e.g. where safety or laboratory findings 
indicate).
Telemetry 
X
X
Continuous at least 24 hr post-evening 
dose. Initiate at least 15 min. prior to 
dosing.
Randomization
X
Study Treatment
X
X
X
X
X
X
X
X
X
X
BID dosing: GSK3186899 or placebo will 
be administered using a 12hr dosing 
interval. If a different dosing regimen is 
used, refer to Appendix 5.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
12-Lead ECG
X
X
T
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, temperature 
and respiration rate. BP will be conducted 
in both a supine and standing position if 
participant develops any signs/symptoms 
which in the investigators opinion are 
suggestive of adrenal insufficiency.
12-Lead ECG and Vital Signs to be 
conducted on Day-1 and pre-dose Day 1
and then at the subsequent time points 
post first-dose: 30 min, 1 hr, 1.5hr, 2hr, 
2.5hr, 4hr, 6hr, 13hr and 14hr
For Days 2-10: pre-dose assessments 
only. 
Timings will be reviewed as cohorts 
progress and may be adjusted to
ensure appropriate measurements 
relative to peak concentrations for
subsequent cohorts
If a different dosing regimen is used, refer 
to Appendix 5 for alternative ECG and 
Vital Signs time-points.
T = Triplicate (for all assessments except 
temperature and respiratory rate).
If any abnormal ECG reading is recorded, 
refer to Section 8.1.6 for appropriate 
action.
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
PK Blood sampling
<=====================X=====================>
PK samples will be collected pre-dose 
and at the following time points post first-
dose:
Day 1: 10min, 30min, 1hr, 1.5hr, 2hr, 
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, and 
12hr 
Days 2 – 9: Pre-dose PK samples 
collected for each dose
Day 10: PK samples will be collected pre-
dose and at the following time points post 
first-dose: 10min, 30min, 1hr, 1.5hr, 2hr, 
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, and 
12hr.
The time points stated may be modified 
depending on emerging SAD PK profiles. 
If a different dosing regimen is used, refer 
to Appendix 5 for alternative PK blood 
sampling time-points.
Blood volumes to be collected include:
2 mL for post first-dose 0-11 hrs, and 
5 mL for post first-dose 12-24 hrs (Days 
1 and 10).
Urine Sampling 
(metabolism)
X
X
A urine sample will be taken pre-dose 
(approx. 20mL).  All urine from each 
participant will be collected from 0-24 hrs 
post dosing. Details of urine collection and 
processing are described in the SRM.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Meals 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If on fed regimen: On Day 1 through to 
D10, participants will receive an adapted 
standard meal 30 mins prior to dosing.
If on fasted regimen: On Day 1 through 
to D10, participants will have fasted 8hr 
overnight prior to dose 1. A breakfast will 
be served approximately 2hr after dose 1. 
Dinner will be served at least 2hr prior to 
dose 2. A snack may be consumed 
approximately 2hr after dose 2. 
Participants will receive standardized 
meals scheduled at the same time in each 
period. If a different dosing regimen is 
used, refer to Appendix 5 for alternative 
meal times.
Meals will be served as per the site 
schedule on Days -1 and Days 11-13.
Water permitted on an ad lib basis up to 
1hr before dosing. No water to be taken in 
the hour prior to dosing except for the 
liquid part of the adapted standard 
breakfast for the Fed regimen. 
At least 8 fl oz (240ml) to be taken 1 hour 
after dosing No water to be taken in the 
hour after dosing except for the rinse of 
the dose.
AE review
============================X============================
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
SAE review
X
============================X============================
X
Concomitant 
medication review
X
============================X============================
X

The timing and number of planned study assessments, including safety, pharmacokinetic or other assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study 
team member and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF).


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3.
INTRODUCTION
3.1.
Study Rationale
Visceral leishmaniasis (VL) is a parasitic disease caused by obligate intracellular 
protozoan parasites, particularly by the species Leishmania donovani and Leishmania 
infantum/chagasi. If left untreated, cases of VL are typically fatal. While therapies are 
available to treat the disease, none are ideal for use (due to toxicity, route of 
administration and cost) in resource poor settings where the disease is endemic. As such 
there is a real unmet medical need for new, short course oral drugs for the treatment of 
this disease. 
The Phase 1 programme will comprise a First Time in Human (FTIH) study of single and 
repeat ascending doses in healthy participants, incorporating a food effect component to 
investigate the influence of food on the pharmacokinetics (PK) of GSK3186899. The 
study will evaluate the safety, tolerability and PK profile of single and repeat ascending 
doses of GSK3186899. Results of this study are intended to be used to identify 
appropriate and well tolerated doses of GSK3186899 to be used in further studies. This 
study will be conducted at a single centre.
3.2.
Background
Visceral leishmaniasis is identified as a Neglected Tropical Disease by the World Health 
Organisation. As a systematic approach to drug discovery is relatively new in this 
neglected disease, GSK3186899 was identified through a phenotypic screening approach.  
Subsequently detailed mode of action studies utilising a variety of approaches, including 
genomics and chemical proteomics, have been undertaken which indicate that 
GSK3186899 acts principally by inhibiting the parasite complex of the cyclin dependent 
kinase; cdc 2 related kinase 12 (CRK12) with CYC9 as the definitive partner cyclin for 
CRK12.  
More detailed information relating to non-clinical pharmacology, safety pharmacology, 
PK and metabolism, toxicology and other pre-clinical data can be found in the 
GSK3186899 
Investigators 
Brochure 
[GlaxoSmithKline 
Document 
Number 
2018N372131_00].
3.3.
Benefit/Risk Assessment
There is no direct benefit to the participants taking part in this study. 
To date, GSK3186899 has not been administered to human participants; therefore, no 
clinical data are available. This is the first single and repeat dose study proposed in 
human participants with GSK3186899. GlaxoSmithKline (GSK) is not aware of any 
compound targeting this pathway having previously been administered in humans.
The risk assessment of GSK3186899 is based on the pre-clinical studies conducted to 
date. Summaries of findings from these pre-clinical studies can be found in the 
Investigators Brochure (IB). Non-adverse vacuolation in the female rat adrenal glands 


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and ovaries was observed at the NOAEL and above, as a result some adrenal function 
monitoring has been added to this study.  However, by observing the safety margin for 
renal findings of 3 to 5-fold below the female rat NOAEL (AUC: 434 g.h/mL, Cmax:
46.2 g/mL), this should reduce the risk of adrenal and ovary effects in humans. Details 
of the risks and the proposed strategy to mitigate/monitor these risks are detailed in 
Section 3.3.1. 
The proposed risk assessment and management plan for the study has been developed in 
accordance with the tenets of European Medicines Agency (EMA) guideline on strategies 
to identify and mitigate risks for FTIH clinical trials with investigational medicinal 
products [European Medicines Evaluation Agency (EMEA)/ Committee for Medicinal 
Products for Human Use (CHMP)/SWP/28367/07]. GSK has assessed this study for any 
risks that may be posed to participants taking part. Only healthy male and female 
participants of non-child bearing potential will participate in this study.
In this study, safety will be monitored closely both by subjective reporting and by 
objective means, i.e. serial assessments of vital signs, clinical laboratory information and
cardiac monitoring. The study will be run in a clinical unit with immediate access to 
hospital facilities for the treatment of medical emergencies. Participants will remain 
monitored in the clinic for the duration of each treatment period and will only be 
discharged from the unit at the end of each treatment period, if the investigator deems it 
safe to do so.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3186899 may be found in the IB
[GlaxoSmithKline Document Number 2018N372131_00].


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
Investigational Medicinal Product (IMP) GSK3186899
Kidney
Kidney tubule dilatation, which involved tubular 
epithelial cell loss, was noted in female rats given 
400 mg/kg/day as spray dried dispersion (SDD), 
for 28 days (mean AUC 1290 µg.h/mL, mean 
Cmax 74.2 µg/mL on Day 28).  This lesion is 
considered adverse in rats.
These findings were associated with lower urine 
volume, with accompanying higher urine-specific 
gravity and lower urine pH, in females given 400 
mg/kg/day.
This lesion was not seen in 7-day rat studies nor 
in monkey toxicology studies of ≤21 days 
duration.
Inclusion/exclusion criteria: 
History of current or past significant renal diseases 
to be excluded.
Screening eGFR (CKD-EPI) > 90 ml / min
Urinary analysis at screening to be free of blood 
and protein. If trace protein is found, a repeat test 
will be performed within 24 hours
Monitoring:
Serum Renal function and urinary analysis 
monitoring
By observing the PK safety margin for renal 
findings of up to 3-fold (during the SAD part of the 
study) and up to 5-fold (during the MAD part of the 
study) for the total daily AUC and Cmax to be below 
the female rat NOAEL (AUC: 434 g.h/mL, Cmax: 
46.2 g/mL).
Participant withdrawal
New onset of any clinically significant and 
persistent haematuria / proteinuria (Spot Urine 
Protein Creatinine (UPC) ratio > 0.5) in the 
absence of another clinical explanation e.g. 
calculus / infection.


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
Change in serum creatinine > 26 µmol/L (0.3 
mg/dl) from baseline or > 50 % from baseline. If 
change in serum creatinine measures at > 26 
µmol/L (0.3 mg/dl), repeat within 24 hours. If 
confirmed, the participant will be withdrawn. If a 
participant meets the withdrawal criteria for serum 
creatinine, then further investigations will be 
performed.
Hypophosphataemia (less than 0.8mmol/L). If 
confirmed, the participant will be withdrawn. If a 
participant meets the withdrawal criteria for 
hypophosphataemia, then further investigations 
will be performed.
Study Stopping criteria
The study will be temporarily halted if 2 or more 
participants across all study parts develop any of 
the above withdrawal criteria. 
Stomach
Stomach erosion/ulceration in the glandular 
region, was noted in female rats given 
400 mg/kg/day (dose conc 40 mg/mL), as SDD, 
for 28 days (mean AUC 1290 µg.h/mL, mean 
Cmax 74.2 µg/mL on Day 28).  This lesion is 
considered adverse in rats.
Erosion/ulceration was not seen in NHPs given 
≤150 mg/kg/day (dose conc 30 mg/mL), as SDD, 
for 21 days (AUC range across all doses 3.34 to 
Contact time with stomach in humans are likely to 
be short (less than 2 hours) and concentrations 
considered in the human study are much lower than 
in the Rat study. 
Participants with current or past history of clinically 
significant gastritis or gastroduodenal ulcers or 
regular NSAID use, will be excluded from the study 
based on medical history at screening.
Participants will be monitored for GI symptoms 


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
187 µg.h/mL on Day 21) nor in male rats given 
≤1000 mg/kg/day (dose conc 100 mg/mL), as free 
base, for 7 days (AUC range across all doses 
26.8 to 273 µg.h/mL on Day 7).
Localized erosion of the pyloric gastric mucosa 
was noted in the male monkey given 500 
mg/kg/day (dose conc 100 mg/mL), as free base, 
for 7 days (mean AUC 896 µg.h/mL on Day 7) 
and focal ulceration of the mucosa at the gastro-
duodenal junction and in the colon in the female 
given 150 mg/kg/day (dose con 30 mg/mL), as 
free base, for 7 days (mean AUC 613 µg.h/mL on 
Day 7).  Erosion in the stomach and ulceration of 
the duodenum was noted in 1 female monkey
given 500 mg/kg/day (dose con 100 mg/mL), as 
free base, for 14 days (mean AUC 545 µg.h/mL 
on Day 14).  
Due to the localised nature and low incidence, 
these lesions are considered to be local, dose 
concentration-related, effects rather than due to 
systemic exposure.
reported as adverse events. Any reported 
symptoms which in the investigator’s opinion raises 
a clinical suspicion of gastric erosion/ulcers, will be
referred to a gastro enterology specialist for further 
management, and endoscopy (if required).
Adrenal gland
Adrenal cortex vacuolation was noted in male and 
female rats given ≥100 mg/kg/day, as SDD, for 
28 days (≥mean AUC 316 µg.h/mL, mean Cmax
44.0 µg/mL on Day 28).
Adrenal cortex vacuolar degeneration was noted 
in male rats given 1000 mg/kg/day, as free base, 
These adrenal findings are considered not adverse 
and did not have any secondary effects in the rats. 
However, these findings were consistently 
observed in rats at all tested doses. The potential 
risk to healthy volunteers is expected to be low 
especially when administered as a single dose. 


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
for 7 days (mean AUC 204 µg.h/mL on Day 7).
This test article-related, non-adverse finding 
correlated with increased adrenal weight following 
28 days dosing in male rats given 
≥100 mg/kg/day, as SDD, and female rats given 
≥25 mg/kg/day, as SDD.
Therefore, no specific monitoring, other than 
standard clinical and laboratory parameters, will be 
implemented for healthy volunteers during SAD part 
of the study. However, for the MAD cohorts, 
adrenal function will be assessed prior to first dose 
and on completion of 10 days dosing. Also, by 
observing the safety margin for renal findings of up 
to 3-fold (during the SAD part of the study) and up 
to 5-fold (during the MAD part of the study) for the 
total daily AUC and Cmax to be below the female rat 
NOAEL (AUC: 434 g.h/mL, Cmax: 46.2 g/mL), 
should reduce the risk of adrenal and ovary effects 
in humans.
Exclusion criteria (Part B only): 
Participants with borderline adrenal glucocorticoid 
function (early morning serum cortisol < 420nmol/L) 
will only be included in the study if after an
adrenocorticotropic hormone (ACTH) stimulation 
test, there is a rise in cortisol level from baseline of 
at least 250nmol/L 
Monitoring: 
Participants will be monitored clinically for any 
symptoms of adrenal insufficiency, (nausea, 
vomiting, dizziness) and objective assessments 
(supine/standing BP). Depending on the 
investigators clinical judgement, a ACTH


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
stimulation test may be done to exclude adrenal 
insufficiency.
Day 11 (Part B only): 
Early morning serum cortisol (+ ACTH stimulation 
test if levels < 420nmol/L) will be performed on all 
participants at Day 11. If during Day 11 early 
morning cortisol is < 420 nmol/L, volunteers will 
undergo a ACTH stimulation test the next day to 
rule out adrenal insufficiency. Participants with 
adrenal insufficiency will be withdrawn from the 
study, refer to Section 8.1.4.
Stopping criteria: 
A stopping criterion has been included if one or 
more volunteers in Part B develop adrenal 
insufficiency with clinical signs and symptoms.
Study Procedures
Bile Sampling (Entero-test)
As the swallowed capsule is attached to string, 
participants may experience a gagging sensation 
when the string is being withdrawn or may 
swallow the whole string. Sometimes streaks of 
blood can be seen on the nylon string after it is 
retrieved from the mouth, due to local irritation. 
Rarely, participants may be unable to swallow the 
capsule because of gagging or will vomit after 
doing so.
Participants will be informed of these study 
procedure risks in the Information and Consent 
Form. 
To minimize the risk of swallowing the string, it will 
be securely taped to the side of the participants 
face. 
In the event of swallowing the whole string, no ill 
effects are anticipated as the nylon string will pass 
out from the body through the faeces.  


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3.3.2.
Benefit Assessment
The proposed study with GSK3186899 will be conducted in healthy volunteers; no 
medical benefit will be derived by volunteers’ participation. Participants will indirectly 
gain through their contribution to the process of developing new therapies in an area of 
unmet need.
3.3.3.
Overall Benefit: Risk Conclusion
The known risks associated with GSK3186899 can be appropriately mitigated by the 
careful selection of study participants and the proposed safety monitoring procedures. As 
such, the risk to potential participants is considered low. Routine safety and tolerability 
will be evaluated from reported AEs, vital sign measurements, cardiac rhythm 
monitoring, 12-lead ECGs, and clinical laboratory test results as well as continued 
observation by clinical staff.
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies. The in-house periods as 
detailed in the SoA (Section 2) will allow for continuous medical monitoring for all 
participants following the first dose in each treatment group. Participants will only be 
discharged from the unit 48 hours post-dose if the Investigator deems it safe to do so.
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with GSK3186899 are justified by 
the anticipated benefits that may be afforded by the future development of a new therapy 
in an area of unmet need.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
single and repeat doses of GSK3186899
in healthy participants

Adverse event reporting, clinical laboratory 
safety data, vital signs, 12 lead ECGs, 24 hr 
telemetry.
Secondary

To evaluate the systemic PK profile of 
single (fasted and fed) and repeat 
doses of GSK3186899 in healthy 
participants

Plasma concentrations of GSK3186899 plus 
derived parameters, as data allow.
For SAD part:  Derived PK parameters for 
GSK3186899 following single dose (fasted 
and fed) including area under the plasma 
drug concentration versus time curve 
(AUC(0-t), AUC(0-∞), maximum observed 
plasma drug concentration (Cmax), time to 
maximum observed plasma drug 
concentration (Tmax),trough plasma 
concentration (Ctau) and apparent terminal 
half-life (T1/2) as data allow. Predicted 


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Objectives
Endpoints

To examine dose proportionality 
following single and multiple doses of 
GSK3186899

To assess accumulation and time-
invariance ratios of GSK3186899 after 
multiple doses
accumulation Ratio (ARpred)# will be 
calculated.
For MAD part: AUC(0-t), AUC(0-∞), AUC(0-
tau), Cmax, Tmax and T1/2.

Dose-proportionality assessment using 
derived PK parameters, as data allow:
For SAD part: AUC(0-∞), Cmax
For MAD part: AUC(0-tau), Cmax, Ctau

Accumulation ratios assessment*, where 
data allow: RAUC(0-tau), RCmax, RCtau.

Time-invariance ratio calculation as AUC(0-
12) on day 10 to AUC(0-∞) on day 1.
Exploratory

To collect residual plasma following 
GSK3186899 analysis, and urine 
samples, for analysis of metabolites of 
GSK3186899

To collect bile samples for analysis of 
metabolites of GSK3186899 (Part A 
Cohort 3 only)

Metabolites of GSK3186899 in plasma and 
urine. These analyses will be run and 
reported separately from this protocol.

Metabolites of GSK3186899 in bile. These 
analyses will be run and reported separately 
from this protocol.
* Accumulation ratios calculated as the ratio of last dose to first dose PK parameters: RAUC(0-tau) = AUC(0-tau)on last 
dose to AUC(0-tau)on first dose, RCmax = Cmax on last dose to Cmax on first dose, RCtau= Ctau on last dose to Ctau 
on first dose. # ARpred = 1/(1-e^(k*tau)) where k is elimination rate constant following the single dose and tau is 
the dosing interval for the intended repeat dosing.
5.
STUDY DESIGN
5.1.
Overall Design
This study will be a randomized, double-blind (sponsor unblinded), placebo-controlled, 
2-part study of the oral administration of GSK3186899 in healthy participants. As this 
will be the first time GSK3186899 is administered to humans, the study design may 
change based on emerging data as the study progresses. 
This study is planned to include approximately 54 participants and will consist of 2 parts:

Part A will include a single-ascending, sequential crossover design in up to 3 cohorts 
of participants (Cohorts 1, 2 and 3). Part A Cohorts 1-2 will comprise of a 4-way 
crossover which includes 4 dosing regimens under fasted conditions. Part A Cohort 3 
will comprise of a 2-way crossover which includes 1 dosing regimen under fasted 
conditions and 1 regimen under fed conditions. The fed conditions regimen will 


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investigate the effect of safety, tolerability and PK of a single dose of GSK3186899
following food administration. 

Part B will be a twice-daily (BID) repeat dose design in up to 3 parallel cohorts of 
participants (Cohorts 4, 5 and 6), although the dosing regimen may be altered 
depending on emerging data (Appendix 5). Part B may include drug administration 
after either fed or fasted conditions, this will be dependent on the interim results from 
Part A. If under fasted conditions, participants will be required to fast at least 2 hours 
before and after drug administration.
All participants in the study will attend a screening visit within 28 days prior to their first 
dose and a follow-up visit within 14-21 days after their final dose. If required, additional 
follow-up visits may be scheduled. Participants that take part in Part A of the study 
cannot participate in Part B.
Part A
For the dose escalation phase in Part A, up to 3 cohorts may be used (Cohorts 1-3). 
Cohorts 1 and 2 will consist of 8 healthy participants each. Cohort 3 will consist of up to 
14 healthy participants.
For Cohorts 1 and 2, each participant will receive a maximum of 3 ascending oral doses 
of GSK3186899 and 1 placebo dose under fasted conditions. At each dose level, 
GSK3186899 and placebo will be administered in a 3:1 ratio, within each period, 
according to the randomization schedule in a blinded manner. Up to a maximum of 7 
dose levels will be studied in Part A as illustrated in Figure 1.
Figure 1
Study Design (Part A)
DL = Dose level; DLX = Dose level to be determined; FD = Fed Conditions; A = Active; P = Placebo
For further information on the dose escalation and safety review meetings refer to Section 
5.6.2. 
Initiation of food effect phase: The selected dose level (DLX) to investigate the effect 
of food on the safety, tolerability and PK of a single dose of GSK3186899 will be one 


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already evaluated from a previous treatment period. Dose selection will be based on in 
silico modelling, where the maximum exposure would not be exceeded following fed 
administration. The decision on the dose level of GSK3186899 to be administered will be 
made by the dose escalation committee (DEC). Bile samples will be collected under both 
fed and fasted conditions for the analysis of GSK3186899 and any metabolites.
Sentinel Dosing: For each cohort and within each treatment period (except Cohort 3), the 
first 2 participants will act as sentinels. No participant will be a sentinel participant more 
than once. On Day 1, 1 of the 2 sentinel participants will receive the active dose and the 
other will receive placebo. Based on the Principal Investigator’s review of the 2 sentinel 
participants after at least the first 24hr post-dose safety data (e.g. vital signs, ECGs and 
AEs), the remaining 6 participants can then be randomized to dosing.
Table 1
Study Duration of Cohorts 1-3
Screening
All screening assessments to be completed within 28 days prior to 
first-dose. 
Treatment Period
Cohorts 1 and 2 will comprise of 4 treatment periods, investigating 4 
dosing regimens under fasted conditions. Cohort 3 will comprise of 2 
treatment periods, investigating 2 dosing regimens under fasted and 
fed conditions. 
Each regimen will consist of a single dose given on Day 1, with 
participants in-house for 4 nights and 5 days. Participants will be 
admitted to the unit the day before dosing (Day -1) and will remain in 
the unit overnight until Day 4, when they will be discharged after 
completion of all assessments. 
Washout Period
At least 10 days between each dose for an individual participant.
Follow-up
At least 14 days and no greater than 21 days after last study drug 
administration. If warranted, additional follow-up visits may be 
scheduled.
Total duration
Cohorts 1 and 2 will be approximately 11-12 weeks each
Cohort 3 will be approximately 8-9 weeks 
Part B
Prior to initiation of Part B, a review of all available safety, tolerability and PK data from 
Part A will be conducted. A formal interim analysis is not planned. 
For the repeat dose escalation phase in Part B, there will be up to 3 cohorts (Cohorts 4, 5 
and 6), each cohort will consist of 8 healthy participants. Participants will only participate 
in one cohort. In each cohort, participants will be randomized to receive repeat doses of 
either GSK3186899 or placebo, administered in a 3:1 ratio according to the 
randomization schedule in a blinded manner. For BID dosing, GSK3186899 or placebo 
will be administered using a 12hr dosing interval. If another dosing regimen is selected 
for Part B based on emerging data, the interval between doses is outlined in Appendix 5.


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Participants will receive each dose after either fed or fasted conditions, dependent upon 
the interim results from Part A. If under fasted conditions, participants will be required to 
fast at least 2 hours before and after drug administration. Up to a maximum of 3 dose 
levels will be studied in Part B as illustrated below:
Figure 2
Study Design (Part B)
DL = Dose level; A = Active; P = Placebo
Sentinel Dosing: We will stagger each new dose level in Part B so that the first 2 
participants will act as sentinels. On Day 1 until Day 10, 1 of the 2 sentinel participants 
will receive the active dose twice daily and the other will receive placebo twice daily. 
Once these participants have completed their first 5-days of dosing, the safety and 
tolerability data will be reviewed by the Principal Investigator. If there are no clinically 
relevant safety or tolerability concerns (e.g. vital signs, ECGs and AEs) in the judgement 
of the Principal Investigator, the remaining 6 participants can then be randomized to 
dosing.


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Table 2
Study Duration of Cohorts 4-6
Screening
All screening assessments to be completed within 28 days prior to 
first-dose. 
Treatment Period
Each Cohort will consist of a 10-day treatment duration (Days 1-10), 
with participants in-house for 14 nights and 15 days. Participants will 
be admitted to the unit the day before dosing (Day -2) and will remain 
in the unit overnight until Day 13, when they will be discharged after 
completion of all assessments. 
Follow-up
At least 14 days and no greater than 21 days after last study drug 
administration. If warranted, additional follow-up visits may be 
scheduled. 
Total duration
Approximately 8-9 weeks 
5.2.
Number of Participants
A sufficient number of participants will be screened to ensure that a planned minimum of 
54 are eligible to be randomized (Part A: 8 participants into each of Cohorts 1-2 and up to 
14 participants for Cohort 3; Part B: 8 participants into each of Cohorts 4-6). A 
participant is considered evaluable if they complete both screening and at least one 
treatment period in Part A, or the 10-day treatment period in Part B. Participants that take 
part in Part A of the study cannot participant in Part B.
If participants prematurely discontinue the study, then additional replacement participants 
may be recruited and assigned to the same treatment sequence, at the discretion of the 
Sponsor in consultation with the Principal Investigator, in both Parts A and B.
5.3.
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 scheduled procedure shown in the SoA (Section 2).
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 SoA for the last participant in the trial.
5.4.
Scientific Rationale for Study Design
This study will be the first administration of GSK3186899 in human participants. The 
primary purpose of the current study is to characterise the safety and tolerability of 
GSK3186899 in healthy participants within a controlled PK range. The study will
additionally seek to understand the secondary and exploratory endpoints. Specific 
scientific considerations which contribute to the study design include:

In Part A, this study employs a randomized sequential crossover design to allow 
for dose comparison between and within participants at different dose levels. In 
addition, this design minimises participant numbers across the SAD part of the 


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study and allows for a shorter washout period between doses of an individual 
Cohort as the estimated half-life of GSK3186899 is ~1.3 hours. 

In Part A, the study employs a repeat of Dose Level 4 in Cohorts 1 and 2, the 
rationale for this is to understand potential variability of drug exposure between 
different cohorts of participants as the projected bioavailability for GSK3186899 
varies between 4-100%. 

Further, a food-effect evaluation is planned to support progression into patient 
studies. An assessment of food effect on the exposure to GSK3186899 will be 
incorporated into the single dose part of the study (Part A). Preliminary 
assessment of food-effect hinted a marginal decrease in the drug exposure which 
could possibly be attributed to high stomach solubility in the fasted acidic 
stomach that is not present in the fed state due to a higher pH. In the presence of 
food, the exposure may be slightly lower or the same in terms of overall trend. 
Please see Section 10.2 for further details on how sample size was determined for 
the food effect cohort. The exact sample size for the evaluation of the food effect 
will be determined based on the variability of the AUC and Cmax observed in 
Cohorts 1 and 2. Up to a maximum of 14 participants will be recruited to allow 
for 12 evaluable participants, however as few as 10 evaluable participants may be 
required, in which case the number of participants recruited could be slightly 
lower. The dose to be determined with food will be selected such that, if there is a 
change in exposure, it would be anticipated to be around the therapeutically 
relevant dose and within safety margins. Participants will receive an adapted
standard meal containing a 35-40% fat content. In Part B, the 10-day BID dosing 
will enable assessment of exposure at PK steady state and will also be informative 
of the likely safety and tolerability in future longer studies.

To characterize potential biliary elimination pathways, this study will also employ 
the Entero-Test for sampling of bile to conduct qualitative assessment of drug 
metabolites in this matrix (Part A, Cohort 3). The Entero-Test is an easy-to-use, 
well tolerated and minimally-invasive method for sampling small volumes of bile 
(ca. 1 mL) from the duodenum. Entero-Test is a FDA approved device for human 
non-invasive sampling of upper gastrointestinal content. Information on the 
biliary disposition of drug-related material derived in the current study may avoid 
the need for invasive methods of bile collection in future studies. Details of bile 
Entero-Test sample collection, processing, storage, and shipping procedures will 
be detailed in the SRM.

Part B is designed to be a repeat dosing part of the study with an intention of 10-
day dosing to support the proposed clinical duration of treatment. GSK3186899 is 
proposed for VL oral short therapy. This study design will provide exposure to 
PK steady state and will be informative for any future longer studies in humans. A 
flexibility is built into this part of the study to determine the required frequency of 
dosing (e.g. Twice-daily [BID] or Three-times daily [TID]) and alter the dosing 
regimen as appropriate based on emerging PK data from part A of the study. 


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5.5.
Justification for Dose
5.5.1.
Human Predicted Pharmacokinetics
The preclinical PK data (mouse, rat and dog) was used to predict human blood 
pharmacokinetic (PK) parameters. Briefly, mouse, rat and dog in vitro and in vivo ADME 
datasets were employed to get the human PK estimates using various scaling approaches 
detailed elsewhere [In Vitro to In Vivo Extrapolation (IVIVE), allometry, Physiologically 
Based Pharmacokinetics (PBPK) using CloePK and Wajima transform of in vivo profiles] 
(N26988-33). 
An average clearance (CL) of 7.3mL/min/kg and steady state volume of distribution 
(VDSS) of 0.8L/kg are used as the human predicted final blood PK parameters from the 
overall predictions. A conservative value of 50% bioavailability (F) has been used for 
human PK calculations given a range of bioavailability values from 4 to 100% observed 
across the preclinical species [GlaxoSmithKline Document Number 2018N372131_00]. 
A first order absorption rate constant (KA) of 0.7h-1 was assumed based on data from 
formulations with immediate release profiles. CL and V are scaled to humans assuming a 
70kg typical subject. The human PK profiles were simulated using a population PK 
analysis approach assuming relevant inter-individual variabilities (IIVs – log normal 
distribution) around the PK parameters as shown in Table 3. Briefly, 1600 participants 
(with varying body weight) were simulated 20 times resulting in 32000 participants with 
CL and V scaled to body weight using the allometric exponents of 0.75 and 1, 
respectively. Maximum blood concentration (Cmax) was determined from the maximum 
simulated concentration and area under the blood concentration curve from time zero to 
24h (AUC0-24h) was calculated using the trapezoidal rule. 
Table 3
Predicted human blood PK parameters for GSK3186899 that were 
employed for simulation of human PK profile
Parameter
Predicted Value
%CV#
Clearance (mL/hr/kg)
438
50
Vdss (mL/kg)
800
30
KA (hr-1)
0.7
10
F (%)
50
NA
# assumedvariability for human PK simulation; NA not applicable
5.5.1.1.
Background on Pharmacology for Human Dose Selection
CRK12 is a key target for GSK3186899. In the in vitro whole cell intracellular 
amastigote assay, GSK3186899 showed a parasitic potency of 400 nM (197 ng/mL) and 
has similar activity to standard of care (SoC) miltefosine when tested in whole cell in 
vitro intracellular amastigote assay as stated in the IB [GlaxoSmithKline Document 
Number 2018N372131_00]. Further, GSK3186899 has shown comparable or more 


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potent activity to miltefosine against isolated clinical strains in mouse macrophages and 
~9-fold more potent activity to miltefosine against a panel of strains in human 
macrophages as per the IB [GlaxoSmithKline Document Number 2018N372131_00]. In 
addition, when tested in the in vivo mouse efficacy models, GSK3186899 achieved 
similar potency to miltefosine (i.e. >95% reduction of parasite load at 25 mg/kg BID for 
10 days). A whole blood concentration was used as surrogate marker of PK at bio-phase 
for human dose prediction. Thus, the desired whole blood concentration PK profile (in 
terms of AUC0-24h) that achieves >95% parasite reduction in BalbC mouse model will 
be leveraged for human dose selection. [Dorlo, 2012] and [Dorlo, 2014] have published a 
description of the clinical efficacy of miltefosine and its association with drug exposures
which has been used to determine the relevance of mouse efficacy model for human 
translation 
as 
described 
elsewhere 
[GlaxoSmithKline
Document 
Number 
2018N372131_00]. No prior data exist for relevance of time over a minimum 
concentration (e.g. IC50) in BalbC mouse for drugs with similar target to GSK3186899 
as the target is novel for visceral leishmaniasis (VL). Human PK projections were done 
assuming BID. dosing (12h) similar to the protocol utilized for the efficacy model in 
female BalbC mouse. Figure 3 shows the exposure (or dose)-response relationship 
between blood AUC0-8h and % reduction of parasitemia. From this relationship, a range 
of target AUC’s can be derived for efficacy consideration as shown in Table 4. For 
simplicity, we approximated observed blood AUC(0-8h) values with blood AUC(0-12h) 
in the mouse to make it simpler to leverage to humans; and this is justifiable given the 
extrapolated AUC from 8-12h is negligible (~1%). Figure 4 shows human predicted 
blood AUC0-24h and Cmax values for a range of human doses from 5 mg to 2500 mg 
doses with anticipated variability assuming two scenarios of dose-independent F (F=0.5 
across doses) and dose-dependent F [F=0.5-((0.3*dose)/(300+dose)) based on solubility 
limited decrease in absorption]. Dose selection for GSK3186899 will be based on blood 
target AUC0-24h values based on mouse efficacy data from minimal to maximum 
pharmacology (Figure 3). Table 4 shows the assumed mouse doses to predict target blood 
AUC0-24h values [using the relationship between doses (x) and AUC(0-12h)(y) as 
y=326.27*x-1057.9] and target blood AUC0-24h as 2XAUC0-12h with minimal to 
maximal pharmacology in terms of % suppression of parasitemia along with average 
steady state concentration (Css) values in relation to in vitro IC50 value (197 ng/mL). 


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Figure 3
GSK3186899 dose (or blood exposure [AUC0-8h])-response 
relationship in in vivo efficacy evaluation of parasitic reduction 
using female BalbC mouse model.
Table 4
Target blood AUC’s from the mouse efficacy model for achieving 
various levels of % parasite reduction and the associated steady 
state average (Css) concentrations in relation to IC50 value (197 
ng/mL)
Assumed 
Mouse Dose 
(mg/kg) 
Target Blood 
AUC(0-12 h)
(ng.h/mL)
Target Blood 
AUC(0-24 h) 
(ng.h/mL)
Css 
(ng/mL)
X IC50
(Css as fold 
of IC50)
4.5
417
833
35
0.18
5.8
833
1667
69
0.35
8.4
1667
3333
139
0.70
16.0
4167
8334
347
1.76
28.8
8333
16667
694
3.53
54.3
16667
33333
1389
7.05


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Figure 4
GSK3186899 predicted human systemic blood exposures (AUC0-24h & 
Cmax) at various doses with anticipated variability assuming two 
scenarios of dose-independent and dose-dependent bioavailability 
(F)
5.5.1.2.
Human Starting Dose Determination
The proposed starting dose is based on anticipated minimum pharmacological activity 
looking at the derived blood AUC0-24h (~2XAUC0-12h) exposures on the exposure-
response relationship from the BalbC mouse efficacy data with an additional 
consideration of uncertainty in assumed bioavailability given the preclinical 
bioavailability range of 4 – 100%. Based on the observed exposures from emergent 
clinical data for a starting dose of 30 mg, appropriate changes to the proposed nominal 
doses will be made during the dose escalation. There were considerable margins of safety 
to the NOAEL exposures (NOAEL dose is 100mg/kg/day based on 28-day GLP 
toxicological study evaluation in female rat) for the starting dose (528-fold for plasma 
AUC0-24h) with consideration of 50% bioavailability (264-fold margins of safety even 
with 100% assumption of bioavailability for 30 mg starting dose). Further, the reported 
off-target pharmacology [few kinase targets e.g. MAPK11(IC50=0.39µM), NLK 
(0.62µM), MAPK14 (1.2µM)   and CDK7(2.4µM)] and hGABA inhibition was found to 
be of less concern at clinically relevant concentrations and further supported from general 
toxicology studies (antagonist of the human GABAA (132) channel at 100 µM but 
not at 5 and 1.5 µM; no CNS-related effects in single and repeat dose in vivo rat and 
monkey studies). The p38/MAPK signalling pathway is known to participate in cell 


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proliferation, apoptosis, migration and differentiation.  Additionally, knockout models for 
a number of these targets have highlighted the theoretic potential for embryolethality 
and/or teratogenicity.  Due to the inconsistent in vitro activity data sets using 
GSK3186899 and lack of related findings in subsequent in vitro studies and animal in 
vivo studies using GSK3186899, these kinase data are considered unlikely to have human 
relevance.  Given the wide margins of safety to NOAEL exposures and with appropriate 
safety mitigation plans in place, the currently proposed starting dose is robustly 
justifiable. In addition, the currently proposed starting dose is approx. 36-fold lower than 
human equivalent dose (HED) calculated for a 70kg human body weight as per (FDA 
Guidance, 2005) using the formula HED (mg/kg) = female rat NOAEL dose (100 mg/kg) 
X [Rat weight in kg (0.25kg) / human weight in kg (70kg)] ^0.33.
5.5.1.3.
Human Anticipated Therapeutic Dose Determination
A target blood exposure of 7632 ng.h/mL [approx. AUC(0-12h)], corresponding to plasma 
AUC0-12h of 12.745 µg.h/mL (i.e. plasma AUC0-24h of 25.49 µg.h/mL following a 25 
mg/kg dose of GSK3186899 to BalbC mice [GlaxoSmithKline Document Number 
2018N377947_00]) will be leveraged to select plausible therapeutic doses for humans. 
These estimates were determined from the data obtained after 10 days treatment of BalbC 
mouse, after which efficacy has been demonstrated. An estimated dose of 600mg 
b.i.d./day was predicted to provide a plasma AUC0-24h of 31.95 µg.h/mL) on day 10 (> 
mouse target plasma AUC0-24h of 25.49 µg.h/mL). Hence, a dose of ~600 mg b.i.d/day 
was considered as anticipated therapeutic dose (ATD) assuming a dose-independent 
bioavailability (F). However, if during dose escalation, clinical doses show a dose-
dependent F, similar exposure are also expected to occur at a dose of 1200mg BID/day.
5.5.2.
Maximum SAD Dose Determination
A nominal maximum SAD dose of 2500mg is proposed for this study to achieve >target 
plasma AUC0-24h for maximum pharmacology. This is based on the consideration that if 
a dose-dependent bioavailability decrease is observed as per the simulations presented, 
then a nominal dose of 1200 mg BID will be anticipated to produce desired therapeutic 
effect. If 1200 mg BID is ATD, then to support this dose in multiple ascending dose 
(MAD) study, exposures coverage from nominal SAD dose is desired. Hence, a 
maximum nominal SAD dose of 2500 mg is considered in this FTIH to support the 
development of GSK3186899. Accumulation following repeat dosing is not evident from 
simulations. The exposures from this dose have several-fold margins to the NOAELs 
from female rat (with dose independent F: 3-fold for Cmax & 7-fold for AUC0-24h; with 
dose dependent F: 7-fold for Cmax & 14-fold for AUC0-24h). The nonclinical data 
support the conduct of clinical studies in healthy volunteers up to 3 weeks duration up to 
3-fold below the mean systemic exposure at the female NOAEL of 100 mg/kg/day in the 
rat 4-week study (AUC:  434 g.h/mL, Cmax:  46.2 g/mL) with appropriate monitoring 
in place. The dose escalation will proceed up to nominal top dose of 2500 mg in dose 
independent F scenario to provided PK stopping criteria is not met; considering the 
PKPD variability and translational uncertainty of the preclinical data to provide flexible 
dosing regimen option. 


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5.5.3.
Dose Escalation Plan
The dose escalation will follow a scheme as shown in Table 5 with target plasma AUC0-
24h determined from the dose-response relationship from the BalbC mouse efficacy 
model. Based on the exposures from starting dose, appropriate modifications will be 
made to the subsequent proposed nominal doses. All available data will be evaluated for 
dose-escalation decisions. Based on emerging clinical data, appropriate changes to the 
dose-escalation step-size will be made. The decision to dose escalate, or to halt 
escalation, will be made by the DEC and will be guided by the safety and SAD PK 
stopping criteria as outlined below ‘Dose escalation/stopping criteria’.
5.5.4.
Safety Margins
Table 5 below lists the predicted safety cover for GSK3186899 at various anticipated 
doses in the SAD FTIH study assuming dose independent and dose dependent 
bioavailability, respectively, and indicate that the anticipated doses have several-fold 
margins of safety to the NOAEL exposures from female rat:
Table 5
Projected mean plasma GSK3186899 AUC0-24h and Cmax assuming 
dose-independent and dose-dependent bioavailability (F) scenarios 
following single oral doses of GSK3186899, with Fold Cover to 
preclinical NOAEL exposures alongside showing the nominal SAD 
doses with the fold dose-escalation
Dose 
Level
Dose#
(mg)
Fold 
Escalation
Predicted Human Plasma 
Exposures*
Safety 
Margins 
(AUC0-24h)
Safety 
Margins 
(Cmax)
AUC0-24h
(µg.h/mL)
Cmax 
(µg/mL)
Dose 
IDP 
F
Dose 
DP 
F
Dose 
IDP 
F
Dose 
DP
F
Dose 
IDP 
F
Dose 
DP 
F
Dose 
IDP 
F
Dose 
DP 
F
1
30
-
0.82
0.78
0.16
0.15
528
558
283
299
2
60
2
1.61
1.45
0.33
0.29
269
299
142
158
3
120
2
3.23
2.68
0.65
0.54
134
162
71
86
4
300
2.5
8.23
5.76
1.64
1.14
53
75
28
40
5
600
2
16.59
9.96
3.28
1.97
26
44
14
23
6
1200
2
32.77
17.04
6.55
3.41
13
25
7
14
7
2500
2.1
68.72
31.91
13.66
6.34
6
14
3
7


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Key: 
IDP = independent; DP = dependent; F = bioavailability
#Actual doses may be altered based on emerging PK data
*The predicted human exposures are in blood and the animal exposures are in plasma. 
Human Blood to plasma ratio (B/P ratio = 0.60) is used for conversion of predicted blood 
exposures (X1.67) to obtain human plasma exposures.
NOAEL exposures in Female rat: AUC = 434 µg.h/mL; Cmax = 46.2 µg/mL. Safety margin = 
NOAEL exposure parameter value/predicted human plasma exposure parameter.
5.5.5.
Multiple Ascending Dose (MAD)
Three dosing cohorts will be used for MAD. The selection of appropriate daily doses will 
be performed upon consideration of available safety, tolerability and PK data from SAD 
part and/or any preceding repeat dose cohorts in MAD and limiting exposure to be no 
less than 5-fold below the NOAEL of the rat 28-day toxicity study (AUC:  434 g.h/mL, 
Cmax:  46.2 g/mL). Twice-daily (BID) dosing is currently planned for MAD, but other 
dosing options may be considered based upon the safety/tolerability 
and 
pharmacokinetics observed in SAD part. For MAD dose selection, three doses based on 
exposures from SAD that support single/repeated dosing will be chosen identifying 
maximum anticipated therapeutic dose. Once this dose is identified, three cohorts will be 
chosen for the MAD doses: cohort 1 (0.5X anticipated therapeutic dose), cohort 2 (0.75X 
maximum anticipated therapeutic dose) and cohort 3 (maximum anticipated therapeutic 
dose). It should be noted that calculated steady state plasma AUC0-24h exposure on day 10 
will be used as part of PK stopping criteria following repeat dosing. PK sampling is 
proposed for 0-12h for BID dosing or 0-7h for TID dosing on day 10 at steady state; 
hence AUC0-24h (day 10) will be derived as 2XAUC0-12h or extrapolated AUC0-8hX3 
for BID or TID dosing, respectively.
5.6.
Dose Escalation 
As part of this decision-making process, the DEC may decide to escalate or de-escalate 
the dose in Part A and/or B. The dosing schedule may also be adjusted to expand a cohort 
to further evaluate safety or PK findings at a given dose level, or to add cohorts to 
evaluate additional dose levels. Dosing may also be halted before all planned dose levels 
have been completed if the stopping criteria has been met or if review of the data 
determines that evaluation of further dose levels is not necessary to meet the study 
objectives.
There will be an open and closed part to the dose escalation meeting. At the beginning of 
the meeting blinded data will be discussed in an open forum with the Principal 
Investigator in attendance. If required, the data will then be reviewed in an unblinded 
fashion by the unblinded members of the DEC. These unblinded members include the 
clinical pharmacology modeling and simulation department (CPMS) pharmacokineticist
and GCSP representative. 


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5.6.1.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK3186899 in each Cohort will be 
made by a DEC consisting of the Principal Investigator (or appropriate designee), 
Medical Monitor, GSK Clinical Investigational lead and/or Study Team Leader, GSK 
pharmacokineticist, a GSK GCSP representative and GSK Statistician. All GSK 
personnel will remain blinded throughout the course of the study, with the exception of 
the CPMS pharmacokineticist and GCSP representative. Additional internal GSK safety 
representatives may be consulted and included in the dose escalation decision making, as 
deemed necessary by the DEC. 
Details of the DEC membership, data to be reviewed and stopping criteria will be 
outlined in the DEC charter.
5.6.2.
Part A
Dose escalation meeting: The decision to proceed to the next dose level of GSK3186899
will be made at a DEC meeting based on:

all available safety and tolerability data from a minimum of 48 hours post-dose 
from a minimum of 4 or more participants who have received GSK3186899 at the 
current dose level. Individual safety data (AEs, laboratory safety tests, telemetry, 
ECGs and vital signs) will be reviewed.

all available safety and tolerability data accumulated from preceding dose levels 
and available PK data from current (minimum of 4 or more participants) and 
preceding dose levels.
Safety review meeting: The decision to proceed from Cohort 1 Period 4 (DL4) to Cohort 
2 Period 1 (DL4), and Cohort 3 Period 1 (DLX) to Cohort 3 Period 2 (DLX-FD) will be 
made by the Principal Investigator and Medical Monitor based on:

all available safety and tolerability data from a minimum of 48 hours post-dose 
from a minimum of 4 or more participants who have received GSK3186899 at the 
current dose level. Individual safety data (AEs, laboratory safety tests, telemetry, 
ECGs and vital signs) will be reviewed.
5.6.3.
Part B
A DEC meeting based on all available safety, tolerability and PK data accumulated from 
Part A of the study and the dose modification / stopping criteria will be used to decide:
-
The progression to Part B
-
The starting dose level of Cohort 4
-
The dosing regimen of Part B
-
Whether dosing will be in a fed or fasted state


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The decision for the next repeat dose level Cohorts (Cohort 5 onwards) will be made at a 
DEC meeting following completion of a minimum 10 days dosing in no fewer than 4 or 
more participants from the previous repeat dose cohort and will be based on:

assessment of safety, plasma GSK3186899 PK concentrations obtained from a 
minimum of 4 or more participants from the previous repeat dose cohort. 
Individual safety data (AEs, laboratory safety tests, ECGs and vital signs) will be 
reviewed.

evaluation of all available safety, tolerability and PK data accumulated from the 
previous repeat dose cohort.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1.
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.
Healthy as determined by the Investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the normal reference 
range for the population being studied may be included only if the Investigator in 
consultation with the Medical Monitor (if required) agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Note: Screened subjects with laboratory values outside of the normal range may be 
repeated once for inclusion into the study at the discretion of the Investigator.
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 18.5 - 28 kg/m2
(inclusive).


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SEX
4.
Male and/or Female Subjects
a. Male participants:
A male participant with a female partner of reproductive potential must agree to use 
contraception as detailed in Appendix 4 of this clinical study protocol during the 
treatment period and for at least 90 days after the last dose of study treatment and 
refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WONCBP) as defined in Appendix 4.
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 ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
History or presence of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
Previous history of leishmaniasis
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.
Current or past history of clinically significant gastritis or gastroduodenal ulcers or 
regular use of non-steroidal anti-inflammatory drugs (NSAID)
7.
QTc >450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), 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 


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MEDICAL CONDITIONS
discontinuation for an individual subject should be determined prior to initiation of 
the study. In other words, several different formulae cannot be used to calculate the 
QTc for an individual subject and then the lowest QTc value used to include or 
discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting and 
Analysis Plan (RAP).
PRIOR/CONCOMITANT THERAPY
8.
Past or intended use of over-the-counter or prescription medication, including herbal 
medications, NSAIDs, PPIs or anti-H2 antagonists within 7 days (or 14 days if the 
drug is a potential enzyme inducer) or 5 half-lives (whichever is the longest) prior to 
dosing. Other concomitant medication may be considered on a case by case basis by 
the investigator in consultation with the medical monitor.
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 a 56-day period.
10. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
11. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
12. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator or GSK Medical Monitor, 
contraindicates participation in the study.
13. Regular use of known drugs of abuse.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
14. Subjects with renal function defined as Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) with an age appropriate GFR ≤90 (ml/min/1.73m2).
15. Presence of Hepatitis B surface antigen (HBsAg) or Positive Hepatitis C antibody 
test result at screening.
16. Positive human immunodeficiency virus (HIV) antibody test.
17. Positive pre-study drug/alcohol screen.
18. Presence of clinically significant haematuria and/or proteinuria. 


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19. Carbon monoxide levels indicative of smoking or history or regular use of tobacco-
or nicotine-containing products within 3 months prior to screening.
20. Abnormally low blood pressure as determined by the Principal Investigator
21. Part A (Food Effect) Cohort 3 only: Participant must have no dietary restrictions 
(e.g., lactose intolerance) or inability to eat an adapted standard meal (includes 35-
40% fat content).
22. Part A (Food Effect) Cohort 3 only: History of gall bladder surgery or gall bladder 
removal, or history of an acute disease state (e.g. cholelithiasis) within 14 days prior 
to receiving the study treatment.
23. Part B only: Early morning cortisol < 420 nmol/L and inadequate response (rise of 
<250mmol/L from baseline) to ACTH stimulation test at Day -1.
6.3.
Lifestyle Considerations
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to 
each first dose of study treatment in Part A up until discharge from the unit. In Part 
B, participants must refrain from consumption of red wine, Seville oranges, 
grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit 
juices from 7 days prior to the first dose of study treatment until after the final dose.

For cohort 3 of Part A, after an overnight fast of at least 8 hours, participants should 
start eating their breakfast 30 minutes prior to the dose of study drug and should 
consume the entire breakfast within 25 minutes. The study drug should be 
administered within 5 minutes of the completion of the meal. Participants will 
receive an adapted standard breakfast. 8 fl oz (240ml) of water is to be taken at the 
time of dosing. Water is allowed ad libitum up to 1 hour before dosing and from 1 
hour after dosing.
6.3.2.
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 PK sample.
During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample. 
Use of tobacco products will not be allowed from 3 months prior to screening until 
after the final follow-up visit.


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6.3.3.
Activity and Travel

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).

Participants must not have travelled to an area (as determined by the investigator) 
with a high prevalence of leishmanial/parasitic infections in the 6 months before 
screening or intend to do so in the 3 months after the final dose of study treatment. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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 at the discretion of the Principal Investigator, and Medical Monitor if 
required. Rescreened participants should be assigned a new participant number.
7.
STUDY TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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7.1.
Study Treatment(s) Administered
Study Treatment
Product name:
GSK3186899
Placebo
Formulation description
Spray dried powder 
Blend
Dosage form:
Powder in bottle 
(Extemporaneous 
Compounding)
Powder in bottle
(Extemporaneous 
Compounding)
Unit dose strength(s)/Dosage 
level(s):
full dose per bottle 
NA
Route of administration:
For oral use only
For oral use only
Dosing instructions:
Suspend in diluent and dose. 
Suspend in diluent and dose. 
Physical description:
White to slightly coloured
powder
White to slightly coloured 
powder
Diluent description:
A mixture of propylene glycol 
and water
A mixture of propylene glycol 
and water
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Study medication is supplied 
by GlaxoSmithKline
Method for individualizing dosage:
Site to assemble
Site to assemble
7.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. Only unblinded 
pharmacy site staff (or designees) may prepare the study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.


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7.3.
Measures to Minimize Bias: Randomization and Blinding
7.3.1.
Randomization
On Day 1, participants will be assigned a unique number (randomization number) in 
ascending numerical order. The randomization number encodes the participant’s 
assignment to either GSK3186899 or placebo, according to the randomization schedule 
generated prior to the study by the Statistics Department at GSK, using validated internal 
software. 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to the site.
Study treatment will be dispensed at the study visits summarized in SoA. Each participant 
will be dispensed blinded study treatment, labelled with his/her unique randomization 
number, throughout the study. Returned study treatment should not be re-dispensed to the 
participants.
In Part A (Cohorts 1 and 2) and Part B (Cohorts 4-6), participants will be randomized in a 
3:1 ratio to either GSK3186899 or placebo. In Part A Cohort 3, although all participants 
will receive GSK3186899, they will be randomized to either a fasted or fed regimen. The 
participants will be unblinded in this part of the study only. 
Once a randomization number has been assigned to a participant, it cannot be reassigned 
to any other participant.
Currently, there is no indication as to the taste of GSK3186899 administered as a 
solution. For this reason, participants receiving GSK3186899 or placebo as a solution (in 
any part of this study) may also need to consume a flavoured sweet (for example a hard 
boiled sweet) prior to and/or immediately following dosing, provided this does not 
interfere with ongoing monitoring or study procedures. The need for ongoing taste 
masking will be determined by the DEC.
7.3.2.
Blinding
This will be a double blind (sponsor unblind) study with respect to allocation of 
GSK3186899 or placebo to participants. The food effect part of the study will be open 
label.
The following will apply:

The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant as judged by the investigator.

Investigators have direct access to the participant’s individual study treatment.


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
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study.

The date and reason for the unblinding must be fully documented in the CRF.

A participant will be withdrawn if the participant’s treatment code is unblinded by 
the investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any participant with an SAE. If the SAE requires that 
an expedited regulatory report be sent to one or more regulatory agencies, a copy 
of the report, identifying the participant’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.

All GSK personnel will remain blinded throughout the course of the study, with 
the exception of the CPMS pharmacokineticist, GCSP representative and 
pharmacy site staff.
7.4.
Study Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive the study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of the study treatment and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study treatment.  Study site personnel will examine the bottle to 
ensure there is no remaining study treatment and will examine each participant’s 
mouth to ensure that the study treatment was ingested.
7.5.
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
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.


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Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements, NSAIDs, PPIs and anti-H2 antagonists) 
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 treatment 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.
7.6.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK, or with GSK3186899, 
after completion of the study because only healthy volunteers are eligible for study 
participation.
8.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
8.1.
Discontinuation of Study Treatment
Discontinuation of study treatment is considered “permanent”. Once a participant is 
discontinued, they shall not be allowed to restart treatment.
8.1.1.
Dose Adjustment/Stopping Pharmacokinetic Criteria
The following dose adjustment / PK stopping criteria will apply:

A maximum Cmax of 15.4µg/mL or 9.24µg/mL and a total daily AUC of 145 
µg.h/mL or 86.8 µg.h/mL for SAD or MAD part, respectively, will not be 
intentionally exceeded and will be used as safety threshold exposures for PK 
stopping criteria as per GSK renal safety panel recommendations. These exposures 
are 3-fold or 5-fold below the NOAEL exposures of 46.2 µg/mL for Cmax and 434 
µg.h/mL for total daily AUC in the 28-day female rat study for SAD or MAD part, 
respectively. 

Dose escalation will be stopped if any single participant reaches exposures greater 
than PK stopping criteria threshold exposures. We intend to use the PK dose 
escalation rule for progression to the next dose or dose adjustment which will 
involve establishing a relationship between dose vs. exposures (AUC0-24h & Cmax) 
using a power model and linear mixed effect modeling once PK data are available 
from a minimum of two prior dose levels. This model will be continually updated 
with incorporation of new dose levels as they become available. This developed 
model will be used to project mean AUC0-24h and Cmax for the next dose level.

If mean group exposure from the maximum total daily dose is predicted to reach the 
PK stopping criteria exposures, dose escalation will be stopped, or dose adjustment 
will be planned, as appropriate. For any dose adjustments for the next dose, an 
increase or decrease in the nominal dose will occur if the projected exposure for the 


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next dose deviates by more than 30% of the initial projected mean systemic 
exposure. The GSK study team will decide based on emerging safety, tolerability 
and PK information whether to evaluate any lower doses or repeat doses already 
evaluated in remaining periods to collect additional safety and PK data. 
8.1.2.
Dose Escalation / Study Progression Stopping Criteria
The Principal Investigator and the GSK Medical Monitor will review the following and 
study dosing will be stopped if any of these criteria is met:

Two or more participants in the same cohort experience a severe non-serious adverse 
reaction (i.e. severe non-serious adverse events considered as, at least, possibly 
related to the IMP administration), independent of within or not within the same 
system-organ-class. 

One or more participants in Part B develop clinical signs/symptoms compatible with 
adrenal insufficiency and meets the adrenal withdrawal criterion defined below 
(Section 8.1.4).

Two or more participants across all study parts develop an adverse renal event as 
defined in the renal withdrawal criteria below (Section 8.1.3). 

One or more participants from any dose level experiences a serious adverse event 
which has a reasonable possibility of relation to study drug.
The dose escalation/study progression will be temporarily halted, and no further dosing 
will occur until a full safety review of the study has taken place. Relevant reporting and 
discussion with the GSK medical monitor, relevant GSK personnel, regulatory authorities
and the Independent Ethics Committee will then take place prior to any resumption of 
dosing.
All other stopping criteria will apply even if no PK stopping criteria have been met. 
8.1.3.
Renal Withdrawal Criteria
A participant that meets any of the following bulleted criteria will be withdrawn from the 
study:

New onset of any clinically significant and persistent haematuria / proteinuria (Spot 
Urine Protein Creatinine (UPC) ratio >0.5) in the absence of another clinical 
explanation e.g. calculus / infection. If trace proteins are detected, repeat test should 
be performed within 24 hours.

If there is any change in serum creatinine > 26 µmol/L (0.3 mg/dl) from baseline or > 
50 % from baseline. If change in serum creatinine measures at > 26 µmol/L (0.3 
mg/dl), repeat within 24 hours. If confirmed, the participant will be withdrawn, and 
further investigations will be performed.

Persistent hypophosphataemia (less than 0.8mmol/L) confirmed by repeat testing. If 
a participant meets the withdrawal criteria for hypophosphataemia, then further 
investigations will be performed.


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8.1.4.
Adrenal Withdrawal Criteria (Part B only)

A participant that develops adrenal insufficiency will be withdrawn from the study. 
Adrenal insufficiency is defined by an early morning serum cortisol < 420 nmol/L 
and following an ACTH stimulation test, serum cortisol does not rise by >250 
nmol/L from baseline. Any case of adrenal insufficiency will be referred to an 
endocrinologist for confirmation.
8.1.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm, or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 
Refer to Appendix 6 for follow-up assessments in the event of a participant meeting the 
liver stopping criteria.
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
8.1.6.
QTc Stopping Criteria
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  


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
QTcF > 500 msec,

Change from baseline: QTc > 60 msec

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 average of triplicate ECG readings obtained over a brief (e.g., 5-10 minute) 
recording period.  

Withdrawal of participants is to be based on an average QTc value of triplicate 
ECGs. If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs 
over a brief period of time and then use the mean QTc values of the 3 ECGs to 
determine whether the participant should be discontinued from the study.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.7.
Individual Safety Stopping / Withdrawal Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

If any of the liver chemistry, QTc, renal and/or adrenal stopping criteria are met
(See Section 8.1.3 -Section 8.1.6).

The participant develops stomach erosion as confirmed clinically and following a 
gastro enterology specialist’s opinion for further management, and endoscopy (if 
required).
8.1.8.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomized participants will 
be regularly reviewed by the DEC in order to ensure appropriate subject safety. Any 
changes to the study due to safety reasons will be promptly communicated to the 
appropriate Regulatory Authorities and Independent Research Ethics Committee.


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8.1.9.
Study Treatment Restart or Rechallenge
If any stopping criteria are met by any participant in this study, study treatment restart or 
rechallenge is not allowed.
8.2.
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.

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 and follow-up and for any further 
evaluations that need to be completed.

The participant will be permanently discontinued both from the study treatment
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.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.


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9.
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 treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.1.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.1.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and 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.


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
Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

In Part A and B on Day 1, vital signs (to be taken before blood collection for 
laboratory tests) will consist of 3 pulse and 3 blood pressure measurements pre-
dose on Day 1 (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will 
be recorded on the CRF.
9.1.3.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 2) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 8 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained at least 2 minutes apart but no more than 10 minutes 
apart. 

Continuous cardiac telemetry will be performed in supine position after at least 
5 minutes rest at the time points indicated in the SoA (Section 2).  Full 
disclosures will be reviewed in detail and the review maintained as part of the 
subject’s source documents.
9.1.4.
Holter Monitoring
Holter monitoring will be performed at screening only. This 48-hour Holter ECG will be 
performed to eliminate participants with non-clinically overt cardiac arrhythmias. If 
necessary, additional or extended monitoring (e.g., telemetry or Holter) may be 
performed at the Investigator or Sponsor’s discretion to further characterize any emerging 
safety signals.
9.1.5.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
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 should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 


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
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.

All protocol-required laboratory assessments (including tests for urine trace 
proteins and safety biomarkers), as defined in Appendix 2, must be conducted in 
accordance with the SRM and the SoA.
9.2.
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 treatment or the study, 
or that caused the participant to discontinue the study treatment or the study (see Section 
8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the 
sponsor.
9.2.2.
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.


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
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. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (namely stomach erosion, adrenal insufficiency or renal impairment as defined 
under the stopping and withdrawal criteria above), will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 3.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female 
partners of male participants will be collected after the start of study treatment
and until the final follow-up visit.

If a pregnancy is reported, the investigator should inform GSK within 24 hours
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.


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9.3.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat an overdose as and when they are made aware of this.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3186899 can no longer be detected systemically (at least 2 days).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Pharmacokinetics
9.4.1.
Blood Sample Collection

Plasma samples of approximately 1 mL (from 2 mL of blood) will be collected for 
measurement of plasma concentrations of GSK3186899 as specified in the SoA.
Plasma samples of approximately 2.5 mL (from 5 mL of blood) will be collected 
from time-points 12 hours and 24 hours post-dose in Part A.

Instructions for the collection and handling of biological samples will be provided 
in the SRM. The actual date and time (24-hour clock time) of each sample will be 
recorded.

Samples collected for analyses of GSK3186899 plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study.

Once the plasma has been analyzed for GSK3186899 any remaining plasma may 
be analyzed for other compound-related metabolites and the results reported under 
a separate protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.4.2.
Urine Sample Collection

Urine samples for analysis of GSK3186899 and its metabolites, or for safety 
biomarkers will be collected at the time-points listed in the SOA. The timing of 
urine samples may be altered and/or samples may be obtained at additional time 
points to ensure thorough PK and/or safety monitoring. 


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
Details of urine sample processing, storage and shipping procedures are provided 
in the SRM. 
9.4.3.
Entero-test: Bile Sample Collection
Bile samples will be collected on Day 1 for the analysis of GSK3186899 and any 
metabolites for participants in Part A Cohort 3 only. 
Bile fluid is recovered on a highly absorbent nylon line which is contained within a 
weighted gelatin capsule. The 140cm line unwinds after capsule swallowing, the capsule 
dissolves in the stomach and the line then passes into the duodenum. During withdrawal, 
the weighted section of the capsule separates from the line and passes in the stool. 
Additional details of the bile Entero-test sample collection, processing, storage and 
shipping procedures will be provided in the SRM.
9.5.
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study.
9.6.
Genetics
Genetics are not evaluated in this study.
9.7.
Pharmacological Biomarkers
Biomarkers are not evaluated in this study.
9.8.
Health Economics / Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GlaxoSmithKline. 
Reporting of study data will be performed in accordance with applicable GSK and/or 
contract research organization (CRO) standards.  
Complete details of the planned statistical analyses will be provided in the Reporting and 
Analysis Plan (RAP).
10.1.
Statistical Hypotheses
The focus of this FTIH study, both single and repeat dose phases, is to evaluate the 
safety, tolerability and PK of GSK3186899. As such no formal statistical hypotheses will 
be tested. 


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Where appropriate, an estimation approach will be taken, and point estimates and 
confidence intervals (CIs) will be constructed.
10.2.
Sample Size Determination
The planned sample size is up to 30 subjects for Part A of this study (8 subjects each for 
Cohorts 1-2 and up to 14 subjects for Cohort 3) and up to 24 subjects for Part B (8 
subjects per cohort). Additional subjects may be recruited as replacement for withdrawn 
subjects.
No statistical techniques were used to calculate the sample size for all cohorts except Part 
A Cohort 3, which was calculated based on the precision estimate for fed versus fasted 
and considering feasibility.
The objective of Part A Cohort 3 is to determine if GSK3186899 has a food effect and to 
inform the dosing regimen for Part B. A precision estimate was therefore used to 
determine the sample size, based on assumed within subject coefficients of variation 
(CVw) for AUC and Cmax (20% and 30% respectively). A maximum of 14 subjects will 
be recruited with the aim of getting evaluable data from 12 subjects. If the estimates for 
the CVw decrease following review of the data from Cohorts 1 and 2, then less subjects 
may be recruited, with the aim of obtaining as few as 10 evaluable subjects. The number
of planned evaluable subjects will not be less than 10, nor will the number of recruited 
subjects be greater than 14.
Assuming a point estimate for (fed versus fasted) of 1 (i.e. no food effect), under the 
variability assumptions described above, and a sample of 12 evaluable subjects, the 
precision estimates and 90% confidence intervals (CI) for AUC and Cmax are: 
Parameter
CVw
Sample size
Precision 
estimate
90% CI
AUC
20%
12
16%
(0.84, 1.19)
Cmax
30%
12
24%
(0.76, 1.32)
10.3.
Sample Size Sensitivity
For the assumed variability of AUC and Cmax respectively, the impact of different 
numbers of evaluable subjects on the precision estimates and 90% confidence intervals
were assessed. Results are presented in Table 6.


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Table 6
Sample size sensitivity for fixed within subject coefficient of 
variation
Parameter
CVw
Sample 
size (n)
Point estimate
(PE)
fed vs fasted
Precision 
Estimate
90% CI of PE
AUC
20%
6
1
26%
(0.74, 1.35)
8
1
21%
(0.79, 1.27)
10
1
18%
(0.82, 1.22)
12
1
16%
(0.84, 1.19)
14
1
14%
(0.86, 1.16)
Cmax
30%
6
1
41%
(0.59, 1.69)*
8
1
32%
(0.68, 1.47)
10
1
27%
(0.73, 1.37)
12
1
24%
(0.76, 1.32)
14
1
22%
(0.78, 1.28)
* Based on a CVw of 30%, it is estimated that for a sample size of 6 subjects, the lower bound of the 90% 
CI will be within approximately 41% of the point estimate and the upper bound of the CI within 68%, i.e. 
assuming a point estimate of 1 (i.e, no difference) the CI would be as wide as (0.59, 1.69).
10.4.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened 

All participants who were screened for eligibility
Enrolled

All participants who passed screening and entered the study. Included are: 
Randomized Participants
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.
Safety

All randomized participants who received at least one dose of study treatment.

This population will be based on the treatment the subject actually received.
Note: Participants who were not randomized but received at least one dose of study 
treatment should be listed.
PK

All participants in the Safety population who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-missing 
values).


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10.5.
Statistical Analyses
10.5.1.
Safety Analyses
The primary analyses are to evaluate safety and tolerability of single and repeat doses of 
GSK3186899. 
The safety population will be used for the primary analyses.
Endpoint
Statistical Analysis Methods
Primary
Safety and tolerability data comprising of 

adverse events

clinical laboratory safety data

vital signs

12 lead ECGs

24 hr telemetry
will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards by part. 
10.5.2.
Pharmacokinetic (PK) Analyses
All PK analyses will be performed on the PK Population. 
Endpoint
Statistical Analysis Methods
Secondary
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, (CPMS), GlaxoSmithKline. Plasma 
GSK3186899 concentration-time data will be analyzed by non-compartmental 
methods with WinNonlin 5.2 or higher.
From the plasma concentration-time data, the following PK parameters will be 
determined, as data permit: 

maximum observed plasma concentration (Cmax)

time to Cmax (Tmax)

area under the plasma concentration time curve [AUC(0-t), AUC(0-tau), 
and AUC(0-∞)]

apparent terminal phase half-life (t1/2)

trough concentration (Ctau). 
Trough concentration (Ctau) samples collected on the specified days may be used 


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Endpoint
Statistical Analysis Methods
to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed 
accumulation ratio for AUC ((RAUC(0-tau))), Cmax (RCmax) and Ctau (RCtau) may 
be determined.   
Statistical analyses of the pharmacokinetic parameter data will be the 
responsibility of Biostatistics, GlaxoSmithKline. No formal hypotheses will be 
tested. Pharmacokinetic data will be presented in graphical and/or tabular form 
and will be summarized descriptively. Full details on the statistical aspects will be 
detailed in the Reporting and Analysis Plan (RAP).
Food Effect (SAD part)
The effect of food on the pharmacokinetics of GSK3186899 will be examined. 
AUC(0-t), AUC(0-∞) and Cmax of GSK3186899 will be analyzed after a loge-
transformation of the data. An analysis of variance model will be fitted along with 
90% confidence intervals using a mixed effects model, with fed/fasted condition 
as a fixed effect and subject as a random effect. Point estimates and 
corresponding 90% confidence intervals will be constructed for the comparisons 
of interest of GSK3186899 fed – GSK3186899 fasted, using the residual 
variance. These will then be back-transformed to provide point estimates and 
corresponding 90% confidence intervals for the geometric mean ratios fed: 
fasted.
Dose Proportionality (SAD and MAD parts)
Dose proportionality will be assessed following single doses of GSK3186899
(SAD part) via analyses of AUC(0-∞) and Cmax. 
Dose proportionality following repeated dosing (MAD part) will be assessed using 
AUC(0-tau), Cmax and Ctau.
A statistical analysis will be performed using the power model. The analysis will 
be performed on loge-transformed data. For each of these parameters a mixed 
effects model will be fitted with loge (dose) as a fixed effect and individual subject 
fitted as random effects. Estimates of the mean slopes of loge (dose) will be 
reported along with corresponding 90% confidence intervals (slope≈1 implies 
dose proportionality).
Accumulation (MAD part)
The extent of accumulation of GSK3186899 will be based on AUC (RAUC(0-tau)), 
Cmax (RCmax) and Ctau (RCtau).
The focus of the statistical analysis will be to estimate the accumulation ratio, Ro, 
on the pharmacokinetics of GSK3186899. Following loge-transformation, AUC(0-
tau) on Day 1 and AUC(0-tau) on the day of last dose will be analysed by a mixed 


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Endpoint
Statistical Analysis Methods
effect model, fitting fixed effect terms for dose, day, and day by dose interaction, 
and fitting subject as a random effect.
For each dose, point estimates and 90% confidence intervals for the differences 
“Day 10 - Day 1” will be constructed using the appropriate error term. The point 
estimates and associated 90% confidence intervals will then be exponentially 
back-transformed to provide point and 90% confidence interval estimates for the 
ratios “Day 10: Day 1” for each active dose. If both the dose and day by dose 
interaction terms are not significant, a single point estimate and confidence 
interval pooled across all doses will also be constructed.
RCmax and RCtau will be estimated in a similar approach.
10.6.
Interim Analyses
No formal interim analyses are planned for this study. However, safety, tolerability, and 
PK data will be reviewed before each dose escalation in Part A (single dose) and Part B 
(repeat dose), prior to the investigation of the food effect and between Part A and Part B.
An informal interim analysis for Part A will be conducted prior to initiating Part B. This 
analysis will support the decision to progress or not progress to Part B and will consist of 
the following displays. Further details, including the function responsible for each 
analysis, will be detailed in the final RAP. The data in this analysis will include:

Listing and table to summarise demography, study disposition, and exposure

Listings for vital signs, ECG, lab, telemetry and AEs including vital signs and 
ECGs of Potential Clinical Importance

Table summarising AEs by SOC and PT

Listings for PK concentration-time data and PK parameters (log transformed and 
untransformed)

Figures for PK concentration-time data

Tables summarising PK parameters (log transformed and untransformed)

Analysis to determine the food effect of Part A Cohort 3
The Reporting and Analysis Plan will describe the planned informal interim analyses in 
greater detail.


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10.7.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.7.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical
principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.7.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.7.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.7.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.7.5.
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.


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
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.7.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.7.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

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).


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
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.7.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement.
10.7.9.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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10.7.10.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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10.8.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by The Doctor’s laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 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.
Table 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean Corpuscular 
Volume (MCV)
Mean Corpuscular 
Haemoglobin (MCH)
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT), Gamma 
GT
Total Protein
Glucose 
(Fasted2) 
Calcium
Alkaline 
phosphatase
Albumin
Magnesium
Phosphate
Creatine 
phosphokinase 
(CPK)
C-reactive protein 
(CRP)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)

Urine Protein : Creatinine ratio, if trace urine protein is identified by dipstick 

Urine creatinine


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Laboratory 
Assessments
Parameters

Urine phosphate
Safety 
Biomarkers4

Kidney injury molecule 1 (KIM1)

Neutrophil gelatinase-associated lipocalin (NGAL)

Urine albumin
ACTH test5

Cortisol 
Other Tests

Follicle-stimulating hormone and oestradiol (as needed in women of non-
childbearing potential only)

Alcohol breath test and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Serology (HIV 1 & 2 antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody). 

Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-
EPI formula
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.5. and Appendix 6.
2.
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).
3.
Non-fasted samples can be collected on Day -1 and at the Follow-up visit (All Parts).
4.
Safety biomarkers will be collected as urine samples.
5.
Cortisol test will be performed in Part B only
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.


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10.9.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.9.1.
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 treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.9.2.
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:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 


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jeopardize the participant or may require medical or surgical treatment to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.9.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


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10.9.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.


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10.10.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.10.1.
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 treatment, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, confirmation 
with more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt should be 
excluded from the study.


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10.10.2.
Contraception Guidance:
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the treatment phase and 
until at least 90 days after the last administration of study drug: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom with an additional method of contraception 
with a failure rate of <1% (see below) per year when having penile-
vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse 

In addition, male participants must refrain from donating sperm for duration of 
study and for 90 days after study completion.
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)c
Bilateral tubal occlusion
Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
oral


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injectable
Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)
10.10.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 


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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 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 
treatment or be withdrawn from the study.


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10.11.
Appendix 5: Part B Assessments Based on an Alternative Dosing Regimen
If an alternative dosing regimen to BID dosing is selected for Part B (i.e. once-daily or three-times daily), the following assessment 
timings will be used to align with the alternative dosing intervals. All other assessments for Part B will be conducted as scheduled in the 
SOA (Section 2.2). 
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose)
/Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
12-Lead ECG
X
X
T
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, temperature 
and respiration rate. BP will be conducted in 
both a supine and standing position if 
participant develops any signs/symptoms 
which in the investigators opinion are 
suggestive of adrenal insufficiency.
12-Lead ECG and Vital Signs to be 
conducted on Day-1 and pre-dose Day 1 and 
then at the subsequent time points post first-
dose: 
If, Once-daily dosing:
Day 1: pre-dose 30min, 1hr, 1.5hr, 2 hr, 2.5 
hr, 4hr, 6 hr, 24 hr, 
Days 3-10: pre-dose samples only.
If, Three-times daily (TID) dosing:
Day 1: pre-dose, the post-first dose at 30min, 
1hr, 1.5hr, 2 hr, 2.5hr, 4hr, 6hr
Then post second-dose: 1hr, 2hr
And post third-dose at:1hr, 2hr
Days 3-10: pre-dose samples only.
T = Triplicate (for all assessments except 
temperature and respiratory rate).
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose)
/Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
If any abnormal ECG reading is recorded, 
refer to Section 8.1.6 for appropriate action.
PK Blood 
sampling
X
PK samples will be collected at the following 
time points:
Once-daily dosing:
Day 1: Pre-dose, 10min, 30min, 1hr, 1.5hr, 
2hr, 2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, 12hr 
Days 2 – 9: Pre-dose PK samples collected 
Day 10: Pre-dose, 10min, 30min, 1hr, 1.5hr, 
2hr, 2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, 12hr
Day 11: 24hr sample post-dose from Day 10.
TID dosing:
Day 1: Pre-dose, 10min, 30min, 1hr, 1.5hr, 
2hr, 2.5hr, 3hr, 4hr, 5hr, 6hr, 7hr (pre-2nd
dose)  
Days 2 – 9: Pre-dose PK samples collected 
prior to the first-dose and second-dose
Day 10: pre-dose, then post first-dose at 
10min, 30min, 1hr, 1.5hr, 2hr, 2.5hr, 3hr, 4hr, 
5hr, 6hr, 7hr (pre-2nd dose). 
The time points stated may be modified 
depending on emerging SAD PK profiles.
Blood volumes to be collected include 2 mL 
for post-dose 0-11 hrs, and 5 mL for post-
dose 12-24 hrs. 
Study 
Treatment
X
X
X
X
X
X
X
X
X
X
Once daily dosing: GSK3186899 or placebo 
will be administered. 


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(14-21 days 
post last 
dose)
/Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
TID dosing: GSK3186899 or placebo will be 
administered using a 7 hr dosing interval 
between each dose.
Meals 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If on fed regimen (both once daily and TID 
dosing): On Day 1 through to D10, 
participants will receive an adapted standard 
meal 30 mins prior to dosing.
If on fasted regimen (once daily dosing):
On Day 1 through to D10, participants will 
have fasted 8hr overnight prior to dose 1. A 
breakfast will be served approximately 2hr 
after dose 1. Lunch, dinner and other snacks 
may be served as per the site schedule.
If on fasted regimen (TID dosing): On Day 
1 through to D10, participants will have fasted 
8hr overnight prior to dose 1. A breakfast will 
be served approximately 2hr after dose 1. 
Lunch and dinner will be served between 2 hr 
prior to dose 2 and 3, respectively. 
Participants will receive standardized meals 
scheduled at the same time in each period.
Meals will be served as per the site schedule 
on Days -1 and Days 11-13.
8 fl oz (240mL) of water to be taken after 
dosing and permitted on an ad lib basis 1hr 
before and 1hr after dosing.


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10.12.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
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

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hr

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 12 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 


2018N385133_01
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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hr

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
James, 2009]. NOTE: not required in 
China.

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 treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 


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10.13.
Appendix 7: Abbreviations and Trademarks
Abbreviations
µg
Micrograms
µmol
Micromolar
ACTH
Adrenocorticotropic hormone
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area Under the concentration time-curve
AUC(0 – ∞)
Area under the plasma concentration-time curve from time 
0 to extrapolated to infinity
AUC(0 – 12)
Area under the plasma concentration-time curve from time 
0 to 12 hrs
AUC(0 – 24)
Area under the plasma concentration-time curve from time 
0 to 24 hrs
BID
Twice-daily
BMI
Body Mass Index
BP
Blood Pressure
Cmax
Maximum Observed Concentration 
CHMP
Committee for Medicinal Products for Human Use
CONSORT
Consolidated Standards of Reporting Trials
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CPK
Creatine Phosphokinase 
CPMS
Clinical Pharmacology Modelling and Simulation 
Department
CRK12
CDC-Related Kinase 12
CRP
C-Reactive Protein
DEC
Dose escalation committee
dL
Decilitre
DL
Dose Level
DLX
Dose Level to be determined 
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EMEA
European Medicines Evaluation Agency


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FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular Filtration Rate
hr
hour(s)
HBsAg
Hepatitis B Surface Antigen
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Adrenal
HPLC
High Performance Liquid Chromatography 
HR
Heart Rate
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IRB
Institutional Review Board
KIM-1
Kidney Injury Molecule 1
kg
Kilograms
L
Litre
LDH
Lactate Dehydrogenase 
MAD
Multiple Ascending Dose
MCH
Mean Corpuscular Haemoglobin
MCV
Mean Corpuscular Volume
mg
Milligrams
min
Minute(s)
mL
Millilitres
mmol
Millimolar
NGAL
Neutrophil gelatinase-associated lipocalin
NOAEL
No Observable Adverse Effect Limit
PK
Pharmacokinetics


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QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate 
using Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate 
using Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells
RAUC
Relative Area Under the Curve
SAD
Single Ascending dose
SAE
Serious Adverse Event
SDD
Spray Dried Dispersion
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SOA
Schedule of Activities
SOP
Standard Operating Procedures
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Events
TID
Three-Times Daily
Tmax
Time Taken to Maximum Observed Plasma Drug 
Concentration
UK
United Kingdom
ULN
Upper Limit of Normal
VL
Visceral Leishmaniasis
WONCBP
Women of Non-Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
CloePK
Entero-Test
SAS
WinNonlin


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10.14.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).


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11.
REFERENCES
Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ. Optimal dosing of miltefosine in 
children and adults with visceral leishmaniasis. Antimicrob Agents Chemother. 2012 
Jul;56(7):3864-72.
Dorlo TP, Rijal S, Ostyn B, de Vries PJ, Singh R, Bhattarai N, et al. Failure of 
miltefosine in visceral leishmaniasis is associated with low drug exposure. J Infect Dis. 
2014 Jul 1;210(1):146-53.
FDA Guidance for industry: Estimating the maximum safe dose in initial clinical trials 
for therapeutics in adult healthy volunteers. 2005 
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf
GlaxoSmithKline Document Number 2018N372131_00 Investigator Brochure; 08 Jan 
2019
GlaxoSmithKline Document Number 2018N377947_00 Summary of the Preliminary 
Preclinical Pharmacokinetics and Drug Metabolism Studies Performed with 
GSK3186899A; 17 Aug 2018
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784

SAP_001.pdf: 
0 
 
 
 
Reporting and Analysis Plan 
Study ID:  208436 
Official Title of Study:  Reporting and Analysis Plan for a randomised, double-blind (sponsor unblinded), 
placebo-controlled, first time in human study to evaluate the safety, tolerability and pharmacokinetics 
of single (in both fed and fasted states) and repeat doses of GSK3186899 in healthy participants 
Date of Document: 21-Nov-2019 


Documentum Id :
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Date (UTC date)
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Documentum Name : 
GSK3186899-208436 Statistical Analysis Plan Reporting and Analysis Plan Version 001
(18-Nov-2019)
Sign  as Approver
19-Nov-2019 10:47:00 AM
Sign  as Approver
1.4
090f45f689e7c46d
21-Nov-2019 10:29:17 AM
PPD
PPD


Documentum Name : 
Documentum Id :
Documentum Version : 
Date (UTC date)
Signed by 
Justification 
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GSK Vaccines Controlled Document
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1.4
090f45f689e7c46d
GSK3186899-208436 Statistical Analysis Plan Reporting and Analysis Plan Version 001
(18-Nov-2019)


CONFIDENTIAL
208436
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a randomised, double-blind 
(sponsor unblinded), placebo-controlled, first time in 
human study to evaluate the safety, tolerability and 
pharmacokinetics of single (in both fed and fasted states) 
and repeat doses of GSK3186899 in healthy participants
Compound Number :
GSK3186899
Effective Date 
:
[15-NOV-2019]
Description:

The purpose of this reporting and analysis plan (RAP) is to describe the planned 
analyses and output to be included in the Clinical Study Report for Protocol 
208436, which is a first time in human (FTiH) study comprising of a single and 
repeat ascending dose regimens in healthy participants, incorporating a food effect 
component.

The key objective is to describe the safety, tolerability and pharmacokinetics of 
GSK3186899. Results from this study will also be used to identify appropriate and 
well tolerated doses of GSK3186899 and to investigate the influence of food on 
the PK of GSK3186899.

This full RAP will be provided to the study team members to convey the content 
of the reporting efforts planned for the study informal interim analysis and final 
analysis deliverables for the Statistical Analysis Complete (SAC).

All sections of the RAP have been populated in this version.


CONFIDENTIAL
208436
2
Author(s)
Author
Date
15-Nov-2019
Study Statistician (Statistics Manager, FPD Clinical Statistics)
16-Oct-2019
Clinical Pharmacokineticist (Scientific Director,
Quantitative Clinical Development (QCD), PAREXEL 
International)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
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RAP Team Review Confirmations (Method: E-mail)
Reviewer
Date
Project Statistician (Principal Statistician, FPD Clinical 
Statistics)
12-Nov-2019
Operational Study Lead and Clinical Investigation Lead 
(Clinical Development Manager, R&D PCPS GCDO Clinical 
Unit Cambridge)
16-Oct-2019
Medical Monitor (Head NCD Open Lab and Global Health 
Futures)
16-Oct-2019
Safety and Medical Governance (SMG) Pharma Safety 
(formerly GCSP) representative (SERM Director, SMG 
Pharma Safety)
16-Oct-2019
16-Oct-2019
DQL (Principal Clinical Data Manager, R&D PCPS GCDO 
DM FPD)
16-Oct-2019
Clinical Pharmacokineticist (Scientific Director
Quantitative Clinical Development (QCD), PAREXEL 
International)
Study Programmer (Principal Programmer, FPD Clinical 
Statistics)
16-Oct-2019
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
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Clinical Statistics & Clinical Programming Line Approvals (Method: Pharma TMF 
eSignature)
Approver
Date
To be updated after 
esigning is 
completed
Diseases of the Developing World (DDW) Statistical Lead
(Statistics Director, FPD Clinical Statistics)
To be updated after 
esigning is 
completed
Lead Programmers Line Manager (Programming Manager, FPD 
Clinical Programming)
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Analyses.....................................................................................12
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Interim Analyses .........................................................................................13
3.1.1.1.
Dose escalation meetings...........................................13
3.1.1.2.
Informal interim analysis.............................................14
3.1.1.3.
Safety review meetings ..............................................16
3.2.
Final Analyses ............................................................................................16
4.
ANALYSIS POPULATIONS ...................................................................................16
4.1.
Protocol Deviations.....................................................................................17
5.2.
Baseline Definitions ....................................................................................20
5.2.1.
Derivations and Handling of Missing Baseline Data.....................20
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................22
6.1.
Overview of Planned Study Population Analyses........................................22
7.
SAFETY ANALYSES .............................................................................................23
7.1.
Adverse Events Analyses ...........................................................................23
7.2.
Adverse Events of Special Interest Analyses..............................................23
7.3.
Clinical Laboratory Analyses.......................................................................23
7.4.
Other Safety Analyses ................................................................................23
8.
PHARMACOKINETIC ANALYSES.........................................................................24
8.1.
Statistical analyses of derived PK parameters ............................................24
8.1.1.
Endpoints / Variables...................................................................24
8.1.1.1.
Drug Concentration Measures....................................24
8.1.1.2.
Derived Pharmacokinetic Parameters.........................24
8.1.2.
Summary Measure ......................................................................26
8.1.3.
Population of Interest...................................................................26
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................26
8.1.5.
Statistical Analyses / Methods .....................................................28
8.2.
Statistical analysis for comparison of food effect – Single dose study 
part .............................................................................................................29
8.2.1.
Endpoints/Variables.....................................................................29
8.2.2.
Summary Measure ......................................................................29
8.2.3.
Population of Interest...................................................................29
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................29
8.2.5.
Statistical Analyses / Methods .....................................................31
8.2.5.1.
Statistical Methodology Specification..........................31


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8.3.
Statistical analysis for dose proportionality – Single and Repeat 
dose study parts .........................................................................................33
8.3.1.
Endpoints/Variables.....................................................................33
8.3.2.
Summary Measure ......................................................................33
8.3.3.
Population of Interest...................................................................33
8.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................33
8.3.5.
Statistical Analyses / Methods .....................................................35
8.3.5.1.
Statistical Methodology Specification..........................35
8.4.
Statistical analysis for dose accumulation – Repeat dose study part...........37
8.4.1.
Endpoints/Variables.....................................................................37
8.4.2.
Summary Measure ......................................................................37
8.4.3.
Population of Interest...................................................................37
8.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................37
8.4.5.
Statistical Analyses / Methods .....................................................39
8.4.5.1.
Statistical Methodology Specification..........................39
8.5.
Statistical analysis for time invariance ratio of GSK3186899 –
Repeat dose study part...............................................................................41
8.5.1.
Endpoints/Variables.....................................................................41
8.5.2.
Summary Measure ......................................................................41
8.5.3.
Population of Interest...................................................................41
8.5.4.
Strategy for Intercurrent (Post-Randomization) Events ................41
8.5.5.
Statistical Analyses / Methods .....................................................43
8.5.5.1.
Statistical Methodology Specification..........................43
9.
REFERENCES.......................................................................................................45
10. APPENDICES........................................................................................................46
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................46
10.1.1.
Exclusions from Analysis Population............................................46
10.2.
Appendix 2: Schedule of Activities ..............................................................47
10.2.1.
Protocol Defined Schedule of Events in PART A (Cohorts 
1-3)..............................................................................................47
10.2.2.
Protocol Defined Schedule of Events in PART B (Cohorts 
4-6)..............................................................................................50
10.3.
Appendix 3: Assessment Windows .............................................................56
10.3.1.
Definitions of Assessment Windows for Analyses........................56
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................57
10.4.1.
Study Phases ..............................................................................57
10.4.1.1.
Study Phases for Concomitant Medication .................57
10.4.2.
Treatment Emergent Flag for Adverse Events .............................58
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................59
10.5.1.
Reporting Process .......................................................................59
10.5.2.
Reporting Standards....................................................................59
10.5.3.
Reporting Standards for Pharmacokinetic....................................60
10.6.
Appendix 6: Derived and Transformed Data ...............................................62
10.6.1.
General........................................................................................62
10.6.2.
Study Population..........................................................................62
10.6.3.
Safety ..........................................................................................63
10.6.4.
Pharmacokinetic ..........................................................................63
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................64


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10.7.1.
Premature Withdrawals................................................................64
10.7.2.
Handling of Missing Data.............................................................64
10.7.2.1.
Handling of Missing and Partial Dates ........................64
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................66
10.8.1.
Laboratory Values........................................................................66
10.8.2.
ECG.............................................................................................67
10.8.3.
Vital Signs....................................................................................67
10.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................68
10.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................68
10.11. Appendix 11: Abbreviations & Trade Marks ................................................68
10.11.1. Abbreviations...............................................................................68
10.11.2. Trademarks .................................................................................70
10.12. Appendix 12: List of Data Displays..............................................................71
10.12.1. Data Display Numbering..............................................................71
10.12.2. Mock Example Shell Referencing ................................................71
10.12.3. Deliverables.................................................................................71
10.12.4. Study Population Tables..............................................................72
10.12.5. Safety Tables...............................................................................74
10.12.6. Pharmacokinetic Tables...............................................................77
10.12.7. Pharmacokinetic Figures .............................................................80
10.12.8. ICH Listings .................................................................................81
10.12.9. Non-ICH Listings..........................................................................86
10.13. Appendix 13: Example Mock Shells for Data Displays ................................89


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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 208436:
Protocol Revision Chronology:
Original Document Number: 
2018N385133_00 
Dated: 09-JAN-2019
Version: Original
Original Document Number: 
2018N385133_01
Dated: 19-MAR-2019
Version: Amendment 01
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no major changes or deviations to the originally planned statistical analysis
specified in the Original Protocol 208436 (Dated: 09-Jan-2019) and the Amendment 01 
(Dated: 19-Mar-2019).
A minor change is made to the first secondary objective where trough plasma 
concentration (Ctau) is removed from the SAD part and added to the MAD part after 
confirmation from the Study Pharmacokineticist.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and 
tolerability of single and repeat 
doses of GSK3186899 in 
healthy participants

Adverse event reporting, clinical laboratory safety data, 
physical examinations, vital signs, 12 lead ECGs, 24 hr 
telemetry
Secondary Objectives
Secondary Endpoints

To evaluate the systemic 
pharmacokinetic (PK) profile of 
single (fasted and fed) and 
repeat doses of GSK3186899 in 
healthy participants

Plasma concentrations of GSK3186899 plus derived 
parameters, as data allow.
For SAD part:  Derived PK parameters for 
GSK3186899 following single dose (fasted and fed)
including area under the plasma drug concentration 
versus time curve (AUC(0-t), AUC(0-∞)), maximum 
observed plasma drug concentration (Cmax), time to 
maximum observed plasma drug concentration (Tmax),
and apparent terminal half-life (T1/2) as data allow. 
Predicted accumulation Ratio (ARpred)# will be 
calculated.
For MAD part: AUC(0-t), AUC(0-∞), AUC(0-tau), 
Cmax, trough plasma concentration (Ctau), Tmax and T1/2.

To examine dose proportionality 
following single and multiple 
doses of GSK3186899

Dose-proportionality assessment using derived PK 
parameters, as data allow:
For SAD part: AUC(0-∞), Cmax


CONFIDENTIAL
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Objectives
Endpoints
For MAD part: AUC(0-tau), Cmax, Ctau

To assess accumulation and 
time-invariance ratios of 
GSK3186899 after multiple 
doses

Accumulation ratios assessment*, where data allow: 
RAUC(0-tau), RCmax, RCtau. Time-invariance ratio 
calculation as AUC(0-12) † on day 10 to AUC(0-∞) on 
day 1.
Exploratory Objectives
Exploratory Endpoints

To collect residual plasma 
following GSK3186899 analysis, 
and urine samples, for analysis 
of metabolites of GSK3186899

Metabolites of GSK3186899 in plasma and urine. 
These analyses will be detailed in a separate analysis 
plan.

To collect bile sample for 
analysis of metabolites of 
GSK3186899 (Part A fed 
regimen only)

Metabolites of GSK3186899 in bile. These analyses will 
be detailed in a separate analysis plan.
* Accumulation ratios calculated as the ratio of last dose to first dose PK parameters: RAUC(0-tau) = AUC(0-tau) on last 
dose to AUC(0-tau) on first dose, RCmax = Cmax on last dose to Cmax on first dose, RCtau= Ctau on last dose to 
Ctau on first dose. # ARpred = 1/(1-e^(k*tau)) where k is elimination rate constant following the single dose and tau 
is the dosing interval for the intended repeat dosing.
† It is AUC(0-12) if dosing is BID, or, AUC(0-8) if dosing is TID.


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2.3.
Study Design
Overview of Study Design and Key Features
Figure 1 Study Design (Part A)
                     
DL = Dose level; DLX = Dose level to be determined; FD = Fed Conditions; A = Active; P = Placebo
Figure 2 Study Design (Part B)
DL = Dose level; A = Active; P = Placebo
Note: DL7 was not dosed in the study due to higher than expected exposures.
Design
Features
This study will be a randomized, double-blind (sponsor unblinded), placebo-controlled, 2-
part study of the oral administration of GSK3186899A in healthy participants. 
Planned to include approximately 54 participants and will consist of 2 parts as below:

Part A will include a single-ascending, sequential crossover design in up to 3 
cohorts of participants (Cohorts 1, 2 and 3). Part A Cohorts 1-2 will comprise of a 
4 period crossover which includes 4 dosing regimens under fasted conditions. Part 
A Cohort 3 will comprise of a 2 period crossover which includes 1 dosing regimen 


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Overview of Study Design and Key Features
under fasted conditions and 1 regimen under fed conditions. The fed conditions 
regimen will investigate the safety, tolerability and PK of a single dose of 
GSK3186899 following food administration. 

Part B will be a twice-daily (BID) 10-day repeat dose design in up to 3 parallel 
cohorts of participants (Cohorts 4, 5 and 6). Part B may include drug 
administration after either fed or fasted conditions, this will be dependent on the 
interim results from Part A. If under fasted conditions, participants will be 
required to fast at least 2 hours before and after drug administration.
Dosing

Part A (single ascending dose)
For Part A, the dose escalation phase, up to 3 cohorts may be used (Cohorts 1-3). 
Cohorts 1 and 2 will consist of 8 healthy participants each. If used, Cohort 3 will 
consist of up to 14 healthy participants.
-
For Cohorts 1 and 2, each participant will receive a maximum of 3 ascending 
oral doses of GSK3186899 and 1 placebo dose under fasted conditions. At each 
dose level, GSK3186899 and placebo will be administered in a 3:1 ratio, within 
each period, according to the randomization schedule in a blinded manner. Up 
to a maximum of 7 dose levels will be studied in Part A as illustrated in Figure 1
above.
-
For Cohort 3, each participant will receive 1 oral dose of GSK3186899 selected 
based on the results from Cohorts 1 and 2, under both fasted and fed conditions.

For each cohort and within each treatment period (except Cohort 3), the
first 2 participants will act as sentinels. No participant will be a sentinel participant 
more than once. On Day 1, 1 of the 2 sentinel participants will receive the active 
dose and the other will receive placebo. Based on the Principal Investigator’s review 
of the 2 sentinel participants after at least the first 24hr post-dose safety data (e.g. 
vital signs, ECGs and AEs), the remaining 6 participants can then be randomized to 
dosing.

Part B (repeat dose)
For the repeat dose escalation phase in Part B, there will be up to 3 cohorts (Cohorts 
4, 5 and 6), consisting of 8 healthy participants randomised to receive repeat doses 
of either GSK3186899 or placebo, administered in a 3:1 ratio according to the 
randomization schedule in a blinded manner. For BID dosing, GSK3186899 or 
placebo will be administered using a 12hr dosing interval. Based on emerging data in 
Part A, an alternate dosing regimen (OD or TID) may be selected if deemed suitable.

The first 2 participants in each cohort in Part B will act as sentinels. On Day 1 
until Day 10, 1 of the 2 sentinel participants will receive the active dose twice 
daily and the other will receive placebo twice daily. Once these participants have 
completed their first 5-days of dosing, the safety and tolerability data will be 
reviewed by the Principal Investigator. If there are no clinically relevant safety or 
tolerability concerns (e.g. vital signs, ECGs and AEs) the remaining 6 
participants will be randomized to dosing.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Part A consists of up to 30 participants in up to 3 cohorts (excluding possible 
replacements):
o
Cohort 1 and 2 will each have 6 participants in active versus 2
participants in placebo (i.e., in a 3:1 ratio)


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Overview of Study Design and Key Features
o
Cohort 3 will contain up to 14 participants in a 1:1 ratio for (fed and 
active) versus (fasted and active)

Part B consists of up to 24 participants in up to 3 cohorts:
o
Cohorts 4, 5 and 6 will each have 6 participants in active versus 2 
participants in placebo (i.e., in a 3:1 ratio)
Interim 
Analysis
No formal interim analyses (IA) are planned for this study. However, safety, tolerability, and 
PK data will be reviewed before each dose escalation in Part A (single dose) and Part B 
(repeat dose), prior to the investigation of the food effect, and between Part A and Part B.
An informal interim analysis for Part A will be conducted prior to initiating Part B. This 
analysis will support the decision to progress or not to progress to Part B.
2.4.
Statistical Analyses
Given that this is a FTiH study, statistical analyses planned will be mainly descriptive 
in nature involving frequencies and percentages for categorical variables and number 
of subjects (n), mean, standard deviation, median, minimum and maximum for 
continuous variables. 
Where appropriate (for e.g., evaluation of dose proportionality, drug accumulation, 
food effect) statistical modelling will be performed and point estimates with 90% 
confidence intervals (CIs) will be constructed.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analyses (IA) are planned for this study. However, regular dose 
escalation meetings, an informal IA and safety review meetings are planned to be 
performed at different time points described below. 

Dose escalation meetings are planned to review the safety, tolerability, and PK data 
prior to: 
o
each dose escalation in Part A (single dose) – Cohorts 1 and 2, 
o
initiation of the food effect Cohort 3, and
o
each dose escalation in Part B (repeat dose) – prior to initiation of Cohorts 5 
and 6.

An informal IA to review the safety, tolerability, and PK data from Part A is planned 
prior to:
o
progression to Part B.

Additional instream safety review meetings including all safety and tolerability data 
only are planned prior to:
o
progression to Cohort 2 in Part A
o
progression to Period 2 in the food effect Cohort 3.
There will not be a formal database freeze performed for this informal IA. Data included 
for these analyses will be as complete and clean as possible based on continuous data 
review and monitoring activities.
The final study analysis post- database freeze will include all data captured in the study 
database.
3.1.1.1.
Dose escalation meetings
Statistical displays will not be produced by Biostatistics for the dose escalation meetings.
During the meeting, safety data (presented by the CUC Principal Investigator or delegate) 
and PK data (presented by Study Pharmacokineticist or delegate) will be reviewed by the 
committee. 
The meeting will discuss blinded data in an open forum with the GSK Study team 
members and Principal Investigator (or their delegate) in attendance. If required, the data 
may be reviewed in an unblinded fashion by the unblinded members including the SMG 
(formally GCSP) Safety representative and Study Pharmacokineticist.
The decision to proceed to the next dose level of GSK3186899 will be made at a DEC 
meeting based on:

all available safety and tolerability data from individuals (including AEs, 
laboratory safety tests, telemetry, ECGs and vital signs) from a minimum of 48 
hours post-dose (10 days for repeat dose) from a minimum of 4 or more 
participants who have received GSK3186899 at the current dose level


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
all available safety and tolerability data accumulated from preceding single/repeat 
dose levels and available PK data from current (minimum of 4 or more 
participants) and preceding single/repeat dose levels.
Further details of the DEC membership, data to be reviewed and stopping criteria are
outlined in the DEC charter.
3.1.1.2.
Informal interim analysis
An informal interim analysis (IA) after completion of Part A will be conducted prior to 
initiation of Part B. This analysis will support the decision to progress, or, not progress to 
Part B and will consist of the following statistical displays on blinded safety and blinded
PK data. Safety tables will therefore be presented by period rather than treatment to 
maintain the blind of the study.
Table 1: Planned Statistical Displays for the Interim analysis
Sl. 
No.
Population
IDSL / 
Example 
Shell
Title
Responsible 
function
1
Safety
ES1A
Summary of Participant Disposition for the 
Participant Conclusion Record – Part A
(Cohort 1 and Cohort 2 only)
Biostatistics
2
Safety
ES3
Listing of Reasons for Study Withdrawal –
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
3
Safety
SD3
Listing of Reasons for Study Treatment 
Discontinuation – Part A (Cohort 1 and 
Cohort 2 only)
Biostatistics
4
Safety
DM3
Summary of Demographic Characteristics –
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
5
Safety
DM4
Listing of Demographic Characteristics - Part 
A (Cohort 1 and Cohort 2 only)
Biostatistics
6
Safety
EX1
Summary of Exposure to Study Treatment -
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
7
Safety
EX4
Listing of Exposure Data – Part A (Cohort 1 
and Cohort 2 only)
Biostatistics
8
Safety
AE1CP
Summary of All Adverse Events by System 
Organ Class and Preferred Term - Part A
(Cohort 1 and Cohort 2 only)
Biostatistics
9
Safety
AE9
Listing of All Adverse Events - Part A (Cohort 
1 and Cohort 2 only)
Biostatistics
10
Safety
EG4
Listing of All ECG Values for Subjects with 
Any Value of Potential Clinical Importance -
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
11
Safety
EG6
Listing of All ECG Findings for Subjects with 
an Abnormal Finding - Part A (Cohort 1 and 
Cohort 2 only)
Biostatistics
12
Safety
LB6
Listing of All Laboratory Data for Participants 
with Any Value of Potential Clinical 
Biostatistics


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Importance – Part A (Cohort 1 and Cohort 2 
only)
13
Safety
UR2B
Listing of All Urinalysis Data for Subjects with 
Any Value of Potential Clinical Importance -
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
14
Safety
VS5
Listing of All Vital Signs for Subjects with 
values Potential Clinical Importance - Part A
(Cohort 1 and Cohort 2 only)
Biostatistics
15
Safety
EG6 (to be 
modified for 
telemetry 
data)
Listing of Telemetry findings - Part A (Cohort 
1 and Cohort 2 only)
Biostatistics
16
Safety
DV2
Listing of Important Protocol Deviations –
Part A (Cohort 1 and Cohort 2 only)
Biostatistics
17
PK
Non 
standard 
shell
Summary of Untransformed Derived 
GSK3186899 Plasma Pharmacokinetic 
Parameters by dose and fed status - Part A
(All Cohorts)
CPMS
18
PK
Non 
standard 
shell
Summary of the ratio of fed versus fasted on 
AUC(0-∞) and Cmax – Part A Cohort 3
CPMS
19
PK
Non 
standard 
shell
Geo Mean (+ SD) GSK3186899 Plasma 
Concentration-Time Plot (Linear and Semi-
Log) – Part A (Cohort 1 and Cohort 2 only)
CPMS
20
PK
Non 
standard 
shell
Box Plot of AUC(0-∞) and Cmax versus 
dose (Linear) – Part A (Cohort 1 and Cohort 
2 only)
CPMS
21
PK
Non 
standard 
shell
Box Plot of dose normalised AUC(0-∞) and 
Cmax versus dose (Linear) – Part A (Cohort 
1 and Cohort 2 only)
CPMS
22
PK
Non 
standard 
shell
Geo Mean (+ SD) GSK3186899 Plasma 
Concentration-Time Plot (Linear and Semi-
Log) grouped by fed and fasted status – Part 
A Cohort 3
CPMS
23
PK
Non 
standard 
shell
Box Plot of AUC (0-∞) and Cmax (Linear) 
grouped by fed and fasted status – Part A 
Cohort 3
CPMS
24
PK
Non 
standard 
shell
Listing of GSK3186899 Plasma 
Pharmacokinetic Concentrations (loge-
transformed) -Time Data by dose - Part A
(All Cohorts)
CPMS
The PK related displays will be prepared by/under the auspices of the CPMS function and 
the safety related displays will be prepared by/under the auspices of the Biostatistics 
function.
The safety related IA displays will include data from Cohort 1 and Cohort 2 only. This is 
because all the doses will be investigated for safety and tolerability during these two 
cohorts and Cohort 3 will provide further information on the fed or fasted regimen to be 
applied in the Part B, for multiple ascending doses.


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The actual treatment information will not be presented in any displays. Aggregated data 
will be reported in the tables of safety endpoints. The PK data will be presented without 
subject IDs. Blinded listings of safety and PK data will be provided.
A blinded dry run will be performed prior to the informal IA. The dry run displays will be 
reviewed by the study team including SMG Pharma Safety representative.
If required and/or requested by the DEC, an independent statistician and programmer(s) 
may be deployed to create unblinded displays. 
However, a support pharmacokineticist in GSK will have access to extract scrambled PK 
data from SMS2000 to PKHARP and transfer the data via secured email to the Study 
pharmacokineticist (in PAREXEL International) for their reviews and analyses during 
study. 
In case, there are any serious adverse events requiring further investigation, the unblinded 
SMG Pharma Safety representative and unblinded Study Pharmacokineticist can support 
further investigation. 
3.1.1.3.
Safety review meetings
The decision to proceed from Cohort 1 Period 4 to Cohort 2 Period 1 and similarly progress 
from Cohort 3 Period 1 (DLX) to Cohort 3 Period 2 (DLX-FD) will be made by the 
Principal Investigator and Medical Monitor based on all available safety and tolerability 
data from a minimum of 48 hours post-dose from a minimum of 4 or more participants 
who have received GSK3186899 at the current dose level. Individual safety data (AEs, 
laboratory safety tests, telemetry, ECGs and vital signs) will also be reviewed. PK data will 
not be included in these reviews.
The study team will remain blinded until the database freeze, except for the unblinded 
site Pharmacist, unblinded study Pharmacokineticist and SMG Pharma Safety
representative.
3.2.
Final Analyses
The final planned 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) have been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
A final blinded dry run will be performed prior to the database lock for review by the 
study team.
4.
ANALYSIS POPULATIONS
For purposes of analysis, the following populations are defined:


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Population
Description
Analyses Evaluated
Screened 

All participants who were screened for eligibility
Screen Failure
Enrolled

All participants who passed screening and entered the study. 
Included are: Randomized Participants
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 
Safety

All randomized participants who received at least one dose of 
study treatment.

This population will be based on the treatment the subject 
actually received.
Note: Participants who were not randomized but received at least 
one dose of study treatment should be listed.

Study Population

Safety
PK

All participants in the Safety population who had at least 1 non-
missing PK assessment* (Non-quantifiable [NQ] values will be 
considered as non-missing values).

PK
Refer to Error! Reference source not found.: List of Data Displays which details the population used for each 
display.
* PK assessments refer to the plasma concentrations and not the PK parameters.
4.1.
Protocol Deviations
Important protocol deviations (PDs), including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 1.0 dated 10 April 
2019 or later].
Exclusion from the analysis sets due to a deviation will be determined programmatically 
using the criteria described in the table of Analysis populations above. These deviations 
will not be included in the SDTM dataset but will be programmed in the protocol 
deviation analysis (ADaM) dataset. This dataset will be the basis for the summaries and
listings of protocol deviations.
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.


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5. CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors


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Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF
PART A
P1 / P2
Placebo cohort 1 / Placebo cohort 2
Placebo Part A
1
D1
GSK3186899 Dose Level 1
GSK 30 mg
2
D2
GSK3186899 Dose Level 2
GSK 60 mg
3
D3
GSK3186899 Dose Level 3
GSK 120 mg
4
D4
GSK3186899 Dose Level 4
GSK 300 mg
5
D5
GSK3186899 Dose Level 5
GSK 600 mg
6
D6
GSK3186899 Dose Level 6
GSK 800 mg
7
D7
GSK3186899 Dose Level 7
(this dose was not investigated)
GSK X.X mg
8
DX-FA
GSK3186899 Dose Level X fasted
GSK X.X mg fasted
9
DX-FE
GSK3186899 Dose Level X fed
GSK X.X mg fed
10
PART B
P4/ P5/ P6
Placebo cohort 4/ Placebo cohort 5/ 
Placebo cohort 6
Placebo Part B
1
R1
GSK3186899 Repeat Dose Level 1
GSK X.X mg BID
2
R2
GSK3186899 Repeat Dose Level 2
GSK X.X mg BID
3
R3
GSK3186899 Repeat Dose Level 3
GSK X.X mg BID
4
Note: Doses levels 1 to 6 were known at the time of RAP finalisation. The later doses 
were unknown, but will be known and detailed in the final study reporting.
For Part A, this order of the treatments will be considered for displays including all 
treatment groups from Cohorts 1, 2 and 3. However, for displays by Cohorts, only 
relevant treatment groups will be presented in the same ascending order mentioned 
above.
Treatment comparisons will be displayed using the descriptors as specified below:

In general, comparison between 2 doses: GSK X.X mg vs GSK X.X mg

In Cohort 3 (same dose different food regimen): GSK X.X mg - fed vs fasted.


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5.2.
Baseline Definitions
Baseline is defined as the last non-missing pre-dose assessment in each cohort. In 
general, assessments on Study day 1 taken prior to first dose are used as baseline. In some
unlikely situations described below, the baseline will be defined as:

when there are multiple assessments captured on Day 1, but the time of the first 
assessments is missing, then this first recorded assessment will be considered as 
the baseline

when only one assessment is captured on Day 1 with time of assessment as 
missing, then conservatively the last available assessment from Day -1 or prior 
will be defined as the baseline

when there are no assessments collected at Day 1, the last available data from 
either Day -1/ Day -2 or screening (as schedule of assessment in each Part/Cohort 
permits) will be defined as baseline

when pre-dose data is completely missing for a subject, then no derivation will be 
performed, and the baseline will be set to missing
In Part A, for each period within a cohort, the period baseline is defined in a similar 
manner, by considering the last available non-missing pre-dose assessment in that period.
For some ECG and Vital Signs parameters, the pre-dose data is captured as triplicate. In 
these cases, the baseline will be defined as the mean of the assessments.
In addition, for some PK endpoint analyses, the adjusted baselines may be considered, if 
the pre-dose PK concentration value in a period is observed to be greater than 5% of the 
previous dose Cmax value: 

Subject level baseline is defined as the mean of baseline across periods for each 
subject. If a period baseline is missing, the mean of available period baselines will 
be considered as baseline.

Period level baseline is defined as the difference between the baseline value and 
subject level baseline for each period and each subject.
5.2.1.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from baseline in the study
Change from Baseline
= Post-dose visit value – Baseline value
% Change from Baseline
= 100 x [(Post-dose visit value – Baseline value) / Baseline value]
Change from baseline within a period
Change from Baseline in Period X
= Period X Post-dose value – Period X baseline value


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% Change from Baseline in 
Period X
= 100 x [(Period X Post-dose value – Period X baseline value) /
Period X baseline value]
NOTES:
o
Unless otherwise specified, the baseline definitions specified in Section 5.2 
Baseline Definitions (the baseline of the study and the baseline of each period 
(unadjusted)) will be used for derivations for endpoints / parameters and 
indicated on summaries. Unless otherwise stated, if baseline data is missing or 
post-dose data is missing no derivation will be performed and (%) change from 
baseline will be set to missing.
o
The relevant baseline definition will be footnoted on all displays involving 
change from baseline.
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
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Schedule of Activities
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.5
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: 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 “Safety” population, unless otherwise 
specified.
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.  In 
this document, Appendix 12 contains a list of data displays and analysis sets planned for 
the informal interim analysis.
Details of the planned displays and analysis sets for final study reporting will be
presented in Error! Reference source not found.: List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, consisting all subjects who 
had a dose (including those who had partial dose) of study treatment.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and common (≥ 5%) AEs by overall frequency will be based on GSK Core Data 
Standards. The details of the planned displays are provided in Error! Reference source 
not found.: List of Data Displays.
7.2.
Adverse Events of Special Interest Analyses
Adverse events of special interest are those considered possibly related to/associated with 
stomach erosion, adrenal insufficiency and renal impairment.
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of final reporting. The details 
of the planned displays are provided in Error! Reference source not found.: List of 
Data Displays.
7.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, Renal and Liver function tests will be based on GSK Core 
Data Standards. The details of the planned displays are in Error! Reference source not 
found.: List of Data Displays.
7.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including vital signs, 12 lead ECG and 
24-hour telemetry will be based on GSK Core Data Standards, unless otherwise specified. 
The details of the planned displays are presented in Error! Reference source not 
found.: List of Data Displays.


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8.
PHARMACOKINETIC ANALYSES
All PK analyses planned for the study are a part of the secondary objectives.
8.1.
Statistical analyses of derived PK parameters
8.1.1.
Endpoints / Variables
8.1.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Standards for Pharmacokinetic).
8.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin version 8.0. All calculations of non-compartmental parameters will be based 
on actual sampling times. 
For dose escalation meeting and interim analysis planned sampling times may be used if 
actual timepoints are not available.
Pharmacokinetic parameters listed will be determined from the plasma concentration-
time data, provided there is enough evaluable data available for the calculations. If the 
concentration data is available partially, then based on scientific judgement the data will 
be assessed for inclusion or exclusion from the analysis. 
Parameter
Parameter Description
Plasma PK Parameters:
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data.
RCmax
Ratio of Cmax on last dose to Cmax on first dose, i.e., 
 =

    

    .
Ctau
Trough concentration determined directly from the concentration data (only for Part B 
of the study). It will be the concentrations at 12h or 8h after first dose (if BID or TID 
administration, respectively) and always concentration at pre-dose on the last dose.
RCtau
Ratio of Ctau on last dose to Ctau on first dose, i.e., 
 =   ℎ   ! 
  ℎ "#$  ! 
tmax
Time to reach Cmax, determined directly from the concentration-time data.
tlag*
Lag time before first observation of drug concentrations (after single dose only)


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Parameter
Parameter Description
Tlast*
Time of last quantifiable concentration
t½
Apparent terminal half-life will be calculated as: 
%/' = ln 2
λ,
(NOTE: λz is the terminal phase rate constant).
AUC(0-24h)
Area under the concentration-time curve from time zero to 24 hours post-dose (after 
single dose only).
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the loge trapezoidal rule for each decremental 
trapezoid.
AUC(0-tau)
Area under the concentration-time curve from time zero to the time of the trough 
concentration (C(tau)) will be calculated for Part 2 of the study only (repeat dose) using
the linear trapezoidal rule for each incremental trapezoid.
RAUC(0-tau)
AUC(0-tau) on last dose to AUC(0-tau) on first dose
-.(0 −) = -.(0 −)  ℎ   ! 
-.(0 −)  ℎ "#$  ! 
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated (after 
single dose only) as: 
-.(0 −∞) = -.(0 −) + ()
λz
(NOTE: λz is the terminal phase rate constant. % of the extrapolated area should not 
exceed 20%. Any value of AUC(0-∞) derived with more than 20% extrapolation should 
be flagged and excluded from summary statistics if >30%).
ARpred
ARpred is calculated as :
-6$! =
1
1 −8∗:
where k is elimination rate constant following the single dose and tau is the dosing 
interval for the intended repeat dosing.
R2adjusted*
The goodness of fit statistic for the terminal elimination phase, adjusted for the 
number of points used in the estimation of λz.
λz
λz is the terminal phase rate constant. A minimum number of three data points in the 
terminal phase will be used starting at any post-Cmax data point. The adjusted 
correlation coefficient (R2 adjusted) in general should be greater than 0.90. Any value 
< 0.90 but ≥0.8 will be flagged but may be used at the PK Scientist’s best knowledge 
and judgment, any value <0.8 should be considered for exclusion from the statistical 
analysis. All the derived parameters that include λz in their calculation (i.e, t½, AUC(0-
∞) will need to be flagged or excluded from statistical analysis accordingly. The 
interval used to determine λz should be equal or greater than 1.5-fold the estimated 
half-life or otherwise flagged and used at the PK Scientist’s best knowledge and 
judgment. 
λz upper limit*
The upper limit on time for values to be included in the calculation of λz.


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Parameter
Parameter Description
λz lower limit*
The lower limit on time for values to be included in the calculation of λz
λz number of 
points*
The number of time points used in computing λz.
% AUCex*
Percent of AUC∞that is extrapolated beyond last quantified concentration
CL/F*
The apparent clearance will be calculated only for Part 1 of the study (single 
dose) as Dose/ AUC(0-∞)
CLss*
The apparent clearance at steady state will be calculated only for day 10 Part 2 
of the study (repeat dose) as Dose/ AUC(0-tau)
Urine PK Parameters:
Ae(t1-tz)*
Amount excreted in the urine at each interval collection (24 h)
fe(0-tz)*
The fraction of unchanged drug excreted in urine will be calculated as 
fe = Ae/Dose, up to tz hours, where tz is the last collection time
CLR*
Renal Clearance calculated as Ae(0-tz) / AUC(0-tz).
NOTES:

*Additional exploratory parameters have been included which will be listed only.
8.1.2.
Summary Measure
All the derived PK parameters will be summarized descriptively. 
Detail methods and displays of the summary measures are specified in Section 8.1.6 
Statistical Analyses/ Methods.
Some of the parameters in the list above will be used for statistical modelling, as
described in the subsequent analyses sections.
8.1.3.
Population of Interest 
These descriptive summaries will be based on the PK population.
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events
In Table 2 below, the possible intercurrent events and the rationale for relating them to 
treatment or otherwise is described. Once a subject discontinues from study treatment, 
they will proceed straight to follow up and no further data will be collected.
Individual subject data will be included in data listings regardless of the strategies 
followed for the analyses. 
If feasible, subjects will be replaced until the desired sample size is attained.
Table 2 Strategies for Intercurrent events


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Intercurrent 
events
Relation to 
treatment and 
rationale
Strategy, rationale and details of action taken
Subject 
withdraws 
study 
consent
Not related to 
treatment/ 
Subject drops out 
due to logistic 
reasons and not 
due to any event 
related to treatment
-
The strategy will be a While-on-Treatment 
strategy, where we are interested in the 
treatment effects prior to the withdrawal only. 
-
Subjects’ data available up to the withdrawal 
will be included in the descriptive PK 
summaries. 
-
If a subject withdraws consent during a 
period, the missing data post withdrawal will 
not be imputed. 
-
The derived PK parameters for e.g., AUC, 
Cmax etc. of that partially completed period 
will be calculated if data permits (See section 
8.1.1.2 Derived Pharmacokinetic Parameters
for details on derivation criteria).
Subject does 
not take the 
full 
treatment
Not related to 
treatment/
The treatment will 
be administered as 
a powder dissolved 
in diluent.  To 
ensure all 
treatment is 
ingested, the bottle 
containing the 
dispersion will be 
rinsed three times 
and the subject 
will be expected to 
ingest this in 
addition to the 
initial dispersion. 
If three rinses are 
not all ingested, 
the subject may 
not take the full 
treatment dose.
In the current formulation, it is hard to measure 
the exact proportion of dose ingested if not all 
rinses are taken. It is also uncertain whether the 
formulation could change in future development. 
To account for this, we propose two different 
strategies described below. If this intercurrent 
event is not observed, then both strategies will 
provide the same results and only the hypothetical 
strategy will be presented for the final analysis.
Primary analysis 
-
The strategy will be a Hypothetical strategy,
where we are interested in the treatment 
effects in a hypothetical scenario where all 
subjects have taken complete dose.
-
In this case, the data from a period in which 
an incomplete dose is taken would be 
considered as missing at random and 
excluded from analyses.
-
If the drug formulation is changed in the 
future studies, this estimate will provide the 
true relationship between the actual dose
intake and its exposure under this strategy.
Supplementary analysis
-
The strategy will be a Treatment policy 
strategy, where we are interested in the 


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treatment effects regardless of the actual 
amount of dose taken.
-
The analysis will include PK parameters 
derived based on concentrations of both 
complete and partial doses (if data permits 
based on criteria described in Section 8.1.1.2) 
and will be analysed using the nominal or 
prescribed dose.
-
If the drug formulation remains unchanged in 
the future studies, this estimate will provide 
the true relationship between a nominal dose 
and its exposure under this strategy, i.e., a 
close to real-world situation.
Subject 
drops out 
due to 
Adverse 
events
Related to 
treatment/
If the adverse 
event is confirmed 
to be related to 
study treatment
-
The primary strategy will be a Hypothetical 
strategy, where we are interested in the 
treatment effects in a hypothetical scenario 
where discontinuation due to an AE would 
not happen. 
-
The missing data after discontinuation will 
assumed to be missing at random
-
The derived PK parameters of the last fully or 
partially completed period will be calculated 
if data permits (See section 8.1.1.2 Derived 
Pharmacokinetic Parameters for details on 
derivation criteria).
8.1.5.
Statistical Analyses / Methods
For parameters tabulated in Section 8.1.2, data will be summarized using the following 
descriptive statistics.

N, n, arithmetic mean, 95% confidence interval (CI) for the arithmetic mean, SD, 
median, minimum, maximum for the untransformed data

Geometric mean, 95% CI for the geometric mean, SD of loge-transformed data 
and %CVb or %CVw for the untransformed data (except Tmax and T½)

Based on the intercurrent events observed in the study, appropriate strategies from 
Table 2 in Section 8.1.4 will be considered for handling of missing data (if any) 
and interpretation of the analysis results. If multiple intercurrent events are 
observed (for e.g., if the subject does not take the full treatment as well he
withdraws study consent), then the data will be handled using more than one 
strategy as described in Table 2 and interpretations of the results will be made 
accordingly.
Graphical presentations will be provided if appropriate. All data will be listed. Details of 
the planned displays are provided in Error! Reference source not found.: List of Data 
Displays and will be based on GSK Data Standards and statistical principles.


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8.2.
Statistical analysis for comparison of food effect – Single 
dose study part
8.2.1.
Endpoints/Variables
To assess the food effect in Cohort 3, the statistical analysis will be based on AUC(0-t), 
AUC(0-∞) and Cmax, only.
8.2.2.
Summary Measure
The summary measure will be the point estimates and 90% CIs of mean differences of 
GSK3186899 fed – GSK3186899 fasted, based on the loge-transformed data, and after 
back-transformation of this estimated differences, the geometric mean ratios of 
(GSK3186899 fed: GSK3186899 fasted) will be presented.
8.2.3.
Population of Interest 
These analyses will be based on the PK population.
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events
In the Table 3 below, the possible intercurrent events and the rationale for relating them 
to treatment or otherwise is described. Once a subject discontinues from study treatment, 
they will proceed straight to follow up and no further data will be collected.
All subjects’ data will be included in data listings irrespective of the strategies followed 
for the analysis. 
If feasible, subjects will be replaced until the desired sample size is attained.
Table 3 Strategies for Intercurrent events
Intercurrent 
events
Relation to 
treatment and 
rationale
Strategy, rationale and details of action taken
Subject 
withdraws 
study 
consent
Not related to 
treatment/ 
Subject drops out 
due to logistic 
reasons and not 
due to any event 
related to treatment
-
The strategy will be a While-on-Treatment 
strategy, where we are interested in the 
treatment effects prior to the withdrawal only. 
-
Subjects’ data available up to the withdrawal 
will be included in the food effect analyses. 
-
If a subject withdraws consent during a 
period, the missing data post withdrawal will 
not be imputed. 
-
The derived PK parameters for e.g., AUC, 
Cmax etc. of that partially completed period 
will be calculated if data permits (See section 
8.1.1.2 Derived Pharmacokinetic Parameters
for details on derivation criteria).


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Subject does 
not take the 
full 
treatment
Not related to 
treatment/
The treatment will 
be administered as 
a powder dissolved 
in diluent.  To 
ensure all 
treatment is 
ingested, the bottle 
containing the 
dispersion will be 
rinsed three times 
and the subject 
will be expected to 
ingest this in 
addition to the 
initial dispersion. 
If three rinses are 
not all ingested, 
the subject may 
not take the full 
treatment dose.
In the current formulation, it is hard to measure 
the exact proportion of dose ingested if not all 
rinses are taken. It is also uncertain whether the 
formulation could change in future development. 
To account for this, we propose two different 
strategies described below. If this intercurrent 
event is not observed, then both strategies will 
provide the same results and only the hypothetical 
strategy will be presented for the final analysis.
Primary analysis 
-
The strategy will be a Hypothetical strategy,
where we are interested in the treatment 
effects in a hypothetical scenario where all 
subjects have taken complete dose.
-
In this case, the data from a period in which 
an incomplete dose is taken would be 
considered as missing at random and 
excluded from analyses. 
-
If the drug formulation is changed in the 
future studies, this estimate will provide the 
true relationship between the actual dose 
intake and its exposure under this strategy.
Supplementary analysis 
-
The strategy will be a Treatment policy 
strategy, where we are interested in the 
treatment effects regardless of the actual 
amount of dose taken.
-
The analysis will include PK parameters 
derived based on concentrations of both 
complete and partial doses (if data permits 
based on criteria described in Section 8.1.1.2) 
and will be analysed using the nominal or 
prescribed dose.
-
If the drug formulation remains unchanged in 
the future studies, this estimate will provide 
the true relationship between a nominal dose 
and its exposure under this strategy, i.e., close 
to a real-world situation.
Subject 
drops out 
due to 
Related to 
treatment/
If the adverse 
event is confirmed 
-
The primary strategy will be a Hypothetical 
strategy, where we are interested in the 
treatment effects in a hypothetical scenario 
where discontinuation due to an AE would 
not happen. 


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Adverse 
events
to be related to 
study treatment
-
The missing data after discontinuation will 
assumed to be missing at random
-
The derived PK parameters of the last fully or 
partially completed period will be calculated 
if data permits (See section 8.1.1.2 Derived 
Pharmacokinetic Parameters for details on 
derivation criteria).
8.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Error! Reference source not found.: List 
of Data Displays and will be based on GSK Data Standards and statistical principles.
Graphical presentations will be provided if appropriate. All data will be listed.
8.2.5.1.
Statistical Methodology Specification
The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department.
(1) Statistical analysis for comparison of food effect – Single dose study part
Endpoint / Variables

AUC (0-t)

AUC(0-∞) 

Cmax
Model Specification

Loge-transformed data will be statistically analysed using a Mixed model. 

The mixed model will contain  
o
Fixed effect: fed or fasted status, period and their interaction term (if tested 
as significant)
o
Random effect: subject

Only data of subjects participating in Cohort 3 will be included in this analysis, all other dose 
level data from Cohorts 1 and 2 will be excluded from this analysis.

The Kenward and Roger method for approximating the denominator degrees of
freedom and correcting for bias in the estimated variance-covariance of the fixed effects will 
be used. 

An unstructured type of the covariance matrices R (accounting for the within subject 
variability) and G (accounting for the between subject variability) will be used.

Based on the intercurrent events observed in the study, appropriate strategies from Table 3 
in Section 8.2.4 will be considered for handling of missing data (if any) and interpretation of 
food effect analysis results. If multiple intercurrent events are observed (for e.g., if the 


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subject does not take the full treatment as well he withdraws study consent), then the data 
will be handled using more than one strategy as described in Table 3 and interpretations of 
the results will be made accordingly.
Model Checking & Diagnostics

For the Mixed model, model assumptions will be checked, and appropriate
adjustments may be applied based on the data.

Distributional assumptions underlying the model used for analysis will be examined
by obtaining a normal probability plot of the residuals and a plot of the residuals
versus the fitted values (i.e. checking the normality assumption and constant
variance assumption of the model respectively) to gain confidence that the model
assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative
transformations, such as data squared or square root of data, will be explored.

Non-parametric analyses will be conducted if the normality assumption does not
hold for any of the alternative transformations.

If this model fails to converge, alternative covariance structures may be considered in the 
following order (1) Compound Symmetry (CS) and (2) Variance Components (VC).
Model Results Presentation

Point estimates and corresponding 90% confidence intervals will be constructed for the 
comparisons of interest of GSK3186899 fed – GSK3186899 fasted, based on the log-
transformed data.

These loge-transformed results will then be exponentially back-transformed to provide point 
estimates and corresponding 90% confidence intervals for the geometric mean ratios 
(GSK3186899 fed: GSK3186899 fasted).


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8.3.
Statistical analysis for dose proportionality – Single and 
Repeat dose study parts
8.3.1.
Endpoints/Variables
To assess the dose proportionality, the statistical analysis will be based on AUC, Cmax
and Ctau variables, as appropriate in the single and repeat dose study part.
8.3.2.
Summary Measure
The summary measure will be the point estimates and 90% CIs of mean slopes of 
loge(dose) in the single and repeat dose study part.
8.3.3.
Population of Interest
These analyses will be based on the PK population.
8.3.4.
Strategy for Intercurrent (Post-Randomization) Events
In the Table 4 below, the possible intercurrent events and the rationale for relating them 
to treatment or otherwise is described. Once a subject discontinues from study treatment, 
they will proceed straight to follow up and no further data will be collected.
All subjects’ data will be included in data listings irrespective of the strategies followed 
for the analysis. 
If feasible, subjects will be replaced until the desired sample size is attained.
Table 4 Strategies for Intercurrent events
Intercurrent 
events
Relation to 
treatment and 
rationale
Strategy, rationale and details of action taken
Subject 
withdraws 
study 
consent
Not related to 
treatment/ 
Subject drops out 
due to logistic 
reasons and not 
due to any event 
related to treatment
-
The strategy will be a While-on-Treatment 
strategy, where we are interested in the 
treatment effects prior to the withdrawal only. 
-
Subjects’ data available up to the withdrawal 
will be included in the dose proportionality 
analyses. 
-
If a subject withdraws consent during a 
period, the missing data post withdrawal will 
not be imputed. 
-
The derived PK parameters for e.g., AUC, 
Cmax etc. of that partially completed period 
will be calculated if data permits (See section 


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8.1.1.2 Derived Pharmacokinetic Parameters
for details on derivation criteria).
Subject does 
not take the 
full 
treatment
Not related to 
treatment/
The treatment will 
be administered as 
a powder dissolved 
in diluent.  To 
ensure all 
treatment is 
ingested, the bottle 
containing the 
dispersion will be 
rinsed three times 
and the subject 
will be expected to 
ingest this in 
addition to the 
initial dispersion. 
If three rinses are 
not all ingested, 
the subject may 
not take the full 
treatment dose.
In the current formulation, it is hard to measure 
the exact proportion of dose ingested if not all 
rinses are taken. It is also uncertain whether the 
formulation could change in future development. 
To account for this, we propose two different 
strategies described below. If this intercurrent 
event is not observed, then both strategies will 
provide the same results and only the hypothetical 
strategy will be presented for the final analysis.
Primary analysis 
-
The strategy will be a Hypothetical strategy,
where we are interested in the treatment 
effects in a hypothetical scenario where all 
subjects have taken complete dose.
-
In this case, the data from a period in which 
an incomplete dose is taken would be 
considered as missing at random and 
excluded from analyses. 
-
If the drug formulation is changed in the 
future studies, this estimate will provide the 
true relationship between the actual dose 
intake and its exposure under this strategy.
Supplementary analysis 
-
The strategy will be a Treatment policy 
strategy, where we are interested in the 
treatment effects regardless of the actual 
amount of dose taken.
-
The analysis will include PK parameters 
derived based on concentrations of both 
complete and partial doses (if data permits 
based on criteria described in Section 8.1.1.2) 
and will be analysed using the nominal or 
prescribed dose.
-
If the drug formulation remains unchanged in 
the future studies, this estimate will provide 
the true relationship between a nominal dose 
and its exposure under this strategy, i.e., in a 
close to real-world setting
Subject 
drops out 
Related to 
treatment/
-
The primary strategy will be a Hypothetical 
strategy, where we are interested in the 


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due to 
Adverse 
events
If the adverse 
event is confirmed 
to be related to 
study treatment
treatment effects in a hypothetical scenario 
where discontinuation due to an AE would 
not happen. 
-
The missing data after discontinuation will 
assumed to be missing at random
-
The derived PK parameters of the last fully or 
partially completed period will be calculated 
if data permits (See section 8.1.1.2 Derived 
Pharmacokinetic Parameters for details on 
derivation criteria).
8.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Error! Reference source not found.: List 
of Data Displays and will be based on GSK Data Standards and statistical principles. 
Graphical presentations will be provided if appropriate. All data will be listed.
8.3.5.1.
Statistical Methodology Specification
The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department.
(2) Statistical analysis for dose proportionality – Single and Repeat dose study parts
Endpoint / Variables

For SAD part: AUC(0-∞), Cmax

For MAD part: AUC(0-tau), Cmax, Ctau
Model Specification

Power model 
; = < ∗! =
where y denotes the PK parameter being analyzed, dose denotes the total dose 
administered to a subject. The < denotes random subject effect in the repeat dose Part B. In 
the crossover single ascending dose Part A, alpha depends upon random subject effect and 
period effect.

Loge transformed data will be analysed by fitting the following terms in the mixed effect 
model:
o
Fixed effect: loge (dose), period (period will be included in SAD part only)
o
Random effect: Subject

Data from all available doses in each part of the study will be considered (as described 
in Section 8.1.1.2). 


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
An unstructured covariance structure will be considered for the G matrix describing the 
between subject variability.

Based on the intercurrent events observed in the study, appropriate strategies from 
Table 4 in Section 8.3.4 will be considered for handling of missing data (if any) and 
interpretation of the analysis results. If multiple intercurrent events are observed (for 
e.g., if the subject does not take the full treatment as well he withdraws study consent), 
then the data will be handled using more than one strategy as described in Table 4 and 
interpretations of the results will be made accordingly.
Model Checking & Diagnostics

For the Mixed Model, model assumptions will be checked, and appropriate
adjustments may be applied based on the data.

Distributional assumptions underlying the model used for analysis will be examined
by obtaining a normal probability plot of the residuals and a plot of the residuals
versus the fitted values (i.e., checking the normality assumption and constant
variance assumption of the model respectively) to gain confidence that the model
assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative
transformations, such as data squared or square root of data, will be explored.

Non-parametric analyses will be conducted if the normality assumption does not
hold for any of the alternative transformations.
Model Results Presentation

Estimates of the mean slopes of loge(dose) will be reported along with corresponding 90% 
confidence intervals (slope ≈ 1 implied dose proportionality).


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8.4.
Statistical analysis for dose accumulation – Repeat dose 
study part
8.4.1.
Endpoints/Variables
To assess the dose accumulation, the statistical analysis will be based on the ratios of 
RAUC(0-tau), RCmax and RCtau respectively.
8.4.2.
Summary Measure
The summary measure will be the point estimates and 90% CIs of mean differences of 
‘Day 10 – Day 1’ based on the log-transformed data and after back-transformation of this 
estimated differences, the geometric means of the ratio ‘Day 10: Day 1’ will be 
presented.
8.4.3.
Population of Interest 
These analyses will be based on the PK population.
8.4.4.
Strategy for Intercurrent (Post-Randomization) Events
In the Table 5 below, the possible intercurrent events and the rationale for relating them 
to treatment or otherwise is described. Once a subject discontinues from study treatment, 
they will proceed straight to follow up and no further data will be collected.
All subjects’ data will be included in data listings irrespective of the strategies followed 
for the analysis. 
If feasible, subjects will be replaced until the desired sample size is attained.
Table 5 Strategies for Intercurrent events
Intercurrent 
events
Relation to 
treatment and 
rationale
Strategy, rationale and details of action taken
Subject 
withdraws 
study 
consent
Not related to 
treatment/ 
Subject drops out 
due to logistic 
reasons and not 
due to any event 
related to treatment
-
The strategy will be a While-on-Treatment 
strategy, where we are interested in the 
treatment effects prior to the withdrawal only. 
-
Subjects’ data available up to the withdrawal 
will be included in the dose accumulation 
analyses. 
-
If a subject withdraws consent during a 
period, the missing data post withdrawal will 
not be imputed. 
-
The derived PK parameters for e.g., AUC, 
Cmax etc. of that partially completed period 
will be calculated if data permits (See section 


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8.1.1.2 Derived Pharmacokinetic Parameters
for details on derivation criteria).
Subject does 
not take the 
full 
treatment
Not related to 
treatment/
The treatment will 
be administered as 
a powder dissolved 
in diluent.  To 
ensure all 
treatment is 
ingested, the bottle 
containing the 
dispersion will be 
rinsed three times 
and the subject 
will be expected to 
ingest this in 
addition to the 
initial dispersion. 
If three rinses are 
not all ingested, 
the subject may 
not take the full 
treatment dose.
In the current formulation, it is hard to measure 
the exact proportion of dose ingested if not all 
rinses are taken. It is also uncertain whether the 
formulation could change in future development. 
To account for this, we propose two different 
strategies described below. If this intercurrent 
event is not observed, then both strategies will 
provide the same results and only the hypothetical 
strategy will be presented for the final analysis.
Primary analysis 
-
The strategy will be a Hypothetical strategy,
where we are interested in the treatment 
effects in a hypothetical scenario where all 
subjects have taken complete dose.
-
In this case, the data from a period in which 
an incomplete dose is taken would be 
considered as missing at random and 
excluded from analyses. 
-
If the drug formulation is changed in the 
future studies, this estimate will provide the 
true relationship between the actual dose 
intake and its exposure under this strategy.
Supplementary analysis 
-
The strategy will be a Treatment policy 
strategy, where we are interested in the 
treatment effects regardless of the actual 
amount of dose taken.
-
The analysis will include PK parameters 
derived based on concentrations of both 
complete and partial doses (if data permits 
based on criteria described in Section 8.1.1.2) 
and will be analysed using the nominal or 
prescribed dose.
-
If the drug formulation remains unchanged in 
the future studies, this estimate will provide 
the true relationship between a nominal dose 
and its exposure under this strategy, i.e., close 
to a real-world setting.
Subject 
drops out 
Related to 
treatment/
-
The primary strategy will be a Hypothetical 
strategy, where we are interested in the 


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due to 
Adverse 
events
If the adverse 
event is confirmed 
to be related to 
study treatment
treatment effects in a hypothetical scenario 
where discontinuation due to an AE would 
not happen. 
-
The missing data after discontinuation will 
assumed to be missing at random
-
The derived PK parameters of the last fully or 
partially completed period will be calculated 
if data permits (See section 8.1.1.2 Derived 
Pharmacokinetic Parameters for details on 
derivation criteria).
8.4.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Error! Reference source not found.: List 
of Data Displays and will be based on GSK Data Standards and statistical principles. 
Graphical presentations will be provided if appropriate. All data will be listed.
8.4.5.1.
Statistical Methodology Specification
The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department.
Statistical analysis for dose accumulation – Repeat dose study part
Endpoint / Variables

RAUC(0-tau)

RCmax 

RCtau
Model Specification

Will be statistically analysed using a mixed model (MM) using a loge-transformation. The 
mixed model will contain:
o
Fixed effects: dose, day and dose*day
o
Random effect: Subject
Here dose denotes the total dose administered per day to a subject.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured type of the covariance matrices R (accounting for the within subject 
variability) and G (accounting for the between subject variability) will be used.

Based on the intercurrent events observed in the study, appropriate strategies from Table 5 
in Section 8.4.4 will be considered for handling of missing data (if any) and interpretation of 
the analysis results. If multiple intercurrent events are observed (for e.g., if the subject does 


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not take the full treatment as well he withdraws study consent), then the data will be handled 
using more than one strategy as described in Table 5 and interpretations of the results will 
be made accordingly.
Model Checking & Diagnostics

For the Mixed Model, model assumptions will be checked, and appropriate
adjustments may be applied based on the data.

Distributional assumptions underlying the model used for analysis will be examined
by obtaining a normal probability plot of the residuals and a plot of the residuals
versus the fitted values (i.e. checking the normality assumption and constant
variance assumption of the model respectively) to gain confidence that the model
assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative
transformations, such as data squared or square root of data, will be explored.

Non-parametric analyses will be conducted if the normality assumption does not
hold for any of the alternative transformations.

If this model fails to converge, alternative covariance structures may be considered in the 
following order (1) Compound Symmetry (CS) and (2) Variance Components (VC).
Model Results Presentation

For each dose, point estimates and 90% confidence intervals for the differences “Day 10 -
Day 1” will be presented based on the log-transformed data.

These point estimates and associated 90% confidence intervals will then be exponentially 
back-transformed to provide point and 90% confidence interval estimates for the ratios “Day 
10: Day 1” for each active dose. 

If both the dose and day by dose interaction terms are not significant, and only day effect is 
significant based on the data, then to evaluate the effect of day, a single point estimate and 
confidence interval pooled across all doses by day will be constructed.


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8.5.
Statistical analysis for time invariance ratio of GSK3186899 
– Repeat dose study part
8.5.1.
Endpoints/Variables
To assess the time invariance dose accumulation, the statistical analysis will be based on 
the ratio of AUC(0-tau) (i.e., AUC(0-12) if dosing is BID or, AUC(0-8) if dosing is TID)
on day 10 to AUC(0-∞) on day 1, if data permits.
8.5.2.
Summary Measure
The summary measure will be the point estimate and 90% CIs of mean difference of 
‘AUC(0-tau) at Day 10 – AUC(0-∞) at Day 1’ based on the log-transformed data and 
after back-transformation of this estimated difference, the geometric mean of the ratio 
‘AUC(0-tau) at Day 10 : AUC(0-∞) at Day 1’ will also be presented.
8.5.3.
Population of Interest 
This analysis will be based on the PK population.
8.5.4.
Strategy for Intercurrent (Post-Randomization) Events
In the Table 6 below, the possible intercurrent events and the rationale for relating them 
to treatment or otherwise is described. Once a subject discontinues from study treatment, 
they will proceed straight to follow up and no further data will be collected.
All subjects’ data will be included in data listings irrespective of the strategies followed 
for the analysis. 
If feasible, subjects will be replaced until the desired sample size is attained.
Table 6 Strategies for Intercurrent events
Intercurrent 
events
Relation to 
treatment and 
rationale
Strategy, rationale and details of action taken
Subject 
withdraws 
study 
consent
Not related to 
treatment/ 
Subject drops out 
due to logistic 
reasons and not 
due to any event 
related to treatment
-
The strategy will be a While-on-Treatment 
strategy, where we are interested in the 
treatment effects prior to the withdrawal only. 
-
Subjects’ data available up to the withdrawal 
will be included in the time invariance 
accumulation rate analyses. 
-
If a subject withdraws consent during a 
period, the missing data post withdrawal will 
not be imputed. 
-
The derived PK parameters for e.g., AUC, 
Cmax etc. of that partially completed period 


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will be calculated if data permits (See section 
8.1.1.2 Derived Pharmacokinetic Parameters
for details on derivation criteria).
Subject does 
not take the 
full 
treatment
Not related to 
treatment/
The treatment will 
be administered as 
a powder dissolved 
in diluent.  To 
ensure all 
treatment is 
ingested, the bottle 
containing the 
dispersion will be 
rinsed three times 
and the subject 
will be expected to 
ingest this in 
addition to the 
initial dispersion. 
If three rinses are 
not all ingested, 
the subject may 
not take the full 
treatment dose.
In the current formulation, it is hard to measure 
the exact proportion of dose ingested if not all 
rinses are taken. It is also uncertain whether the 
formulation could change in future development. 
To account for this, we propose two different 
strategies described below. If this intercurrent 
event is not observed, then both strategies will 
provide the same results and only the hypothetical 
strategy will be presented for the final analysis.
Primary analysis 
-
The strategy will be a Hypothetical strategy,
where we are interested in the treatment 
effects in a hypothetical scenario where all 
subjects have taken complete dose.
-
In this case, the data from a period in which 
an incomplete dose is taken would be 
considered as missing at random and 
excluded from analyses. 
-
If the drug formulation is changed in the 
future studies, this estimate will provide the 
true relationship between the actual dose 
intake and its exposure under this strategy.
Supplementary analysis 
-
The strategy will be a Treatment policy 
strategy, where we are interested in the 
treatment effects regardless of the actual 
amount of dose taken.
-
The analysis will include PK parameters 
derived based on concentrations of both 
complete and partial doses (if data permits 
based on criteria described in Section 8.1.1.2) 
and will be analysed using the nominal or 
prescribed dose.
-
If the drug formulation remains unchanged in 
the future studies, this estimate will provide 
the true relationship between a nominal dose 
and its exposure under this strategy, i.e. close 
to a real-world setting.


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Subject 
drops out 
due to 
Adverse 
events
Related to 
treatment/
If the adverse 
event is confirmed 
to be related to 
study treatment
-
The primary strategy will be a Hypothetical 
strategy, where we are interested in the 
treatment effects in a hypothetical scenario 
where discontinuation due to an AE would 
not happen. 
-
The missing data after discontinuation will 
assumed to be missing at random
-
The derived PK parameters of the last fully or 
partially completed period will be calculated 
if data permits (See section 8.1.1.2 Derived 
Pharmacokinetic Parameters for details on 
derivation criteria).
8.5.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Error! Reference source not found.: List 
of Data Displays and will be based on GSK Data Standards and statistical principles. 
Graphical presentations will be provided if appropriate. All data will be listed.
8.5.5.1.
Statistical Methodology Specification
The following statistical analyses will only be performed if sufficient data is available 
(i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department.
Statistical analysis for time invariance ratio of GSK3186899 – Repeat dose study part
Endpoint / Variables

Ratio of AUC(0-tau) on day 10 to AUC(0-∞) on day 1
(This will be calculated only if AUC(0-∞) on day 1 is appropriately estimated)
Model Specification

Will be statistically analysed using a mixed model (MM) using a loge-transformation. The 
mixed model will contain:
o
Fixed effects: day
o
Random effect: Subject

AUC(0-∞) on day 1 will be the reference phase in the analysis, while AUC(0-tau) on day 10 
will be the test phase for BID (or, TID) regimen respectively, using loge-transformed AUC.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured type of the covariance matrices G (accounting for the between subject 
variability) will be used.


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
Based on the intercurrent events observed in the study, appropriate strategies from Table 6 
in Section 8.5.4 will be considered for handling of missing data (if any) and interpretation of 
the analysis results. If multiple intercurrent events are observed (for e.g., if the subject does 
not take the full treatment as well he withdraws study consent), then the data will be handled 
using more than one strategy as described in Table 6 and interpretations of the results will 
be made accordingly.
Model Checking & Diagnostics

For the Mixed Model, model assumptions will be checked, and appropriate
adjustments may be applied based on the data.

Distributional assumptions underlying the model used for analysis will be examined
by obtaining a normal probability plot of the residuals and a plot of the residuals
versus the fitted values (i.e. checking the normality assumption and constant
variance assumption of the model respectively) to gain confidence that the model
assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative
transformations, such as data squared or square root of data, will be explored.

Non-parametric analyses will be conducted if the normality assumption does not
hold for any of the alternative transformations.

If this model fails to converge, alternative covariance structures may be considered in the 
following order (1) Compound Symmetry (CS) and (2) Variance Components (VC).
Model Results Presentation

The summary measure will be the point estimate and 90% CIs of mean difference of 
‘AUC(0-tau) at Day 10 – AUC(0-∞) at Day 1’ based on the log-transformed data and after 
back-transformation of this estimated difference, the geometric mean of the ratio ‘AUC(0-
tau) at Day 10 : AUC(0-∞) at Day 1’ will also be presented.


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9.
REFERENCES

Alves F, Bilbe G, Blesson S et al.  Recent development of visceral leishmaniasis 
treatments: success, pitfalls and perspectives. Clin Microbiol Rev. 2018 Aug 29; 
31(4):e00048-18. 

Committee for Human Medicinal Products. ICH E9 (R1) addendum on estimands and 
sensitivity analysis in clinical trials to the guideline on statistical principles for clinical 
trials, Step 2b. London: European Medicines Evaluation Agency, August 2017. 

Dorlo TP, Rijal S, Ostyn B, de Vries PJ, Singh R, Bhattarai N, Uranw S, Dujardin JC, 
Boelaert M, Beijnen JH, Huitema AD. Failure of miltefosine in visceral leishmaniasis 
is associated with low drug exposure. J Infect Dis. 2014 Jul 1;210(1):146-53.

Dorlo TP1, Huitema AD, Beijnen JH, de Vries PJ. Optimal dosing of miltefosine in 
children and adults with visceral leishmaniasis. Antimicrob Agents Chemother. 2012 
Jul;56(7):3864-72.

FDA Guidance for industry: Estimating the maximum safe dose in initial clinical trials 
for therapeutics in adult healthy volunteers. 2005
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf


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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
10.1.1.
Exclusions from Analysis Population
Per protocol population is not defined in this protocol. 
Important protocol deviations and violations of the inclusion and exclusion criteria will 
be listed.


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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events in PART A (Cohorts 1-3)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
======X======
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams made full 
exams, by the Investigator, as deemed necessary (e.g. where safety or 
laboratory findings indicate). Tests will be conducted within site 
specified standards.
Brief Physical Examination
X
X
X
X
Drug/Alcohol/Smoking Screen
X
X
Tests include alcohol breath test, smoking breath test and urine drug 
screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
FSH + Oestradiol
X
Females only, if required
Holter Monitoring (48 hours)
X
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
If trace protein in urine is detected, a repeat test can be performed 
(within 24 hours). If tests are considered abnormal, further 
quantification is required.
Non-fasted samples can be collected on Day -1 and the Follow-Up 
Visit. All other samples to be collected in a fasted state.
Urine Sampling (metabolism)
X
X
A urine sample will be taken pre-dose (approx. 20mL) All urine from 
each participant will be collected from 0-24 hrs post dosing. Details of 
urine collection and processing are described in the SRM.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Safety biomarkers (KIM1, NGAL, 
Urinary albumin)
X
X
First urine sample of the morning to be collected (Day 1 sample 
collection should be pre-dose). 
Additional samples may be collected, as deemed necessary by the 
Investigator (e.g. where safety or laboratory findings indicate).
PK Blood Sampling
X
X
PK blood samples to be taken pre-dose on Day 1 and then at the 
following time points post first-dose:  10min, 30min, 1hr, 1.5hr, 2hr, 
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, 12hr; 24hr. 
The time points stated may be modified depending on emerging SAD 
PK information as appropriate.
Blood volumes to be collected include 2 mL for all time-points from pre-
dose to 10 hrs, and 5 mL for time-points 12hr and 24 hr.
12-Lead ECG
X
X
T
X
X
Vital signs to include HR, BP, temperature and respiration rate. BP will 
be conducted in both a supine and standing position if participant 
develops any signs/symptoms which in the investigator’s opinion are 
suggestive of adrenal insufficiency.
12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose 
on Day 1 and then at the subsequent time points post-dose: 
30 min, 1 hr, 1.5hr, 2hr, 2.5hr, 4hr, 8hs, 12hr, 24 hr, 48 hr
Timings will be reviewed as cohorts progress and may be adjusted to
ensure appropriate measurements relative to peak concentrations for
subsequent cohorts.
T = Triplicate (for all assessments, except temperature and respiratory 
rate).
If any abnormal ECG reading is recorded, refer to Section Error! 
Reference source not found. for appropriate action. 
Vital Signs
X
X
T
X
X
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up 
(14-21 days post 
last dose)
/Early 
Withdrawal
Notes
-1
1
2
3
4
Telemetry
X
Continuous at least 24hr post-dose. Initiate at least 15 min. prior to 
dosing.
Meals
X
X
X
X
X
Fasting regimen: On Day 1, participants will have fasted 8hr overnight 
prior to dosing. An adapted standard breakfast will be served 
approximately 3 hours after dosing.
Fed regimen: On Day 1, participants will fast 8hr overnight and an 
adapted standard breakfast will be served approximately 30 minutes 
prior to dosing. 
Meals will be served as per the site schedule on Days -1, 2, 3 and 4.
Water permitted on an ad lib basis up to 1hr before dosing. No water 
to be taken in the hour prior to dosing except for the liquid part of the 
adapted standard breakfast for the Fed regimen. At least 8 fl oz 
(240ml) to be taken 1 hour after dosing. No water to be taken in the 
hour after dosing except for the rinse of the dose.
Bile Sampling (Entero-test)
X
Cohort 3 only. Entero-test bile string swallowed 2 hr post-dose, after 
5 hr the bile string will be removed.
Randomization
X
Study Treatment
X
AE Review
=======X=======
X
SAE Review
X
=======X=======
X
Concomitant Medication Review
X
=======X=======
X


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10.2.2.
Protocol Defined Schedule of Events in PART B (Cohorts 4-6)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Outpatient Visit
X
X
Admission to 
Clinical Unit
X
Inpatient Stay at 
Clinical Unit
=========================X=========================
Discharge from 
Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and 
Exclusion Criteria
X
Demography
X
Full Physical 
Examination
X
Additional exams/screens may be 
performed, or brief exams made full 
exams, by the Investigator, as deemed 
necessary (e.g. where safety or laboratory 
findings indicate). Tests will be conducted 
within site specified standards.
Brief Physical 
Examination
X
X
X
X
X
Drug/Alcohol/Smoki
ng Screen
X
X
Tests include alcohol breath test, smoking 
breath test and urine drug screen.
Medical/Medication/
Drug/Alcohol 
History
X
HIV, Hepatitis B 
and C Screening
X
FSH + Oestradiol 
X
Females only, if required
Holter Monitoring 
(48 hour)
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Haem/Chem/
Urinalysis Test 
(Include Liver 
Chemistries)
X
X
X
X
X
X
X
X
X
X
If trace protein is detected, a repeat test 
can be performed.
Sample to be drawn pre-dose on Days 2, 
4, 6, 8 and 10.
Non-fasted samples can be collected on 
Day -1 and Follow-Up Visit. All other 
samples to be collected in fasted state.
Cortisol Test
X
X
Tests to be performed in the early 
morning on Day -1 and Day 11. 
If levels are <420 nmol/L, then a ACTH 
stimulation test will be performed to 
assess hypothalamic pituitary adrenal 
(HPA) axis.
Safety biomarkers 
(KIM1, NGAL, 
Urinary albumin)
X
X
First urine sample of the morning to be 
collected (pre-dose). 
Additional samples may be collected, as 
deemed necessary by the Investigator 
(e.g. where safety or laboratory findings 
indicate).
Telemetry 
X
X
Continuous at least 24 hr post-evening 
dose. Initiate at least 15 min. prior to 
dosing.
Randomization
X
Study Treatment
X
X
X
X
X
X
X
X
X
X
BID dosing: GSK3186899 or placebo will 
be administered using a 12hr dosing 
interval. If a different dosing regimen is 
used, refer to Appendix 5 of Protocol.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
12-Lead ECG
X
X
T
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, temperature 
and respiration rate. BP will be conducted 
in both a supine and standing position if 
participant develops any signs/symptoms 
which in the investigators opinion are 
suggestive of adrenal insufficiency.
12-Lead ECG and Vital Signs to be 
conducted on Day-1 and pre-dose Day 1
and then at the subsequent time points 
post first-dose: 30 min, 1 hr, 1.5hr, 2hr, 
2.5hr, 4hr, 6hr, 13hr and 14hr
For Days 2-10: pre-dose assessments 
only. 
Timings will be reviewed as cohorts 
progress and may be adjusted to
ensure appropriate measurements 
relative to peak concentrations for
subsequent cohorts
If a different dosing regimen is used, refer 
to Appendix 5 for alternative ECG and 
Vital Signs time-points.
T = Triplicate (for all assessments except 
temperature and respiratory rate).
If any abnormal ECG reading is recorded, 
refer to Section Error! Reference source 
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
not found. of protocol for appropriate 
action.
PK Blood sampling
<=====================X=====================>
PK samples will be collected pre-dose 
and at the following time points post first-
dose:
Day 1: 10min, 30min, 1hr, 1.5hr, 2hr, 
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, and 
12hr 
Days 2 – 9: Pre-dose PK samples 
collected for each dose
Day 10: PK samples will be collected pre-
dose and at the following time points post 
first-dose: 10min, 30min, 1hr, 1.5hr, 2hr, 
2.5hr, 3hr, 4hr, 5hr, 6hr, 8hr, 10hr, and 
12hr.
The time points stated may be modified 
depending on emerging SAD PK profiles. 
If a different dosing regimen is used, refer 
to Appendix 5 of Protocol for alternative 
PK blood sampling time-points.
Blood volumes to be collected include:
2 mL for post-dose 0-11 hrs, and 
5 mL for post-dose 12-24 hrs (Days 1 
and 10).
Urine Sampling 
(metabolism)
X
X
A urine sample will be taken pre-dose 
(approx. 20mL).  All urine from each 
participant will be collected from 0-24 hrs 
post dosing. Details of urine collection and 
processing are described in the SRM.


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
Meals 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If on fed regimen: On Day 1 through to 
D10, participants will receive an adapted 
standard meal 30 mins prior to dosing.
If on fasted regimen: On Day 1 through 
to D10, participants will have fasted 8hr 
overnight prior to dose 1. A breakfast will 
be served approximately 2hr after dose 1. 
Dinner will be served at least 2hr prior to 
dose 2. A snack may be consumed 
approximately 2hr after dose 2. 
Participants will receive standardized 
meals scheduled at the same time in each 
period. If a different dosing regimen is 
used, refer to Appendix 5 for alternative 
meal times.
Meals will be served as per the site 
schedule on Days -1 and Days 11-13.
Water permitted on an ad lib basis up to 
1hr before dosing. No water to be taken in 
the hour prior to dosing except for the 
liquid part of the adapted standard 
breakfast for the Fed regimen. 
At least 8 fl oz (240ml) to be taken 1 hour 
after dosing No water to be taken in the 
hour after dosing except for the rinse of 
the dose.
AE review
============================X============================
X


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Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up 
(14-21 days 
post last 
dose) / 
Early 
Withdrawal
Notes
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
SAE review
X
============================X============================
X
Concomitant 
medication review
X
============================X============================
X

The timing and number of planned study assessments, including safety, pharmacokinetic or other assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any 
safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF).


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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
Nominal time will be used for all analysis except PK analysis where planned and actual 
time will be used.


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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
For each period in Part A Cohorts 1, 2 and 3, assessments and events will be classified 
according to the following phases:
Study Phase
Definition
Pre-Treatment 
Date and time < Study Treatment Start Date and time of each period
Treatment
Study Treatment Start Date and time ≤ Date and time ≤ Study Treatment End Date
and time + 24 hours, in each period
Post-Treatment
Date and time > Study Treatment End Date and time + 24 hours, within each period
Note: Estimated half-life of GSK3186899 is approx. 1.3 hours. The maximum of (5 half-
lives (~ 6.5 hours) and 24 hours) after the Study Treatment End Date and time have been 
considered to define the end of treatment phase. If half-life is longer than 5 hours, then 
the definition will be revised accordingly.
Post-treatment phase will additionally include any events occurring in the washout period 
before start of the next treatment dose.
For the interim, the start of the period will be defined from the first dose of the period and 
then the end of the period is just before the first dose in the next period. For the final 
period the end date is just before the withdrawal/follow up visit.
For Part B Cohorts 4, 5 and 6, assessments and events will be classified according to the 
following:
Study Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date of each Cohort
Treatment
Study Treatment Start Date and time ≤ Date and time ≤ Study Treatment End Date
and time + 24 hours, in each cohort
Post-Treatment
Date and time > Study Treatment End Date and time 24 hours, in each cohort
Note: Estimated half-life of GSK3186899 is approx. 1.3 hours. The maximum of (5 half-
lives (~ 6.5 hours) and 24 hours) after the Study Treatment End Date and time have been 
considered to define the end of treatment phase. If half-life is longer than 5 hours, then 
the definition will be revised accordingly.
10.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before to the screening visit
Concomitant
Any medication that is not a prior


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NOTES: 

Please refer to Appendix 7: 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.
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment Emergent

If AE onset date is on or after treatment start date and time, it is considered as 
treatment emergent

For Part A, if AE onset is during one period and worsens during a later period it 
would be counted in both periods. 
o
For the initial period the logic would be as above. 
o
For the later period the logic would use the treatment dates 
associated with the later period:
Treatment Period Start Date ≤ AE Worsening Date ≤ Study 
Treatment Stop Date 
NOTES: 

If the study treatment stop date is missing, then the AE will be considered as On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: \\UK1SALX00175.corpnet2.com\
HARP Compound
: \arprod\gsk3186899\mid208436\
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 for SAC.
10.5.2.
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 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings
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 as 
indicated below but may be adjusted to a clinically interpretable number of DP’s.

Display all numeric variables with the same number of decimal places as the collected 
precision.

Display minimum and maximum values with the same number of decimal places as the 
collected precision.

Display the mean and percentiles (e.g. median, Q1, and Q3) with one additional 
decimal place.

Display the standard deviation and standard error with two additional decimal places.

Within a column, align all data values or summary statistics along the decimal point.


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The reported precision for PK concentration data will be 1 decimal place but may be altered by 
parameter depending on the significant digits.
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 figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
10.5.3.
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
[SOP_514512]. 
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
None. All PK parameters will be derived by the CPMS Pharmacokineticist.
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters guidance.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Loge-transformed data:
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) of loge
transformed data and between subject


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geometric coefficient of variation (CVb (%)) will be reported.
CVb (%) = √ (exp(SD2) – 1) * 100
[NOTE: SD = SD of loge transformed data]
Parameters Not Being Loge Transformed: Tmax and T1/2.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
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 and Period Study Day

In PART A for each period: Period Study day is calculated as the number of days from first Dose 
Date in the period for each subject as follows:

Ref Date = Missing              →Period Study Day = Missing 

Ref Date < First Dose Date in the period →Period Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date in the period→Period Study Day = Ref Date – First Dose Date + 1    

In Part A and Part B: Study day is calculated as the number of days from First Dose Date in each 
Cohort for each subject as:

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    
10.6.2.
Study Population
Treatment Exposure and Compliance
For Parts A and B:

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Doses taken/ (Planned Treatment Duration in Days * 
Frequency)
where Frequency will be 1 for OD, 2 for BID or 3 for TID. Treatment compliance could be greater 
than 100% if there are events of overdose. 

Planned Treatment Duration is defined as 10 days, for each Cohort in Part B. As Part A is single 
dose this would be one day.

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure (in Days) = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
For Part B:

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)


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Treatment Exposure and Compliance

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’. 
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2
10.6.3.
Safety
Adverse Events
[AE’S OF Special Interest]

Stomach erosion

Adrenal insufficiency

Renal impairment (Note: Protocol defines renal stopping and withdrawal criteria which are not “renal 
impairment” in the strict sense)
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes,
has a non-detectable level reported in the database, where the numeric value is
missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less
than x or greater than x in the comment field) is present, the number of decimal places
in the observed values will be used to determine how much to add or subtract in order
to impute the corresponding numeric value.
o
Example 1: 2 Decimal Places = ‘< x’ becomes x – 0.01
o
Example 2: 1 Decimal Places = ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
o
For values ‘<=x’ or ‘>=x’ the value itself (‘x’) should be imputed as the numeric value.

Renal biomarker data will be included in the final study analysis. The parameters will be 
corrected using the following formula, and the units are ng/mg
Corrected KIM-1=8.8*Urine KIM-1(pG/mL)/Urine Creatinine (umol/L)
Corrected NGAL=8800*Urine NGAL(nG/mL)/Urine Creatinine (umol/L)
10.6.4.
Pharmacokinetic
PK parameters

The PK Population will include all subjects who undergo PK sampling and have
evaluable PK concentration results.

See Section 8.1 for derived Pharmacokinetic parameters


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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as the 
completion of all phases of the study including the last scheduled procedure shown in 
SoA (Appendix 2). The end of study is defined as the date of the last visit of the last 
participant in the study or last scheduled procedure shown in the SoA for the last 
participant in the trial.

Withdrawn subjects 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.
10.7.2.
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. Unless specified otherwise,
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.
Missing safety data (for e.g., lab, ECG, Vitals, etc.) will not be imputed.
Missing PK data may be imputed (if required) by the Estimand strategy and will be 
outlined in the final RAP.
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.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Missing or Partial start/end date and time are not expected for Adverse events.
Concomitant 
Medications/
Medical 
History
Partial dates for any concomitant medications recorded in the CRF will be imputed using the 
following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month

If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.
The recorded partial date will be displayed in listings.

For assigning periods:


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Element
Reporting Detail

If start date is completely missing, then we assume the medication has been taken 
from the beginning of the study

If stop date is completely missing, then we assume the medication has been taken 
until the end of the study
If start and stop date are completely missing, then we assume the medication has been 
taken for the duration of the study


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10.8.
Appendix 8: Values of Potential Clinical Importance
The values of potential clinical importance for Laboratory, ECG and Vital signs are listed 
in this section.
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
%
Male
<37
>50
Female
<33
>45
∆from BL
N/A
> 7.5%
Hemoglobin 
g/L
Male
<130
>170
Female
<115
>155
∆from BL
N/A
> 30 g/L
Lymphocytes 
x109/ L
<1.2
>3.65
Neutrophils
x109/ L
<2
>7.5
Monocytes
x109/ L
<0.2
>1
Basophils
x109/ L
<0.0
>0.1
Platelet Count 
x109/ L
<150
>400
While Blood Cell Count (WBC)
x109/ L
<3.0
>10
Red Blood Cell Count (RBC)
x1012/L
Male
<4.4
>5.8
Female
<3.95
>5.15
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
< 34
> 50
Calcium
mmol/L
< 2.2
> 2.6
Creatinine
umol/L
Male
< 66
> 112
Female
< 49
> 92
Glucose (Fasted)
mmol/L
< 3.9
> 5.8
Magnesium
mmol/L
< .6
> 1
Phosphate
mmol/L
< 0.87
> 1.45
Potassium
mmol/L
< 3.5
> 5.1
Sodium
mmol/L
< 135
> 145
Gamma GT
g/L
< 7.7
> 17.3


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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Alkaline phosphatase
U/L
Female
< 35
> 104
Male
< 40
> 129
AST/SGOT 
U/L
Male
< 0
> 37
Female
< 0
> 31
ALT/SGPT
U/L
Male
< 10
> 50
Female
< 10
> 35
Total Bilirubin 
µmol/L
< 0
> 20
Direct Bilirubin 
µmol/L
< 0
> 20
Total Protein
g/L
< 63
> 83
10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTcF during the 
study (i.e. post dose)
msec
>500
Absolute PR Interval
msec
< 110
>220
Absolute QRS Interval
msec
< 75
>120
Change from Baseline
Increase from Baseline QTc
msec
>60
10.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
<85
>160
Diastolic Blood Pressure
mmHg
<45
>100
Heart Rate
bpm
<40
>110
Tympanic temperature
°C
<35
>38
Respiratory rate
Breaths/min
<10
>25


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10.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
Not applicable.
10.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
Not applicable.
10.11.
Appendix 11: Abbreviations & Trade Marks
10.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
AUC
Area under the concentration-time curve
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DEC
Dose escalation committee
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FTIH
First Time in Human
GSK
GlaxoSmithKline
IA
Interim Analysis
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System


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Abbreviation
Description
IP
Investigational Product
LDH
Lactate Dehydrogenase 
MAD
Multiple Ascending Dose
MCH
Mean Corpuscular Haemoglobin
MCV
Mean Corpuscular Volume
NGAL
Neutrophil gelatinase-associated lipocalin
NOAEL
No Observable Adverse Effect Limit
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTc
Electrocardiogram QT interval corrected for heart rate
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RBC
Red Blood Cells
RAUC
Relative Area Under the Curve
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SAD
Single Ascending dose
SAE
Serious Adverse Event
SDD
Spray Dried Dispersion
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SOA
Schedule of Activities
SOP
Standard Operation Procedure
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Events
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TID
Three-Times Daily
Tmax
Time Taken to Maximum Observed Plasma Drug Concentration
Tlag
Lag time before observation of drug concentrations
t1/2 
Terminal phase half-life

Dosing interval
UK
United Kingdom
ULN
Upper Limit of Normal
VL
Visceral Leishmaniasis


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Abbreviation
Description
WONCBP
Women of Non-Child Bearing Potential
10.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
WinNonlin
SAS
NONMEM


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10.12.
Appendix 12: List of Data Displays
10.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.22
None
Efficacy
Not applicable
Not applicable
Safety
3.1 to 3.34
None
Pharmacokinetic
4.1 to 4.11
4.1 to 4.10
Section
Listings
ICH Listings
1 to 65
Other Listings
66 to 80
10.12.2.
Mock Example Shell Referencing
Non-integrated data standards library (IDSL) specifications will be referenced as 
indicated and if required example mock-up displays provided in 
Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ column as ‘[Non-Standard] + Reference.’
10.12.3.
Deliverables
Delivery
Description
IA
Informal Interim Analysis (displays to be prepared by 
Biostatistics function)
SAC
Final Statistical Analysis Complete


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10.12.4.
Study Population Tables
Study Population Tables
No.
Populati
on
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Participant Disposition for the Participant 
Conclusion Record – Part A
ICH E3, FDAAA, EudraCT
IA, SAC
1.2.
Safety
ES1
Summary of Participant Disposition for the Participant 
Conclusion Record – Part B
ICH E3, FDAAA, EudraCT
SAC 
1.3.
Safety
SD1
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment – Part B
ICH E3
SAC
1.4.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch –
Part A
ICH E3
SAC
1.5.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch –
Part B
ICH E3
SAC
1.6.
Screene
d
ES6
Summary of Screening Status and Reasons for Screen 
Failure – Part A
SAC
1.7.
Screene
d
ES6
Summary of Screening Status and Reasons for Screen 
Failure – Part B
SAC
Protocol Deviation
1.8.
Safety
DV1
Summary of Important Protocol Deviations – Part A
ICH E3
SAC
1.9.
Safety
DV1
Summary of Important Protocol Deviations – Part B
ICH E3
SAC
Population Analysed
1.10.
Enrolled
SP1
Summary of Study Populations – Part A
IA, SAC


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Study Population Tables
No.
Populati
on
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
Enrolled
SP1
Summary of Study Populations – Part B
SAC
Demographic and Baseline Characteristics
1.12.
Safety
DM3
Summary of Demographic Characteristics – Part A
ICH E3, FDAAA, EudraCT
IA, SAC
1.13.
Safety
DM1 
Summary of Demographic Characteristics – Part B
ICH E3, FDAAA, EudraCT
SAC
1.14.
Enrolled
DM11
Summary of Age Ranges – Part A
EudraCT
SAC
1.15.
Enrolled
DM11
Summary of Age Ranges – Part B
EudraCT
SAC
1.16.
Safety
DM5
Summary of Race and Racial Combinations – Part A
ICH E3, FDA, FDAAA, EudraCT
SAC
1.17.
Safety
DM5
Summary of Race and Racial Combinations – Part B
ICH E3, FDA, FDAAA, EudraCT
SAC
Prior and Concomitant Medications
1.18.
Safety
CM1
Summary of Concomitant Medications – Part A
ICH E3
SAC
1.19.
Safety
CM1
Summary of Concomitant Medications – Part B
ICH E3
SAC
Exposure and Treatment Compliance
1.20.
Safety
EX1
Summary of Exposure to Study Treatment – Part A
ICH E3
IA, SAC
1.21.
Safety
EX1
Summary of Exposure to Study Treatment - Part B
ICH E3
SAC
1.22.
Safety
COMP1
Summary of Overall Compliance Based on Exposure –Part 
B
SAC


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10.12.5.
Safety Tables
Safety: Tables
No.
Populat
ion
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1.
Safety
AE1CP
Summary of All Adverse Events by System Organ Class and
Preferred Term – Part A
ICH E3
IA, SAC
3.2.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term – Part B
ICH E3
SAC
3.3.
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part A
FDAAA, EudraCT
SAC
3.4.
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part B
FDAAA, EudraCT
SAC
3.5.
Safety
AE1
Summary of All Drug Related Adverse Events by System Organ 
Class and Preferred Term – Part A
ICH E3
SAC
3.6.
Safety
AE1
Summary of All Drug Related Adverse Events by System Organ 
Class and Preferred Term – Part B
ICH E3
SAC
Serious and Other Significant Adverse Events
3.7.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) –
Part A
FDAAA, EudraCT
SAC
3.8.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) –
Part B
FDAAA, EudraCT
SAC
Laboratory: Chemistry 
3.9.
Safety
LB1
Summary of Chemistry Changes from Baseline – Part A
ICH E3
SAC
3.10.
Safety
LB1
Summary of Chemistry Changes from Baseline – Part B
ICH E3
SAC


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Safety: Tables
No.
Populat
ion
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
3.11.
Safety
LB17
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline – Part A
ICH E3
SAC
3.12.
Safety
LB17
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline – Part B
ICH E3
SAC
Laboratory: Haematology
3.13.
Safety
LB1
Summary of Haematology Changes from Baseline – Part A
ICH E3
SAC
3.14.
Safety
LB1
Summary of Haematology Changes from Baseline – Part B
ICH E3
SAC
3.15.
Safety
LB17
Summary of Worst-Case Haematology by PCI Criteria Post-
Baseline Relative to Baseline – Part A
ICH E3
SAC
3.16.
Safety
LB17
Summary of Worst-Case Haematology by PCI Criteria Post-
Baseline Relative to Baseline – Part B
ICH E3
SAC
Laboratory: Urinalysis
3.17.
Safety
LB1
Summary of Urine Concentration Changes from Baseline – Part 
A
ICH E3
Includes Baseline values.
SAC
3.18.
Safety
LB1
Summary of Urine Concentration Changes from Baseline – Part 
B
ICH E3
Includes Baseline values.
SAC
3.19.
Safety
UR3a
Summary of Urinalysis Dipstick and Microscopy Results – Part A
SAC
3.20.
Safety
UR3a
Summary of Urinalysis Dipstick and Microscopy Results – Part B
SAC
3.21.
Safety
UR1
Summary of Worst-Case Urinalysis Results Post-Baseline 
Relative to Baseline – Part A
ICH E3
SAC
3.22.
Safety
UR1
Summary of Worst-Case Urinalysis Results Post-Baseline 
Relative to Baseline – Part B
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)


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Safety: Tables
No.
Populat
ion
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
3.23.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – Part A
SAC
3.24.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting – Part B
SAC
3.25.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities – Part A
SAC
3.26.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities – Part B
SAC
ECG
3.27.
Safety
EG1
Summary of ECG Findings – Part A
SAC
3.28.
Safety
EG1
Summary of ECG Findings – Part B
SAC
3.29.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit –
Part A
Includes Baseline values.
SAC
3.30.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit –
Part B
Includes Baseline values.
SAC
Vital Signs
3.31.
Safety
VS1
Summary of Change from Baseline in Vital Signs - Part A
ICH E3
Includes Baseline values.
SAC
3.32.
Safety
VS1
Summary of Change from Baseline in Vital Signs - Part B
ICH E3
Includes Baseline values.
SAC
3.33.
Safety
VS7
Summary of Worst-Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline – Part A
SAC
3.34.
Safety
VS7
Summary of Worst-Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline – Part B
SAC


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10.12.6.
Pharmacokinetic Tables


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Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic Concentration Data
4.1.
PK
PK01
Summary of GSK3186899 Plasma Pharmacokinetic 
Concentration-Time Data - Part A
SAC
4.2.
PK
PK01
Summary of GSK3186899 Plasma Pharmacokinetic 
Concentration-Time Data - Part B
SAC
Derived Pharmacokinetic Parameters
4.3.
PK
PK06
Summary of Non-transformed Derived GSK3186899 Plasma 
Pharmacokinetic Parameters by Dose - Part A
SAC
4.4.
PK
PK06
Summary of Non-transformed Derived GSK3186899 Plasma 
Pharmacokinetic Parameters by Dose - Part B
SAC
4.5.
PK
PK05
Summary of Loge-Transformed Derived GSK3186899 Plasma 
Pharmacokinetic Parameters by Dose - Part A
SAC
4.6.
PK
PK05
Summary of Loge-Transformed Derived GSK3186899 Plasma 
Pharmacokinetic Parameters by Dose - Part B
SAC
4.7.
PK
Non-standard
PK_T1
Statistical analysis for comparison of food effect in Part A 
Cohort 3
SAC
4.8.
PK
Non-standard
PK_T2
Statistical Analysis of Log Transformed Plasma GSK3186899
Pharmacokinetic Parameters Assessing Dose Proportionality 
(Power Model) – Part A
SAC
4.9.
PK
Non-standard
PK_T3
Statistical Analysis of Log Transformed Plasma GSK3186899
Pharmacokinetic Parameters Assessing Dose Proportionality 
(Power Model) – Part B
SAC
4.10.
PK
Non-standard
PK_T4
Statistical Analysis of Log-transformed Plasma GSK3186899
Parameters Assessing Steady-State – Part B
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.11.
PK
Non-standard
PK_T4
Time invariance analysis of log-transformed Plasma 
GSK3186899 Parameters – Part B
Update the parameters for time 
invariance analysis
SAC


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10.12.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic Concentration Data
4.1.
PK
PK16
Individual Plasma GSK3186899 Concentration-Time Plot 
(Linear and Semi-Log)– Part A
SAC
4.2.
PK
PK16
Individual Plasma GSK3186899 Concentration-Time Plot 
(Linear and Semi-Log)– Part B
SAC
4.3.
PK
PK19
Mean (+ SD) Plasma GSK3186899 Concentration-Time Plots 
(Linear and Semi-Log)- Part A
SAC
4.4.
PK
PK19
Mean (+ SD) Plasma GSK3186899 Concentration-Time Plots 
(Linear and Semi-Log)- Part B
SAC
4.5.
PK
PK20
Median (range) Plasma GSK3186899 Concentration-Time 
Plots (Linear and Semi-Log)- Part A
SAC
4.6.
PK
PK20
Median (range) Plasma GSK3186899 Concentration-Time 
Plots (Linear and Semi-Log)- Part B
SAC
Derived Pharmacokinetic Parameters
4.7.
PK
Non-standard
PK_F1
Box Plot of AUC(0-∞) and Cmax versus dose (Linear) – Part A
SAC
4.8.
PK
Non-standard
PK_F1
Box Plot of AUC(0-∞) and Cmax versus dose (Linear) – Part B
AUC(0-tau) on day 10
SAC
4.9.
PK
Non-standard
PK_F1
Box Plot of dose normalised AUC(0-∞) versus dose (Linear) –
Part A
SAC
4.10.
PK
Non-standard
PK_F1
Box Plot of dose normalised AUC(0-∞) and Cmax versus dose
(Linear) - Part B
AUC(0-tau) on day 10
SAC


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10.12.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure – Part A
SAC
2.
Screened
ES7
Listing of Reasons for Screen Failure – Part B
SAC
3.
Screened
ES9
Listing of Subjects Who Were Rescreened by Cohort – Part 
A
SAC
4.
Screened
ES9
Listing of Subjects Who Were Rescreened in Part B by 
Cohort – Part B
SAC
5.
Safety
ES3
Listing of Reasons for Study Withdrawal – Part A
ICH E3
IA, SAC
6.
Safety
ES2
Listing of Reasons for Study Withdrawal – Part B
ICH E3
SAC
7.
Safety
SD3
Listing of Reasons for Study Treatment Discontinuation –
Part A
ICH E3
IA, SAC
8.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation –
Part B
ICH E3
SAC
9.
Enrolled
BL1 
Listing of Participants for Whom the Treatment Blind was 
Broken – Part A
ICH E3
SAC
10.
Enrolled
BL1 
Listing of Participants for Whom the Treatment Blind was 
Broken – Part B
ICH E3
SAC
11.
Enrolled
TA1
Listing of Planned and Actual Treatments - Part A
SAC
12.
Enrolled
TA1
Listing of Planned and Actual Treatments - Part B
SAC
Protocol Deviations
13.
Safety
DV2
Listing of Important Protocol Deviations – Part A
ICH E3
IA, SAC
14.
Safety
DV2
Listing of Important Protocol Deviations – Part B
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
15.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations - Part A
ICH E3
SAC
16.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations – Part B
ICH E3
SAC
Populations Analysed
17.
Safety
SP3
Listing of Subjects Excluded from Any Population – Part A
ICH E3
SAC
18.
Safety
SP3
Listing of Subjects Excluded from Any Population – Part B
ICH E3
SAC
Demographic and Baseline Characteristics
19.
Safety
DM4
Listing of Demographic Characteristics – Part A
ICH E3
Include BMI and smoking status. 
IA, SAC
20.
Safety
DM2
Listing of Demographic Characteristics – Part B
ICH E3
Include BMI and smoking status. 
SAC
21.
Safety
DM9
Listing of Race – Part A
ICH E3
SAC
22.
Safety
DM9
Listing of Race – Part B
ICH E3
SAC
Prior and Concomitant Medications
23.
Safety
CP_CM3
Listing of Concomitant Medications– Part A
IDSL
SAC
24.
Safety
CP_CM3
Listing of Concomitant Medications– Part B
IDSL
SAC
Exposure and Treatment Compliance
25.
Safety
EX4
Listing of Exposure Data - Part A
ICH E3
IA, SAC
26.
Safety
EX3
Listing of Exposure Data - Part B
ICH E3
SAC
27.
Safety
COMP2
Listing of Compliance Based on Exposure –Part B
Adverse Events
28.
Safety
AE9
Listing of All Adverse Events – Part A
ICH E3
IA, SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
29.
Safety
AE8
Listing of All Adverse Events – Part B
ICH E3
SAC
30.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events –
Part A
ICH E3
SAC
31.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events –
Part B
ICH E3
SAC
Serious and Other Significant Adverse Events
32.
Safety
AE8CP
Listing of Serious Adverse Events – Part A
ICH E3
SAC
33.
Safety
AE8CP
Listing of Serious Adverse Events – Part B
ICH E3
SAC
34.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event- Part A
ICH E3
SAC
35.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event- Part B
ICH E3
SAC
36.
Safety
AECP8
Listing of Adverse Events Leading to Withdrawal from Study 
– Part A
ICH E3
SAC
37.
Safety
AECP8
Listing of Adverse Events Leading to Withdrawal from Study 
– Part B
ICH E3
SAC
38.
Safety
AECP8
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment – Part A
ICH E3
SAC
39.
Safety
AECP8
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment – Part B
ICH E3
SAC
Hepatobiliary (Liver)
40.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events - Part A
IDSL
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
41.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events - Part B
IDSL
SAC
42.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events - Part A
IDSL
SAC
43.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events - Part B
IDSL
SAC
All Laboratory
44.
Safety
LB6
Listing of All Laboratory Data for Participants with Any Value 
of Potential Clinical Importance – Part A
ICH E3
Display ALL chemistry data for a 
subject who experienced a value of 
potential clinical importance.
IA, SAC
45.
Safety
LB5
Listing of All Laboratory Data for Participants with Any Value 
of Potential Clinical Importance – Part B
ICH E3
Display ALL chemistry data for a 
subject who experienced a value of 
potential clinical importance.
SAC
46.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance
– Part A
SAC
47.
Safety
LB5
Listing of Laboratory Values of Potential Clinical Importance
– Part B
SAC
48.
Safety
LB14
Listing of Laboratory Data with Character Results – Part A
ICH E3
SAC
49.
Safety
LB14
Listing of Laboratory Data with Character Results – Part B
ICH E3
SAC
50.
Safety
UR2B
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance – Part A
ICH E3
Display ALL urinalysis data for a 
subject who experienced a value of 
potential clinical importance.
IA, SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
51.
Safety
UR2A
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance – Part B
ICH E3
Display ALL urinalysis data for a
subject who experienced a value of 
potential clinical importance.
SAC
52.
Safety
UR2B
Listing of Urine Biomarker data for all Subjects – Part A
Only present urine biomarker data
SAC
53.
Safety
UR2A
Listing of Urine Biomarker data for all Subjects – Part B
Only present urine biomarker data
SAC
ECG
54.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance – Part A
IDSL
Display ALL ECG data for a subject 
who experienced a value of potential 
clinical importance.
IA, SAC
55.
Safety
EG3
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance – Part B
IDSL
Display ALL ECG data for a subject 
who experienced a value of potential 
clinical importance.
SAC
56.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance – Part 
A
IDSL
SAC
57.
Safety
EG3
Listing of ECG Values of Potential Clinical Importance – Part 
B
IDSL
SAC
58.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding – Part A
IDSL
IA, SAC
59.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding – Part B
IDSL
SAC
Vital Signs


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
60.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance – Part A
IDSL
Display ALL vital signs data for a 
subject who experienced a value of 
potential clinical importance.
IA, SAC
61.
Safety
VS4
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance – Part B
IDSL
Display ALL vital signs data for a 
subject who experienced a value of 
potential clinical importance.
SAC
62.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance – Part A
IDSL
SAC
63.
Safety
VS4
Listing of Vital Signs of Potential Clinical Importance – Part B
IDSL
SAC
64.
Safety
EG6
Listing of Telemetry findings - Part A
Example shell to be modified for 
telemetry data
IA, SAC
65.
Safety
EG5
Listing of Telemetry findings - Part B
Example shell to be modified for 
telemetry data
SAC
10.12.9.
Non-ICH Listings


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Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Safety
66.
Safety
HM10
Listing of Clinically Significant Holter Abnormalities – Part A
SAC
67.
Safety
HM10
Listing of Clinically Significant Holter Abnormalities – Part B
SAC
68.
Safety
MH3
Listing of Medical conditions – Part A
SAC
69.
Safety
MH2
Listing of Medical conditions – Part B
SAC
Pharmacokinetic
70.
PK
PK07
Listing of Plasma GSK3186899
Pharmacokinetic Concentration-Time Data – Part A
SAC
71.
PK
PK07
Listing of Plasma GSK3186899
Pharmacokinetic Concentration-Time Data – Part B
SAC
72.
PK
PK13
Listing of Derived Plasma GSK3186899 Pharmacokinetic 
Parameters – Part A
SAC
73.
PK
PK13
Listing of Derived Plasma GSK3186899 Pharmacokinetic 
Parameters – Part B
SAC
74.
PK
PK07
Listing of Urine GSK3186899
Pharmacokinetic Concentration-Time Data – Part A
Only include 3 Urine PK parameters:
Ae(t1-tz), fe(0-tz), CLR
SAC
75.
PK
PK07
Listing of Urine GSK3186899
Pharmacokinetic Concentration-Time Data – Part B
Only include 3 Urine PK parameters:
Ae(t1-tz), fe(0-tz), CLR
SAC
76.
PK
Non-standard
Raw SAS output of Statistical Analysis for Comparison of Food 
effect - Part A Cohort 3
SAC


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Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
77.
PK
Non-standard
Raw SAS output of Statistical Analysis of Log Transformed 
Plasma GSK3186899 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part A
SAC
78.
PK
Non-standard
Raw SAS output of Statistical Analysis of Log Transformed 
Plasma GSK3186899 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part B
SAC
79.
PK
Non-standard
Raw SAS output of Statistical Analysis of Log-transformed 
Plasma GSK3186899 Parameters Assessing Steady-State –
Part B
SAC
80.
PK
Non-standard
Raw SAS output of Time invariance analysis of log-
transformed Plasma GSK3186899 Parameters – Part B
SAC


CONFIDENTIAL
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10.13.
Appendix 13: Example Mock Shells for Data Displays
Example 
: PK_T1
Population : Pharmacokinetic 
Table 4.7
Statistical analysis for comparison of food effect in Part A Cohort 3
Parameter 
(Units)
Fed
Fasted
GSK X.X mg
Fed vs 
Fasted
(Difference)
90% CI of 
the 
difference
GSK X.X 
mg
Fed vs 
Fasted
(Ratio)
90% CI 
of the 
Ratio
n
LS Mean
n
LS Mean
AUC(0-t) 
(µg.h/mL)
x
xx.xx
x
xx.xx
x.xx
(x.xx, 
x.xx)
x.xx
(x.xx, 
x.xx)
Cmax 
(µg/mL)
x
xx.xx
x
xx.xx
x.xx
(x.xx, 
x.xx)
x.xx
(x.xx, 
x.xx)
…………..
Log-transformed parameter is modelled with fed or fasted status and period as fixed effects and 
subject as a random effect. Unstructured covariance structures are considered describing within and 
between subject variability.
A ratio of 1 indicates same PK response is seen in both the fed and fasted subjects. A ratio > 1 
indicates a higher PK response was seen in the fed subjects.
USER ID:directory/program.sas  01JAN2002 12:01


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Example 
: PK_T2
Population : Pharmacokinetic 
Table 4.8
Statistical Analysis of Log Transformed Plasma GSK3186899 Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) – Part A
   
Parameter (Units)
Slope
Log Parameter vs Log Dose
90% CI of the Slope
<AUC(0-t) (µg.h/mL)>
x.xx
(x.xx, x.xx)
Cmax (µg/mL)
x.xx
(x.xx, x.xx)
…………
A Power model is used to assess the dose proportionality. 
Loge(dose) and period are fitted as fixed effects and subject as a random effect. An unstructured 
covariance structure is considered describing between subject variability. 
A slope of 1 indicates the pharmacokinetics are dose proportional. A slope greater than 1 indicates 
the increase in PK is greater than proportional to dose.
USER ID:directory/program.sas  01JAN2002 12:01


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Example 
: PK_T3
Population : Pharmacokinetic 
Table 4.9
Statistical Analysis of Log Transformed Plasma GSK3186899 Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) – Part B
Parameter (Units)
Timepoint
Slope
Log Parameter vs Log Dose
90% CI of the 
Slope
<AUC(0-t) (µg.h/mL)>
Day 1
x.xx
(x.xx, x.xx)
Day 10
x.xx
(x.xx, x.xx)
Cmax (µg/mL)
Day 1
x.xx
(x.xx, x.xx)
Day 10
x.xx
(x.xx, x.xx)
…………
A Power model is used to assess the dose proportionality. 
Loge(dose) is fitted as a fixed effect and subject as a random effect. An unstructured covariance 
structure is considered describing between subject variability. 
A slope of 1 indicates the pharmacokinetics are dose proportional. A slope greater than 1 indicates 
the increase in PK is greater than proportional to dose.
USER ID:directory/program.sas  01JAN2002 12:01


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Example 
: PK_T4
Population : Pharmacokinetic 
Table 4.10
Statistical Analysis of Log Transformed Plasma GSK3186899 Trough Concentration Assessing Steady-
State – Part B
Parameter 
(Units)
Treatment
Day 10
Day 1
Log-
transformed
Day 10 –
Day 1
90% 
Confidence 
Interval
Back-
Transformed 
Ratios
90% 
Confidence 
Interval
n
LS 
Mean
n
LS Mean
Ctau 
(ug/mL)
<Dose 1>
x
xx.xx
x
xx.xx
x.xx
(x.xx, 
x.xx)
x.xx
(x.xx, 
x.xx)
<Dose 2>
x
xx.xx
x
xx.xx
x.xx
(x.xx, 
x.xx)
x.xx
(x.xx, 
x.xx)
<Dose 3>
x
xx.xx
x
xx.xx
x.xx
(x.xx, 
x.xx)
x.xx
(x.xx, 
x.xx)
……………
A Mixed effect model including dose, day and dose-by-day interaction as fixed effects and subject as 
a random effect is used to assess accumulation ratios. Unstructured covariance structures are used
to describe within and between subject variabilities. A ratio of 1 indicates no accumulation. A 
ratio > 1 indicates drug accumulation.
USER ID:directory/program.sas  01JAN2002 12:01


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Example 
: PK_F1
Population : Pharmacokinetic 
Figure 4.7
Box Plot of AUC and Cmax versus doses (Linear) – Part A
Programming notes: this is an example shell to be updated to present each dose level.
USER ID:directory/program.sas  01JAN2002 12:01